Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Reexamination Certificate
2001-01-02
2002-08-13
Vollano, Jean F. (Department: 1621)
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
C260S66500B
Reexamination Certificate
active
06432326
ABSTRACT:
This application is a 371 of PCT/EP99/04593 filed Jul. 2, 1999, now WO 00/029,281.
The present invention relates to a process for the stereoselective preparation of Grignard compounds of the formula I. The invention also relates to polymer-immobilized compounds of the formula Ia. The invention further relates to the use of the process for producing substance reference libraries and to the use of the compounds of the formulae I and Ia in stereoselective chemical synthesis.
Grignard compounds are valuable intermediates in organic synthesis. They are one of the most important classes of compounds in organic synthetic chemistry. Their reaction with electrophilic substances allows the preparation of a wide variety of compounds. Many syntheses in which Grignard compounds are used are known from the literature (see: Handbook of Grignard Reagents, Eds. G. S. Silverman, P. E. Rakita, Marcel Dekker, Inc., 1996). Grignard compounds have a good reactivity at a satisfactory chemoselectivity (cf. Posner G. H. 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. Soc., Vol. 94, 1972: 4374).
Alkenyl Grignard compounds are usually prepared by reacting a corresponding alkenyl halide with metallic magnesium or another source of magnesium. A further method starts from acetylenes which are carbometallated with Grignard compounds in the presence of suitable promoters. The methods for this are known to those skilled in the art and may be found, for example, in Houben-Weyl, Vol. XIII/2a and the literature cited therein and in Handbook of Grignard Reagents, Eds. G. S. Silverman, P. E. Rakita, Marcel Dekker, Inc., 1996 or in J. Organomet. Chem. 1976, 113: 107 or in J. Fluorine Chem. 1982, 20, 699.
The preparation of vinylic Grignard compounds by these methods is, however, often accompanied by secondary reactions (e.g. eliminations) and is not applicable to all vinyl halides. Thus, for example, terminal, vinylic halides usually react very unsatisfactorily to give the desired Grignard compound. Under the reaction conditions employed, an isomerization as shown in Scheme I is often observed.
Scheme I: Isomerization of Grignard Compounds
A cis halide (based on halogen and R
1
′) gives a mixture of the trans/cis isomeric Grignard compounds which then in the further reaction with the electrophil (=E1) give a trans/cis mixture of the desired products. The radicals R
1
′, R
2
′ and R
3
′ are shown only schematically in Scheme I.
A further disadvantage of the methods available hitherto is that they do not allow the preparation of Grignard compounds having further functional groups, for example esters, nitriles or amides, which would react with an electrophil, since such groups would react in the preparation of the Grignard compound.
It is an object of the present invention to make available a process for the synthesis of vinylic Grignard compounds which provides a stereoselective route to these compounds with retention of the original trans/cis geometry. A further object is to make possible the further stereoselective reaction of these compounds with electrophils. Another object is to provide a process which tolerates many additional functional groups in the molecule in order to be able to prepare synthetically and pharmacologically interesting compounds. We have found that this object is achieved by a process for preparing compounds of the formula I
which comprises stereoselectively reacting compounds of the formula II
with compounds of the formula R
3
MgX (III) at below +30° C. to give compounds of the formula I,
where the substituents and variables in the formulae I, II and III have the following meanings:
X=halogen such as Cl or R
3
,
R
1
=substituted or unsubstituted, branched or unbranched C
1
-C
10
-alkyl, C
3
-C
10
-cycloalkyl, C
1
-C
4
-alkylaryl, C
1
-C
4
-alkylheteroaryl, aryl or heteroaryl,
R
2
=hydrogen, —CH
2
—R
4
,
R
3
=branched or unbranched C
1
-C
10
-alkyl, C
3
-C
10
-cycloalkyl,
R
4
=hydrogen, substituted or unsubstituted, branched or unbranched —OC
1
-C
10
-alkyl, —OC
3
-C
10
-cycloalkyl, —OC
1
-C
4
-alkylaryl, —OC
1
-C
4
-alkylheteroaryl, —OCNR
1
R
5
, R
6
,
R
5
=as R
1
, but independently thereof,
R
6
=a solid support.
In the compounds of the formulae I and II, R
1
is substituted or unsubstituted, branched or unbranched C
1
-C
10
-alkyl, C
3
-C
10
-cycloalkyl, C
1
-C
4
-alkylaryl, C
1
-C
4
-alkylheteroaryl, aryl, heteroaryl or R
5
.
Examples of alkyl radicals are substituted or unsubstituted, branched or unbranched C
1
-C
10
-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, 1,1,2-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 substituted or unsubstituted, branched or unbranched C
3
-C
10
-cycloalkyl chains having from 3 to 7 carbon atoms in the ring or ring system, e.g. 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. The cycloalkyl radicals can also have heteroatoms such as S, N and O in the ring. The cycloalkyl radicals can have branched or unbranched alkyl groups.
Examples of C
1
-C
4
-alkylaryl are substituted or unsubstituted, branched or unbranched C
1
-C
4
-alkylphenyl 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.
Examples of alkylheteroaryl radicals are substituted or unsubstituted, branched or unbranched C
1
-C
4
-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 aromatic rings or ring systems having from 6 to 18 carbon atoms in the ring system and also up to 24 further carbon atoms which can form further nonaromatic rings or ring systems having from 3 to 8 carbon atoms in the ring. Preference is given to substituted or unsubstituted phenyl or naphthyl.
Examples of heteroaryl radicals are simple or condensed aromatic ring systems having one or more heteroaromatic 3- to 7-membered rings which may contain one or more heteroatoms such as N, O or S.
Possible substituents on the radicals R
1
are in principle all conceivable substituents except for ketones or aldehydes, for example one or more substituents such as halogen, e.g. fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, alkyl, cycloalkyl, aryl, alkoxy, benzyloxy, phenyl or benzyl.
R
2
in the formulae I and II is hydrogen or —CH
2
—R
4
.
In the formula R
3
MgX (III), R
3
is branched or unbranched C
1
-C
10
-alkyl or C
3
-C
10
-cycloalkyl.
Examples of alkyl radicals are substituted or unsubstituted, branched or unbranched C
1
-C
10
-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
Boymond Laure
Cahiez Gerard
Knochel Paul
Rottländer Mario
BASF - Aktiengesellschaft
Keil & Weinkauf
Vollano Jean F.
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