LT3276B - Fungicides for the control of take-all disease of plants - Google Patents

Abstract

A method to control plants affected by Gaeumannomyces sp., in which the efficient amount of fungicide is applied for the plant focus. The fungicide formula:<IMAGE>where Z1 and Z2 is marked as C or N and is a part of an aromatic ring, selected from benzene, pyridine, tiophene, furan, pyrol, pyrazole, tyazole and izotyazole;A is selected from -C(X)-amino, -C(O)-SR3, -NH-C(X)R4, and -C(=NR3)-XR7;B marks -Wm-Q(R2)3 or is selected from o-tolyl, 1-naphtyl, 2-naphtyl and 9-phenantrail, where each one can be changed into halogen or R4;Q marks C, Si, Ge, or Sn;W marks -C(R3)pH(2-p)-; or when Q marks C, W is selected from -C(R3)pH(2-p)-, -N(R3)mH(1-m)-, -S(O)p- and -O-;X marks O or S;n is square to 0, 1, 2 or 3;m is square to 0 or 1;p is square to 0, 1 or 2;each R is independently selected froma) halogen, formyl, cyan, amino, nitro, thiocyanate, isothiocyanate, trimethylsilyl and hydroxyl;b) C1-C4 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl and cycloalkenyl, where one of them can be changed into a halogen, hydroxyl, tio, amino, nitro, cyan, formyl, phenyl, C1-C4 alkoxyl, alkyl carbonyl, alkylite, alkyl amino, dialkylamino, alkoxycarbonyl, (alkylite) carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl, or alkylsulfonyl groups;c) Phenyl, furyl, tionyl, pirolyl, where each one can be changed into a halogen, formyl, cyan, amino, nitro, C1-C4 alkyl, alkenyl, alkynyl, alkoxyl, alkylite, alkyl amino, dialkylamino, halogen alkyl, and halogenoalkenyl groups;d) C1-C4 alkoxyl, alkenoxyl, alkinoxyl, C3-C6 cycloalkyloxyl, cycloalkenyloxyl, alkylite, alkylsulfinyl, alkylsulfonyl, alkyl amino, dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl-carbonyl, alkylcarbonyloxyl, alkoxycarbonyl, (alkylite) carbonyl, phenylcarbonylamino, phenyl amino, where each one can be changed into a halogen;where two R groups can be connected to make a united ring;each R2 is independently selected from alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl and phenyl, where each one can be changed into R4 or into a halogen, alkyloxyl, alkylite, alkyl amino and dialkylamino;where two R2 groups can be connected to make a cyclic group with Q;R3 is a C1-C4 alkyl;R4 is a C1-C4 alkyl; halogen alkyl, alkyloxyl, alkylite, alkyl amino or dialkylamino: andR7 is a C1-C4 alkyl, halogen alkyl, or phenyl can be changed into halogen, nitro or R4 groups;or its agronomical salt.

Description

The invention relates to the control of plant shoot disease (ophiobolosis), in particular to cereal crops, by the use of certain modified aryl compounds, some of them new, and fungicidal compositions.

Plant root diseases are a serious problem for cereal crops, especially rye and barley. It is caused by a soil-borne fungus Gaeumannomyces graminis (Gg). The fungus infects the plant’s roots and grows throughout the root tissue, causing black rot. The growth of fungi in the roots and in the lower stem prevents the plant from obtaining sufficient water and / or nutrients from the soil, and the plant appears poor and, in severe cases of disease, the plants are fruitless or have few shriveled grains during ophthalmic formation. Yields do not produce the expected results. Gaeumannomyces species also infects other cereals such as rice and oats, as well as turf.

Currently, the main measures to prevent crop losses due to soil contamination with Gg are to replace cultivated crops with resistant Gg crops.

However, in areas where cereals are the main crop, crop rotation is undesirable and effective ways to combat the disease are particularly needed.

The object of the present invention is to provide an effective method for controlling plant fever disease. A second object of the invention is to provide formulations suitable for combating the spread of Gg in soil in order to reduce crop losses. A third object of the present invention is to provide fungicidal compositions which can be used to combat scabies.

The present invention provides a method of controlling a disease agent in a plant of Gaeumannomyces species by acting on a locus of the plant, i.e. the plant itself, its seeds or its soil in a fungicidally effective amount of a fungicide of the formula

A

wherein Z _x and Z ₂ represent C or N and are part of an aromatic ring selected from benzene, pyridine, thiophene, furan, pyrrole, pyrazole, thiazole and isothiazole;

A is selected from -C (X) -amino, -C (O) -SR ₃ ,

-NH-C (X) R ₄ and -C (= NR ₃ ) -XR ₇ ;

B is -W _m -Q (R ₂ ) ₃ or selected from o-tolyl,

1-naphthyl, 2-naphthyl and 9-phenanthryl, each optionally substituted with halogen or R ₄ ;

Q is C, Si, Ge or Sn;

W is -C (R ₃ ) _p H ₍₂ _ _p) - or when Q is C, W is selected from -C (R ₃ ) _p H _{(2. P)} -, -N <R ₃ ) _m H _{( first m)} -, -S (O) _p -, and -O-;

X is O or S;

n is 0, 1, 2 or 3;

m is 0 or 1;

p is 0, 1 or 2;

each R is independently selected from

(a) halogen, formyl, cyano, amino, nitro, focyanate, isothiocyanate, trimethylsilyl and hydroxyl;

b) C 1 -C 4 alkyl, alkenyl, alkynyl, C 3 -C 6 cycloalkyl and cycloalkenyl, each of which may be substituted by halogen, hydroxyl, thio, amino, nitro, cyano formyl, phenyl, C 1 -C 4 alkoxyl, alkylcarbonyl, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, (alkylthio) carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl or alkylsulfonyl groups;

c) phenyl, furyl, thienyl, pyrrolyl, each optionally substituted by halogen, formyl, cyano, amino, nitro, C 1 -C 4 alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, dialkylamino, haloalkyl and haloalkenyl;

d) C 1 -C 4 alkoxyl, alkenoxyl, alkinoxyl, C 3 -C 6 cycloalkyloxy, cycloalkenylloxyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, in groups, each may be substituted by halogen;

wherein the two R groups may be joined to form a single ring; each R ₂ is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and phenyl, each of which may be substituted with R ₄ or halo;

and wherein when Q is C, R ₂ may also be selected from halogen, alkoxyl, alkylthio, alkylamino and dialkylamino;

wherein the two R ₂ groups may be joined to form a cyclic group with Q;

R ₃ is C 1 -C 4 alkyl;

R ₄ is C 1 -C 4 alkyl, haloalkyl, alkoxy, alkylthio, alkylamino or dialkylamino;

R ₇ is C 1 -C 4 alkyl, haloalkyl or phenyl, optionally substituted with halo, nitro or R ₄ ;

or also agronomic salt.

The term amine -C (X) -amine denotes an unsubstituted amino radical or substituted with one or two amino substituents to include heterocyclic nitrogen. Examples of substituents on the amino radical include, but are not limited to, hydroxyl, alkyl, alkenyl, and alkynyl groups which may be linear, branched, or cyclic; alkoxyalkyl; haloalkyl; hydroxyalkyl; alkylthio; alkylthioalkyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonyl; alkylaminocarbonyl; cyanoalkyl; mono- or dialkylamine; phenyl; phenylalkyl or phenylalkenyl, each of which may be substituted by one or more C 1 -C 6 alkyl, alkoxyl, haloalkyl, C 3 -C 6 cycloalkyl, halogen or nitro groups; C 1 -C 4 alkyl or alkenyl groups are substituted by heterocycles, and may be substituted by one or more C 1 -C 4 alkyl, alkoxyl, haloalkyl, halogen or nitro groups. Examples of the included nitrogen hetero rings which are nitrogen-bonded to -C (X) - include but are not limited to morpholine, piperazine, piperidine, pyrrole, pyrrolidine, imidazole and triazoles, each of which may be substituted by one or two C 1 -C 6 alkyl groups. .

Specific examples of amino radicals useful in the present invention include, but are not limited to, ethylamino, methylamino, propylamino, 2-methylethylamino, 1-propenylamino, 2-propenylamino, 2-methyl-2-propenylamino, 2-propynylamino, butylamino, 1,1-. dimethyl-2-propynylamino, diethylamino, dimethylamino, N- (methyl) ethylamino, N- (methyl) -1,1- (dimethyl) ethylamine dipropylamino, octylamino, N- (ethyl) -1-methylethylamino, 2-hydroxyethylamine, -methylpropylamino, chloromethylamino, 2-chloroethylamino, 2-bromoethylamino, 3-chloropropylamino, 2,2,2-trifluoroethylamino, cyanomethyl, methylthiomethylamino, (methylsulfonyl) oxyethylamine, 2-ethoxyethylamino, 2-methoxyethylamino, N- (ethyl) -2-ethoxyethylamine, 1-Methoxy-2,2-dimethylpropylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, methoxymethylamino, N (methoxymethyl) ethylamino, N- (1-methylethyl) propylamino, 1-methylheptylamino, N- (ethyl) -1-methylheptylamino, 6,6-dimethylamine For -2-hepten-4-ynylamino, 1,1-dimethyl-2-propynylamino. Further examples include benzylamino, ethylbenzylamino, 3-methoxybenzylamino, 3- (trifluoromethyl) benzylamino, N-methyl-3- (trifluoromethyl) benzylamino, 3,4,5-trimethoxybenzylamino, 1,3-benzodioxol-5-ylmethylamino, phenylamine, 3 - (1-methylethyl) phenylamino, ethoxyphenylamino, cyclopentylphenylamino, methoxyphenylamino, nitrophenylamino, 1-phenylethylamino, N- (methyl) -3-phenyl-2-propenylamino, benzotriazolylphenylmethyl, 2-pyridinylmethylamino, N- (ethyl) -2-pyridinylmethylamine thienylmeLT 3276 B tylamine and furylmethylamine groups. Further examples of amino radicals include methylhydrazine, dimethylhydrazine, N-ethylaniline and 2-methylaniline. The amine may be substituted by diethyl-N-ethylphosphoric acid, t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like. Of these examples of the amino radical, ethylamine is preferred.

Examples of B include, but are not limit trimethylsilyl, etildimetilsililo, dietilmetilsililo triethylsilyl, dimetilpropilsililo, dipropilmetilsililo, dimethyl-1 (methyl) etilsililo, tripopilsililo, butyldimethylsilyl, pentildimetilsililo, heksildimetilsililo, ciklopropildimetilsililo, ciklobutildimetilsililo, ciklopentildimetilsililo, cyclohexyldimethylsilyl, dimetiletenilsililo, dimetilpropenilsililo, chlormetildimetilsililo,

2-chloroethyldimethylsilyl, bromomethyldimethylsilyl, bicycloheptyldimethylsilyl, dimethylphenylsilyl, dimethyl 2- (methyl) phenylsilyl, dimethyl-2-fluorophenylsilyl and other similar silyl groups of formula Si (R ₂ ) ₃ ; any silyl group attached to the ring by a methylene group; and any of these groups in which germanium or tin is replaced by silicon. Of these B examples, trimethylsilyl is preferred.

Other examples B include 1,1-dimethylethyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 1,1-dimethylpentyl, 1-ethyl-1-methylbutyl, 2,2-dimethylpropyl, 2,2-dimethylbutyl, 1-methyl- 1-ethylpropyl, 1,1-diethylpropyl, 1,1,2-trimethylpropyl, 1,1,2-trimethylbutyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethyl-2-propenyl, 1,1,2- trimethyl-2-propenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-2-propynyl, 1,1-dimethyl-2-butynyl, 1-cyclopropyl-methyl-ethyl, 1-cyclobutyl-1-methylethyl, 1- cyclopentyl-1-methylethyl, 1- (1-cyclopentenyl) -1-methylethyl, 1-cyclohexyl-1-methylethyl, 1- (1-cyclohexenyl) -1-methylethyl, 1-methyl-1-phenylethyl, 1,1-dimethyl- 2-chloroethyl, 1,1LT 3276 B dimethyl-3-chloropropyl, 1,1-dimethyl-2-methoxyethyl,

1,1-dimethyl-2- (methylamino) ethyl, 1,1-dimethyl-2- (dimethylamino) ethyl, 1,1-dimethyl-3-chloro-2-propenyl, 1-methyl-1-methoxyethyl, 1-methyl- 1- (methylthio) ethyl, 1-methyl-1- (methylamino) ethyl, 1-methyl-1- (dimethylamino) ethyl, 1-chloro-1-methylethyl, 1-bromo-1-methylethyl and 1-iodo-1-methylethyl. Of these B examples, 1,1-dimethylethyl is preferred.

Other examples B include 1,1-dimethylamino, 1,1-dimethylpropylamino, 1,1-dimethylbutylamino, 1,1-dimethylpentylamino, 1-ethyl-1-methylbutylamino, 2,2-dimethylpropylamino, 2,2-dimethylbutylamino, 1-. methyl-1-ethylpropylamino, 1,1-diethylpropylamino, 1,1,2-trimethylpropylamino, 1,1,2-trimethylbutylamino, 1,1,2,2-tetramethylpropylamino, 1,1-dimethyl-2-propenylamino, 1, 1,2-trimethyl-2-propenylamino, 1,1-dimethyl-2-butenylamino, 1,1-dimethyl-2-propynylamino, 1,1-dimethyl-2-butynylamino, 1-cyclopropyl-1-methylethylamino, 1-cyclobutyl-1- methylethylamino, 1-cyclopentyl-1-methylethylamino, 1- (1-cyclopentyl) -1-methylethylamino, 1-cyclohexyl-1-methylethylamino, 1- (1-cyclohexenyl) -1-methylethylamino, 1-methyl-1-phenylethylamino, 1,1-dimethyl-2-chloroethylamino, 1,1-dimethyl-3-chloropropylamino, 1,1-dimethyl-2-methoxyethylamino, 1,1-dimethyl-2- (methylamino) -ethylamino, 1,1-dimethyl-2- (dimethylamino) ) ethylamine and 1,1-dimethyl-3-chloro-2-propenylamine. Any of these groups may also have a methyl substituent on nitrogen, as in the N- (methyl) -1,1-dimethylethylamine and N- (methyl) -1,1-dimethylpropylamine groups. Of these B examples, 1,1-dimethylethylamine and N (methyl) -1,1-dimethylethylamine are most preferred.

Other examples B include 1,1-dimethylethoxyl, 1,1-dimethylpropoxyl, 1,1-dimethylbutoxyl, 1,1-dimethylpentoxyl, 1-ethyl-1-methylbutoxyl, 2,2-dimethylpropoxyl, 2,2-dimethylbutoxyl, 1-methyl- l-ethylpropoxyl, 1,1-diethylpropoxyl, 1,1,2-trimethylpropoxyl,

1,1,2-trimethylbutoxyl, 1,1,2,2-tetramethylpropoxyl,

1,1-dimethyl-2-propenoxyl, 1,1,2-trimethyl-2-propenoxyl, 1,1-dimethyl-2-butenoxyl, 1,1-dimethyl-2-propynyloxyl, 1,1-dimethyl-2-butynyloxyl, 1-cyclopropyl-1-methylethoxy, 1-cyclobutyl-1-methylethoxyl, 1-cyclopentyl-1-methylethoxy, 1-cyclopentyl-1-methylethoxy, 1- (1-cyclopentenyl) -1-methylethoxy, 1-cyclohexyl-1- methylethoxyl, 1- (1-cyclohexenyl) -1-methylethoxy, 1-methyl-1-phenylethoxyl, 1,1-dimethyl-2-chloroethoxyl, 1,1-dimethyl-3-chloropropoxyl, 1,1-dimethyl-2-methoxyethoxyl, 1, l-dimethyl-2- (methylamino) ethoxyl, 1,1-dimethyl-2- (dimethylamino) ethoxyl, 1,1-dimethyl-3-chloro-2-propenoxyl. Of these B examples, 1,1-dimethylethoxyl is preferred.

Other examples B include 1-methyl-cyclopropyl, 1-methylcyclobutyl, 1-methylcyclopentyl, 1-methylcyclopropylamino, 1-methylcyclobutylamino, 1-methylcyclopentylamino, 1-methylcyclohexylamino, N- (methyl) -1-methylcyclopropylamino, N- (methyl) ) -1-methylcyclobutylamino, N- (methyl) -1-methylcyclopentylamine and N- (methyl) -1-methylcyclohexylamine.

R _n can be any substitute (s) that appropriately reduce the efficacy of the compounds to be effective in the fight against scabies. R _{n is} usually a small group: n is most suitable for 1 benzene rings, and 2 for furan and thiophene. R is more preferably methyl or halogen, and most preferably adjacent to A.

The present invention also relates to novel compounds of the above formula. However, when Z _x and Z ₂ are part of the benzene ring, the following are excluded as novel compounds: 1) n is not zero, when B is trimethylsilyl and A is N, N-diethylaminocarbonyl, N, N-bis (1-methylethyl) aminocarbonyl , N-methylaminocarbonyl, N-ethylaminocarbonyl, 1-piperidinylcarbonyl or N-phenylaminoLT 3276 B carbonyl, or when B is orthotolyl and A is N, N-diethylaminocarbonyl, Ν, Ν-bis (1-methylethyl) aminocarbonyl, N-methylaminocarbonyl, or O -methylcarbamyl; or when B is 1,1-dimethylethyl and A is N, N-dimethylaminocarbonyl or N-phenylaminocarbonyl; or when B is trimethylstanyl and A is N, N-diethylaminocarbonyl or 0- (1,1-dimethylethyl) carbamyl;

2) when B is 2-trimethylsilyl and A is N, N-diethylaminocarbonyl, R _n is not 3-fluoro-6-formyl, 3-fluoro-6-methyl, 3-chloro-6-formyl, 3-fluoro-6-methyl,

3-chloro-6-formyl, 3-fluoro, 3-chloro, 3-chloro-6-methyl, 6-trimethylsilyl, or 6-methyl;

3) when A is 0- (1,1-dimethylethyl) carbamyl and B is 2-trimethylsilyl, R _n is not 5-trifluoromethyl;

4) when A is N-phenylaminocarbonyl and B is 2,2-dimethylpropyl, R _n is not 3-methyl; and

5) R is not an isothiocyanate when A is -C (O) -amine and W _m is -O-.

When Z _x and Z ₂ are part of a thiophene, furan or pyrrole ring, the novel compounds of the present invention do not include B equal to trimethylsilyl, when A is (diethylamino) carbonyl.

The invention also describes fungicidal compositions for use in said method.

The term alkyl, as used herein, unless otherwise indicated, means an alkyl radical, linear or branched, having 1 to 10 carbon atoms, unless otherwise specified. The terms alkenyl and alkynyl refer to unsaturated radicals having from 2 to 7 carbon atoms. Examples of such alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-propenyl, 1-methyl-ethenyl and the like. Examples of such alkynyl groups include ethynyl, 1-propynyl, 2-propynyl,

1,1-dimethyl-2-propynyl and the like. Substituent groups may be both alkenyl and alkynyl, such as 6,6-dimethyl-2-hepten-4-ynyl. * As used in the description, the term alkoxyl means an alkyl group having, unless otherwise stated, 1 to 10 carbon atoms bonded in the ether. Examples of such alkoxy groups include methoxyl, ethoxyl, propoxyl, 1-methylethoxyl and the like.

As used in the specification, the term alkoxyalkyl means an ether radical having, unless otherwise stated, 1 to 10 carbon atoms. Examples of such alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like.

As used in the description, the terms monoalkylamino and dialkylamino each refer to an amino group having 1 or 2 hydrogens, respectively, substituted with an alkyl group.

As used in the description, the term haloalkyl means an alkyl radical containing one or more hydrogen atoms substituted by halogens, which contains all hydrogen atoms substituted by halogen. Examples of such haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl and the like.

As used in the description, the term halogen means a radical selected from chlorine, bromine, fluorine and iodine.

u

The fight against Gg disease, including sting disease, by chemical means can be accomplished in a variety of ways. The measure can be applied directly to soil contaminated with Gg, such as during planting, through sowing. Alternatively, the product can be used after planting and germination. However, this remedy is best used for seeded seeds before sowing. This technique is commonly used in many cultures to apply fungicides to combat various phytopathological fungi.

The compositions of the present invention include a fungicidally effective amount of one or more compounds described above and one or more substituents. The active ingredient may be present in such compositions in an amount of 0.01 to 95 percent by weight. Other fungicides may also be included to provide a broader range to combat fungi. The choice of fungicides will depend on the culture and the diseases known to threaten that culture in the particular area.

The fungicidal compositions of the present invention, including the concentrates to be reconstituted before use, may contain at least one active ingredient and an adjuvant in liquid or solid form. The compositions are prepared by mixing the active ingredient with an adjuvant comprising diluents, fillers, carriers, and conditioning agents to form the compositions in the form of finely divided solid particles, pellets, solutions, dispersions or emulsions. Thus, it is expected that the active ingredient may be used with an adjuvant such as a solid solid, organic solution, water, liquid agent, dispersion agent, emulsion agent, and any suitable combination thereof.

Suitable liquid agents include, of course, alkyl benzene and alkylnaphthalene sulfonates, sulfated fatty alcohols, amines or acid amides, long chain sodium isothionate esters, sodium sulfosuccinate esters, sulfated or sulfonated fatty acid esters, petroleum sulfonates, sulfonated vegetable oils glycols, polyoxyethylene derivatives of alkylphenols (especially isooctylphenol and nonylphenol); and polyoxyethylene derivatives of higher fatty mono-acid esters of hexitol anhydride (e.g. sorbitan). Preferred dispersants include methyl, cellulose, polyvinyl alcohol, lignin sulfonates sodium, polymeric alkyl naphthalene sulfonates, naphthalene sodium sulfonates, and polymethylene bisnaphthalene sulfonate. Stabilizers can also be used to make stable emulsions such as magnesium aluminum silicate and xanthan glue.

Other compositions include dust concentrates containing from 0.1 to 60% by weight of the active ingredient in a suitable excipient; there may be other additives to improve application properties, such as graphite. When used, this dust can be diluted to a concentration of about 0.1-10% by weight.

The concentrates may also be aqueous emulsions prepared by mixing the anhydrous solution of the water-insoluble active ingredient and the emulsifying agent with water to a homogeneous weight, followed by homogenization to give a very fine particle-stable emulsion. The concentrates may also be in the form of aqueous suspensions prepared by grinding a mixture of the water-insoluble active ingredient and the liquid agent to form a suspension characterized by extremely small particle size such that the surface coating is homogeneous upon dilution. Suitable concentrations of this composition are about 0.1-60%, preferably 5-50% by weight of the active ingredient.

Concentrates may be solutions of the active ingredient in appropriate solvents in association with the active surfactant. Suitable solvents for the active ingredients of the present invention for seed dressing include propylene glycol, furfuryl alcohol, other alcohols and glycols, and other solvents which do not substantially impede seed germination. If the active ingredient is applied to a soil, then the solvents are: N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, hydrocarbons, and water-immiscible ethers, esters and ketones.

Concentrate formulations generally contain from about 1.0 to 95 parts (most effective 5 to 60 parts) of the active ingredient, about 0.25 to 50 parts (most effective 1 to 25 parts) of a surfactant and, where necessary, about 4 to 94 parts of a solvent; all parts by weight must be based on the total weight of the concentrate.

The granular mixture is used to apply the composition to the soil during planting. Granules are physically stable fine particle formulations comprising at least one active ingredient bonded or distributed through the parent matrix of an inert, fine particulate filler. In order to facilitate the washing of the active ingredient from fine particles, the composition must contain an active surfactant as described above or, for example, propylene glycol. Natural clay, pyrophyllites, hits and vermiculites are examples of classes of mineral fillers in the form of fine particles. Preferred fillers are porous, absorbent, preformed particles such as preformed and screened fine particulate atapulgites or heat-enhancing fine particulate vermiculites, and finely divided clays such as kaolin, hydrated atapulgites, or bentonite clays. These fillers are sprayed or mixed with the active ingredients to form fungicidal granules.

The granular compositions of the present invention may contain from about 0.1 to about 30 parts by weight of active ingredient, about 100 parts by weight of mole, about 0 to 5 parts by weight of surfactant, and about 100 parts by weight of fine clay.

The method of the present invention may be implemented by admixing the composition comprising the active ingredient into the seeds, prior to sowing, at a rate of 0.01 to 50 g per kilogram of seed, preferably 0.1 to 5 g per kilogram, and preferably 0.2 to 2 g per kilogram. If desired for soil application, the compounds may be applied at rates of 10-1000 g / ha, preferably 50-500 g / ha. Higher application rates are appropriate for light soils or with higher rainfall, or both.

The compounds of the present invention may be prepared by methods known to those skilled in the art. The following examples illustrate some of these methods and are illustrative; in any case, they do not limit the invention.

Percentages are given by weight. Melting points and boiling points are not specified. Thin layer chromatography was performed by varying the concentrations of ethyl acetate / hexanes eluent. Tetrahydrofuran and ether solvents were distilled from sodium metal / benzophenone just before use. N, N, N *, N '- (Tetramethyl) -ethylenediamine was distilled from calcium hydride before use. All other reagents were purchased from Aldrich and Lancaster and used without purification. The identified physical property is provided for each sample or elemental analysis is given at the back of the samples.

Abbreviations used in the examples have the following meanings:

n-BuLi n-Butillitis s-BuLi 2-Butillitis t-BuLi 3-Butillitis DAS T Diethylamino sulfur trifluoride DEAD Diethylazodicarboxylate DMF Dimethylformamide DMSO Dimethisulfoxide TMSCI Trimethylsilyl chloride THF Tetrahydrofuran TMEDA N, N, N ', N' - (tetramethyl) ethylenediamine eq equivalent (s) min minutes Mel Methyl iodide Lawesson's [2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4- Reagent diphosphetane-2,4-disulfide] TLC thin-layer chromatography HPLC high pressure liquid chromatography RC radial chromatography GLC gas-liquid chromatography RT room temperature i.e. melting point

The term conventionally treated means treating the reaction mixture with 10% aqueous citric acid solution, extracting with diethyl ether, rinsing the combined organic extracts with concentrated brine, drying the organic extract in vacuo to give crude product. to the final reaction product.

Method A. Introduction of electrophiles into the ortho-position of N, Ndialkylbenzamides.

1.3M s-BuLi in cyclohexane (1.1-1.2 mol eq) was added to dry ice / acetone or ether / liquid nitrogen cooled 1.0M TMEDA solution (1.0-1.2 molar) in THF, followed by dropwise addition of the corresponding N, N-dialkylbenzamide (1.0 eq) in THF. The resulting reaction mixture was stirred for 30-60 min at -78 ° C to ensure formation of the aryl anion, then cooled to <90 ° C with ether / liquid nitrogen bath and carefully quenched with the appropriate electrophile. The reaction was allowed to slowly warm to 0 ° C and then worked up in the usual manner. If necessary, the crude product was purified by chromatography, recrystallization or distillation.

Method B.

Introduction of electrophiles into the ortho-position of N, Ndialkylbenzamides via reverse coupling.

1.3M s-BuLi in cyclohexane (1.2 eq) was added to ether / liquid nitrogen cooled with 1.0M TMEDA solution (1.2 eq) in THF followed by addition of the corresponding N, Ndialkylbenzamide (1.2 eq) in THF. The internal reaction temperature was maintained between -80 and -95 ° C in both cases. After the addition, the cooling bath was replaced by dry ice / acetone and the resulting reaction was stirred for 1 hour. At -78 ° C. This solution was added dropwise to a solution of the corresponding electrophiles (with excess electrophiles) in THF at a rate that maintained an internal temperature below -80 ° C in ether / liquid nitrogen bath. The resulting reaction mixture was allowed to slowly warm to 0 ° C and then purified for each component as described below.

Method C. Introduction of electrophiles into ortho-position in N-alkylbenzamides.

1.3M s-BuLi in cyclohexane (2.1-2.2 eq) was added to dry ice / acetone or ether / liquid nitrogen cooled 1.0M TMEDA in THF (1.0-1.2 eq), followed by the addition of the corresponding A solution of N-alkylbenzamide (1.0 eq) in THF. The resulting reaction mixture was stirred for 30-60 min. At -78 ° C to guarantee -.the complete formation of the aryl anion was then cooled to. <90 ° C in ether / liquid nitrogen bath and the corresponding electrophile was carefully added. The reaction was allowed to slowly warm to -30 ° C and then worked up in the usual manner. If necessary, the crude product was purified by chromatography, recrystallization or distillation.

Method D. Methods for attachment of boron derivatives.

Example f (5.0 g, 27.2 mol), TMEDA (6.6 g, 57.1 mol), and THF (100 mL) were stirred at -78 ° C under nitrogen and treated with 1.3M s-BuLi cyclohexane (44 mL, 57.1 mol). The mixture was stirred for 15 min and trimethylborate (3.1 g, 29.9 mol) was added all at once. The mixture was then stirred for 30 min. At -78 ° C before warming to room temperature. This mixture was poured into 100 mL of 10% HCl, basified with saturated aqueous NaHCO ₃ and extracted with ether. The aqueous layer was re-acidified and extracted with CH ₂ Cl ₂ . The combined organic layers were dried (MgSO ₄ ), concentrated and recrystallized to give 4.2 g of 4-chloro-2-ethyl-1-hydroxy.

1H-2,1-benzazaborol-3 (2H)-white solid, m.p. 210-211 ° C.

This compound (1.05 eq) in ethanol (2 ml) is added to the corresponding aryl, benzyl or vinyl bromide (1 eq) with a catalytic amount of tetrakis (triphenylphosphine) palladium (0) in toluene (20 ml) under an atmosphere of RT. Aqueous sodium carbonate (4 mL 2M) was then added and the resulting mixture was refluxed (4-24 h) and checked by TLC. The mixture was then cooled to room temperature, diluted with additional toluene (20 mL), filtered through celite / silica, washed with water, dried (MgSO ₄ ), and concentrated. If necessary, the crude product is purified by chromatography or recrystallization from ethyl acetate / hexanes.

EI Method, Amination of Benzoyl Chlorides.

The corresponding acid chloride solution (1 eq) in toluene or CH ₂ Cl ₂ was added to an ice-water-cooled solution of the corresponding amine (> 2 eq) in the same solvent. The mixture was stirred for 1-16 h at RT until GLC was formed, then partitioned between ethyl acetate and dilute acid. The organic phase was dried (MgSO ₄ ) and concentrated. If necessary, the crude product is purified by chromatography, recrystallization or distillation.

Method E2. Amination of benzoyl chlorides.

To a solution of the corresponding amine (> 1 eq) in 50 ml of CH ₂ C1 ₂ is added an appropriate benzoyl chloride (1 eq) and benzyltriethylammonium chloride or catalytic amount of pyridine. The mixture was cooled to 5 ° C and> 1 eq NaOH (50% aqueous solution) was added. The mixture was stirred for 3-16 hours, washed with 10% HCl and water, dried and concentrated. The crude product is purified by chromatography, recrystallization or distillation to give the purified product.

Example of starting material a. 2-Chloro-6- (trimethylsilyl) benzoic acid.

2-Chlorobenzoic acid (3.91 g, 25 mol), THF (60 mL), and TMEDA (8.6 mL, 57 mol) were stirred under nitrogen and cooled to -100 ° C. 1.3M s-BuLi in cyclohexane (0.055 mol, 42.3 mL) was added maintaining the temperature below -80 ° C. After the addition was complete, TMSC1 (2.7 g, 25 mol) was added and the resulting mixture was stirred and allowed to slowly warm to -30 ° C. 25% Citric Acid (100 mL) was added and the mixture was extracted with two portions of 50 mL of ether, which were then combined and washed three times with water, dried (MgSO ₄ ) and concentrated. The crude product was purified by HPLC eluting with 2: 3 ethyl acetate / hexanes. The product is obtained in the form of a white solid. Yield 63%, mp 129-131 ° C.

Example b. Chloro-β- (trimethylsilyl) benzoyl chloride.

Example a compound (2.4 g, 0.01 mol), thionyl chloride (3.57 g, 0.03 mol), toluene (50 mL), and 1 drop of DMF were stirred at RT overnight. The reaction mixture was concentrated twice in vacuo from toluene (50 mL) to give the desired product as a brown oil. Yield 100%.

Example c. 2-Bromo-6- (trimethylsilyl) benzoic acid.

2-Bromobenzoic acid (30.15 g, 150 mol), TNF (400 mL), diisopropylamine (33.4 g, 330 mol) were stirred under a nitrogen atmosphere and cooled to -78 ° C. 10M n-BuLi in hexanes (31 mL, 0.31 mol) was added followed by TMSC1 (17.4 g, 160 mol). The mixture was allowed to warm slowly to -30 ° C, stirred for 1 h, then poured into 25% citric acid (100 mL) and stirred for 15 min. The mixture was extracted with two portions of 100 ml of ether, which were combined and washed 3 times with a saturated aqueous solution of NaHCO ₃ . The bicarbonate solution was acidified with 25% citric acid and extracted with three portions of 100 ml of ether. These extracts were combined, dried (MgSO ₄ ) and concentrated. The crude product was purified by recrystallization from ether / hexanes to give the desired product as a white solid. Yield 35%, m.p. 139-141 ° C.

Example d. 2-Bromo-6- (trimethylsilyl) benzoyl chloride.

The title compound is prepared from the compound of Example c by the procedure of Example b.

Example e. N, N-Diethyl-2-chlorobenzamide.

2-Chlorobenzoyl chloride reacts with diethylamine using the general method EI or E2 to produce the title compound.

Example f. N-ethyl-2-chlorobenzamide.

2-Chlorobenzoyl chloride reacts with ethylamine using the general method EI or E2 to produce the title compound.

Example g. (2- (2,6-Difluorophenyl) -4,4-dimethyl-2-oxazoline.

A solution of 2,6-difluorobenzoyl chloride (50 g, 283 mol) in CH ₂ Cl ₂ (200 mL) was added rapidly to a solution of 2-amino-2-methyl-1-propanol (63.1 g) in ice-water.

708 mol) CH ₂ Cl ₂ (400 mL). The resulting mixture was stirred at RT and followed by GLC followed by extraction twice with 10% HCl and once with saturated aqueous NaHCO ₃ . The organic phase was dried (MgSO ₄ ) and concentrated to give 61.9 N- (1,1-dimethyl-2-hydroxyethyl) -2,6-difluorobenzamide as a white solid.

This compound (60 g, 283 mol) was added portionwise to ice-water-cooled thionyl chloride (65 mL). The resulting yellow solution was stirred at RT for 1 h then poured into stirring ether. The solid was collected and washed with ether, then partitioned between dilute aqueous NaOH and ether. The latter ether extract was dried (MgSO ₄ ), concentrated to give 52.39 g of the title compound as a white solid. Yield 88%.

Example h. 2-Chloro-6- (trimethylsilyl) phenyl isocyanate.

Compound b (5.0 mol) was dissolved in 50 mL acetonitrile and tetrabutylammonium azide (Bu ₄ N ₃ ) (5.2 mol) was added. The mixture was stirred at RT for 0.5 h. The solvent was removed and the resulting oil was dissolved in 100 mL of toluene. After addition of 100 ml of hexane, the precipitate was filtered off; the filtrate was concentrated to give 1.5 g of the title compound.

Example i. 2-Chloro-6- (trimethylsilyl) benzaldehyde.

A 2.0M solution of borane-dimethylsulfide in THF (100 mL) was added over 15 min. A solution of the compound of Example a (11.4 g, 0.05 mol) in THF (200 mL). The mixture was refluxed for 2 days, cooled with methanol (500 mL) and allowed to stand at RT for 2 days. The solvent was then removed and 2-chloro-α-hydroxy-6LT 3276 B (trimethylsilyl) toluene was recrystallized from hexane; 8.9 g of crystals were obtained. Yield 83%, 1st temp. 40-42 ° C.

This compound (6.4 g, 29.9 mol) was added to a solution of pyridine chlorochromate (7.5 g) in CH ₂ Cl ₂ (500 mL). The mixture was stirred for 2 days and ether (500 mL) was added. The mixture was filtered through silica gel and the solvent removed in vacuo. Ether (200 mL) was added again and the mixture was filtered through silica gel. The solvent was removed to give 6.2 g of the title compound as an oil. Yield 98%.

Example j. 2- (2,6-Difluorophenyl) -2-oxazoline.

2,6-Difluorobenzoyl chloride (100 g, 566 mol) was added dropwise over 2 hours. into a vigorously stirred and ice water cooled mixture brometilaminohidrobromido (116.05 g, 566 mmol), benzyltriethylammonium chloride (5 g, 22.0 mol) was added 10% aqueous NaOH solution (680 mL, 1.7 mol) and CH ₂ C1 ₂ (1.5 L). The resulting mixture was stirred at RT overnight, then washed with water (3 x 200 mL), dried (MgSO ₄ ), concentrated, and kugelrohr distilled to give 51.8 g of 2- (2,6-difluorophenyl) -2-oxazoline as a colorless oil . Yield 50%.

Example k. N-ethyl-t-butylmethylenimine.

70% EtNH ₂ (20.0 g, 310 mol) was carefully added to trimethylacetaldehyde (24.35 g, 283 mol) under cooling with ice water to control the exothermic effect. When the exothermic reaction was complete, the organic layer was separated and treated with additional 70% EtNH ₂ (1-2 g). The organic layer was separated and distilled (see 96-98 ° C) from CaH ₂ to give 28.3 g of N-ethyl-t-butylmethylenimine as a colorless oil. Yield 88%.

Examples 1-4

These compounds were prepared as described in Mills et al., Directed Ortho Metallation of N, N-Diethylbenzamides. Silicon Protection of Ortho S i continued and the o-Methyl Group. J. of Organic Chemistry 54: 4372-4385, 1989.

For example,

No.

The compound

N, N-Diethyl-3-fluoro-6-methyl-2- (trimethylsilyl) benzamide

N, N-Diethyl-2- (trimethylsilyl) benzamide

N, N-Diethyl-2-methyl-6- (trimethylsilyl) benzamide

Example of N, N-Diethyl-3-fluoro-2- (trimethylsilyl) benzamide

N- (1,1-Dimethylethyl) -3-fluoro-N-methyl-2 (trimethylsilyl) benzamide.

3-Fluorobenzoyl chloride is treated with N-methyl-N-tert-butylamine using the basic method EI and E2 to give N-methyl-N- (tert-butyl) -3-fluorobenzamide. This compound was used in main method A to give the title compound. After distillation of kugelrohr, 12.07 g of analytically pure desired product are obtained,

i.e. 32-35 ° C.

example

2- (1,1-Dimethylethyl) -N, N-diethyl-6-methylbenzamide.

A 1.7M solution of t-BuLi in pentane (161 mL, 274 mmol) was added to a solution of 2- (2-fluorophenyl) -4,4-dimethyl-2-oxazoline (see Meyers A.l. and Williams B.E., Tetrahedron

Letters, 223-226 (1978)] (48.0 g, 249 mmol) in THF (320 mL) while maintaining the reaction temperature between -45 and -40 ° C in a dry ice / acetone cooled bath. The resulting reaction mixture was stored in a <-40 ° C dry ice / acetonitrile bath and followed by GLC for 20 min. This mixture was poured into ice and extracted three times with ether. These extracts were combined, dried (MgSO ₄ ), concentrated and distilled in vacuo to give 56.87 g of 2- (2-tert-butylphenyl) -4,4-dimethyl-2-oxazoline in 93% yield.

A solution of 2M trifluoromethanesulfonic anhydride (1 eq) in CH ₂ Cl _{2 was} added to ice-water-cooled 0.67M solution of 2- (2-tert-butylphenyl) -4,4-dimethyl-2-oxazoline (1 eq) in CH ₂ Cl ₂ . The resulting solution was stirred at 0 ° C for 10 min, then poured into an equal volume of ice water and stirred vigorously for 10 min. The CH ₂ Cl ₂ layer was washed twice with 10% HCl, dried (MgSO ₄ ), and concentrated to give 15.59 g of N- [2- (2-tert-butylphenylcarboxy) -1,1-dimethylethyl] -trifluoromethanesulfonamide, a white solid. further purification, yield 95%, en 69-71 ° C.

A freshly prepared solution of excess diazomethane in dry ether was added to a solution of N- [2- (2-tert-butylphenylcarboxy) -1,1-dimethylethyl] -trifluoromethanesulfonamide (13.1 g) in ether. The resulting yellow solution was allowed to settle at RT overnight, then washed with 10% HCl followed by 2.5N aqueous NaOH. The organic solution was dried (MgSO ₄ ) and concentrated to give 13.0 g of pure N-methyl-N- [2- (2-tert-butylphenylcarboxy) -1,1-dimethylethyl] -trifluoromethanesulfonamide as a white solid, 96% yield mp 42-44 ° C.

N-Methyl-N- [2- (2-tert-butylphenylcarboxy) -1,1-dimethylethyl] trifluoromethanesulfonamide (1 eq) was saponified in 2.0M KOH solution (3 eq) in DMSO at 110 ° C for 4 h. The resulting solution was cooled, diluted with water and extracted twice with ether. These ether extracts were removed. The aqueous phase was then acidified to pH 1 almost. HCl and extracted twice with ether. These latter ether extracts were dried (MgSO ₄ ) and concentrated to give 4.47 g of 2-tert-butylbenzoic acid as a pure white solid, without further purification, yield 96%, m.p. 58-60 ° C.

A solution of 2-tert-butylbenzoic acid (4.0 g, 22.5 mmol) in thionyl chloride (8.2 mL, 112 mmol) was stirred at RT for 2 h, then concentrated three times from carbon tetrachloride to remove any excess thionyl chloride traces. A solution of diethylamine (4.93 g, 67.4 mmol) in CH ₂ Cl ₂ (10 mL) was added dropwise over 10 min. in ice-water, cooled in a solution of crude acid chloride in CH ₂ Cl ₂ (35 mL) for 10 min. after the addition, the reaction mixture was partitioned between ether and 10% HCl. The ether phase is then washed with a saturated aqueous solution of NaHCO ₃ , then dried (MgSO ₄ ) and concentrated to give a quantitative yield of N, N-diethyl-2-tert-butylbenzamide as an off-white solid, en 38.5-40.5 ° Cm

N, N-Diethyl-2-tert-butylbenzamide (1.00 g, 4.3 mmol) was used in main method A to obtain 1.05 g of the title compound as a yellow oil. Yield 99%.

example

2-Chloro-N, N-diethyl-6- (trimethylstanyl) benzamide.

1.3M s-BuLi in cyclohexane (4.8 mL, 6.2 mmol) was added to a -78 ° C cooled solution of Example e compound (1.0 g, 4.7 mmol) and TMEDA (930 mL, 6.2 mmol) ) THF (15 mL). The resulting yellow mixture was stirred at -78 ° C for 45 min then cooled by dropwise addition of trimethyltin chloride (1.41 g, 7.1 mmol) in THF (5 mL) while maintaining an internal reaction temperature of <-65 ° C. The resulting green solution was warmed to RT to give a yellow solution which was diluted with ether and extracted twice with 10% HCl and once with saturated aqueous NaHCO ₃ . The ether solution was dried (MgSO ₄ ), concentrated and purified by HPLC eluting with 1: 4 ethyl acetate / hexanes to give 1.37 g of the title compound as a colorless oil. Yield 81%.

example

2- (1,1-Dimethylethyl) -N-ethyl-6-methylbenzamide.

A solution of 2-tert-butyl-6-methylaniline (1 eq) and 97% formic acid (4 eq) was refluxed for 16 h, then concentrated in vacuo and recrystallized from methanol / water to give 2-tert-butyl-6- methyl formanilide.

Phosphorus oxychloride (0.67 eq) was added to an ice-cooled, stirred suspension of this compound (1 eq) in a mixture of pyridine (11 eq = 1 volume) and pentane (0.5 volume). The resulting mixture was briefly heated to about 40 ° C for 10 min then cooled. Carefully add ice water (0.5 volumes) and separate the two layers. The aqueous layer was extracted with pentane (0.25 vol), then the combined organic solutions were washed three times with water (0.5 vol), dried (MgSO ₄ ), and concentrated to give 2-tert-butyl-6-methylphenyl isocyanide.

This compound is heated at 250-253 ° C for 6 hours to complete the rearrangement as evidenced by infrared analysis. After recrystallization from hexanes, pure 2-tert-butyl-6-methylbenzonitrile was obtained, m.p. 60-62 ° C.

A solution of this compound (500 mg, 2.9 mmol) and 1.0 M triethyloxonium tetrafluoroborate in CH ₂ Cl ₂ (5.8 mL, 5.8 mmol) was stirred at RT for several days under a nitrogen atmosphere. The reaction mixture was diluted with CH ₂ Cl ₂ and extracted with saturated aqueous NaHCO ₃ solution, then dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 1: 4 ethyl acetate / hexanes to give the title compound as a white solid (430 mg). Yield: 68%, m.p. 110.5-111.5 ° C.

example

2 - [(1,1-Dimethylethyl) dimethylsilyl] -N, N-diethyl-3-fluorobenzamide.

1.3M s-BuLi in cyclohexane (7.7 mL, 0.01 mol) was added to THF (30 mL) and TMEDA (1.28 g, 0.011 mol) cooled to -78 ° C under a nitrogen atmosphere with stirring. To this mixture was added 0.0097 mol of N, N-diethyl-3-fluorobenzamide (prepared from

3-fluorobenzoic acid and diethylamine according to the procedures of Examples b and f) dissolved in a minimum amount of THF. The mixture was stirred for 10 min. and injected with t-butyldimethylsilyl chloride (3.01 g, 0.02 mol). The reaction mixture was stirred and heated to RT overnight. 25% citric acid (15 ml) was added and the mixture was extracted three times with ether. The ether extracts were combined and washed twice with water, dried (MgSO ₄ ), concentrated, and purified by RC eluting with 7:15 ethyl acetate / hexanes. The title compound is obtained in the form of a tan solid. Yield 81%, m.p. 50-51 ° C.

example

2 - [(1,1-Dimethylethyl) dimethylsilyl] -N, N-diethyl-3-fluoro-6-methylbenzamide.

1.3M s-BuLi in cyclohexane (1.8 mL, 2.3 mmol) was added under stirring to THF (20 mL) and TMEDA (0.32 g, 2.7 6 mmol) cooled to -78 ° C under a nitrogen atmosphere. . To this mixture was added Example 9 (0.6 g, 2 mmol) dissolved in a minimal amount of THF. After 10 minutes. stirring was injected with Mel (0.98 g, 6.9 mmol). The mixture was stirred for 1 h, 15 mL of 25% citric acid was added and the mixture was extracted with ether 3 times. The ether extracts were combined and washed twice with water, dried (MgSO ₄ ), and concentrated. The crude product was purified by RC eluting with 3: 7 ethyl acetate / hexanes. The title compound was obtained as a light yellow oil. Yield 31%.

example

2- (1,1-Dimethylethyl) -3-fluoro-N, 6-dimethyl-2- (trimethylsilyl) benzamide.

1.3M s-BuLi in cyclohexane (31.4 mL, 41 mmol) was added to THF (100 mL) and TMEDA (5.35 g, 46 mmol) cooled to -100 ° C under nitrogen with stirring. To this mixture was added Example 5 (10.45 g, 37 mmol) dissolved in a minimal amount of THF. After 10 minutes. stirring was injected with Mel (15.8 g, 0.1114 mol). The mixture is stirred for 1 hour. and 15 ml of 25% citric acid were added. The mixture was extracted with ether 3 times; The ether extracts were combined and washed twice with water, dried (MgSO ₄ ), and concentrated. The crude product was purified by RC eluting with 1: 9 ethyl acetate / hexanes. The title compound was obtained as a light yellow solid. Yield 99%, m.p. 44-47 ° C.

example

N-Ethyl-3-fluoro-2- (trimethylsilyl) benzamide.

N-ethyl-3-fluorobenzamide (4.18 g, 0.025 mol) (prepared from 3-fluorobenzoic acid using the procedures of Examples b and f), dissolved in a minimum amount of THF, used in Basic Method C and purified by HPLC eluting with 3: 7 ethyl acetate. acetate / hexanes. The title compound is obtained as a white solid. Yield 53%, m.p. 80-82 ° C.

example

N, N-Dipropyl-2- (trimethylsilyl) benzamide.

N, N- (Dipropyl) benzamide (4.0 g, 0.0195 mol) (prepared from benzoyl chloride and dipropylamine using basic method EI and E2) was used in main method A to give the desired compound which was purified by HPLC eluting with 1: 9 ethyl acetate / hexanes to give a light yellow oil. Yield 65%, n _D ²⁵ = 1.5094.

example

2- Methyl-N, N-dipropyl-6- (trimethylsilyl) benzamide.

the compound of the example was reacted with Mel using the main method A to give the title compound.

example

3-Chloro-N, N-diethyl-2- (trimethylsilyl) benzamide.

N, N-Diethyl-3-chlorobenzamide (10.45 g, 50 mmol) (prepared from 3-chlorobenzoic acid and diethylamine using the procedures described above) was treated with TMSC1 (16.30 g, 150 mmol) using Principal Method A, to give 13.4 g of the title compound as an orange oil. Yield 95%.

16-36 Examples

The following compounds were obtained by treating compound b of Example b with the corresponding amine using the basic method

El or E2 methodologies or similar methodologies. The melting points of solids that are solid at ambient temperature are given in ° C.

Example # Name of the compound Physical property 16th 2-Chloro-N-phenyl-6- (trimethylsilyl) benzamide 158-160 17th 2-Chloro-N-octyl-6- (trimethylsilyl) benzamide 94-96 18th 2-Chloro-N-ethyl-N- (1-methylethyl) -6- (trimethylsilyl) benzamide - 19th 2-Chloro-N-methyl-6- (trimethylsilyl) benzamide 125-127 20th N-Butyl-2-chloro-6- (trimethylsilyl) benzamide 107-110 21st 2-Chloro-N- (1-methylethyl) -6- (trimethylsilyl) benzamide 140-143 22nd 2-Chloro-N-ethyl-N-methyl-6- (trimethylsilyl) benzamide - 23rd 2-Chloro-N- (1,1-dimethylethyl) -N- methyl-6- (trimethylsilyl) benzamide - 24th 2-Chloro-N-ethyl-N-phenyl-6- (trimethylsilyl) benzamide 95-98 25th 2-Chloro-N- (2,2,2-trifluoroethyl) -6- (trimethylsilyl) benzamide 105-107 26th 2-Chloro-N-propyl-6- (trimethylsilyl) benzamide 108-109

27th 2-Chloro-N- (2-hydroxyethyl) -6- (trimethylsilyl) benzamide 138-140 28th 2-Chloro-N- (1-methylpropyl) -6- (trimethylsilyl) benzamide 144-145 29th 2-Chloro-N- (2-chloroethyl) -6- (trimethylsilyl) benzamide 111.5-113 30th 2-Chloro-N- (3-chloropropyl) -6- (trimethylsilyl) benzamide 128-131 31st 2-Chloro-N- (femylmethyl) -6- (trimethylsilyl) benzamide 112-114 32 2-Chloro-N- (2-furylmethyl) -6- (trimethylsilyl) benzamide 113-115 33 2-Chloro-N- (2-methylphenyl) -6- (trimethylsilyl) benzamide 116.5-118 34 2-Chloro-N-cyclopropyl-6- (trimethylsilyl) benzamide 101-104 35 2-Chloro-N-ethyl-N- (phenylmethyl) -6- (trimethylsilyl) benzamide - 36 2-Chloro-N, N-dipropyl-6- (trimethylsilyl) benzamide -

37-39 Examples

The following compounds were prepared using the main method A or B. Starting materials are N, N-diethyl-3-fluorobenzamide, which is obtained from 3-fluorobenzoic acid as described above, and the corresponding electrophile.

Example # Name of the compound L.t. 37 6-Bromo-N, N-diethyl-3-fluoro-2- (trimethylsilyl) benzamide 53.0-54.0 38 6-Chloro-N, N-diethyl-3-fluoro-2- (trimethylsilyl) benzamide 39 2-Chloro-N, N-diethyl-6- (trimethylsilyl) benzamide

example

N, N-Diethyl-3-fluoro-6-iodo-2- (trimethylsilyl) benzamide.

4.99 g of the compound of Example 4 and 20.3 g of iodine were combined according to the main method B. The resulting reaction mixture was poured into ice water. CH ₂ Cl ₂ was added and the mixture was extracted twice with thiosulfate to remove the iodine organic solution, brine dried (MgSO ₄ ), and concentrated to give the title compound as a 5.6 g yellow solid. Yield 77%, m.p. 58.5-64 ° C.

excess water.

two sodium followed by times sample

N, N-Diethyl-3-fluoro-6-formyl-2- (trimethylsilyl) benzamide.

5.34 g of the compound of Example 4 and 1.7 ml of DMF were combined according to the basic method B. The resulting reaction mixture was poured into ice water. CH ₂ Cl _{2 was added} and the mixture was extracted with aqueous NaHCO ₃ solution, then brine, then dried (MgSO ₄ ), concentrated and purified by HPLC eluting with 1: 3 ethyl acetate / hexanes to give 3.5 g of the title compound as a clear oil. . Yield 60%.

example

2 - [(Diethylamine) carbonyl] -4-fluoro-3- (trimethylsilyl) benzoic acid, methyl ester.

20.06 g of the compound of Example 4 and excess CO ₂ gas were combined according to Main Method A. The resulting reaction mixture was poured into water and acidified with 2N HCl. The resulting solid was concentrated by filtration and dried to give the corresponding acid.

A couple of drops of DMF were added to a mixture of this acid (9.34 g, 30.0 mmol) and thionyl chloride (11.89 g, 100 mmol) in toluene (100 mL).

The reaction was completed in 1 h. At 70-74 ° C. This mixture was concentrated in vacuo to remove excess thionyl chloride. The resulting crude acid chloride (0.98 g, 3.0 mmol) was dissolved in methanol (25 mL) and triethylamine (2 eq) was added. The reaction mixture was then diluted with ethyl acetate and extracted with dilute HCl followed by saturated aqueous NaHCO ₃ . The organic solution was dried (MgSO ₄ ) and concentrated to give 0.54 g of the title compound as a solid. Yield 55%, m.p. 46 ° C.

example

2 - [(Diethylamino) carbonyl] -4-fluoro-3- (trimethylsilyl) benzoic acid, 1-methylethyl ester.

Acid chloride (0.98 g, 3.0 mmol) was prepared as in Example 42 dissolved in isopropyl alcohol (25 mL) and triethylamine (1 mL, 7.0 mmol) was added. After stirring overnight at room temperature, the mixture was diluted with ethyl acetate and extracted with dilute HCl followed by saturated aqueous NaHCO ₃ . The organic solution was dried (MgSO ₄ ), concentrated, and purified by RC eluting with 7: 3 hexanes / ethyl acetate to give the title compound as a colorless oil.

example

N, N, 2-Triethyl-6- (trimethylsilyl) benzamide.

Example 24 (2.49 g, 10 mmol) and ethyl iodide (4.68 g, 30 mmol) were combined according to main method B. The resulting reaction mixture was poured into ice water. Ether was added and the mixture was extracted with aqueous NaHCO ₃ solution, then brine, then dried (MgSO ₄ ) and concentrated to give 2.83 g of the title compound as a colorless oil. Yield 100%.

example

2-Chloro-N-ethyl-6- (trimethylsilyl) benzamide.

Example f (2.2 g, 0.012 mol) was treated with TMSC1 (3.91 g, 0.036 mol) using main method A. The title compound was recrystallized from ether / hexanes as a solid, m.p. 105-107 ° C.

example

2-Chloro-N-ethyl-N- (methoxymethyl) -6- (trimethylsilyl) benzamide.

A 2M solution of THF tert-butylmagnesium chloride (2.5 mL, 5 mmol) was added to an ice-water-cooled solution of Example 45 (1.28 g, 5 mmol) in THF (25 mL). Chloromethyl methyl ether (0.44 g, 5.5 mol) was added and the reaction mixture was stirred at ambient temperature for 1 h. and then partitioned between water and ethyl acetate. The organic solution was dried (MgSO ₄ ), concentrated and purified by RC 1: 9 ethyl acetate / hexanes to give 0.80 g of the title compound as a colorless oil. Yield 53%.

example

N-Acetyl-2-chloro-n-ethyl-6- (trimethylsilyl) benzamide.

1M Sodium bis (trimethylsilyl) amide in THF (5.5 mL, 5.5 mmol) was added dropwise over several minutes. to a solution of the compound of Example 45 (1.28 g, 5 mmol) in THF (30 mL). The resulting mixture was cooled in a water bath until acetyl chloride solution (0.432 g, 5.5 mmol) in THF (10 mL) was added while maintaining the internal reaction temperature at -25 ° C. After 1 or. the resulting reaction mixture was partitioned between saturated aqueous NaHCO ₃ solution and ether. The ether phase was dried (MgSO ₄ ), concentrated and purified by RC 1: 4 ethyl acetate / hexanes to give 0.25 g of the title compound as a pale yellow oil. Yield 17%.

example

N-Ethyl-2-methyl-6- (trimethylsilyl) benzamide.

1.3M s-BuLi in cyclohexane (25.4 mL, 0.033 mol) was added to THF (50 mL), TMEDA (3.83 g, 0.033 mol) and Example c (4.10 g, 0.005 mol), which were cooled. to -78 ° C under nitrogen with stirring. After 20 minutes of Mel was added all at once (2.45 g, 0.01725 mol). The mixture was stirred for 1 h and 25% citric acid (50 mL) was added. The mixture was extracted three times with CH ₂ Cl ₂ . The combined extracts were washed twice with water, dried (MgSO ₄ ), and concentrated. To the resulting mixture was added 30 mL of thionyl chloride and 5 drops of DMF. After stirring overnight at RT, the mixture was concentrated to dryness; 50 ml of toluene was added and the mixture again concentrated. This process was repeated 3 times. The crude product was diluted with 30 ml of toluene in the form of a brown oil and poured into 100 ml of a 70% solution of 70% ethylamine in water cooled to 5 ° C in an ice bath. After stirring overnight, the mixture was washed with 10% HCl and three times with water, dried (MgSO ₄ ), concentrated and purified by HPLC eluting with 1: 3 ethyl acetate / hexanes. Two fractions were obtained. When each was concentrated, compound 48 crystallized as a white solid in 20% yield, 115-117 ° C. Compound 49 crystallized in the form of a white solid. Yield 42%, m.p. 64-66 ° C.

example

N-Ethyl-2- (trimethylsilyl) benzamide.

N-Ethylbenzamide (74.5 g, 500 mmol) and TMSC1 (135.8 g, 1.25 mol) were combined according to Method C and purified by HPLC eluting with 1: 4 ethyl acetate / hexanes to give 75.75 g of the title compound. , in the form of a white solid. Yield: 68%, m.p. 64.0-66.0 ° C.

example

N-Ethyl-N- (methoxymethyl) -2- (trimethylsilyl) benzamide.

1M Sodium bis (trimethylsilyl) amide THF solution (52.5 mL, 52.5 mmol) was added dropwise over 5 min. to a solution of the compound of Example 49 (11.07 g, 50 mmol) in THF (100 mL). The resulting mixture was cooled in a dry ice / acetone bath until undiluted chloromethyl methyl ether (4.83 g, 60 mmol) was added maintaining an internal reaction temperature of <-70 ° C. The ice bath was removed and the resulting reaction mixture allowed to warm for 1 h, then partitioned between saturated aqueous NaHCO ₃ solution and ether. The ether phase was dried (MgSO ₄ ), concentrated and purified by HPLC with 3:17 ethyl acetate / hexanes to give 6.55 g of the title compound as a colorless oil. Yield 49%.

example

N, N-Diethyl-2-methyl-6- (trimethylsilyl) thiobenzamide.

A mixture of the sample compound (2.0 g, 7.6 mmol) and Lawesson's reagent (2.3 g, 5.7 mmol) in xylene (50 mL) was refluxed for 16 h, then cooled and filtered. The filtrate was distributed between ether and water. The organic layer was washed with 10% HCl and brine, dried (MgSO ₄ ) and concentrated. The crude product was purified by RC eluting with 1: 9 ethyl acetate / hexanes to give 1.4 g of the title compound as a yellow oil which crystallized on standing. Yield 66%, m.p. 82-83 ° C.

example

N, N-Diethyl-6- (difluoromethyl) -3-fluoro-2- (trimethylsilyl) benzamide.

To a solution of DAST (55 mg, 0.34 mmol) in 1 mL of CH ₂ Cl ₂ at 0 ° C was added Example 41 (100 mg,

O, 34 mmol). The solution was refluxed for 16 hours and a second molar equivalent of DAST was added. This procedure followed until the reaction was completed by GC analysis. The mixture was added to 10 g of ice and the aqueous solution was extracted with CH ₂ Cl ₂ . The extracts were combined, washed with brine, dried (MgSO ₄ ), and concentrated. The product was purified by RC eluting with 1: 9 ethyl acetate / hexanes to give 800 mg of the title compound as a yellow solid. Yield 92%, m.p. 65-67 ° C.

example

N, N-Diethyl-3-fluoro-6-methyl-2- (trimethylsilyl) thiobenzamide.

The title compound was prepared from the compound of Example 1 and Lawesson's reagent according to the procedure of Example 51. The crude product was purified by flash column chromatography on silica gel 6 eluting with 1:19 ethyl acetate / hexanes and then recrystallized from hexanes to give 820 mg of the title compound as a white solid. Yield 78%, m.p. Mp S8-69 ° C.

example

N, N-Diethyl-3-fluoro-6- (hydroxymethyl) -2 (trimethylsilyl) benzamide.

Example compound (1.2 g, 4.1 mmol) and sodium borohydride (200 mg, 5.3 mmol) in ethanol (20 mL) were stirred at ambient temperature for 2 h. The solution was concentrated and partitioned between ether and 10% citric acid. The ether layer was washed with water and then with brine, dried (MgSO ₄ ), concentrated and recrystallized from cold hexanes to give 1.0 g of the title compound. Yield 82%, m.p. 107108 ° C.

example

N, N-Diethyl-3-fluoro-6- (fluoromethyl) -2- (trimethylsilyl) benzamide.

DAST solution (400 mg, 2.5 mmol) and Example 54 (660 mg, 2.2 mmol) in CH ₂ Cl ₂ (30 mL) were stirred for 2 h. At 25 ° C. The solution was poured into ice water (50 mL) and extracted with CH ₂ Cl ₂ . The organic extracts were combined, washed with brine, dried (MgSO ₄ ), concentrated and purified by RC eluting with 1: 9 ethyl acetate / hexanes to give 550 mg of the title compound as a yellow oil. Yield 83%.

example

N, N-Diethyl-3,6-difluoro-2- (trimethylsilyl) benzamide.

Diethylamine (15.4 g, 210 mmol) was treated with 2,5-difluorobenzoyl chloride (17.6 g, 100 mmol) using the basic method EI to give 20.0 g of N, N-diethyl-2,5-difluorobenzamide as a clear oil, yield 94%.

The title compound was prepared from this compound and 2.0 eq of TMSC1 according to basic method A. The crude product was purified by HPLC eluting with 1: 9 ethyl acetate / hexanes to give 4.8 g of the desired product as a clear oil. Yield 84%.

example

N, N-Diethyl-3-fluoro-4-methyl-2- (trimethylsilyl) benzamide.

1.3M s-BuLi (9.2 mL, 12 mmol) was added to a -78 ° C cooled solution of Example 4 (3.48 g, 10 mmol) and TMEDA (1.8 mL, 12 mmol) in THF. The reaction mixture was heated to -60 ° C, stirred for 3 hours, cooled to -78 ° C, and Mel (5.0 g, 36 mmol) was added. After heating the exotherm to -58 ° C, the reaction mixture was allowed to warm to 0 ° C and was worked up in the usual manner. The crude product was purified by HPLC eluting with 1: 4 ethyl acetate / hexanes to give 300 mg of the title compound as a clear oil, yield 71%.

example

N, N-Diethyl-4-methyl-2- (trimethylsilyl) benzamide.

N, N-Diethyl-4-methylbenzamide is prepared from 4-methylbenzoyl chloride and diethylamine according to the basic method EI. The crude product was recrystallized from cold hexanes to give 30.4 g of the title compound as a white solid, yield 98%, m.p. 54 ° C.

The title compound was prepared from this compound and 3.0 eq TMSC1 according to basic method A. The crude product was purified by HPLC eluting with 3:17 ethyl acetate / hexanes to give 7.0 g of the title compound as a clear oil. Yield 89%.

example

N, N-Diethyl-2-chloro-4-methyl-6- (trimethylsilyl) benzamide.

The title compound was prepared from the compound of Example 58 and 1.2 eq of hexachloroethane according to General Method A. Purification by HPLC eluting with 1: 9 ethyl acetate / hexanes afforded 1.6 g of the title compound as a clear oil. Yield 54%.

example

N, N-Diethyl-2,4-dimethyl-6- (trimethylsilyl) benzamide.

The title compound was prepared from the compound of Example 58 and Mel (4.0 eq) by basic method A. Purification by HPLC eluting with 3:17 ethyl acetate / hexanes afforded the title compound.

1.4 g of the title compound as a clear oil. Yield 83%.

example

N, N-Diethyl-2- (trimethylsilyl) -6 (trifluoromethyl) benzamide.

N, N-Diethyl-2- (trifluoromethyl) benzamide was prepared from 2-trifluoromethylbenzoyl chloride and diethylamine according to the basic method EI. Purification is not required to give 17.2 g of this compound, 97% yield.

The title compound was prepared from this compound and 3.0 eq TMSC1 according to basic method A. The crude product was purified by HPLC eluting with 3:17 ethyl acetate / hexanes to give 2.7 g of the title product as a clear oil. Yield 85%.

example

N, N-Diethyl-2- (trimethylsilyl) -3,6bis (trifluoromethyl) benzamide.

N, N-Diethyl-2,5-bis (trifluoromethyl) benzamide is prepared from 2,5-bis (trifluoromethyl) benzoyl chloride and diethylamine according to the basic method Ei. The desired intermediate was isolated without further purification, yield 11.3 g.

The title compound was prepared from this compound and 3.7 eq of TMSC1 according to basic method A. Purification by HPLC with 1:19 ethyl acetate / hexanes followed by kugelrohr distillation (90 ° C / 0.1 mm Hg) afforded 2.0 g of the title compound. of the compound in the form of a white solid. Yield 52%, m.p. 5556 ° C.

and 64 examples

Compound 63: N, N-Diethyl-5-methyl-2- (trimethylsilyl) -benzamide.

Compound 64: N, N-Diethyl-3-methyl-2- (trimethylsilyl) benzamide.

These compounds were prepared from N, N-diethyl-3-methylbenzamide and 2.0 eq TMSC1 according to basic method A. Purification by HPLC eluting with 1: 9 ethyl acetate / hexanes afforded two products. Compound 63 was isolated as a clear oil in 46% yield. Compound 64 was isolated as a clear oil (2.3 g, 17%).

example

N, N-Diethyl-2-chloro-3-methyl-6- (trimethylsilyl) benzamide.

The title compound was prepared according to Principal Method A from Example 63 and 1.3 eq of hexachloroethane. Purification by RC eluting with 1: 4 ethyl acetate / hexanes afforded 500 mg of the title compound as a yellow solid. Yield 44%, m.p. 42-44 ° C.

example

N, N-Diethyl-2-chloro-6- (triethylsilyl) benzamide.

The title compound was prepared according to Principal Method A from the compound of Example e and 1.4 eq of chlorthriethylsilane. Purification by HPLC eluting with 1:19 ethyl acetate / hexanes afforded 6.0 g of the desired product as a clear oil. Yield 92%.

example

N, N-Diethyl-2-chloro-6- (dimethylphenylsilyl) benzamide.

The title compound is prepared according to the main method A from the compound of example e and 1.1 eq of dimethylphenylsilyl chloride. Purification by HPLC with 1: 9 ethyl acetate / hexanes provided 6.3 g of the desired product as a clear oil. Yield 91%.

example

N, N-Diethyl-2-chloro-6- [tris (1-methylethyl) silyl] benzamide.

The title compound was prepared according to Principal Method A from the compound of Example e and 1.1 eq of triisopropylsilyl chloride. Purification by HPLC eluting 1:19 with ethyl acetate / hexanes afforded 5.5 g of the desired product as a clear oil. Yield 75%.

example

N, N-Diethyl-2-chloro-6 - [(chloromethyl) dimethylsilyl] benzamide.

The title compound was prepared according to the main method A from the compound of example e and 1.5 eq (chloromethyl) dimethylsilyl chloride. Purification by HPLC eluting with 1:19 ethyl acetate / hexanes gave 5.4 g of the desired product as a clear oil. Yield 85%.

example

N-Ethyl-2- (trimethylsilyl) -3-thiophenecarboxamide.

A mixture of thiophene-3-carboxylic acid (20.0 g, 178 mmol), thionyl chloride (30 mL, 411 mmol) and catalytic DMF (5 drops) was stirred at RT overnight. This solution was concentrated in vacuo and purified several times from toluene to remove any traces of excess thionyl chloride. Ethyl amine hydrochloride (29.03 g, 356 mmol) was then added to this crude acid chloride dissolved in CH ₂ Cl ₂ (50 mL). Pyridine (31.64g, 400 mmol) was added and after 1 h. the reaction mixture was washed with 10% HCl followed by water, dried (MgSO ₄ ), concentrated and recrystallized from EtOAc / hexanes to give 14.9 g of N-ethyl-3-thiophenecarboxamide as a tan solid. Yield 76%, m.p. 115-117 ° C.

1.3M s-BuLi in cyclohexane (37.23 mL, 48.4 mmol) was added to a dry ice / acetone cooled solution of N-ethyl-3-thiophenecarboxamide (3.41 g, 22 mmol) and TMEDA (5.62 g, 48, 4 mmol) in THF (100 mL). After 30 minutes with stirring at -78 ° C, one portion of TMSCl (5.26 g, 48.4 mmol) was added. The reaction was allowed to warm slowly over 1 h. to -10 ° C, then cooled with dilute aqueous citric acid solution and extracted with ethyl acetate (3X). The combined organic solutions were dried (MgSO 4, concentrated, and purified by HPLC eluting with 3: 7 EtOAc / hexanes to give 1.4 g of the title compound as a white solid, yield 28%, m.p. 114-116 ° C.

example

N, N-Diethyl-6-chloro-3-methyl-2- (trimethylsilyl) benzamide.

The title compound was prepared according to Principal Method A from 1.1 eq of hexachloroethane from Example 64. Purification by HPLC with 1: 9 ethyl acetate / hexanes provided 1.5 g of an oil which crystallized on standing. Yield 83%, m.p. 36-37 ° C.

example

3-Chloro-N-ethyl-2 '-methyl- [1,1' -biphenyl] -2-carboxamide.

The title compound was prepared according to the main method using 1-butanol intermediate boron intermediate, subsequently treated with 2D except for the presence of CH ₂ Cl ₂ , by extraction of the crude bromo toluene intermediate as described in Method D to give the title compound as a white solid (recrystallized from toluene), overall yield 55%, en 131-134 ° C.

example

2-Chloro-N-ethyl-6- (1-naphthalenyl) benzamide.

The title compound was prepared from the compound of Example f and 1-bromonaphthalene (0.76 g, 3.65 mmol) according to Principal Method D. 0.28 g of a white solid was obtained. Yield 28%, m.p. 181-182 ° C.

example

N, N-Diethyl-3-fluoro-2- (trimethylsilyl) thiobenzamide.

Mixture of N, N-diethyl-3-fluorobenzamide (4.69 g, 24 mmol) (see Mills et al., Directed Ortho Metallization of N, N-Diethylbenzamides. Silicon Protection of Ortho Sites and the O-Methyl Group, J. of Organic Chemistry 54: 4372-4385 (1989), Lawesson's reagent (6.47 g, 16 mmol) and xylene (150 mL) was refluxed overnight, then concentrated and kugelrohr distilled (105-110 ° C at 0, 25 tor) to give 4.8 g

N, N-diethyl-3- (fluoro) thiobenzamide as a yellow oil in 95% yield.

This mixture and 1.8 eq of TMSC1 were combined according to Principal Method A and purified by HPLC eluting with 1: 9 ethyl acetate / hexanes to give 3.7 g of the title compound as a yellow oil. Yield 77%, m.p. 71-73 ° C.

example

N, N-Diethyl-3-fluoro-4-methyl-2- (trimethylsilyl) thiobenzamide.

The title compound was prepared from Example 74 and 3.0 eq Mel according to Principal Method A and recrystallized from cold hexanes / ethyl acetate to give 2.5 g of the title compound. Yield 82%, m.p. 9697 ° C.

example

2-Chloro-N-ethyl-6- (trimethylsilyl) thiobenzamide.

The title compound was prepared from the compound of Example 45 using the procedure of Example 51, m.p. 158.0-159.0 ° C.

example

2-Chloro-6- (trimethylsilyl) benzolecarbothiolic acid, Cetyl ester.

Example compound b (1.48 g, 0.006 mol), CH ₂ Cl ₂ (50 mL), ethanolothiol (0.44 g, 0.007 mol) and 4- (N, N-dimethylamino) pyridine (0.86 g, 0.007 mol). stirred at RT overnight. The mixture was washed with 10% HCl and three times with water, dried (MgSO ₄ ) and concentrated.

The crude product is purified by RC eluting with 1: 3 ethyl acetate / hexanes. The title compound is obtained in the form of a clear oil. Yield 61%.

78-81 Examples

These compounds were prepared according to Example 77 using the corresponding thiol ester; the yields below.

For example, No. Name of the compound Yield 78 2-Chloro-6- (trimethylsilyl) - benzolecarbothiolic acid, S— (1— methylethyl) ester 35% 79 / .................. 2-Chloro-6- (trimethylsilyl) - benzolecarbothiolic acid, S-propyl ester 80% 80 2-Chloro-6- (trimethylsilyl) - benzolecarbothiolic acid, S- (1- methylpropyl) ester 47% 81 2-Chloro-6- (trimethylsilyl) - benzolecarbothiolic acid, S- (2- methylpropyl) ester 81%

example

N-Ethyl-2- (trifluoromethyl) -6- (trimethylsilyl) -benzamide.

2- (Trifluoromethyl) benzoyl chloride and ethyl amine were combined according to the basic method EI and recrystallized from cold hexanes to give 7.7 g of N-ethyl-2- (trifluoromethyl) benzamide as a white solid, yield 67%, m.p. 73-76 ° C.

This compound was coupled with 2.0 eq of TMSC1 according to basic method C. Recrystallization from ethyl acetate / hexanes provided 2.0 g of the title compound as a white solid. Yield 69%, m.p. 134-135 ° C.

example

N-Ethyl-chloro-6 - [(chloromethyl) dimethylsilyl] -benzamide.

The title compound was prepared from the compound of Example f and 2.0 eq (chloromethyl) dimethylsilyl chloride according to General Method C. Recrystallization from ethyl acetate afforded 3.0 g of the desired product as a white solid. Yield 52%, m.p. 88-89 ° C.

example

N, N-Diethyl-2,3-dichloro-6- (trimethylsilyl) benzamide.

The title compound was prepared from the compound of Example 39 and 1.5 eq of hexachloroethane according to General Method A. Purification by RC eluting with 1: 4 ethyl acetate / hexanes afforded 320 mg of the desired product as a white solid. Yield 14%, m.p. 143-147 ° C.

example

N, N-Diethyl-2-chloro-3-ethyl-6- (trimethylsilyl) benzamide.

The title compound was prepared from Example 39 and 8.5 eq ethyl iodide according to General Method A. Purification by RC eluting with 1: 4 ethyl acetate / hexanes afforded 1.3 g of the desired product as a crude oil. Yield 57%.

example

N, N-Diethyl-2-chloro-3, β-bis (trimethylsilyl) benzamide.

The title compound was prepared from Example 39 and 2.0 eq TMSC1 according to Principle A. Purification by HPLC eluting with 1: 4 ethyl acetate / hexanes afforded 0.9 g of the title product as a white solid. Yield: 37%, m.p. 93-96 ° C.

example

N-Ethyl-2-chloro-6- (ethenyldimethylsilyl) benzamide.

The title compound was prepared from the compound of Example f and 1.5 eq of vinyldimethylsilyl chloride according to General Method C. Purification by HPLC eluting with 1: 4 ethyl acetate / hexanes afforded 630 mg of the desired product as a white solid. Yield 9%, m.p. 8689 ° C.

example

N, N-Diethyl-2-chloro-3-fluoro-6- (trimethylsilyl) benzamide.

N, N-Diethyl-2-chloro-3-fluorobenzamide was prepared from N, N3-fluorobenzamide (prepared from 3-fluorobenzoic acid and diethylamine as described above) and 1.4 eq of hexachloroethane according to basic method A. Purification by HPLC Elution 1 : 4 ethyl acetate / hexanes gave 3.3 g of the title compound as a clear oil in 56% yield.

This compound was coupled with 2.0 eq of TMSC1 according to basic method A. Purification by HPLC eluting with 3: 7 ethyl acetate / hexanes provided 2.2 g of the title compound as a clear oil. Yield 50%.

example

N-Ethyl-2-chloro-6- (1,1-dimethylethoxy) benzamide.

To a solution of the compound of Example f (3.7 g, 20 mmol) and TMEDA (6.0 mL, 40 mmol) in anhydrous THF (100 mL) at -78 ° C was added 1.3M s-BuLi (34 mL, 44 mL) under nitrogen. mmol). After 30 minutes MgBr ₂ .Et ₂ O (15.5 g, 60 mmol) was added and the solution was warmed to ambient temperature, then cooled to -78 ° C and stirred for 1 h with t-Butyl peroxybenzoate (4.3 g, 22 mmol) ). The solution was heated to -30 ° C and treated in the usual manner. Purification by HPLC eluting with 3:17 ethyl acetate / hexanes afforded 1.7 g of the title compound as a white solid. Yield 33%, mp 126-127 ° C.

example

2- [1,1-Dimethylethyl) thio] -N-ethyl-6-fluorobenzamide.

A solution of 2-methyl-2-propanediol (2.7 g, 0.03 mol), THF (100 mL), sodium hydride (0.79 g, 0.033 mol) and g of the title compound (3.17 g, 0.015 mol). mol) was stirred at RT overnight, then refluxed overnight. The mixture was allowed to cool over an aqueous solution of NaHCO ₃ (50 extracted with 3 50 mL ethyl and saturated mL added). This mixture is in portions of acetate.

The organic layers were combined and washed twice with water and dried. The concentrate was purified with acetate / hexanes. This (MgSO ₄ ) is concentrated. HPLC eluting with 1: 4 ethyl oxazoline gave yellow oil in 83% yield.

This product was then prepared in steps 1, 2,3 and 4:

stage. Termination of Oxazoline Ring Connections:

A solution of 2M trifluoromethanesulfonic anhydride (1.5 eq) in CH ₂ Cl _{2 was} added to ice-water-cooled 0.67M oxazoline compound solution (1 eq) in CH ₂ Cl ₂ . The resulting solution was stirred at 0 ° C for 1 min, then poured into an equal volume of ice water and stirred vigorously for 15 min. The organic layer was washed twice with 10% HCl, dried (MgSO ₄ ), and concentrated. Purification was by HPLC eluting with ethyl acetate / hexanes on silica.

stage. Diazomethane methylation:

A freshly prepared solution of diazomethane in anhydrous ethyl ether was added to the ether solution of the product of Step 1. The resulting yellow solution was allowed to settle overnight at RT before being treated with acetic acid (5 mL). The organic layer was then washed with 10% HCl followed by 2.5N aqueous NaOH, dried (MgSO ₄ ) and concentrated to give N-methylated sulfonamide.

stage. Saponification of N-methylated sulfonamide:

Potassium hydroxide (3 eq) and N-methylated sulfonamide from Stage 2 DMSO were stirred at 110 ° C for 3-4 h. The resulting solution was cooled, diluted with an equal volume of water and extracted 3 times with ether. The aqueous layer was then acidified with 10% HCl and extracted 3 times with ether. The latter mixtures were combined, dried (MgSO ₄ ) and concentrated to give 2,6-disubstituted-benzoic acid.

stage. Preparation of 2, β-Disubstituted-N-ethyl-benzamide:

Oxalyl chloride (2.2 eq) and 2,6-disubstituted benzoic acid (1 eq) from Step 3 were stirred in toluene with catalytic DMF at RT for 1 h under nitrogen. The solvent was removed in vacuo before additional toluene (50 mL) was added followed by similar removal. The resulting acid chloride was dissolved in CH ₂ Cl ₂ (50 mL), treated with 70% ethylamine (3.3 eq) and stirred for additional 30 min. RT. The organic layer was then washed twice with 10% HCl and twice with water, dried (MgSO ₄ ), and concentrated to a white solid. Purification was by recrystallization from ether / hexanes. The resulting final product was recrystallized from ether / hexanes. The title compound was obtained as a white solid, mp 107-109 ° C.

example

2- (2,2-Dimethylpropyl) -N-ethyl-6-fluorobenzamide.

A mixture of p, p'-di-t-butyl biphenyl (5.559 g, 0.021 mol) and THF (100 mL) was stirred at 0 ° C under argon. Add lithium wire (0.021 mol, 0.15 g) to the mixture and stir for 24 hours. At 0 ° C. The mixture was cooled to -78 ° C and neopentyl chloride (2.0 g, 0.01875 mol) was added. The mixture is stirred for 1 hour. At -78 ° C and the compound of Example g (3.17 g, 0.015 mol) was added all at once. The mixture is stirred continuously for 4 hours. and 50 ml of a saturated aqueous solution of NaHCO _{3 are added} . This mixture was extracted with three portions of 50 mL of ethyl acetate. The combined extracts were washed twice with water, dried (MgSO ₄ ), and concentrated. The product was purified by HPLC eluting with 1: 4 ethyl acetate / hexanes. Oxazoline was obtained as a clear oil in a yield of 27%.

This product was then treated according to Steps 1-4 of Example 90. The resulting final product was recrystallized from ether / hexanes. The title product is obtained in the form of a white solid, m.p. 125-126 ° C.

example

N-Ethyl-2-fluoro-6- (2-methylphenyl) benzamide.

A solution of 2-bromo-toluene (2.82 g, 0.0165 mol) and THF (100 mL) was stirred with a magnet under argon at -78 ° C. 1.3M s-BuLi in cyclohexane (0.018 mol, 13.85 mL) was added. The mixture is stirred for 0.5 h. and the compound of Example g (3.17 g, 0.015 mol) was added all at once. The mixture was stirred continuously for 4 h and saturated aqueous NaHCO ₃ solution (50 mL) was added. The mixture was extracted with three portions of 50 mL of ethyl acetate. The combined extracts were washed with water, dried (MgSO ₄ ), and concentrated. The concentrate was purified by HPLC eluting with 1: 4 ethyl acetate / hexanes. Oxazoline was obtained as a clear oil in a yield of 73%.

This product was then treated according to Steps 1-4 of Example 90. The resulting final product was recrystallized from ether / hexanes. The title product is obtained in the form of a white solid, m.p. 75-77 ° C.

example

N-Chloro-N- (1-methylethyl) -N-propyl-6- (trimethylsilyl) benzamide.

A solution of propionyl chloride (23.13 g, 250 mmol) in ether (100 mL) was added to ice-water-cooled isopropylamine solution (29.56 g, 500 mmol) in ether (200 mL). The resulting mixture is stirred for 1 hour. RT, then filtered to remove isopropylamine hydrochloride. A solution of N-isopropylpropionamide (37% filtrate, mmol) was diluted with THF (90 mL) and cooled in an ice-water bath followed by the addition of 2M borane-dimethylsulfide THF solution (100 mL, 200 mmol). The resulting solution was stirred for 1 h. RT, then refluxed for 2 hours. Under ice-water cooling, the excess boranodimethylsulfide was quenched by dropwise addition of methanol (30 mL) and the mixture was allowed to settle overnight at RT. HCl gas is injected into the solution and Npropyl-N-isopropylamine hydrochloride is collected.

To a mixture of Example b (2.47 g, 10 mmol) and N-propyl-N-iso-propylamine hydrochloride (~ 92 mmol) in toluene (100 mL) was added triethylamine (27.89 mL, 200 mmol). Stir overnight at ambient temperature, then partition between ethyl acetate and dilute citric acid. The organic phase is washed with brine, dried (MgSO ₄ ) and concentrated to give 2.50 g of the title compound as a wax-amber solid. Yield 80%.

example

2-Chloro-N-ethyl-N- (1-methylheptyl) -6- (trimethylsilyl) benzamide.

A solution of acetyl chloride (7.11 g, 100 mmol) was added to a solution of 1-methylheptylamine (8.30 g, 64 mmol) and triethylamine (20.91 mL, 150 mmol) in THF (100 mL) in ice-water. The resulting mixture is stirred for 1 hour. RT, then diluted with ethyl acetate and washed twice with 10% HCl, twice with saturated aqueous NaHCO _3, and then twice with brine. The organic solution was dried (MgSO ₄ ) and concentrated to give 8.13 g of N- (1-methylhept-1-yl) acetamide in 73% yield.

A 2M solution of borane-dimethylsulfide in THF (31.5 mL, 63 mmol) was added to an ice-water-cooled solution of N- (1-methylheptyl) acetamide (5.13 g, 30 mmol) in THF (60 mL). The resulting solution is stirred for 1 hour, then refluxed overnight. Under ice-water cooling, the excess borane-dimethylsulfide was quenched by dropwise addition of methanol (10 mL) and the mixture was allowed to settle overnight at RT. The amine hydrochloride cannot be precipitated by passing HCl gas, so the amine hydrochloride is extracted into dilute HCl. The acidic aqueous solution was extracted with ether, then basified and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO ₄ ) and concentrated to give 3.70 g of N-ethyl-N- (methylhept-1-yl) amino as an amber oil.

Triethylamine (2.02 g, 20 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-ethyl-N- (1-methylheptyl) amino (3.15 g, 20 mmol) in toluene. (25 mL).

Mix 2,5 or. at ambient temperature, then partitioned between ethyl acetate and dilute citric acid. The organic phase is washed twice with saturated water, NaHCO ₃ solution, then brine, then dried (MgSO ₄ ), concentrated and the kugelrohr distilled in vacuo. The fraction which was distilled at 157 ° C was concentrated to give 1.16 g of the title compound as an amber oil. Yield 38%.

Example 97

2- (Difluoromethyl) -N, N-diethyl-6- (trimethylsilyl) benzamide.

Example 2 (9.96 g, 40 mmol) and DMF solution (3.65 g, 50 mmol) in THF (20 mL) were combined according to basic method A. The resulting reaction mixture was partitioned between ethyl acetate and dilute citric acid. The organic phase is washed with a saturated aqueous solution of NaHCO ₃ , then brine, dried (MgSO ₄ ) and concentrated to give 8.35 g of N, N, -diethyl-2-trimethylsilyl-6-formylbenzamide as a white solid. Yield 75%, m.p. 63.5-65.5 ° C.

DAST (0.63 mL, 4.8 mmol) was added to ice-water-cooled N, N-diethyl-2-trimethylsilyl-6-formylbenzamide solution (0.665 g, 2.4 mmol) in CH ₂ Cl ₂ (20 mL). . The solution was warmed to RT and stirred for 17 h, followed by addition of additional DAST (1.0 mL, 7.6 mol). This mixture was stirred for another 1 day, then cooled with ice water. The CH ₂ Cl ₂ solution was dried (MgSO ₄ ) and concentrated to give 0.69 g of the title compound as an amber oil. Yield 96%.

example

N, N-Diethyl-2- (fluoromethyl) -6- (trimethylsilyl) -benzamide.

Sodium borohydride (1.0 g, 26.4 mmol) was added to N, N-diethyl-2-trimethylsilyl-6-formylbenzamide prepared as

In Example 97 (5.54 g, 20th mmol) , solution in pure ethanol (100 mL). After 3 or. blend diluted ether, extracted three times salts solution,

dried (MgSO ₄ ), concentrated and recrystallized from 1: 1 ethyl acetate / hexanes to give 4.12 g of N, N-diethyl-2-trimethylsilyl-6-hydroxymethylbenzamide as a white solid. Yield 74% m.p. 81-82.5 ° C.

DAST (0.66 mL, 5.0 mmol) was added to an ice-water-cooled solution of the resulting compound (1.395 g, 5.0 mmol) in CH ₂ Cl ₂ (40 mL). The solution was warmed to RT and stirred for 4 h, then cooled with ice water and extracted with CH ₂ Cl ₂ . The CH ₂ Cl ₂ extracts were combined, dried (MgSO ₄ ), and concentrated to give 1.38 g of the title compound as an amber oil. Yield 98%.

example

2-Chloro-6- (trimethylsilyl) -2,2-dimethylhydrazidobenzoic acid.

Example b (1.48 g, 0.006 mol), CH ₂ Cl ₂ (50 mL), 1,1- (dimethyl) hydrazine (0.42 g, 0.007 mol) and pyridine (0.55 g, 0.007 mol) the solution was stirred overnight at RT. The reaction mixture was washed with 10% HCl solution and three times with water, dried (MgSO ₄ ) and concentrated. The title compound is recrystallized as a white solid. Yield 43%, m.p. 134135 ° C.

101-108 Examples

The following examples are prepared by reaction of the compound of example b with the appropriate amine, refluxing in toluene or overnight at ambient temperature with dioxane in the presence of an acid acceptor such as triethylamine. Melting points are given in ° C.

For example, No. Name of the compound i.e. 101 2-Chloro-N- [[4- (4- (1,1- dimethylethyl) phenyl] methyl] -N-methyl-6- (trimethylsilyl) -benzamide 102 2-Chloro-N - [[4- (trifluoromethyl) phenyl] - methyl] -6- (trimethylsilyl) -benzamide 159-160 103 2-Chloro-N-methyl-N - [[4- (trifluoromethyl) phenyl] methyl] -6- (trimethylsilyl) -benzamide 85-86

104 2-Chloro-N- (6,6-dimethyl-2-hepten-4-ynyl) - N-ethyl-6- (trimethylsilyl) benzamide - 105 2-Chloro-N-methyl-N- (3-phenyl-2-propenyl) -6- (trimethylsilyl) benzamide - 106 2-Chloro-N-2-propenyl-6- (trimethylsilyl) benzamide 97-99 107 2-Chloro-N- (1,1-dimethyl-2-propynyl) -6- (trimethylsilyl) benzamide 155-157 108 2-Chloro-N- (2-propynyl) -6- (trimethylsilyl) benzamide 112-114

Example 109

2-Chloro-6- (trimethylsilyl) phenyl] carbamic acid, ethyl ester.

A mixture of Example h (10 mmol) and ethanol (75 mL) was refluxed for 1 h. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution is washed twice with water and the solvent removed to give a product which is recrystallized from hexane. GC / MS showed some of the remaining isocyanates so the solid was dissolved in ethanol and refluxed with about 0.1 g of diazobisbicyclooctane. FID / GC showed complete reaction, ethanol removed, to give the title compound, m.p. 109-110 ° C.

Example 110

N- [2-Chloro-6- (trimethylsilyl) phenyl] -N'-ethylurea.

To a solution of the compound of Example h (4 mmol) in toluene (50 mL) was added 70% ethylamine (4 mL). The solution was stirred for 0.5 h. and then stood overnight. Ethyl acetate is added and the mixture is washed with water. The organic layer is concentrated to a semi-solid which is removed with hexanes. The title compound was concentrated by filtration in the form of 0.9 g of crystals. Yield 83%, m.p. 161-163 ° C.

Example 111 [2-Chloro-6- (trimethylsilyl) phenyl] carbamic acid 1,1-dimethylethyl ester.

O-Chlorophenyl isocyanate (0.16 mol) was dissolved in toluene (250 mL) and butanol (12.9 g, 0.174 mol) was added. After refluxing overnight, the cooled solution is filtered. The solvent is removed from the filtrate to give (2-chlorophenyl) carbamic acid, 1,1-dimethylethyl ester.

This compound is coupled to t-BuLi THF at -71 ° C using the procedures described above, followed by exposure to TMSC1. The title compound is obtained in the form of 1.3 g of crystals, m.p. 90-91 ° C.

Examples 112-114

Compound 112: (Z) -2-Chloro-N-1-propenyl-6- (trimethylsilyl) benzamide.

Compound 113: (E) -2-Chloro-N-1-propenyl-6- (trimethylsilyl) benzamide.

Compound 114: A mixture of compounds 112 and 113 (50:50).

With the catalyst of Example 106, chloride] (compound 80 (17 mmol) with Wilkinson's [tris (triphenylphosphine) rhodium (I) mg) was dissolved in 100 mL of toluene and refluxed for 4 days. The mixture was filtered through silica gel which was washed with ethyl acetate and combined with the filtrate. The solvent is removed and the mixture is partitioned in RC eluting with 1: 9 ethyl acetate / hexane to give two fractions having different stains. The first fraction is concentrated to a solid which is recrystallized from hexane to give 1.9 114 (m.p. 100, 0-105, 0 ° C). This solid (0.25 g) was purified by RC using hexane as solvent. Pure isomers of Compound 112 (m.p. 140.0-141.0 ° C) and Compound 113 (m.p. 101.0-102.0 ° C) are obtained.

Example 115

2-Chloro-N-ethyl-6- (trimethylsanyl) benzamide.

1.3M s-BuLi in cyclohexane (25.8 mL, 33.5 mmol) was added to a cooled to -78 ° C solution of Example f (2.80 g, 15.3 mmol) and TMEDA (3.55 g, 30 mL). , 6 mmol) in THF (100 mL). After stirring the resulting reaction mixture for 15 min. At -78 ° C, hexamethyl tin (5.0 g, 15.3 mmol) was added. It is heated to -60 C and then partitioned between ether and water. The ether was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography eluting with 1: 4 ethyl acetate / hexanes to give 4.10 g of the title compound as a white solid. Yield 77%, m.p. 78-80 ° C.

Example 116

2-Chloro-N-ethyl-6- (9-phenanthrenyl) benzamide.

The title compound was prepared by treatment with 9-bromophenanthrene (0.94 g, 3.65 mmol) according to Principal Method D. 0.55 g of a white solid was obtained. Yield 56%, m.p. 189-191 ° C.

Example 117

N-Ethyl-2-fluoro-6- (trimethylsilyl) benzamide.

12.6 mmol) and 70%

27.7 mmol) combine EI and kugelrohr

2-Fluorobenzoyl chloride (2 g, aqueous ethylamine (1.78 g,

CH ₂ Cl ₂ distilled according to the main method to give 1.85 g of N-ethyl-2-fluorobenzamide as a colorless oil in a yield of 87%.

A solution of 1.3M s-BuLi in cyclohexane (20.3 mL, 26.4 mmol) was added to a solution of N-ethyl-2-fluorobenzamide (2.00 g, 11.98 mmol) in THF (75 mL) and ether (75 mL) and 75 mL) while maintaining an internal reaction temperature <-95 ° C. The resulting mixture was stirred at this temperature for 30 min, then TMSC1 (1.43 g, 13.2 mmol) was added and the mixture was warmed to -60 ° C. After 2 or. the reaction mixture was poured into water (200 mL). The organic layer was dried (MgSO ₄ ), concentrated, and purified by silica gel chromatography eluting with 3: 7 ethyl acetate / hexanes to give 0.45 g of the title compound as a white solid. Yield 16%, m.p. 86-87 ° C.

Example 118 1- [3-Fluoro-2,6-bis (trimethylsilyl) benzoyl] pyrrolidine.

3-Fluorobenzoyl chloride is treated with pyrrolidine using basic method EI or E2 to produce N- (3-fluorobenzoyl) pyrrolidine.

A 1.3M solution of s-BuLi in cyclohexane (23.91 mL, 31.1 mmol) was added to ether / liquid N ₂ cooled (-90 ° C) TMEDA solution (3.97 g, 34.2 mmol) in THF (40 mL), followed by the addition of N- (3-fluorobenzoyl) pyrrolidine (5.0 g, 25.9 mmol) in a minimal volume of THF. The resulting reaction mixture was stirred for 15 min. At -90 ° C, then all of TMSCl (6.75 g, 62.2 mmol) was added all at once. Warm to RT, quench with dilute citric acid, then extract with ether (3X). The combined ether extracts were dried (MgSO ₄ ), concentrated and purified by HPLC eluting with 3: 7 EtOAc / hexanes to give 0.45 g of the title compound as an oil (45% yield) which solidified on standing to a white solid. ° C.

Example 119

2-Chloro-N, N-diethyl-6- (trimethylermyl) benzamide.

A 1.3M solution of s-BuLi in cyclohexane (21.8 mL, 28.3 mmol) was added to dry ice / acetone cooled Example e (4.6 g, 21.7 mmol) in THF (60 mL) while maintaining the internal reaction temperature. <-65 ° C. The mixture was stirred for 45 min. At -78 ° C, then cooled by dropwise addition of trimethylchlorgermanium solution (5.0 g, 32.6 mmol) in THF (30 mL) while maintaining the internal reaction temperature again at <-65 ° C. Warmed to 0 ° C, diluted with ether and extracted with 10% HCl (2X) followed by saturated aqueous NaHCO ₃ . The ether was dried (MgSO ₄ ), concentrated and purified by HPLC in 6% EtOAc in hexanes to give 3.2 g of the title compound as a white solid. Yield 45%, m.p. 47-48 ° C.

Example 120

2-Bromo-N- (2-methylphenyl) -6- (trimethylsilyl) benzamide.

Example c (0.0035 mol, 0.95 g), 15 mL of thionyl chloride, and 1 drop of DMF were added and stirred overnight at RT. Toluene (50 mL) was added and the mixture was concentrated to dryness. This process was repeated three times and the residue was dissolved in CH ₂ Cl ₂ (50 mL).

2-Methylaniline (0.0035 mol, 0.37 g) and triethylamine (0.0035 mol, 0.39 g) were added and the mixture was stirred overnight at RT. The mixture was washed with 10% HCl and twice with water; dried (MgSO ₄ ) and concentrated. The title compound is recrystallized from hexanes to give a tan solid. Yield 71%, m.p. 113-115 ° C.

Example 121

N- (2-Methylphenyl) -2- (trimethylsilyl) benzamide.

Example 120 (0.0021 mol, 0.75 g) and 50 mL of THF were cooled to -78 ° C under nitrogen with stirring. 1.3M s-BuLi (0.0026 mol ·, 2 mL) in cyclohexane was added dropwise. After 30 minutes 25 ml of 25% citric acid solution was added with stirring. The mixture was then extracted three times with ethyl acetate, the extracts combined and washed with brine and twice with water, dried (MgSO ₄ ) and concentrated. The title compound is recrystallized from ethyl acetate / hexanes to give a white solid. Yield: 54%, m.p. 117-119 ° C.

Example 122

2-Chloro-N-ethyl-6- (2-naphthalenyl) benzamide.

The title compound was prepared by treatment with 2-bromonaphthalene (0.76 g, 3.65 mol) according to Principal Method D. 0.68 g of a white solid was obtained. Yield 60%, m.p. 182-184 ° C.

Example 123

N-Ethyl-2-fluoro-β- (1-methylcyclopentyl) benzamide.

To lithium sand (0.44 g, 63.0 mmol) in THF (100 mL) at 0 ° C was added 4,4'-di-tert-butylbiphenyl (13.27 g, 51.0 mmol) under argon and the resulting mixture was stirred overnight at 0 ° C. The mixture was then cooled to -78 ° C and 1-chloro-1-methylcyclopentane (3.0 g, 25.3 mmol) in THF (25 mL) was added. [1-Chloro-1-methyl-cyclopentane in the form of a clear oil with 87-88 ° C / 15T was obtained by chlorination of 1-methyl-cyclopentanol with HCl gas. This mixture was stirred for 15 min. and the compound of Example g (5.34 g, 25.3 mmol) was added. The resulting solution was stirred at -78 ° C for 1 h. before being poured into water (250 ml). The aqueous layer was extracted three times with ether and the combined extracts dried (MgSO ₄ ) and concentrated to give 2- [2-fluoro-6- (1-methyl-cyclopentyl) -phenyl] -4,5-dihydro-4,4-dimethyloxazole, clear. in oil, yield 40%. This oxazoline is treated according to steps 1-4 of Example 90. The resulting final product is recrystallized from ether / hexanes to give a white solid, mp 116-117 ° C.

Example 124

N-Ethyl-3- (trimethylsilyl) -4-pyridinecarboxamide.

4-Pyridinecarboxylic acid (20 g, 0.16 mol) in 60 mL of thionyl chloride was stirred for 24 h. RT. The excess thionyl chloride is then removed in vacuo. The solid residue is added portionwise to 60 g of 70% ethylamine in water and 200 ml of CH ₂ Cl _{2 at} -5 ° C and then stirred for 18 hours. RT. Add water. The organic solution was separated, washed with water, brine, dried and concentrated to give 9.5 g of N-ethyl-4-pyridinecarboxamide.

A solution of N-ethyl-4-pyridinecarboxamide in THF is treated with lithium diisopropylamide (prepared from diisopropylamine and 2.5M n-BuLi in hexane according to the method of Example 250) and quenched with TMSC1 as in Example 248, step c. The title compound is purified by flash chromatography eluting first with 20% then 70% ethyl acetate / hexane to give a white solid, m.p. 93-95 ° C.

Example 125

2-Chloro-N-ethyl-N- (2-furylmethyl) -6- (trimethylsilyl) benzamide.

1.0M THF Sodium bis (trimethylsilyl) amide solution (7.7 mL, 7.7 mmol) was added to Example 32 (2.15 g, 7.0 mmol) in THF (30 mL). After 1 or. a solution of ethyl iodide (1.21 g, 8.4 mmol) in THF (15 mL) was added with stirring. Stir overnight at RT, then partition between ethyl acetate and dilute aqueous citric acid. The organic layer was washed twice with saturated aqueous NaHCO ₃ solution twice with brine, then dried (MgSO ₄ ) and concentrated to give 1.8 g of the title compound as an amber oil. Yield 77%.

Example 126

2-Chloro-N, N-bis (1-methylethyl) -6- (trimethylsilyl) benzamide.

The compound of Example b (2.47 g, 10 mmol), diisopropyl amine (2.23 g, 22 mol) and toluene (25 mL) are combined according to the basic method E2. The product was recrystallized from ethanol / water to give 1.75 g of the title compound as a white solid. Yield 58%, m.p. 9697.5 ° C.

Example 127

N-Ethyl-N- (methoxymethyl) -2-methyl-6- (trimethylsilyl) benzamide.

Example 1 (1.33 g, 5.0 mmol) and Mel (2.8 g, 20 mmol) were added according to General Method B. The resulting reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO ₃ solution. The organic phase is washed with brine, dried (MgSO ₄ ) and concentrated to give a quantitative yield of the title compound as an oil.

Example 128

2-Chloro-N- (2-ethoxyethyl) -N-ethyl-6- (trimethylsilyl) benzamide.

The compound of Example b (4.94 g, 20 mmol), 2-ethoxyethylamine (3.92 g, 44 mol) and toluene (35 mL) are combined according to the basic method Ei. The product was recrystallized from aqueous ethanol to give 3.97 g of N- (2-ethoxyethyl) -2-chloro-6- (trimethylsilyl) -benzamide as a white solid in 66% yield, m.p. 71-73 ° C.

M THF sodium bis (trimethylsilyl) amide solution (7.7 mL, 7.7 mmol) was added dropwise over 5 min. to a solution of N- (2-ethoxyethyl) -2-chloro-6- (trimethylsilyl) benzamide (2.1 g, 7 mmol) in THF (30 mL). The resulting mixture is stirred for 1 hour. RT, followed by the addition of ethyl iodide solution (1.31 g, 8.4 mmol) in THF (15 mL) under mild exotherm. The resulting reaction mixture was stirred overnight, then partitioned between ethyl acetate and dilute citric acid. The ethyl acetate phase is washed with saturated aqueous NaHCO ₃ solution, then brine, then dried (MgSO ₄ ) and concentrated to give 1.9 g of the title compound as an amber oil. Yield 83%.

Examples 129-134 and 144-163

The following examples were prepared by reacting the compound of Example b with the corresponding amine according to the basic method EI. Melting points are given at 0 ° C.

For example, No. Name of the compound i.e. 129 2-Chloro-N-cyclohexyl-6- (trimethylsilyl) benzamide 198.5-200.5 130 N- [2-Chloro-6- (trimethylsilyl) benzoyl] - 2,6-dimethylmorpholine - 131 N- [2-Chloro-6- (trimethylsilyl) benzoyl] 2,6-dimethylpiperidine 187.5-190 132 N- [2-Chloro-6- (trimethylsilyl) benzoyl] - morpholine 110-111.5 133 N- [2-Chloro-6- (trimethylsilyl) benzoyl] - 4-methylpiperazine 76-77.5 134 N- [2-Chloro-6- (trimethylsilyl) benzoyl] piperidine 111-113

135-142 Examples

The following examples were prepared by reacting the compound of example b with the corresponding amine in dioxane with a small molar excess of triethylamine using the amination methods described above. Melting points are given in ° C.

For example, No. Name of the compound i.e. 135 2-Chloro-N- (2-pyridinylmethyl) -6- (trimethylsilyl) benzamide 84-88 136 2-Chloro-N - [(4-methoxyphenyl) methyl] -6- (trimethylsilyl) benzamide 100-103 137 2-Chloro-N - [(4-nitrophenyl) methyl] -6- (trimethylsilyl) -benzamide 131-135 138 2-Chloro-N- (2-thienylmethyl) -6- (trimetiisiiii) benzamide 120-122 139 2-Chloro-N - [(3-methoxyphenyl) methyl] -6- (trimethylsilyl) benzamide 85-87 140 2-Chloro-N - [(3,4,5-trimethoxy) phenyl) methyl] -6- (trimethylsilyl) benzamide 128-130 141 2-Chloro-N - [(3-nitrophenyl) methyl] -6- (trimethylsilyl) -benzamide 121-122 142 2-Chloro-N- (cyanomethyl) -6- (trimethylsilyl) benzamide 145-147 144 N- (1,3-benzodioxol-5-ylmethyl) -2-chloro- 6- (Trimethylsilyl) benzamide 138-140 145 2-Chloro-N- (4-pyridinylmethyl) -6- (trimethylsilyl) benzamide 122-125 146 2-Chloro-N- (2-methoxyethyl) -6- (trimethylsilyl) benzamide 75-77 147 2-Chloro-N- (2-methyl-2-propenyl) -6- (trimethylsilyl) benzamide 118-121 148 1- [2-Chloro-6- (trimethylsilyl) benzoyl] - 1,2,3,6- (Tetrahydro) pyridine 109-111 149 1- [2-Chloro-6- (trimethylsilyl) benzoyl] 2,5-dihydro-2,5-dimethyl-1H-pyrrole 75-77

150 2-Chloro-N- (cyclopropylmethyl) -6- (trimethylsilyl) benzamide 99-101 151 2-Chloro-N- (1-methylpropyl) -6 (trimethylsilyl) benzamide, (r) - 148-149 152 2-Chloro-N- (1-methylpropyl) -6- (trimethylsilyl) benzamide, (s) - 149-150 153 N- (2-Bromethyl) -2-chloro-6- (trimethylsilyl) benzamide 101-103 154 2-Chloro-N- (2-hydroxy-1-methylethyl) -6- (trimethylsilyl) benzamide 108-111 155 2-Chloro-N- (2-fluoroethyl) -6- (trimethylsilyl) benzamide 103-105 156 2-Chloro-N- [2- (1-methylethyl) phenyl] -6- (trimethylsilyl) benzamide 92-94 157 2-Chloro-N- (2-ethoxyphenyl) -6- (trimethylsilyl) benzamide 73-76 158 2-Chloro-N- (2-cyclopentylphenyl) -6- (trimethylsilyl) benzamide 110-113 159 2-Chloro-N- (methoxyphenyl) -6- (trimethylphenyl) benzamide 75-76 160 2-Chloro-N- (2-nitrophenyl) -6- (trimethylsilyl) benzamide 88-90 161 2-Chloro-N- (1-phenylethyl) -6- (trimethylsilyl) benzamide 129-132 162 2-Chloro-N- (2-methylpropyl) -6- (trimethylsilyl) benzamide 132-133 163 2-Chloro-N-cyclobutyl-6- (trimethylsilyl) benzamide 145-146

Example 143

N-Ethyl-N- (hydroxymethyl) -2-methyl-6- (trimethylsilyl) benzamide.

Example 127 (0.80 g, 2.9 mmol) was refluxed in acetonitrile (20 mL) with 2N HCl (20 mL). Within 2 or. the reaction is complete by GLC and the reaction mixture is cooled and partitioned between ether and water. The ether phase was concentrated and purified by RC eluting with 1: 4 ethyl acetate / hexanes followed by recrystallization from hexanes to give 160 mg of the title compound as a solid. Yield 21%.

Example 164

2-Chloro-N-methyl-N- (1-methylethyl) -6- (trimethylsilyl) benzamide.

Thionyl chloride (1.5 g, 12 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ and the compound of Example 154 (dissolved in 50 mL of CH ₂ Cl ₂ ) was added slowly. A drop of DMF was added and the mixture was stirred overnight. Water was added and the mixture was extracted with ethyl acetate to give a solid which was recrystallized from 5% ethyl acetate / hexane. 2-Chloro-N- (2-chloro-1-methylethyl-6- (trimethylsilyl) benzamide (2.2 g, 7.3 mmol), yield 73%) is obtained, m.p. 150-151 ° C.

This compound (1.5 g, 5.0 mmol) was dissolved in 50 mL of THF and 5.5 mL of 1M (THF) potassium t-butoxide (5.5 mmol) was added after 4 h of standing water and the mixture was extracted with ethyl acetate. After removal of the solvent, the resulting oil was identified as 2- [2-chloro-6- (trimethylsilyl) phenyl] -4,5-dihydro-4-methyl-oxazole.

This compound (2.67 g, 10 mmol) and trimethyl oxonium fluoroborate (1.5 g, 10 mmol) were dissolved in CH ₂ Cl ₂ and stirred for 18 days. Ether was added to the mixture and the precipitate was collected. The product identified as 2- [2-chloro-6- (trimethylsilyl) phenyl] -4,5-dihydro-3,4-dimethyl-oxazole tetrafluoroborate was recrystallized by redissolving it in CH ₂ Cl ₂ and adding ether until it became cloudy, mp 155-157 ° C.

This compound (1.9 g, 5.1 mmol) and sodium cyanoborohydride (0.32 g) were added to methanol and stirred overnight. This mixture was filtered and water was added to the mother liquor. Extraction with ethyl acetate gave the oil after removal of the solvent. The oil was dissolved in 50% ethyl acetate / hexane and filtered through silica gel. Removal of the solvent gave an oil which was purified on RC (20% ethyl acetate / hexane).

Example 165

2-Chloro-N - [(2-propenylamino) carbonyl] -6 (trimethylsilyl) benzamide.

Silver cyanate (3.0 g, 20 mmol) was dried overnight at 140 ° C, added to dry toluene, followed by the addition of 2-chloro-6-trimethylsilylbenzoyl chloride (Example b) (2.46 g, 10 mmol). After 4 or. under reflux, allyl amine (0.6 g, 10 mmol) was added and the mixture was refluxed overnight. After filtration through silica gel to remove the silver salts, the solvent was removed to give an oil. Purification with hexane gives 0.7 g of the title compound as a solid, m.p. 68-71 ° C.

Example 166

2-Chloro-N, N-diethyl-6 - [(trimethylsilyl) methyl] -benzamide.

The compound of Example e (1.0 eq) and Mel (3.0 eq) are combined as in Method A. The product is purified by HPLC eluting with 1: 4 EtOAc / hexanes to give 5.2 g of Ν, Ν-diethyl 2-chloro-6-methylbenzamide yellow colors in the form of a solid. Yield 92%, m.p. 48-49 ° C.

This compound (1.0 eq) and TMSC1 (2.0 eq) are combined as in Method A and purified by HPLC eluting with 1: 9 EtOAc / hexanes to give 2.1 g of the title compound as a clear oil. Yield 59%.

Example 167

2-Chloro-N-hydroxy-N- (methylethyl) -6- (trimethylsilyl) benzamide.

The title compound is prepared by treating the compound of Example b with i-propylhydroxylamine hydrochloride in dioxane in the presence of two equivalents of triethylamine using the amination methods described above, m.p. 175-179 ° C.

Example 168

2-Chloro-N-hydroxy-N- (1-methylethyl) -6- (trimethylsilyl) benzamide, compound with iron hydroxide (1: 1).

Example 167 (0.47 g, 1.6 mmol) was added to 40 mL of 0.5 M sodium acetate solution. To this suspension was added acetone to a total volume of 80 mL. Slightly homogeneous solution obtained by heating. Iron (III) chloride (0.44 g, 1.6 mmol) was dissolved in 10 mL of water. A precipitate formed which was naturally colloidal. Removal of acetone gave a precipitate which was easily filtered and dried under vacuum overnight; 0.50 g of the title compound is obtained, m.p. 260 ° C.

Example 169

2-Chloro-N-ethyl-6- (trimethylsilyl) benzoicarboximidothionic acid ethyl ester.

A solution of 9.66 g (36 mmol) of the sample compound and 40 mL of trimethyloxonium tetrafluoroborate (1.0 M, 40 mol) was maintained overnight at RT. The light fractions were distilled to 40 ml and 300 ml of ether were added; the precipitated product was identified as 9.5 g of a 1: 1 compound of N - [[2-chloro-6- (trimethylsilyl) phenyl] (ethylthio) -methylenethanamine (1: 1) with tetrafluoroborohydrate, m.p. 160-161 ° C.

To this compound, 3.87 g (10 mmol) of 100 mL of CH ₂ Cl _{2 was} added 1.5 g (15 mmol) of triethylamine. After standing for several minutes, the mixture was extracted with 100 mL of water, the solvent removed, and the oil obtained. Purification was carried out in RC (10% ethyl acetate / hexane) to give 2.5 g of pure oil.

Example 170

N- (1H-Benzotriazol-1-ylphenylmethyl) -2-chloro-6- (trimethylsilyl) benzamide.

Of 2-chloro-6-trimethylsilylbenzamide (2.27 g, 10 mmol) which is readily prepared by reacting the compound of example b with ammonium hydroxide, benzaldehyde (1.1 g, 10 mmol), and benzotriazole (1.2 g, 10 mmol). the mixture) was refluxed for 5 days in toluene using a Dean-Stark device to remove water. The solvent is removed to give an oil which crystallizes. Recrystallization from ethyl acetate gives 0.5 g of the title compound, m.p. 184-186 ° C.

Example 171

2-Chloro-N- (2-chloro-1-methylethyl) -6- (trimethylsilyl) benzamide.

This compound was prepared in the first step of Example 164, m.p. 150-151 ° C.

Example 172

2-Chloro-N-ethyl-N- (methylthio) -6- (trimethylsilyl) benzamide.

Example compound (2.55 g, 10 mmol) was dissolved in 50 mL of dry THF and N-thiomethyl phthalimide (1.93 g, 10 mmol) was added followed by 12 mL of 1M LiN (TMS) ₂ (THF) (12 mmol). . All operations were performed under a nitrogen atmosphere. After stirring at RT overnight, gc / mc analysis confirmed a mixture of the desired product and phthalimide. Water was added and the mixture was extracted with ethyl acetate. Removal of the solvent gave a semi-solid. Addition of 15% ethyl acetate / hexane gave a solid which was filtered off and removed. The mother liquor was purified by RC (eluting with 15% ethyl acetate / hexane) to give 0.2 g.

Example 173

2-Chloro-N- (isopropylaminocarbonyl) -6- (trimethylsilyl) benzamide.

To 0.1 m 2 of 2-chloro-6- (trimethylsilyl) benzamide obtained by reaction of the compound of example b with ammonium hydroxide was added 1.2 eq of oxalyl chloride and 2 drops of DMF in ethylene dichloride. After refluxing overnight, the solvent was removed and the resulting Kugelrohred oil was distilled at 0.2 mm (87-92 °) to give 21 g (84%) of isocyanate. It is important to remove moisture, otherwise the primary amide is formed.

2-Chloro-6-trimethylsilylbenzoyl isocyanate (1.3 g, 5 mmol) was dissolved in 40 mL of toluene and isopropyl amine (1 g) was added over 30 seconds. After 30 minutes the mixing solvent is removed to give an oil. The oil was dissolved in hexane and cooled in dry ice to give 1.2 g of crystals of the title compound, m.p. 113-116 ° C.

Example 174

2-Chloro-N- (methylthio) -6- (trimethylsilyl) benzamide.

To 1.1 g of 2-chloro-6- (trimethylsilyl) benzamide from Example b and ammonium hydroxide (5 mmol) in 50 mL

THF, 5.5 mL of 1M (THF) potassium t-butoxide (5.5 mmol) was added followed by 0.95 g of N-thiomethylphthalimide (5 mmol). After standing overnight, gc / ms confirmed a near 50/50 mixture of product and starting benzamide. Water was added and the mixture was extracted with ethyl acetate. Removal of the solvent gave a semi-solid. Grinding with 50 mL of 15% ethyl acetate / hexane gave a solid which was filtered and collected. The mother liquor was purified by RC (eluting with 20% ethyl acetate / hexane). The first portion was also collected by distillation of a light fraction; the resultant oil which crystallizes on rubbing with hexane; 0.3 g of the title compound is obtained, m.p. 92-94 ° C.

Example 175

2,2,2-Trichloro-N- [2-chloro-6- (trimethylsilyl) phenyl] acetamide.

V

To a solution of 53.0 g (215 mmol) of Example b) in 500 mL of acetone was added 15.3 g (235 mmol) of sodium azide and 50 mL of water. The mixture was stirred for 15 min. and the gas evolution was weakened. The mixture was then heated to reflux for 22 hours. The acetone is then removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered through silica gel. The filtrate was evaporated in vacuo to give 42.8 g (100%) of a colorless oil identified as 2- (trimethylsilyl) -6-chloroaniline.

To a solution of this compound (2.0 g, 10.0 mmol) and 0.8 g (10.1 mmol) of pyridine in 30 mL of dry THF was added 1.82 g (10.0 mmol) of trichloroacetyl chloride. The mixture was stirred at ambient temperature for 4 hours. and then partitioned between ether and water. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered through silica gel. The filtrate was evaporated in vacuo and the residue triturated with ether / hexane to give 2.9 g of white crystals of the title compound, mp 188.5189 ° C.

Example 176

2-Bromo-N-ethyl-6- (trimethylsilyl) benzamide.

Example d (38.19 g, 0.13 mol) was treated with 70% aqueous ethylamine (53 mL) according to the basic method EI and recrystallized from methylcyclohexane to give the title compound as light tan crystals in 92% yield, m.p. 121-122 ° C.

Example 177

2-Chloro-N-ethyl-4- (trimethylsilyl) -3-thiophenecarboxamide.

3-Thiophenecarboxylic acid (20 g, 178 mmol). Thionyl chloride (30 mL), and DMF (5 drops) were stirred overnight, then concentrated in vacuo and distilled several times from toluene to remove any traces of excess thionyl chloride. To a mixture of this acid chloride and ethylamine hydrochloride in toluene (5 mL) and CH ₂ Cl ₂ (50 mL) was added pyridine (31.64 g, 400 mmol). After 1 or. the mixture was washed with 10% HCl solution followed by water; then dried (MgSO ₄ ), concentrated and crystallized from ethyl acetate / hexanes to give 14.9 g of N-ethyl-3-thiophenecarboxamide as a tan solid. Yield 76%, m.p. 115-117 ° C.

A 1.3M solution of s-BuLi in cyclohexane (44 mL, 57.2 mmol) was added dropwise to -78 ° C with N-ethyl-3-thiophenecarboxamide (4.04 g, 26 mmol) and TMEDA (6.65 g, 57 mmol). , 2 mmol) in THF (100 mL). After 30 minutes a solution of hexachloroethane (13.54 g, 57.2 mmol) in THF (20 mL) was added dropwise at -78 ° C. The resulting reaction mixture was warmed to RT for 1 h, quenched with dilute citric acid and extracted with EtOAc (3X). The combined organic extracts were dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 3: 7 EtOAc / hexanes to give 2.8 g of N-ethyl-2-chloro-3-thiophenecarboxamide as a yellow oil. Yield 57%.

A solution of 1.3 M s-BuLi in cyclohexane (16.15 mL, 21 mmol) was added dropwise to a solution of N-ethyl 2-chloro-3-thiophenecarboxamide (1.90 g, 10 mol) in ether-liquid N ₂ cooled (-100 ° C) TMEDA (3.17 mL, 21 mol) in THF (100 mL). After 30 minutes with stirring at -100 ° C, TMSCl (2.28 g, 21 mmol) was added immediately. The resulting reaction mixture was heated to -25 ° C for 1 h, quenched with dilute citric acid, and extracted with EtOAc (3X). The combined organic extracts were dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 3:17 EtOAc / hexanes to give

0.3 g of the title compound as a white solid. Yield 11%, m.p. 46-48 ° C.

Example 178

N-Ethyl-2- (trimethylsilyl) -1H-pyrrole-1-carboxamide.

60% NaH in mineral oil (1.8 g, 45 mmol) was added to ice-water-cooled pyrrole (2.01 g, 30 mmol) in THF (100 mL) over 15 min. After 1 or. the reaction mixture was cooled to -78 ° C and ethyl isocyanate (1.78 g, 25 mmol) was added. The mixture was allowed to warm to RT and stirred overnight, then partitioned between ether and dilute citric acid. The ether phase was dried (MgSO ₄ ), filtered through silica gel, concentrated and recrystallized from ether / hexanes to give 39% yield of pyrrole-1- (N-ethylcarboxamide).

1,3 s-BuLi in cyclohexane (18.5 m, 24 mmol) was added to dry ice / acetone cooled pyrrole-1- (N-ethylcarboxamide) (1.38 g, 10 mmol) and 2,2,6,6 -Tetramethylpiperidine (1.55 g, 11 mmol) in THF (50 mL). After 30 minutes with stirring at -78 ° C, TMSCl (1.63 g, 15 mmol) was added all at once. The reaction was allowed to warm to RT slowly over 30 min, then quenched with dilute citric acid and extracted with ethyl acetate (3X). The combined organic solutions were dried (MgSO ₄ ), concentrated and crystallized from ether / hexanes to give 0.8 g of the title compound as a white solid. Yield 38%, m.p. 100-103 ° C.

Example 179

2-Chloro-6- (dimethyl-2-propenylsilyl) -N-ethylbenzamide.

A solution of 1.3 M s-BuLi in cyclohexane (10.5 mL, 13.6 mmol) was added dropwise to dry ice / acetone-cooled TMEDA solution (1.0 mL, 6.5 mmol) in THF (10 mL), followed by dropwise addition of A solution of the sample compound (1.0 g, 5.45 mmol) in THF (10 mL). The reaction mixture was stirred at -78 ° C for 30 min, then allyldimethylchlorosilane (10.9 mmol) was added and the mixture stirred for 2.5 h. At -78 ° C, citric acid diluted with water was added, diluted with water, and extracted with EtOAc (2X). The combined organic extracts were dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 1:19 EtOAc / cyclohexane to give the title compound as a white solid, mp 61-63 ° C.

Example 180

2-Chloro-6- [dimethyl (1-methylethyl) silyl] -N-ethylbenzamide.

The title compound was prepared as in Example 179 from isopropyldimethylchlorosilane in 62% yield, m.p. 98-100 ° C.

Example 181

2-Chloro-6- (cyclohexyldimethylsilyl) -N-ethylbenzamide.

The title compound was prepared as in Example 179 from cyclohexyldimethylchlorosilane in 71% yield, m.p. 111113 ° C.

Example 182

2-Chloro-6- (dimethyloctylsilyl) -N-ethylbenzamide.

The title compound was prepared as in Example 179 from octyldimethylchlorosilane in 78% yield, m.p. 62-63 ° C.

Example 183

2- (Bicyclo [2,2,1] hept-2-yldimethylsilyl) -6-chloro-Nethylbenzamide.

The title compound was prepared as in Example 179 from 2-bicycloheptyldimethylchlorosilane in 58% yield, m.p. 124-125 ° C.

Example 184

2-Chloro-6- (dimethylphenylsilyl) -N-ethylbenzamide.

The title compound was prepared as in Example 179 from phenyldimethylchlorosilane in 44% yield, m.p. 89-91 ° C.

Example 185

2-Chloro-6 - [(1,1-dimethylethyl) dimethylsilyl) -Nethylbenzamide.

The title compound was prepared as in Example 179 from tert-butyldimethylchlorosilane in 28% yield, m.p. 140142 ° C.

Example 186

2- (1,1-Dimethylethyl) -N-ethyl-N- (1-methoxy-2,2-dimethylpropyl) benzamide.

A mixture of 2-tert-butylbenzoic acid (15.7 g, 88.2 mmol) and thionyl chloride (19.3 mL, 265 mmol) was stirred at RT for 1 day, then concentrated and distilled from toluene (2X) in vacuo. The compound from Example k (19.94 g, 176.5 mmol) was added to a solution of this crude 2-tert-butylbenzoyl chloride in toluene (90 mL) and the mixture was heated at 100 ° C for 3 h, then stirred at RT overnight. The resulting mixture was cooled in an ice-water bath, and Et ₃ N (13.4 g, 132.4 mmol) was added followed by methanol (5.65 g, 176.6 mmol). The resulting reaction mixture was stirred at RT and completed by GLC, then partitioned between ether and saturated aqueous NaHCO ₃ solution. The ether extract was dried (MgSO ₄ ), concentrated and purified by flash chromatography eluting with 1: 9 EtOAc / hexanes to give 20.8 g of the title compound as a pale yellow oil. Yield 77%.

Example 187

N-Ethyl-N- (1-methoxy-2,2-dimethylpropyl) -2 (trimethylsilyl) benzamide.

A solution of Example k (30 g, 265 mmol) in CH ₂ Cl ₂ (60 mL) was added to ice-water-cooled benzoyl chloride solution (36 g, 256 mmol) in CH ₂ Cl ₂ (180 mL). The cooling bath was then removed and continued under mild exothermic conditions. After 1 or. ice-cold bath, and Et ₃ N (4.44 g, 43.9 mmol) was added simultaneously, followed by dropwise addition of methanol.

79.7 mmol) which caused the precipitate to form for 30 min then partitioned between ethereal aqueous NaHCO ₃ solution. (MgSO ₄ ), and concentrated in vacuo to give 61.23 g (2.55 g, stirred at RT and saturated

The kugelrohr ether phase is distilled in the form of pure N-ethyl-N- (1-methoxy-2,2-dimethylpropyl) benzamide oil in 96% yield.

A solution of 1.3M s-BuLi in cyclohexane (140.6m, 182.8mmol) was added dropwise to ice-water / acetone cooled N-ethyl-N- (1-methoxy-2,2-dimethylpropyl) benzamide (35g, 140.6mol). ) and TMEDA (25, 44 g, 168.6 mol) in THF (280 mL) while maintaining an internal reaction temperature of <-60 ° C. The yellow solution was stirred at -78 ° C for 1 h, then added to dry ice / acetone-cooled TMSC1 solution (26.72 mL, 210.6 mol) in THF (140 mL) at a rate that maintained an internal reaction temperature of <-55 ° C. The resulting mixture was heated to 0 ° C and partitioned between ether and saturated aqueous NaHCO ₃ solution. The ether solution was dried (MgSO ₄ ), concentrated and kugelrohr distilled in vacuo to give 44.8 g of the title compound as a pale yellow oil. Yield 99%, m.p. 76-78 ° C.

Example 188

2 - [(1,1-Dimethylethyl) methylamino] -N-ethylbenzamide.

70% Perchloric acid (22.5 g, 157 mmol) was added to a solution of anthranil (9.53 g, 80 mmol) and tertiary butanol (5.93 g, 80 mmol) in ice-water. The resulting mixture was stirred at RT overnight, then diluted with ether to form a liquid mass. The solid was concentrated by filtration and dried in vacuo to give 16.0 g of N-tert butyl anthranil perchlorate as a white solid.

N-tert-Butyl anthranil perchlorate (15.6 g, 56.6 mmol) was added portionwise to a solution of triethylamine (17.2 g, 170 mmol) in CH ₂ Cl ₂ (150 mL). The mixture was stirred at RT for 1 h. then concentrated to low volume, triturated with ether, and filtered to remove salts. The filtrate was concentrated and distilled under vacuum to give 1.8 g of N-tert-butyl b-lactam as a yellow oil, see 89-90 ° C. 0.2 Torr.

This N-tert-butyl b-lactam (0.52 g, 3 mmol) was added to a 70% aqueous solution of EtNH ₂ (0.58 g, 9 mmol) and CH ₂ Cl ₂ (50 mL). After stirring for 3 days, the RT mixture was concentrated and crystallized from hexanes to give 0.61 g of N-ethyl

2- (N-tert-butylamine benzamide) as a white solid, m.p. 37-40 ° C.

A mixture of this material potassium carbonate (0.4 g, 2.86 mmol) and methyl iodide (0.45 g, 3.15 mmol) in DMF (10 mL) was stirred at RT overnight, then partitioned between ether and water. The ether was dried (MgSO ₄ ), concentrated and purified by RC eluting with 3: 7 ethyl acetate / hexanes followed by recrystallization from hexane to give 100 mg of the title compound as a white solid, mp 45-48 ° C.

Example 189

2-Chloro-6 - [(1,1-dimethylethyl) methylamino] -N-ethyl-Nmethyl) benzamide.

A solution of N-tert-butyl b-lactam (1.1 g, 6.3 mmol) prepared in Example 188 and a solution of N-ethyl-N-methylamine (1.2 g, 20.8 mmol) in CH ₂ Cl ₂ (50 mL) ) stirred at RT overnight. The solvent was evaporated and the residue was purified by RC eluting with EtOAc / cyclohexane to give 1.277 g of N-ethyl-N-methyl-2- (N-tert-butylamino) benzamide as an orange oil in 86% yield.

N-Ethyl-N-methyl 2- (N-tert-butylamino) benzamide (1.89 g, 8.1 mmol), potassium carbonate (2.2 g, 15.9 mmol) and methyl iodide (2.3 g) , 16.2 mmol) in DMF (40 mL) was heated overnight at 40 ° C, then partitioned between EtOAc and water. The EtOAc was dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 3: 7 ethyl acetate / hexane to give 1.923 g of N-ethyl-N-methyl-2- (N-methyl-N-tert-butylamino) benzamide as a yellow oil. Yield 96%.

A 1.3M solution of s-BuLi in cyclohexane (3.7 mL, 4.8 mmol) was added to dry ice / acetone-cooled TMEDA solution (0.7 mL, 4.8 mmol) in THF (10 mL) followed by N- A solution of ethyl N-methyl 2- (N-methyl-N-tert-butylamino) benzamide (1.0 g, 4.0 mmol) in THF (5 mL). The reaction mixture was briefly heated to -30 ° C, then cooled to -78 ° C and stirred for 15 min. A solution of hexachloroethane (2.8 g, 12.1 mmol) in THF (5 mL) was added. This mixture is stirred for 1 hour. At -78 ° C, then warmed to -30 ° C, diluted with water and extracted with EtOAc (2X). The combined extracts were dried (MgSO ₄ ), concentrated and purified by HPLC eluting with 1: 4 EtOAc / cyclohexane to give 528 mg of the title compound as a yellow oil. Yield 99%.

Example 190

2-Chloro-6 - [(1,1-dimethylethyl) methylamino] -Nethylbenzamide.

A 1.3M solution of s-BuLi in cyclohexane (5.7 mL, 7.5 mmol) was added to dry ice / acetone-cooled TMEDA solution (0.5 mL, 3.6 mmol) in THF (10 mL) followed by the addition of Example 188. A solution of compound (0.7 g, 3.0 mmol) in THF (5 mL) was added. The reaction mixture was stirred at -78 ° C for 30 min then hexachloroethane (2.1 g, 9.0 mmol) in THF (5 mL) was added. This mixture was stirred for 30 min. At -78 ° C, then warmed to -30 ° C, diluted with water and extracted with EtOAc (2X). The combined extracts were dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 3:17 EtOAc / cyclohexane to give 495 mg of the title compound as a yellow solid. Yield 61%, mp 106-108 ° C.

Example 191

2-Ethyl-2 - [(1,1-dimethylethyl) methylamino] -6-methylbenzamide.

A 1.3M solution of s-BuLi in cyclohexane (9.8 mL, 12.8 mmol) was added to dry ice / acetone-cooled TMEDA solution (0.6 mL, 3.8 mmol) in THF (10 mL) followed by the addition of Example 188. Compound solution (0.75 g, 3.2 mmol) in THF (5 mL). The reaction mixture was stirred at -78 ° C for 30 min before methyl iodide (2.3 g, 16 mmol) was added all at once. This mixture is stirred for 2.5 hours. At -78 ° C, followed by extraction with EtOAc (2X). The combined extracts were dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 1: 4 EtOAc / cyclohexane to give 146 mg of the title compound as a light yellow solid. Yield 18%, m.p. 101-103 ° C.

Example 192

2-Chloro-6 - [(1,1-dimethylethyl) amino] -N-ethylbenzamide.

A mixture of 2-chloro-6-fluorobenzaldehyde (99.1 g, 625 mmol) and NaN ₃ (81.2 g, 1249 mmol) in DMSO (900 mL) was slowly heated to 75 ° C for 2 h. The reaction temperature was then raised to 100 ° C and the formation of chlorantranil was monitored after 3 hours. ¹ H-NMR by aromatic zone analysis. The dark solution was partitioned between water (2 liters) and ether, then filtered through celite to disperse the emulsion. The aqueous layer was extracted with additional ether, then the combined organic extracts were washed with water, dried (MgSO ₄ ), concentrated and kugelrohr distilled to give 81.65 g of chlorantranil as a light yellow solid. Yield 85%, m.p. 4547 ° C.

A mixture of this chlorantranil (81.65 g, 532 mmol) and tert-butanol (43.4 g, 586 mmol) was heated to give a solution, then cooled in an ice-water bath; 70% perchloric acid was added at a rate to maintain an internal reaction temperature <35 ° C. After the addition, the cold bath was removed and the reaction continued exothermically for 1 h until a precipitate formed. After 2 or. the resulting mixture was cooled in an ice-water bath and suspended in ether (100 mL). The salts were concentrated by filtration, washed with dry ether and dried in vacuo to give 155.91 g of N-tert-butyl chloroanthranil perchlorate salt as a pale yellow solid. Yield 95%.

this N-tert-butyl chloroanthranil perchlorate salt (155.91 g, 503 mmol) was added portionwise to a solution of Et ₃ N (152.7 g, 1509 mmol) in CH ₂ Cl ₂ (1 liter) in ice-water-cooled solution. The resulting amber solution was stirred at RT for 30 min, then concentrated to low volume, diluted with dry ether (500 mL), filtered to remove salts, and concentrated to give 101.11 g of the desired b-lactam as a golden oil. Yield 96%.

A solution of this b-lactam (101.11 g, 483 mmol) in ether (100 mL) was added dropwise to ice-water-cooled 70% EtNH ₂ (465 g, 7233 mmol) while maintaining an internal reaction temperature of <-20 ° C. The resulting mixture was stirred at RT for 30 min then diluted with water and extracted with ether (3X). The combined extracts were dried (MgSO ₄ ), concentrated to low volume, then suspended in hexanes (1 liter) and filtered to give 111.75 g of the title compound as a white solid. Yield 91%, m.p. 139-140 ° C.

Example 193

2-Chloro-N-ethyl-4-formyl-6- (trimethylsilyl) benzamide.

A mixture of 2-chloro-4-bromobenzoic acid (5.0 g, 21.2 mmol) and hexamethylsilazane (5.0 mL, 23.7 mmol) was heated at 135 ° C for 3 h, then distilled under vacuum to give 6.32 g of O-trimethylsilyl 2-chloro-4-bromobenzoate in the form of a colorless oil are obtained in a yield of 97%.

A 2.5M solution of n-BuLi in hexanes (3.25 mL, 8.13 mmol) was added to dry ice / acetone cooled solution of 2,2,6,6-tetramethylpiperidine (1.20 g, 8.5 mmol) in THF (6 mL). . This solution was stirred at -78 ° C for 15 min, then cooled to -100 ° C with ether / liquid N ₂ and slowly added with O-trimethylsilyl 2-chloro-4-bromobenzoate (2.00 g, 6.5 mol) ) in THF (6 mL) while maintaining an internal reaction temperature <-95 ° C. The resulting reaction mixture was stirred at -100 ° C for 15 min, then poured into dilute citric acid and extracted with ether (2X). The combined extracts were dried (MgSO ₄ ) and concentrated to give 2-chloro-4-bromo-6-trimethylsilylbenzoic acid as a golden oil.

2-Chloro-4-bromo-6-trimethylsilylbenzoic acid was diluted with thionyl chloride (3 mL, 41.1 mmol) and warmed. When gas evolution was complete, the solution was concentrated and distilled from toluene (2X) in vacuo to remove excess thionyl chloride. The remaining dark oil was dissolved in toluene (12 mL), followed by addition of Example k (2.2 g, 19.5 mmol) and heating at 100 ° C until GLC indicated completion of the reaction. The resulting mixture was cooled to 0 ° C and Et ₃ N (1.32 g, 13.0 mmol) was added simultaneously, followed by dropwise addition of methanol (0.62 g, 19.4 mmol) in toluene (1 mL). Heated to RT and Controlled to GLC shows completion; and then diluted with ether and extracted with saturated aqueous NaHCO ₃ solution and dried (MgSO _4), concentrated and the residue was dissolved in hexane. The hexane solution was cooled to -78 ° C and filtered to remove insoluble impurities, then the filtrate was concentrated and purified by RC eluting with 1:49 EtOAc / hexanes to give 820 mg of N-ethyl-N- (1-methoxy-2,2- dimethylpropyl) 2-chloroLT 3276 B

4-Bromo-6- (trimethylsilyl) benzamide as a yellow oil.

A solution of N-ethyl-N- (1-methoxy-2,2-dimethylpropyl) -2-chloro-4-bromo-6- (trimethylsilyl) -benzamide (820 mg, 1.89 mmol) in THF (2 mL) was added to dry ice / acetone-cooled 2.5M n-BuLi in hexanes (1 mL, 2.5 mmol) in THF (2 mL). The resulting red solution was stirred at -78 ° C for 15 min, then DMF (500 mL, 6.5 mmol) was added at one time. After 5 minutes the reaction mixture was poured into a saturated aqueous solution of NaHCO ₃ , and extracted with ether (2X). The combined organic extracts were dried (MgSO ₄ ) and concentrated, then a solution of this protected amide in acetone (5 mL) was added to 6N HCl and stirred at RT overnight. The resulting mixture was poured into a saturated aqueous NaHCO ₃ solution and extracted with ether (2X), then the combined extracts were dried (MgSO ₄ ), concentrated and purified by RC eluting with 3: 7 EtOAc / hexanes to give 220 mg of the title compound as a white solid. . Yield 40%, m.p. 95-97 ° C.

Example 194

2 - [(1,1-Dimethylethyl) sulfinyl] -N-ethyl-6-fluorobenzamide.

A mixture of 2-methyl-2-propanediol (2.7 g, 30 mmol), g of the sample compound (3.17 g, 15 mmol) and NaH (0.79 g, 33 mmol) in THF (100 mL) was stirred at RT for 1 day , then reflux for 1 day. The mixture was then quenched with saturated aqueous NaHCO ₃ solution (50 mL) and extracted with EtOAc (3 X 50 mL). The combined organic extracts were dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 1: 4 EtOAc / hexanes to give 3.5 g of 2- [2-fluoro-6- (1,1-dimethylethylthio) phenyl] -4,4. -dimethyl-2-oxazoline as a yellow oil in 83% yield.

According to the procedure of Example 6, 2- [2-fluoro-6- (1,1-dimethylethylthio) phenyl] -4,4-dimethyl-2-oxazoline (3.5 g, 12.5 mol) is converted to N-ethyl-2-fluoro -6- (1,1-dimethylethylthio) benzamide-white solid, en Mp 107-109 ° C.

A solution of N-ethyl-2-fluoro-6- (1,1-dimethylethylthio) benzamide (3.45 g, 13.51 mmol) in methanol (100 mL) was added to a 0 ° C solution of ΟΧΟΝΕ® (8.31). g, 13.51 mmol) in water (100 mL). This mixture was stirred for 2 min then poured into 25% sodium metabisulfite solution (100 mL) and extracted with ether (3 X 100 mL). The combined organic extracts were washed with brine then water, then dried (MgSO ₄ ), concentrated and recrystallized from ethyl acetate / hexanes to give 2.2 g of the title compound as a white solid, mp 114-116 ° C.

195 Example

Ν, Ν-Diethyl 2 - [(1,1-dimethylethyl) sulfinyl] -6-fluorobenzamide.

The title compound was obtained according to an analogous procedure to Example 194 and purified by RC eluting with 1: 1 ethyl acetate / hexanes to give a crude oil.

Example 196

N - (1-Methylethyl) -2 - [(1,1-dimethylethyl) sulfinyl] -6-fluorobenzamide.

The title compound was obtained according to a procedure analogous to Example 194 and purified by recrystallization from ether / hexanes to give a white solid, m.p. 120-135 ° C.

197 Example

N- (2-Chloroethyl) -2-fluoro-6- (2-methylphenyl) benzamide.

A 2.5M solution of n-BuLi in cyclohexane (6.4 mL, 16 mmol) was added to an ether / liquid N ₂ cooled solution of 2-bromo-toluene (2.74 g, 16 mmol) in THF (100 mL) while maintaining an internal reaction temperature. .85 ° C. The resulting solution was added dropwise to an ether / liquid N ₂ cooled solution of the sample compound (2.93 g, 16 mmol) in THF (25 mL). The resulting reaction mixture was heated to -60 ° C and poured into a saturated aqueous solution of NaHCO ₃ , followed by extraction with ether (3 X 100 mL). The combined organic extracts were washed with water (2 X 25 mL), dried (MgSO ₄ ), concentrated, then purified by HPLC eluting with 3: 7 EtOAc / hexanes to give 3.2 g of 2- [2-fluoro-6- (2) -methylphenyl)] -2-oxazoline in the form of a white solid. Yield: 78%, m.p. 65-68 ° C.

Excess gaseous HCl was added to a solution of 2- [2-fluoro-6- (2-methylphenyl)] -2-oxazoline (3.2 g, 12.5 mmol) in ether (50 mL). The resulting mixture was stirred overnight, then crystallized by the addition of hexanes to give 2.4 g of the title compound as a white solid. Yield 51%, m.p. 78-81 ° C.

198 Example

N- (2-Chloroethyl) -2 - [(1,1-dimethylethyl) sulfinyl] -6-fluorobenzamide.

LiH (0.12 g, 16 mmol) was carefully added to a solution of 1,1-dimethylethylthiol (1.44 g, 16 mmol) in THF (100 mL). When gas evolution stopped, a sample compound (2.93 g, 16 mmol) was added at one time. The mixture was refluxed overnight, then cooled and partitioned between ether and saturated aqueous NaHCO ₃ solution. The ether is dried (MgSO ₄ ) and concentrated, then dissolved in ether and

The HCl gas was stirred overnight at room temperature, after addition of the 2.2 addition mixture allowed to pass through hexanes to give the fluoro-6- (1,1-dimethyllethylthio) benzamide as a material, yield 47%.

surplus. The resultant crystallized, g N- (chloroethyl) -2 white solid

A solution of N- (chloroethyl) -2-fluoro-6- (1,1-dimethylethylthio) benzamide (2.0 g, 7.0 mmol) in methanol (50 mL) was added to a 0 ° C solution of tirp® (4). , 24 g, 7.0 mmol) in water (50 mL). This mixture was stirred for 2 min then poured into 25% sodium metabisulfite solution (100 mL) and extracted with ether (3 X 100 mL). The combined organic extracts were washed with brine, then water, then dried (MgSO ₄ ), concentrated and purified by HPLC eluting with 1: 3 ethyl acetate / hexanes to give 2.1 g of the title compound as a white solid. Yield 98%, m.p. 80-90 ° C.

199 Example

N- (2-Chloroethyl) -2-fluoro-6- (1-methylcyclobutyl) benzamide.

A 0.2M solution of lithium 4,4 '- (di-t-butyl) biphenyl (50 mL, 10 mmol) was added to dry ice / acetone cooled solution of 1chloro-1-methylcyclobutane (1.04 g, 10 mmol) in THF (25 mL). ml) while maintaining an internal temperature of <-55 ° C. The resulting mixture was stirred at -78 ° C for 30 min, after which the compound of Example (1.65 g, 9 mmol) was added simultaneously. After 1 or. after keeping at -78 ° C, the reaction mixture was poured into a saturated aqueous solution of NaHCO ₃ (50 mL) and extracted with ether (3 X 50 mL). The combined organic extracts were washed with water, dried (MgSO ₄ ), concentrated and purified by RC to give 0.8 g of 2- [2-fluoro-6- (1-methylcyclobutyl)] -2-oxazoline as a colorless oil in 34% yield. An excess of gaseous HCl is added to the ether in a solution of this oxazoline in ether. The resulting mixture was stirred overnight and then crystallized by adding hexanes to give 0.5 g of N- (2-chloroethyl) -2-fluoro-6- (1-methylcyclobutyl) benzamide as a white solid. Yield 62%, m.p. 108110 ° C.

Example 200

3,6-Dichloro-N-ethyl-2- (trimethylsilyl) benzamide.

chloride (51 mmol) and 70% (130 mmol) were combined according to EI to give 9.4 g of N-ethyl-2.5 as a beige solid.

2,5-Dichlorobenzoyl aqueous method of EtNH ₂ basic dichlorobenzamide, yield 85%.

A 1.5M solution of LDA in THF (13 mL, 19.5 mmol) was added dropwise to ether / liquid N ₂ cooled N-ethyl 2,5-dichlorobenzamide (2.0 g, 9.2 mmol) and TMSC1 (1.5 mL, 11.5 mmol) in THF (50 mL) while maintaining an internal reaction temperature <-80 ° C. The resulting reaction mixture was stirred at -100 ° C for 30 min then partitioned between ether and saturated aqueous NaHCO ₃ solution. The ether solution was dried (MgSO ₄ ), concentrated and crystallized from EtOAc / hexanes to give 1.15 g of the title compound as a white solid, mp 150-153 ° C.

Example 201

2-Chloro-N-ethyl-N- (1-methoxy-2,2-dimethylpropyl) -6 (trimethylsilyl) benzamide.

A solution of compound k (3.55 g, 31.4 mmol) in CH ₂ Cl ₂ (10 mL) was added dropwise to a solution of _2- chlorobenzoyl chloride (5.0 g, 28.6 mmol) in CH ₂ Cl ₂ (20 mL) in ice water. . The reaction was heated to RT and maintained exothermically for 10-15 min. The resulting solution was cooled in an ice-water bath and treated with Et ₃ N (3.0 g, 29.6 mmol) followed by addition of MeOH (1.83 g, 57.2 mmol). The reaction was allowed to warm to RT and completion was monitored by GLC, then diluted with ether and extracted with saturated aqueous NaHCO ₃ solution, dried (MgSO ₄ ), concentrated and kugelrohr distilled in vacuo to give 7.54 g of N-ethyl-N- (l-). methoxy-2,2-dimethylpropyl) -2-chlorobenzamide, a colorless oil, 93% yield.

A 1.3M solution of s-BuLi in cyclohexane (3.53 m, 4.59 mmol) was added to dry ice / acetone cooled TMEDA (639 mL, 4.23 mmol) and N-ethyl-N- (1-methoxy-2). 2-dimethylpropyl) -2-chlorobenzamide (1.0 g, 3.53 mmol) in THF (7 mL). The reaction mixture was stirred for 45 min. At -78 ° C, then TMSCl (671 mL, 5.29 mmol) was added at one time. The reaction was allowed to warm to 0 ° C and partitioned between ether and 10% HCl. The ether solution was then extracted with saturated aqueous NaHCO ₃ solution, dried (MgSO ₄ ) and purified by RC eluting with 1:49 EtOAc / hexanes to give 750 mg of the title compound as a white solid. Yield 60%, m.p. 82-83 ° C.

Example 202

2-Chloro-6- (ethenylmethylphenylsilyl) -N-ethylbenzamide.

A 1.3M solution of s-BuLi in cyclohexane (10.5 mL, 13.6 mmol) was added to dry ice / acetone-cooled TMEDA (1 mL, 6.5 mmol) in THF (10 mL) followed by the addition of a solution of Example f. (1.0 g, 5.45 mmol) in THF (10 mL), after 30 min. phenylmethylvinyl chlorosilane (1.5 g, 8.2 mmol) was added and the mixture was stirred for 2 h. At -78 ° C. This contents was poured into 25% citric acid solution and partitioned between EtOAc and water. The EtOAc was dried (MgSO ₄ ), concentrated, and purified by HPLC eluting 1:19

EtOAc / cyclohexane to give 0.56 g of a white solid which is recrystallized from EtOAc / petroleum ether at low temperature to give 0.194 g of the title compound. Yield 11%, m.p. 85-87 ° C.

Example 203

2,3-Dichloro-N-ethyl-6- (trimethyl-III-yl) -benzamide.

2,3-Dichloro-6- (trimethylsilyl) benzoic acid was prepared from 2,3-dichlorobenzoic acid according to the procedure of Example a in 45% yield, 3.07 g of a white solid,

i.e. 117-119 ° C.

This acid was converted to the acid chloride according to the procedure of Example b. The acid chloride is treated with aqueous ethylamine using the EI basic method to give the title compound. Purify by recrystallization from hexanes to give 0.42 g of the title compound as white crystals. Yield 58%, m.p. 96-98 ° C.

Example 204

2,3-Dichloro-N- (2-propenyloxy) -6 (trimethylsilyl) benzamide.

The acid prepared in Example 203 is converted to the acid chloride according to the procedure of Example b. The acid chloride is treated with aqueous 0-allylhydroxylamine using the EI basic method to give the title compound. Purification by recrystallization from ether / hexanes gave 0.68 g of the title compound as a white solid. Yield 86%, m.p. 92-94 ° C.

Example 205

2,3-Dichloro-6- (trimethylsilyl) benzoic acid 2,2-dimethylhydrazide.

The acid prepared in Example 203 is converted to the acid chloride according to the procedure of Example b. The acid chloride is treated with 1,1-dimethylhydrazine using the EI basic method to give the title compound. Purification by recrystallization from ether / hexanes gave 0.62 g of the title compound as off-white crystals. Yield 81%, m.p. 144-145 ° C.

Example 206

2-Bromo-N-2-propynyl-6- (trimethylsilyl) benzamide.

Example d is treated with propargylamine (3 eq) according to EI basic method, and the product is recrystallized from hexanes to give 0.55 g of the title compound as off-white needles. Yield 81%, m.p. 120-121 ° C.

Example 207

N-Ethyl-2-iodo-6- (trimethylsilyl) benzamide.

A mixture of 2-iodobenzoic acid, hexamethyldisilazane (0.550.60 eq) and TMSC1 (5 drops) was heated at 135 ° C for 2-4 hours. The reaction mixture was distilled in vacuo to give the trimethylsilyl ester 2-iodobenzoic acid in 95% yield.

To a solution of 2,2,6,6-tetramethylpiperidine (1.1 eq) in THF at 78 ° C was added 1.6 M BuLi in hexanes (1.1 eq). The reaction solution was placed in an ice bath (0 ° C) for 1 hour. and cooled to -78 ° C. The trimethylsilyl benzoate prepared earlier was added and stirred at -78 ° C for 10-90 min. The reaction was quenched with dilute citric acid and extracted with ether. The ether layers were extracted with 0.5 N NaOH: the basic aqueous layer was acidified with 2 N HCl and extracted with ether. The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give 2-iodo-6- (trimethylsilyl) benzoic acid. The product is purified by recrystallization from hexane to give 3.62 g of white needles, yield 75%, mp 126-133 ° C.

This acid is converted to the acid chloride according to the procedure of Example b. The acid chloride is treated with 70% aqueous ethylamine using the EI basic method to give the title compound. Purification by recrystallization from hexane gave 0.48 g of white crystals of the title compound. Yield 88%, m.p. 135-137 ° C.

Example 208

2-Iodo-N-2-propynyl-6- (trimethylsilyl) benzamide.

The acid chloride prepared in Example 207 was treated with propargylamine (3 eq) using the EI basic method to give the title compound. Purification by recrystallization from hexane gave 0.48 g of the title compound as an off-white solid. Yield 85%, m.p. 109-111 ° C.

Example 209

N-Cyclopropyl-2-iodo-6- (trimethylsilyl) benzamide.

The acid chloride prepared in Example 207 was treated with cyclopropylamine (3 eq) using the EI basic method to give the title compound. Purification by recrystallization from hexane gave 0.49 g of the title compound as white needles. Yield 87%, m.p. 162-164 ° C.

Example 210

2 - [(Bromethyl) dimethylsilyl] -6-chloro-N-ethylbenzamide.

To a solution of Example 45 (1.28 g, 5 mmol) in THF (30 mL) at -78 ° C was added a 1.7M solution of t-BuLi in pentane (6.5 mL, 11 mmol, 2.2 eq) so that the temperature would not rise above -70 ° C. Stir for 1.5 or. At -78 ° C, and ethylene dibromide (0.52 mL, 6.0 mmol, 1.2 eq) was added. The reaction was stirred for 15 min. 78 ° C and completed in the usual manner. The product was purified by RC and recrystallized from aqueous methanol to give the title compound as white needles (0.30 g, 18%), m.p. 98-99 ° C.

Example 211 [2-Chloro-6- (trimethylsilyl) benzoyl] ethylcarbamic acid 1,1-dimethylethyl ester.

To a solution of the compound of Example 45 (3.83 g, 15 mmol) and di-t-butyl carbonate (3.60 g, 16.5 mmol) in acetonitrile was added 4-dimethylaminopyridine (0.18 g, 1.5 mmol). The solution was stirred at RT for 1 day, di-t-butyl carbonate (3.60 g) was added and stirring continued for 3 days. Additional dt-butyl carbonate (3.60 g) was added, stirred overnight and concentrated. The residue was diluted with ether, washed with saturated citric acid solution, saturated NaHCO ₃ brine, dried (MgSO ₄ ) and concentrated to give the title compound. The product was purified by flash chromatography (ethyl acetate / hexanes) and recrystallized from hexanes (-78 ° C) to give the title compound as a white solid (2.65 g, 50%), mp 51-52 ° C.

Example 212

2-Chloro-N-ethyl-6- (ethyldimethylsilyl) benzamide.

To a solution of the compound of Example 45 (1.28 g, 5 mmol) and TMEDA (0.91 mL, 6.0 mmol, 1.2 eq) in THF at -78 ° C was added a 1.7M solution of t-BuLi in pentane (7, 1 mL, 12 mmol, 2.4 eq) so that the temperature does not rise above -70 ° C. Stir in 2 or. At -78 ° C, and methyl iodide (0.44 mL, 7.0 mmol, 1.4 eq) was added. The reaction was stirred for 15 min. At -78 ° C and completed in the usual manner. The product was recrystallized from aqueous methanol and then from hexanes to give the title compound as white crystals (0.62 g, 46%), m.p. 94-95 ° C.

Example 213

5-Chloro-N-ethyl-2- (trimethylsilyl) benzamide.

The 2-bromo-5-chlorobenzoic acid is converted to the acid chloride according to the procedure of Example b. The acid chloride is treated with 70% aqueous ethylamine using the EI basic method to give the amide. Purification from methylcyclohexane / ethyl acetate, recrystallization of 2-bromo-5-chloro-N-ethylbenzamide-white gave 4.69 g of solid, 75% yield, m.p. 98-99 C.

To a solution of this amide (1.05 g, 4.0 mmol) in THF (20 mL) was added dropwise a solution of 1.6M n-BuLi in hexanes (5.5 mL, 8.8 mmol, 2.2 eq) at -78 ° C. so that the temperature does not rise above -70 ° C. The yellow solution was stirred for 30 min. At -78 ° C and dropwise with TMSCI (0.61 mL, 4.8 mmol, 1.2 eq). The solution was stirred for 45 min. -78 ° C, and completed in the usual manner. The product was purified by RC (ethyl acetate / hexanes) and recrystallized from hexanes to give the title compound as white needles (0.27 g, 26%), m.p. 104-105 ° C.

Example 214

N-Ethyl-5-nitro-2- (trimethylsilyl) benzamide.

A solution of the amide from Example 49 (1.10 g, 5 mmol) in CH ₂ Cl ₂ (50 mL) was added dropwise at 0 ° C over 2 min. cold mixture of 70% nitric acid (0.95 mL, 15 mmol) and concentrated sulfuric acid (5 mL). The mixture was stirred for 10 min. At 0 ° C and poured into ice. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, saturated NaHCO ₃ , brine, dried (MgSO ₄ ), and concentrated to a dry solid / (2.68 g, 101%) consisting of 2: 1 5-nitro -and 3-nitro isomers. The title compound is purified by RC (ethyl acetate / hexanes) in 60% yield as a white solid, mp 100-102 ° C.

Example 215

6-Chloro-N-ethyl-3-nitro-2- (trimethylsilyl) benzamide.

To a solution of the amide 45 in Example 45 (1.28 g, 5 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added a cold mixture of 70% nitric acid (0.64 mL, 10 mmol) and concentrated sulfuric acid (5 mL). . The mixture was stirred for 10 min. At 0 ° C and poured into ice. The mixture was extracted with ether, the combined organic layers were washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated to a solid, dry (1.52 g, 101%). The title compound was obtained by recrystallization from ethyl acetate / hexanes, 83% yield, as a white solid, mp 147-149 ° C.

100

Example 216

6-Chloro-N-ethyl-3-nitro-6- (trimethylsilyl) benzamide.

The mother liquors of Example 215 were purified by RC (ethyl acetate / hexanes) to give 0.11 g of the title compound in 7% yield as a white solid. Recrystallization from ethyl acetate / hexanes gave the pure title compound, m.p. 126-127 ° C.

Example 217

5-Amine-N-ethyl-2- (trimethylsilyl) benzamide.

A solution of the crude amide of Example 214 (2.67 g, 10 mmol) in ethanol (50 mL) with 10% palladium on carbon (0.3 g) was hydrogenated at 50 psi for 3 h. The catalyst is filtered through Celite and the solution is concentrated. The product was purified by RC (ethyl acetate / hexanes) and recrystallized from ethyl acetate / hexanes to give the title compound as a white solid (0.64 g, 27%), m.p. 143-145 ° C.

Example 218

3-Chloro-N-ethyl-2-fluoro-6- (trimethylsilyl) benzamide.

The trimethylsilyl ester of 3-chloro-2-fluorobenzoic acid (11.66 g) was obtained in 84% yield using the procedure described in Example 207. This ester (2.47 g) was converted to 0.45 g of 3-chloro-2-fluoro-6- (trimethylsilyl) benzoic acid in 18% yield using the procedure of Example 207. The product is converted to the acid chloride according to the procedure of Example b. The acid chloride is treated with 70% aqueous ethylamine using the EI basic method to give the title compound. Purify by flash chromatography (ethyl acetate / hexanes) followed by

Recrystallization of 101 from pentane gave 84 mg of the title compound as an off-white solid (18%), m.p. 96-97 ° C.

Example 219

3-Chloro-N-ethyl-3-methoxy-6- (trimethylsilyl) benzamide.

2-Bromo-5-methoxybenzoic acid is converted into the acid chloride according to the procedure of Example b. The acid chloride is treated with 70% aqueous ethylamine using the EI basic method to give 24.44 g of 2-chloro-N-ethyl-3-methoxybenzamide in 95% yield.

This amide (2.58 g, 10 mmol) was dissolved in concentrated sulfuric acid (5 mL) and N-chloro-succinamide (1.47 g, 11 mol) was added in portions over 15 min. The mixture is stirred for 2 hours. and poured into iced water. The mixture was extracted with ethyl acetate, washed with 1.25 N NaOH, saturated sodium sulfite, brine, dried (MgSO ₄ ), and concentrated to give a white solid. The product was purified by recrystallization from ethyl acetate / hexanes to give 6brom-2-chloro-N-ethyl-3-methoxybenzamide as white needles (1.92 g, 66%), mp 181-182 ° C.

To a solution of this amide (0.58 g, 2.0 mmol) in THF (20 mL) at -78 ° C was added a 1.6 M solution of n-BuLi in hexanes (2.8 mL, 4.4 mmol). The reaction was stirred for 1 h. At -78 ° C, then allowed to warm to -30 ° C and cooled to -78 ° C. TMSC1 (0.30 mL, 2.4 mmol) was added and the reaction mixture was allowed to warm to

-30 C, completed as usual. (ethyl acetate / hexanes) and hexanes to give the title

The product is purified by RC recrystallization from an off-white solid (45 mg, 4%), m.p. 136-137 C.

102

Example 220

3-Bromo-2-chloro-N-ethyl-6- (trimethylsilyl) benzamide.

To a solution of Example 201 (0.79 g, 2.2 mmol) and TMEDA (0.44 mL, 2.9 mmol) in THF (20 mL) at -78 ° C was added a solution of 0.86 M s-BuLi in cyclohexane ( 3.3 mL, 2.9 mmol). Stir for 30 min. At -78 ° C, and 1,2-dibromoethane (0.26 mL, 3.0 mmol) was added. The reaction was stirred for 15 min. At -78 ° C and quenched with saturated NaHCO ₃ . The mixture was extracted with ether, washed with brine, dried (MgSO ₄ ) and concentrated to give a yellow oil. This oil was dissolved in a mixture of acetone (30 mL and 6 N HCl (15 mL)) and stirred overnight. The mixture was concentrated, extracted with ether, and the organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound as a clear oil. The product was purified by RC (ethyl acetate / hexanes) and recrystallized from pentane (-78 ° C) to give 76 mg of a white solid (yield 10%), mp 105-106 ° C.

Example 221

N-Ethyl-2-phenyl-6- (trimethylsilyl) benzamide.

The 2-phenylbenzoic acid is converted to the acid chloride according to the procedure of Example b. The acid chloride was treated with 70% aqueous ethylamine using the EI basic method to give 10.59 g of N-ethyl-2-phenylbenzamide in 94% yield, m.p. 77-79 ° C.

This amide (2.25 g, 10 mmol) and TMEDA (1.2 eq) in THF were mixed and cooled to -78 ° C, and a 1.3 M solution of sBuLi in cyclohexane (2.2 eq) was added. The resulting reaction mixture was stirred for 30 min. At -78 ° C, and

103 added TMSC1 (1.2 eq). The reaction was stirred for 30 min. At -78 ° C and allowed to warm to -30 ° C, completed in the usual manner. The product was purified by flash chromatography and recrystallized from hexanes to give the title compound as a white solid (1.15 g, 39%), m.p. 159-160 ° C.

Example 222

5- (Dimethylamino) -N-ethyl-N- (1-methoxy-2,2-dimethylpropyl) -2- (trimethylsilyl) benzamide.

Example 201 (0.72 g, 2.0 mmol) and TMEDA (1.20 mL, 8.0 mmol) in THF (30 mL): At -78 ° C, treated with 1.7 M t-BuLi pentane (5.6 mL, 9.6 mmol) and allowed to warm slowly to -20 ° C over 4 h. The reaction was quenched with 1,2-dibromoethane (0.86 mL, 10 mmol) diluted with saturated NaHCO ₃ , extracted with ether, the organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound. The product was purified by RC (ethyl acetate / hexanes) and recrystallized from pentane (-78 ° C) to give the title compound as a white solid (0.14 g, 20%), mp 96-98 ° C.

Example 223

2-Chloro-N-ethyl-3-formyl-6- (trimethylsilyl) benzamide.

To obtain the title compound, the method of Example 230 was applied by substituting DMF (2 eq) for Mel. The product is purified by recrystallization from ethyl acetate / hexanes to give 1.16 g of the title compound as white needles, 82%, m.p. 140-142 ° C.

104

Example 224

2-Chloro-3- (difluoromethyl) -N-ethyl-6- (trimethylsilyl) benzamide.

A solution of Example 223 (0.26 g, 0.92 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C was treated with DAST (0.12 mL, 0.92 mmol) and maintained for 22 h. The reaction was poured into water, extracted with ether, and the organic layers were washed with saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated to give the title compound. The product was purified by recrystallization from hexane to give 0.20 g (70%) of the title compound as off-white crystals, mp 120-121 ° C.

Example 225

N-Ethyl-5- (trifluoromethyl) -2- (trimethylsilyl) benzamide.

3- Trifluoromethylbenzoic acid is converted to the acid chloride according to the procedure of Example b. The acid chloride is treated with 70% aqueous ethylamine using the basic method EI to give the title compound. Purification by recrystallization from hexane gave 2.24 g of N-ethyl3- (trifluoromethyl) benzamide as white needles, yield 19%, m.p. 98-99 ° C.

This amide was treated with TMSC1 (1.3 eq) as in Example 221 to afford the title compound. The product was purified by RC (ethyl acetate / hexanes) and recrystallized from pentane (-78 ° C) to give 0.14 g (5%) of the title compound as a white solid, m.p. 101-102 ° C.

Example 226

5- (Dimethylamino) -N-ethyl-2- (trimethylsilyl) benzamide.

105

Example 222 (0.31 g, 0.85 mmol) was dissolved in CH ₂ Cl ₂ (20 mL) and treated with iodotrimethylsilane (2.1 mL, 15 mmol) in a Petri dish-stoppered flask. The reaction was stirred for 2 h. and stopped with saturated NaHCO ₃ . The mixture was extracted with ether and the organic layers were washed with brine and saturated sodium bisulfite, dried (MgSO ₄ ) and concentrated to give the title compound. The product was purified by RC (ethyl acetate / hexanes) and recrystallized from hexane to give 68 mg (5%) of the title compound as a white solid, mp 141-143 ° C.

Example 227

2-Chloro-N-ethyl-3- (hydroxymethyl) -6- (trimethylsilyl) benzamide.

To a solution of sodium borohydride (50 mg, 1.2 mmol) in ethanol (20 mL) was added Example 222 (0.62 g, 2.2 mmol). The mixture was stirred for 45 min, diluted with water and treated with potassium dihydrogen phosphate. The mixture was extracted with ethyl acetate, and the organic layers were washed with brine, dried (MgSO ₄ ), and concentrated to give the title compound. The product was purified by recrystallization from ethyl acetate / hexanes to give white crystals (0.51 g, 82%), mp 244-245 ° C.

Example 228

2-Chloro-N-ethyl-3- (fluoromethyl) -6- (trimethylsilyl) benzamide.

A solution of the compound of Example 227 (0.29 g, 1.0 mmol) in CH ₂ Cl ₂ (20 mL) was treated with DAST (0.26 mL, 2.0 mmol) and stirred for 1 h. The reaction was poured into water, extracted with ether, and the organic layers washed with brine,

106 were dried (MgSO ₄ ) and concentrated to give the title compound. The product is purified by RC (ethyl acetate / hexanes) and recrystallized from hexanes to give 0.20 g of the title compound (71%) as white crystals, mp 104-105 ° C.

Example 229

2-Chloro-3-cyano-N-ethyl-6- (trimethylsilyl) benzamide.

A solution of Example 223 (0.28 g, 1.0 mmol) and hydroxylamine hydrochloride (0.12 g, 1.7 mmol) in pyridine (10 mL) was stirred for 2 h. RT. Acetic anhydride (0.75 mL, 8.0 mmol) was added and the solution heated for 1.5 h. At 100 ° C. The mixture was concentrated, water was added and the mixture was extracted with ether. The organic layers were washed with 0.5 N HCl, saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated to give the title compound. The product was purified by recrystallization from ethyl acetate / hexanes to give 0.21 g of white needles (74%), mp 111-112 ° C.

Example 230

2-Chloro-N-ethyl-3-methyl-6- (trimethylsilyl) benzamide.

To a solution of the compound of Example 201 and TMEDA (1 eq) in THF / ether (1: 1) at -100 ° C was added a solution of 1.3 M s-BuLi in cyclohexane in hexanes (2.0-2.2 eq) without increasing the temperature. above -95 ° C. Stir for 30 min. At -100 ° C, Mel (2.2 eq) was added and the reaction was allowed to warm to -30 ° C. The reaction was completed in the usual manner. The product is hydrolyzed to N-ethylbenzamide by dissolving in dioxane (7.5 mL / mmol) and adding almost. HCl (2.5 mL / mmol). The mixture was stirred at RT for 1.5 h. and a salt solution is added. Mixture

Extract with ether, wash the organic extracts with saturated NaHCO ₃ , brine, dry (MgSO ₄ ), and concentrate. The product was purified by recrystallization from hexanes followed by recrystallization from aqueous methanol (2 times) to give 0.18 g of the title compound as white needles, m.p. 120-122 ° C.

Example 231

2-Chloro-N-ethyl-3- (methylthio) -6- (trimethylsilyl) benzamide.

Conversion of methyl methanediol sulfonate (2.2 eq) to methyl iodide followed the procedure of Example 230 to give the title compound. The product is purified by recrystallization from ethyl acetate / hexanes to give 1.12 g of the title compound as white needles, yield 74%, m.p. 137-139 ° C.

Example 232

3- Bromo-6-chloro-N-ethyl-2- (trimethylsilyl) benzamide.

2-Chloro-5-bromobenzoic acid (20 g, 0.08 mol) in CH ₂ Cl ₂ (50 mL) was treated with oxalyl chloride (30 mL, 0.34 mol) and DMF (catalytic) for 2 h. RT. The reaction mixture was concentrated in vacuo to give the acid chloride. The acid chloride is treated with ethylamine as described in Method E2 to give 2-chloro-5-bromo-N-ethylbenzamide.

LDA was prepared by adding 2.5 M n-BuLi (1.7 mL, 0.004 mol) to diisopropylamine (0.6 mL, 0.004 mol) in 10 mL THF at −78 ° C. The mixture is rapidly heated to 0 ° C, then cooled to -78 ° C. A solution of the title compound in THF (5 mL) was added. After 0.5 or. TMSC1 (0.31 mL, 0.0024 mol) was added at -78 ° C. The reaction mixture was heated to -40 ° C, poured into aqueous NaHCO ₃ and

108 was extracted with ether. The ether extract was washed with water and brine, dried (MgSO ₄ ), and concentrated. The product was purified by flash chromatography (0-15% ethyl acetate / hexanes) to give the title compound as a white solid. Yield 32%, m.p. 155-157 ° C.

Example 233

3-Amine-6-chloro-N-ethyl-2- (trimethylsilyl) benzamide.

A mixture of Example 215 (6.85 g, 0.023 mol) and PtO ₂ (catalytic) in ethanol was placed in a Parr Hydrogenator for 16 h. The reaction mixture was filtered through celite and concentrated. The resulting solid was dissolved in CH ₂ Cl ₂ and filtered through silica gel three times. The filtrate was concentrated to give the title compound as a yellow solid in 13% yield, mp 147-149 ° C.

Example 234

2,4-Dichloro-N-ethyl-6- (trimethylsilyl) benzamide.

2,4-Dichloro-N-ethyl-benzamide (5.8 g, 0.027 mol) was prepared in 92% yield from 2,4-dichlorobenzoyl chloride (4 mL, 0.03 mol) and ethylamine (70 wt% H ₂ O). ) using the E2 method.

1.5 M LDA was added to a solution of said amide (2 g, 0.01 mol) and TMSCl (1.5 ml, 0.011 mol) in THF, cooled to

-100 C under nitrogen atmosphere was poured into water extracted and

After 30 minutes reaction mixture was diluted with aqueous NaHCO ₃ solution and ether. The ether extract is washed with brine, dried and concentrated. The product was filtered through (MgSO ₄ ) and silica gel with gradient elution with ethyl acetate / hexanes and

109 concentrated to give the title compound as a white solid, yield 19%, m.p. 101-103 ° C.

Example 235

2-Chloro-4- (1,1-dimethylethyl) -N-ethyl-6- (trimethylsilyl) benzamide.

4-t-Butyl-N-ethylbenzamide (9 g, 0.044 mol) was prepared in 97% yield from 4-t-butylbenzoyl chloride (9 mL, 0.045 mol) and ethylamine (70% w / w in water) using Method E2.

1.3M s-BuLi in cyclohexane (41 mL, 0.053 mol) was added dropwise to 1 above amide (5 g, 0.024 mol) and TMEDA (4 ml, 0, _f 027 mol) in THF: cooled to -78 ° C in a nitrogen atmosphere. After 30 minutes hexachloroethane solution (6.4 g, 0.027 mol) in THF was added. After 0.5 h at -78 ° C, the reaction mixture was warmed to -30 ° C and poured into dilute aqueous NaHCO ₃ and extracted with ether. The ether extract was washed with water and brine, dried (MgSO ₄ ), and concentrated. The resulting solid was recrystallized from cyclohexane to give 5 g of 2-chloro-4-t-butyl-N-ethylbenzamide as a white solid.

To a solution of the previous compound (2.5 g, 0.01 mol) and TMEDA (1.66 mL, 0.011 mol) in THF cooled to -78 ° C under nitrogen was added dropwise to 1.3 M s-BuLi in cyclohexane (17 mL, 0.022 mol). After 0.5 or. TMSC1 (1.6 mL, 0.0125 mol) was added. The reaction mixture was stirred for 45 min at -78 ° C, then thawed to -30 ° C and poured into dilute aqueous NaHCO ₃ solution and extracted with ether. The ether extract was washed with water and brine, dried (MgSO ₄ ), and concentrated. The product was purified by flash chromatography (0-10% ethyl acetate / hexanes) to give the title compound

110 as a white solid (0.78 g), yield 25%, m.p. 124-125 ° C.

Example 236

6-Bromo-N-ethyl-3-methoxy-2- (trimethylsilyl) benzamide.

2-Bromo-5-methoxybenzoic acid is converted to the acid chloride according to example b and then to the ethyl amide using the EI method.

A solution of ethyl amide (1 g, 0.004 mol) and TMSC1 (0.63 mL, 0.005 mol) in THF (15 mL) was cooled to -100 ° C under a nitrogen atmosphere and 2M LDA (4.5 mL, 0.009 mol) was added. After 0.5 or. after stirring at -78 ° C, the reaction mixture was poured into aqueous NaHCO ₃ and extracted with ether. The ether extract was washed with water and brine, dried (MgSO ₄ ), and concentrated. The product was triturated with ether and the resulting solid was recrystallized from aqueous ethanol to give the title compound as a white solid (100 mg), 8%, 200 ° C.

Example 237

6-Chloro-3- (dimethylamino) -N-ethyl-2- (trimethylsilyl) benzamide.

2-Chloro-5-nitro-N-ethylbenzamide was prepared from the corresponding acid using the method of Example 232. A solution of this compound (25 g, 0.11 mol) in ethyl acetate (250 mL), water (75 mL) and glacial acetic acid (325 mL) was heated, followed by the addition of iron powder (25 g, 0.44 mol). The reaction was exothermic and the gas evolution was strong for 1 h, although the ice bath was frozen. When gas evolution stopped, the reaction mixture was poured into water and CH ₂ Cl ₂ and filtered to remove the remaining

111 iron. The filtrate was extracted with CH ₂ Cl ₂ several times. The organic layers were combined and washed with water and brine, dried (MgSO ₄ ) and concentrated to give 2-chloro-5-amino-N-ethylbenzamide as an oil (12.5 g, 57% yield).

A mixture of said amine (3 g, 0.015 mol), potassium carbonate (3.8 g, 0.028 mol) and Mel (1.4 ml, 0.022 mol) in DMF was stirred at RT overnight. The reaction mixture was poured into water and extracted with ether. The ether layer was washed with water and brine, dried (MgSO ₄ ) and concentrated to give an oil. Purification by flash chromatography (0-50% ethyl acetate / hexanes) afforded N-ethyl 2-chloro-5- (dimethylamino) benzamide, a yellow solid, 29% yield.

The title compound is stirred

A -78 C solution (0.65 g, 0.003 mol) in THF under nitrogen.

Added 1.7 M t-BuLi in pentane. After 0.5 or. TMSC1 solution in THF was added at a storage temperature of 78 ° C. After 1 or. At -78 ° C, the reaction mixture was poured into aqueous NaHCO ₃ and extracted with ether. The ether extract was washed with water and brine, dried (MgSO ₄ ), and concentrated. The product was triturated with hexanes / CH ₂ Cl ₂ / ethyl acetate and filtered to give the title compound as a white solid (0.100 g), 11% yield, mp 179180 ° C.

Example 238

2-Chloro-N-ethyl-3- (methylsulfonyl) -6- (trimethylsilyl) benzamide.

M-Chloroperbenzoic acid was added to a solution of Example 231 (0.30 g, 1.0 mmol) in CH ₂ Cl ₂ (20 mL) RT

112 (0.59 g, 3.4 mmol). Stir for 7 h, wash with saturated NaHCO ₃ , brine, dry (MgSO ₄ ) and concentrate to give the title compound. The product was purified by recrystallization from ethyl acetate / hexanes to give the title compound as white needles (0.26 g, 79%), mp 139-140 ° C.

Example 239

2-Chloro-N-ethyl-3-iodo-6- (trimethylsilyl) benzamide.

To obtain the title compound, the method of Example 230 was applied by substituting 1,2-diiodoethane (2.3 eq) for Mel. The product was purified by flash chromatography (ethyl acetate / hexanes) and recrystallized from aqueous methanol to give 2.72 g of the title compound as white crystals, 71% yield, m.p. 128-130 ° C.

Example 240

5- (Benzoylamino) -N-ethyl-2- (trimethylsilyl) benzamide.

To a solution of Example 217 (0.118 g, 0.5 mmol) in CH ₂ Cl ₂ (10 mL) was added triethylamine (0.14 mL, 1.0 mmol), banoyl chloride (70 mL, 0.6 mol), and 4-dimethylaminopyridine. (12 mg). The reaction was stirred at RT for 16 h, diluted with water and extracted with ethyl acetate. The extracts were washed with 0.04 N HCl, saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated to give the title compound. The product was purified by recrystallization from ethyl acetate / hexanes to give the title compound as fluffy white crystals (0.129 g, 76%), mp 185-187 ° C.

113

Example 241

2-Chloro-N-ethyl-3- (2- (E) -nitro-ethenyl) -6- (trimethylsilyl) benzamide.

To a solution of the compound of Example 223 (0.199 g, 0.7 mmol) in methanol (5 mL) at 0 ° C was added nitromethane (0.3 mL, 5.0 mol) and 2.5 N NaOH (2.3 mL, 5 mL). 8 mol) in portions over 2 hours. The suspension was dissolved by addition of ice-water and cold 2N HCl (10 mL) was added. The precipitate was filtered and washed with water to give the title compound. The product was purified by recrystallization from aqueous methanol to give the title compound as a light yellow fluffy crystalline solid (60 mg, 26%), m.p. 104-106 ° C.

Example 242

2-Chloro-N-ethyl-3-phenyl-6- (trimethylsilyl) benzamide.

To a solution of the compound of Example 239 (0.191 g, 0.5 mmol) and palladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) in toluene (10 mL) was added 2 M sodium carbonate (0.5 mL) and phenylboronic acid (73 mg, 0 mL). , 6 mmol). The mixture was heated at 90 ° C for 30 h, additional portions of the catalyst (20 mg) and 2 M sodium carbonate (0.5 mL) were added and heating was continued for 24 h. The cold reaction mixture was diluted with CH ₂ Cl ₂ and washed with 2 M sodium carbonate (50 mL with 5 mL almost NH ₄ OH). The organic layer was dried (MgSO ₄ ) and concentrated. The product was purified by RC (ethyl acetate / hexanes) and recrystallized from hexanes to give the title compound as white needles (98 mg, 59%), mp 134-135 ° C.

114

Example 243

3-Acetyl-2-chloro-N-ethyl-6- (trimethylsilyl) benzamide.

To a solution of the compound of Example 223 (0.284 g, 1.0 mmol) in THF (20 mL) at -78 ° C was added a solution of 1.4 M in methyl ether (3.2 mL, 4.4 mmol) in portions over 1 h. The reaction mixture was stirred for an additional hour at -78 ° C and quenched with saturated citric acid solution. The mixture was extracted with ethyl acetate, and the organic layers were washed with brine, dried (MgSO ₄ ), and concentrated to give a secondary alcohol as an oil.

A solution of the crude alcohol in ethyl acetate was added to a suspension of pyridine chlorochromate (0.54 g, 2.5 mmol) in CH ₂ Cl ₂ (50 mL). The suspension was stirred for 3 days, ether (100 mL) was added and the suspension filtered through silica gel solvent and concentrated to give the title compound as an oil. The product was purified by RC (ethyl acetate / hexanes) then recrystallized from ether / hexanes to give the title compound as white needles (0.126 g, 42%), mp 78-80 ° C.

Example 244

2-Chloro-3 - [(ethylamino) carbonyl] -4- (trimethylsilyl) benzoic acid methyl ester.

To a solution of silver nitrate (0.71 g, 4.2 mmol) in water (20 mL) was added 2.5 N NaOH (3.4 mL, 8.2 mmol) to give a brown suspension. A solution of the aldehyde of Example 223 (0.56 g, 2.0 mmol) in THF (25 mL) was added and the mixture was stirred at RT for 2 h. The mixture was filtered through Celite, diluted with water and washed with CH ₂ Cl ₂ . The aqueous solution was acidified with 2 N HCl and extracted with CH ₂ Cl ₂ . Organic layers are washed with brine,

115 were dried (MgSO ₄ ) and concentrated to give the carboxylic acid as a white solid (0.57 g, 95%).

The carboxylic acid is converted to the acid chloride according to the procedure of Example b.

To a solution of the acid chloride (0.48 mmol) in toluene (10 mL) was added triethylamine (0.139 mL, 1.0 mmol) in methanol (0.08 mL, dilute)

2.0 mmol). NaHCO ₃ and layers (MgSO ₄ ) and

The reaction was stirred at RT 16 or extracted with ethyl acetate, washed with brine, concentrated to give the title compound. The product was purified by recrystallization from ether / hexanes at -78 ° C to give the title compound as a white solid (0.104 g, 69%), m.p. 103-104 ° C.

Example 245

N-Ethyl-5-isothiocyanato-2- (trimethylsilyl) benzamide.

To a solution of Example 217 (0.354 g, 1.5 mmol) in CH ₂ Cl ₂ (25 mL) was added 1,1'-thiocarbonyl-2 (1H) pyridone (0.35 g, 1.5 mmol). The solution was stirred for 40 min. RT, diluted with CH ₂ Cl ₂ and washed with water, brine, dried (MgSO ₄ ) and concentrated to give the title compound. The product was purified by flash chromatography (CH ₂ Cl ₂ ) followed by recrystallization from hexanes to give the title compound as white needles (0.336 g, 81%), mp 106.5-108 ° C.

Example 246

N-Ethyl-3-nitro-2- (trimethylsilyl) benzamide.

116

The title compound was obtained as a by-product from Preparation 214 using RC (ethyl acetate / hexanes). The product was recrystallized from ether / hexanes and dried at 65 ° C for 0.05 mm to give the title compound as white needles (0.656 g, 25%), m.p. 84-86 ° C.

Example 247

N-Ethyl-2- (1,1-dimethylethoxy) benzamide.

2-Iodobenzoic acid (65.92 g, 0.266 mol), oxalyl chloride (40.5 g, 0.319 mol), CH ₂ Cl ₂ (200 mL) and DMF (10 drops) were stirred overnight at room temperature. The reaction solution was concentrated, toluene was added and the solution was further concentrated to give 2-iodobenzoyl chloride.

The acid chloride was treated with 70% ethylamine using the EI basic method to give N-ethyl-2-iodobenzamide as a tan solid (70.80 g, 97%).

Potassium t-butoxide (12.25 g, 0.109 mol) was dissolved in pyridine (50 ml) and copper (I) chloride (10.81 g, 0.109 mol) was added. The black suspension was stirred for 30 min. RT, and N-ethyl-2-iodobenzamide (10.00 g, 36.4 mmol) dissolved in pyridine (20 mL) was added. The mixture is stirred for 1 hour. at room temperature, poured into aqueous ammonium hydroxide and extracted with ether. The organic extracts were washed with 1 N NaOH, brine, dried (MgSO ₄ ) and concentrated to give a brown semi-solid. The product was purified by flash chromatography (ethyl acetate / hexanes) to give the title compound as a light yellow solid (2.36 g, 29%), mp 34.5-36 ° C.

117

Examples 248 and 249

Example 248: N-Ethyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

Example 249: N-Ethyl-3,5-bis (trimethylsilyl) -2-thiophenecarboxamide.

(a) A mixture of 20 g of 2-thiophenecarboxylic acid and 30 ml of thionyl chloride was heated under reflux for 2.5 hours, then cooled and concentrated in vacuo to give 21 g of 2-thiophenecarboxylic acid chloride, an amber oil.

(b) A solution of 2-thiophenecarboxylic acid chloride (7.3 g, 50 ml) in 30 ml CH ₂ Cl _{2 was} added to 70% ethylamine in water (11 g) at -5 ° C and the resulting solution was stirred for 18 hours. RT. Water was then added. The organic layer was separated, washed with water, brine, dried and concentrated. The residue is purified by flash chromatography eluting with 25% ethyl acetate / hexane; 6.4 g (83.1% yield) of N-ethyl-2-thiophenecarboxamide are obtained in the form of a white solid, m.p. 75-78 ° C.

(c) A 2.5 M solution of n-BuLi in hexane (18 mL) was added dropwise to a solution of N-ethyl-2-thiophenecarboxamide (3.1 g, 20 mmol) in 50 mL of THF at -65 ° C under a positive nitrogen atmosphere, and the resulting solution was stirred for 45 min. At -70 ° C. . Then TMSC1 (9 mL) was added slowly at below -60 ° C and stirring was continued at below -60 ° C for 15 min. The solution was allowed to warm to 0 ° C, then poured into water and extracted with CH ₂ Cl ₂ . The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue eluting with 5% ethyl acetate-hexane gave 3.1 g

118

Example 248 in the form of a white solid, m.p. 81-84 ° C, and 1.1 g in the form of a colorless oil, Example 249, n _D ²⁴ 1.5228.

Example 250

N, N-Diethyl-2,4-bis (trimethylsilyl) -3-furancarboxamide.

a) To a solution of diisopropylamine (10 g, 0.1 mol) in 90 mL of THF under a positive nitrogen atmosphere at -20 ° C was added 2.5M n-BuLi in hexane (40 mL, 0.1 mol) to give a solution of 0.5 mL. or. stirred below -20 ° C, then cooled to -70 ° C and poured

A solution of 3-furancarboxylic acid (5.1 g, 46 mmol) in 50 mL of THF while maintaining the temperature below -70 ° C. Stirring at -70 ° C is continued for another 1 hour. after the addition is complete. 20 ml of TMSCI are then added dropwise at -70 ° C and the reaction mixture is stirred

O, 5 or. At -70 ° C, it was allowed to warm to RT and poured into a mixture of CH ₂ Cl ₂ , ice water and 2N HCl. The aqueous layer was separated and extracted with CH ₂ Cl ₂ . The organic layers are combined and washed with brine, dried and concentrated; a mixture of 2- (trimethylsilyl) -3-furancarboxylic acid and 2,4-bis- (trimethylsilyl) -3-furancarboxylic acid is obtained.

b) A mixture of 3-furancarboxylic acid chlorides prepared from the mixture of the acids of step a) (1.4 g), 6 ml of thionyl chloride and catalytic amount of DMF according to the procedure of Example 248a, treated with 4 g of diethylamine as in Example 248b. Purify by flash chromatography using 10% ethyl acetate / hexane to give 0.1 g of the title compound as a green oil, Πρ ²⁵ 1.4812.

119

Examples 251 and 252

For example, 251: N-Ethyl-3,5-bis (trimethylsilyl) -2-furancarboxamide.

For example, 252:

N-Ethyl-3- (trimethylsilyl) -2-furancarboxamide.

Using the procedure of Examples 248 and 249, 2-furancarboxylic acid is converted to 2.7 g of Example 251 (white solid, m.p. 99-102 ° C) and 1 g of Example 252 (white solid, m.p. 69-72 ° C).

Example 253

N-Ethyl-1 - [(trimethylsilyl) methyl] -1H-pyrrole-2-carboxamide.

A mixture of l-methyl-2-pyrrolecarboxylic acid (10 g, 80 mmol) in 25 mL of oxalyl chloride containing 6 drops of DMF was refluxed for 1 h, then cooled to RT and the excess oxalyl chloride removed in vacuo. The acid chloride was dissolved in CH ₂ Cl ₂ and added slowly to 40 mL of 70% aqueous ethylamine at -15 to -10 ° C. The reaction solution was stirred at RT for 1 h, then poured into water and extracted with CH ₂ Cl ₂ . The organic solution is washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with 25% ethyl acetate / hexane to give 9.5 g of the desired product as a light yellow solid.

To ethyl amide (1.5 g, 10 mmol) in 16 mL of THF under a positive nitrogen atmosphere was added 12 mL of 2.5 M n-BuLi in hexane at about 30 ° C and the resulting solution was stirred

120 at ambient temperature for 1 hour. Then 6 ml of TMSC1 was slowly added at 0 ° C and stirring was continued at ambient temperature for 1 hour. The solution was then poured into ice water and extracted with CH ₂ Cl ₂ . The organic solution was washed with water, brine, dried and concentrated in vacuo. Flash chromatography of the residue with 10% ethyl acetate / hexane gave 0.6 g of the desired product, orange oil, nu ²⁵ 1, 5185.

Example 254

5-Chloro-N-ethyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

The title compound was prepared from 5-chloro-2-thiophenecarboxylic acid using the procedures of Example 248; 1.5 g of white solid were obtained, l.t. 105-108 ° C.

Example 255

N, N-Diethyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

To a solution of the compound of Example 248 (1.1 g, 5 mmol) was added dropwise 2.4 mL of 2.5 M n-BuLi in hexane at -40 ° C in 10 mL of THF. Stirring is continued in the mix. at temperatures between -30 and -20 ° C. Then g of ethyl iodide was added. The resulting reaction solution was allowed to warm to RT with stirring at RT for 18 h. and then poured into water and CH ₂ Cl ₂ . The organic layer was separated, washed with brine, dried and concentrated in vacuo. The residue was purified on a silica gel column, eluting with 10% ethyl acetate / hexane to give 1 g of the title compound as a colorless oil, Πβ ²⁵ 1.5218.

Example 256

N-Ethyl-5-methyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

121

The title compound was prepared from 5-methyl-2-thiophenecarboxylic acid using the procedures of Example 248; yielded 3, 6 g of a white solid, l.t. 1125-1158 ° C.

Example 257

N-Ethyl-5-iodo-3- (trimethylsilyl) -2-thiophenecarboxamide.

Example 248 is treated with iodine using the method of Example 248, step c to give 0.5 g of the title compound as a white solid, m.p. 85-88 ° C.

Example 258

N-Ethyl-formyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

(a) To diisopropylamine (12.6 g, 0.125 mol) was slowly added 248 and 100 ml of THF in 2.5 M n-BuLi in hexane (52 ml, 0.13 mol) and stirring.

At -40 ° C and stir for 0.5 h. in the rat. The solution was cooled to -60 ° C, a solution of the sample (12.1 g) in 60 mL of THF was continued at -50 to 60 ° C for 1 h. The reaction mixture was then poured into ether-dry ice and extracted with water. The aqueous layer is almost acidified. HCl and extracted with CH ₂ Cl ₂ . The organic layer was washed with brine, dried and concentrated in vacuo to give 5 - [(ethylamino) carbonyl] -4- (trimethylsilyl) -2-thiophenecarboxylic acid.

b) To a solution of the acid in step a (3.6 g, 12 mmol) in 30 mL of THF was added 30 mL of 1 M diborane in THF at 0 ° C. After the addition was complete, the resulting reaction mixture was stirred at RT for 1 h, then carefully poured into ice water and extracted with CH ₂ Cl ₂ . The organic solution was washed with brine, dried and concentrated in vacuo. The product is cleaned with pulsed chromeLT 3276 B

122 to 30% ethyl acetate-hexane as eluent to give 2.5 g of N-ethyl-5- (hydroxymethyl) -3 (trimethylsilyl) -2-thiophenecarboxamide.

c) To this compound (b) (1.3 g, 5 mmol) in 40 mL of CH ₂ Cl ₂ containing 1.8 g of celite was added 2.4 g of pyridine chlorochromate and the resulting reaction mixture was stirred at RT for 2 h. The CH ₂ Cl ₂ solution is filtered through celite, washed with water, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10% ethyl acetate-hexane to give 1.1 g of the desired product as a light yellow solid, m.p. 62-65 ° C.

Example 259

N-Ethyl-4- (trimethylsilyl) -5-isothiazolecarboxamide.

a) 5-Isothiazole carboxylic acid is prepared from isothiazole, n-BuLi and dry ice according to the procedure of Example 258, step a.

b) This compound was converted to the title compound by treatment with 70% aqueous ethylamine followed by TMSC1 using the method of Example 248; 0.3 g of the title compound is obtained in the form of a yellow oil, 1.5275.

Example 260

N-Ethyl-5- (methylsulfinyl) -3- (trimethylsilyl) -2-thiophenecarboxamide.

To a solution of 3.4 g of a 50:50 mixture of the compound of Example 248 and

Sodium periodate (1 g) in 5- (methylthio) -3- (trimethylsilyl) -2-thiophenecarboxamide (obtained from the reaction of Example 248 with methyl methanthiosulfonate using Example 248 (c)) was added in 30 mL of methanol.

123 mmol) and the resulting mixture was stirred at RT for 18 h. The solvent was then removed in vacuo and the residue chromatographed on a silica gel column eluting with 10%, 30% and then 70% ethyl acetate-hexane to give 1 g of the title compound as a white solid, m.p. 71-76 ° C.

Example 261

N-Ethyl-5- (methylthio) -3- (trimethylsilyl) -2-thiophenecarboxamide.

To a solution of the compound of Example 260 (0.6 g) and NaJ (0.8 g) in 10 ml of acetone is slowly added 0.4 ml of trifluoroacetic anhydride

At 0 ° C, and the mixture is stirred for an additional hour at 0 ° C. Add CH ₂ Cl ₂ and saturated aqueous sodium metabisulfite. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue gave 0.5 g of material, m.p. 58-61 ° C.

with 10% ethyl acetate-hexane afforded the title compound as a white solid

Example 262

5-Chloro-N- (2-propenyl) -3- (trimethylsilyl) -2-thiophenecarboxamide.

The title compound was prepared from 5-chloro-2-thiophenecarboxylic acid and allylamine, followed by reaction with TMSC1 in the same manner as in Example 248 to give 0.7 g of the title compound, a white solid, m.p. Mp 63-66 ° C.

Example 263

5-Chloro-N- (2-hydroxyethyl) -3-trimethylsilyl-2-thiophenecarboxamide.

124

According to Example 248, step c, a solution of 5-chloro-2-thiophenecarboxylic acid (3.3 g, 20 mmol) in THF is treated with 20 mL of 2.5 M n-BuLi in hexane and then quenched with 8 mL of TMSC1 to give 5-chloro-3 - (trimethylsilyl) -2-thiophenecarboxylic acid.

This acid and the catalytic amount of DMF in 10 ml of thionyl chloride were refluxed for 2 hours, then cooled to RT and the excess thionyl chloride removed in vacuo. The acid chloride is treated with 2aminethanol according to Example 248, step b, to give 0.9 g of the title compound as a white solid,

i.e. 110-114 ° C.

Example 264

5-Chloro-N- (2-chloroethyl) -3- (trimethyl) -2-thiophenecaboxamide.

A solution of compound 263 (0.4 g) and 1 mL of thionyl chloride was refluxed in 6 mL of CH ₂ Cl ₂ for 1 h, then cooled and poured into ice water. Addition of CH ₂ C1 ₂ . The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue, eluting with 5% ethyl acetate-hexane, afforded 0.4 g of the desired product as a white solid, m.p. 68-72 ° C.

Example 265

5-Chloro-N- [2 [(methylsulfonyl) oxyethyl] -3 (trimethylsilyl) -2-thiophenecarboxamide.

The compound of Example 263 (0.4 g), and 0.5 ml of triethylamine in 10 ml of CH ₂ C1 ₂ at 0 ° C is added methanesulfonyl chloride (0.2 mL) and the resulting reaction

The solution is stirred at RT for 2 hours. Water was added and the two layers were separated. The organic solution is washed with brine, dried and concentrated. Purification by flash chromatography with 30% ethyl acetate-hexane gave 0.4 g of product as a white solid, m.p. 8286 ° C.

Example 266

5-Bromo-N-ethyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

The title compound is prepared from the compound of Example 248 and bromine according to Step 248 of Example 248. Purification by flash chromatography with 5% ethyl acetate-hexane afforded 0.6 g of product as a white solid, m.p. 96-98 ° C.

Example 267

4-Bromo-N-ethyl-2- (trimethylsilyl) -3-thiophenecarboxamide.

(a) To a solution of 3,4-dibromothiophene (15 g, 62 mmol) in ether (80 ml) was added 75 ml of 1.7 M t-BuLi pentane at -73 ° C under a positive nitrogen atmosphere and the resulting reaction solution was stirred for 0.5 h. . At -78 ° C. The ether solution was then poured into dry ice and extracted with water. The aqueous solution was washed with ether and then acidified with concentrated HCl. The solid was air-dried to give filtered and 9 g of 4-bromo-3-thiophenecarboxylic acid in 70.3% yield.

b) N-Ethyl-4-bromo-3-thiophenecarboxamide was prepared from 4bromo-3-thiophenecarboxylic acid (7 g, 34 mmol) and 70% ethylamine in water according to Example 248, steps a and b, yield 64.5%.

126

A solution of this compound (1.9 g, 8.1 mmol) in THF was treated with LDA (prepared from diisopropylamine and 2.5 M n-BuLi in hexane using the method of Example 250) and TMSCl according to the method of Example 248, step c to afford 1.1. g of the title compound, white solid, 44.5% yield 93-96 ° C.

Example 268

5-Bromo-N-ethyl-2- (trimethylsilyl) -3-thiophenecarboxamide.

(a) To a solution of 3-thiophenecarboxylic acid (7.7 g, 60 mmol) in 70 ml of acetic acid was added a solution of 9.6 g of bromine in 50 ml of acetic acid RT and stirring was continued.

RT 0.5 or. The reaction mixture was then poured into 600 mL of ice water. The precipitate was filtered off, washed with water and air dried to give 7.9 g of 5bromo-3-thiophenecarboxylic acid.

b) 5-Bromo-N-ethyl-thiophenecarboxamide was prepared from 5-bromo-3-thiophenecarboxylic acid (2.1 g, 10 mmol) and 70% ethylamine in water according to Example 248, steps a and b, in 70% yield.

c) The compound of Step b (1.3 g, 5.6 mmol) is treated with LDA (prepared from diisopropylamine and 2.5 M n-BuLi in hexane using the method of Example 250) and TMSCl according to the method of Example 248, step c to afford 70, 6 g of the title compound as a white solid, en 9698 ° C.

270 Example

N-Ethyl-2- (trimethylsilyl) -4,5,6,7-tetrahydrobenzo [B] thiophene-3-carboxamide.

127

(a) To a mixture of cyclohexanone (20 g, 0.2 mol), ethyl cyanoacetate (22.6 g, 0.2 mol) and sulfur (6.8 g, 0.22 mol) is added rapidly 70 ml of absolute ethanol to 20 ml of diethylamine. . The reaction mixture was cooled in a water bath to maintain a temperature below 60 ° C and then stirred for 2 hours. maintaining a temperature between 30 and 46 ° C. Water was then added. The precipitate was filtered, air dried and recrystallized from ethanol to give 31 g of ethyl 2-amino-4,5,6,7-tetrahydrobenzo [B] -3-carboxylate.

b) Copper (II) bromide (14 g) and 90% t-butyl nitrite (10 mL) were treated with 40 g of acetonitrile at 50 ° C in portions of 11 g of step a amine so that the temperature did not exceed 65 ° C. After the addition was complete, the resulting reaction mixture was stirred for an additional 0.5 h, then partitioned between water and ethyl acetate. The ethyl acetate solution is then washed with water, brine, dried and concentrated. The product is chromatographed using 2% ethyl acetate / hexane to give 6.5 g of a 3: 1 mixture of ethyl 2-bromo-4,5,6,7-tetrahydrobenzo [B] thiophene-3-carboxylate and ethyl 4,5,6,7-tetrahydrobenz - [B] thiophene-3-carboxylate.

A solution of a mixture of ethyl esters (5 g) and potassium hydroxide (3 g) was refluxed in 20 ml of ethanol for 2 hours, cooled, and the solvent removed in vacuo. Water was added to the solid residue and the aqueous solution was almost acidified. HCl. The solid was filtered, washed with water, and air-dried to give 3.8 g of the acid mixture.

A mixture of the two acids (3.3 g) and a catalytic amount of DMF in 10 ml of thionyl chloride was refluxed for 2 hours, then cooled and concentrated in vacuo. This mixture of acid chlorides was dissolved in 20 ml of CH ₂ Cl ₂ and added to 20 ml of 70% ethylamine in water,

128 at below -20 ° C and stir for 18 hours. RT. The organic layer was separated, washed with water, brine, dried and concentrated. Flash chromatography of the product with 15% ethyl acetate-hexane afforded 3.2 g of 2-bromo-N-ethyl-4,5,6,7-tetrahydrobenzo [B] thiophene-3-carboxamide;

0.4 g of N-ethyl-4,5,6,7-tetrahydrobenzo [B] thiophene-3-carboxamide.

c) The 2-bromo compound is treated with TMSC1 according to the procedure of Example 248, step c. Purification by column chromatography, eluting with 12% ethyl acetate-hexane, afforded 1.1 g of the title compound as a white solid, m.p. 107112 ° C.

Example 271

4,5-Dimethyl-N-ethyl-2- (trimethylsilyl) -3-thiophenecarboxamide.

Using procedures for the synthesis of the compound of Example 270 and methyl ethyl ketone as starting material, the title compound was obtained as a solid, m.p. 9094 ° C.

Example 272

N-Ethyl-N- (methylthio) -3- (trimethylsilyl) -2-thiophenecarboxamide.

To a solution of the compound of Example 248 (1.6 g, 6.5 mmol) in 20 mL of THF under a positive nitrogen atmosphere was added 3 mL of 2.5 M n-BuLi in hexane at below -70 ° C and the resulting solution was stirred for 1 h. At -78 ° C. Methyl methantiosulfonate solution (0.9 g,

7.1 mmol) THF at below -70 ° C and stirring is continued for an additional 1 h. At -78 ° C.

129

The solution was then heated to 0 ° C and poured into water. Water added CH ₂ C1 ₂ layer was separated and extracted with CH ₂ C1 _2nd The combined organic layers were washed with brine, dried (MgSO ₄ ), and concentrated. Purification of the product on a silica gel column eluting with 10% ethyl acetate-hexane afforded 1.2 g of the title compound as a colorless oil, n _D 1.5519.

Example 273

5-Chloro-N- (methylthio) -N-2-propenyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

Example 262 (1.1 g) is treated with 0.52 g of methyl methantiosulfonate using the procedure described for Example 272. The title compound (0.6 g) was purified by flash chromatography with 2% ethyl acetate-hexane to give the title compound as a colorless oil, n _D ² 1.5698.

Example 274

N-Ethyl-3- (trimethylsilyl) -4,5,6,6,7-tetrahydrobenzo [B] thiophene-2-carboxamide.

To 9.4 ml of DMF was added 30 ml of 1,2-dichloroethane to 9.3 ml of phosphorus oxychloride at a temperature below 10 ° C. The mixture was allowed to warm to RT and 10.3 mL of cyclohexanone was added to 10 mL of 1,2-dichloroethane. After the addition, the mixture is heated for 3 hours. At 60-65 ° C, then cooled to RT and add a solution of 30 g of sodium acetate in 60 ml of water at a temperature below 20 ° C. The organic layer was separated, washed with water, brine and dried.

To the aldehyde in 1,2-dichloroethane was added 1 part of 9 ml of methyl thioacetate followed by the addition of 20 ml of triethylamine.

130

Exotherm was maintained and the mixture was stirred for 18 h. at ambient temperature. The organic layer was then washed with 3N HCl, water, brine, dried and concentrated.

To this oil was added 20% sodium methoxide in methanol and 60 ml methanol and the resulting solution was refluxed for 2 hours. with reflux. The solution was cooled and the solvent removed in vacuo. Water and CH ₂ C1 _{2 were added} . The organic layer was separated, washed with brine, dried and concentrated to give 12.6 g of methyl 4,5,6,7-tetrahydrobenzo [B] thiophene-2-carboxylate as an oil.

A mixture of 2.2 g of this methyl ester and 20 ml of 70% ethylamine in water was stirred for 72 hours. RT. Thereafter, Water and CH ₂ Cl _{2 were added} . The organic layer was separated, washed with brine, dried and concentrated to give 2 g of ethylamide, a light yellow solid, mp 133-135 ° C.

The title compound was prepared from this ethylamide (1.1 g, 5 mmol) and TMSCl according to Example 248, step c. Purification by flash chromatography with 10% ethyl acetate / hexane gave 1 g of product as a white solid, m.p. 126-128 ° C.

Example 275

N-Ethyl-5- (methylamino) -2- (trimethylsilyl) benzamide.

To a solution of Example 217 (0.29 g, 1.2 mmol) and benzotriazole (0.143 g, 1.2 mmol) in absolute ethanol (5 mL) was added 37% aqueous formaldehyde (0.090 mL, 1.2 mmol). An aliquot is injected to form a precipitate by freezing and adding a small amount of water. The precipitate is poured back into the reaction mixture,

131 which is stirred at RT overnight and refrigerated for 6 hours. The resulting mixture was filtered and dried under vacuum (P ₂ O ₅ ) to give 5 - [(1H-benzotriazol-1-ylmethyl) amino] -N-ethyl-2- (trimethylsilyl) benzamide as a white solid (0.308 g, 70%). %), mp 207-208 ° C.

A mixture of this compound (0.222 g, 0.6 mmol) and sodium borohydride (45 mg, 1.2 mmol) in THF (10 mL) was refluxed for 30 min. The cold reaction was poured into water, mixed with 2.5 N NaOH and extracted with ether.

The organic layers were washed with brine, dried (MgSO ₄ ), and concentrated. The product was purified by recrystallization from hexanes to give the title compound as a white solid (0.114 g, 76%), mp 101-102 ° C.

Example 276

2-Chloro-N-ethyl-6- (trimethylsilyl) -3 - [(trimethylsilyl) ethynyl] benzamide.

To a suspension of Example 239 (0.763 g, 2.0 mmol), bis (triphenylphosphine) palladium dichloride (28 mg, 0.04 mmol) and copper iodide (15 mg, 0.08 mmol) was added trimethylsilylacetylene in anhydrous triethylamine (10 mL). (0.236 g, 2.4 mmol). The brown suspension is stirred for 3.5 hours. RT, concentrated, suspended in ether and filtered through silica gel (ether). The product was further purified by flash chromatography (ethyl acetate / hexanes) followed by recrystallization from hexanes to give the title compound as white crystals (0.618 g, 88%), m.p. 131-132 ° C.

Example 277

2-Chloro-3-ethenyl-N-ethyl-6- (trimethylsilyl) benzamide.

132

Example 239 (0.382 g, 1.0 mmol), tetrakis (triphenylphosphine) palladium (O) (23 mg, 0.02 mmol) and 2,6di-t-butyl-4-methylphenol (1.5 mg) To a solution of toluene (10 mL) was added vinyl tributyltin (0.349 g, 1.1 mmol). The light yellow solution is refluxed for 24 h, tetrakis (triphenylphosphine) palladium (O) (15 mg) is added and reflux is continued for 24 h. The cold mixture was diluted with ether, filtered through celite, concentrated, and purified by RC (ethyl acetate / hexanes). The product is further purified by recrystallization from pentane to give the title compound as white needles (0.060 g, 21%), m.p. 127-128 ° C.

Example 278 [2-Chloro-6- (trimethylsilyl) benzoyl] ethylphosphoic acid diethyl ester.

To a solution of 5.0 g (29.0 mmol) of diethyl chlorophosphate in 70 ml of dichloroethane was cooled in an ice bath, 4.1 g (63.8 mmol) of ethylamine (70% aqueous solution) were added. The mixture was stirred for 30 min at RT and partitioned between ether and water. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered. The filtrate was evaporated in vacuo and the residue was distilled with kugelrohr (0.8 tor, 90 ° C) to give 2.7 g (52%) of diethyl N-ethyl phosphoramidate as a colorless oil.

To a solution of 0.8 g (4.4 mmol) of this phosphoramidate in 40 mL of anhydrous THF cooled to -70 ° C was added 1.8 mL (4.5 mmol) of n-BuLi (2.5 M in hexane). The mixture was stirred at 70 ° C for 10 min and a solution of 1.0 g (4.05 mmol) of Example b) in 10 mL of anhydrous THF was added. The mixture was allowed to warm to RT and stirred for an additional 45 min. The mixture was then refluxed for 30 min and allowed to cool to RT. Mixture

133 distributed between ether and water. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered through silica gel. The filtrate was evaporated in vacuo and the residue was chromatographed (HPLC eluting with 35% ethyl acetate / hexane) to give 1.0 g (62%) of a colorless oil, n = 1.5060.

Example 279

2-Chloro-N-ethyl-N - [(methylthio) methyl] -6- (trimethylsilyl) benzamide.

Sodium bis (trimethylsilyl) amide (1.0 M in THF) (7.9 mL, 7.9 mmol) was added to a solution of Example 45 (2.0 g, 7.8 mmol) in dry THF (30 mL). To the resulting mixture was added 1.0 g (10.4 mmol) of chloromethyl methyl sulfide. The mixture was stirred for 15 min. and 0.65 g (6.7 mmol) of chloromethyl methyl sulfide was added. Stirring at RT is continued for 1 hour. and the mixture was then refluxed for 28 hours. The mixture was allowed to cool to RT and then partitioned between ether and water. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered through silica gel. The filtrate was evaporated in vacuo and the residue was chromatographed (HPLC eluting with 8% ethyl acetate / hexane) to give 1.1 g (45%) of a colorless oil, n = ⁵ 1.5526.

280 Example

2 - [(1,1-Dimethylethyl) sulfonyl] -N-ethyl-6-fluorobenzamide.

At 0 ° C, a solution of N-ethyl 2-fluoro-6- (1,1-dimethylethylthio) benzamide described in Example 194 (0.15 g, 0.59 mmol) in methanol (5 mL) was combined with 0 ° C. (1.08 g, 1.76 mmol) in water (5 mL). The mixture was stirred overnight, then poured into 25% aqueous

134 mg of sodium metabisulfite (100 mL) and extracted with ether (3 X 100 mL). The combined organic compounds are washed with brine, then with water, then dried (MgSO ₄ ) and concentrated to give the title compound as a clear oil.

Example 281

2-Chloro-6 - [(1,1-dimethylethyl) methylamino] -N, N (diethyl) benzamide.

A solution of N-tert-butyl b-lactam (3.3 g, 18.9 mmol) as described in Example 188 and diethylamine (4.6 g, 62.4 mmol) in CH ₂ Cl ₂ (100 mL) was stirred overnight at RT . The solvent was evaporated, then the residue was triturated with cyclohexane and the filtrate was concentrated to an oil. 500 mg of this material is purified by RC eluting with EtOAc / cyclohexane to give 478 mg of N, N-diethyl-2- (N-tert-butylamine) benzamide as an orange oil in 95% yield.

A mixture of N, N-diethyl-2- (N-tert-butylamino) benzamide (4.2 g, 17 mmol), potassium carbonate (3.1 g, 22 mmol) and Mel (3.1 g, 22 mmol) DMF (75 mL) was heated at 40 ° C overnight. The reaction was incomplete, so additional Mel (3.1 g, 22 mmol) was added and the reaction was heated for 1 day at 40 ° C, then partitioned between EtOAc and water. EtOAc was dried (MgSO ₄ ), concentrated, and purified by HPLC eluting with 1: 4 ethyl acetate / cyclohexane to give 3.22 g of N, N-diethyl-2- (N-methyl-N-tert-butylamino) benzamide as a yellow oil. , yield 72%.

A solution of 1.3 M s-BuLi in cyclohexane (3.5 mL, 4.6 mmol) was added dropwise to dry ice / acetone-cooled TMEDA solution (0.7 mL, 4.8 mmol) in THF (10 mL) followed by addition of N , A solution of N-diethyl-2- (N-methyl-N-tert-butylamino) benzamide (1.0 g, 3.8 mmol) in THF (5 mL). The reaction mixture

135 stirred for 50 min. At -78 ° C, then a solution of hexachloroethane (2.7 g, 11.4 mmol) in THF (5 mL) was added. This mixture was stirred for 30 min. At -78 ° C, then warmed to -30 ° C, diluted with water and the combined organic extracts were concentrated and purified by HPLC eluting with 3:17 EtOAc / cyclohexane to give 577 mg of the title compound as a yellow oil in 51% yield.

EtOAc (2X) dried (MgSO ₄ ) dried,

Example 282

2-Chloro-N-ethyl-5- (trimethylsilyl) -4-thiazolecarboxamide.

(a) 90% Ethyl Bromopyruvate (54.2 g, 0.25 mol) and Thiourea (20 g, 0.263 mol) in 500 ml absolute ethanol was refluxed for 1 hour. and then stirred for 2 hours. at ambient temperature. The ethanol was removed in vacuo and the residue suspended in ice water, neutralized with solid potassium carbonate to the basic product. The solid was filtered, thoroughly washed with water and air dried to give 42 g of ethyl 2-amino-4-thiazolecarboxylate.

b) To a mixture of copper (II) chloride (20 g, 0.15 mol) and 90% t-butyl nitrite (24 ml, 0.18 mol) in ethyl acetate (500 ml) at 60 ° C was added portionwise ethyl 2-amino-4-thiazolecarboxylate ( 21 g, 0.12 mol) while maintaining the temperature between 60-65 ° C. After the addition, the reaction mixture was heated for 1 h. At 80 ° C, then cooled to RT and poured into water, CH ₂ Cl ₂ and 25 mL almost. HCl mixture- The combined organic layers were washed with water, brine, dried and concentrated to give 21.5 g of ethyl 2-chloro-4-thiazolecarboxylate.

136

c) A mixture of NaOH (1.9 g, 47.5 mmol) and ethyl 2-chloro-4-thiazolecarboxylate (7.6 g, 40 mmol) in 100 mL of absolute ethanol was stirred for 4 h. RT. The ethanol was then removed in vacuo and the residue dissolved in water. The aqueous layer was washed with ether and then acidified. HCl. The solid was filtered and air-dried to give 4 g of 2-chloro-4-thiazolecarboxylic acid.

d) 2-Chloro-4-thiazolecarboxylic acid chloride (prepared from a catalytic amount of 2-chloro-4-thiazolecarboxylic acid, thionyl chloride and DMF) is treated with 70% ethylamine in water to give 2-chloro-N-ethyl-4-thiazolecarboxamide. This compound is treated with TMSCl using the method of Example 248, step c. Purification by flash chromatography with 3% ethyl acetate-hexane afforded 2.5 g of the title compound as a light yellow oil, yield 55.6%, n _D 1.5313.

Example 283

2-Chloro-N-ethyl-3- (trimethylsilyl) -4-thiazolecarboxamide.

2-Chlorothiazole was prepared from 2-aminothiazole according to Example 282, step b. Clear liquid from distillation v. t. 145-150 ° C. This compound was treated with n-BuLi and dry ice using the procedure of Example 258, step a to give 2-chloro-5-thiazolecarboxylic acid.

This compound was treated with 70% ethylamine followed by TMSCl using the procedures of Example 248 to afford 0.9 g of the title compound as a white solid. Yield 54.2%, m.p. 101-103 ° C.

Example 284

N-Ethyl-5- (trimethylsilyl) -1H-pyrazole-1-carboxamide.

137

To a solution of pyrazole (1.7 g, 25 mmol) and 4 mL of triethylamine in 50 mL of dry THF was added ethyl isocyanate (2 g, 28 mmol) at 0 ° C and the resulting reaction solution was stirred for 18 h. RT. Add ethyl acetate and the aqueous 2N HCl layer was separated and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and concentrated in vacuo to give an oil. The oil was triturated with cold hexane to give 2.5 g of N-ethyl-1H-pyrazole-1-carboxamide, a white solid.

A solution of this compound in THF was treated with lithium diisopropylamide (prepared from diisopropylamine and 2.5M n-BuLi in hexane as in Example 250 a) and cooled in TMSC1 as Example 248 to give 0.6 g of the title compound as an orange oil, n _D 1.6627.

Example 285

2-Chloro-N-ethyl-6- (1,1-dimethylethyl) benzamide.

2-tert-Butyl-N-ethylbenzamide was prepared from 2-tert-butylbenzoyl chloride obtained in Example 186 and 70% ethylamine in water according to Example 248, step b.

To a solution of 2-tert-butyl-N-ethylbenzamide (44 g, 215 mmol) and TMEDA (70 mL, 446 mmol) in THF (500 mL) at -70 ° C and under a positive nitrogen atmosphere, 520 mL of 1.3M s-BuLi was added rapidly. in cyclohexane, keeping the temperature below -60 ° C. After the addition was complete, the resulting reaction solution was warmed to -30 ° C and stirred for 50 min maintaining the temperature between -30 ° C. and -26 ° C. The solution was then cooled to below -70 ° C and hexachloroethane solution (80 g) in 250 mL of THF was added maintaining the temperature between -70 ° C and 65 ° C. Stirring is continued for 0.5 hours. below -70 ° C.

138

The resulting reaction solution was then poured into water. Add CH ₂ C1 ₂ and 3N HCl. The combined organic layers were washed with water, dried, and concentrated in vacuo. The solid is triturated with hexane and then purified by flash chromatography eluting with 15% ethyl acetate / hexane to give the desired product as a white solid, mp 121-123 ° C.

Example 286

4,5-Dimethyl-N-ethyl-3- (trimethylsilyl) -2-thiophenecarboxamide.

The title compound was prepared from methyl ethyl ketones using the methods of Example 274 and was obtained in the form of a white solid, m.p. 77-80 ° C.

Example 287

5-Chloro-N-hydroxy-N- (1-methylethyl) -3- (trimethylsilyl) -2-thiophenecarboxamide.

5-Chloro-3- (trimethylsilyl) -2-thiophenecarboxylic acid chloride prepared by reacting 1 g of 5-chloro-3- (trimethylsilyl) -2-thiophenecarboxylic acid (prepared as in Example 263 and 6 ml of thionyl chloride according to the procedure of Example 248, step a). This product was dissolved in CH ₂ Cl _{2 at} 0 ° C and poured into a mixture of N-isopropylhydroxyamine hydrochloride (0.55 g, 5 mmol) with 4 g of NaHCO ₃ , 20 mL of CH ₂ Cl ₂ , and 20 mL of water. stirring for an additional 3 h RT The organic layer was separated, washed with brine, dried and concentrated The residue was purified by flash chromatography eluting with 8% ethyl acetate / hexane to give 80 mg of the title compound, mp 146-150 ° C.

139

Example 288

N-Ethyl-1-methyl-5- (trimethylsilyl) -1H-pyrazole-4-carboxamide.

A solution of ethyl (ethoxymethylene) cyanoacetate (68 g, 0.4 mol) and methylhydrazine (18.5 g, 0.4 mol) in 200 mL of absolute ethanol was refluxed for 1.5 h, then cooled to RT and filtered. The filtrate was concentrated in vacuo and the residue triturated with ether to give 54 g of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate in 75.4% yield.

To a 90% solution of t-butyl nitrite (50 mL, 0.37 mol) in 200 mL

DMF was added portionwise to pyrazole-4-carboxylate (39 at ca.

30 ° C.

The ethyl 5-amino-l-methyl-LHG, 0.23 mol) while maintaining the addition of the resulting mixture was heated to 50 ^u C and stirred at this temperature for 0.5 h. The mixture was poured into 100 ml. HCl and 40 mL of water and extracted with CH ₂ Cl ₂ . The organic solution was washed with water, brine, dried and concentrated. Vacuum distillation of the residue afforded 32.4 g of ethyl 1-methyl-1H-pyrazole-4-carboxylate in the form of a clear solution, m.p. 65-80 ° C, at 0.1 tor.

A solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (20.2 g, 131 mmol) and NaOH (6.3 g, 158 mmol) in 200 mL of absolute ethanol was refluxed for 2 h. and the mixing continued for 18 hours. RT. The solvent was then removed in vacuo. The residue was dissolved in water. The aqueous solution was washed with ether and acidified with concentrated HCl. The solid was filtered, washed with water and air dried to give 14.2 g of l-methyl-1H-pyrazole-4-carboxylic acid in 86% yield.

N-Ethyl-1-methyl-1H-pyrazole-4-carboxamide prepared from 1-methyl-1H-pyrazole-4-carboxylic acid and 70%

140 ethylamine in water using the procedures of Example 248 steps a and b. The product was purified by flash chromatography eluting with 10% ethyl acetate-hexane to give the product as a white solid. Yield 54.7%, m.p.

103-106 ° C.

This compound was treated with TMSC1 as in Example 248 to give 1.2 g of the title compound as a white solid, m.p. 77-81 ° C.

ELEMENTAL ANALYSIS DATA

For example, Items (Calculated / Found)

No.

2 C 67.41, 66.98, H 9.29, 9.31; N 5.62, 5.52. 3 C 68.38, 38.36, H 9.56, 9.59; N 5.62, 5.31. 4 c 62.88, 62.95, H 8.29, 8.31; N 5.24, 5.21. 6th c 77.68, 76.22, H 10.19, 10.18; N, 5.66, 5.50. 7th c 44.90, 44.91, H 5.92, 5.93. 10th c 66.82, 66.65, H 9.35, 9.37; N 4.33, 4.24. 14th c 70.04, 69.94, H 10.03, 10.04; N, 4.80, 4.75. 15th c 59.23, 59.42, H 7.81, 7.97; N 4.93, 4.78. 18th c 60.48, 60.37, H 8.12, 8.12; N 4.70, 4.76. 22nd c 57.86, 58.00 H 7.47, 7.52; N 5.19, 5.26. 23rd c 60.48, 60.34, H 8.12, 8.08; N 4.70, 4.75. 35 c 65.97, 65.74, H 6.99, 6.94; N 4.05, 3.99. 36 c 61.61, 61.93, H 8.40, 8.17; N 4.49, 4.23. 38 c 55.70, 55.90, H 7.01, 7.07; N 4.64, 4.68. 39 c 59.23, 59.36, H 7.81, 7.85. 41 c 60.98, 60.88, H 7.51, 7.52; N 4.74, 4.73.

141

C c

c c

c c

c c

c c

c c

c c

c c

c c

c c

c c

c c

c c

61.16, 61.13 H 7.98, 7.99; N 3.96, 3.94. 69.26, 69.22 H 9.81, 9.82; N 5.05, 5.03. 56.07, 55.96 H 7.39, 7.44. 63.35, 63.41 H 8.73, 8.77. 60.17, 59.91 H 7.74, 7.80; N 4.68, 4.63. 58.91, 58.62 H 7.42, 7.35; N 4.91, 4.94. 64.01, 63.88 H 8.60, 8.65; N 4.98, 4.94. 68.38, 68.20 H 9.56, 9.62; N 5.32, 5.27. 60.48, 60.56 H 8.12, 8.14; N 4.70, 4.68. 69.26, 69.31 H 9.81, 9.83; N 5.05, 5.06. 56.76, 56.79 H 6.99, 7.02; N 4.41, 4.43. 68.38, 68.25 H 9.56, 9.47; N 5.32, 5.58. 68.38, 68.14 H 9.56, 9.4 6; N 5.32, 5.61. 62.64, 62.4 9 H 8.66, 8.56; N 4.30, 4.57. 65.97, 66.01 H 6.99, 7.00; N 4.05, 4.11. 65.27, 65.30 H 9.31, 9.17; N 3.81, 3.90. 52.82, 52.97 H 6.65, 6.61; N 4.40, 4.44. 52.82, 52.88 H 6.28, 6.27. 54.42, 54.48 H 6.68, 6.63. 54.42, 54.35 H 6.68, 6.63. 55.88, 55.99 H 7.03, 7.05. 55.88, 55.70 H 7.03, 6.99. 61.61, 61.63 H 8.40, 8.37; N 4.49, 4.47. 55.70, 55.80 H 7.01, 7.02; N 4.64, 4.69. 61.61, 61.50 H 8.40, 8.41; N 4.49, 4.75. 65.27, 64.62 H 9.31, 9.16.

142

97 C 60.17, 60.42, H 7.74, 7.80. 98 C 64.01, 63.76, H 8.60, 8.52. 101 C 68.10, 68.21, H 7.79, 7.81; N 3.61, 3.66. 104 C 67.08, 66.83 H 8.04, 7.99. 105 C 67.11, 67.00 H 6.76, 6.78. 125 C 60.79, 60.95, H 6.60, 6.56. 127 C 64.47, 64.58 H 9.02, 9.06. 128 C 58.60, 58.31 H 7.99, 7.94. 130 C 58.96, 59.11 H 7.42, 7.40; N 4.30, 4.25. 164 C 59.23, 59.35 H 7.81, 7.78. 166 C 60.48, 60.59 H 8.12, 8.13; N 4.70, 4.71. 169 C 56.06, 56.26 H 7.39, 7.33. 172 C 51.72, 51.98 H 6.68, 6.75. 186 C 74.71, 73.93 H 10.23 , 10.08. 189 C 63.70, 63.78 H 8.20, 8.15; N 9.91, 9.86. 195 c 60.17, 57.51 H 7.41, 6.65. 249 c 52.12, 51.45 H 8.41, 8.32; N 4.68, 4.62. 281 c 64.74, 64.65 H 8.49, 8.48; N 9.44, 9.47.

Biological tests

The compounds obtained in the examples described above showed Gg control in one or both assay modes.

The results are presented in the following tables.

In vitro sample

Test compounds (0.25 mL of the corresponding stock solution in acetone) are inoculated into 25 mL of minimum medium agar [prepared by autoclaving 17.5 g Czapek Dox broth

143 solution (Difco), 7.5 g purified agar or Bacto-agar (Difco) and 500 ml distilled / deionized water, followed by addition of 50 ml 1 mg / ml thiamine hydrochloride and 50 ml 1 mg / ml biotin in 5% ethanol ] and prepare the plates.

Each plate is inoculated by placing three triangular 4-mm plugs in Gaeumannomyces grominis var. tritici (Ggt) grown on minimal medium agar as described above. The plates are incubated in the dark at 19-20 ° C for 4 to 5 days. Fungus growth is measured by the fungal growth diameter. The result is expressed as the percentage inhibition calculated as [l- [(mm growth in the test plate - 4) / (mm growth in the control dish - 4)]] X 100.

In vivo sample

The compounds are tested for Ggt control with Bergen or Anza wheat species grown in 76.2 mm (3-inch) square pots containing soil contaminated with Ggt. Infestation was done by mixing the soil with seeds prepared by growing Ggt on 1/4 potato glucose agar (4.875 g potato glucose agar, 5.0 g Bacto agar, 500 ml distilled, deionized water) and using plugs to contaminate. sterile oats (400 cm ³ oats, 350 ml deionized water, autoclaved). After an incubation period of one month at room temperature, the oats are dried and mixed with soil in a volume ratio of 4%. 4 wheat seeds are placed on top of each pot soil. Test compounds are formulated as a 1: 9 acetone / water (vol) solution containing 0.18% Tween® 20, providing a rate of 0.5 mg of active ingredient per pot. Five pots are used for each treatment level and control: untreated, seeded and untreated pots. After one hour of drying, the seeds are more germinated

144 relevant soil and vermiculite. The pots are placed in the growth room and watered daily. After four weeks, each pot is evaluated for disease by examining the root of each plant through the preparation lip. A rating scale of 0 to 5 is used, with the following values:

= no branching hyphae or lesions = is branching hyphae and some minor lesions on <10% of root system = is branching hyphae and minor lesions on

10-25% root system = is hifa branching and lesions on 2550% root system = is hifa branching and many large adults on> 50% root system = root system and stem is completely filled with lesions and branching hypha.

From the results of the five replicates in each group, the highest and lowest scores are discarded and the mean of the duplicate test is calculated from the average of the remaining three results. This mean is then compared to the untreated control mean and the percentage of successful disease control is calculated. These results are shown in the table below. If the count ends at 0 or less relative to the untreated control, N is used to express control inefficiency.

145

Test results

In vitro (d / 1)

For example, No. 10th 1 0.1 In vi vo 1 74 53 6th 91 2 72 36 14th 74 3 75 58 19th 100 4 57 N N 54 5 29th N N 24th 6th 47 2 7th 37 7th 100 77 42 93 8th 100 97 19th 85 9th 71 N 3 10th 50 N N 11th 24th N N 12th 100 83 29th 95 13th 64 17th 7th 13th 14th 79 40 7th 92 15th 44 N N 16th 76 27th 11th 3 17th 64 64 59 N 18th 100 N N 97 19th 29th 7th N 38 20th 61 14th 7th 36 21st 100 100 100 100

146

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 22nd 46th N 13th 91 23rd 71 N N 24th 100 N N - 25th 89 15th 19th 56 26th 97 95 95 99 27th 64 13th 15th 33 28th 100 100 60 86 29th 100 100 100 97 30th 80 60 N 31st 96 4 N 32 100 100 75 85 33 100 44 N 12th 34 100 100 97 100 35 93 7th 3 46th 36 100 69 26th 88 37 87 63 17th 83 38 100 79 53 95 39 92 82 49 99 40 53 N N 41 52 21st 24th 42 30th N N 43 63 N N

147

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 44 39 N N. 45 100 100 100 97 46th 44 11th 15th 47 70 N N 48 100 100 74 97 49 100 100 100 97 50 20th 10th 3 51 100 19th N 77 52 98 81 53 96 53 95 19th 9th 65 54 43 2 N 52 55 100 81 49 100 56 74 31st 10th 91 57 90 N 10th 58 55 6th 13th 59 26th N 6th 60 19th N N 61 49 29th 9th 1 62 69 3 8th 9th 63 69 40 N 64 31st 14th 20th 65 100 56 39 95

148

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 66 58 N N 3 67 100 19th N N 68 41 N 8th N 69 100 81 51 67 70 44 15th N 71 N 8th 14th 50 72 69 59 N 73 83 60 13th 74 93 31st 7th 47 75 31st 26th 5 76 79 45 N 77 100 47 13th N 78 62 12th 12th 79 65 12th 12th 80 46th 4 N 81 46th N N 82 57 N 30th 58 83 100 100 100 99 84 100 66 N 85 59 7th 7th 86 72 24th N 87 100 100 93 96

149

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 88 73 N N 89 100 85 19th 96 90 89 34 6th 93 26th N N 94 86 63 9th 95 100 62 N 63 96 48 15th 7th 97 100 70 7th 98 100 81 22nd 97 99 95 72 5 59 101 62 21st 10th 102 28th 52 28th 103 92 55 N 26th 104 71 26th N 105 84 37 3 106 97 95 95 100 107 24th N N 108 97 86 90 109 83 10th 10th 110 45 17th 7th 111 100 66 14th 48 112 100 96 81

150

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 113 96 26th N 114 100 85 38 115 97 97 97 116 33 . N N 117 97 94 36 118 38 N N 119 100 88 40 120 100 26th N 121 31st 8th 4 122 67 N N 123 89 78 11th 124 * 62 N N 125 89 N N 126 93 4 15th 127 74 21st N 128 50 8th 4 129 26th 35 9th 130 39 13th 16th 1 131 3 6th N 132 46th 15th 54 N 133 18th 3 13th N 134 39 3 N N

151

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 135 39 17th 22nd 136 100 26th 3 137 100 61 17th 138 97 36 14th 139 100 53 11th 140 81 19th 19th 141 100 64 19th 142 59 N N 143 74 13th 5 144 59 11th N 145 27th N N 146 84 65 14th 147 58 N N 148 53 N N 149 80 N N 150 83 74 34 96 151 57 71 N 97 152 86 71 N 54 153 91 88 N 29th 154 69 N N 155 90 64 N 93 156 72 33 9th

152

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 157 91 23rd 7th 0 158 44 33 2 159 100 55 12th 0 160 88 63 17th 5 161 61 17th 22nd 162 57 N 3 163 100 85 24th 164 70 3 3 165 100 76 N 63 166 73 N 4 15th 167 96 86 46th 93 168 100 96 57 169 100 31st N 170 63 9th 12th 171 97 88 48 87 172 100 100 94 99 173 92 12th 4 174 100 65 12th 0 175 60 48 35 176 97 97 83 177 100 19th 11th 178 54 15th N

153

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vi vo 179 91 88 85 97 180 90 82 85 96 181 58 33 12th 182 73 58 30th 183 56 35 24th 184 83 11th -N 185 72 56 48 186 67 N N 187 97 27th 13th 24th 188 100 71 29th 15th 189 65 13th 4 190 80 76 24th 191 88 88 60 88 192 95 95 86 99 193 57 30th 35 194 100 100 82 195 56 29th 35 196 100 56 3 197 85 23rd 3 198 75 32 7th 199 74 29th 9th 200 100 100 92 65

154

Test results

In vitro (d / 1)

For example, No. 10th 1 0.1 In vivo 201 100 50 31st 65 202 88 58 33 3 203 91 84 79 204 74 N N 43 205 81 47 5 206 100 97 86 207 97 90 31st 208 97 83 N 209 100 90 28th 210 94 88 85 74 211 90 82 N 96 212 90 54 77 96 213 79 82 9th 87 214 77 6th 3 215 100 96 46th 57 216 92 54 25th 68 217 100 68 16th 0 218 100 94 18th 99 219 100 94 50 97 220 100 100 75 97 221 85 46th 15th 222 96 N N

155

Test results

In vitro (d / 1)

For example, No. 10th 1 0.1 In vivo 223 96 93 48 82 224 93 27th N 21st 225 95 64 18th 226 100 91 32 227 100 68 36 34 228 96 87 N 84 229 88 28th N 230 96 96 88 231 96 76 N 232 95 97 92 78 233 76 24th 28th 234 81 32 N 235 70 N 3 236 86 68 N 237 96 93 44 238 72 N N 239 87 57 22nd 240 65 22nd 26th 241 100 87 13th 242 67 N 27th 243 83 10th 23rd 244 53 20th 10th

156

Test results

In vitro (d / t)

For example, No. 10th 1 0.1 In vivo 245 100 100 50 246 61 2 N 247 59 16th N 248 100 10th 10th 249 100 48 17th 60 250 41 N N 251 97 36 3 252 100 28th 5 253 62 14th N 254 100 97 97 40 255 73 N N 256 100 N N 257 100 23rd 3 258 42 19th 19th 259 * 80 11th 19th 260 77 N N 261 78 25th 14th 262 100 70 13th 2 63 50 N 7th 264 100 88 2 265 100 14th 5 266 100 61 21st 4

157

Test results

In vitro (d / 1)

For example, No. 10th 1 0.1 In vi vo 267 61 64 18th 268 100 N N 269 100 91 N 4 270 100 100 96 87 271 100 100 95 97 272 100 23rd 14th 0 273 100 48 35 274 67 10th N 275 94 81 22nd 276 84 63 N 277 94 81 69 278 75 50 N 279 47 N N 280 38 21st 24th 281 43 N 4 282 78 15th 3 283 42 3 N 284 * 91 35 23rd 285 75 50 N 286 100 93 76 287 78 71 64 288 53 N N

* Tested at 50 ppm.

158

Field tests

The compounds of Examples 1-90, 93-99 and 101-288 are combined with 5 different stimulants, carriers and other additives and mixed with wheat and barley seeds in a ratio of 0.01 to 50 g of active ingredient per kilogram of seeds, thus attenuating the effect of Gg on previously infested fields. , compared to control fields sown with untreated seeds.

Examples of compositions

Suspension Concentrate:% by weight

Compound no. 45 48,900

Polyoxypropylene-polyoxyethylene block copolymer 2,550

Sodium lignin sulphonate 2,040

10% Dimethylpolylsiloxane Emulsion 1.020

1% Xanthan Resin Solution 0, 990

Water 43,250

Emulsion Concentrate: Weight%

Compound no. 26 13.5

Ethoxylated Sorbitan (20EO) 5.0

Aromatic substances

Moisturizing powder: Weight%

Compound no. 12 75.0

Sodium lignin sulphonate 3.0

Sodium N-methyl-N-oleyl taurate 1.0

Baltmol

11.0

159

Granule: Weight%

Compound no. 138 1.0

Propylene Glycol 5.0

Monmorillonitis (24/48 porosity) 94.0

Powder Weight%

Compound no. 48 50.0

Graphite 10.0

Baltmol 40.0

From the whole description, it is clear that the present invention is best adapted to achieve all the above objectives and advantages inherent in the present invention.

It is understood that particular features and subcombinations are used and may be adapted without reference to other features and subcombinations. This is intended and reflected in the claims of the invention.

As more embodiments of the invention are possible within the scope of the present invention, it should be understood that any information, as explained or shown in the accompanying illustrative material, should in any event be construed as illustrative rather than restrictive.

Claims (3)

DEFINITION OF INVENTION Priority 1, 2, 5, 7, 11 Items 18.10.1991 1. A method of controlling a plant disease caused by Gaeumannomyces sp. A wherein Z _x and Z ₂ are C or N and are part of an aromatic ring selected from benzene, pyridine, thiophene, furan, pyrrole, pyrazole, thiazole and isothiazole; A is selected from -C (X) -amino, -C (O) -SR ₃ , -NHC (X) R _4, and -C (= NR ₃ ) -XR ₇ ; B is -W _m -Q (R ₂ ) ₃ or selected from o-tolyl, 1-naphthyl, 2. Buddha by the fact that Z _x and Z ₂ Item 1, b contains benzene you are ring s k i part. r i a n t i s 3. The method according to claim characterized in that Z and Z _{x 2} Item 1, b contains thiophene you are ring s k i part. r i a n t i s 4. The method according to claim characterized in that Z and Z _{x 2} Claim 1, characterized in is part of the furan ring. r i a n t i s 5. The method according to any of the 2-4 wherein t b e s i s wherein A is -C (O) -amine and the amino radical is substituted with one or two groups selected from hydroxy, alkyl, alkenyl 163 and alkynyl, which may be linear or branched, or may be cyclic; alkoxyalkyl; haloalkyl; hydroxyalkyl; alkylthio; alkylthioalkyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonyl; alkylaminocarbonyl; alkoxycarbonyl; aminocarbonyl; alkylaminocarbonyl; cyanoalkyl; mono or dialkylamino; phenyl, phenylalkyl or phenylalkenyl, each of which may be substituted by one or more C 1 -C 4 alkyl, alkoxyl, haloalkyl, C 3 -C 6 cycloalkyl, halogen or nitro groups; and C 1 -C 4 alkyl or alkenyl substituted by pyridinyl, thienyl or furanyl; and wherein the amino radical may be on an N-linked heterocycle selected from morpholine, piperazine, piperidine, pyrrole, pyrrolidine, imidazole, and triazoles, each of which may be substituted with C 1 -C 6 alkyl groups; In group B, m is equal to 0 and Q is Si or C or W _m is -O- and Q is C, or W _m is -NH- or -N (CH ₃ ) - and Q is C; R ₂ is C 1 -C 4 alkyl or haloalkyl; and R _{n in} group n is 1 and R is methyl or halogen. 6. An adjuvanted fungicidal composition for use in a method according to any one of the preceding claims, wherein the amount of the compound described in the above claims is effective in combating plant frostbite. 164 A compound of the formula A wherein Z _x and Z ₂ are C or N and are part of a benzene ring; A is selected from -C (X) -amino, -C (O) -SR ₃ , -NHC (X) R _4, and -C (= NR ₃ ) -XR ₇ ; B is -W _m -Q (R ₂ ) ₃ or selected from o-tolyl, 1-naphthyl, 2-naphthyl and 9-phenanthryl, each of which may be substituted by halogen or R ₄ ; Q is C, Si, Ge or Sn; W is -C (R ₃ ) _p H _{(2. P)} -; or when Q is C, W is selected from -C (R ₃ ) _p H _{(2. p)} -, -N (R ₃ ) _m H _{(X- m)} -, -S (O) _p -, and -O-; X is O or S; n is equal to 0, 1, 2 or 3; m is equal to 0 or 1; p is equal to 0, 1 or 2; each R is independently selected from 165 (a) halogen, formyl, cyano, amino, nitro, thiocyanate, isothiocyanate, trimethylsilyl and hydroxyl; b) C 1 -C 4 alkyl, alkenyl, alkynyl, C 3 -C 6 cycloalkyl and cycloalkenyl, each of which may be substituted by halogen, hydroxy, thio, amino, nitro, cyano, formyl, phenyl, C 1 -C 4 alkoxyl, alkylcarbonyl, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, (alkylthio) carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl or alkylsulfonyl groups; c) phenyl, furyl, thienyl, pyrrolyl, each of which may be substituted by halogen, formyl, cyano, amino, nitro, C 1 -C 4 alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, dialkylamino, haloalkyl and haloalkenyl; d) C 1 -C 4 alkoxyl, alkenoxyl, alkinoxyl, C 3 -C 6 cycloalkyloxy, cycloalkenyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, , each of which may be substituted by halogen; wherein the two R groups may be joined to form a single ring; each R ₂ is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and phenyl, each of which may be substituted with R ₄ or halo; and wherein, when Q represents C, R ₂ may also be selected from halogen, alkoxyl, alkylthio, alkylamino and dialkylamino; 166 in which the two R ₂ groups may be joined to form a cyclic group with Q; r ₃ is C 1 -C 4 alkyl; r ₄ is C 1 -C 4 alkyl, haloalkyl, alkoxy, alkylthio, alkylamine or dialkylamine; and r ₇ is C 1 -C 4 alkyl, haloalkyl or phenyl, optionally substituted with halo, nitro, or R ₄ ; or his agronomic salt; with the proviso that n is not zero when B is trimethylsilyl and A is Ν, Ν-diethylaminocarbonyl, Ν, Ν-bis (1-methylethyl) aminocarbonyl, N-methylaminothiocarbonyl, N-ethylaminocarbonyl, 1-piperidinylcarbonyl, or N-phenylcarbonyl; or when B is ortho-tolyl and A is Ν, Ν-diethylaminocarbonyl, Ν, Ν-bis- (1-methylethyl) aminocarbonyl, N-methylaminocarbonyl or 0-methylcarbamyl; or when B is 1,1-dimethylethyl and A is Ν, Ν-dimethylaminothiocarbonyl or N-phenylaminocarbonyl; or when B is trimethylstanyl and A is Ν, Νdiethylaminocarbonyl or O- (1,1-dimethylethyl) carbamyl; with the proviso that when B is 2-trimethylsilyl and A is Ν, Ν-diethylaminocarbonyl, R _n is not 3-fluoro-6-formyl, 3-fluoro-6-methyl, 3-chloro-6-formyl, 3fluoro-, 3- chloro, 3-chloro-6-methyl, 6-trimethylsilyl or 6-methyl; With the further proviso that when A is 0- (1,1-dimethylethyl) carbamyl and B is 2-trimethylsilyl, R _n is not 5-trifluoromethyl; with the proviso that when A is -C (O) -amine and W _m is -O-, R is not an isothiocyanate; and finally with the proviso that when A is N-phenylcarbonyl and B is 2,2-dimethylpropyl, R _n is not 3-methyl. A compound of the formula A wherein Z _L and Z ₂ are carbon atoms of the thiophene ring; A is selected from -C (X) -amino, -C (O) -SR ₃ , -NHC (X) R _4, and -C (= NR ₃ ) -XR ₇ ; B is -W _m -Q (R ₂ ) ₃ or selected from o-tolyl, 1-naphthyl, 2-naphthyl and 9-phenanthryl, each of which may be substituted by halogen or R ₄ ; Q is C, Si, Ge or Sn; 168 W is -C (R ₃ ) _p H ₍₂ _ _p) · selected from -S (O) _p - and -O-; -; or when Q is C, W is C (R ₃ ) pH ₍₂ -p) ^- , -N (R ₃ ) _m H _(1- m) -, X is 0 or S; n equal to 0, 1 or 2; m equal to 0 or 1; P equal to 0, 1 or 2; each R is independently selected from (a) heptogen, formyl, cyano, amino, nitro, thiocyanate, isothiocyanate, trimethylsilyl and hydroxyl; b) C 1 -C 4 alkyl, alkenyl, alkynyl, C 3 -C 6 cycloalkyl and cycloalkenyl, each of which may be substituted by halogen, hydroxy, thio, amino, nitro, cyano, formyl, phenyl, C 1 -C 4 alkoxyl, alkylcarbonyl, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, (alkylthio) carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl or alkylsulfonyl groups; c) phenyl, furyl, thienyl, pyrrolyl, each of which may be substituted by halogen, formyl, cyano, amino, nitro, C 1 -C 4 alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, dialkylamino, haloalkyl and haloalkenyl; d) C 1 -C 4 alkoxyl, alkenoxyl, alkinoxyl, C 3 -C 6 cycloalkyloxy, cycloalkenyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylLT 3276 B 169 amino each of which may be substituted by halogen; wherein the two R groups may be joined to form a 5-membered ring; each R ₂ is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and phenyl, each of which may be substituted by R ₄ 10 or halogen; and wherein when Q is C, R ₂ may also be selected from halogen, alkoxyl, alkylthio, alkylamino and dialkylamino; wherein the two R ₂ groups may be joined to form an eastern cyclic group with Q; R ₃ is C 1 -C 4 alkyl; R ₄ is C 1 -C 4 alkyl, haloalkyl, alkoxy 20 alkyl, thio, alkylamine or dialkylamine; and R ₇ is C 1 -C 4 alkyl, haloalkyl or phenyl, optionally substituted by halo, nitro 25 or R ₄ ; or an agronomic salt thereof; with the proviso that B is not trimethylsilyl when A is present 30 (diethylamino) carbonyl. A compound of the formula 170 The t wherein Z _x and Z ₂ are carbon atoms of the furan ring; A is selected from -C (X) -amino, -C (O) -SR ₃ , -NHC (X) R _4, and -C (= NR ₃ ) -XR _? ; B is -W _m -Q (R ₂ ) ₃ or selected from o-tolyl, 1-naphthyl, 2-naphthyl and 9-phenanthryl, each of which may be substituted by halogen or R ₄ ; Q is C, Si, Ge or Sn; W is -C (R ₃ ) _p H _{(2. P)} -; or when Q is C, W is selected from -C (R ₃ ) _p H ₍₂ - _p) -, -N (R ₃ ) -, -S (O) _p - and -O-; X is O or S; n is equal to 0, 1, 2 or 3; m is equal to 0 or 1; p is equal to 0, 1 or 2; each R is independently selected from (a) halogen, formyl, cyano, amino, nitro, thiocyanate, isothiocyanate, trimethylsilyl and hydroxyl; 171 b) C 1 -C 4 alkyl, alkenyl, alkynyl, C 3 -C 6 cycloalkyl, and cycloalkenyl, each of which may be substituted by halogen, hydroxy, thio, amino, nitro, cyano, formyl, phenyl, C 1 -C 4 alkoxyl, alkylcarbonyl, (alkylthio) carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl or alkylsulfonyl groups; c) phenyl, furyl, thienyl, pyrrolyl, each of which may be substituted by halogen, formyl, cyano, amino, nitro, C 1 -C 4 alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, dialkylamino, haloalkyl and haloalkenyl; d) C 1 -C 4 alkoxyl, alkenoxyl, alkynyloxyl, C 3 -C 6 cycloalkyloxy, alkylamino, dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, (alkylthio) carbonyl, phenylamino, substituted; wherein the two R groups may be joined to form a single ring; each R ₂ is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and phenyl, each of which may be substituted with R ₄ or halo; and wherein when Q is C, R ₂ may also be selected from halogen, alkoxyl, alkylthio, alkylamino and dialkylamino; wherein the two R ₂ groups may be joined to form a cyclic group with Q; r ₃ is C 1 -C 4 alkyl; 172 R ₄ is C 1 -C 4 alkyl, haloalkyl, alkoxy, alkylthio, alkylamine or dialkylamine; and R ₇ is C 1 -C 4 alkyl, haloalkyl or phenyl, optionally substituted with halo, nitro or R ₄ ; or an agronomic salt thereof; with the proviso that B is not trimethylsilyl when A is (diethylamino) carbonyl. A compound of the formula A wherein Z _x and Z ₂ are carbon and nitrogen atoms of the thiazole, isothiazole, pyrrole, pyridine or pyrazole ring; A is selected from -C (X) -amino, -C (O) -SR ₃ , -NHC (X) R _4, and -C (= NR ₃ ) -XR ₇ ; B is -W _m -Q (R ₂ ) ₃ or selected from o-tolyl, naphthyl, 2-naphthyl and 9-phenanthryl, each of which may be substituted by halogen or R ₄ ; Q is C, Si, Ge or Sn; 173 is -C (R ₃ ) _p H _{(2- p)} -; or when Q is C, W is selected from -C (R ₃ ) _p H _{(2. p)} -, -N (R ₃ ) -, -S (O) _p - and -O-; is O or S; equal to 0, 1, 2 or 3; equal to 0 or 1; equal to 0, 1 or 2; each R is independently selected from (a) halogen, formyl, cyano, amino, nitro, thiocyanate, isothiocyanate, trimethylsilyl and hydroxyl; b) C 1 -C 4 alkyl, alkenyl, alkynyl, C 3 -C 6 cycloalkyl and cycloalkenyl, each of which may be substituted by halogen, hydroxy, thio, amino, nitro, cyano, formyl, phenyl, C 1 -C 4 alkoxyl, alkylcarbonyl, alkylthio, alkylamino, dialkylamino , alkoxycarbonyl, (alkylthio) carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl or alkylsulfonyl; c) phenyl, furyl, thienyl, pyrrolyl, each of which may be substituted by halogen, formyl, cyano, amino, nitro, C 1 -C 4 alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, dialkylamino, haloalkyl and haloalkenyl; d) C 1 -C 4 alkoxyl, alkenoxyl, alkinoxyl, C 3 -C 6 cycloalkyloxy, cycloalkenyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylLT 3276 B 174 carbonyl, alkylcarbonyloxy, alkoxycarbonyl, (alkylthio) carbonyl, phenylcarbonylamino, phenylamino, each of which may be substituted by halogen; wherein the two R groups may be joined to form a single ring; each R ₂ is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and phenyl, each of which may be substituted with R ₄ or halo; and wherein when Q is C, R ₂ may also be selected from halogen, alkoxyl, alkylthio, alkylamino and dialkylamino; wherein the two R ₂ groups may be joined to form a cyclic group with Q; R ₃ is C 1 -C 4 alkyl; R ₄ is C 1 -C 4 alkyl, haloalkyl, alkoxy, alkylthio, alkylamine or dialkylamine; and R ₇ is C 1 -C 4 alkyl, haloalkyl or phenyl, optionally substituted with halo, nitro or R ₄ ; or an agronomic salt thereof; with the proviso that B is not trimethylsilyl, when A is (diethylamino) carbonyl. A compound according to any one of claims 7 to 10, wherein A is -C (O) amine and the amino radical is substituted with one or two groups selected from hydroxyl, alkyl, 175 alkenyl and alkynyl, which may be linear or branched, or may be cyclic; alkoxyalkyl; haloalkyl; hydroxyalkyl; alkylthio; alkylthioalkyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonyl; alkylaminocarbonyl; cyanoalkyl; mono or dialkylamino; phenyl, phenylalkyl or phenylalkenyl, each of which may be substituted by one or more C 1 -C 4 alkyl, alkoxyl, haloalkyl, C 3 -C 6 cycloalkyl, halogen or nitro groups; and C 1 -C 4 alkyl or alkenyl substituted by pyridinyl, thienyl or furanyl; and wherein the amino radical may be on an N-linked heterocycle selected from morpholine, piperazine, piperidine, pyrrole, pyrrolidine, imidazole and triazoles, each of which may be substituted with C 1 -C 6 alkyl groups; In group B, m is equal to 0 and Q is Si or C or W _m is -O- and Q is C, or W _m is -NH- or -N (CH) ₃ - and Q is C; R ₂ is C 1 -C 4 alkyl or haloalkyl; and R _{n in} group n is 1 and R is methyl or halogen. 2-naphthyl and 9-phenanthryl, each of which may be substituted by halogen or R ₄ r Q is C, Si, Ge or Sn; W is -C (R ₃ ) _p H ₍₂ _ _p) -; or when Q is C, W is selected from -C (R ₃ ) _p H ₍₂ _ _p) -, -N (R ₃ ) _ffl H ₍₁ _ _m) -, -S (O) _p -, and -O-; X is O or S; n is equal to 0, 1, 2 or 3; 161 m equals 0 or 1; p is equal to 0, 1 or 2; each R is independently selected from (a) halogen, formyl, cyano, amino, nitro, thiocyanate, isothiocyanate, trimethylsilyl and hydroxyl; b) C 1 -C 4 alkyl, alkenyl, alkynyl, C 3 -C 6 cycloalkyl and cycloalkenyl, each of which may be substituted by halogen, hydroxy, thio, amino, nitro, cyano, formyl, phenyl, C 1 -C 4 alkoxyl, alkylcarbonyl, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, (alkylthio) carbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl or alkylsulfonyl groups; c) phenyl, furyl, thienyl, pyrrolyl, each of which may be substituted by halogen, formyl, cyano, amino, nitro, C 1 -C 4 alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, dialkylamino, haloalkyl and haloalkenyl; d) C 1 -C 4 alkoxyl, alkenoxyl, alkinoxyl, C 3 -C 6 cycloalkyloxy, cycloalkenyloxyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, phenylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl, groups each of which may be substituted by halogen; wherein the two R groups may be joined to form a single ring; 162 each R ₂ is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and phenyl, each of which may be substituted with R ₄ or halo; and wherein when Q is C, R ₂ may also be selected from halo, alkoxyl, alkylthio, alkylamino and dialkylamino; wherein the two R ₂ groups may be joined to form a cyclic group with Q; is C 1 -C 4 alkyl; is C 1 -C 4 alkyl, haloalkyl, alkoxy, alkylthio, alkylamine or dialkylamine; and R? is C 1 -C 4 alkyl, haloalkyl or phenyl which may be substituted by halogen, nitro or R ₄ ; or an agronomic salt thereof. Priority 3, 4, 6, 8, 9, 10 Items 02.10.1992