CA1248538A

CA1248538A - Chloroacetamides

Info

Publication number: CA1248538A
Application number: CA000421147A
Authority: CA
Inventors: Karl Seckinger; Fred Kuhnen; Karlheinz Milzner
Original assignee: Sandoz AG
Current assignee: BASF SE
Priority date: 1982-02-09
Filing date: 1983-02-08
Publication date: 1989-01-10
Also published as: FR2523967B1; DK171559B1; JPS58148868A; PL240481A1; EG16720A; HU193036B; NL350007I2; KR840003634A; NL190919C; IE55108B1; SK86783A3; CZ86783A3; AU1119483A; IE830247L; CZ278361B6; KR880002359B1; IT1163085B; PL140272B1; NL190919B; IT8319474A0

Abstract

HERBICIDAL N-THIENYL CHLOROACETAMIDES

Abstract of the Disclosure The invention provides novel 5-membered heteroaromatic compounds of formula I
ArN(Y)COCH2Cl I
wherein Ar is a 5-membered heteroaromatic group comprising 1 S
heteroatom and linked by a ring C-atom to the N-atom of the N(Y)COCH2Cl group to which it is bound, and Y is as specified in the description, the use of these novel compounds as herbicides, compositions for facilitating such use and the preparation of the novel chloroacetamides.

Description

Case 130-3938 HERBICIDAL N-THIENYL CHLOROACETAMIDES
-The present invention relates to novel 5-membered heteroaromatic compounds bearing at one ring C-atom a N-substituted chloroacetylamino group, their use as herbicides, agricultural compositions for facilitating such 5 use and the preparation of the novel compounds of the invention.
Various herbicidal N-substituted a-halogenacetanilides are known.
The U.S. Patent Spec. 4,282,028 discloses N-substituted-N-2,5-dialkyl-pyrrol-l-yl)haloacetamides having herbicidal and plant-growth-regulating activity. The need exists for still more effective herbicides. The novel 10 5-membered heteroaromatic compounds are particularly effective herbicides having an appropriate soil persistence.
The present invention provides compounds of formula I
COCH2Cl Ar - N ~

wherein Ar is a 5-membered heteroaromatic group comprising 1 S heteroatom, and linked by a C-ring atom to the N-atom of the N(Y)COCH2Cl group to which it is bound, and Y is a group A-O-R3, wherein R3 is H, hydrocarbon selected from the group consisting of Cl 8alkyl, C3 8alkenyl~ C3 8alkinyl, C3 8cycloalkyl, C5 8cycloalkenyl or C3 8cycloalkyl-C1 5alkyl, whereby the hydrocarbon is unsubstituted or monosubstituted by F, Cl, Br, cyano or Cl 4alkoxy;
and A is a hydrocarbon moiety, whereby the N and O atoms to which it is bound are separated by up to 3 C-atoms.
The Ar group may be unsubstituted or substituted. Where Ar is substi-tuted it may bear substituents in any possible position; preferred positions 25 Of such substituents are in o-position, particularly in o,o'-position of the chloroacetamide group, whereby additional substituents may be present.
Examples of suitable substituents of Ar are halogen selected from F, C1 and Br; C1 4alkyl unsubstituted or substituted by halogen (F, Cl, Br), C1 4alkoxy or C3 6cycloalkyl; C2 4alkenyl unsubstituted or 30 substituted by Cl 4alkoxy; C3 6cycloalkyl; formyl or C2 4alkanoyl and functional derivatives such as oximes, acetals and ketals ~ J~ ~e 1248S3~

~ -z- 130-3938 thereof (e.g. C~=NOCl 4alkyl)-C1 3alkyl, C(O-Cl 4alkyl)2-Cl 3alkyl, CH(O-Cl 4alkyl)2 etc.); Cl 4alkyl-S, Cl 4alkyl-SO, Cl 4alkyl-S02; Cl 5alkoxy-carbonyl; Cl 4alkoxy unsubstituted or substituted by halogen or C1 4alkoxy;
C2 4alkenyloxy, C2 4alkinyloxy; hydroxy and hydroxymethyl and esters 5 thereof (e.g. esters with an organic carboxylic acids, for example formic acid, a C2 5alkane carboxylic acid or an halogenated derivative thereof, such as acetic acid or chloroacetic acid).
Any optional substituent(s) of Ar which is not in o-position of the N-substituted chloroacetylamino group is preferably selected from Cl 4alkyl (e.g. CH3), halogen (e.g. Cl, Br) and Cl 4alkoxycarbonyl (e.g. COOCH3).
The N-substituted chloroacetylamino group is preferably tied to the ring C-atom in ~-position of the ring heteroatom. A preferred sub-group of the latter group are those compounds wherein the Ar-group is substituted in ortho-, more preferably in ortho-ortho'-position of the N-substituted acetylamino group, especially when the substituent(s) are selected from the group specified hereinbefore. A particularly preferred sub-group of compounds of formula I, are compounds wherein Ar is 3-thienyl which is at least

2,4-disubstituted, especially those 3-thienyl compounds wherein the substi-tuents in 2- and 4-position are selected from Cl 4alkyl and Cl 4alkoxy.
Where R3 is substituted by halogen, such halogen is preferably Cl or Br.
Where R3 is Cl 8alkyl, C3 8alkenyl or C3 8alkinyl, it preferably has up to 5 C-atoms. Where R3 is or contains cycloalkyl or cycloalkenyl such cyclic hydrocarbon group contains preferably up to 6 C-atoms.
Where R3 is monosubstituted hydrocarbon, it signifies e.g. CH2CH2Cl or CH2CH2CN.
A is preferably a Cl 8alkylene moiety separating the 0- and N-atom to which it is bound by 1 to 2 C-atoms. A suitable significance of A is a CH2 or CH2-CH2 group or monomethylated derivatives thereof, particularly CH2, CH(CH3), CH2CH2 and CH(CH3)CH2; R3 is then especially Cl 3alkyl, such as CH3, C2H5 and nc3H7 1;~48~3~3

3 130-3938 The present invention also provides processes for producing a compound of formula I comprising a) substituting in a compound of formula II
COCH OH
Ar - N < 2 II

wherein Ar and Y are as defined above.
the HO group of the N-hydroxyacetyl group by C1, b) reacting a compound of formula III
Ar-NH-COCH2Cl III
where~n Ar is as defined above, with a compound of formula IV
Ly IY
wherein Y is as tefined above, and L ~s a leaving group capable of be;ng sptitt off under the N-alkylation reaction conditions, c) obtaining a compound of formula Ia CO-CH Cl Ar - N ~ 2 Ia R'~
wherein R'"is H or Cl 3alkyl, Y2 is OR3 and Ar and R3 are as defined above, .
~J
`''` ' ' .

- .

1~4~53~

4 130-3938 by reacting a compound of formula Y
CO-CH2Cl Ar - N ~
CH - Cl R"' wherein Ar and R'Uare as defined above, with a reactive derivatiYe of a compound of formula YI

wherein Y2 is as defined above, d) N-acylation of a compound of formula YII
Ar - NH - Y jYlI
wherein Ar and Y are as def1ned above, w;th chloroacetyl chloride, or a react;ve functional derivatiYe thereof.
Process a) of the invent;on can be carried out by conventional manner under conditions known for the subs~;tution of an OH group by a Cl.
Such substitution can for example be effected by treat,ng a compound of formula II w;th a chlorinating agent, such as th;onyl chlor;de under cond1tions known p~r se for analogous reactions.
According to a variant of this chlorin~tion process, the compounds of formula II are f;rst converted into the corresponding sulphonyloxy derivatives, e.g. by O-sulphonation with the aid of a sutphonyl halide, and such sulphonyloxy derivatives then converted into the desired compounds of formula I by nucleophilic substitu-tion of the sulphonyloxy group by chlorine.
Reactants supplying the Cl anions requiret for such nucleophilic substitution are e.g. alkalimetal chlorides such as NaCl, quaternary tetrabutylammonium chloride or 4-dimethylaminopyridine-hydrochloride. Such substitution is conveniently carried out in CH2Cl2 or in an aqueous/organic two-phase system, wherein the organic phase is e.g. a hydrocarbon such as toluene, ;n the presence of a suitable phase transfer catalyst, preferably with heating . .

1~1853~3

-5- 130-3938 e.g. at 40~ to 120C.
Process b) may be carried out by conventional manner under conditions known for the N-alkylation of amides. The reaction is advantageously carried out in a solvent which is inert ur,aer the reaction conditions e.g. dimethoxyethane or acetonitrile or in an aqueous/organic two-phase system in the presence of a phase transfer catalyst.
Suitable meanings of L (in formula IV) are Cl, Br or the sulphonyloxy moiety of an organic sulphonic acid such as mesyloxy or p-tosyloxy.
The compounds of formula llI are preferably used in salt form, more preferably 1n alkalimetal salt form, e.g.ithe sodium salt form.
Such salts are obtained in conventlonal manner by reaction of the compound of formula III with a base such as an alkalimetal amide, hydride, hydroxide or alcoholate.
For the preparation of compounds of formula Ia according to process c), the compounds of formula Y are suitably used in the form of the alkalimetal salt, e.g. as sodium salt.
The reaction of process d) can likewise bè effected in 20 conventional manner, under conditions known for the N-chloroacetyla-tion of amines. Where ClCOCH2Cl is uset as N-chloroacetylation agent such reaction is conveniently carried out in the presence of an acid binting agent, such as ~2C03.
The compounds of formula I may be recovered from the reaction 25 mixture in which it is formed by working according to established procedures.
It will be appreciated that interconversion of one compound of the invention to another, e.g. conversion of an acid group to an ester group, of a carbonyl group to an oxime, of a halo-alkyl group to an ether group ~or vice versa) etc., may becarried out in conventional manner. As will also be appreciated, the compounds of the invention may possess one or more asymmetric .,.. ~ ~,~ ,. .. .. .

lZ4~353~

-6- 130-3938 centres and may therefore exist in optically active, diasteromeric, racemic or geometric isomer forms. In general such compounds are employed as mixtures in the herbicide method and compositions of the invention, even though separation may be effected by known procedures.
The compounds of for~ulae II, III, V and VII are novel and are part of the invention.
The compounds of formula II may be obtained by ammonolysis of an ester of the compounds of fonmula VIII
Ar NHCOCH20H VIII
wherein Ar is as defined above, with a carboxylic acid, and subsequent introduction of the group Y
(as defined above) in the compounds of formula VIII by N-alkylation.
Such esters are obtained by acylation of the corresponding compounds of formula IX
ArNH2 IX
wherein Ar is as defined above, with the appropriate ester of H0-CH2COCl, e.g. with CH3C0-OCH2-COCl.
The compounds of formula III may also be obtained by acylation of a compound of formula I% with chloroacetyl chloride.
Compounds of formula V (which are in fact a sub-group of compounds of formula I) may be obtained by reaction of a compound of formula IX
with an appropriate aldehyde and reaction of the Schiff base thus obtained-with chloroacetyl chloride.
The co~pounds of formula YII may be obtainet by N-alkylation of a compound of formula IX. Such alkylation can be carried out in conventional manner, with the corresponding alkylating agents (e.g.
halogenides~, or where appropriate, reductively via the Schiff base or amide.
Many of the compounds of formula IX are novel.
A particular group of valuable novel compounds of formula IX
are 3-aminothiophenes substituted in 2- and 4-position by a group selected from Cl 4alkyl and Cl 4alkoxy (compounds of formula IXa).
The compounds of formula IXa also fo m part of the invention.

lZ'~35

7 1 ~0-393 The co~pounds of formula IX may be obtained by reduction of the corresponding N02 compounds, e.g. by catalytic hydrogenation under hydrogen pressure in the presence of palladium. Compounds of formula IXa having a CH3 group in 2- or 4-position may be obtained by reduction of the corresponding thiophene-carboxylate with the aid of a complex hydride such as sodium bis(methoxyethoxy)aluminium hydride. Where appropriate, the compounds of formula IXa may also be obtained from the correspsnding carbamates esters, e.y. the benzyl carbamate, by hydrolysis. The carbamates, used as starting 10 material, may for example be obtained starting from the corresponding acids, via their azides followed; by a Curtius reaction.
Insofar as the production of starting material is not described herein, these compounds are known, or may be produced and purified in accordance with known processes or in a manner analogous to 15 processes described herein or to known processes.
The compounds of formula I are useful because they control or modify the growth of plants. By plants it is meant germinating seeds, emerging seedlings and established vegetation including underground pGrtions.
In particular, the compounds are useful as herbiGides as indicated by i.a. the damage caused to both monocotyledoneous and di-cotyledoneous plants such as Lepidium sativu~, Avena sativa, Agrostis alba and Loliu~ perenne in tests by test dosages equivalent to an application rate of from 1.4 to 5.6 kg/ha after pre- or post-25 emergence application. In view of their herbicidal effect thecompounds of the lnYention are indicated for use in combatting dicotyledoneous and grassy weeds, as confirmed by further evaluation with representative compounds w;th test dosages equivalent to an application rate of from 0.2 to 5.0 ks active 30 ingredient, e.g. test dosages equivalent to a rate of 0.2, 1.0 l ~''''' :

35 3~

- 8 - 130-3938 and 5.0 kg active ingredientlha, in dicotyledoneous weeds such as Amaranthus retroflexus, Capsella bursa-pastoris, Chenopodium alba, Stellaria media, Senecio vulgaris and Galium aparine, and, especially, grassy weeds such as Agropyron repens, Agrostis alba, Alopecurus myosuroides, Apera spica-venti, Avena fatua, Echinochloa crus-c,alli, Bromus tectorum, Sorghum halepense, Digitaria spp and Setaria spp. Additional tests indicate a favourable soil persistence of the compounds of the invention.
The compounds of the invention are relatively less toxic towards lO crops than towards weeds. Selective herbicidal activity is i.a.
observed in corn (0aize), soybean, cotton, sugar beet, potato, alfal~a, sunflower, rape, peanuts or flax, depending i.a. on the compound ;nvolved and on the application rate. The compounds of the invention are therefore also 1ndicated for use as selective herbicides 15 in a crop locus.
The present invention therefore also provides a method of combatting weeds in a locus, preferably in a crop locus,particularly in a crop locus as mentioned above, whicn comprises applying to the tocus a herbicidally effective amount (a selective herbicidally 20 effective amount where the locus is a crop locus) of a compound of the invention. A partlcularly preferred and advantageous embodiment of the invention is the pre-emergence (both crops and weeds) use of a compound of formula I in selectively combatting weeds in a crop locus.
For general herbicidal as well as for selective herbicidal use of 30 compounds of the invention, the amount to be applied to attain the desired effect will vary depending on the particular crop if employed for selective use and other standard variables such as the compound employed, mode of application, conditions of treatment and the like.
The appropriate application rates can be determined by routine proce-35 dures by those skilled in the art, or by comparing the activity of thecompounds of the invention with standards for which the application , ~ . ~ ,~
. ~... ..

1248~3~3

-9 - 130-3938 rate is known, e.g. in greenhouse tests However. in general, satisfactory resutls are usually obtained when the compound is applied at a rate in the range of from about 0.1 to 5 kg/ha, prefer-ably from about 0.2 to 4 kglha, more preferably from 0.5 to 3.0 kg/ha, 5 the application being repeated as necessary. Ilhen used in a crop locus, the application rate should preferably not exceed 3 kg/ha.
The compounds of formula I may be and preferably are employed as herbicidal compositions in association with herbicidally accept-able diluent(s). Suitable formulations contain O.OlX to 99~O by

10 weight of active ingredient, from 0 to 20~ herbicidally acceptable surfactant and 1 to 99.99X solid or liquid di,luent(s). Higher ratios of surfactant to active ingredient are sometimes desirable and are achieved by incorporation into the formulation or by tan~
mixing. Application forms of composition generally contain between 0.01 and 25X by weight of active ingredient. Lower or h;gher levels of active ingredient can, of course, be present depending on the intended use and the physical properties of the compound. Concen-trate forms of composition intended to be diluted before use generally contain between 2 and 90t, preferably between 10 and 80~ by weight of active ingredient.
Useful formulations of the compounds of the invention incl~de tusts, granules, pellets, suspens~on concentrates, wettable powders, emulsifiable concentrates and the like. They are obtained by conventional manner, e.g. by mixing the compounds of the invention with the dituent(s). More specifically liquid compositions are obtained by mixing the ingredients, fine solid compositions by blending and, usually grinding, suspensions by wet milling and ~ granules ant pellets by impregnating or coating (preformed) granular ;~ carriers with the active ingredient or by agglomeration techniques.

~ . .

~:
,~

.

1248~3~

Alternatively, the compounds of the invention may be used in microencapsu1ated form.
Herbicidally acceptable additives may be employed in the herbicidal compositions to improve the performance of the active ingredient and to reduce foaming, caking and corrosion.
Surfactant as used herein means a herbicidally acceptable material which imparts emulsifiability, spreading, wetting, dispersibility or other surface-modifying properties. Examples or surfactants are sodium lignin sulphonate and lauryl sulphate.
Diluents as used herein mean a liquid or solid herbicidally acceptable material used to dilute a concentrated material to a usable or desirable strength. For dusts or granules it can be e.g.
talc, kaol;n or diatomaceous earth, for liquid concentra~e forms, for example a hydrocarbon such as xylene or an alcohol such as 15 isopropanol, and for liquid application forms i.a. water or diesel oil.
The compositions of this invention can also comprise other compounds having biological activity, e.g. compounds having similar or complementary herbicidal activity or compounds havir.g antidotal, 20 fungicidal or insecticidal activity.

,~

,J

.,, .
.

- 11 130-3938 Specific Examples of herbicidal compositions will now be described.
EXAMPLE A : Wettable Powder .
25 Parts of a compound of formula I, e.g. Compound No. 25 5 here;nafter given, are mixed and milled with 25 parts of synthetic fine silica, 2 parts of sodium lauryl sulphate, 3 parts of sodium ligninsulphonate and 45 parts of finely divided kaolin until the mean particle size is about 5 micron. The resulting wettable po~Jder is diluted with water before use to a spray liquor with the desired 10 concentration.
EXAMPLE B : Emulsion Concentrate _ j 20 Parts of a compound of formula I, e.g. Compound No. 25 hereinafter given, 40 parts of xylene, 30 parts of dimethyl formamide and 10 parts of emulsifier (e.g. ATLOX 4851 B a blend of 15 Ca alkylarylsulphonate and a polyethoxylated trislyceride o~ Atlas Chemie GmbH) are throughly mixed until a homoseneous solution is obtained. The resulting emulsion concentrate is diluted with water before use.
EXAMPLE C : Granules _ _ _ 2D 5 Kg of a compound of formula I, e.g. Compound No. 25 herein-after given, are d;ssolved in 25 ~ methylene chloride. The solution is then added to 95 kg of granulated attapulgite (mesh size 24/48 mesh/
inch) and thoroughly mixed. The solvent is then evaporated off under retuced pressure.
The invention is further illustrated by the follow;ng Examples where~n temperatures are in C, pressures are in Torr and Rf values are on silica gel, so far not otherwise ind~cated.
FINAL COMPOUNDS
Example 1 N-~2,4-dimet_yl-thien-3-yl)-N-(1~3_dioxo1ane-2-ylmethyl2-chloro-acetamide ~Qroce-s---a2 .
B` ,~

lZ~3S3~

-12- 130-3938 To the well stirred mixture of 1.7 9 (0.0063 mol) of N-(2,4-di-methyl-thien^3-yl)-N-(1,3-dioxolane-2-ylmethyl)-hydroxyacetamide, 58 mg of benzyltriethylammonium chloride, 7 ml of toluene and 7 ml of 30X NaOH are added dropwise without cooling 1.31 9 (0.0069 mol) 5 of p-toluene sulfonyl chloride in 3.5 ml of toluene. After the exothermic reaction has subsided, stirring is continued for a further 2D houns at ambient temperature.
The toluene layer is then separated, washed with water and dried over anhydrous Na2S04.
The crude residue left on rotevaporation of the solvent is recrystallised from diethyl ether to give N-(?,4-dimethyl-thien-3-yl)-N-(1,3-dioxolane-2-ylmethyl)-tosyloxyacetamide ("tosylate") having a m.p. of 101-103 A stirred mixture of 2.16 9 (0.0051 mol) of said tosylate, 1.849 (0.0066 mol) of tetrabutylammonium chloride, 8 ml of water and 16 ml of toluene is heated at 90 over a period of 6 hours. The toluene layer is then separated, dried (Na2S04) and evaporated in vacuo.
The residue is chromatographed on a silica gel column. Elution 20 with hexane-ethylacetate 2:1 affords the title compound as analyti-cally pure crystals, ha~ing a m.p. of 76-78.
Example 2 N-~2~4-t1methyl thien 3-yl) N methoxyetbyl chloroacetamide (process a) To a stirred solution of 2.0 9 (0.008 mol) of N-~2,4-dimethyl-25 thien-3-yl)-N-methoxyethyl-hydroxyacetamid and 0.92 9 (0.008 mol) of 4-timethylaminopyridine (=DMAP) in 80 ml of dry methylene chloride are added without cooling 0.93 9 (0.008 mol) of mesyl chloride in 20 ml of dry CH2C12.
The resulting mixture containing DMAP-hydrochloride and the . ~ .

~ .
~, .:, ....

12~853~3 -~ 130-3938 methanesulphonate of the starting compound is heated under reflux for 25 hours and then evaporated in vacuo.
The residual oil, after column chromatography on silica gel (elution with diethylether), solidified on chilling at -20, m.p.
54-55.
Example 3 : N-~ch1Oroac~tyl2-N-~2-carbo~ethoxy-4_methyl-thien-3 Y12 alan!ne e~hy!ester (process b) To a well stirred suspension of 1.5 9 (0.05 mol) sodiu~hydride (80 % tispersion in mineral oil) in 250 ml of dry 10 d~methoxyethane (=D,-lE) are added portionwise, 9.9 9 (0.04 mo~) of solid N-(2-carbomethoxy-4-methyl-thien-3:yl)-chloroacetamide.
After the addition is completed the resulting solution of the Na-salt is stirred 2n additional hour at 50, then allowed to reach room temperature and treated with the solution of 7.25 9 (0.04 mol) of ethyl-2-bromopropionate in S0 ml of dry D:~E.
After a reaction period of 4 hours at 50, the mixture is filtered and evaporated in vacuo (50/0.01 Torr.~. The residual brown oil, after chromaSography on silica gel (elution with diethyl ether-hexane 2:1),is sub~ected to ball tube distillat~on, giYing the analytically pure title compound, b.p. 135/0.005 Torr.
Example 4 : N ~ yrazol l-ylmethyl2 N-~2,4 dimathyl-thien-3 yll-chlQroacetam de (process b) To a well stirred mixture of 19.35 9 (0.095 mol) of N-(2,4-di-methyl-thien-3-yl)-chloroacetamide, 4.15 9 (0.01 mol) of benzyldi-~3 ,~, 2 4~ 3~

-14_ 13C-3938 methythexadecyl-a~monium ch1Oride, 40 9 (1 mol) of sodium hydroxide, 200 ml of ~ethylene chloride and 40 ml of water are added 17 9 (0.11 mot) of solid l-chloromethyl pyrazolehydroch~oride at such a rate, that the temperature does not rise above 25.
When the addit;on is completed, the reaction m;xture ;s stirred an additional 21/2 hours at ambient temperature. Then 100 mt of water are added. The or~anic layer is separated, washed with three 200 ml portions of water, dried over Na2S04 and evaporated to dryness. The residue is chromatographed on a silica 10 gel column. Elution with hexane-diethylether 1:1 affords the title compound as an analytically pure syrup wh kh crystallized on chilling overnight at -20, m.p. 88-89 (recrystallized fro~ diethyl ether).
Example 5 : r~-~chloroacetvl2-~ 315-dimethyl-isoxazol-4-yl~-_ _ _ _ .. _ _ _ ~ _ . _ _ _ _ _ _ _ _ ala~nineethylester (process b) 9.4 9 (0.05 mol) of N-(3,5-dimethyl-isoxazol-4-yl)-chlolo-acetamide in 150 ml of dry acetonitrile (=CH3Ct~) are added drop-wise to a well stirred suspension of 1.8 9 (0.06 mol) of sod;um hydride (80X dispersion in mineral oil) in 25 ml of dry CH3CN.
After the exothermic reaction (34~ has suhsided the solution 20 Of the sodium salt ~s allowed to reach rocm temperature 2nd then treated with the solution of 9.05 g ~0.05 mol) of ethyl 2-bromo-propionat~ in 25 ml of dry CH3CN.
After the addition is completed the reaction mixture ~s heated at 50~ for three hours and then evaporated to dryness. The residue 25 is taken up with 100 ml of diethyl ether and filtered. The residual oil left bn evaporating the filtrate is chromatographed on a silîta gel column. Elution with diethylether-hexane 1:1 affords the title compound, having a m.p. of 49-50.

B~;~

... .

3~

-15_ 130-3938 ~xample 6 : N-[l-~ -eyrazol~l-yl~ethyl~-N-~2,4-dimethyl-thien-3-yl~-_ _ _ _ _ _ chloroacetamide (process c) To a stirred solut;on of 12.7 9 (0.1 mol) of 2,4-dimethyl-3-amino-th,ophene in 100 ml of dry benzene, which contains 16 9 of 5 moleculzr sieves (3A) and two drops of conc. H2504, are added dropwise 8.5 ml (0.15 mols) of acetaldehyde, taking care that the temperature does not rise above 25.
When all the acetaldehyde has been introduced, the reaction mixture is stirred 24 hours longer at ambient temperature and is 10 then filtered. Removal of the solvent leaves the Schiff base as a light brown llquid.
To the stirred solution of 13 9 (0.085 mols)o~ this material in 75 ml of dry toluene are added dropwise at -30 9.7 9 (0.086 mols) of chloroacetyl chloride.
When the addition is complete, the reaction solution ;s stirred for a further 30 minutes at -30 and then treated dropwise at the same temperature with 12 9 (0.085 mols) of l-trimethylsilyl-pyrazole. After the addition, the solid C02/acetone bath is removed, the mixture allowed to warm to ambient temperature and 2D left to stir for a further period of 20 hours.
The reactlon mixture is then filtered and evaporatet in vacuo.
The resldual syrup is chromatographed on a s;lica gel column.
Elutlon with hexane/diethyl ether 3 : 2 affords colourless crystals of the title compound which, upon recrystallization from diethyl 25 ether haYe a melt~ng point of 76-78.

-16- 130-~938 Exam~e 7 : N-~4 methoxy-2-methy!-thlen 3-yl2 ~ 2 ethoxyethyl2 chloroacetamide (process d) To a well stirred mixture of 6,05 9 (0.03 mol) N-(2-ethoxyethyl)-4-methoxyw2-methyl-thiophene-3-amine, 4.15 g (0.03 mol) o~ K2~03, 10 ml of water and 100 ml of CH2C12 is added dropwise without cooling the solution of 3.4 9 (0.03 mol) of chloroacetyl chloride in 10 mt of CH2C12. After the exothermic reaction t27) has subsided, stirring is continued for a further hour at ambient temperature.
The methylene chloride layer is then separated, washed twice 10 with 100 ml of ~ater, dried ~Na2S04) and evapqrated ~n vacuo. The residual crude title compound is analytically pure;
RF= 0.23 (hexane-diethyl ether 1:2). A small portion of this material was sub~ected to ball tube distillation : b.p. 168-170 /
0.05 Torr.
The following compounds of formula I are obtained according to one or more of the procedures of the Examples 1 to 7, as indicated hereinbefore: (Me is CH3 and Et is C2H5) TABLE A ~see next page).

... ..

: ' 353~
.

CNmOpd. Aryl Y Characterization ~ .
1 4-Me-thien-3-yl CH20C2H5 m.p. 25-26 2 ,. CH2CH20CH3 Rf=0.45(cyclohexane/
ethylacetate 1:1~
3 2-Me-thien-3-yl CH2CH20CH3 Rf=0.3(cyclohexane/
ethylacetate 6:4) 4 2,4-diMe-thien-3-yl CH2CH20H m.p. 79-80 ~ CH20Et b.p.ll5/O.OOl Torr 6 " CH20C3H7n n2=1.5280 7 " CH20C4Hgn b.p.llO-11tO.OOl Torr 8 " CH(Me)OMe m.p. 48-50 g ~ CH(Et)OMe m.p. 55-57 " CH2CH20Me m.p. 54-55 11 " CH2CH20Et b.p.llO/O.Ol Torr 12 CH2CH20C3H7n Rf=0.36(diethyle.her/
hexane 1:1)

13 " CH(Me)CH20Me b.p.l48-150/0.03Torr

14 C(Me)2CH20Me " CH~Me)OCH2CH2Cl m.p. 62-64 16 " CH2CH2CH2Me b.p.ll7-18/0.005 Torr 17 CH(Me)OCH2CH2CN m.p. 59-64 18 2-Me-4-Et-thien-3-yl CH(Me)CH~OMe b.p.l42-44~0.2 Torr 19 ~ CH20Et m.p. 49-soo 2-Et-4-Me-thien-3-yl CH OC H5 Rf=0.47(diethylether/
2 2 hexane 7:3) 21 -~ CH(Me)CH20Me Rf=0.47(diethylether/
hexane 7:3) 22 2,4-diEt-thien-3-yl CH2-OEt nD-1.5242 23 CH2CH20Me nD3=1.5328 ~ ; B`-~

..

. . , 3L~ 3~;3 ~.

Nopd. Aryl Y Characterization 24 4-OH-2-Me-thien-3-yl CH(Me)CH20Me 2-Me-4-MeO-thien-3-yl CH2-OEt m.p. 24 26 " CH2CH2-OEt b.p.l68-170/0.05 Torr 27 2-Me-4-nC4HgO-thien- CH20Et m . p . 44-45 3-yl 28 2-MeS-4-Me-thien-3-Yl CH20Et b.p. 135/0.001 Torr 29 " CH2CH20Me b.p. 148-140/0.001 Torr 2-MeS(0)-4-Me-thien- CH20Et m.p. 100 3-yl 31 2-MeS02-4-Me-thien- CH20Et 3-yl 32 2-MeCO-4-Me-thien- CH20Et m.p. 37-38 3-y1 33 2-MeC(=NOMe)-4-Me- CH20Et syn : m.p. 89-91 thien-3-yl anti: m.p. 75-76 34 2-MeC(OEt)2-4-Me- CH20Et m.p. 46-47 thien-3-yl 2-Me-4-0-COMe-thien- CH(Me)CH20Me 3-yl 36 2-COO~e-4-Me-thien-3-yl CH20Et m.p. 20-22 37 2-Et-4,5-diMe-thien- CH20Et n2=1.5273 3-yl 38 2,4-diMe-5-Cl-thien- CH20Et nD=1.5412 thien-3-yl 39 " CH20CH2CH20CH3 nD=1.5321 2,5-diBr-4-Me-thien- CH20Et m.p. 75-77 3-yl 41 2,4-diMe-5-COOMe- CH20Et b.p.l40/0.005 Torr thien-3-yl $

INTERt~EDIATES

Example 8 : Methyl 3 5-direthyl-4-amino-thioehene-2-carboxylate _ ~ _ _ _ _ A solution of 45.2 9 (0.21 ~ol) methyl 3,5-dimethyl-4-nitro-thiophene-2-carboxylate in 1000 ml methanol is hydrogenated for two hours at 10 bar in the presence of 4.5 9 pa11adium (1a X on carbon).
~ hen the retuct~on is completed the mixture is f~ltered, the catalyst washed with methanol and the filtrate evaporated to dryness.
The crystalline residue is treated with diethyl ether, yieldin~ the analytically pure title compoundim.p. 88-89 Example 9 2 4-D;methyl-3-aminothio~hene _~ _ _ _ _ _ _ _ ___ To 890 ml (3 mol) of sodium bis(2-methoxyethoxy)aluminium

15 hydride (70X solution in toluene)and 6C0 ml of dry toluene is added,dropwise with vigorous stirring, a solution of lC0 9 (0.58 mol~
of methyl 3-amino-4-methy~hiophene-2-carboxylate in 7C0 ml of dry toluene at such a rate that the temperature does not rise aboYe 55.
After the addition is completed stirring is continued for a 20 further 30 minutes and the reaction mixture then cautiously added in small portions at 0 to 1200 ml of 20X potassium hydroxide solut~on;
The toluene layer is separated, dried oYer MgS04 and eYaporated in Yacuo. The residuat brown liquid is distilled under 25 diminished pressure, affording the analytical1y pure title compound, b.p.49-52/0.01 Torr.

.

':
' `

~L~4~3~3~3 Example 10: 4 Metboxy 2-methyl-3 amino-thiQehene The well stirred mixture of 55.4 9 (0.2 mol) of benzyl N-(4-methoxy-2-methyl-thien-3-yl)carbamate, 40 9 (0.7 mol) of ~OH, 600 ml of ethanol and 120 ml of water is heated under reflux for two hours.
The resulting solution is then eYaporated in vacuo and the residue diluted with 500 ml of water. The separating lisht yellow oil is taken up in 400 ml of diethyl ether and the aqueous phase extracted once with 400 ml of ether.
The combined etherea1 solutions are dried (Na2S04) and 10 filtered. A slow current of dry hydrogen chlorlde is then passed through the filtrate for a period of 30 minutes, taking care - by intermittent colling in an ice bath - that the temperature does not rise above 10.
The prec~pitated hydrochloride of the title compound has a 15 m.p. of 230 (the free base a m.p. of 61-63).
Example 11 : 2 ~!ethylthio 4 m~thyl 3 am nothlo~hene 6 9 (0.22 gram atoms) fresnly prepared aluminium amalgam are addet over a period of about two minutes to 18.9 g (0.1 mol) of 2-methylthio-4-methyl-3-nitrothiophene tissolved in 200 ml of 20 moist diethylether. The vigorous reaction which sets in after 5-10 minutes is kept under control by cooling the flask in ice.
After 45 minutes, when the exothermic reaction has subsided and all the aluminium has reacted, another six grams of amalgamated aluminium are adted.

3L~4 ~ 3~

- 21 - 13~-3938 The reaction mixture is then gently refluxet for 2 hours;
during this period the formation of the thiophene amine is complete.
The orqanic phase is decanted and the remainder washed with two S0 ml portions of diethy?ether. The combined ethereal solutions are dried 5 (MgS04) and eYaporated in vacuo. The residual crude title compound is distilled under reduced pressure, having a boiling point of 79-81/0.5 Torr.
Example 12 In the following table are listed compounds of formula IX that are obtained according to one or more of the procedures of Examples 8 to 11.
Ex. 12.1 4-C2H5-2-CH3-3-aminothiophene, Rf=0.25 (diethylether:
Ex. 12.2 4-n-butoxy-2-methyl-3-amino-thiophene, m.p. 25;
(Rf=0.25 (diethylether/hexane 2:1) Ex. 12.3 (3-NH2-4-Me-thien-2-yl)ethanone, m.p. 80-81 Ex. 12.4 (3-NH2-4-Et-thien-2-yl)ethanone, m.p. 68 Ex. 12.5 (3-NH2-4,5-diMb-thien-2-yl)ethanone, m.p. 120-23 Ex. 12.6 2-Et-4-Me-3-NH2-thiophene, b.p. 74-76/0.01 Torr Ex. 12.7 2,4-diEt-3-NH2-thiophene, Rf = 0 24 (CH2C12) n2=1.5511 Ex. 12.8 2-Et-4,5-diMe-3-NH2-thiophene, nD =1.5581 ~,' ~24~5~

Example_13 N~2~4-dime-thyl--thien-3-yll-acetoxyaceta~lde - To 12.7 9 (0.1 mol) of 2,4-dimethyl-3-aminoth;ophene, 13.8 9(0.1 mol) of K2C03, 20 ml of water and 150 ml of methylene chloride are added dropw1se at ambient temperature 15 9 (0.11 mol~ o~
acetoxyacetyl chloride.
After the exothermic react;on has subsided, stirring is continued for a further hour. Then the organic layer is evapvrated, washed with water, dried (MgS04) and evaporated in vacuo. The solid residue is treated with hexane affording the analytlcally pure title 10 compound, m.p. 110-112.

Example 14 : N ~2~g dimethyl_tblen_3_y!~_hydrOxyacetamid2 Through a stirred solution of 15.9 9 (0.07 mol) of~2,4-di-methyl-thien-3-yl)-acetoxyaceta~ide in 300 ml of methanol is bubbled a gentle stream of a~monia gas for 30 minutes.
After the exothermic ~40) reaction (moderated by intermittent cooling in cold water) has subsided, stirring is continued for additional 30 minutes and the reaction solution then evaporated to dryness. The resulting sol~d is recrystallized from ethylacetate, giving the analytically pure title compound as colourless crystals, 20 m.p. 85-87.

~f ' '~: .
;

lZ4~3~3~

Example 15 : N-~2-ethoxyethy1i-4-methoxy-2-methyl-thioehene-3-amine To 70 ml (0.245 mol) of sodium bis(2-methoxyethoxy)aluminiu~
hydride (70g solution in toluene) and 30 ml of dry toluene is added dropwise with stirring a solution of 9.4 9 (0.041 mol) of N-~4-methoxy-2-methyl-thien-3-yl)-ethoxyacetamide in 125 ml of dry toluene. After the exother~ic reaction has subsidedl stirring i5 continued for a further 90 minutes and the reaction sclution then cautiously added in small portions at -10 to 100 ml of 20X KOH
solution.
The toluene layer is separated and the aqueous phase extracted twice with 100 ml of toluene. The combined toluene solutions are dried (Na2504) and evaporated in vacuo. The residual l~sht brown liquid is analyt~cally pure, Rf = 0.32 (hexane-d~ethyl ether 1:2).

Example 16 : N Ç~Methoxymethy!~ethyl~ 2~4_d~methy! th~oehene-3_amine ~he solution of 6.4 9 (0.05 mo1) of 2,4-dimethyl-3-amtno-thio-phene and 513 9 (0.06 mol) of methoxyacetone in 100 ml of dry toluene is boiled under reflux until the ~heore~ical amount of water has separated in the water trap (21/2 hours). The toluene solution is then allowed to cool to ambient temperature and 20 evaporated in vacuo. ~he residual crude Schiff base is sufficiently pure for the next step.
9.2 9 (0.048 mol) of this materiql are dissolved in 100 ml of dry toluene and added without cooling to a well stirred solution of 28 ml tO.098 mol) of sodium bis(2-methoxyethoxy)aluminium 25 hydr~de (70X solution in toluene) in 15 ml of dry toluene.
After the exothermic reaction (44) has subsided, stirring is continued for a further 90 minutes and the brown reaction solution ~2(1853~

-24 - 130-3~38 then cautiously added in small portions at -10 to 40 ml of 20X
KOH solution.
The toluene layer is then separated, dried (Na2S04) and evaporated in vacuo. The residual oil, after column chro~atography 5 on silica gal (elution with hexane-diethyl ether 3:1) is distilled under diminished pressure ~ball tube), having a b.p. of 94-95/
0.01 Torr.

Example 17 N ~5-Et-hyl:ll3>4--ox-dlazol-2:ylmethyl~-2~4 thioehene-3-amine The mixture of 12.7 9 (0.1 mol) of 2,4-dimethyl-3-amino-thio-phene, 14.6 9 (0.1 mol) of 2-chloromethyl-5-ethyl-1,3,4-oxdiazole and 13.8 9 (0.1 mol) of K2C03 in 150 ml of dry dimethylformamide (=DMF) is stirred for 20 hours at 80.
The reaction 0ixture is then cooled to ambient temperature 15 poured into 400 ~1 of water and the water-DMF solution extracted with three 150 ml portions of diethyl ether. The combined ethereal extracts are dried over anhydrous Na2S04 and evaporated in vacuo.
The residual brown oil is chromatographed on a silica ge1 column, elution with hexane/diethyl ether 1:1 affords the title compound as 20 an analytically pure orange liquid, R~-0.2 (ether-hexane 1:1).
Example 18 : N~l214-dimetbyl tbien 3-yl2glycine hydrazide 82 g (0.412 mol) N-(2,4-dimethyl-thien^3-yl)glycine-methylester and 42 g ~1.3 mol) hydrazine hydrate in 350 ml alcohol are stirred for 24 hours at room temperature. The mixture is evaporated in 25 vacuo. After adding 150 ml water the residue is treated with 4 x 500 ml portions of ether. The ether phase is dried over Na2S04 and evapora~ed to dryness gi~ing the analytically pure title compound, m.p. 68-70C

3'~, "

.

~L Z 4 ~3~j~3 - 25 - 130-393~
Example 19 : N-~2,4-dimethyl-thien-3-yl2-N-I4-methyl-5-merca~to-lL2,4-triazol-3-yl-methyl~-amine A mixture of 15 9 (0.075 mol) N-(2,4-dimethyl-thien-3-yl)glycine hydrazide and 5.59 (0.075 mol) methylisothiocyanate in 100 ml ethanol 5 is refluxed for 4 hours. The reaction mixture is cooled to 6C and the precipitate formed separated by filtration giving the pure com-pound, m.p. 184-87C.
Example 20 : N-~2~4-dimethyl-thien-3-yl~-N-~4-methyl-5-methylmercaeto-1~2~4 tria3ol-3 yl methyl~-am ne To a mixture of 9.5 9 (0.037 mol) N-(2,4-dimethyl-thien-3-yl)-N-(4-methyl-5~mercapto-1,2,4-triazol 3-yl-methyl)-amine, 1.19 tri-ethyl-benzyl ammonium chloride in 100 ml toluene and 30 ml aqueous 50X sodium hydroxide solution are added 4.79 (0.037 mol) dimethyl-sulfate. The reaction mixture is stirred at room temperature for 5 15 hours, the organic layer is separated, washed with three 100 ml portions of water, dried over Na2S04 and evaporated to dryness. The residue is recrystallized ~ice from ether giving the pure title compound, m.p. 92-96C.
Example 21 : N-~2~4 dimetbyl-th en-3 yll N ~5 metbyl 1~3~g tb_adiazol 2-yl_methyl~ am ne To 109 (0.05 mol) N-(2,4-dimethyl-thien-3-yl)-glycine hydrazide in 175 ml methylene chloride is added dropwise 5.59 (0.05 mol) acetic acid anhydride. The mixture is stirred for 1 hour at 20C and evaporated to dryness. The oily residue is dissolved in 150 ml pyridlne and 11.19 (0.05 mol) phosphorous pentasulfide is added ;n small portions. During the course of the addition the temperature reached 48C. The mixture is refluxed for two hours and stirred at room temperature for another 16 hours. After evaporation to dryness . . .

the residue is dissolved in methylene chloride and the solution treated successively with ice water, diluted cold sodium hydroxide solution and water, dried over Na2S04 and evaporated to dryness.
Chromatography on a silica gel column afforded the pure compound as 5 an oil, Rf = 0.23 (ethylacetate/hexane 6:4).
Example 22 N-(2~4-dimethyl-th~en-3-yll-N- S-methyl-l ,2,4-triazol-3-yl-methyl2amine To a stirred solution of 2.29 (0.055 mol) NaOH in 125 ml methano1 is added 5 9 (0.05 mol) acetamidine hydrochloride. After 15 minutes 10 9 (0.05 mol) N-(2,4-dimethyl-thien-3-yl)-glycine hydrazide is added and the mixture refluxed for 18 hours. After evaporation to dryness the residue is treated with methylene chloride and freed from insoluble by-products by filtration. Evaporation of the methylene chloride gives the title compound, m.p. 8S-87~C.
5 Example 23: N ~2?4 dimethyl-th en 3 yl291ycine soero~yl_dene-hydrazide _ 79 (0.035 mol) N-(2,4-dimethyl-thien-3-yl)-glycine hydra~ide in 50 ml acetone is stirred at room temperature for 2 hours. The pure title compound which crystallized was obtained by filtration, m.p.
20 126-28C.
Example 24 The follcwing compounds of formula VII are obtained according to one or more of the preceding Examples 13 to 23:

4b~53~3 -27 - ~30-3938 Ex. Ar y Characteriza-tion _ _ _ 24.1 2,4-di-CH3-thien-3-yl CH2CH2 OCH3 Rf=0.~2(diethyl ether-hexane 3:1) 24.2 ~ C2H5 Rf=0.23(diethyl ether-hexane 1 : 1 ) 24.3 2,4-di-CH3-thien-3 yl CH2CH2C2H5 Rf-0 48(diethyl 24. 4 " CH2CH20C3H7-n Rf-0 57(diethyl 24- 5 2,4-di-C2H5-thien-3-yl CH2CH20CH3 n2D=1.5238 24. 6 2-CH -4-C H -thien-3-yl CH ~ CH20CH3 b.p. 98-100/
3 2 5 0.09 Torr 24.7 2-C2 H5-4-CH3-thien-3-yl CH - CH20CH3 Rf=0.52 (ether-hexane Example 25 : N-~2 carbomethoxy-3~5-dimet~ thien-4 yl)-chloro-acetamide _ ____ ____ To 12.25 g (0.066 mol) of methyl 3,5-dimethyl-4-aminothiophene-2-carboxylate, 9.1 9 (0.066 mol) of K2C03, 25 ml of water and 150 ml of methylene chloride are added without cooling 7.5 9 (0.066 mol) of chloroacetyl chloride.
After the exothermic reaction (36) ~as subsided stirring is continued for a further hour. Then the organic layer is separatet~
washed with water and dried over anhydrous Na2S04. After removal of the solvent the desired product is obtained as colourless crystals, m.p. 157-58.

J

~3S 3~3 Example 26 : N-~2-chloro-3,5-dimethyl-thien-4-yl2-chloroacetamide _ . _ _ _ _ _ _ _ .. _ _ _ To the stirred solution of S.Og (0.0245 mol) of N-~2,4-dimethyl-thien-3-yl)-chloroacetamide in 50 ml o~ dry CH2C12 are added dropwise at 0 3.39 (0.0245 mol) of sulfuryl chloride.
When the addition is complete, the reaction mixture is allowed to warm to ambient temperature and stirred for a further period of 20 hours. Then the solvent is removed in vacuo and the crystalline residue triturated with hexane, yielding the analyticalty pure title compound, m.p. 166, decomp.
0 Example 27 : N-~2-~111-d ethoxy2ethyl 4-methyl-thien 3 yl ] cbloro-acetamide 15 9 (0.065 mol) of N-(2-acetyl-4-methyl-thien-3-yl)-chloro-acetamide are dissolved in the warm (50) mixture of 60 9 of dry ethyl alcohol, 60 9 of triethyl orthoformate and 7 drops of concentrated 15 HCl.
Upon standing for 30 hours at room temperature thé reaction mixture is evaporated in vacuo (50/0.01 Torr) and the residual brown syrup chromatographed on a sil~ca gel column. Elution with hexane-diethylether 2:1 afforts the title compound as colourless 20 crystals, having a m.p. of 57-58.
Example 28 : N-S2-(l-methQxyiminolethyl-4-methyl thien-3 yl~ chlQro-ac_tamlde The s~lut~on of 1.5 9 (0.0065 mol) of N-(2-acetyl-4-methyl-thien-3-yl)-chloroacetamide and 6.6 9 (0.14 mol) of methoxyamine in 50 ml 25 of try toluene, which contains 5 9 of molecular sieves (3A) is refluxed for 7 hours.
The yellow reaction solution is then filtered and evaporated in vacuo. The resulting crude syn~anti isomer mixture is separated by chromatography with hexane-diethylether as the mobile phase.

~ .. . .
~ ~ J

~91853~

First are eluted 0.69 of the pure iso~er (syn isomer) with the m.p. of 101-102 (Rf=0.33, hexane-ether 1:1). Continued elution of the silica gel column affords the other analytically pure anti isomer (0.4 9) having a melting point of 87-~9 (Rf=0.21).
Example 29 .

S The following compounds of formula III are obtained according to one or more of the Examples 25 to 28:

Ex. Ar Characterization _ 29.1 2-COOCH3-4-CH3-thien-3-yl m.p. 118-119 29.2 2-CH3S - 4-CH3-thien-3-yl m.p. 105-106 10 29.3 2,4-di-CH3-thien-3-yl m.p. 128-129 29.4 4-CH3-thien-3-yl m.p. 93-96 29.5 2-cH3-4-c2H5-thien-3-yl m.p. 114 29.6 2-CH3-4-OCH3-thien-3-yl m.p. 144-45 29.7 2-C2H5-4-CH3-thien-3-yl m.p. 105 29.8 2,4-di-C2H5-thien-3-yl m.p. 145 29.9. 2-COCH3-4-CH3-thien-3-yl m.p. 110 29.10 2-CH3-4-OC4Hgn-thien-3-yl m.p. 129-30 29.11 2-c2H5-4~5-dicH3-thien-3-yl m-p- 147-48 5;3~

30- l30-3938 Example 30 : N-~2,4-d~eth~!thien-3-yl~-N-~ethoxyethyl hydroxy-acetam1de 18.4 9 (O.l mol) of N-~2,4-dimethylthien-3-yl)-hydroxyacetamide ;n 50 ml of dry d;methylformamide (=D~F) are added dropwise to a well stirred suspension of 3.0 9 (O.l mol) of sodium hydroxide ~80 dispersion in mineral oil) in S0 ml of dry DMF.
After the exothermic reaction (50) has subsided, the solution of the Na-salt is allowed to reach room temperature and then treated with the solution of 10.4 g (O.ll mol) of 2-chloroethyl-lO methylether in 20 ml of dry DMF. When the addition is completed, the resùlting mixture is heated at 100 for 4 hours and then evaporated to dryness (40/O.l Torr).
The residue is taken up with 200 ml of diethyl ether, washed with 250 ml of water, dried (MgS04) and filtPred. The residual lS oil left on evaporating the filtrate is chromatographed on a silica gel column. Elution with ether affords the desired product asan analytically pure viscous liquid (Rf=0.25/ether).
.
Example 3l : N-~g Methoxy-2-methyl-thien-3-yl2etho~yacetamide To 9.8 g (0.068 mol) 4-methoxy-2-methyl-3-amino-thiophene, 9.45 9 (0.068 mol) K2C03, 35 ml of water and lG0 ml of CH2Cl2 is addet without cooling the solution of 8.4 9 (0.069 mol) of ethoxy-- acetyl chloride in 20 ml of CH2Cl2.
After the exothermic reaction (32) has subsided, stirring is continued for a further hour. Then the organic layer is separated, washed twice with 150 ml of water and dried over anhydrous Na2S04.
The residue left on rotevaporation of the solvent is subjected to column chromatography on silica gel. Elution with hexane-diethyl-ether l:l affords the analytically pure title compound having a m.p. of 40-41.

~;r~

~ 35 3~

_31 - 130-3938 Example 32 Analogous to the procedure of Example 33, the following am;des of formula ArNHCOY3 are obtained.

Ex. Ar Y3 Characterization 32.1 2,4-di-CH3-thien-3-yl -CH2-OCH3 m.p.62-63 32.2 1,3,5-tri-CH3-pyrazol-4-yl -CH20CH3 m.p.85-87 32.3 1-CH3-3,5-di-C2H5- " b.p.l20/0.001 Torr pyrazol-4-yl 32-4 3-CH3-s-0c2H5- -CH20CH3 m.p.l23-30 pyrazol-4-yl 32.5 2,4-di-CH3-thien-3-yl -CH20C2H5 m.p. 37-38 32.6 ~ -CH20C3H7-n m.p. 43-45 32.7 2,4-di-C2H5-thien-3-yl -CH20CH3 m.p. 48-49 Example 33 : Benzyl ~y-4-methoxy-2-meth~thien 3-yl~carbam_te 63.6 9 (0.23 mol) of diphenylphosphoryl azide and 24.4 9 (0.23 mol) of triethylamine are added all at once to the stirred susPenSion of 36.5 9 (0.21 mol) of 4-methoxy-2-methyl-thiophene-3-carboxylic acid in 300 ml of dry benzene.
The resulting mixture i5 refluxed for one hour and then treated with 25 9 (0.?3 mol) of benzyl alcohol.

12~853~3 After a reaction period of 3Y2 hours at 78 the reaction mixture is cooled to ambient temperature, diluted with diethyl ether (350 ml) and washed successively with 250 ~1 of 5X HCl, 250 ml of saturated NaHC03 solution and 200 ~1 of saturated NaCl solution. The crystalline residue left on rotevaporation of the dried (Na2S04) solvent is triturated with pentane, yielding the analytically pure title compound, m.p. 107-108.
Example 34 Following the procedure of Example 33, employing the appropriate carboxylic acid, the following carbamate is obtained.

10 Ex. 3~.1 Benzyl (N-4-n-butoxy-2-methy~thien-3-yl)carbamate, m.p. 83.
Example 35 : 4 Metboxy 2-methyl thioehene 3 carboxyliç acid The title compound is obtained by saponification (KOH) of the corresponding ethyl ester; m.p. 127.
Example 36 Analogous to the procedure of Example 35 is obtained 4-n-butoxy-2-~ethyl-thiophene-3-carboxyl;c acid, m.p. 66-68.

Example 37 : Ethyl 4-methox~-2-methyl-thiophene-3-carboxy!ate _ _ ____ _ __ _ _ 20 ml of 50X sodium hydroxide solution are added dropwise to a mixture of 18.6 9 (0.1 mol) of ethyl 4-hydroxy-2-methyl-thiophene-3-carboxylate, 10 ml (0.105 mol) of dimethyl sulphate and 2.3 9 ~0.01 mol) of benzyltriethylammonium chloride in 100 ml of CH2C1 at ambient temperature.
After about 15 minutes of reflux, the reaction mixture is worked up to give the title compound, Rf = 0.36 (diethyl ether:hexane 2 : 1).

B~

~L~ 8 S ~3~

Example 38 : Methyl 3,5-dimethyl-4-nitrothioehene-2-rarboxylate To a wel1 stirred, c.hilled (0) solution of 51.4 g (0.3 mol) of methyl 3,5-dimethylthiophene-2-carboxylate in 200 ml of glacial 5 acetic acid are added dropwise over a period of 40 minutes, a mixture of 30 ml of fuming nitric acid (specific gravity = l.S) and 120 ml of acetic anhydride. After the addition is completed the resulting brown solution is stirred a further two hoùrs at 5 and then poured into 3000 ml of ice water.
The aqueous phase is extractet twice with l500 ml of diethyl ether. The ethereal extracts are washed with water and 3Z sodium bicarbonate solution, dried (Na2S04) and evaporated in vacuo.
The residue is subjected to column chromatography on silica gel. Elution with hexane-diethylether (10:1) afforded the ti~le lS compound having a melting point of 87-88.

Example 39 Analogous to the process of Example 38 but employing 1,3-dimethyl-5-ethoxypyrazole as starting material is obtained 1,3-dimethyl-5-ethoxy-4-nitropyrazole; Rf = 0.37 with diethylether on silica gel.

~','' 3LZ~3~3~

Herbic~dal Tests Example 4~ : Weed control - Pre-emersence trqatment Seed pots (7 cm diameter) are filled with a mixture of peat culture substrate and sand. The exposed surface of the peat 5 culture substrate and sand mixture is sprayed with a test liquid of a test compound (e.g. formulated in accordancè with Example 8) and seeds of Lepidium sativum, Agrostis alba, Avena sativa and Lolium perenne are sown in each pot, whereby the Avena sativa and Lolium perenne seeds are, after sowing covered with a thin layer 10 (0.5 cm) of peat culture substrate/sand mixture. The pots are kept for 21 days at room temperature with 14 to 17 hours light (daylight or its equivalent) per day.
Determination of the herbicidal effect of the particular herbicide is made after the 21 day period. The determination lS involves a visual evaluation of the degree and quality of dam3ge to the various seed plants.

,, ,J
, . .~ O` ' ~L~4 ~ S 3~3 The compounds of formula I are applied in the above manner at dosages equivalent to 1.4 and 5.6 kg of active agent/hectare.

Herbicidal activity, that is to say, significant damage to the test plants is observed.

Example 41 : Weed control - Post-emergence treatment A procedure similar to that employed in Example 40 is followed with the exception that the test compounds (herbicides) are applied hen the plants are at the 2-4 leaf stage, the sowing of the plant seeds being st2ggered to ensure that the plants reach the 2-4 leaf 10 stage at about the same time.
Again the compounds of formula I are applied in the above manner at dosages corresponding to 1.4 kg/ha and 5.6 kg/ha. The determination of the herbicidal effe t is made 21 days after application of the test compounds and involYes an 15 analogous evaluation as described in Example 40. Heroicldal activity is observed.
Example 42 Representative compounds of the invention are evaluated in the following pre-emergence test procedure.
Seed dishes measuring 30 x 40 cm are filled to a depth of 6 cm with a mixture of peat culture substrate and sand. The exposed surCace of the peat culture substrate and sand mixture is sprayed with an aqueous test liquid (e.g. formulated in accordance with Example B) comprising a compound of the invention in a given concentration. The s?ray volume corresponds to 600~ aqueous test liquidtha. The same test is repeated with various concentrations of test l;quid, whereby tbe concentrations are selected in such a manner that the desired B~

application rates are realized. Six species of seed are then sown in each dish. The number of seeds sown for each plant species depends on the seed germination potential and also the initial growth size of the particular seed plant. After sowing of the seeds, the treated surface is covered with a thin layer about 0.5 cm deep of the peat culture substrate and sand mixture.
The prepared seed dishes are kept for 28 days at a temperature of 20 to 24C and 14 to 17 hours light each day.
Determination of the herbicidal effect of the particular compound of the invention is made after the 28 day period. The determination involves a visual evaluation ofithe degree and quality of damage to the various plants. Particular advantageous herbicidal properties are i.a. observed with the Compound Nos. 5, 6, 13, 19 and 26 of Table A. Some of the results obtained with an application rate corresponding to 1 kg active ingredient/hectare are summarised in the follow;ng Table B.
Example 43: Post-emergence Treatment _ _ _ _ _ _ _ _ A further evaluation of representative compounds of the formula I
is effec~ed in a post-emergence test procedure similar t~ that of the pre-emergence test described in Example 42. except that the herbicide test tiquid is appliet when the plants are at a 2 - 4 leaf stage. For that purpose the various plants species are sown in time-staggered relationship. The greenhouse conditions (temperature, light) are as in Example 42. Determination of the herbicidal effect is also effect~d 28 days after application according to the method of Example 40.
Particular advantageous herbicidal properties are i.a. observed with the Compound Nos. 5, 6, 13, 19 and 26 of Table A.
Some of the results obtained with application rates corresponding to 5 kg active ingredient/hectare are summarised in the following Table C.

' lZ~353~

T~ B Pre-emergence application 1 kg/ha Compound Tested - ~ damage Plant _ treated _ 5 6 13 19 26 Amaran.re~rofl._ _ 100 100 100 100 90 Capsella b.p. 100 80 90 70 90 _ __ _ _ _ _ __ ~ _ r--Chenop. alb, _ 90 50 20 50 _ 60 Galium aparine - 50 O 10 10 10 . _ _ Senecio vulg. 80 80 80 100 100 ,_ Stellarla medla 70 80 50 50 90 _ Alfalfa 60 50 80 10 90 ............ . . . _ Bean 20 20 0 - O 10 Carrot 90 90 70 100 _ 90 Cotton _ 10 0 0 0 0 ~'lax = = 6 ~ 50 30 0 = 10 Potato 1O 0 0 ; 0¦ 'J
. _ _ so~a 30 30 0 lO 30 .
Sugar ~eet 10 0 0 0 30 _ _ l~ape _ _ 20 0 0 0 10 Sunflower 30 50 0 0 10 ~gropyron repen~ 90 60 80 90 _ 70 .grositi~i alba _ 100 100 100 100 _ 1OO
Alopec. myos.80 20 50 ao so Apera sp.ventl. _ 100 100 100 1OO 100 . l Avena fatua 80 40 80 90 90 . . .
Echinochloa c.g. 90 90 90 100 90 _, _ l . . _ Corn 50 30 0 50 60 _ _ _ Wheat 90 90 0 100 70 __ . I .

?
"~ ,, 3~.~

-38 ~ 130 3938 ~E C Post-emergence apolication 5 ~g~ha Compound Tested - % damage treated 1 6 13* 19 26*
_ .
~maran.retrofl. _ _ 70 50 80 60 . 90 Capsella b.p. 20 20 80 50 60 .. .. _ _ Chenop. alb. _ 40 20 20 40 60 Galium aparlne 40 30 80 20 60 . .
Senec~o vulg. 70 80 90 90 90 Stellarla medla 60 10 30 40 40 _ _ . _ _ Alfalfa . 20 10 50 20 70 _ _ Bean 30 20 20 30 50 Carrot _ _ 30 100 80 100 80 Cotton _ 50 40 50 60 ~ 70 Flax 90 100 8C 90 80 _ _ __ __ __ .
Potato _ 20 1010 10 . 10 So~a -- _ 30 30 20 30 _ .
Sugar beet 70 0. 10 10 10 ... _ nape _ 10 10 30 60 40 Sunflower 30 80 40 60 50 . ...... _ .. _ _ ~gropyron repens _ 70 50 50 50 _ 50 P~rostis alba _ _ _ _ _ _ ~
Alope~. myos. 80 70 60 90 90 l _ _ . .
Apera sp.ventl. 100 100 100 10090 . _ _ _ Avena fatua 90 80 90 100 . 100 Echinochloa c.g. 1~ _ _ 80 80 90 70 _ 90 2) 80 S0 100 80 100 . .. _ Corn _ 100 90 30 30 80 Wheat 80 50 10 60 80 Rice 2) 10 50 30 30 40 * 4 kg/ha 1) upland conditionsi 2) paddy conditions ~,.'1 3~

- 39 - 130-3~38 The above results indicate an herbicidal activity which is equal or superior to that tound with commercially available standards against monocotyledonous weeds, and is superior to that of such standards against dicotyledonous weeds. The herbicidal activity is selective in soybean, cotton and at the lowest application rate also in corn.

Claims

Claims:

1. A compound of the formula wherein R and R' are each independently H; F; Cl; Br;
C1-4alkyl; C1-4alkyl substituted by F, Cl, Br, C1-4 alkoxy C3-6cycloalkyl; C2-4alkenyl; C2-4alkenyl substituted by C1-4alkoxy; C3-6cycloalkyl; formyl;
C2-4alkanoyl; C(=NOC1-4alkyl)-C1-3alkyl; C(OC1-4 alkyl)2-C1-3alkyl; CH(OC1-4alkyl)2; C1-4 alkylthio; C1-4alkylsulfinyl; C1-4alkylsulfonyl;
C1-5alkoxycarbonyl; C1-4alkoxy; C1-4alkoxy substituted by F, Cl, Br or C1-4alkoxy; C2-4alkenyl-oxy; C2-4alkynyloxy; hydroxy; hydroxymethyl; or an ester of hydroxy or hydroxymethyl with formic acid, acetic acid or chloroacetic acid, R" is H, C1-4alkyl, F, Cl, Br or C1-4alkoxycarbonyl, R3 is H or a hydrocarbon group selected from the group consisting of C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, C5-8cycloalkenyl and C3-8cycloalkyl-C1-5alkyl, said R3 hydrocarbon group being unsubstituted or monosubstituted by F, Cl, Br, cyano or C1-4alkoxy, and A is branched or unbranched C1-8alkylene separating the N and O atoms to which it is attached by 1 to 3 carbon atoms.

2. A compound of claim 1 in which both R and R' are other than H.

3. A compound of claim 2 in which A is CH2, CH2CH2 or a monomethylated derivative thereof and R3 is C1-3alkyl.

4. A compound of claim 2 in which R3 is C1-8alkyl.

5. A compound of claim 4 in which R and R' are independently C1-4alkyl or C1-4alkoxy and R" is H or C1-4alkyl.

6. A compound of claim 5 in which A is CH2, CH2CH2 or a monomethylated derivative thereof and R3 is C1-3alkyl.

7. A compound of claim 6 in which R is CH3 or CH2CH3 and R' is CH3, CH2CH3, OCH3 or OCH2CH3.

8. A compound of claim 7 in which R" is H.

9. A compound of claim 8 in which A is CH(CH3)CH2, R3 is CH3, and X and R' are each methyl.

10. The compound of claim 8 in which A is CH2, R3 is CH2CH3 and R and R' are each methyl.

11. The compound of claim 8 in which A is CH2, R3 is CH2CH2CH3 and R and R' are each methyl.

12. The compound of claim 8 in which A is CH2, R3 is CH2CH3, R is methyl and R' is ethyl.

13. The compound of claim 8 in which A is CH2CH2, R3 is CH2CH3, R is methyl and R' is methoxy.

14. A herbical composition, comprising a herbicidally effective amount of a compound of claim 1 in association with an herbicidally acceptable diluent.

15. A method of combatting weeds in a locus which comprises applying to the locus a herbicially effective amount of a compound of claim 1.

16. The method of claim 15 in which both R and R' are other than H.

17. The method of claim 16 in which A is CH2, CH2CH2 or a monomethylated derivative thereof, R3 is C1-3alkyl, R and R' are independently C1-4alkyl or C1-4alkoxy and R" is H or C1-4alkyl.

18. The method of claim 17 in which R is CH3 or CH2CH3, R' is CH3, CH2CH3, OCH3 or OCH2CH3 and R" is H.

19. The method of claim 18 in which R and R' are each CH3, A is CH(CH3)CH2 and R3 is CH3.

20. The method of claim 19 in which the locus is a crop locus and the compound is applied pre-emergence both the crop and weeds in an amount sufficient to combat weeds therein without substantially damaging the crop.

21. The method of claim 20 in which the crop is selected from the group consisting of corn, soybean, cotton, sugar beet, potato, sunflower, rape, peanuts and flax.

22. The method of claim 21 in which the crop is cotton.

23. The method of claim 21 in which the crop is soybean.

24. The method of claim 21 in which the crop is corn.

25. The method of claim 15 in which the locus is a crop locus and the compound is applied pre-emergence to both the crop and weeds in an amount sufficient to combat weeds therein without substantially damaging the crop.