Mechanistic comparison of aluminium based catalysts for asymmetric cyanohydrin synthesis

A kinetic analysis of the asymmetric addition of trimethylsilyl cyanide to benzaldehyde using three aluminium based catalysts has been carried out. All three catalysts displayed rate equations, which were first order in trimethylsilyl cyanide concentration and zero order in benzaldehyde concentration. The results are consistent with a common mechanism for effective asymmetric catalysis of cyanohydrin synthesis, involving combined activation of the aldehyde by a Lewis acid and activation of the trimethylsilyl cyanide by a Lewis base. The mechanistic analysis was also applied to a magnesium-based catalyst system to demonstrate its general applicability.     

Synthetic and mechanistic studies on asymmetric cyanohydrin synthesis using a titanium(salen) bimetallic catalyst

A bimetallic titanium(salen) complex 1 was found to catalyse the asymmetric addition of ethyl cyanoformate to aldehydes. Best results were obtained using 5 mol% of the catalyst at −40 °C and under these conditions, both aromatic and aliphatic aldehydes were converted into cyanohydrin carbonates with up to 99% enantiomeric excess. The same catalyst could also be used to catalyse the asymmetric addition of potassium cyanide to aldehydes in the presence of propionic anhydride, leading to cyanohydrin esters. Mechanistic studies showed that the enantiomeric excess of the product increased during the early stages of this reaction. However, by adding a ‘sacrificial aldehyde’ this effect could be eliminated. The structure of the catalyst in solution was investigated using variable concentration, variable temperature and variable solvent NMR studies. These experiments showed that the catalyst exists as a mixture of monometallic 4 and bimetallic 1 species, a result which is consistent with previous mechanistic studies on the asymmetric addition of trimethylsilyl cyanide to aldehydes and ketones catalysed by the same catalyst. A mechanistic rationale for all of these observations is reported.     

Asymmetric cyanohydrin formation from aldehydes catalyzed by manganese Schiff base complexes

The catalyst generated in situ from Mn(OAc)₂ and a chiral Schiff base ligand exhibited excellent catalytic abilities in asymmetric cyanohydrin formation from aldehydes with sodium cyanide in up to 99% enantioselectivity and good yield.     

Investigation of Lewis Acid versus Lewis Base Catalysis in Asymmetric Cyanohydrin Synthesis

The asymmetric addition of trimethylsilyl cyanide to aldehydes can be catalysed by Lewis acids and/or Lewis bases, which activate the aldehyde and trimethylsilyl cyanide, respectively. It is not always apparent from the structure of the catalyst whether Lewis acid or Lewis base catalysis predominates. To investigate this in the context of using salen complexes of titanium, vanadium and aluminium as catalysts, a Hammett analysis of asymmetric cyanohydrin synthesis was undertaken. When Lewis acid catalysis is dominant, a significantly positive reaction constant is observed, whereas reactions dominated by Lewis base catalysis give much smaller reaction constants. [{Ti(salen)O}₂] was found to show the highest degree of Lewis acid catalysis, whereas two [VO(salen)X] (X=EtOSO₃ or NCS) complexes both displayed lower degrees of Lewis acid catalysis. In the case of reactions catalysed by [{Al(salen)}₂O] and triphenylphosphine oxide, a non‐linear Hammett plot was observed, which is indicative of a change in mechanism with increasing Lewis base catalysis as the carbonyl compound becomes more electron‐deficient. These results suggested that the aluminium complex/triphenylphosphine oxide catalyst system should also catalyse the asymmetric addition of trimethylsilyl cyanide to ketones and this was found to be the case.     

Cyanide ion cocatalysis in Ti(salen) catalysed asymmetric cyanohydrin carbonate synthesis

In the presence of potassium cyanide or the potassium cyanide/18-crown-6 complex as a cocatalyst, 1-2 mol% of titanium(salen) complex catalyses the asymmetric addition of achiral cyanoformates to aldehydes, giving cyanohydrin carbonates with high enantiomeric excesses; and catalyses the diastereoselective addition of chiral cyanoformates derived from alpha-methylbenzyl alcohol to aldehydes, a reaction which exhibits double asymmetric induction.     

Catalytic, asymmetric synthesis of α-acetoxy amides

Non-racemic cyanohydrin acetates are readily available from aldehydes and potassium cyanide/acetic anhydride by use of bimetallic titanium (salen) catalyst 1. Treatment of the cyanohydrin acetates with a platinum(II) phosphinito catalyst 3 under neutral conditions results in chemoselective hydrolysis to the corresponding α-acetoxy amides in a racemization free process.     

Enantioselective and diastereoselective syntheses of cyanohydrin carbonates

A new and general synthesis of alkyl cyanoformates is presented starting from the appropriate alcohol and oxalyl chloride. This is used to prepare enantiomerically pure cyanoformates from enantiomerically pure primary and secondary alcohols. Optimal conditions for the addition of various achiral cyanoformates to aldehydes catalysed by an enantiomerically pure titanium(salen) catalyst in the presence of potassium cyanide as a cocatalyst are developed. Under these conditions, two chiral cyanoformates also reacted with aldehydes to give cyanohydrin carbonates. The stereochemistry of this process is predominantly determined by the stereochemistry of the titanium(salen) catalyst and the stereochemistry of two of the cyanohydrin carbonates was confirmed by X-ray crystallography. In a further extension of the chemistry, a homogeneous system in which the potassium cyanide/18-crown-6 complex is used as the cyanide cocatalyst has been developed and the kinetics of this reaction show that it displays first order kinetics, provided at least 2 mol % of the potassium cyanide complex are employed.     

Asymmetric synthesis of polymer-supported cyanohydrin acetates

A bimetallic titanium(salen) complex has been used to catalyze the asymmetric addition of potassium cyanide to aldehydes attached to Wang resin giving polymer supported cyanohydrin propionates with up to 91% enantiomeric excesses.     

Enantioselective cyanosilylation of ketones catalyzed by double-activation catalysts with N-oxides

Enantioselective addition of trimethylsilyl cyanide to ketones by a catalytic double-activation method is described. By combinatorially using 2.0 mol% of a chiral salen-titanium complex and 1.0 mol% of an achiral tertiary amine N-oxide, aromatic, aliphatic and α,β-unsaturated ketones are converted into corresponding cyanohydrin trimethylsilyl ethers with 50-93% yield and 59-86% ee. The effects of ligand structure, catalyst loading and substrate concentration, solvents, the nature of Lewis base, counter ion and other additives, temperature, and substrate structure on the enantioselectivity are discussed. Three possible paths to achieve the asymmetric version of double-activation catalysis and two independent examples of it are proposed.     

Remarkable acceleration of cyanosilylation by the mesoporous Al-MCM-41 catalyst

The presence of the heterogeneous mesoporous Al-MCM-41 catalyst remarkably accelerated the cyanosilylation of various aldehydes and ketones with trialkylsilyl cyanide, giving the corresponding cyanohydrin silyl ethers in quantitative yields under mild reaction conditions.     

Solvent‐free cyanosilylation of aldehydes catalyzed by SmI2

A novel method to obtain racemic cyanohydrin silylethers by reaction of trimethylsilyl cyanide with a variety of aldehydes promoted by catalysis of SmI₂ is reported. The corresponding cyanosilylethers were obtained in high yields (up to 99%) in solvent‐ free conditions at room temperature within a relatively short time using 0.01–0.5 mol% catalyst loadings. Copyright © 2007 John Wiley & Sons, Ltd.     

Fe(Cp)2PF6: An efficient catalyst for cyanosilylation of carbonyl compounds under solvent free condition

An efficient method for the addition of trimethylsilyl cyanide (TMSCN) to various aldehydes and ketones has been described using Fe(Cp)₂PF₆ (2.5 mol%) as a catalyst under solvent free condition. Excellent yields of trimethylsilylether of cyanohydrin up to (94%) was achieved within 10 min.     

Rapid additions of bulky tert-butyldimethylsilyl cyanide to hindered ketones promoted by heterogeneous tin ion-exchanged montmorillonite catalyst

Tin ion-exchanged montmorillonite (Sn-Mont) was found to be a powerful heterogeneous catalyst for the cyanosilylation of various ketones including congested ones with a bulky cyanide source, tert-butyldimethylsilyl cyanide (TBDMSCN), giving the corresponding cyanohydrin tert-butyldimethylsilyl ethers in good (85%) to excellent (>98%) yields at room temperature. Compared to the previously reported catalysts, Sn-Mont is easy to prepare, environmentally benign, nontoxic, noncorrosive, and recyclable.     

Phase transfer catalyzed enantioselective Strecker reactions of alpha-amido sulfones with cyanohydrins

A study into the use of a chiral phase-transfer catalyst in conjunction with acetone cyanohydrin to effect the enantioselective formation of alpha-amino nitriles from alpha-amido sulfones is described. This novel catalytic asymmetric Strecker reaction is analyzed with regard to the possible mechanistic basis.     

Vanadium-catalyzed asymmetric cyanohydrin synthesis

Based on a mechanistic understanding of asymmetric cyanohydrin synthesis catalyzed by chiral titanium-salen complexes, a new catalyst based on vanadium(IV) has been developed. The chiral (salen)VO catalyst is more enantioselective than the titanium-based systems, 0.1 mol % of the catalyst being sufficient to convert aromatic and aliphatic aldehydes into the corresponding trimethylsilyl ethers of cyanohydrins with 68-95% enantiomeric excess at room temperature.     

Kinetics and mechanism of the racemic addition of trimethylsilyl cyanide to aldehydes catalysed by Lewis bases

The mechanism by which four Lewis bases, triethylamine, tetrabutylammonium thiocyanate, tetrabutylammonium azide and tetrabutylammonium cyanide, catalyse the addition of trimethylsilyl cyanide to aldehydes is studied by a combination of kinetic and spectroscopic methods. The reactions can exhibit first or second order kinetics corresponding to three different reaction mechanisms. Spectroscopic evidence for the formation of hypervalent silicon species is obtained for reaction between all of the tetrabutylammonium salts and trimethylsilyl cyanide. The reactions are accelerated by the presence of water in the reaction mixture, an effect which is due to a change in the reaction mechanism from Lewis to Br?nsted base catalysis. Tetrabutylammonium thiocyanate is shown to be an excellent catalyst for the synthesis of cyanohydrin trimethylsilyl ethers on a preparative scale.     

Asymmetric cyanohydrin synthesis using heterobimetallic catalysts obtained from titanium and vanadium complexes of chiral and achiral salen ligands

Titanium(IV)(salen) and vanadium(V)(salen) complexes are both known to form catalysts for asymmetric cyanohydrin synthesis. When a mixture of titanium and vanadium complexes derived from the same or different salen ligands is used for the asymmetric addition of trimethylsilyl cyanide to benzaldehyde, the absolute configuration of the product and level of asymmetric induction can only be explained by in situ formation of a catalytically active heterobimetallic complex, and is not consistent with two monometallic species acting cooperatively. Combined use of complexes containing chiral and achiral salen ligands demonstrates that during the asymmetry inducing step of the mechanism, the aldehyde is coordinated to the vanadium rather than the titanium ion. The titanium complexes also catalyse the asymmetric addition of ethyl cyanoformate to aldehydes, a reaction in which vanadium(V)(salen) complexes are not active. For this reaction, use of a mixture of titanium and vanadium(salen) complexes results in a complete loss of catalytic activity, a result which again can only be explained by in situ formation of a heterometallic complex. Both the titanium and vanadium based catalysts also induce the asymmetric addition of potassium cyanide/acetic anhydride to aldehydes. For this reaction, combined use of chiral and achiral complexes indicates that during the asymmetry inducing step of the mechanism, the aldehyde is coordinated to titanium rather than vanadium, a result which contrasts with the observed results when trimethylsilyl cyanide is used as the cyanide source.     

Internal oxidation-reduction of quinoxaline-2- carboxaldehyde 1,4-dioxide

Reaction of carboxaldehyde 1 with acetone cyanohydrin gives carboxylic acid 2. Reaction of 1 with acetone cyanohydrin in methanol affords the methyl ester 3. The structural assignment for 2 is supported by ¹³C nmr data and by the decarboxylation of deuterated 2 to give 4b. The internal oxidation-reduction upon going from 1 to 2 is explained in terms of a mechanism whereby 1 is converted into its cyanohydrin 5 and then to acyl cyanide 6. Acyl cyanide 6 then reacts with either water or methanol to give 2 or 3.     

Asymmetric Cyanation of Aldehydes,Ketones, Aldimines,and Ketimines Catalyzed by a Versatile Catalyst Generated from Cinchona Alkaloid,Achiral Substituted 2,2′‐Biphenol and Tetraisopropyl Titanate

Full investigation of cyanation of aldehydes, ketones, aldimines and ketimines with trimethylsilyl cyanide (TMSCN) or ethyl cyanoformate (CNCOOEt) as the cyanide source has been accomplished by employing an in situ generated catalyst from cinchona alkaloid, tetraisopropyl titanate [Ti(OiPr)₄] and an achiral modified biphenol. With TMSCN as the cyanide source, good to excellent results have been achieved for the Strecker reaction of N‐Ts (Ts=p‐toluenesulfonyl) aldimines and ketimines (up to >99 % yield and >99 % ee) as well as for the cyanation of ketones (up to 99 % yield and 98 % ee). By using CNCOOEt as the alternative cyanide source, cyanation of aldehyde was accomplished and various enantioenriched cyanohydrin carbonates were prepared in up to 99 % yield and 96 % ee. Noteworthy, CNCOOEt was successfully employed for the first time in the asymmetric Strecker reaction of aldimines and ketimines, affording various α‐amino nitriles with excellent yields and ee values (up to >99 % yield and >99 % ee). The merits of current protocol involved facile availability of ligand components, operational simplicity and mild reaction conditions, which made it convenient to prepare synthetically important chiral cyanohydrins and α‐amino nitriles. Furthermore, control experiments and NMR analyses were performed to shed light on the catalyst structure. It is indicated that all the hydroxyl groups in cinchona alkaloid and biphenol complex with Ti^IV, forming the catalyst with the structure of (biphenoxide)Ti(OR*)(OiPr). The absolute configuration adopted by biphenol 4 m in the catalyst was identified as S configuration according to the evidence from control experiments and NMR analyses. Moreover, the roles of the protonic additive (iPrOH) and the tertiary amine in the cinchona alkaloid were studied in detail, and the real cyanide reagent in the catalytic cycle was found to be hydrogen cyanide (HCN). Finally, two plausible catalytic cycles were proposed to elucidate the reaction mechanisms.     

Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide and cyanoformate as cyanide sources

Dual activation by a chiral Lewis acid and an achiral or chiral Lewis base enabled cyanation of both aromatic and aliphatic aldehydes with acetyl cyanide and ethyl cyanoformate to provide direct access to O-acetylated and O-alkoxycarbonylated cyanohydrins, respectively, under mild conditions. With a combination of a Ti-salen catalyst and Et3N, benzaldehyde was converted to the O-acetylated cyanohydrin with 94% ee within 10 h at -40 degrees C in 89% isolated yield.