Process for preparing electron deficient olefin precursors

Abstract

This invention relates to a process for producing electron deficient olefin precursors, such as 2-cyanoacetates, using an acid catalyzed transesterification reaction.

Claims

1. A process for the preparation of a cyanoacetate, steps of which comprise: (a) reacting an ester of cyanoacetic acid and an alcohol, in the presence of a catalyst comprising a lanthanide element, wherein the lanthanide element comprises ytterbium, under appropriate conditions and for a time sufficient to yield a cyanoacetate; wherein the alcohol is present in an amount of from about 0.5 to about 2.0 equivalents relative to the ester of the cyanoacetic acid; and wherein the catalyst is present in an amount of up to about 20 mol %; (b) optionally, separating the so-formed cyanoacetate from the reaction mixture to be substantially free from the ester of cyanoacetic acid the alcohol and/or the catalyst, and by-products.

2. The process of claim 1, wherein the catalyst comprising a lanthanide element has one or more ligands bound to the element(s).

3. The process of claim 2, wherein the one or more ligands is selected from halogens, triflates, mesylates, nitrates or tosylates.

4. The process of claim 1, wherein the alcohol is any mono-, di- or multi-functional hydroxyl compound.

5. The process of claim 1, wherein the alcohol is any mono-, di- or multi-functional C.sub.1-20 alkanol, C.sub.2-20 alkenol, or C.sub.2-20alkynol.

6. The process of claim 1, wherein the alcohol is an aromatic alcohol.

7. The process of claim 1, wherein the alcohol is phenol, benzyl alcohol or derivatives thereof.

Description

BRIEF DESCRIPTION OF THE FIGURE

(1) FIG. 1 depicts a synthetic scheme according to the present invention. More specifically, FIG. 1 shows the reaction of an ester of cyanoacetic acid with an alcohol at ambient temperature in the presence of ytterbium trifluoromethane sulfonate [Yb(OTf).sub.3]. The reaction generates the target 2-cyanoacetate. In the FIGURE, R in the alcohol and the cyanoacetate each represents straight chain, branched, cyclic or fused C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, and C.sub.6-20 aryl or C.sub.7-20 alkaryl, with or without substitution or interruption by one or more heteroatoms, however they are not the same.

DETAILED DESCRIPTION

(2) As noted above, the present invention provides a process for the preparation of a reactive electron deficient olefin precursor. The process for the preparation of a reactive electron deficient olefin precursor is provided herein. In one, more focused, aspect, the invention includes the steps of:

(3) (a) reacting an ester of cyanoacetic acid and an alcohol in the presence of a catalyst comprising a lanthanide element or a transition metal halide, under appropriate conditions and for a time sufficient to yield a cyanoacetate;

(4) (b) optionally, separating so-formed cyanoacetate substantially free from the ester of cyanoacetic acid, the alcohol, and/or catalyst, and by-products.

(5) In another, more broad, aspect, the invention provides a process for the preparation of a reactive electron deficient olefin precursor that includes the steps of:

(6) (a) reacting: (i) a 2-electron withdrawing group-substituted methylene compound embraced by:

(7) ##STR00003##
where EWG represents an electron withdrawing group; and R here represents chain, branched, cyclic or fused C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, and C.sub.6-20 aryl or C.sub.7-20 alkaryl, with or without substitution or interruption by one or more heteroatoms; and (ii) an alcohol, in the presence of a catalyst comprising a lanthanide element or a transition metal halide, under appropriate conditions and for a time sufficient to yield an electron deficient olefin precursor embraced by:

(8) ##STR00004##
where EWG represents an electron withdrawing group; and R here represents straight chain, branched, cyclic or fused C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, and C.sub.6-20 aryl or C.sub.7-20 alkaryl, with or without substitution or interruption by one or more heteroatoms, provided it is different from R in step (a)(i);

(9) (b) optionally, separating the so-formed electron deficient olefin precursor substantially free from the 2-electron withdrawing group-substituted methylene compound, the alcohol, and/or the catalyst, and by-products.

(10) By the processes of the present invention yields of electron deficient olefin precursors may be greater than 70%, desirably 80% and more desirably 90%.

(11) In the more broad aspect noted above, the electron deficient olefin precursor so-formed is embraced by:

(12) ##STR00005##
where EWG represents an electron withdrawing group, such as cyano or nitrile, alkoxy or aryloxy (which may itself be substituted by an EWG in the ortho and/or para position on the aromatic ring), carboxyl (e.g., carboxylic acids or carboxylic esters), sulphonic acids, carbonyls, halogens (e.g., F, Cl, Br, and I), nitro, isocyanate, sulfoxide and phosphine oxide; and R here represents straight chain, branched, cyclic or fused C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, and C.sub.6-20 aryl, or C.sub.7-20 alkaryl, with or without substitution or interruption by one or more heteroatoms.

(13) Reference to FIG. 1 may be useful to appreciate further the present invention, which is described in more detail below and in the Examples section that follows.

(14) As an initial reactant in the inventive processes is the so-described ester of the 2-electron withdrawing group-substituted carboxylic acid. Representative examples of the ester of the 2-electron withdrawing group-substituted carboxylic acid used as a reactant include malonic acid, glycolic acid, an alkyl (e.g., ethyl) nitroacetic acid, an alkyl (e.g., ethyl) haloacetic (like bromoacetic, chloroacetic, and iodoacetic), and cyanoacetic acid, some of which are commercially available for instance from Aldrich Chemical Co. A particularly desirable example of the ester of the 2-electron withdrawing group-substituted carboxylic acid is an ester of cyanoacetic acid.

(15) The amount of the ester of the 2-electron withdrawing group-substituted carboxylic acid that should be used in the inventive process is in the range of about 0.5 to about 2 equivalents, such as about 0.8 equivalents.

(16) Together with the ester of the 2-electron withdrawing group-substituted carboxylic acid as an initial reactant in the inventive processes is an alcohol.

(17) The alcohol may be any mono-, di- or multi-functional hydroxyl compound. Mono-, di- or multi-functional C.sub.1-20 alkanols, C.sub.2-20 alkenols, and C.sub.2-20 alkynols, whether straight chain, branched, cyclic or fused, may be used. Aromatic alcohols, such as phenol, benzyl alcohol and derivatives thereof, may be used.

(18) The alcohol should be used in an amount of about 0.5 to about 2 equivalents, such as about 0.8 equivalents.

(19) The alcohol and the compound should be used in a molar ratio of about 0.5 to about 2 equivalents, such as about 0.8 equivalents.

(20) As noted, the catalyst is one that comprises a lanthanide element or a transition metal halide. The catalyst is acidic in nature, as measured or determined by its ability to donate a hydrogen (proton or hydrogen ion, H.sup.+), or, alternatively, its ability to form a covalent bond with an electron pair.

(21) To the lanthanide element or the transition metal halide is bonded, coordinated or complexed, as appropriate, one or more ligands. The ligands may be selected for instance from conventional leaving groups used in organic synthetic schemes. Halogens, tosylates, mesylates, nitrates, and triflates are chief among ligands that are suitable for use herein.

(22) A prime example of a lanthanide element suitable for use in this connection is ytterbium, though others may also be useful, such as lanthanum, cerium, samarium, europium, and dysprosium. Prime examples of a transition metal halide suitable for use in this connection is niobium, zirconium or scandium, with niobium being particularly desirable in this regard.

(23) Desirable catalysts for use in the inventive process include ytterbium trifluoromethane sulfonate [Yb(OTf).sub.3] and niobium halides, such as niobium chloride.

(24) The catalyst should be used in an amount of up to about 20 mol %, such as about 10 mol %.

(25) The electron deficient olefin precursor so formed by the inventive processes may be a variety of olefins having an electron withdrawing group attached to a carbon atom that is alpha to the carbonyl of a carboxylic acid ester.

(26) Representative examples of these electron deficient olefin precursors include esters of malonic acid, esters of glycolic acid, esters of nitroacetic acid (such as ethyl nitroacetate), esters of haloacetic acids (such as ethyl haloacetatelike bromoacetates, chloroacetates, and iodoacetates), and esters of cyanoacetic acid (such as cyanoacetates), some of which are commercially available for instance from Aldrich Chemical Co.

(27) In a desirable embodiment, the reactive electron deficient olefin precursor so formed will be a 2-cyanoacetate.

(28) Representative examples of 2-cyanoacetates so formed by the inventive processes include those having ester groups of methyl, ethyl, propyl, isoamyl, propargyl, butyl, pentyl, hexyl, octyl, nonyl, oxononyl, decyl, dodecyl, allyl, ethynyl, butenyl, cyclohexyl, phenyl, phenethyl, tetrahydrofurfuryl, chloroethyl, 2,2,2-trifluoroethyl, hexafluoroisopropyl, methoxymethyl, methoxyethyl, thiomethoxyethyl, methoxybutyl, thiomethoxybutyl, ethoxyethyl, thioethoxyethyl, propoxyethyl, thioproxyethyl, butoxymethyl, thiobutoxymethyl, butoxyethyl, thiobutoxyethyl and dimethyl siloxane esters of 2-cyanoacetate. This recitation is by no means however exhaustive.

(29) While no solvent is ordinarily needed, the reaction of the inventive processes may proceed in solvent either forming a solution or a suspension. Solvents that may be used include acetonitrile, benzonitrile, chlorobenzene, nitromethane, tetrachloroethene, toluene, THF, 1,4-dioxane, and (poly)ethylene glycol dialkyl ethers or esters, and of course combinations thereof. Ionic liquids may also be used as a solvent. The reaction of the inventive processes may proceed with or without heating or cooling, depending of course on the specific reactants and the scale of the reaction.

(30) While the reaction ordinarily occurs at ambient temperature, gentle heating up to a temperature of 70 C. may be applied. The temperature may be reached through an external heating element or internally by means of the exotherm that may be generated depending on the identity of the reactants. The temperature of the reaction should be controlled however to accommodate any such exothermic processes.

(31) The time of reaction may be monitored by reference to the formation of the desired electron deficient olefin precursor product. .sup.1H NMR spectrometer is a particularly useful tool in this regard. The time of reaction may be as little as 30 minutes, for instance, or longer or shorter for that matter depending again on the identity of the specific reactants, the scale of the reaction and whether heat is added to the reaction conditions.

(32) Once formed, the electron deficient olefin precursor may be isolated as a product or may be used directly in situ to form an electron deficient olefin. The in situ use would be for instance as a reactant in a Knoevenagel condensation reaction with an aldehyde source conducted under conventional base catalyzed conditions or under state of the art acid catalyzed conditions.

(33) The following examples are intended to illustrate but in no way limit the present invention.

EXAMPLES

Example 1

(34) To a 25 ml round bottomed flask is added 7.01 g (0.062 mol) of ethyl cyanoacetate, 4.15 g (0.056 mol) of n-butanol and 10 mL of nitromethane. The flask is fitted with a reflux condenser and magnetic stirrer before being immersed in an oil bath at a temperature of 105 C. The mixture is stirred at this temperature for a period of time of 30 minutes before a mixture of 3.47 g (6.75 mmol, 10 mol %) of ytterbium triflate in 5 ml of acetonitrile is added. The reaction is stopped after a period of time of 6 hours. The conversion to butyl cyanoacetate is determined by 500 MHz .sup.1H NMR.

Example 2

(35) To a 25 ml round bottomed flask is added 7.01 g (0.062 mol) of ethyl cyanoacetate, 4.936 g (0.056 mol) of 2-pentanol and 10 mL of nitromethane. The flask is fitted with a reflux condenser and magnetic stirrer before being immersed in an oil bath at a temperature of 105 C. The mixture is stirred at this temperature for a period of time of 30 minutes before a mixture of 3.47 g (6.75 mmol, 10 mol %) of ytterbium triflate in 5 ml of acetonitrile is added. The reaction is stopped after a period of time of 6 hours. The conversion to 2-pentyl cyanoacetate is determined by 500 MHz .sup.1H NMR.

Example 3

(36) To a 25 ml round bottomed flask is added 7.01 g (0.062 mol) of ethyl cyanoacetate, 6.84 g (0.056 mol) of phenyl ethanol and 10 mL of nitromethane. The flask is fitted with a reflux condenser and magnetic stirrer before being immersed in an oil bath at a temperature of 105 C. The mixture is stirred at this temperature for a period of time of 30 minutes before a mixture of 3.47 g (6.75 mmol, 10 mol %) of ytterbium triflate in 5 ml of acetonitrile is added. The reaction is stopped after a period of time of 6 hours. The conversion to phenyl ethyl cyanoacetate is determined by 500 MHz .sup.1H NMR.