KR100921196B1 - A Method To Inhibit Ethylene Responses In Plants - Google Patents

Abstract

The present invention relates generally to methods of inhibiting ethylene reactions in plants and plant materials, in particular, 1) at least one substituent of the cyclopropene ring comprises a carbocyclic or heterocyclic ring, and 2) the substituents 3) at least one substituent contains 1-4 non-hydrogen atoms and at least one substituent contains more than 4 non-hydrogen atoms The present invention relates to methods of inhibiting various ethylene reactions, including plant maturation and degradation, by exposing plants to derivatives and compositions.

Ethylene Reaction Suppression

Description

A Method To Inhibit Ethylene Responses In Plants             

The present invention relates to a method for inhibiting the ethylene reaction in plants and plant materials, and in particular, cyclopropene derivatives having at least one substituent of a cyclopropene ring having a carbocyclic or heterocyclic ring and a composition thereof. Exposure to methods of inhibiting a variety of ethylene reactions, including plant maturation and degradation.

It is well known that ethylene causes premature maturation and death of plants and plant parts, including flowers, leaves, fruits and vegetables. Ethylene also promotes leaf yellowing and growth inhibition, as well as the ripening of ripe fruits, flowers and leaves. Such action is understood to be by reaction with specific ethylene receptors in plants. Many other compounds than ethylene react with these receptors: some mimic the action of ethylene; Some interfere with the binding of ethylene and are therefore reacted to inhibit the reaction of ethylene.

With regard to these ethylene-induced effects, measures to prevent or reduce the deleterious effects of ethylene on plants are currently the subject of further research.

A method for inhibiting ethylene reaction in plants with diazocyclopentadiene and derivatives thereof is disclosed in US Pat. No. 5,100,462 to Sisler et al. US Pat. No. 5,518,988 to Sisler et al. Discloses the use of cyclopropene including 1-methylcyclopropene and its derivatives as effective blocking agents for ethylene bonds. An important problem with these compounds, however, is that they are typically unstable gases which present an explosion hazard when compressed.

Despite these efforts, there is a need in the art for compounds and compositions that control the maturation and degeneration of plants. Preferably, the new compound is free from the risk of explosion of 1-methylcyclopropene and further provides other means of delivery via liquid or solid formulation.

We have discovered new cyclopropene derivatives that provide many of the advantages described above. These compounds and compositions thereof can be used to provide plants with effective ethylene reaction-inhibitory amounts of cyclopropene derivatives of the formula, enantiomers, stereoisomers, salts and mixtures thereof; Or a method of inhibiting an ethylene reaction in a plant comprising contacting with their composition:

In the above formula,

a) ^one of R ¹ and R ³ is hydrogen and R ² , R ⁴ and the other of R ¹ and R ³ are independently selected from H and a group of the formula-(L) _n -Z,

Iii) n is an integer from 0 to 12,

Ii) L is each independently selected from members of the D1, D2, E or J groups;

D1 is a chemical formula

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,

D2 is a chemical formula

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,

E is a chemical formula

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Is;

J is a chemical formula

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,

A) X and Y are each independently a group of the formula-(L) _m -Z;

 B) m is an integer from 0 to 8;

 C) no more than two D2 or E groups are adjacent to each other and J groups are not adjacent to each other;

Z) Z is each independently

  A) hydrogen, halo, cyano, nitro, nitroso, azido, chlorate, bromate, iodate, isocyanato, isocyanato, isothiocyanato, pentafluorothio, or

 B) G is unsubstituted or substituted; Unsaturated, partially saturated or saturated; Group G which is a monocyclic, bicyclic, tricyclic or fused 3 to 14 membered carbocyclic or heterocyclic ring system;

    1) when the ring system has a 4 membered heterocyclic ring, the heterocyclic ring has 1 heteroatom;

    2) when the ring system has 5 or more members of a heterocyclic ring or a polycyclic heterocyclic ring, the heterocyclic or polycyclic heterocyclic ring has 1 to 4 heteroatoms;

    3) each heteroatom is independently selected from N, O and S;

    4) the number of substituents is 0 to 5 and each substituent is independently selected from X;

b) the total number of non-hydrogen atoms in each compound is 50 or less;

c) the total number of heteroatoms in-(L) _n -Z is 0-4;

d) ⅰ) R ¹ or R ³ has at least one G group;

   Ii) at least one L group is E group; or

Iii) at least one of R ¹ , R ² , R ³ and R ⁴ has 1 to 4 non-hydrogen atoms and at least one of R ¹ , R ² , R ³ and R ⁴ has more than 4 non-hydrogen atoms Has an atom.

는 두개의 다른 원자와 산소 원자의 결합을 나타내며; 이는 디메틸에테르부를 나타내는 것이 아니다. In the present invention, in the structure of various L groups, each open bond represents a bond to another L group, Z group or cyclopropene moiety. For example, in structure

Represents a bond of two other atoms with an oxygen atom; This does not represent a dimethyl ether moiety.

Typical R ¹ , R ² , R ³ and R ⁴ groups include, for example, alkenyl, alkyl, alkynyl, acetylaminoalkenyl, acetylaminoalkyl, acetylaminoalkynyl, alkenoxy, alkoxy, alkoxy Alkynoxy, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkylcarbonyloxyalkyl, alkyl ( Alkoxyimino) alkyl, carboxyalkenyl, carboxyalkyl, carboxyalkynyl, dialkylamino, haloalkoxyalkenyl, haloalkoxyalkyl, haloalkoxyalkynyl, haloalkenyl, haloalkyl, haloalkynyl, hydroxyalkenyl, Hydroxyalkyl, hydroxyalkynyl, trialkylsilylalkenyl, trialkylsilylalkyl, trialkylsilylalkynyl, dialkylphosphonato, dialkylphosphato, dialkylthiophosphato, dialkylaminoalkyl , Alkylsulfonylalkyl, alkylti Oalkenyl, alkylthioalkyl, alkylthioalkynyl, dialkylaminosulfonyl, haloalkylthioalkenyl, haloalkylthioalkyl, haloalkylthioalkynyl, alkoxycarbonyloxy; Cycloalkenyl, cycloalkyl, cycloalkynyl, acetylaminocycloalkenyl, acetylaminocycloalkyl, acetylaminocycloalkynyl, cycloalkenoxy, cycloalkoxy, cycloalkynoxy, alkoxyalkoxycycloalkyl, alkoxycycloalkenyl , Alkoxycycloalkyl, alkoxycycloalkynyl, alkoxycarbonylcycloalkenyl, alkoxycarbonylcycloalkyl, alkoxycarbonylcycloalkynyl, cycloalkylcarbonyl, alkylcarbonyloxycycloalkyl, carboxycycloalkenyl, carboxycycloalkyl , Carboxycycloalkynyl, dicycloalkylamino, halocycloalkoxycycloalkenyl, halocycloalkoxycycloalkyl, halocycloalkoxycycloalkynyl, halocycloalkenyl, halocycloalkyl, halocycloalkynyl, hydroxycycloalkenyl Hydroxycycloalkyl, hydroxycycloalkynyl, trialkylsilylcycloalkenyl, Trialkylsilylcycloalkyl, trialkylsilylcycloalkynyl, dialkylaminocycloalkyl, alkylsulfonylcycloalkyl, cycloalkylcarbonyloxyalkyl, cycloalkylsulfonylalkyl, alkylthiocycloalkenyl, alkylthiocycloalkyl, alkyl Thiocycloalkynyl, dicycloalkylaminosulfonyl, haloalkylthiocycloalkenyl, haloalkylthiocycloalkyl, haloalkylthiocycloalkynyl; Aryl, alkenylaryl, alkylaryl, alkynylaryl, acetylaminoaryl, aryloxy, alkoxyalkoxyaryl, alkoxyaryl, alkoxycarbonylaryl, arylcarbonyl, alkylcarbonyloxyaryl, carboxyaryl, diarylamino, halo Alkoxyaryl, haloaryl, hydroxyaryl, trialkylsilylaryl, dialkylaminoaryl, alkylsulfonylaryl, arylsulfonylalkyl, alkylthioaryl, arylthioalkyl, diarylaminosulfonyl, haloalkylthioaryl; Heteroaryl, Alkenylheteroaryl, Alkylheteroaryl, Alkynylheteroaryl, Acetylaminoheteroaryl, Heteroaryloxy, Alkoxyalkoxyheteroaryl, Alkoxyheteroaryl, Alkoxycarbonylheteroaryl, Heteroarylcarbonyl, Alkylcarbonyloxy Heteroaryl, carboxyheteroaryl, diheteroarylamino, haloalkoxyheteroaryl, haloheteroaryl, hydroxyheteroaryl, trialkylsilylheteroaryl, dialkylaminoheteroaryl, alkylsulfonylheteroaryl, heteroarylsulfonylalkyl, Alkylthioheteroaryl, heteroarylthioalkyl, diheteroarylaminosulfonyl, haloalkylthioheteroaryl; Heterocyclyl, alkenylheterocyclyl, alkylheterocyclyl, alkynylheterocyclyl, acetylaminoheterocyclyl, heterocyclyloxy, alkoxyalkoxyheterocyclo, alkoxyheterocyclyl, alkoxycarbonylheterocyclyl, hetero Cyclylcarbonyl, alkylcarbonyloxyheterocyclyl, carboxyheterocyclyl, diheterocyclylamino, haloalkoxyheterocyclyl, haloheterocyclyl, hydroxyheterocyclyl, trialkylsilylheterocyclyl, dialkyl Aminoheterocyclyl, alkylsulfonylheterocyclyl, alkylthioheterocyclyl, heterocyclylthioalkyl, diheterocyclylaminosulfonyl, haloalkylthioheterocyclyl; Hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, nitroso, azido, chlorato, bromeito, iodate, isocyanato, isocyanato, isothiosi Anato, pentafluorothio; Acetoxy, carboethoxy, cyanato, nitrato, nitrito, perchlorato, alkenyl; Butyl mercapto, diethylphosphonato, dimethylphenylsilyl, isoquinolyl, mercapto, naphthyl, phenoxy, phenyl, piperidino, pyridyl, quinolyl, triethylsilyl, trimethylsilyl; And substituted analogs thereof.

Typical G groups include, for example, cyclopropyl, cyclobutyl, cyclopent-3-en-1-yl, 3-methoxycyclohexan-1-yl, phenyl, 4-cyclophenyl, 4-fluorophenyl, 4 Bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-methyl-3-methoxyphenyl, 2,4-dibromo Phenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl , 4- (trifluoromethyl) phenyl, 2-iodo-4-methylphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazinyl, pyrimidin-2-yl, pyrimidine -4-yl, pyrimidin-5-yl, pyridazinyl, triazol-1-yl, imidazol-1-yl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, Furan-3-yl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxdiazolyl, thiadiazolyl, quinolyl, isoquinolyl, tetrahydrofuryl, Saturation such as lolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl and 5-methyl-6-chromanyl, adamantyl, norbornyl Or unsaturated cycloalkyl, bicyclic, tricyclic, polycyclic, saturated or unsaturated heterocycles, unsubstituted or substituted phenyl, naphthyl, or heteroaryl ring systems and, for example, 3 Substituted analogues thereof such as -butyl-pyridin-2-yl, 4-bromo-pyridin-2-yl, 5-carboethoxy-pyridin-2-yl, 6-methoxyethoxy-pyridin-2-yl It includes.

Preferably, two of R ¹ , R ² , R ³ and R ⁴ are hydrogen. More preferably, R ¹ and R ² are hydrogen or R ³ and R ⁴ are hydrogen. Even more preferably, R ² , R ³ and R ⁴ are hydrogen or R ¹ , R ² and R ³ are hydrogen. Most preferably, R ² , R ³ and R ⁴ are hydrogen.

Preferably, n is from 0 to 8. Most preferably, n is 1 to 7. Preferably, m is 0-4. Most preferably, m is 0-2.

Preferably, D1 is -CXY, -CO-, or -CS-. More preferably, D1 is -CXY-. Preferably, D2 is -O- or -NX-. Preferably, E is -S-, -SiXY- or -SO _2- . A preferably, X and Y are, independently, H, halo, OH, SH, -C (O ) (C 1 -C 4) alkyl -, -C (O) O ( C 1 -C 4) alkyl-, - O- (C ₁ -C ₄ ) alkyl, -S- (C ₁ -C ₄ ) alkyl or substituted or unsubstituted (C ₁ -C ₄ ) alkyl. Preferably, Z is H, halo or G. More preferably, Z is H or G.

Preferably, each G is independently substituted or unsubstituted; 5, 6 or 7 atoms; Aryl, heteroaryl, heterocyclic, or cycloalkyl ring. More preferably, each G is independently substituted or unsubstituted phenyl, pyridyl, cyclohexyl, cyclopentyl, cycloheptyl, pyrrolyl, furyl, thiophenyl, thiazolyl, pyrazolyl, 1,3-dioxola Nil or morpholinyl. Even more preferably, G is unsubstituted or substituted phenyl, cyclopentyl, cycloheptyl, or cyclohexyl. Most preferably, G is cyclopentyl, cycloheptyl, cyclohexyl, phenyl or substituted phenyl, wherein the substituents are independently selected from 1 to 3 methyl, methoxy and halo.

Another aspect of the invention is a method of blocking ethylene receptors in a plant comprising applying the plant to an effective ethylene receptor blocking amount of a cyclopropene derivative or composition thereof.

In addition, the method comprising the step of applying to the plant an effective amount of cyclopropene derivatives or compositions thereof Methods of inhibiting abscission of plants, extending cut flower lifespan, and inhibiting ripening of harvested fruits and vegetables are disclosed.

The method of the present invention comprises contacting a plant with a cyclopropene derivative or a composition thereof in a solid, liquid or gaseous state, Cut flowers, harvested fruits, or harvested vegetables can be done in a variety of ways, such as exposing the cyclopropene derivatives or compositions thereof to the atmosphere infused. The above mentioned methods and other suitable application methods are described in detail below. In the present invention, "cntacting" means that cyclopropene and plants are closely associated with each other such that a sufficient number of ethylene acceptors are affected by cyclopropene.

Agricultural compositions comprising the compounds of the invention are also within the scope of the invention. Preferably, the composition comprises 0.005 to 99% by weight of the active compound of the present invention; Preferably 1 to 95% by weight; More preferably, it is 2 to 90 weight%; Even more preferably 3 to 80% by weight; Or most preferably 4 to 70% by weight. These compositions include, for example, carriers, extenders, binders, lubricants, surfactants and / or dispersants, wetting agents, spreading agents, dispersing agents, stickers, Adhesives, antifoams, thickeners and emulsifiers. Such adjuvants commonly used in the art are John W. McCutcheon, Inc. Publication Detergents and Emulsifiers, Annual, Allured Publishing Company, Ridgewood, New Jersey, U.S.A.

Unless specifically stated otherwise, as used herein, all percentages are by weight and all parts are parts by weight and can be included and combined. All ratios are by weight and all ratio ranges can be included and combined. All molar ranges can be included and combined.

For example, hexane, benzene, toluene, xylene, kerosene, diesel oil, hydrocarbons such as fuel oil and petroleum naphtha, ketones such as acetone, methyl ethyl ketone and cyclohexanone, chlorination such as methylene chloride Esters such as hydrocarbons, ethyl acetate, amyl acetate and butyl acetate, for example ethers such as ethylene glycol monomethyl ether and diethylene glycol monomethyl ether, ethanol, methanol, isopropanol, amyl alcohol, ethylene glycol, propylene glycol, butyl carbox Many organic solvents can be used as carriers for the active compounds of the present invention, such as alcohols such as bititol acetate and glycerin.

Mixtures of water and organic solvents may also be used as inert carriers for the active compounds in solution or in emulsion.

Solid, liquid and gas blends may also be prepared by a variety of conventional methods. Thus, the active ingredient, in solid form, can be combined with this finely divided solid carrier. In addition, the active ingredient in liquid form, including mixtures, solutions, dispersions, emulsions and suspensions of the active ingredient can be mixed with the solid carrier in finely divided form. Furthermore, the active ingredient in solid form can be mixed with the liquid carrier to form a mixture, solution, dispersion, emulsion, suspension and the like.

The active compounds of the present invention can be applied to plants by various suitable means. For example, the active compound may be applied alone in gaseous, liquid or solid form by contacting the plant with which the compound is to be treated. Moreover, the active compound can be converted into the salt form and then applied to the plant. In addition, compositions containing one or more active compounds of the invention can be prepared. The composition can be applied in gaseous, liquid or solid form by contact with the plant to be treated. Such compositions may comprise inert carriers. Likewise, in gaseous form, the compound may be dispersed in an inert gas carrier to provide a gaseous solution. The active compound may be suspended in a liquid solution, such as an organic solvent or an aqueous solution, which can act as an inert carrier. The solution containing the active compound may be heterogeneous or uniform and may be in various forms including mixtures, dispersions, emulsions, suspensions and the like.

The cyclopropenes can also be encapsulated into molecular encapsulating agents. Preferred encapsulating agents include cyclodextrins, crown ethers, polysiloxanes and zeolites. More preferred encapsulating agents include α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. The most preferred encapsulating agent can vary depending on the size of the R substituent. However, as will be appreciated by those skilled in the art, any cyclodextrin, cyclodextrin mixture, cyclodextrin polymer, as well as modified cyclodextrins may also be used in the present invention. Cyclodextrins are available from Wacker Biochem Inc., Adrian, MI or Cerestar USA, Hammond, IN, as well as other distributors. When encapsulated, the preferred concentration of cyclopropene is typically lower than in other compositions due to the capacity limit of the molecular encapsulating agent.

The active compounds and their compositions can also be applied as aerosols, for example by dispersing them in air using a compressor such as nitrogen, carbon dioxide, dichlorodifluoromethane, trichlorofluoromethane or other halocarbons.

The amount of cyclopropene needed to inhibit the action of ethylene can vary depending on the particular cyclopropene, the type and amount of plant material present, the cyclopropene composition used and the amount to be treated. In general, a gasification (volume / volume measurement) concentration of cyclopropene of about 0.1 ppm to 1000 ppm (part per million) in the chamber being treated provides sufficient ethylene inhibition. Likewise, an applied spraying (measured by weight / weight) concentration of cyclopropene from about 0.01 parts per billion to 1000 ppm provides sufficient ethylene inhibition.

The term “plant” is used herein in its general sense and includes, for example, trees and shrubs; Herbs; Vegetables, fruits and crops; And woody-stemmed plants, such as ornamental plants. Plants treated by the method of the present invention include whole or any portion thereof, such as crops, potted plants, seeds, cut flowers (stems and flowers) and harvested fruits and vegetables.

Plants treated with the compounds and methods of the invention are preferably treated with a non-phytotoxic amount of the active compound.

The present invention includes, for example, ripening and / or aging of flowers, fruits and vegetables; Abscission of leaves, flowers, and fruits; Shortening the life of ornamental plants such as potted plants, cut flowers, shrubs, seeds and dormant seedlings; In some plants (e.g., legumes such as peas), growth inhibition, growth promotion (e.g. rice), auxin activity, late growth inhibition, apical dominance control, increased branching, and increased tillering , Modification of plant forms, modifying infectivity of plant pathogens such as fungi, changes in the biochemical composition of plants (increasing leaf area relative to stem area), pausing or inhibiting flowering and seed development, doping It can be used to modulate a variety of different ethylene reactions, such as lodging effects, promoting seed germination and dormancy and hormonal or epinasty effects.

The active compounds of the present invention have been surprisingly demonstrated to act as potent inhibitors of ethylene action on plants, fruits and vegetables even when applied at very low concentrations. Among other things, the compounds of the present invention exhibit nonresponsive results for ethylene for longer periods of time compared to compounds known in the art. This longer term insensitivity is true even when the compounds of the present invention are applied at lower concentrations than conventional compounds.

Another embodiment of the invention is directed to novel cyclopropene member compounds. These compounds include compounds of the formula, enantiomers, stereoisomeric salts thereof and mixtures thereof; Or these compositions.

In the above formula,

a) ^one of R ¹ and R ³ is H and R ² , R ⁴ and the other of R ¹ and R ³ are independently selected from H and a group of the formula-(L) _n -Z,

Iii) n is an integer from 0 to 12,

Ii) L is each independently selected from members of the D1, D2, E or J groups;

D1 is a chemical formula

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D2 is a chemical formula

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,

E is a chemical formula

; 이며

; And

J is a chemical formula

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,

A) X and Y are each independently a group of the formula-(L) _m -Z;

 B) m is an integer from 0 to 8;

 C) no more than two D2 or E groups are adjacent to each other and J groups are not adjacent to each other;

Z) Z is each independently

  A) hydrogen, halo, cyano, nitro, nitroso, azido, chlorate, bromate, iodate, isocyanato, isocyanato, isothiocyanato, pentafluorothio, or

 B) G is unsubstituted or substituted; Unsaturated, partially saturated or saturated; Monocyclic, bicyclic, tricyclic or fused; A G group which is a 3 to 14 membered carbocyclic or heterocyclic ring system;

    1) when the ring system has a 4 membered heterocyclic ring, the heterocyclic ring has 1 heteroatom;

    2) when the ring system has 5 or more members of a heterocyclic ring or a polycyclic heterocyclic ring, the heterocyclic or polycyclic heterocyclic ring has 1 to 4 heteroatoms;

    3) each heteroatom is independently selected from N, O and S;

    4) the number of substituents is 0 to 5 and each substituent is independently selected from X;

b) the total number of non-hydrogen atoms in each compound is 50 or less;

c) the total number of heteroatoms in-(L) _n -Z is 0-4;

d) ⅰ) R ¹ or R ³ has at least one G group;

   Ii) at least one L group is E group; or

Iii) at least one of R ¹ , R ² , R ³ and R ⁴ has 1 to 4 non-hydrogen atoms and at least one of R ¹ , R ² , R ³ and R ⁴ has more than 4 non-hydrogen atoms Has an atom;

a)-(L) _n -Z is not trimethylsilyl, trimethylsilylsulfonyl or thiol;

b) R ¹ is phenylsulfonyl, phenylthioethyl, diphenylhydroxymethyl, benzo [g] quinoline-7-ol-1-methyl, malonate derivative, substituted 3-aminocyclohexenone, dialkoxybenzylamino Not carbonyl; And

c) R ³ is 2-phenyl-ethenyl, phenylthio, (4-bromo-2-methylphenyl) carbamic acid N-carbonyl, (4-bromo-2-methylphenyl) carbamic acid ethyl ester N-carbonyl , Malonate derivatives, aryloxy or dialkoxybenzylaminecarbonyl.

The compounds of the present invention can be prepared in a variety of ways. Generally, Closs, G.L. Advan. Alicyclic Chem. 1966, 1, 53-127 and Al Dulayymi, A. R .; Al Dulayymi, J. R; Baird, M. S .; And Koza, G. Russian Jouranl of Organic Chemistry 1997, 33, 798-816.

As shown, the reaction of the bromo-olefin with dibromocarbene forms tribromocyclopropane, which can be converted to cyclopropene by methyllithium or other organolithium compounds. (Baird, MS; Hussain, HH; Nethercott, WJ Chem. Soc.Perkin Trans. 1 1986, 1845-1854 and Baird, MS; Fitton, HL; Clegg, W; McCamley, AJ Chem. Soc.Perkin Trans. 1 1993, 321-326 ). If one equivalent of methyllithium or other alkyllithium is used, the mono-brominated cyclopropene is obtained. As two or more equivalents of alkyl lithium, lithiated cyclopropene is formed. This can be quenched with water to obtain the cyclopropene (E = H) shown.

In addition, the cyclopropenyl lithium reacts with an electrophile to form derived cyclopropenes. Examples of such electrophiles include alkylating agents, trisubstituted chlorosilanes, borate, dialkyl or diaryl disulfides, ketones, aldehydes, esters, amides and nitriles.

The bromo-olefins can be prepared by standard methods. Chloro-olefins can be used in place of bromo-olefins.

The tribrominated cyclopropane can also be converted to mono-brominated cyclopropane using a reducing agent such as diethylphosphite. Other reducing agents can be used.

The 1,1-disubstituted olefins also give dibrominated intermediates by reaction with dibromocarbenes. It can be reduced to mono-brominated cyclopropane using zinc. Cyclopropene is obtained by removing bromine with a base (see Binger, P. Synthesis 1974, 190).

Cyclopropene is deprotonated with a strong base such as sodium amide in liquid ammonia to yield cyclopropene substituted by reaction with an alkyl halide or other electrophile. (Schipperijn, AJ; Smael, P . ; Recl. Trav. Chim. Pays-Bas, 1973, 92, 1159). Substituted cyclopropenes can be deprotonated with alkyllithium reactants and reacted with electrophiles.

Tribromocyclopropane or cyclopropene containing alcohol can be converted to good leaving groups such as sulfonate derivatives. The leaving group is substituted with an electrophilic agent to obtain another substituted cyclopropene.

1-trialkylsilyl-2-hydroxycyclopropane obtained from vinyltrialkylsilane can act as a precursor to cyclopropane. (Mizojiri, R .; Urabe, H .; Sato, F. J. Org Chem. 2000, 65, 6217)

1-trialkylsilyl-2-halocyclopropane is also fluorine-catalyzed to yield cyclopropene. (Billups, WE; Lee, GA; Arney, BE; Whitmire, KH J. Am. Chem. Soc., 1991, 113, 7980 and Banwell, MG; Corbett, M .; Gulbis, J .; Mackay, MF; Reum, ME J. Chem. Soc.Perkin Trans. 1, 1993, 945).

Adding diazo compounds to acetylene is another method that can be used for the synthesis of cyclopropene. (Mueller, P .; Cranisher, C; Helv. Chim. Acta 1993, 76, 521).

The ester can be hydrolyzed to carboxylic acid.

Likewise, dihalocarbene can be added to acetylene to give 1-alkyl-3,3-dihalocyclopropene (Bessard, Y .; schlosser, M .; Tetrahedron, 1991, 47, 7323).

The compounds of the present invention can also be obtained from malonate derivatives as shown.

Other methods of preparing cyclopropenes can be found in the following documents: Duerr, H., Angew. Chem. 1967, 24, 1104; J. Am. Chem. 1963, 85, 3796; Baird, MS; Dale, CM; Al Dulayymi, JR J. Chem. Soc. Perkin Trans. 1, 1993, 1373-1374; Koster, R. et al. Liebigs Annalen Chem. 1973, 1219-1235; Closs, GL; Closs, LE, J. Am. Chem. Soc., 1961, 83, 1003-1004; Stoll, AT; Negishi, E., Tetrahedron Lett. 1985, 26, 5671-5674.

Hereinafter, the present invention will be described in detail through examples.

General: All cyclopropenes were stored at -80 ° C. All reactions were carried out under nitrogen crisis. Flash chromatography of cyclopropene was carried out under a nitrogen atmosphere. All target compounds are at least 80% pure unless otherwise noted. The monosubstituted cyclopropenes are never heated and care should be taken to minimize the time for which these compounds are at room temperature.

Example 1 Preparation of 1-Chloro-4-cycloprop-1-enylmethyl-benzene (Compound 1)

a. 1- (2-Bromo-allyl) -4-chloro-benzene

A 8 ml (0.0622 mol) solution of 2,3-dibromopropene dissolved in 50 ml of diethyl ether was placed under a nitrogen atmosphere using a Firestone valve. While cooling in an ice bath, a 62 mL (0.062 mol) solution of 1M 4-chlorophenylmagnesium bromide dissolved in diethyl ether was added slowly through an addition funnel. After stirring for 2 hours warming to room temperature, the reaction was recooled in an ice bath and then 50 ml of 1N hydrochloric acid was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo. The residue was triturated with cold pentane to give 12.0 g of 1- (2-bromo-allyl) -4-chloro-benzene as an oil, which was used without further purification.

b. 2- (4-chlorophenylmethyl) -1,1,2-tribromocyclopropane

0.686 g (0.00213 mol) of tetrabutyl ammonium bromide was added to 11.4 g (0.0494 mol) of 1- (2-bromo-allyl) -4-chloro-benzene dissolved in 20 ml of bromoform. After heating to 58.5 ° C. for 1 hour, 10.7 ml of 50% aqueous sodium hydroxide was added. This was repeated seven times over two hours. After cooling to room temperature, hexanes and water were added. The mixture was gravity filtered through qualitative pullroot filter paper. The resulting mixture was transferred to a separatory funnel and the phases separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo. The residue was purified by column chromatography with hexane to give 2.3 g of 2- (4-chlorophenylmethyl) -1,1,2-tribromochloropropane.

c. 1- (4-chlorophenylmethyl) -cyclopropene

A 1.20 g solution of 2- (4-chlorophenylmethyl) -1,1,2-tribromochloropropane dissolved in 6 ml of diethyl ether was placed under a nitrogen atmosphere using a Firestone valve. While cooling in an ice bath, 6.38 ml (0.00893 mol) of 1.4 M methyllithium dissolved in diethyl ether was added using a syringe. After 15 minutes, 2 ml of water was added using a syringe. The resulting mixture was transferred to a separatory funnel and the phases separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo at 20 ° C. water bath temperature to give 0.430 g of 1- (4-chlorophenylmethyl) -cyclopropene as an oil.

Example 2: Preparation of 1- (2-thienyl) methyl-cyclopropene (Compound 2)

The Grignard yard reagent of 2-bromothiophene was prepared and converted to 1- (2-thienyl) methyl-cyclopropene according to the same reaction procedure as used for the preparation of compound 1.

Example 3: Preparation of 2- (3-cycloprop-1-enyl-propyl)-[1,3] dioxane (Compound 3)

2- (3-cycloprop-1-enyl-propyl) was prepared according to the same reaction procedure as for the preparation of Grignard yard reagent of 2- (2-bromoethyl) -1,3-dioxane and used for preparing Compound 1. -[1,3] dioxane was converted.

Example 4: Preparation of 1- (6- (phenyldimethylsilyl) -hexyl) -cyclopropene (Compound 4)

a. 2-bromo-8- (phenyldimethylsilyl) -oct-1-ene

Commercially available pentamethylenebis (magnesium bromide) (37 mL, 0.5 M in THF, 18.5 mmol) was cooled in an ice bath. A solution of 3.16 g (18.5 mmol) of phenyldimethylchlorosilane dissolved in approximately 7 mL of THF was added. The reaction mixture was stirred at 5 ° C. for 15 minutes, then at room temperature for 35 minutes, and then cooled to 5 ° C. again. To the reaction mixture was added 2,3-dibromopropene (3.7 g, 18.5 mmol) dissolved in approximately 5 ml of THF and held at 5 ° C. for 5 minutes, then warmed to room temperature and stirred overnight. The reaction mixture was quenched with water. Ether and a small amount of 1N HCl were added. The phases were separated and the organic phase was washed with water and brine, dried over magnesium chloride and stripped. Column chromatography gave 1.47 g of 2-bromo-8- (phenyldimethylsilyl) -oct-1-ene as a colorless oil.

b. N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide and N, N'-dibenzyl-N, N, N', N'-tetraethylethylenediammonium di Bromide (Transfer Catalyst)

50.1 g (292 mmol) of benzyl bromide was added to a stirred solution of 16.5 g (142 mmol) of N, N, N ', N'-tetramethylethylenediamine dissolved in 60 g of acetonitrile. The mixture was warmed up and stirred for 2.5 h. At this time a large amount of precipitation was observed. The slurry was diluted with diethyl ether, filtered, washed with diethyl ether and dried to afford the desired N, N'-dibenzyl-N, N, N ', N'-tetramethylethylene as a white solid at mp 230-232 ° C. 61.8 g of diammonium dibromide were obtained.

In a similar manner, N, N'-dibenzyl-N, N, N ', N'-tetra is a white solid at mp 190-193 ° C, using N, N, N', N'-tetraethylethylenediamine. Ethylethylenediammonium dibromide is obtained.

c. 2- (6- (phenyldimethylsilyl) -hexyl) -1,1,2-tribromocyclopropane

1.4 g of 2-bromo-8- (phenyldimethylsilyl) -oct-1-ene, 3.2 g of 45% aqueous potassium hydroxide solution (25.6 mmol), N, N'-dibenzyl-N, N, N ', A mixture of 0.2 g of N'-tetraethylethylenediammonium dibromide and 7.5 ml of methylene chloride was treated with 1.1 ml (12.6 mmol) of bromoform. The well-stirred reaction mixture was kept at room temperature overnight. Water and methylene chloride were added and the phases separated. The methylene chloride phase was stripped by drying over magnesium sulfate. A small amount of heptane was added during the strip to help remove residual bromoform. Column chromatography gave 1.02 g of 2- (6- (phenyldimethylsilyl) -hexyl) -1,1,2-tribromocyclopropane as a colorless oil.

d. 1- (6- (phenyldimethylsilyl) -hexyl) -cyclopropene

A 0.95 g (1.9 mmol) solution of 2- (6-phenyldimethylsilyl) -hexyl) -1,1,2-tribromocyclopropane dissolved in ether was cooled to -78 ° C. Excess methyllithium (1.4 M, 4.1 mL, 5.7 mmol) was added and the reaction mixture was left in an ice bath for 30 minutes and then quenched with water. The phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 200 mg of a colorless liquid 1- (6- (phenyldimethylsilyl) -hexyl) -cyclopropene.

Example 5: Preparation of 1- (α, α-dimethylbenzyl) -cyclopropene (Compound 5)

a. α, α-dimethylbenzyl cyanide

To a 1000 ml three-necked flask equipped with mechanical agitation, external water bath, internal thermometer, condenser and fractional funnel, 250 g of dimethyl sulfoxide, 59 g (504 mmol) of benzyl cyanide, and 160 g (1127 mmol) of methyl iodide were added. The internal temperature was raised to + 45 ° C. and then 83 g of 50% aqueous NaOH was added dropwise at 0.7 drops per second. The addition was complete after two hours. The concentrated slurry was cooled and diluted with 1000 ml of water, 500 ml of diethyl ether, and 500 ml of hexane. The organic layer was separated and concentrated. This included mono and dimethylated compounds. To this concentrate 250 g of dimethyl sulfoxide, 60 g of methyliodide, and 37 g of 50% aqueous NaOH were further added for 2 hours as above. After cooling, the organic layer was washed with 1000 ml of water, 500 ml of diethyl ether, and 500 ml of hexane, the organic layer was washed with 500 ml of water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 69 g of α, α-dimethylbenzylcyanide.

b. α, α-dimethylbenzyl methyl ketone

Under a dry nitrogen atmosphere, 30 g (207 mmol) of α, α-dimethylbenzyl cyanide and 200 ml of diethyl ether were added to a 500 ml round bottom flask equipped with magnetic stirring, a reflux condenser and septum. Methyllithium (1.4M, 160ml, 224mmol) dissolved in diethyl ether was added via cannula over 3 minutes. The reaction exothermed to mild reflux during the addition. After stirring for 20 minutes, the reaction was terminated by the slow addition of 45 ml of concentrated aqueous hydrochloric acid diluted with 100 ml of water. After stirring for 1 hour, the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 32 g of α, α-dimethylbenzyl methyl ketone.

c. 1- (α, α-dimethylbenzyl) -1-chloroethylene

15 g (98 mmol) of POCl ₃ , 30 g (145 mmol) of PCl ₅ and 19.9 g (123 mmol) of α, α-dimethylbenzyl methyl ketone were placed in a 250 ml round bottom flask equipped with magnetic stirring and a reflux condenser. The reaction was heated in an oil bath to bring the external temperature to 110 ° C. After 1 hour the gas generation stopped. The reaction was cooled and carefully poured into ice and aqueous ammonium hydroxide. Extraction work up with diethyl ether gave a mixture of 1- (α, α-dimethylbenzyl) -1-chloroethylene and 1- (α, α-dimethylbenzyl) -1,1-dichloroethane . Vacuum distillation yielded purified 1- (α, α-dimethylbenzyl) -1-chloroethylene (bp (23torr) 110-120 ° C).

d. 1- (α, α-dimethylbenzyl) -1-chloro-2,2-dibromocyclopropane

In a 100 ml round bottom flask equipped with magnetic stirring, 4.5 g (25 mmol) of 1- (α, α-dimethylbenzyl) -1-chloroethylene, 25 g (100 mmol) of bromoform, 27 g of methylene chloride, N, N'-di 0.37 g of benzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide, and 12.4 g (100 mmol) of 45% aqueous KOH were added. Rapid stirring overnight afforded 20% of the desired cyclopropane converted. The aqueous layer was washed with water and fresh bromoform, catalyst and KOH were provided again overnight to obtain further conversion. The third offering was considered sufficient. The aqueous washed organic layer was evaporated in vacuo and chromatographed with silica gel, dissolved in 2% diethyl ether in hexane, to give 1- (α, α-dimethylbenzyl) -1-chloro-2,2-dibromosi. 4.2 g of clopropane was obtained.

e. 1- (α, α-dimethylbenzyl) -cyclopropene

Under dry nitrogen, 1.73 g (4.9 mmol) of 1- (α, α-dimethylbenzyl) -1-chloro-2,2-dibromocyclopropane, and 12 ml of diethyl ether, in a 50 ml flask equipped with a stir bar and septum. Was added. After cooling for 10 minutes in an ice bath, 9.0 ml (12.6 mmol) of 1.4 M methyllithium dissolved in diethyl ether were added by syringe. A precipitate formed immediately. After stirring for 10 minutes, the reaction was terminated with 3 ml of water. The aqueous layer was removed and the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo at a water bath temperature of + 25 ° C. to obtain 0.94 g of 1- (α, α-dimethylbenzyl) -cyclopropene.

Example 6: Preparation of 3-methyl-3-phenylcyclopropene (Compound 6)

a. 2,2-dibromo-1-methyl-1-phenylcyclopropane

20.9 ml (0.400 mol) of 50% aqueous sodium hydroxide in a solution of 12.5 ml (0.0963 mol) of α-methylstyrene and 1.34 g (0.00416 mol) of tetrabutylammonium bromide dissolved in 30.4 ml (0.348 mol) of bromoform Was added slowly. After heating to 55 ° C. for 1 hour, 20.9 ml (0.400 mol) of 50% aqueous sodium hydroxide were added. After an additional 2 hours of heating, the reaction was cooled to room temperature when hexane and water were added. The resulting mixture was transferred to a separatory funnel and the phases separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo. The product was isolated by vacuum distillation to give 24.1 g of 2,2-dibromo-1-methyl-1-phenylcyclopropane as an oil.

b. 2-bromo-1-methyl-1-phenylcyclopropane

To a solution of 6.40 g (0.0221 mol) of 2,2-dibromo-1-methyl-1-phenylcyclopropane dissolved in 22 g of methanol, 2.16 g (0.0360 mol) of glacial acetic acid and 2.11 g (0.0323 mol) of zinc dust were added. . After stirring for 4 hours at room temperature, the solvent was removed in vacuo. Hexane and water were added to the resulting residue. The resulting mixture was transferred to a separatory funnel and the phases separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to yield 3.24 g of 2-bromo-1-methyl-1-phenylcyclopropane as an oil which was used without further purification.

c. 3-methyl-3-phenylcyclopropene

1.429 g (0.0127 mol) of potassium tert-butoxide was added to a solution in which 1.56 g (0.00739 mol) of 2-bromo-1-methyl-1-phenylcyclopropane was dissolved in 5 ml of dimethyl sulfoxide. The reaction was heated to 72 ° C. for 4 h, then diethyl ether and water were added. The resulting mixture was transferred to a separatory funnel and the phases separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to yield 0.88 g of 70% pure 3-methyl-3-phenylcyclopropene as an oil. The main byproduct (about 20%) was 1-methyl-1-phenylcyclopropane.

Example 7: Preparation of 3-methyl-3-phenoxymethylcycloprop-2-ene (Compound 7)

3-methyl-3-phenoxymethylcycloprop with 90% purity of the metalyl phenyl ether in a similar manner to the conversion of α-methylstyrene to 3-methyl-3-phenylcyclopropene (Example 6). It was converted to -2- yen.

Example 8: Preparation of 1-methyl-2-benzylcyclopropene (Compound 8)

To a 50 ml flask equipped with a stir bar and cetum under dry nitrogen, 1 mg of 1,10-phenanthroline, 1.34 g (11.5 mmol) of N, N, N'N'-tetramethylethylenediamine and 25 ml of tetrahydrofuran were added. . The mixture was cooled to −30 ° C. and 1-methylcyclopropene (prepared from 3-chloro-2-methyl-propene; Hopf, H .; Wachholz, G; Walsh, R. Chem. Ber . 1985, 118 , 3579, and Koster, R et al ., Liebigs Annalen Chem , 1973, 1219-1235) 1.5 ml (22 mmol) were added using a syringe. 1.0 ml of 1.6 M butyllithium dissolved in hexane was added to give a dark green solution. 6.0 ml of 1.6 M butyllithium solution (9.6 mmol) was further added and stirred at -30 [deg.] C. for 15 minutes to obtain a lithiated 1-methylcyclopropene solution. Benzyl bromide 1.64g was added and the temperature was raised slowly at +5 degreeC over 20 minutes, and the bright color was obtained. The reaction separated by diethyl ether and dilute hydrochloric acid was terminated with 0.5 ml of methanol, rapidly evaporated in vacuo at a water bath temperature of + 25 ° C., dried over anhydrous magnesium sulfate and evaporated again in vacuo to 1-methyl-2-benzyl. 1.3 g of cyclopropenes were obtained.

Example 9: Preparation of 1- (2- (4-chlorophenylthio) ethyl) cyclopropene (Compound 9)

a. 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene

In an ice bath, a solution of 10.38 g (0.0687 mol) of 3-bromo-3-buten-1-ol dissolved in 20 ml of diethyl ether in which 50 mg (0.000263 mol) of p-toluene sulfonic acid monohydrate was dissolved was cooled, followed by ethyl vinyl ether. 19 ml (0.199 mol) was slowly added dropwise while maintaining the internal temperature at <10 ° C. After 1 hour at 0 ° C., several drops of triethylamine were added. The reaction mixture was poured into water. The resulting mixture was transferred to a separatory funnel to separate phases. The separated organic layer was washed with brine, dried over potassium carbonate and filtered. The solvent was removed from the filtrate in vacuo to afford 14.04 g of 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene as an oil.

b. 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane

14.02 g (0.0682 mol) of 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene in 108 ml of methylene chloride containing 0.5-0.9 ml of 45% aqueous potassium hydroxide 16.4 ml (0.118 mol) of bromoform, 2.88 g (0.00628 mol) of N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammoniumdibromide and 28 ml of 45% aqueous potassium hydroxide (0.314 mol) was added. After 3 days, the reaction mixture was poured into water. The resulting mixture was transferred to a separatory funnel to separate phases. 2.88 g (0.00628 mol) of N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide and 28 ml (0.314 mol) of 45% aqueous potassium hydroxide were added to the separated organic layer. It was. After 24 hours, hexanes and water were added. This mixture was gravity filtered with qualitative fluted filter paper. The resulting mixture was transferred to a separatory funnel to separate phases. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 17.0 g of 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane as an oil.

c. 1,1,2-tribromo-2- (2-hydroxyethyl) cyclopropane

P-toluene sulfonic acid mono in a slurry of 16.5 g (0.0418 mol) of 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane in 145 ml of methanol and 40 ml of water 0.306 g (0.00161 mol) hydrate and 145 ml 6M hydrochloric acid were added. After stirring for 1 hour at room temperature, the solvent was removed from the reaction mixture in vacuo. To the residue was added ethyl acetate and water. The resulting mixture was transferred to a separatory funnel to separate phases. The separated organic layer was washed with brine, dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 11.9 g of 1,1,2-tribromo-2- (2-hydroxyethyl) cyclopropane as an oil.

d. 1,1,2-tribromo-2- (2-benzenesulfonyloxyethyl) cyclopropane

A solution of 3.00 g (0.00929 mol) of 1,1,2-tribromo-2- (2-hydroxyethyl) cyclopropane dissolved in methylene chloride in which 0.901 ml (0.0111 mol) of pyridine was dissolved was cooled to 0 ° C, 1.18 ml (0.00929 mol) of benzenesulfonyl chloride was added dropwise by pipette. The temperature was raised to room temperature. After 3 days, water was added. The resultant mixture was transferred to a separatory funnel to separate phases. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 3.10 g of 80% pure 1,1,2-tribromo-2- (2-benzenesulfonyloxyethyl) cyclopropane as an oil.

e. 2- (2- (4-chlorophenylthio) ethyl) -1,1,2-tribromocyclopropane

To a solution of 0.234 g (0.162 mol) of 4-chlorothiophenol in 3 ml of methanol was added 0.371 ml (0.00162 mol) of 25% sodium methoxide dissolved in methanol. After stirring at room temperature for about 1 hour, the solvent was removed in vacuo. A solution in which 0.750 g (0.00151 mol) of 1,1,2-tribromo-2- (2-benzenesulfonyloxyethyl) -cyclopropane was dissolved in anhydrous N, N-dimethylformamide was added to the residue. After stirring for 24 hours at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 0.750 g as an oil, which was subsequently purified by column chromatography with 0.5% to 1% diethyl ether / hexanes to give 2- (2- (4-chlorophenyl). 0.500 g of -thio) ethyl) -1,1,2-tribromocyclopropane was obtained.

f. 1- (2- (4-chlorophenylthio) ethyl) cyclopropene

In a nitrogen atmosphere, a solution obtained by dissolving 0.500 g (0.0011 mol) of 2- (2- (4-chlorophenylthio) ethyl) -1,1,2-tribromocyclopropane in 6 ml of diethyl ether was firestone. It was added using a valve. While cooling in an ice bath, 2.38 ml (0.00334 mol) of 1.4 M methyllithium dissolved in diethyl ether was slowly added by syringe. After 15 minutes, 2 ml of water was added by syringe. The resulting mixture was transferred to a separatory funnel to separate phases. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate by vacuum in a water bath of 20 DEG C or lower to give 0.100 g of 1- (2- (4-chlorophenylthio) ethyl) cyclopropene as an oil.

Example 10: 2- (2-benzenesulfonyloxyethyl) -cyclopropene (Compound 10)

A solution obtained by dissolving 0.745 g (0.00150 mol) of 1,1,2-tribromo-2- (2-benzenesulfonyloxyethyl) -cyclopropane in 4 ml of diethyl ether was carried out using a firestone valve under a nitrogen atmosphere. Put it in. Cool to -78 ° C in a dry ice / acetone bath, and slowly add 23.45 ml (0.00450 mol) of 1.4 M methyllithium dissolved in diethyl ether into the syringe. After 15 minutes, the temperature was raised to 0 ° C. using an ice bath, and again maintained at −78 ° C. for 30 minutes, and then 2 ml of water was added to the syringe. The resulting mixture was transferred to a separatory funnel to separate phases. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate by vacuum in a water bath having a temperature of 20 ° C. or lower, and 30% impurity 1- (2-hydroethyl) cyclopropene as oil and 70% pure 2- (2-benzenesulfonyloxy Ethyl) -cyclopropene was obtained> 0.155 g.

Example 11: Preparation of 2- (1- (4-bromopyrazole))-1-ethylcyclopropene (Compound 11)

a. 2-hydroxy-1-ethylcyclopropene

A solution in which 1.15 g (3.6 mmol) of 1,1,2-tribromo-2- (2-hydroethyl) cyclopropane (prepared above) was dissolved in 40 ml of ether was cooled to -78 ° C. Methyllithium (1.4M, 10.3 ml, 14.4 mmol) was added. The reaction mixture was raised to 5 ° C. and maintained for 1 and a half hours. The reaction was terminated with water and the phases separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped. The crude product was used for the next reaction.

b. 2-methanesulfonyl-1-ethylcyclopropene

The crude product of the reaction was dissolved in 5 ml of ether and cooled in an ice bath. Triethylamine (1 ml) was added followed by 0.49 g (4.3 mmol) methanesulfonylchloride. The reaction mixture was stirred for 1 hour. Water and additional ether were added and the phases separated. The ether phase was washed twice with water, brine, dried over magnesium sulfate and stripped to give 380 mg of 2-methanesulfonyl-1-ethylcyclopropene as a pale yellow liquid.

c. 2- (1- (4-bromopyrazole))-1-ethylcyclopropene

0.51 g (3.5 mmol) of 4-bromopyrazole was added to a suspension of 60% sodium hydride (0.13 g, 3.3 mmol) dissolved in 5 ml of DMF. The reaction was stirred at room temperature for 15 minutes and then cooled in an ice bath. 2-methanesulfonyl-1-ethylcyclopropene (280 mg, 1.7 mmol) was added. The ice bath was removed and the reaction stirred at room temperature for 2 hours. Ether and water were added to the reaction mixture and the phases were separated. The aqueous phase was extracted with additional ether. The combined ether phases were washed three times with water, brine, dried over magnesium sulfate and stripped. The product was chromatographed to give 30 mg of 72% pure 2- (1- (4-bromopyrazole))-1-ethylcyclopropene.

Example 12 Preparation of 7- (1-imidazole) -1-heptylcyclopropene (Compound 12)

a. 1- (1-ethoxyethoxy) -6-bromohexane

To a cooled solution in which 80 mg of toluenesulfonic acid was dissolved in 40 ml of ether, 20 g (110 mmol) of 6-bromohexanol and 40 ml of ethyl vinyl ether were simultaneously supplied using an addition funnel. For about 1 hour of feeding, the temperature of the reaction mixture was kept below 7 ° C. The reaction mixture was stirred for about 20 minutes and then about 1 ml of triethylamine was added. The reaction mixture was washed with water and brine, dried over potassium carbonate, filtered and stripped to give 25.7 g of a pale yellow liquid which was used without further purification.

b. 9- (1-ethoxyethoxy) -2-bromonone-1-ene

A slurry of 5.6 g (230 mmol) of magnesium turnings was treated with a small amount of 1,2-dibromoethane in 100 ml of THF. 1- (1-ethoxyethoxy) -6-bromohexane (38.5 g, 152 mmol) was slowly fed into the reaction mixture and the temperature was maintained at 40-50 ° C. At the end of the addition, the reaction mixture was held for 20 minutes and then transferred using cannula to a solution in which 33.4 g (167 mmol) of 2,3-dibromopropene was dissolved in 25 ml THF at 0 ° C. The reaction mixture was stirred at 0 ° C. for 15 minutes, then at room temperature for 15 minutes and terminated with water. The reaction mixture was transferred to a separatory funnel. A small amount of 1N HCl was added, the phases were separated, the ether phase was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 33.63 g of a yellow liquid, which was further purified. Used without.

c. 1,1,2-tribromo-2- (7-hydroxyheptyl) cyclopropane                 

9- (1-ethoxyethoxy) -2-bromonone-1-ene (33.63 g, 115 mmol), N, N'-dibenzyl-N, N, N'N'-tetraethylethylenediammonium dibromide A mixture of 4.1 g, 45 g potassium hydroxide 42 g (337 mmol), 93 g (368 mmol) bromoform, and 280 g methylene chloride was stirred rapidly for 2 days at room temperature. When the reaction was stopped, the reaction mixture was transferred to a separatory funnel and washed with water. The methylene chloride phase was transferred to a flask and treated with an equal amount of phase transfer catalyst and 45% potassium hydroxide, followed by stirring for an additional 3 days at room temperature. The reaction mixture was washed with water and the methylene chloride phase was dried over magnesium sulfate and stripped. The product was treated with 320 ml of methanol and 40 ml of 1N HCl for 1 hour at room temperature. The methanol was stripped and ethyl acetate was added. The organic phase was washed with water and brine and then treated with 200 ml of silica gel. Filtration followed by stripping gave 38 g of the assay product. This was chromatographed with silica gel to give 19.0 g of 1,1,2-tribromo-2- (7-hydroxyheptyl) cyclopropane as a pale yellow liquid.

d. 1- (7-hydroxyheptyl) -cyclopropene

A solution of 1.0 g (2.5 mmol) of 1,1,2-tribromo-2- (7-hydroxyheptyl) cyclopropane dissolved in 25 ml of ether was diluted to 7.2 ml (1.4 M, 10 mmol) of methyllithium at -78 ° C. Treated. After 5 minutes, the reaction mixture was raised to 0 ° C. and maintained at this temperature. The reaction was terminated with saturated ammonium chloride. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 240 mg of 1- (7-hydroxyheptyl) -cyclopropene.                 

e. 1- (7-methanesulfonyloxyheptyl) -cyclopropene

A solution of 3.8 mmol of 1- (7-hydroxyheptyl) -cyclopropene dissolved in 50 ml of ether was cooled in an ice bath. Triethylamine (1 ml) and 0.48 g (4.2 mmol) methanesulfonylchloride were added and the reaction mixture was stirred at 0 ° C. for 2 and a half hours. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 1- (7-methanesulfonyloxyheptyl) -cyclopropene, which was used without further purification.

f. 7- (1-imidazole) -1-heptylcyclopropene

0.14 g (2 mmol) of imidazole was added to a suspension of 60% sodium hydride (0.08 g, 2 mmol) dissolved in 5 ml of DMF in an ice bath. The reaction was stirred for 15 minutes, then 0.3 g (1.3 mmol) of 1- (7-methanesulfonyloxyheptyl) -cyclopropene dissolved in 3 ml of DMF. The reaction mixture was stirred at room temperature for 10 minutes, then the ice bath was removed and the reaction was stirred at room temperature for 1 hour. Ether and water were added to the reaction mixture and the phases were separated. The aqueous phase was extracted with additional ether. The combined ether phases were washed three times with water, brine, dried over magnesium sulfate and stripped. The product was chromatographed to give 80 mg of 7- (1-imidazole) -1-heptylcyclopropene.

Example 13: Preparation of 7- (diphenylamino) -1-heptylcyclopropene (Compound 13)

Diphenylamine (0.42 g, 2.5 mmol) dissolved in 10 ml of THF was cooled to -78 ° C and treated with 1.6 ml (1.4 M, 2.2 mmol) of methyl lithium. 1- (7-methanesulfonyloxyheptyl) -cyclopropene was added, the water bath was removed, and the temperature of the reaction mixture was raised to room temperature. The reaction was held for 5.5 hours and then terminated with water. Ether and water were added to the reaction mixture and the phases were separated. The ether phase was washed twice with water, brine, dried over magnesium sulfate and stripped. The product was chromatographed to give 80 mg of 7- (diphenylamino) -1-heptylcyclopropene as a colorless liquid.

Example 14 Preparation of 1-cyclohexylcyclopropene (Compound 14)

Mizojiri, R .; Urabe, H .; Sato, F. J. Org Chem . 1-cyclohexyl-2- (trimethylsilyl) cyclopropanol was prepared from methylcyclohexylcarboxylate and vinyltrimethylsilane as disclosed in 2000, 65, 6217. This material was converted to cyclopropene in a similar manner to the above reference.

Example 15 Preparation of 1-((2-carboxy-N-morpholino) ethyl) -cyclopropene (Compound 15)

a. 2- (2-Bromo-allyl) -malonic acid diethyl ester

The oil was removed by washing with hexane from 21.70 g (0.542 mol) of 60% sodium hydride in the oil. To the residue suspended in 200 ml of tetrahydrofuran, 84.38 ml (0.556 mol) of diethylmalonate were slowly added with an addition separatory funnel. While cooling the reaction to −35 ° C. to −10 ° C., 100 g of 2,3-dibromopropene 100 g (0.400 mol) was slowly added with an addition separatory funnel. After heating to reflux for 1 hour, the reaction was cooled to room temperature and concentrated in vacuo. Hexane and water were added to the residue and the resultant mixture was transferred to a separatory funnel to separate phases. The separated organic layer was washed with 1N HCl, dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to give 154 g of 2- (2-bromo-allyl) -malonic acid diethyl ester of oil.

b. 2- (2-Bromo-allyl) -malonic acid

A mixture of 10.5 g (0.0376 mol) of 2- (2-bromo-allyl) -malonic acid diethyl ester and 37.6 ml (0.470 mol) of 50% aqueous sodium hydroxide was stirred at room temperature for 4 days. The reaction mixture was extracted with diethyl ether. The separated aqueous layer was acidified by addition of concentrated hydrochloric acid and diethyl ether was added. The resulting mixture was transferred to a separatory funnel and the phases separated. The separated organic layer was dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to yield 5.3 g of 2- (2-bromo-allyl) -malonic acid as a solid, which was used without purification.

c. 4-Bromo-pent-4-enoic acid

5.3 g (0.0238 mol) of neat, unrefined 2- (2-bromo-allyl) -malonic acid was heated to 125-130 ° C. for 8 hours to afford 3.73 g of 4-bromo-pent-4-enoic acid. Obtained, which was used without purification.

d. 4-Bromo-pent-4-enoic acid ethyl ester

1.18 ml (0.0162 mol) of thionyl chloride in a solution of 3.73 g (0.0208 mol) of unpurified 4-bromo-pent-4-enoic acid in 3 ml of chloroform added with 1 drop of N, N'-dimethylformamide. Was added. After the mixture was heated to 60 ° C. for 30 minutes, it was added to a solution of 2.46 ml (0.0436 mol) of ethanol, 1.97 ml (0.024 mol) of pyridine, and 13 ml of methylene chloride. After stirring 30 minutes, the reaction mixture was concentrated in vacuo. To the residue was added diethyl ether and water. The resulting mixture was transferred to a separatory funnel and the phases separated. The separated organic layer was dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo and 3.5 g of 4-bromo-pent-4-enoic acid ethyl ester of oil was obtained via vacuum distillation.

e. 1,1,2-tribromo-2-((3-carboethoxy) ethyl) -cyclopropane

1,1,2-tribromo-2-((3-carboethoxy) ethyl) -cyclopropane was prepared in a similar manner as described for the corresponding intermediate in Example 9.

The obtained residue was purified by column chromatography with diethyl ether / hexanes.

f. 1,1,2-tribromo-2-((2-carboxy) ethyl) -cyclopropane

10.2 g (0.0269 mol) of 1,1,2-tribromo-2-((3-carboethoxy) -ethyl) cyclopropane dissolved in 40 ml (0.736 mol) of 48% hydrobromic acid and 40 ml of water After heating to reflux for 8 hours, it was cooled to room temperature and then vacuum filtered with Shark Skin® filtration paper. The separated solid was washed with water and then diethyl ether was added. The solution was transferred to a separatory funnel which was washed with saturated aqueous sodium bicarbonate and separated and made acidic by addition of 1N hydrochloric acid. The aqueous solution was returned to the separatory funnel and extracted with diethyl ether. The separated organic layer was dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to give 5.9 g of 1,1,2-tribromo-2-((2-carboxy))-ethylcyclopropane solid, which was used as such.

g. 1,1,2-tribromo-2-((2-carboxy-N-morpholino) ethyl) -cyclopropane

1 ml of 1,1,2-tribromo-2-((2-carboxy))-ethyl-cyclopropane in a slurry of 0.97 g (0.00276 mol) in 2 ml of chloroform and thionyl chloride 0.434 ml (0.00596 mol) were added. After 15 minutes of reflux heating, the reaction mixture was concentrated in vacuo. The residue solution dissolved in 2 ml of methylene chloride was added to a solution in which 0.486 ml (0.00552 mol) of morpholine was dissolved in 1 ml of methylene chloride cooled to −20 ° C. After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting residue was extracted from 1N HCl with minimal amount of ethyl acetate. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to yield 1.08 g of 1,1,2-tribromo-2-((2-carboxy-N-morpholino) ethyl) -cyclopropane as an oil.

h. 1-((-2-carboxy-N-morpholino) ethyl) -cyclopropene

0.460 g of 60% pure 1-((2-carboxy-N-morpholino) ethyl) -cyclopropene was prepared in a similar manner as compound 1.

3-hydroxycarbonylmethyl-1,2,3-triphenylcyclopropene (Compound 40) is commercially available.

Example 16: Preparation of 1- (7- (N-piperidinoimino-heptyl))-cyclopropene (Compound 36)

a. 1- (7- (heptanal))-cyclopropene

1- (7-hydroxyheptyl) -cyclopropene (prepared in Example 12) was prepared using Arrowood, TL; Oxidation to 1- (7- (heptanal) -cyclopropene using Swern oxidation by the method disclosed in Kass, SR Tetrahedron , 1999 , 55 , 6739-48.

b. 1- (7- (N-piperidinoimino-heptyl) -cyclopropene

To 100 mg of 1- (7- (heptanal))-cyclopropene (0.66 mmol) dissolved in ethanol was added 70 mg (0.70 mmol) of N-aminopiperidine. The reaction mixture was stirred for 2 hours and then a few drops of ether, water and acetic acid were added. The aqueous phase was separated and the ether phase was washed with water and brine, then dried over magnesium sulfate and filtered. The solvent was stripped to give 70 mg of 1- (7- (N-piperidinoimino-heptyl))-cyclopropene.

Example 17 Preparation of 1- (3-trifluoromethylphenoxymethyl) -2-ethylcyclopropene (Compound 37)

a. 1,1,2-tribromo-2-ethylcyclopropane

1,1,2-tribromo-2-ethylcyclopropane was prepared from 2-bromo-1-butene in the same manner as in Example 4c.

b. 1- (hydroxymethyl) -2-ethylcyclopropene

A solution of 3.0 g (10 mmol) of 1,1,2-tribromo-2-ethylcyclopropane dissolved in 50 ml of ether was cooled to -78 deg. Methyllithium (1.4M, 21.4 ml, 30 mmol) was added. The reaction mixture was raised to 5 ° C. Solid paraformaldehyde (1.20 g, 40 mmol) was added and the reaction mixture was stirred at 5 ° C. for 1 h, then raised to room temperature and stirred for a further 1 h. The reaction was terminated with water and the phases separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 900 mg of 1- (hydroxymethyl) -2-ethylcyclopropene as a yellow oil.

c. 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene

0.86 g (7.5 mmol) of methanesulfonyl chloride in a solution of 0.70 g (7.13 mmol) of 1- (hydroxymethyl) -2-ethylcyclopropene (Compound 3) in 2 ml of ether and 2 ml of triethylamine in an ice bath. Was added. The reaction mixture was maintained for 1.5 hours and then terminated with water. The phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 840 mg of 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene as a yellow oil.

d. 1- (3-trifluoromethylphenoxymethyl) -2-ethylcyclopropene

At room temperature, 3-trifluoromethylphenol (0.41 g, 2.5 mmol) was added to a suspension of 0.07 g (1.8 mmol) of sodium hydride dissolved in 3 ml of DMF. After 15 minutes, a solution of 0.3 g (1.7 mmol) of 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene in 2 ml of DMF was added and the reaction mixture was stirred for 2 hours. Ethyl acetate and water were added. The phases were separated and the ethyl acetate phase was washed with 1N aqueous sodium hydroxide and brine, dried over magnesium sulfate, filtered and stripped to give 1- (3-trifluoromethylphenoxymethyl) as a tan liquid. 160 mg of 2-ethylcyclopropene were obtained.

Example 18 Preparation of 2-Octyl-1- (2- (2-boro-1,3-dioxetane))-cyclopropene (Compound 38)

a. 2-octyl-1- (boronic acid) -cyclopropene

1.30 g (3.3 mmol) of an ethereal solution of 2-octyl-1,1,2-tribromocyclopropane prepared in the same manner as in Example 1 was cooled to -78 ° C. Methyllithium (1.4 M, 5.9 ml, 8.3 mmol) was added and the reaction mixture was stirred for 10 minutes, then placed in an ice bath and held for 30 minutes, then cooled to -78 ° C. Triisopropylborate (0.9 ml, 3.9 mmol) was added and the reaction mixture was stirred for 15 minutes, then raised to 0 ° C. Water, ether and 1N aqueous HCl (sufficient to make the solution acidic) were added. The phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped. The product was dissolved again in ether and extracted three times with 1N aqueous sodium hydroxide solution. The aqueous extract was acidified with 6N aqueous hydrochloric acid and extracted three times with ether. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 400 mg of 2-octyl-1- (boronic acid) -cyclopropene as a pale yellow solid.

 b. 2-octyl-1- (2- (2-boro-1,3-dioxetane))-cyclopropene

A mixture of 270 mg (1.4 mmol) of 2-octyl-1- (boronic acid) -cyclopropene in 10 ml of pentane was treated with 0.3 ml of 1,3-dihydroxypropane at room temperature. After 1.5 hours, the reaction mixture was transferred to a separatory funnel. The pentane solution was washed with water and brine, dried over magnesium sulfate, filtered and stripped to 50% pure 2-octyl-1- (2- (2-boro-1,3-dioxetane))-cyclo Propene 90 mg was obtained.

Expected NMR: 0.88 (t, 3H), 0.98 (s, 2H), 1.1-1.3 (m, 10H), 1.55 (m, 2H), 1.9 (m, 2H), 2.5 (m, 2H), 4.1-4.4 (m, 4H)

Example 19 Preparation of 1-Methyl-2- (hydroxy (3-methoxyphenyl) methyl) cyclopropene (Compound 39)

Diisopropylamine (2.5 ml, 17.9 mmol), diethyl ether (3 ml), 1-methyl in a mixture of about 2 mg of 1,10-phenanthroline dissolved in 50 ml of diethyl ether while maintaining the temperature at −40 ° C. under a nitrogen atmosphere. Cyclopropene (1.1 g, 20.4 mmol; prepared from 3-chloro-2-methyl-propene, Hopf, H et al. Chem. Ber . 1985, 118, 3579 and Koster, R et al. Liebigs Annalen Chem. 1973, 1219 (See -1235) were added sequentially using a syringe. Thereafter, 1.0 ml of N-butyllithium (1.6 M dissolved in hexane) was added until brown. Different proportions of the same butyllithium (10.0 ml, 16 mmol) were added. After stirring at −40 ° C. for 15 minutes, the reaction was cooled to −70 ° C. and 3-methoxybenzaldehyde (1.9 ml, 15.6 mmol) was added. After 3 minutes, the reaction was terminated by addition of 3 ml of additional water. After raising the temperature to room temperature, the layer was separated. The organic phase was dried over magnesium sulfate and dried in vacuo. This residue was dissolved in diethyl ether and washed with 1M hydrochloric acid, brine and finally saturated aqueous sodium bicarbonate. The layer was separated. The organic phase was dried over magnesium sulfate and dried in vacuo to yield 1.0 g of 1-methyl-2- (hydroxy (3-methoxyphenyl) methyl) cyclopropene.

Comparative Example 1: 1-phenyl-2,3,3-trichlorocyclopropene (Compound 41)

1-phenyl-2,3,3-trichlorocyclopropene is obtained from Eicher, theophil; Huch, Volker; Schneider, Volker; Veith, Michael. It was prepared by the method disclosed in Synthesis , 1989 , 5, 367-72.

Example 21 1- (4-Methylphenylcarbonyloxybutyl) -cyclopropene (Compound 44)

a. 5,6-dibromo-hexan-1-ol

Bromine (5.80 ml + 12 drops, 112.3 + mmol) dissolved in about 20 ml of methylene chloride was added to a solution of 5-hexen-1-ol (11.23 g, 112.3 mmol) dissolved in about 20 ml of cooled methylene chloride in an ice bath. It was. After complete addition, the mixture was dried in vacuo to give 29.1 g of 5,6-dibromo-hexan-1-ol.

b. 5-bromo-hex-5-en-1-ol

20% potassium dissolved in tetrahydrofuran (62.4g, 112mmol) in a solution of 5,6-dibromo-hexane-1-ol (29.1g, 112mmol) in about 59ml of tetrahydrofuran cooled in an ice bath. t-butoxite was added. After completion of the addition, the temperature of the reaction was raised to room temperature and stirred for about 30 minutes. Diethyl ether and water were added followed by phase separation. The separated organic layer was dried over magnesium sulfate and then dried in vacuo. The residue was vacuum distilled off with a 5-porous plate column to give 23.16 g of 87% pure 5-bromo-hex-5-en-1-ol.

c. 4-Methyl-benzoic acid 5-bromo-hex-5-enyl ester

4-toluoylchloride (3.95 g, 25.6 mmol) and triethylamine (3.3 g) in a solution of 5-bromo-hex-5-en-1-ol (4.39 g, 24.5 mmol) dissolved in 10.6 g of methylene chloride , 33 mmol) was added. After stirring at room temperature for about 2 hours, the mixture was diluted with diethyl ether, then washed with 1N hydrochloric acid and washed with brine. The phases were separated and the organic layer was dried over magnesium sulfate and then dried in vacuo to give 7.3 g of 4-methyl-benzoic acid 5-bromo-hex-5-enyl ester.

d. 4-Methylbenzoic acid 4- (1,2,2-tribromo-cyclopropyl) -butyl ester

4-Methyl-benzoic acid 5-bromo-hex-5-enyl ester (7.3 g, 24.6 mmol), N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide ( 0.30 g, 0.66 mmol), methylene chloride (25 g), bromoform (25 g, 98.9 mmol) and 45% aqueous potassium hydroxide (11.5 g, 92 mmol) were charged to a round bottom flask and stirred at room temperature for 4 days. . After addition of water, the layers were separated. N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide (0.30 g, 0.66 mmol), bromoform (27 g, 107 mmol), and 45% aqueous in the separated organic layer Potassium hydroxide (12 g, 96 mmol) was added. After stirring for an additional day at room temperature, water and hexanes were added. The mixture was gravity filtered through qualitative filtration paper and the layers were separated. The separated organic layer was dried over magnesium sulfate and then dried in vacuo. The residue was purified by column chromatography with ethyl acetate / hexanes to give 4.9 g of 61% pure 4-methyl-benzoic acid 4- (1,2,2-tribromo-cyclopropyl) -butyl ester.

e. 4- (1,2,2-tribromo-cyclopropyl) -butan-1-ol

In a solution of 4-methyl-benzoic acid 4- (1,2,2-tribromo-cyclopropyl) -butyl ester (45.5 g, 97 mmol) in 250 g of methanol, 50% aqueous potassium carbonate (30 g, 107 mmol), and 30 g of water Was added. The reaction was heated to 60 ° C. for 2 hours and then cooled to room temperature. After about 15 hours, 50% aqueous potassium carbonate (30 g, 107 mmol) and 30 g of water were added and the reaction was heated at 60 ° C. for 2 hours and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with diethyl ether. The organic layer was washed with basicized water (pH 10). The phases were separated and the organic phase was dried over magnesium sulfate and then in vacuo. The residue was purified by column chromatography with diethyl ether / hexanes to give 14.5 g of 74% pure 4- (1,2,2-tribromo-cyclopropyl) -butan-1-ol.

f. 1- (4-hydroxybutyl) -cyclopropene

A solution of 4- (1,2,2-tribromo-cyclopropyl) -butan-1-ol (5.11 g, 14.5 mmol) dissolved in 4 ml of diethyl ether was cooled to 0 ° C. under a nitrogen atmosphere. Using a syringe, 1.4 M methyllithium dissolved in diethyl ether (41.6 ml, 58.2 mmol) was added. After 15 minutes, the reaction was terminated by addition of about 2 ml of water. The phases were separated. The separated organic layer was dried over magnesium sulfate and dried in vacuo to give 2.51 g of 1- (4-hydroxybutyl) -cyclopropene as an oil.

g. 1- (4-methylphenylcarbonyloxybutyl) -cyclopropene                 

A solution of 1- (4-hydroxybutyl) -cyclopropene (810 mg, 7.23 mmol) dissolved in 5-10 ml of methylene chloride was cooled to 0 ° C. Triethylamine (0.895 ml, 7.88 mmol) was added thereto, and 4-toluoyl chloride (0.794 ml, 7.30 mmol) was added. After stirring at about 10 ° C. for 1 hour, the reaction was cooled to 0 ° C. and triethylamine (0.895 ml, 7.88 mmol) was added followed by 4-toluoylchloride (0.794 ml, 7.30 mmol). After stirring for about 1 hour at room temperature, the reaction mixture was concentrated in vacuo. To this was added diethyl ether and water, and the phases were separated. The separated organic layer was washed with 1N hydrochloric acid, dried over magnesium sulfate and dried in vacuo to give 2.05 g of an oil. This was subjected to column chromatography using ethyl acetate / hexanes with silica gel to give 470 mg of 50% pure 1- (4-methylphenylcarbonyloxybutyl) -cyclopropene with residue p-toluic acid.

Example 22 1-benzyl-2-bromocyclopropene (Compound 45)

a. 1-benzyl-1,2,2-tribromocyclopropane

1-benzyl-1,2,2-tribromocyclopropane was prepared from 1- (2-bromo-allyl) -benzene in the same manner as in Example 1b.

b. 1-benzyl-2-bromocyclopropene

1-benzyl-1,2,2-tribromocyclopropane (1.21 g, 3.27 mmol), and diethylphosphite (1.69 ml, 13.1 mmol) and triethylamine (0.455 ml, 3.26 mmol) at room temperature 24 Mix for hours. Hexane was added to the reaction mixture and washed with 1N hydrochloric acid. The phases were separated. The aqueous layer was extracted with diethyl ether and this phase was separated. The combined organic layers were purified by column chromatography on silica gel with diethyl ether / hexane to obtain 300 mg of 1-benzyl-2-bromocyclopropene as an oil.

Example 23 1-benzyl-2-chlorocyclopropene (Compound 46)

a. 1- (2-Bromo-allyl) -benzene

1- (2-Bromo-allyl) -benzene was prepared from 2,3-dibromopropene and phenylmagnesium bromide in the same manner as in Example 1a.

b. 1-benzyl-1-bromo-2,2-dichlorocyclopropane

45% aqueous potassium hydroxide (16.2 ml, 189 mmol) and N, N 'in a solution of 1- (2-bromo-allyl) -benzene (6.80 g, 34.5 mmol) dissolved in chloroform (39.4 ml, 493 mmol). -Dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide (790 mg, 1.72 mmol) was added. After stirring for 3 days at room temperature, chloroform (2 ml) and 45% aqueous potassium hydroxide (16.2 ml, 189 mmol) and N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium Dibromide (790 mg, 1.72 mmol) was added. After stirring for a further day at room temperature, hexane and water were added. The phases were separated. The separated organic layer was dried over magnesium sulfate and dried in vacuo to give 6.7 g of 1-benzyl-1-bromo-2,2-dichlorocyclopropane as an oil.

c. 1-benzyl-2-chlorocyclopropene

A solution of 1-benzyl-1-bromo-2,2-dichlorocyclopropane (1.45 g, 5.18 mmol) dissolved in about 4 ml of diethyl ether was cooled to 0 ° C. and placed under nitrogen atmosphere. To this was added 1.4 M methyllithium dissolved in diethyl ether (3.70 ml, 5.18 mmol). After 15 minutes, the reaction was terminated by addition of 2 ml of water. The phases were separated. The separated organic layer was dried over magnesium sulfate and dried in vacuo to yield 720 mg of 1-benzyl-2-chlorocyclopropene as an oil.

Example 24 Preparation of 1- (2- (furan-2-ylcarbonyloxyethyl) -cyclopropene (Compound 47)

a. 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene

While cooling a solution of 10.38 g (0.0687 mol) of commercially available 3-bromo-3-buten-1-ol in 20 ml of diethyl ether in which 50 mg (0.000263 mol) of p-toluenesulfonic acid monohydrate was dissolved, was cooled in an ice bath. 19 ml (0.199 mol) of ethylvinyl ether was slowly added dropwise while maintaining the internal temperature <10 ° C. After 1 hour at 0 ° C., several drops of triethylamine were added. The reaction mixture was poured into water. The resulting mixture was transferred to a separatory funnel and the phases separated. The separated organic layer was washed with brine, dried over potassium carbonate and filtered. The solvent was removed from the filtrate in vacuo to give 14.04 g of 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene of oil.

b. 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane

A solution of 14.02 g (0.0628 mol) of 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene in 108 ml of methylene chloride containing 0.5-0.9 ml of 45% aqueous potassium hydroxide. 16.4 ml (0.118 mol) of bromoform and 2.88 g (0.00628 mol) of N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide and 28 ml of 45% aqueous potassium hydroxide (0.314 mol) was added. After 3 days, the reaction mixture was poured into water. The resulting mixture was transferred to a separatory funnel and the phases separated. 2.88 g (0.00628 mol) of N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide and 28 ml (0.314 mol) of 45% aqueous potassium hydroxide were added to the separated organic layer. Added. After 24 hours, hexanes and water were added. This mixture was gravity filtered through qualitative fluted filter paper. The resulting mixture was transferred to a separatory funnel and the phases separated. The layer was separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 17.0 g of 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane as an oil.

c. 2- (2-hydroxyethyl) -1,1,2-tribromocyclopropane

P-toluene in a slurry of 16.5 g (0.0418 mol) of 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane dissolved in 145 ml of methanol and 40 ml of water 0.306 g (0.00161 mol) of sulfonic acid monohydrate and 145 ml of 6M hydrochloric acid were added. After stirring for 1 hour at room temperature, the solvent was removed in vacuo. To the residue, ethyl acetate and water were added. The resulting mixture was transferred to a separatory funnel and the phases separated. The separated organic layer was washed with brine and then filtered dry with MgSO ₄ . The solvent was removed from the filtrate in vacuo to give 11.9 g of 2- (2-hydroxyethyl) -1,1,2-tribromocyclic ropeophane as an oil.

d. 1- (2-hydroxyethyl) -cyclopropene

A solution of 1.15 g (3.6 mmol) of 2- (2-hydroxyethyl) -1,1,2-tribromocyclopropane (prepared as above) dissolved in 40 ml of ether was cooled to -78 ° C. Methyllithium (1.4M, 10.3 ml, 14.4 mmol) was added. The reaction mixture was raised to 5 ° C. and maintained for 1 and a half hours. The reaction was terminated with water and the phases separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped. The crude product was used for the next reaction.

e. 1- (2- (furan-2-yl-carbonyloxyethyl) -cyclopropene

A solution of 1- (2-hydroxyethyl) -cyclopropene (300 mg, 3.56 mmol) dissolved in about 10 ml of methylene chloride was cooled to 0 ° C., triethylamine (0.540 ml, 3.88 mmol) and furan-2 Carbonyl chloride (0.356 ml, 3.60 mmol) was added. After stirring at room temperature for about 2 hours, the reaction mixture was concentrated in vacuo. Diethyl ether and water were added to this residue. The phases were separated. The organic layer was washed with 1N hydrochloric acid. After phase separation, the organic layer was dried over magnesium sulfate and dried in vacuo to give 430 mg in oil form. This was purified by column chromatography on silica gel using diethyl ether / hexane to give 20mg of 1- (2- (furan-2-ylcarbonyloxyethyl) -cyclopropene in oil form.

Example 25 Preparation of 1- (7- (4-methanesulfonyloxyphenyl) -carbonyloxyheptyl) -cyclopropene (Compound 53)

a. 1- (1-ethoxyethoxy) -6-bromohexane

To a cooled solution of 80 mg of toluenesulfonic acid dissolved in 40 ml of ether, 20 g (110 mmol) of 6-bromohexanol and 40 ml of ethyl vinyl ether were sequentially supplied using a separating addition funnel. The temperature of the reaction mixture was kept below 7 ° C. during the feed consumed for 1 hour. The reaction mixture was stirred for 20 minutes and then about 1 ml of triethylamine was added. The reaction mixture was washed with water and brine, dried over potassium carbonate, filtered and stripped to give 25.7 g of a pale yellow liquid which was used without further purification.

b. 9- (1-ethoxyethoxy) -2-bromonone-1-ene

A slurry of 5.6 g (230 mmol) of magnesium turning dissolved in 100 ml of THF was treated with a small amount of 1,2-dibromoethane. The temperature was maintained at 40-50 ° C. while slowly feeding 1- (1-ethoxyethoxy) -6-bromohexane (38.5 g, 152 mmol) to the reaction mixture. At the end of the addition the reaction mixture was maintained for 20 minutes and transferred to a solution of 33.4 g (167 mmol) of 2,3-dibromopropene in 25 ml THF using cannula at 0 ° C. The reaction mixture was stirred at 0 ° C. for 15 minutes, then at room temperature for 15 minutes and terminated with water. The reaction mixture was transferred to a separatory funnel. A small amount of 1N HCl was added, the phases were separated, the ether phase was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 33.63 g of a yellow liquid which was used without further purification. .                 

c. 1,1,2-tribromo-2- (7-hydroxyheptyl) -cyclopropane

9- (1-ethoxyethoxy) -2-bromonone-1-ene (33.63 g, 115 mmol), N, N'-dibenzyl-N, N, N ', N'-tetraethylethylenediammonium di A mixture of 4.1 g bromide, 42 g 45% potassium hydroxide (337 mmol), 93 g bromoform (368 mmol) and 280 g methylene chloride was stirred rapidly for 2 days at room temperature. When the reaction was stopped, the reaction mixture was transferred to a separatory funnel and washed with water. The methylene chloride phase was transferred to a flask and treated with the same amount of phase transfer catalyst and 45% potassium hydroxide, followed by stirring for an additional 3 days at room temperature. The reaction mixture was washed with water and the methylene chloride phase was dried over magnesium sulfate and then stripped. The product was treated with 320 ml of methanol and 40 ml of 1N HCl for 1 hour at room temperature. The methanol was stripped and ethyl acetate was added. The organic phase was washed with water and brine and then treated with 200 ml of silica gel. Filtration followed by stripping gave 38 g of black product. Chromatography with silica gel gave 19.0 g of a pale yellow liquid 1,1,2-tribromo-2- (7-hydroxyheptyl) cyclopropane.

d. 1- (7-hydroxyheptyl) -cyclopropene

A solution of 1.0 g (2.5 mmol) of 1,1,2-tribromo-2- (7-hydroxyheptyl) cyclopropane dissolved in 25 ml of ether was added to 7.2 ml (1.4 M, 10 mmol) of methyllithium at -78 ° C. Treated. After 5 minutes, the reaction mixture was raised to 0 ° C. and maintained at this temperature. The reaction was terminated with saturated ammonium chloride. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 240 mg of 1- (7-hydroxyheptyl) -cyclopropene.

e. 1- (7- (4-methanesulfonyloxyphenyl) carbonyloxyheptyl) -cyclopropene

At 15 ° C., 1- (7-hydroxyheptyl) -cyclopropene (537 mg, 3.47 mmol), and 4-methylsulfonylbenzoic acid (764 mg, 3.82 mmol) and N, N-dimethylamino in about 30 ml of methylene chloride N, N'-dicyclohexylcarbodiimide (85.8 mg, 4.16) dissolved in about 10 ml of methylene chloride in a solution of pyridine (42.1 mg, 0.347 mmol) and p-toluenesulfonic acid monohydrate (33.0 mg, 0.173 mmol) mmol) was added. After stirring for 90 minutes at room temperature, the reaction mixture was vacuum filtered through a sufficient retention filter paper. Water was added to this filtrate and the mixture was stirred for about 30 minutes. After phase separation, the organic layer was dried over magnesium sulfate and dried in vacuo to give 1.5 g of 70% pure 1- (7- (4-methanesulfonyloxyphenyl) -carbonyloxyheptyl) -cyclopropene Got.

Example 26 1- (2-Pyridylthiopropyl) -cyclopropene (Compound 55)

a. Ethyl 4-bromopent-4-enoate

Ethyl 4-bromopent-4-enoate was prepared by the method disclosed in Mori, M .; et al. Journal of Organic Chemistry , 1983 , 48, 4058-4067.

b. 3- (1,2,2-tribromo-cyclopropyl) -propionic acid ethyl ester

In a solution of ethyl 4-bromopent-4-enoate (24.24 g, 11.7 mmol) dissolved in 148 ml of methylene chloride, bromoform (35.3 ml, 35.1 mmol), N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide (4.40 g, 1.17 mmol) and 45% aqueous potassium hydroxide (54.2 ml, 58.5 mmol) were added. After stirring for 3 days at room temperature, water was added and the layers were separated. Bromoform (35.5ml, 35.1mmol), N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide (4.40g, 1.17mmol) in the separated organic layer, and 45% aqueous potassium hydroxide (54.2 ml, 58.5 mmol) was added. After stirring for an additional 3 days at room temperature, water and hexane were added. The mixture was gravity filtered through qualitative filter paper and the layers were separated. The separated organic layer was dried over magnesium sulfate and then dried in vacuo. The residue was purified by column chromatography on silica gel using diethyl ether / hexane to give 20.5 g of 3- (1,2,2, -tribromo-cyclopropyl) -propionic acid ethyl ester in oil form.

c. 3- (1,2,2-Tribromo-cyclopropyl) -propionic acid

A solution of 3- (1,2,2-tribromo-cyclopropyl) -propionic acid ethyl ester (20.5 g, 54.0 mmol) dissolved in about 80 ml of water and 80 ml of bromic acid was heated to reflux. After about 4 hours, the reaction was cooled to room temperature and diethyl ether was added. The phases were separated. The separated organic layer was washed with aqueous sodium hydroxide diluted to a sufficient basic basicity using a pH test paper. The phases were separated and the aqueous layer was acidified by addition of diluted hydrochloric acid. Diethyl ether was added to this aqueous layer. The phases were separated. The separated organic layer was dried over magnesium sulfate and concentrated in vacuo. This residue was titrated with hexane and then with diethyl ether to give 3.23 g of 3- (1,2,2-tribromo-cyclopropyl) -propionic acid as a solid.                 

d. 1- (3-hydroxypropyl) -1,2,2-tribromocyclopropane

A solution of 3- (1,2,2-tribromo-cyclopropyl) -propionic acid (850 mg, 2.42 mmol) dissolved in about 1 ml of tetrahydrofuran was cooled to -10 ° C. To this was slowly added dropwise 1M borane dissolved in tetrahydrofuran (1.97 ml, 1.96 mmol). After stirring overnight at room temperature, about 1 ml of a 1: 1 mixture of glacial acetic acid and water was added. This mixture was concentrated in vacuo. The resulting residue was poured into 10 ml of saturated aqueous sodium bicarbonate in ice. Ethyl acetate was added and the phases were separated and repeated. The separated organic layer was dried over magnesium sulfate and then concentrated in vacuo. This residue was dissolved in diethyl ether and washed twice with saturated aqueous sodium bicarbonate. The phases were separated and the separated organic layer was dried over magnesium sulfate and concentrated in vacuo to give 540 mg of 1- (3-hydroxypropyl) -1,2,2-tribromocyclopropane as an oil.

e. 1- (3-benzenesulfonyloxypropyl) -1,2,2-tribromo-cyclopropane

Pyridine (0.155 ml, 1.92 mmol) and benzenesulphate in a solution cooled to 0 ° C. of 1- (3-hydroxypropyl) -1,2,2-tribromocyclopropane (540 mg, 1.60 mmol) in 3 ml of methylene chloride Ponylchloride (0.203 ml, 1.60 mmol) was added. After stirring for 3 days at room temperature, water was added and the phases were separated. The separated organic layer was dried over magnesium sulfate and concentrated in vacuo. This residue was dissolved in diethyl ether and washed with 1N hydrochloric acid. The phases were separated and the separated organic layer was dried over magnesium sulfate and concentrated in vacuo to give 500 mg of 1- (3-benzenesulfonyloxypropyl) -1,2,2-tribromo-cyclic lotropane as an oil. Got it.

f. 1- (2-pyridylthiopropyl) -1,2,2-tribromo-cyclopropane

To about 3 ml of methanol was added 25% sodium methoxide dissolved in methanol (0.239 ml, 1.04 mmol) to a solution of 2-mercaptopyridine (0.117 g, 1.04 mmol). After stirring for 1 hour at room temperature, the reaction mixture was concentrated in vacuo. To this residue dissolved in 3 ml of N, N-dimethylformamide 1- (3-benzenesulfonyloxypropyl) -1,2,2-tribromo- dissolved in 3 ml of N, N-dimethylformamide A solution of cyclopropane (500 mg, 1.04 mmol) was added. After stirring for 16 hours at room temperature, water and diethyl ether were added and the phases were separated. The separated organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on ethyl acetate / hexanes with silica to give 200 mg of 1- (2-pyridylthiopropyl) -1,2,2-tribromo-cyclopropane as an oil.

g. 1- (2-pyridylthiopropyl) -cyclopropene

A solution of 1- (2-pyridylthiopropyl) -1,2,2-tribromo-cyclopropane (200 mg, 0.465 mmol) dissolved in 2 ml of diethyl ether was cooled to 0 ° C. and placed in a nitrogen atmosphere. . 1.4M methyllithium (1.00 ml, 1.39 mmol) was added to this solution. After 15 minutes, the reaction was terminated by addition of 1 ml of water. The phases were separated and the separated organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 50 mg of 1- (2-pyridylthiopropyl) -cyclopropene as an oil.

Example 27 1- (8-benzenesulfonyloxyoctyl) -cyclopropene (Compound 56)

a. 9,10-dibromo-decan-1-ol

Of bromine (13.3 ml, 0.258 mol) dissolved in about 20 ml of methylene chloride in a solution of deck-9-en-1-ol (40.34 g, 0.258 mol) dissolved in about 70 ml of methylene chloride cooled in an ice / brain bath. The solution was added. After stirring at room temperature for about 15 minutes, the reaction was concentrated in vacuo to give 9,10-dibromo-decan-1-ol as an oil which was used without further purification.

b. 9-bromo-deck-9-en-1-ol

Potassium dissolved in tetrahydrofuran (24.8 g, 0.258 mol) in a solution of 9,10-dibromo-decan-1-ol (81.7 g, 0.258 mol) dissolved in about 140 ml of cooled tetrahydrofuran in an ice bath. 20% solution of t-butoxide was added. After stirring at 5 ° C. for about 10 minutes, it is stirred at room temperature for about 15 minutes and the reaction mixture is concentrated in vacuo. To this residue was added water and diethyl ether. The phases were separated. The separated organic layer was dried over magnesium sulfate and concentrated in vacuo to give 66.1 g as an oil. This was vacuum distilled to obtain 35.3 g of about 66% pure 9-bromo-deck-9-en-1-ol.

c. 2-Bromo-10- (1-ethoxy-ethoxy) -dec-1-ene

To a solution of 9-bromo-deck-9-en-1-ol (11.75 g, 50.0 mmol) dissolved in about 15 ml of diethyl ether was added about 37 mg of p-toluenesulfonic acid monohydrate. After cooling this solution to about −10 ° C., ethylvinyl ether (13.8 ml, 144 mol) was slowly added to maintain the internal temperature below 10 ° C. After adding a few drops of triethylamine, the solution was washed with water and then brine. The separated organic layer was dried over potassium carbonate, and then concentrated in vacuo to give about 72% pure 2-bromo-10 (1-ethoxy-ethoxy) -dec-1-ene 16.2 g oil.

d. 1,1,2-tribromo-2- [8- (1-ethoxy-ethoxy) -octyl] -cyclopropane

Bromoform (13.2 ml, 158 mmol), N in a solution of 2-bromo-10- (1-ethoxy-ethoxy) -dec-1-ene (16.2 g, 52.7 mmol) dissolved in 90.9 ml methylene chloride , N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide (2.41 g, 5.27 mmol) and 45% aqueous potassium hydroxide (22.6 ml, 263 mmol) were added. After stirring for 2 days at room temperature, water was added and the layers were separated. N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide (2.41 g, 5,27 mmol), and 45% aqueous potassium hydroxide (22.6 ml) were added to the separated organic layer. 263 mmol) was added. After stirring for another 2 days at room temperature, water and hexanes were added. The mixture was gravity filtered using qualitative filter paper and the layers were separated. The separated organic layer was dried over magnesium sulfate and then dried in vacuo to give an oil form of 1,1,2-tribromo-2- [8- (1-ethoxy-ethoxy) -octyl] -cyclopropane 24.7 g was obtained, which was used without further purification.

e. 1- (8-hydroxyethyl) -1,2,2-tribromo-cyclopropane

About 44 ml of water in a solution of 1,1,2-tribromo-2- [8- (1-ethoxy-ethoxy) -octyl] -cyclopropane (24.7 g, 51.5 mmol) dissolved in about 160 ml of methanol , 337 mg of p-toluene sulfonic acid monohydrate and about 160 ml of 6M hydrochloric acid were added. After stirring for about 1 hour at room temperature, the reaction mixture was concentrated in vacuo. The residue was distilled under vacuum to give 15.6 g of 65% pure 1- (8-hydroxyethyl) -1,2,2-tribromo-cyclopropane as an oil, which was used as such.

f. 1- (8-benzenesolfonyloxyoctyl) -1,2,2-tribromo-cyclopropane

Pyridine (3.72 ml, 45.9 mmol) is added to a solution of 1- (8-hydroxyethyl) -1,2,2-tribromo-cyclopropane (15.6 g, 38.3 mmol) dissolved in about 50 ml of methylene chloride It was. The solution was cooled to −20 ° C. in an acetone / dry ice bath and benzenesulfonylchloride (4.89 ml, 38.3 mmol) was added. After stirring for 16 hours at room temperature, pyridine (3.72 ml, 45.9 mmol) and benzenesulfonylchloride (4.89 ml, 38.3 mmol) were added. After stirring for 5 hours at room temperature, pyridine (3.72 ml, 45.9 mmol), and benzenesulfonylchloride (4.89 ml, 38.3 mmol) were added. After stirring for 16 hours at room temperature, water was added and then the phases were separated. The separated organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in diethyl ether and washed with saturated aqueous sodium bicarbonate. The phases were separated and the separated organic layer was dried over magnesium sulfate and concentrated in vacuo to give 14.5 g of 1- (8-benzenesulfonyloxyoctyl) -1,2,2-tribromo-cyclopropane as an oil. Got it.

g. 1- (benzenesulfonyloxyoctyl) -cyclopropene

A solution of 1- (benzenesulfonyloxyoctyl) -1,2,2-tribromo-cyclopropane (2.7 g, 4.94 mol) dissolved in about 8 ml of diethyl ether was cooled to 0 ° C. and placed under nitrogen atmosphere. . To this solution was added 1.4 M methyllithium dissolved in diethyl ether (10.6 ml, 14.8 mmol). After 15 minutes, the reaction was terminated by addition of about 4 ml of water. The phases were separated and the separated organic layer was dried over magnesium sulfate and concentrated in vacuo to give 1.2 g of 1- (benzenesulfonyloxyoctyl) -cyclopropene as an oil.

Example 28 1- (4-Methylphenylthiooctyl) -cyclopropene (Compound 57)

a. 1- (benzenesulfonyloxyoctyl) -cyclopropene

1- (benzenesulfonyloxyoctyl) -cyclopropene was prepared from 1- (benzenesulfonyloxyoctyl) -1,2,2-tribromo-cyclopropane by the method of Example 27.

b. 1- (4-methylphenylthiooctyl) -cyclopropene

P-thiocresol dissolved in N, N-dimethylformamide (2 ml) in a suspension of sodium hydride (60% in oil, 73.2 mg, 1.83 mmol) dissolved in N, N-dimethylformamide (2 ml) 189 mg, 1.52 mmol) was added. After stirring for 15 minutes at room temperature, when the formation of bubbles was stopped, 1- (benzenesulfonyloxyoctyl) -cyclopropene (470 mg, 1.52 mmol) dissolved in N, N'-dimethylformamide (2 ml) Was added. After stirring for about 2 hours, water and ethyl acetate were added and the phases were separated. The separated organic layer was washed twice with water, dried over magnesium sulfate and concentrated in vacuo to give 200 mg of 1- (4-methylphenylthiooctyl) -cyclopropene as an oil.

Example 29 1- (1H-1,2,4-triazol-2-ylthiooctyl) -cyclopropene (Compound 58)

a. 1- (benzenesulfonyloxyoctyl) -cyclopropene

1- (benzenesulfonyloxyoctyl) -cyclopropene was prepared from 1- (benzenesulfonyloxyoctyl) -1,2,2-tribromo-cyclopropane in the same manner as in Example 27.                 

b. 1- (1H-1,2,4-triazol-2-ylthiooctyl) -cyclopropene

To a solution of 1- (benzenesulfonyloxyoctyl) -cyclopropene (480 mg, 1.55 mmol) dissolved in about 2 ml of N, N'-dimethylformamide, potassium t-butoxide (19.8% in tetrahydrofuran, 734 mg) , 1.55 mmol) and 1H-1,2,4-triazole-3-thiol (172 mg, 1.71 mmol) were added. After stirring at room temperature for about 2 hours, sodium iodide (87.7 mg, 755 mmol) was added. After the reaction was heated to about 50 [deg.] C. for about 2 hours, water and ethyl acetate were added and the phases separated. The separated organic layer was washed twice with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane / ethyl acetate to give 30 mg of 70% pure 1- (1H-1,2,4-triazol-2-ylthiooctyl) -cyclopropene as an oil. Got it.

Example 30 1- (1-Methyl-2-pyrrolecarbonyloxypropyl) -cyclopropene (Compound 59)

a. 1- (3-hydroxypropyl) -1,2,2-tribromocyclopropane

1- (3-hydroxypropyl) -1,2,2-tribromocyclopropane was prepared from 3- (1,2,2-tribromo-cyclopropyl) -propionic acid by the method described in Example 26d. .

b. 1- (3-hydroxypropyl) -cyclopropene

A solution of 1- (3-hydroxypropyl) -1,2,2-tribromocyclopropane (750 mg, 2.22 mmol) dissolved in about 4 ml of diethyl ether was cooled to 0 ° C. and placed under nitrogen atmosphere. 1.4 M methyllithium (6.36 ml, 8,90 mmol) was added by syringe. After 15 minutes, about 2 ml of water was added and the phases separated. The separated organic layer was dried over magnesium sulfate and concentrated in vacuo to give 1- (3-hydroxypropyl) -cyclopropene, which was used as such.

c. 1- (1-Methyl-2-pyrrolecarbonyloxypropyl) -cyclopropene

In a solution of 1- (3-hydroxypropyl) -cyclopropene (221 mg, 2.22 mmol) dissolved in about 15 ml methylene chloride, 1-methyl-2-pyrrolecarboxylic acid (306 mg, 2.42 mmol), 4-dimethylaminopyridine (27.0 mg, 0.222 mmol) and p-toluenesulfonic acid monohydrate (21.2 mg, 0.111 mmol) were added. After cooling the mixture to about 15 ° C., a solution of N, N′-dicyclohexylcarbodiimide (550 mg, 2.66 mmol) dissolved in about 10 ml of methylene chloride was slowly added. After stirring at room temperature for about 2 hours, the reaction mixture was vacuum filtered using sufficiently retaining filter paper. Water was added followed by phase separation. The separated organic layer was dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to give 15 mg of 1- (1-methyl-2-pyrrolecarbonyloxypropyl) -cyclopropene in oil form.

Example 31 1-ethyl-2- (3- (4-chlorophenyl) -pyridaz-6-one-1-yl) -cyclopropene (Compound 60)

a. 3- (4-Chlorophenyl) -pyridaz-6-one

3- (4-chlorophenyl) -pyridaz-6-one is described in DE Pat. No. Prepared as disclosed in Example 3 of 2435244 (1976).

b. 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene

1- (methanesulfonyloxymethyl) -2-ethylcyclopropene was prepared from the method known in Example 17c.

c. 1-ethyl-2- (3- (4-chlorophenyl) -pyridaz-6-one-1-yl) -cyclopropene

In an ice bath, a suspension of sodium hydride (60% in oil, 0.08 g, 2 mmol) dissolved in N, N-dimethylformamide (4 ml) was added to 3- (4-chlorophenyl) -pyridaz-6-one ( 0.41 g, 2 mmol) was added. After stirring for 15 minutes, 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene (0.35 g, 2 mmol) was added. After stirring for 45 minutes at room temperature, water and ethyl acetate were added. The phases were separated. The separated organic phase was washed sequentially with water and brine, then dried over magnesium sulfate and finally dried in vacuo. The residue was purified by column chromatography on silica gel with hexane / ethyl acetate to give 1-ethyl-2- (3- (4-chlorophenyl) -pyridaz-6-one-1-yl)-as an off-white solid. 340 mg of cyclopropene were obtained.

Example 32 Preparation of 1-triethylsilylmethylcyclopropene (Compound 63)

a. 3-trichlorosilyl-2-bromopropene

This compound is Hollingworth, GJ; It was prepared as disclosed in Lee, TV Sweeney, JB Synthetic Commun , 1996, 26, 1117. The product was mixed with hexane and filtered. The filtrate was stripped and used without further purification (no distillation).

b. 3-triethylsilyl-2-bromopropene

In an ice bath, 7 ml (3.0 M, 21 mmol) of ethylmagnesium bromide was added to a solution of 1.3 g (5 mmol) of 3-trichlorosilyl-2-bromopropene dissolved in 20 ml of THF. The reaction was raised to room temperature, stirred overnight and then terminated with water. Ether was added and the reaction mixture was transferred to a separatory funnel. A small amount of 1N HCl was added, the phases were separated and the ether phase was washed with water and brine, then dried over magnesium sulfate, filtered and stripped. Chromatography gave 300 mg of 3-triethylsilyl-2-bromopropene.

c. N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide and N, N'-dibenzyl-N, N, N'N, -tetraethylethylenediammonium dibromide ( Phase transfer catalyst)

50.1 g (292 mmol) of benzylbromide was added to a solution of 16.5 g (142 mmol) of N, N, N'N'-tetramethylethylenediamine dissolved in 60 g of acetonitrile. The temperature of the mixture itself was raised and stirred for 2.5 hours, at which time a heavy precipitate was observed. The slurry was diluted with diethyl ether, filtered, washed with diethyl ether and dried to give 61.8 g of desired N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide. It was obtained as a white solid, mp is 230-232 ℃.

In a similar manner, N, N'-dibenzyl-N, N, N ', N'-tetraethylethylenediammonium dibromide was obtained using N, N, N'N'-tetraethylethylenediamine, This is a white solid, mp is 190-193 ℃.

d. 2-triethylsilylmethyl-1,1,2-tribromocyclopropane

3-triethylsilyl-2-bromopropene 300 mg (1.27 mmol), 0.47 g (3.8 mmol) 45% aqueous potassium hydroxide solution, N, N'-dibenzyl-N, N, N'N'- A mixture of 75 mg of tetraethylethylenediammonium dibromide and 3 ml of methylene chloride was treated with 0.33 ml (3.8 mmol) bromoform. The stirred reaction mixture was kept at room temperature for 5.5 hours. Water and methylene chloride were added and the phases were separated. The methylene chloride phase was placed in a reaction flask, additional 0.47 g (3.8 mmol) of 45% aqueous potassium hydroxide solution, and N, N'-dibenzyl-N, N, N ', N'-tetraethylethylenedi Treated with 75 mg ammonium dibromide. The reaction mixture was stirred overnight, then water and additional methylene chloride were added and the phases were separated. The methylene chloride phase was dried over magnesium sulfate and stripped. A small amount of heptane was added to the stripping step to remove residual bromoform. Column chromatography gave 390 mg of 2-triethylsilylmethyl-1,1,2-tribromocyclopropane as a colorless liquid.

e. 1-triethylsilylmethylcyclopropene

A solution of 0.36 g (0.9 mmol) of 2-triethylsilylmethyl-1,1,2-tribromocyclopropane dissolved in 5 ml of ether was cooled to -78 ° C. Excess methyllithium (1.4 M, 2.0 ml, 2.8 mmol) was added and the reaction mixture was placed in an ice bath for 5 minutes and then sampled. The reaction mixture was cooled back to -78 ° C while sampling. The reaction was terminated with a small amount of methanol and the temperature was raised to room temperature. Additional ether and water were added. The phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 100 mg of 1-triethylsilylmethylcyclopropene as a colorless liquid.

Example 33 Preparation of 1-trimethylsilylmethylcyclopropene (Compound 64)

In the same manner as in Example 1, commercially available 3-trimethylsilyl-2-bromopropene was converted to 1-trimethylsilylmethylcyclopropene.

Example 34 Preparation of 6- (trimethylsilyl) -hexylcycloprop-2-ene (Compound 65)

a. 2-bromo-8- (trimethylsilyl) -oct-1-ene

In an ice bath, commercially available pentamethylenebis (magnesium bromide) (50 ml, 0.5 M in THF, 25 mmol) was cooled. A solution of 2.72 g (25 mmol) of trimethylchlorosilane dissolved in 10 ml of THF was added. The reaction mixture was stirred at 5 ° C. for 30 minutes, then at room temperature for 1 hour and cooled to 5 ° C. again. 2,3-Dibromopropene (5.0 g, 25 mmol) dissolved in 6 ml of THF was added to the reaction mixture, which was raised to room temperature and stirred for 2 hours. The reaction mixture was terminated with water. Ether and small amount of 1N HCl were added. The phases were separated and the organic phase was washed with water and brine then dried over magnesium chloride and stripped. Column chromatography gave 1.62 g of 2-bromo-8- (trimethylsilyl) -oct-1-ene as a colorless oil.

b. 2- (6- (trimethylsilyl) -hexyl) -1,1,2-tribromocyclopropane

1.52 g (5.8 mmol) 2-bromo-8- (trimethylsilyl) -oct-1-ene, 4.3 g (34 mmol) 45% aqueous potassium hydroxide solution, N, N'-dibenzyl-N, N, A mixture of 0.2 g of N ', N'-tetraethylethylenediammonium dibromide, and 10 ml of methylene chloride was treated with 1.5 ml (17.4 mmol) of bromoform. The stirred reaction mixture was kept at room temperature overnight. An additional 4 g of 45% aqueous potassium hydroxide solution was added and the reaction was stirred for an additional hour at room temperature. Water and methylene chloride were added and the phases were separated. The methylene chloride phase was dried over magnesium sulfate and stripped. A small amount of heptane was added during the strip to remove residual bromoform. By column chromatography, 1.13 g of 2- (6- (trimethylsilyl) -hexyl) -1,1,2-tribromocyclopropane as a colorless oil was obtained.

c. 6- (trimethylsilyl) -hexylcycloprop-2-ene

A solution of 0.96 g (2.2 mmol) of 2- (6- (trimethylsilyl) -hexyl) -1,1,2-tribromocyclopropane dissolved in 10 ml of ether was cooled to -78 ° C. Excess methyllithium (1.4 M, 5.1 ml, 7.1 mmol) was added and the reaction mixture was left in an ice bath for 30 minutes and then terminated with water. The phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 370 mg of a colorless liquid 6- (trimethylsilyl) -hexylcycloprop-2-ene.

Example 35 Preparation of 2- (trimethylsilyl) -ethylcycloprop-2-ene (Compound 66)

a. 2-bromo-4- (trimethylsilyl) -but-1-ene

To a solution of 5.0 g (50 mmol) of 2,3-dibromopropene dissolved in 20 ml of ether cooled in an ice bath was added 30 ml (1 M, 30 mmol) of commercially available trimethylsilylmethylmagnesium chloride. The reaction mixture was stirred at 0 ° C. for 30 minutes and then raised to room temperature. THF (10 ml) was added and the reaction mixture was stirred overnight. It was terminated with water. The reaction mixture was transferred to a separatory funnel. A small amount of 1N HCl is added, the phases are separated, the ether phase is washed with water and brine, then dried over magnesium sulfate, filtered and stripped to 2-bromo-4- (trimethylsilyl) -butyrate. 4.5g of -1-ene was obtained, which was used without additional purification.

b. 2- (trimethylsilyl) -ethylcycloprop-2-ene

2-Bromo- in a similar manner (Example 3) converting 2-bromo-8- (trimethylsilyl) -oct-1-ene to 6- (trimethylsilyl) -hexylcycloprop-2-ene 4- (trimethylsilyl) -but-1-ene was converted to 2- (trimethylsilyl) -ethylcycloprop-2-ene.

Example 36 Preparation of 2-octyl-1-trimethylsilylcyclopropene (Compound 67)

a. 2-bromodedec-1-en

17 g (700 mmol) of magnesium turning was added to a 500 ml three-necked flask equipped with magnetic stirring, addition separatory funnel and reflux condenser. The atmosphere was exchanged with dry nitrogen and the turning was covered with 20 ml of diethyl ether. 2 g of 1,2-dibromoethane was added, and it was confirmed that the reaction occurred by clouding and turbidity. After 5 minutes, 200 ml of diethyl ether was added and the mixture was refluxed. It took 50 minutes to slowly add 90 g (503 mmol) of 1-bromoheptane dissolved in 100 ml of diethyl ether at a rate sufficient to maintain reflux. The reaction was further refluxed for 30 minutes, giving a heptyl magnesium bromide solution.

In a nitrogen atmosphere, 75 g (375 mmol) of 2,3-dibromopropene dissolved in 200 ml of diethyl ether were added to a 1000 ml three-necked flask equipped with a magnetic stirring, a cetum, and a reflux condenser. Heptyl magnesium bromide solution was transferred to the reaction using cannula at a rate to control reflux. After reflux for another 60 minutes, the reaction was stirred overnight at room temperature. The reaction was terminated with aqueous hydrochloric acid solution, washed with brine, dried over anhydrous magnesium sulfate, rotovapped and distilled at 12torr through a 5-tray perforated plate column to give a bp (12torr) of 105-115 ° C. 52 g of bromodedec-1-ene were obtained.

b. 2-octyl-1,1,2-tribromocyclopropane

In a 125 ml single-necked flask equipped with magnetic stirring, 20 g (91 mmol) of 2-bromodedec-1-ene, 75 g (297 mmol) of bromoform, 200 g of methylene chloride, N, N'-dibenzyl-N, N, N 2.2 g of 'N'-tetramethylethylenediammonium dibromide and 20 g (161 mmol) of 45% aqueous potassium hydroxide were added. The mixture is stirred for 3 days, 100 ml of water is added, the organic layer is separated, 30 g of bromoform, N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium di Treated again with 2.0 g bromide, and 25 g 45% aqueous potassium hydroxide. After stirring for a further 2 days, the reaction was washed with water, dried, rotabob and silica gel chromatography was diluted with hexanes. 41g of 2-octyl-1,1,2-tribromocyclopropane was obtained.

c. 2-octyl-1-trimethylsilylcyclopropene

A solution of 0.98 g (2.5 mmol) of 2-octyl-1,1,2-tribromocyclopropane dissolved in 10 ml of ether was cooled to -78 ° C. Methyllithium (1.4M, 5.35 ml, 7.5 mmol) was added and the reaction mixture was stirred for 30 minutes and then placed in an ice bath and held for 30 minutes. Tri methylsilylchloride (0.81 g, 7.5 mmol) was added and the reaction mixture was maintained for 45 minutes and then terminated with water. Additional ether was added and the phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 370 mg of 2-octyl-1-trimethylsilylcyclopropene as a yellow liquid.

Example 37 Preparation of 1- (2-methanesulfonyloxyethyl) -cyclopropene (Compound 68)

a. 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene

In an ice bath, 10.38 g (0.0687 mol) of a commercially available solution of 3-bromo-3-buten-1-ol in 20 ml of diethyl ether in which 50 mg (0.000263 mol) of p-toluenesulfonic acid monohydrate was dissolved was cooled. 19 ml (0.199 mol) of ethylvinyl ether were slowly added while maintaining the internal temperature <10 ° C. After 1 hour at 0 ° C., a few drops of triethylamine were added. The reaction mixture was poured into water. The resulting mixture was transferred to a separatory funnel and the phases separated. The separated organic layer was washed with brine, dried over potassium carbonate and filtered. The solvent was removed from the filtrate in vacuo to yield 14.04 g of 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene as an oil.

b. 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane

In a solution of 14.02 g (0.0628 mol) of 2-bromo-4- (1-ethoxy-ethoxy) -but-1-ene in 108 ml of methylene chloride dissolved in 0.5-0.9 ml of 45% aqueous potassium hydroxide. 16.4 ml (0.118 mol) of bromoform, and 2.88 g (0.00628 mol) of N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide and 28 ml of 45% aqueous potassium hydroxide (0.314 mol) was added. After 3 days, the reaction mixture was poured into water. The resulting mixture was transferred to a separatory funnel and the phases separated. To the separated organic layer, 2.88 g (0.00628 mol) of N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide and 28 ml (0.314 mol) of 45% aqueous potassium hydroxide were added. It was. After 24 hours, hexanes and water were added. This mixture was gravity filtered through qualitative fluted filter paper. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 17.0 g of 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane as an oil.

c. 2- (2-hydroxyethyl) -1,1,2-tribromocyclopropane

P-toluenesulfonic acid in a slurry of 16.5 g (0.0418 mol) of 1,1,2-tribromo-2- [2- (1-ethoxy-ethoxy) -ethyl] -cyclopropane in 145 ml of methanol and 40 ml of water 0.306 g (0.00161 mol) of monohydrate and 145 ml of 6M hydrochloric acid were added. After stirring for 1 hour at room temperature, the solvent was removed from the reaction mixture in vacuo. To the residue, ethyl acetate and water were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The separated organic layer was washed with brine, dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 11.9 g of 2- (2-hydroxyethyl) -1,1,2-tribromocyclopropane in oil form.

d. 1- (2-hydroxyethyl) -cyclopropene                 

A solution in which 1.15 g (3.6 mmol) of 2- (2-hydroxyethyl) -1,1,2-tribromocyclopropane (prepared above) was dissolved in 40 ml of ether was cooled to -78 ° C. Methyllithium (1.4M, 10.3 ml, 14.4 mmol) was added. The reaction mixture was raised to 5 ° C. and maintained for 1 and a half hours. The reaction was washed with water and the phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped. The crude product was used for the next reaction.

e. 1- (2-methanesulfonyloxyethyl) -cyclopropene

The crude product of the reaction was dissolved in 5 ml of ether and cooled in an ice bath. Triethylamine (1 ml) was added followed by 0.49 g (4.3 mmol) methanesulfonyl chloride. The reaction mixture was stirred for 1 hour. Water and additional ether were added and the phases separated. The ether phase was washed twice with water, brine, dried over magnesium sulfate and stripped to give 380 mg of 1- (2-methanesulfonyloxyethyl) -cyclopropene as a pale yellow liquid.

Example 38 Preparation of 1- (7-Methanesulfonyloxyheptyl) -cyclopropene (Compound 69)

a. 1- (1-ethoxy-ethoxy) -6-bromohexane

To a cooled solution of 80 mg of toluenesulfonic acid dissolved in 40 ml of ether, 20 g (110 mmol) of 6-bromohexanol and 40 ml of ethyl vinyl ether were sequentially supplied using a separating addition funnel. The feed took 1 hour and the temperature of the reaction mixture was kept below 7 ° C. The reaction mixture was stirred for 20 minutes and then about 1 ml of triethylamine was added. The reaction mixture was washed with water and brine then dried over potassium carbonate, filtered and stripped to give 25.7 g as a pale yellow liquid, which was used without further purification.

b. 9- (1-ethoxyethoxy) -2-bromonone-1-ene

A slurry of 5.6 g (230 mmol) of magnesium turning dissolved in 100 ml of THF was treated with a small amount of 1,2-dibromoethane. 1- (1-ethoxyethoxy) -6-bromohexane (38.5 g, 152 mmol) was slowly added to the reaction mixture while maintaining the temperature at 40-50 ° C. At the end of the addition, the reaction mixture was held for 20 minutes and then transferred to a solution of 33.4 g (167 mmol) of 2,3-dibromopropene dissolved in 25 ml of THF using cannula at 0 ° C. The reaction mixture was stirred at 0 ° C. for 15 minutes, then at room temperature for 15 minutes and terminated with water. The reaction mixture was transferred to a separatory funnel. A small amount of 1N HCl was added, the phases were separated, the ether phase was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 33.63 g of yellow oil which was used without additional purification.

c. 1,1,2-tribromo-2- (7-hydroxyheptyl) -cyclopropane

9- (1-ethoxyethoxy) -2-bromonone-1-ene (33.63 g, 115 mmol), N, N'-dibenzyl-N, N, N'N'-tetraethylethylenediammonium dibromide A mixture of 4.1 g, 45 g potassium hydroxide 42 g (337 mmol), 93 g (368 mmol) bromoform and 280 g methylene chloride was stirred rapidly at room temperature for 2 days. When the reaction was stopped, the reaction mixture was transferred to a separatory funnel and washed with water. The methylene chloride phase was transferred to a flask, treated in equal amounts with a phase transfer catalyst and 45% potassium hydroxide, followed by stirring at room temperature for an additional 3 days. The reaction mixture was washed with water and the methylene chloride phase was dried over magnesium sulfate and then stripped. The product was treated with 320 ml of methanol and 40 ml of 1N HCl for 1 hour at room temperature. The methanol was stripped and ethyl acetate was added. The organic phase was washed with water and brine and then treated with 200 ml of silica gel. After filtration, stripping gave 38 g of a black product. This was chromatographed with silica gel to give 19.0 g of a pale yellow liquid 1,1,2-tribromo-2- (7-hydroxyheptyl) cyclopropane.

d. 1- (7-hydroxyheptyl) -cyclopropene

A solution of 1.0 g (2.5 mmol) of 1,1,2-tribromo-2- (7-hydroxyheptyl) -cyclopropane in 25 ml of ether was treated with 7.2 ml (1.4 M, 10 mmol) of methyllithium at -78 ° C. It was. After 5 minutes, the reaction mixture was raised to 0 ° C. and maintained at this temperature. The reaction was terminated with saturated ammonium chloride. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 240 mg of 1- (7-hydroxyheptyl) -cyclopropene.

e. 1- (7-methanesulfonyloxyheptyl) -cyclopropene

A solution of 4.3 mmol of 1- (7-hydroxyheptyl) -cyclopropene in 50 ml of ether was cooled in an ice bath. Triethylamine (1 ml) and 0.54 g (4.7 mmol) of methanesulfonyl chloride were added and the reaction mixture was stirred at 0 ° C. for 2 and a half hours. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 0.83 g of 1- (7-methanesulfonyloxyheptyl) -cyclopropene.

Example 39 Preparation of 1- (7-ethanethioheptyl) -cyclopropene (Compound 70)

A mixture of 0.35 g (1.5 mmol) of 1- (7-methanesulfonyloxyheptyl) -cyclopropene and 0.36 g (4.5 mmol) of 80% sodium ethanethiolate dissolved in DMF was stirred at room temperature for 1 hour. Ether and water were added and the phases were separated. The organic phase was washed with 1N sodium hydroxide solution, twice with water, brine, dried over magnesium sulfate, filtered and stripped. Chromatography gave 140 mg of 1- (7-ethanethioheptyl) -cyclopropene as a colorless liquid.

Example 40 Preparation of 1-Bromo-2-octyl-cyclopropene (Compound 71)

a. 2-bromodedec-1-en

17 g (700 mmol) of magnesium turning was added to a 500 ml three-necked flask equipped with magnetic stirring, an addition fractionation funnel, and a reflux condenser. The atmosphere was exchanged with dry nitrogen and the turning was covered with 20 ml of diethyl ether. 2 g of 1,2-dibromoethane was added and the reaction was observed by turbidity with the bubbles. After 5 minutes, 200 ml of diethyl ether was added and the mixture was refluxed. It took 50 minutes to slowly add 90 g (503 mmol) of 1-bromoheptane dissolved in 100 ml of diethyl ether at a sufficient rate to maintain reflux. The reaction was further refluxed for 30 minutes to obtain heptyl magnesium bromide solution.

Under a nitrogen atmosphere, 75 g (375 mmol) of 2,3-dibromopropene dissolved in 200 ml of diethyl ether were added to a 1000 ml three-necked flask equipped with a magnetic stirring, a cetum, and a reflux condenser. The heptyl magnesium bromide solution was transferred to the reaction using a cannula at a rate to control reflux. After refluxing for another 60 minutes, the reaction was stirred overnight at room temperature. The reaction was terminated with aqueous hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, rotabab and distilled at 12torr through a 5-tray perforated plate column to give 2-bromodedec having a bp of 105-115 ° C. 52 g of 1-yen were obtained.

b. N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium dibromide (phase transfer catalyst)

50.1 g (292 mmol) of benzyl bromide was added to a stirred solution of 16.5 g (142 mmol) of N, N, N ', N'-tetramethylethylenediamine dissolved in 60 g of acetonitrile. The heated mixture itself was stirred for 2.5 hours, at which time a heavy precipitate was observed. The slurry was diluted with diethyl ether, filtered, washed with diethyl ether and dried to give the desired N, N'-dibenzyl-N, N, N ', N' with a white solid as mp of 230-232 ° C. 61.8 g of tetramethylethylenediammonium dibromide were obtained.

c. 2-octyl-1,1,2-tribromocyclopropane

In a 125 ml single-necked flask equipped with magnetic stirring, 20 g (91 mmol) of 2-bromodedec-1-ene, 75 g (297 mmol) of bromoform, 200 g of methylene chloride, N, N'-dibenzyl-N, N, 2.2 g N ', N'-tetramethylethylenediammonium dibromide and 20 g (161 mmol) of 45% aqueous potassium hydroxide were added. The mixture was stirred for 3 days, to which 100 ml of water was added and the organic layer was separated, 30 g of bromoform, N, N'-dibenzyl-N, N, N ', N'-tetramethylethylenediammonium Reprocessed with 2.0 g dibromide and 25 g 45% aqueous potassium hydroxide. After stirring for 2 days, the reaction was washed with water, dried and rotabab, then silica gel chromatography was diluted with hexanes. 41g of 2-octyl-1,1,2-tribromocyclopropane was obtained.

d. 1-bromo-2-octyl-cyclopropene

A solution of 3.18 g (0.00813 mol) of 1,1,2-tribromo-2-octyl-cyclopropane dissolved in 6 ml of diethyl ether was placed in a nitrogen atmosphere using a firestone valve. While cooling in an ice bath, 5.81 ml (0.00813 mol) of 1.4 M methyllithium dissolved in diethyl ether was slowly added by syringe. After 15 minutes, 2 ml of water was added by syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate by vacuum at a water bath temperature of 20 ° C. or lower to give 1.43 g of 1-bromo-2-octyl-cyclopropene as an oil.

Example 41 Preparation of 3-Methyl-3-pentyl-cyclopropene (Compound 72)

a. 1,1-dibromo-2-methyl-2-pentyl-cyclopropane

0.635 g (0.00193 mol) of tetrabutylammonium bromide and 15.1 ml of 50% aqueous sodium hydroxide in a solution of 7.01 ml (0.0446 mol) of 2-methyl-hept-1-ene in 14.4 ml (0.162 mol) of bromoform. (0.185 mol) was added. After heating to 55 ° C. for 1 hour, the reaction was cooled to room temperature and hexane and water were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo. The residue was purified by vacuum distillation to give 10.9 g of 1,1-dibromo-2-methyl-2-pentyl-cyclopropane.

b. 2-bromo-1-methyl-1-pentyl-cyclopropane

In a solution of 6.59 g (0.0232 mol) of 1,1-dibromo-2-methyl-2-pentyl-cyclopropane dissolved in about 20 ml of methanol, 1.47 ml (0.0255 mol) of glacial acetic acid and 1.49 g (0.0227 mol) of zinc dust were added. Added. After stirring for 1 hour, 1.47 ml (0.0255 mol) glacial acetic acid and 1.49 g (0.0227 mol) zinc dust were added to the reaction mixture. After stirring for 2 hours, the reaction mixture was concentrated in vacuo. After addition of hexanes and water, the resulting mixture was transferred to a separatory funnel and the phases separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to give 2.2 g of 95% pure 2-bromo-1-methyl-1-pentyl-cyclopropane as an oil.

c. 3-methyl-3-pentyl-cyclopropene

0.563 g (0.502 mol) of potassium t-butoxide was added to a solution in which 1.03 g (0.502 mol) of 2-bromo-1-methyl-1-pentyl-cyclopropane was dissolved in 5 ml of dimethyl sulfoxide. After heating to 85 ° C. for 2 hours, additional 0.075 g (0.00516 mol) of potassium t-butoxide was added. After heating at 85 ° C. for 1 hour, water and diethyl ether were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo. The residue was dissolved in 4 ml of dimethyl sulfoxide and 0.6 g (0.536 mol) of potassium t-butoxide was added thereto. After heating at 90 ° C. for 7 hours, water and ethyl acetate were added and the resulting mixture was transferred to a separatory funnel for phase separation. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to yield 180 mg of 3-methyl-3-pentyl-cyclopropene as a 50% mixture with t-butanol.

Example 42 Preparation of 3-Methyl-3-nonyl-cyclopropene (Compound 73)

This compound was prepared in a similar manner to compound 2. This is a mixture of 40% 3-methyl-3-nonyl-cyclopropene, 30% 1-methyl-1-nonyl-cyclopropane and 20% 1-methyl-1-nonyl-2-bromocyclopropane Obtained.

Example 43 Preparation of 1-heptyl-2-methyl-cyclopropene (Compound 74)

A solution of 1 mg of 1,10-phenanthroline, 1.74 ml of tetramethylethylenediamine, and 20 ml of tetrahydrofuran was placed in a nitrogen atmosphere using a firestone valve. 1-methylcyclopropene (prepared from 3-chloro-2-methyl-propene; Hopf, H .; Wachholz, G .; Walsh, R. Chem. Ber. 1985, 118, 3579), while cooling to -30 ° C. And Koster, R et al., Liebigs Annalen Chem. 1973, 1219-1235) 1.5 ml were added with a plastic syringe. While cooling to -40 [deg.] C., 8 ml (11.5 mmol) of 1.6 M n-butyllithium dissolved in hexane were added slowly by syringe. After 15 minutes at −30 ° C., 1.90 ml (11.5 mmol) of 1-iodoheptane was added dropwise by syringe. After stirring for 30 minutes, the reaction mixture was dried in vacuo at a water bath temperature of 20 ° C. or lower while naturally raising the temperature to 5 ° C. After addition of diethyl ether and 1N hydrochloric acid, the resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature of 20 ° C. or less. This residue was column chromatographed with hexane to give 0.700 g of 1-heptyl-2-methyl-cyclopropene as an oil.

Example 44 Preparation of 1-Bromo-2- (2- (carbo (acetoxymethyl)) ethyl-cyclopropene (Compound 75)

a. 2- (2-Bromo-allyl) -malonic acid diethyl ester

The oil was removed by washing with hexane from 21.70 g (0.542 mol) of 60% sodium hydride in oil. To the residue suspended in 200 ml of tetrahydrofuran 84.38 ml (0.556 mol) of diethylmalonate were added slowly through an addition separatory funnel. While cooling the reaction to −35˜10 ° C., 100 g (0.400 mol) of 2,3-dibromopropene were added slowly through an addition separatory funnel. After heating to reflux for 1 hour, the reaction was cooled to room temperature and concentrated in vacuo. Hexane and water were added to the residue and the resulting mixture was transferred to a separatory funnel and the phases separated. The separated organic layer was washed with 1N hydrochloric acid, dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to give 154 g of 2- (2-bromo-allyl) -malonic acid diethyl ester as an oil.

b. 2- (2-Bromo-allyl) -malonic acid

A mixture of 10.5 g (0.0376 mol) of 2- (2-bromo-allyl) -malonic acid diethyl ester and 37.6 ml (0.470 mol) of 50% aqueous sodium hydroxide was stirred at room temperature for 4 days. The reaction mixture was extracted with diethyl ether. The separated aqueous layer was acidified by addition of concentrated hydrochloric acid and diethyl ether was added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The separated organic layer was dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to give 5.3 g of 2- (2-bromo-allyl) -malonic acid as a solid, which was used without additional purification.

c. 4-bromo-pent-4-enoic acid

3.73 g of 4-bromo-pent-4-enoic acid was heated by heating 5.3 g (0.0238 mol) of neat, unrefined 2- (2-bromo-allyl) -malonic acid at 125 to 130 ° C. for 8 hours. It was obtained and used without additional purification.

d. 4-Bromo-pent-4-enoic acid ethyl ester

1.18 ml (0.0162 mol) of thionyl chloride in a solution of 3.73 g (0.0208 mol) of unrefined 4-bromo-pent-4-enoic acid in 3 ml of chloroform containing one drop of N, N'-dimethylformamide. Was added. The mixture was heated at 60 ° C. for 30 minutes and then added to a solution of 2.46 ml (0.046 mol) ethanol, 1.97 ml (0.024 mol) pyridine, and 13 ml methylene chloride. After stirring for 30 minutes, the reaction mixture was concentrated in vacuo. Diethyl ether and water were added to the residue. The resulting mixture was transferred to a separatory funnel and the phases were separated. The separated organic layer was dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to yield 3.5 g of 4-bromo-pent-4-enoic acid ethyl ester as an oil, which was purified by vacuum distillation.                 

e. 1,1,2-tribromo-2- (2- (carboethoxy)) ethyl-cyclopropene

1,1,2-tribromo-2- (2- (carboethoxy)) ethyl-cyclopropene with a method similar to 2-octyl-1,1,2-tribromocyclopropane (Example 1 )

f. 1,1,2-tribromo-2- (2- (carboxy)) ethyl-cyclopropene

A solution of 10.2 g (0.0269 mol) of 1,1,2-tribromo-2- (2- (carboethoxy)) ethyl-cyclopropene dissolved in 40 ml of 48% hydrochloric acid and 40 ml of water for 8 hours After heating to reflux, it was cooled to room temperature and then vacuum filtered using Shark Skin ^® filter paper. The separated solid was washed with water before adding diethyl ether. The solution was transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate, then separated and made acidic by addition of 1N hydrochloric acid. The aqueous solution was returned to a separatory funnel and extracted with diethyl ether. The separated organic layer was dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to yield 5.9 g of 1,1,2-tribromo-2- (2- (carboxy)) ethyl-cyclopropene as a solid, which was used without further purification.

g. 1,1,2-tribromo-2- (2- (carbo (acetosylmethyl)) ethyl-cyclopropene

In a solution containing 0.800 g (0.00228 mol) of 3-1,1,2-tribromo-2- (2- (carboxy)) ethyl-cyclopropene dissolved in about 2 ml of anhydrous N, N-dimethylformamide 0.224 ml (0.00228 mol) of mother methyl acetate was added followed by 0.396 ml (0.00228 mol) of diisopropylethylamine. After heating at 60 ° C. for 2 hours, water and diethyl ether were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and brine. The organic layer was dried over MgSO ₄ and filtered. The solvent was removed from the filtrate in vacuo to yield 0.900 g of 1,1,2-tribromo-2- (2- (carbo (acetosylmethyl))-ethyl-cyclopropene.

h. 1-Bromo-2- (2- (carbo (acetosylmethyl))-ethyl-cyclopropene

A solution of 0.800 g (0.00202 mol) of 1,1,2-tribromo-2- (2- (carbo (acetosylmethyl))-ethyl-cyclopropene dissolved in 1.04 ml (0.00808 mol) of diethyl phosphite To the mixture was added 0.281 ml (0.00202 mol) of triethylamine, after stirring for 16 hours, the reaction mixture was dissolved in hexane and washed with 1N hydrochloric acid, after which the aqueous layer was extracted with diethyl ether. The organic phase was washed with 3N aqueous sodium carbonate The organic layer was dried over MgSO ₄ and filtered The solvent was removed from the filtrate by vacuum in a water bath having a temperature of 20 ° C. or lower The residue was again subjected to the above reaction conditions. The residue was subjected to column chromatography purification with diethyl ether / hexanes to give 1-bromo-2- (2- (carbo (acetosylmethyl))-ethyl-cyclo Propene 180 mg was obtained as an oil.

Example 45 Preparation of 1-Bromo-2- (2- (carboethoxy) -ethyl-cyclopropene (Compound 76)

1-Bromo-2- (2-carbo (acetosylmethyl))-ethyl-cyclopropene to 1,1,2-tribromo-2- (2-carbo (acetosylmethyl))-ethyl 1-Bromo-2- (2- (carboethoxy) -ethyl-cyclopropene was converted to 1,1,2-tribromo- in a similar manner to that prepared from cyclopropene (Example 5). Prepared from 2- (2- (carboethoxy) -ethyl-cyclopropene.

Example 46 Preparation of 1-Bromo-2- (2- (carboxy) -ethyl-cyclopropene (Compound 77)

0.0768 g (1.37 mmol) of potassium hydroxide was added to a solution of 200 mg (0.913 mmol) of 1-bromo-2- (2- (carboethoxy) -ethyl-cyclopropene in 2 ml of anhydrous ethanol. After stirring for 1 h, diethyl ether and water were added, the resulting mixture was transferred to a separatory funnel and the phases were separated The separated aqueous layer was acidified by addition of 1N hydrochloric acid and diethyl ether was added. The resulting mixture was transferred to a separatory funnel and the phases separated The organic layer was dried over MgSO ₄ and filtered The solvent was removed from the filtrate by vacuum at a bath temperature below 20 ° C. to> 70% pure 1-bro 160 mg of mother-2- (2- (carboxy) -ethyl-cyclopropene were obtained as an oil.

Example 47 Preparation of 1-octyl-3-carboxy-cyclopropene (Compound 78)

a. 1-octyl-3- (carboxyethoxy) -cyclopropene

Mueller, P .; Pautex, N .; Helv. 1-Octyl-3- (carboxyethoxy) -cyclopropene was prepared from 1-decyne and ethyl diazoacetate by the method of Chim Acta 1990, 73, 1233.

b. 1-octyl-3-carboxy-cyclopropene                 

100 ml of 1-octyl-3- (carboxyethoxy) -cyclopropene (1.12 g, 5 mmol) and 0.2 N potassium hydroxide were stirred for 1 week at room temperature. Ether was added to separate the phases. The aqueous phase was acidified and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and stripped to yield 0.8 g of 1-octyl-3-carboxy-cyclopropene.

Comparative Example 2: Preparation of 1-trimethylsilyl-2,3,3-trimethylcyclopropene (Compound 79)

Compound 79 was prepared in 36% solution dissolved in ether from 2-bromo-3-methyl-2-butene using the same method prepared from 2-bromodedec-1-ene.

Example 49 Preparation of 1- (butyldimethylsilyl) -2-methylcyclopropene (Compound 80)

Compound 80 was prepared from 2-bromopropene using the method prepared from compound 2-bromodec-1-ene.

Example 50 Preparation of 1-triethylsilyl-2-methylcyclopropene (Compound 81)

Compound 81 was prepared from 2-bromopropene using the method prepared from compound 5-bromodec-1-ene.

Example 51 Preparation of 1- (7-T-Butyldimethylsilyloxyheptyl) -cyclopropene (Compound 82)

a. 1- (7-hydroxyheptyl) -cyclopropene

1- (7-hydroxyheptyl) -cyclopropene was prepared by the same method already described in Example 7.                 

b. 1- (7-T-butyldimethylsilyloxyheptyl) -cyclopropene

In 19.4 ml of methylene chloride, a solution of 1- (7-hydroxyheptyl) -cyclopropene (1.07 g, 3.47 mmol) was added to t-butyldimethylsilylchloride (0.562 g, 3.75 mmol) and N, N-dimethylaminopyridine ( 0.213 g, 1.74 mmol) and triethylamine (0.368 ml, 2.64 mmol) were added. After the reaction mixture was stirred at room temperature for 2 hours, N, N-dimethylaminopyridine (0.213 g, 1.74 mmol) and triethylamine (0.368 ml, 2.64 mmol) were added. After an additional 45 minutes, the reaction was terminated by addition of 3 ml of saturated aqueous ammonium chloride. The phases were separated. The separated organic layer was washed successively with brine, saturated aqueous sodium bicarbonate and water. The organic layer was separated again, dried over magnesium sulfate and concentrated in vacuo to give 1.2 g. This residue was purified by column chromatography with 5% ethyl acetate / hexanes to give 440 mg (47% of theory) of 1- (7-t-butyldimethylsilyloxyheptyl) -cyclopropene as an oil.

Example 52 Preparation of 1- (Methanesulfonyloxymethyl) -2-ethylchloropropene (Compound 83)

a. 1,1,2-tribromo-2-ethylcyclopropane

1,1,2-tribromo-2-ethylcyclopropane was prepared from 2-bromo-1-butene as in Example 5.

b. 1- (hydroxymethyl) -2-ethylcyclopropene

A solution of 3.0 g (10 mmol) of 1,1,2-tribromo-2-ethylcyclopropane dissolved in 50 ml of ether was cooled to -78 deg. Methyllithium (1.4M, 21.4 ml, 30 mmol) was added. The reaction mixture was raised to 5 ° C. Solid paraformaldehyde (1.20 g, 40 mmol) was added and the reaction mixture was stirred at 5 ° C. for 1 h, then raised to room temperature and stirred for a further 1 h. The reaction was terminated with water and the phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 900 mg of 1- (hydroxymethyl) -2-ethylcyclopropene as a yellow oil.

a. 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene

In an ice bath, 0.86 g (7.5 mmol) of methanesulfonyl chloride in a solution of 0.70 g (7.13 mmol) of 1- (hydroxymethyl) -2-ethylcyclopropene (Compound 3) and 2 ml of triethylamine in 15 ml of ether. ) Was added. The reaction mixture was maintained for 1.5 hours and then terminated with water. The phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 840 mg of 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene as a yellow oil.

Example 53 Preparation of 1- (diethoxy-thiophosphorylthiomethyl) -2-ethylcyclopropene (Compound 84)

a. 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene

In the same manner as in Example 13, 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene was prepared from 1- (hydroxymethyl) -2-ethylcyclopropene.

b. 1- (diethoxy-thiophosphorylthiomethyl) -2-ethylcyclopropene

4.4 ml of 1- (methanesulfonyloxymethyl) -2-ethylcyclopropene (0.66 g, 3.75 mmol) and dithiophosphoric acid O, O'-diethyl ester, potassium salt (0.84 g, 3.75 mmol) Mix in dimethyl formamide. After stirring the reaction mixture for 4 h, water then diethyl ether was added. The phases were separated. The ether phase was washed two more times with water, dried over magnesium sulfate and stripped to give 510 mg (51% of theory) of 1- (diethoxy-thiophosphorylthiomethyl) -2-ethylcyclopropene as an oil. .

Example 54 Preparation of 1- (4-Methanesulfonyloxybutyl) -cyclopropene (Compound 85)

a. 5,6-dibromo-hexan-1-ol

To a solution of 5-hexene-1-ol (11.23 g, 112.3 mmol) dissolved in 20 ml of cooled methylene chloride in an ice bath is added bromine (5.80 ml + 12 drops, 112.3 + mmol) dissolved in about 20 ml of methylene chloride. It was. Upon complete addition, the mixture was dried in vacuo to afford 29.1 g of 5,6-dibromo-hexane-1-ol.

b. 5-bromo-hex-5-en-1-ol

20% dissolved in tetrahydrofuran (62.4 g, 112 mmol) in a solution of 5,6-dibromo-hexane-1-ol (29.1 g, 112 mmol) dissolved in 59 ml of tetrahydrofuran cooled in an ice bath. Potassium t-butoxide was added. Upon completion of the addition, the reaction was raised to room temperature and stirred for 30 minutes. Diethyl ether and water were added, then the phases were separated. The separated organic layer was dried over magnesium sulfate and then dried in vacuo. The residue was vacuum distilled off in a five-pore plate column to give 23.16 g of 87% pure 5-bromo-hex-5-en-1-ol.

c. 4-Methyl-benzoic acid 5-bromo-hex-5-enyl ester

4-toluoylchloride (3.95 g, 25.6 mmol), and triethylamine (3.3 g) in a solution of 5-bromo-hex-5-en-1-ol (4.39 g, 24.5 mmol) in 10.6 g methylene chloride , 33 mmol) was added. After stirring at room temperature for 2 hours, the mixture was diluted with diethyl ether and then washed with 1N hydrochloric acid and washed with brine. The phases were separated and the organic layer was dried over magnesium sulfate and then dried in vacuo to give 7.3 g of 4-methyl-benzoic acid 5-bromo-hex-5-enyl ester.

d. 4-Methyl benzoic acid 4- (1,2,2, -tribromo-cyclopropyl) -butyl ester

4-Methyl-benzoic acid 5-bromo-hex-5-enyl ester (7.3 g, 24.6 mmol), N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide (0.30 g, 0.66 mmol), methylene chloride (25 g), bromoform (25 g, 98.9 mmol) and 45% aqueous potassium hydroxide (11.5 g, 92 mmol) were charged to a round bottom flask and stirred at room temperature for 4 days. . After addition of water, the layers were separated. N, N'-dibenzyl-N, N, N'N'-tetramethylethylenediammonium dibromide (0.30 g, 0.66 mmol), bromoform (27 g, 107 mmol) and 45% aqueous potassium hydroxide were separated in the separated organic layer. Loxide (12 g, 96 mmol) was added. After stirring for an additional day at room temperature, water and hexanes were added. The mixture was gravity filtered with qualitative filter paper and the layers were separated. The separated organic layer was dried over magnesium sulfate and then dried in vacuo. This residue was purified by column chromatography using ethyl acetate / hexanes to give 4.9 g of 61% pure 4-methyl benzoic acid 4- (1,2,2, -tribromo-cyclopropyl) -butylester.

e. 4- (1,2,2, -Tribromo-cyclopropyl) -butan-1-ol

50% aqueous potassium carbonate (30 g, 107 mmol) and water in a solution of 4-methyl benzoic acid 4- (1,2,2, -tribromo-cyclopropyl) -butyl ester (45.5 g, 97 mmol) dissolved in 250 g of methanol 30 g was added. The reaction was heated to 60 ° C. for about 2 hours and then cooled to room temperature. After 15 minutes, 50% aqueous potassium carbonate (30 g, 107 mmol) and 30 g of water were added and the reaction was heated to 60 ° C. for 2 hours and then cooled to room temperature. The reaction mixture was concentrated in vacuo, then the resulting residue was extracted with diethyl ether. The organic layer was washed with basicized water (pH 10). The phases were separated and the organic phase was dried over magnesium sulfate and then in vacuo. The residue was purified by column chromatography using diethyl ether / hexanes to give 14.5 g of 74% pure 4- (1,2,2, -tribromo-cyclopropyl) -butan-1-ol.

f. 1- (4-hydroxybutyl) -cyclopropene

A solution of 4- (1,2,2, -tribromo-cyclopropyl) -butan-1-ol (5.11 g, 14.5 mmol) dissolved in 4 ml of diethyl ether was placed in a nitrogen atmosphere and cooled to 0 ° C. . Using a syringe, 1.4 M methyllithium (41.6 ml, 58.2 mmol) dissolved in diethyl ether was added. After 15 minutes, the reaction was terminated by addition of about 2 ml water. The phases were separated. The separated organic layer was dried over magnesium sulfate and dried in vacuo to give 2.51 g of 1- (4-hydroxybutyl) -cyclopropene in the form of an oil.

g. 1- (4-methanesulfonyloxybutyl) -cyclopropene

A solution of 1- (4-hydroxybutyl) -cyclopropene (2.43 g, 21.6 mmol) dissolved in about 10 ml of methylene chloride was cooled in a -20 ° C bath. To this mixture was added triethylamine (3.32 ml, 23.7 mmol) and methanesulfonylchloride (1.67 ml, 21.6 mmol). After about 1 hour, water was added to the reaction and the phases were separated. The separated organic layer was dried over magnesium sulfate and dried in vacuo. To this residue was added 8 ml of methylene chloride, triethylamine (1.39 ml, 10 mmol) and methanesulfonylchloride (0.701 ml, 9.1 mmol). After 1 hour, water was added to the reaction and then the phases were separated. The separated organic layer was dried over magnesium sulfate and dried in vacuo to yield 2.9 g of 70% pure 1- (4-methanesulfonyloxybutyl) -cyclopropene in oil form.

Example 55 Preparation of 2-octyl-1- (boronic acid) -cyclopropene (Compound 86)

A solution of 1.30 g (3.3 mmol) of 2-octyl-1,1,2-tribromocyclopropane (Example 5) dissolved in 20 ml of ether was cooled to -78 ° C. Methyllithium (1.4 M, 5.9 ml, 8.3 mmol) was added and the reaction mixture was stirred for 10 minutes, then placed in an ice bath and held for 30 minutes, then cooled back to -78 ° C. Triisopropylborate (0.9 ml, 3.9 mmol) was added and the reaction mixture was stirred for 15 minutes, then raised to 0 ° C. Water, ether and 1N aqueous HCl (sufficient to make an acidic solution) were added. The phases were separated. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped. The product was dissolved again in ether and extracted three times with 1N aqueous sodium hydroxide solution. The aqueous extract was acidified with 6N aqueous hydrochloric acid and extracted three times with ether. The ether phase was washed with water, brine, dried over magnesium sulfate and stripped to give 400 mg of 2-octyl-1- (boronic acid) -cyclopropene as a pale yellow solid.

Example 56 Preparation of 2-methyl-1- (boronic acid, monoisopropyl ester) -cyclopropene (compound 87)

A solution of 2 mg of 1,10-phenanthroline dissolved in about 50 ml of diethyl ether was cooled to −40 ° C. and placed in a nitrogen atmosphere. Here is a syringe with diisopropylamine (3.33 ml, 23.8 mmol) and 1-methylcyclopropene (1.90 ml, 27.8 mmol; prepared from 3-chloro-2-methyl-propene; Hopf, H .; Walchholz, G Walsh, R. Chem. Ber. 1985, 118. 3579 and Koster, R. et al., Liebigs Annalen Chem. 1973, 1219-1235). Thereafter, 1.7 ml of N-butyllithium (1.6 M in hexane) was added until brown. To this was added the same butyllithium in different ratios (14.9 ml, 23.8 mmol). After stirring at −40 ° C. for 15 minutes, triisopropylborate (4.60 ml. 19.8 mmol) was added. After about 10 minutes, 12 ml of 6N hydrochloric acid was added. After stirring at −10 ° C. for 15 minutes, the phases were separated. The separated organic layer was dried over magnesium sulfate, and then concentrated in vacuo to obtain 3.5 g of 2-methyl-1- (boronic acid, monoisopropyl ester) -cyclopropene in the form of an oil.

In a similar manner the following compounds were prepared:

Table 1: Additional Compounds

The compounds have been characterized using various spectroscopy techniques. NMR data of compound 1-35 are shown in Table 2. In the case of compounds containing impurities, chemical shifts of the impurities were not recorded, but only integral was adjusted to show the contribution of the desired compound.

Table 2: NMR Data

Biological Activity:

Tomato Epinasty Test

Purpose: This test is designed to measure the performance of a test compound against blocking ethylene-induced epinasty reactions in tomato plants when the test compound is administered as a volatile gas or spray solution component.

The treatment chamber is of a suitable size for the test plant and is all sealed. Each is equipped with a reusable septum used for ethylene injection. The test plants are two Patio species tomato seedlings planted in a 3 square inch plastic pot.

Volatile tomatoes were placed in two 4.8 L volumetric processing chambers along a half (top or bottom section) of a 50 × 9 mm plastic Petri dish with Gelman filter pads for volatile gas treatment.

A suitable amount of test compound dissolved in 1.0 ml acetone was pipetted into the filter pad and the chamber was immediately sealed. After 4 hours ethylene gas corresponding to a 10 ppm v / v final concentration is injected into the sealed chamber. After 16 hours, the chamber was opened in an exhaust hood to allow air to enter, and the plant was grown with ethylene imparted by ethylene imparted by the test compound with the ethylene and non-ethylene standards on a scale of 0-10. A score was scored visually for degree of protection against epinasty. Class 10 means fully protected. A zero grade means no protection from the action of ethylene. Gas treatment concentration is volume / volume.

Spray application using a DeVilbiss sprayer to ensure that all leaves and stems of the two Patio species tomato plants are completely covered with test compound dissolved in 10% acetone / 90% water using an appropriate amount of 0.05% Silwett L-77 surfactant Treated. The plants are air dried in a drying hood for 4 hours, then transferred to a 4.8 L polystyrene chamber and sealed.

 Ethylene gas corresponding to a final concentration of 10 ppm v / v is injected into the sealed chamber. After 16 hours, the chamber was opened in an exhaust hood to allow air to enter, and the plants were placed on higher growth due to ethylene imparted by the test compound with ethylene and non-ethylene standards on a scale of 0 to 10. A score was scored with the naked eye for the degree of protection. Class 10 means fully protected. A zero grade means no protection from the action of ethylene.

When applied by gas or spray, the activity of the compounds of the present invention in tomato epithelial growth tests is shown in Table 3 below:                 

Table 3: Activity of Compounds of the Invention in Tomato Whip Growth Tests

test at ^a 600ppm

^b testing at 850ppm

^c testing at 500ppm

NT indicates not tested.

NT indicates not tested.

NT indicates not tested.

Claims (10)

delete Cyclopropene derivatives of the following formulas of plants and effective ethylene reaction-inhibitory amounts, enantiomers, stereoisomers, salts, mixtures thereof; Or inhibiting ethylene reaction in a plant comprising contacting the composition:

Where a) (x) ^one of R ¹ and R ³ is hydrogen and ^{two of} R ¹ , R ² , R ³ and R ⁴ are hydrogen; or (y) R ² , R ³ and R ⁴ are hydrogen; or (z) R ¹ , R ² and R ³ are hydrogen, R ² , R ⁴ , And when ^one of R ¹ and R ³ is hydrogen, the other is independently selected from H and a group of the formula-(L) _n -Z, wherein Iii) n is an integer from 0 to 12, Ii) each L is independently selected from members of the D1, D2, E or J groups; D1 is a chemical formula

, D2 is a chemical formula

, E is a chemical formula

Is; J is a chemical formula

, A) X and Y are each independently a group of the formula-(L) _m -Z;  B) m is an integer from 0 to 8;  C) more than two D2 groups are not adjacent to each other, more than two E groups are not adjacent to each other, more than two groups selected from groups D2 and E are not adjacent to each other, and J is adjacent to each other Not; Z) Z is each independently   A) hydrogen, halo, cyano, nitro, nitroso, azido, chlorate, bromate, iodate, isocyanato, isocyanato, isothiocyanato, pentafluorothio, or  B) G is unsubstituted or substituted; Unsaturated, partially saturated or saturated; Group G which is a monocyclic, bicyclic, tricyclic or fused 3 to 14 membered carbocyclic or heterocyclic ring system;     1) when the ring system has a 4 membered heterocyclic ring, the heterocyclic ring has 1 heteroatom;     2) when the ring system has 5 or more members of a heterocyclic ring or a polycyclic heterocyclic ring, the heterocyclic or polycyclic heterocyclic ring has 1 to 4 heteroatoms;     3) each heteroatom is independently selected from N, O and S;     4) the number of substituents is 0 to 5 and each substituent is independently selected from X; b) the total number of non-hydrogen atoms in each compound is 50 or less; c) the total number of heteroatoms in-(L) _n -Z is 0-4; d) ⅰ) R ¹ or R ³ has at least one G group; Ii) at least one L group is E group; or Iii) at least one of R ¹ , R ² , R ³ and R ⁴ has 1 to 4 non-hydrogen atoms and at least one of R ¹ , R ² , R ³ and R ⁴ has more than 4 non-hydrogen atoms Has an atom. The method of claim 2, wherein the ethylene reaction comprises: ripening or aging of flowers, fruits, and vegetables; Abscission of leaves, flowers, and fruits; Shortening the life of ornamental plants, cut flowers, shrubs, seeds or dormant seedlings; Growth inhibition; Growth promotion; Auxin activity; Late growth inhibition; Apical dominance control; Increased branching; Increased tillering; Modification of plant forms, modifying infectivity of plant pathogens such as fungi, changes in biochemical composition, arrest or inhibition of flowering or seed development; Lodging effects; Promoting seed germination; Dormant block; Hormonal effect; And an epinasty effect. The method of claim 2, wherein R ² , R ³ , and R ⁴ are hydrogen or R ¹ , R ² and R ³ are hydrogen. The method of claim 2, wherein n is 1-7. The method of claim 2, wherein m is 0 to 2. The method of claim 2, a) D1 is -CXY-, -CO-, or -CS-, respectively; b) D2 is -NX- or -O-, respectively; c) E is -S-, -SiXY- or -SO _2- , respectively; d) X and Y are each independently H, halo, OH, SH, -C (O) (C ₁ -C ₄ ) alkyl, -C (O) O (C ₁ -C ₄ ) alkyl, -O- ( C ₁ -C ₄ ) alkyl, -S- (C ₁ -C ₄ ) alkyl, or substituted or unsubstituted (C ₁ -C ₄ ) alkyl; And e) Z is each independently H, halo, or G Method characterized by that. The compound of claim 2, wherein each G is independently substituted or unsubstituted; 5, 6, or 7 members; A aryl, heteroaryl, heterocyclyl, or cycloalkyl ring. The compound of claim 8, wherein each G is independently substituted or unsubstituted phenyl, pyridyl, cyclohexyl, cyclopentyl, pyrrolyl, furyl, thiophenyl, triazolyl, pyrazolyl, 1,3-dioxolanyl Or morpholinyl. 9. The method of claim 8, wherein, where present, the substituents are independently 1-3 methyl, methoxy and halo.