MXPA01000028A - Method for the stereoselective production of grignard compounds and use thereof - Google Patents

Abstract

The invention relates to a method for the stereoselective production of grignard compounds of formula (I), to polymer-bonded compounds of formula (Ia), to the use of the method for producing libraries of substances and to the use of the compounds of formulae (I) and (Ia) in stereoselective chemical synthesis.

Description

STEREOSELECTIVE PREPARATION OF GRIGNA D COMPOUNDS AND THEIR USE DESCRIPTION OF THE INVENTION The present invention relates to a process for the stereoselective preparation of Grignard compounds of the formula I. The invention also relates to immobilized polymer compounds of the formula la. The invention further relates to the use of the process for producing libraries of reference substances and for the use of the compounds of the formulas I and the stereoselective chemical synthesis. The Grignard compounds are valuable intermediates in organic synthesis. They are one of the most important classes of compounds in synthetic organic chemistry. Its reaction with electrophilic substances allows the preparation of a wide variety of compounds. Many syntheses in which Grignard compounds are used are known in the literature (see Handbook by Grignard Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekker, Inc., 1996). The Grignard compounds have a good reactivity to a satisfactory chemoselectivity (see, Posner GH Org. React., Vol. 22, 1975: 253, Lipshutz et al., Org. React., Vol. 41, 1992: 135, Luh T Y. Chem. Res., Vol. 24, 1991: 257 or Tamao et al., J. Am. Chem. Sot., Vol. 94, 1972: 4374). The Grignard alkenyl compounds are usually prepared by reacting a corresponding alkenyl halide with metallic magnesium or another magnesium source. An additional method starts from acetylenes which are carbometalated with Grignard compounds in the presence of suitable promoters. Methods for these are known to those skilled in the art and can be found, for example, in Houben-Weyl, Vol. XIII / 2a and La literature cited herein and in Handbook of Grignatrd Reagents, Eds. G.S. Silverman, P.E. Rakita, Marcel Dekkec, Inc., 1996 or J. Organomet. Chem. 1976, 113: 107 or in J. Fluorine Chem. 1982, 20, 699. The preparation of vinyl compounds from Grignard However, these methods are often accompanied by secondary reactions (for example, eliminations) and do not apply to all vinyl halides. Thus, for example, the terminal vinyl halides usually react very unsatisfactorily to give the Grignard compound desired. Under the reaction conditions employed, an isomerization as shown in Scheme I is frequently observed.

^ I * - "* -« * «.» -. Mftl * ..-? ^ -C 0 -C 0 cycloalkyl 0, -C 1 -C 4 -alkylaryl, -C 1 -C 4 -alkylheteroaryl, -OCNR 5, R 6, substituted or unsubstituted, branched or unbranched, R 5 = as R 1, but independently thereof, R6 = a solid support. In the compounds of formulas I and II, R 1 is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkylaryl, C 1 -C 4 alkylheteroaryl, aryl or heteroaryl, or substituted or unsubstituted R 5, branched or unbranched. Examples of alkyl radicals are substituted or unsubstituted, branched or unbranched C1-C10 alkyl chains, such as methyl, ethyl, n-propyl, L-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, L-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl :, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl , 2-methylpentyl, 3-methylpentyl, 4-methyl-pentyl, 1, -dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-Ethylbutyl, 2-ethylbutyl, 1,1-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n -nonyl or n-decyl. Examples of cycloalkyl radicals in the formula are C3-C? Cycloalkyl chains or substituted or unsubstituted, branched or unbranched, having from 3 to 7"• * - • - * - * • * - - ^ ^? ^ Tiffr ^ frf [r, 'tt-_? _jg carbon atoms in the ring or ring system, eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-methylcyclopropyl, 1,2-dimethylcyclopropyl, 1-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl. Cycloalkyl radicals can also have heteroatoms such as S, N and O in the ring. The cycloalkyl radicals can have branched or unbranched alkyla groups. Examples of C 1 -C 4 alkylaryl are substituted or unsubstituted branched or unbranched C 1 -C 4 alkylcarbaryl or C 1 -C 4 alkylnaphthyl radicals such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2- methylpropylphenyl, 1,1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, 1-methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl or 1,1-dimethylethylnaphthyl. Example of alkylheteroaryl radicals are substituted or unsubstituted, branched or unbranched C1-C4 alkylheteroaryl radicals which have one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system. Examples of aryl radicals are substituted or unsubstituted aryls such as phenyl, naphthyl or rings ^ - ^ - ^. ^^^^ a ^^ ,,. ^^, .. ^., ^, Aromatics or ring systems that have 6 to 18 carbon atoms in the ring system and also up to 24 atoms of additional carbon which can form additional non-aromatic rings or ring systems having from 3 to 8 carbon atoms in the ring. Preference is given to the substituted or unsubstituted phenyl or naphthyl. Examples of heteroaryl radicals are fused aromatic ring systems having one or more 3 to 7 membered heteroaromatic rings which may contain one or more heteroatoms such as N, O or S. The possible substituents on the radicals R1 are in principle all the conceivable substituents except for ketones or aldehydes, for example one or more substituents such as halogen, for example fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, benzyloxy, phenyl or benzyl. R2 in formulas I and II is hydrogen or -CH2-R4. In the formula R3MgX (III), R3 is C3-C6alkyl or C3-C3cycloalkyl or branched or unbranched. Examples of alkyl radicals are C?-C? Or substituted or unsubstituted, branched or unbranched alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl- 2-methylpropyl, n-heptyl, n-octyl, n-nonyl or n-decyl. Examples of cycloalkyl radicals in the formula III are substituted or branched or unbranched C3-C10 cycloalkyl chains having from 3 to 7 carbon atoms in the ring or ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1,2-dimethylcyclopropyl, 1-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl. In principle, the radicals mentioned under R3 can also produce substituents, but since these compounds are complicated to prepare and the radical R3 is not present in the products synthesized from the Grignard compounds, it is more sensitive from an economic point of view to use the unsubstituted compounds which are commercially available or can be simply synthesized. R 4 is hydrogen, -O-C 1 -C alkyl-0, -C 3 -C 10 -cycloalkyl, -C 1 -C 4 -alkylaryl, C 1 -C 4 -alkheteroaryl, -OCNR 5, or R 6 = 4-hydroxybenzyl-polystyrene substituted or unsubstituted, branched or unbranched. Examples of radica is -O-alkyl are C1-C10 -O-alkyl chains, substituted or unsubstituted, branched or unbranched. In these -O-alkyl radicals, the C 1 -C 10 alkyl chains are, for example: methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl , n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl , 3- methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2 -ethylbutyl, 1, 1, 2-trimethylpropyl, 1,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-n-nyl or n-decyl . Examples of -O-cycloalkyl radicals in radicals R4 are C3-C-cycloalkyl chains or substituted or unsubstituted, branched or unbranched which have from 3 to 7 carbon atoms in the ring or ring system, in wherein the C3-C10 cycloalkyl chains in these C3-C10 -cycloalkyl chains are, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, L-propylcyclopropyl, 1-butylcyclopropyl, L-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1,1-dimethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl. Cycloalkyl radicals can also have hoteroatoms such as S, N and O in the ring. The cycloalkyl radicals may have branched or unbranched alkyl groups. Examples of C1-C4-O-alkylaryl are radicals -C1-C4 substituted or unsubstituted, branched or unbranched C1alkylaryl, wherein C1-C4 alkylaryl chains are, for example: C1-C4 alkylphenyl radicals, or C1-C4 alkylnaphthyl, such as methylphenyl, ethylphenyl , propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 1,1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propylnaphthyl, 1-methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl or 1,1-dimethylethylnaphthyl. Examples of -O-alkylheteroaryl radicals are substituted or unsubstituted, branched or unbranched C1-C4-alkyl-alkylcarbon radicals which have one or more nitrogen, sulfur and / or oxygen atoms in the ring or ring system. The heteroaromatic part may comprise rings or simple aromatic ring systems or .... «. .. ». * ^ - ^ ...- ..». rfA ^. ^^ - ito condensed together with one or more heteroaromatic rings of 3 to 7 members. All the radicals mentioned above have R4 substituent linked by means of oxygen. R4 can also be a polymer (= solid support) R6 (for definition of the support, see the following). The polymer used is advantageously 4-hydroxybenzyl polystyrene. OCNR1R5 are carbamates [sic] in which R1 and 5 are, independently of one another, as defined above. The possible substituents on the specified radicals R4 are, in principle, all conceivable substituents other than ketones or aldehydes, for example one or more substituents such as halogen, for example fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl , cycloalkyl, aryl, alkoxy, benzyloxy, phenyl or benzyl. The reaction of the process of the present invention is advantageously carried out by reacting the compounds of the formula II, advantageously in an inert aprotic solvent, for example ethers such as tetrahydrofuran (= THF), diethyl ether, dioxane, dimethoxyethane or methylter-butyl ether (= MTB), below 30 ° C, preferably from -100 ° C to + 30 ° C, particularly preferably from -90 ° C to + 30 ° C, very particularly preferably from -80 ° C to +25 ° C, with a compound of the formula R3MgX (III) to give a compound of the formula I. In the case of compounds in which the radical R4 is linked by means of an oxygen atom, it is advantageous to select a reaction temperature of less than -20 ° C, preferably from -100 ° C to -20 ° C, particularly preferably -80 ° C to -40 ° C. In the case of compounds in which the radical R 4 is linked by means of a carbon atom, it is advantageous to select a reaction temperature of less than + 30 ° C, preferably from -40 ° C to + 30 ° C, particularly from preference from -20 ° C to + 30 ° C, very particularly preferably from 0 ° C to + 30 ° C. In principle, all compounds of the formula R3MgX known to those skilled in the art can be used to prepare the Grignard compound; preference is given to use diisopropylmagnesium chloride or isopropylmagnesium. Under these moderate conditions, the halogen-magnesium exchange occurs without the Grignard compounds of formula I (see above) which are formed by reacting with additional functional groups present in the molecule. The compounds react only in the desired form, stereoselectively with the electrophile (see Examples in Table I). Trans / cis ratios of more than 85:15, preferably 90:10, particularly preferably 98: 2, are achieved. The reaction time is from 1 hour to 18 horis, depending on the vinyl halide used.

IÍÉII n i iÜilüITIíiiiflIf Tr An advantage is that this process alcohols linked by polymer (= R4 = R6 = polymer, solid support) also experience halogen-magnesium exchange into the desired shape. As the free alcohols, these alcohols serve as initial compounds for the synthesis of compounds of the formula II. The use of alcohols linked by polymer allows the following compounds of the formula to be prepared: BS RrMgRi wherein radical R2 is -CH2-R4, R4 is R6 and R6 is a solid support. The compounds of the formula can be advantageously linked to a solid support (= R6) as is known from solid phase pde synthesis. The possible supports can consist of a wide variety of materials as long as they are compatible with the synthetic chemistry used. In these, the size, size distribution, and shape of the supports can be varied within a wide range depending on the material. Preference is given to spherical particles which advantageously have a homogeneous size distribution. Examples of preferred solid supports are functionalized cross-linked polystyrenes such as 4-hydroxybenzyl polystyrene. i-ßüiíáÉ? IELI ^ íaEttttíé ^ ttÉili The compound can bind to the support or polymeric support through known to those skilled in the art reactions such as can be found, for example, in the review by Balkenhohl et "al. (Angew. Chem ., Vol. 106, 1996: 2436) and the literature cited therein.In the case of resin ang, the compound can be linked, for example, by means of an ester.After the synthesis is complete, it can unfold. of the resin using, for example, trifluoroacetic acid This method makes it possible to use the advantages of solid phase synthesis, ie the ability to carry out the reaction automatically and to work the reaction mixture by simple washing and filtration. of the processes of the present invention thus makes it possible to easily produce libraries of reference substance.This reaction is thus very suitable for producing libraries of reference substances by the rinciples of combinatorial chemistry or HSA (Angew. Chem., Vol. 108, 1996: 2436), in which the exchange of halogen or magnesium is carried out first on an initial material bound to a polymer and the product is then reacted with many electrophiles (in a vessel to produce mixtures). After washing and filtering, the target products are separated after the polymer under suitable conditions for splitting the bond that unites. The novel compounds of formula I or (= R4 = R6 = solid support, preferably polymeric support l, can advantageously be used in chemical synthesis as starting materials or intermediates which can be employed in a wide variety of subsequent reactions. Examples are synthesis carotinoids, vitamins or active compounds, for example, active compounds for pharmaceuticals or crop protection products The following examples illustrate the invention without being a limitation of the method: Examples: A. Preparation of trans-4- (4-carbetoxibenciloxi) -2-phenyl-1-iodopropene A solution of 700 mg (1.66 mmol) of trans-4- (4-carbetoxibenciloxi) -2-phenyl-1 -iodopropene in 4 ml of THF was cooled to -85 ° C and 3.9 ml (3.32 mmol) of a diisopropylmagnesium solution in THF (0.85 M) were added. After 16 hours at -70 ° C, 0.48 ml (4.65 mmoles) of benzaldehyde was added. After 3 hours, the reaction mixture was hydrolyzed and the organic phase was evaporated. Chromatography of the product without purification using CH2Cl2 / ether 95: 5 4/1 gave 528 mg (79%) of the alcohol. ^ ¡Áí? im ^ ám ^^^? U i ^^ Table I shows the results of analogous reactions with various electrophiles. The starting compounds (Grignard compounds) were prepared by an iodine-magnesium exchange for 7-28 hours. The temperature of the reaction solutions is within the range of -78 to + 25 ° C. Good conversions at these temperatures could be achieved. The yields given in Table I are based on the chemically pure end product. 10 Table I: Preparation of Grignard compounds and reaction with electrophiles The products shown in Table I were obtained with a trans / cis or cis / trans ratio of more than 98: 2 in each case. B. Preparation of Grignard compounds on a polymer support and reaction with electrophiles. 150t-mg of functionalized ang resin was mixed with cis-iodalileter with 2ml of THF and cooled to -40 ° C. 1.25 ml (0.9 mmol) of a 0.72 M solution of isopropylmagnesium bromide in THF was added dropwise and, after 4 hours, 0.2 ml (1.88 mmol) of benzaldehyde was added. After incubation for one hour, the mixture was filtered, the residue was washed with THF and MeOH and the product was unfolded from the polymer using 4 ml of 95% strength trifluoroacetic acid. Filtration and evaporation gave the corresponding products. The substances shown in Table II were prepared analogously. The yield of the free product was generally 90% or more (see Table, Column 5). Table II: Preparation of Grignard compounds and reaction with electrophiles on a solid support. vj * ..¿a.y. ^. ^ »Z ^ i3t¿i ¿LM * Spontaneous cyclization to dihydrofuran occurs after the acid cleavage of the polymer. The abbreviations for the electrophiles in tables I and II have the following meanings: PhCHO = benzaldehyde, TsCN = tosyl cyanide and PhsSPh = diphenyl disulfide.

. - ....- ^. ^ -. ^ "^. ^. * T * & ? > ! * tm *

Claims (9)

CLAIMS 1. A process for preparing compounds of Formula I which comprises reacting stereoselectively compounds of the formula II with compounds of the formula R3MgX (III) below + 30 ° C to give the compounds of the formula I, wherein the substituents and variables in the formulas I, II and III, have the following meanings: X = halogen such as Cl or R3, R1 = Ci-Cio alkyl, C3-C10 cycloalkyl, C1-C4 alkylaryl, C1-C4 alkylheteroaryl, aryl or heteroaryl, substituted or unsubstituted, branched or unbranched R2 = hydrogen, -CH2- R4, R3 = C1-C10 alkyl, C3-C1 cycloalkyl, branched or unbranched R4 = hydrogen, -C1-C10 alkyl,
1. -C3-C10-cycloalkyl, -C1-C4-O-alkylaryl, -C1-C4-O-alkylheteroaryl, -OCNR1R5, R6, substituted or s: .n ^ - ^ «.-« > - ^ .- »- * - fcA. * »- * -» - replace, branched or unbranched, R5 = as R1, but independently of it, R = a solid support.
2. 2. The process as claimed in claim 1, carried out in an inert aprotic solvent.
3. 3. The process as claimed in claim 1 or 2 carried out from -100 ° C to + 30 ° C.
4. 4. The process as claimed in any of claims 1 to 3, wherein the reaction to form compounds of the formula I as claimed in claim 1 is completed within 18 hours.
5. 5. The process as claimed in any of claims 1 to 4 carried out on a solid support (= R6).
6. 6. A compound of the formula wherein the variables and substituents have the meanings specified in claim 1 and R2 is - , £? Aei £? CH2-R4, R4 is R6 and R6 is a solid support,
7. 7. The use of a process as claimed in any of claims 1 to 5 to produce libraries of reference substances.
8. 8. The use of a compound of formula I or formula la as claimed in claim 1 or claim 7 for chemical synthesis.
9. 9. The use as claimed in claim 8, for synthesis of carotenoids, vitamins or active compounds. ÜüiNMtMMÉMM ^