Use of ylides of phosphorus as slightly nuceophilic strong...

Details Use of ylides of phosphorus as slightly nuceophilic strong... Use of ylides of phosphorus as slightly nuceophilic strong...

1999-11-04

2001-04-24

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C548S543000, C564S012000, C564S014000, C558S177000, C558S183000, C558S185000

Reexamination Certificate

active

06222032

ABSTRACT:

The present invention relates to the use of phosphorus ylides as slightly nucleophilic strong bases. The invention also relates to new phosphorus ylides and their preparation.
Strong organic bases are generally necessary to functionalize organic or organometallic molecules; and the stronger the base, the better it traps the protons. In order to limit parasitic reactions, it is preferable and even desirable to choose a base which is only slightly nucleophilic. Moreover, the ease with which the acid obtained is separated from the reaction medium is a determinant factor in order to simplify the purification stages.
Phosphorus ylides were studied by Wittig in the 1950's (Johnson, A. W., 1993, Series, Editor,
Ylides and Imines of phosphorus
, Wiley & Wiley: New York). These molecules are quite simple and even if some are presented as colorants (U.S. Pat. No. 3,274,228), they are usually prepared to be used for Wittig's reaction (U.S. Pat. Nos. 3,681,428, 3,725,365) where their strong nucleophilic action is involved. But these compounds have never been used as bases in organic synthesis, and a fortiori as slightly nucleophilic strong bases.
The strong neutral organic bases known to date are essentially proton sponges (Alder, R. et al.,
J. Chem. Soc. Chem. Commun.,
1968, 723), guanidines, phosphatranes and polyphosphazenes.
Guanidines constitute the class of strong organic bases most frequently used in organic synthesis. The best known are DBN (1,5-diazabicyclo [4.3.0] non-5-ene) and DBU (1,8-diazabicyclo [4.3.0] undec-5-ene). Other guanidines are also mentioned in the literature (Oediger, H. et al.,
Synthesis,
1972, 593; Schwesinger, R.,
Angew. Chem. Int. Ed. Eng.,
1987, 26, 1164). These bases are used in elimination reactions or in oligomerization or polymerization processes as a reaction initiator (Oediger, H. et al.,
Synthesis,
1972, 593; Wöhrle, D. et al.,
Dyes and Pigments,
1992, 18, 91).
Phosphatranes are more recent compounds (Verkade, J., 1991,
Phosphatranes as proton abstracting reagents
, U.S. Pat. No. 5,051,533). Their basicity is much greater than that of guanidines, which extends their field of application. The drawback of such phosphines lies in the difficulty in obtaining them and their purification.
As regards polyphosphazenes, recently developed by Schwesinger, these are the most basic organic molecules demonstrating a very slight nucleophilic action. They are however very difficult to synthesize and their cost is very high (Schwesinger, R. et al.,
Liebigs Ann.,
1996, 1055; Schwesinger, R. et al.,
Angew. Chem. Int. Ed. Engl.,
1991, 30, 1372; Schwesinger, R. et al.,
Angew. Chem. Int. Ed. Engl.,
1987, 26, 1167; Schwesinger, R. et al.,
Angew. Chem. Int. Ed. Engl.,
1987, 26, 1165; Schwesinger, R.,
Chimia,
1985, 39, 269). Their uses are very varied: they range from simple elimination to the benzylation of oligopeptides (Schwesinger, R.,
Chimia,
1985, 39, 269; Pietzonka, T. et al.,
Angew. Chem. Int. Ed. Engl.,
1992, 31, 1481). The basicity of these molecules is sufficient to remove the slightly acidic protons and their organic character avoids the undesirable effects of salts in certain alkylations (Pietzonka, T. et al.,
Chem. Ber.,
1991, 124, 1837).
Alkaline bases such as BuLi, LiHMDS, NaHMDS, LDA also represent another large family of bases. They are often used with good yields to functionalize lactames, ketones or Schiff bases (Stork, G. et al.,
J. Org. Chem.,
1976, 41, 3491; Myers, A. et al.,
J. Am. Chem. Soc.,
1994, 116, 9361; Myers, A. et al.,
J. Am. Chem. Soc.,
1995, 117, 8488; Yaozhong, J. et al.,
Synth. Commun.,
1990, 20, 15; Butcher, J., Liverton, N., Selnick, H., Helliot, J., Smith, G., et al.,
Tet. Lett.,
1996, 37, 6685; Davis, F., Sheppard, A. et al.,
J. Am. Chem. Soc.,
1990). The effects of salts are very frequent and often vary from one reaction to another and these bases retain a strong nucleophilic character even at low temperatures. (Meyers, A., Kunnen, K.,
.J Am. Chem. Soc.,
1987, 109, 4405).
The problem is therefore to find slightly nucleophilic strong bases, which are easy to synthesize and at a low cost, which would be susbstituted on the one hand for commonly used bases which are too nucleophilic and on the other hand for recent bases which are too expensive.
The invention therefore relates to the use of products of general formula I′
in which
R′
1
, R′
2
and R′
3
represent, independently, a lower alkoxy or amino radical of formula R′R″N in which R′ and R″ independently represent one of the following radicals, non-substituted or substituted (by one or more identical or different substituents): lower alkyl, lower alkoxy, cycloalkyl, lower aryl-alkyl, aryl, in which the substituent is a halogen atom or a lower alkyl, lower alkoxy, cyano, nitro or dialkylamino radical;
R′
4
represents the hydrogen atom, a lower alkyl radical or lower alkoxy;
R′
5
represents the hydrogen atom, a lower alkyl radical, lower alkoxy or a polymeric support;
as a slightly nucleophilic strong base.
In the definitions indicated above, the expression halogen represents a fluorine, chlorine, bromine or iodine atom, preferably chlorine or bromine. The expression lower alkyl represents a linear or branched alkyl radical having 1 to 6 carbon atoms and in particular an alkyl radical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals.
The lower alkoxy radicals can correspond to the alkyl radicals indicated above. Among the linear radicals, there can be mentioned the methoxy, ethoxy, propyloxy, n-butyloxy or n-hexyloxy radicals. Among the branched alkoxy radicals, there can be mentioned the isopropyloxy, sec-butyloxy, isobutyloxy, ter-butyloxy, isopentyloxy, neopentyloxy or ter-pentyloxy radicals.
The term cycloalkyl includes any non-aromatic cyclic hydrocarbon fragment having 3 to 10 carbon atoms and preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term aryl designates radicals which are unsaturated, monocyclic or constituted by condensed rings, carbocyclic or heterocyclic, it being understood that the heterocyclic radicals can include one or more identical or different heteroatoms chosen from oxygen, sulphur or nitrogen. Examples of such groups include the phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl, thiatriazolyl, oxazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzaxozolyl, indolyl, purinyl, naphthyl, thionaphthyl, phenanthrenyl, anthracenyl, biphenyl, indenyl, quinolyl, isoquinolyl or quinolizinyl radicals. The lower arylalkyl radicals designate the radicals in which the aryl and lower alkyl radicals respectively are as defined above such as for example benzyl, phenethyl or naphthylmethyl.
The term dialkylamino represents the amino radical substituted by two alkyl radicals, identical or different, as defined above, such as for example dimethylamino, (methyl)(ethyl)amino, diethylamino.
The expression slightly nucleophilic means non nucleophilic with respect to other centres than protons. The term strong base corresponds to the term commonly used by a person skilled in the art in the technical field considered. The polymeric support can be, for example, of methacrylic, acrylic or styrenic type.
The invention relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′ as defined above characterized in that R′
1
, R′
2
and R′
3
represent, independently, an amino radical of formula RR′N as defined above. Preferably, R′
1
, R′
2
and R′
3
represent, independently, the dimethylamino, (methyl)(ethyl)amino or diethylamino radical.
The invention relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′as defined above characterized in that R′
4
represents the hydrogen atom or an alkyl radical. Preferably, R′
4
represents

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