Aldehydes cyanosilylation with TMSCN

Although HCN also adds to these unsaturated bonds to afford cyanohydrins and a-amino nitriles, use of TMSCN instead of HCN provides an efficient and safer route to these compounds. Cyanosilylation with TMSCN is accelerated by acid and base catalysts. In recent years a variety of organic and inorganic compounds have been found to work as effective catalysts, and much attention has been devoted for the development of chiral catalysts for asymmetric cyanosilylation of aldehydes, ketones, and imines. 

Mori et al.149 also reported the asymmetric cyanosilylation of aldehyde with TMSCN using 132 (X = CN) as the precatalyst. The chiral dicyano complex was generated in situ, and the asymmetric cyanosilylation gave ee values of up to 75%. Scheme 2-58 depicts the proposed reaction process. 

Song et al. extended this methodology to include cyanosilylation of aldehydes and ketones (Eq. 32) [160], They propose that NHC 276 interacts with TMSCN to form complex LXXVIII followed by cyano group transfer to the aldehyde (Scheme 48). The carbene is then regenerated and the desired product is obtained when LXXIX fragments. Concurrently, Kondo, Aoyama and co-workers describe similar reaction conditions for the synthesis of cyanohydrins in high yields [161, 162], while Suzuki and co-workers reported a cyanosilylation of aromatic and aliphatic aldehydes in good yields [163]. 

Cyanosilylation of imines (Strecker-type reaction) is efficiently promoted by conventional Lewis acids such as ZnX2, AlCl , and TiCLj [604]. Kobayashi et al. recently disclosed that Yb(OTf)3 has high catalytic activity in this cyanosilylation (Scheme 10.237) [622]. In the competitive reaction of aldehydes and the corresponding imines with TMSCN, Yb(OTf)3 activates imines to give only a-aminoni-... 

The Lewis acid-Lewis base bifunctional catalyst 178a, prepared from Ti(Oi-Pr)4 and diol 174 (1 1), realizes highly enantioselective cyanosilylation of a variety of ketones to (R)-cyanohydrin TMS ethers (Scheme 10.241) [645]. The proposed mechanism involves Ti monocyanide complex 178b as the active catalyst this induces reaction of aldehydes with TMSCN by dual activation. Interestingly, the catalyst prepared from Gd(Oi-Pr)3 and 174 (1 2) serves for exclusive formation of (S)-cyanohy-drin TMS ethers [651]. The catalytic activity of the Gd complex is much higher than that of 178a. The results of NMR and ESI-MS analyses indicate that Gd cyanide complex 179 is the active catalyst. It has been proposed that the two Gd cyanide moieties of 179 play different roles - one activates an aldehyde as a Lewis acid and the other reacts with the aldehyde as a cyanide nucleophile. 

Strong base (66, R = Me, pAT, of conjugate acid = 32.9) catalyses the cyanosilylation of aldehydes and ketones, using TMSCN in THF at 0 °C.267 Even better results are obtained with isopropyl as R group, but the isobutyl case is a much poorer catalyst, indicating a very fine balance between basicity and steric bulk in the action of these catalysts. 

Asymmetric cyanosilylation of ketones and aldehydes is important because the cyanohydrin product can be easily converted into optically active aminoalcohols by reduction. Moberg, Haswell and coworkers reported on a microflow version of the catalytic cyanosilylation of aldehydes using Pybox [5]/lanthanoid triflates as the catalyst for chiral induction. A T-shaped borosilicate microreactor with channel dimensions of 100 pm X 50 pm was used in this study [6]. Electroosmotic flow (EOF) was employed to pump an acetonitrile solution of phenyl-Pybox, LnCl3 and benzal-dehyde (reservoir A) and an acetonitrile solution of TMSCN (reservoir B). LuC13-catalyzed microflow reactions gave similar enantioselectivity to that observed in analogous batch reactions. However, lower enantioselectivity was observed for the YbCl3-catalyzed microflow reactions than that observed for the batch reaction (Scheme 4.5). It is possible that the oxophilic Yb binds to the silicon oxide surface of the channels. 

Lanthanide Lewis acids catalyze many of the reactions catalyzed by other Lewis acids, for example, the Mukaiyama-aldol reaction [14], Diels-Alder reactions [15], epoxide opening by TMSCN and thiols [14,10], and the cyanosilylation of aldehydes and ketones [17]. For most of these reactions, however, lanthanide Lewis acids have no advantages over other Lewis acids. The enantioselective hetero Diels-Alder reactions reported by Danishefsky et al. exploited one of the characteristic properties of lanthanides—mild Lewis acidity. This mildness enables the use of substrates unstable to common Lewis acids, for example Danishefsky s diene. It was recently reported by Shull and Koreeda that Eu(fod)3 catalyzed the allylic 1,3-transposition of methoxyace-tates (Table 7) [18]. This rearrangement did not proceed with acetates or benzoates, and seemed selective to a-alkoxyacetates. This suggested that the methoxy group could act as an additional coordination site for the Eu catalyst, and that this stabilized the complex of the Eu catalyst and the ester. The reaction proceeded even when the substrate contained an alkynyl group (entry 7), or when proximal alkenyl carbons of the allylic acetate were fully substituted (entries 10, 11 and 13). In these cases, the Pd(II) catalyzed allylic 1,3-transposition of allylic acetates was not efficient. 

From analogy with the cyanosilylation of aldehydes a working model for the catalytic cycle has been proposed in which the Lewis acid (Al) and the Lewis base (phosphine oxide) activate the imine and TMSCN respectively. 

In the presence of 168 a (9mol%) and a phosphine oxide (Bu),P(O) and Ph2P(O)Me for aromatic and ahphatic aldehydes, respectively, 36 mol%), slow addition of TMSCN achieves excellent enantioselectivity with a wide range of aldehydes (86-100%, 83-98% ee). The Al complex has been proposed to work as a bifunctional catalyst for dual activation of the two reactants - the Lewis acidic Al center enhances the electrophilicity of aldehydes and the Lewis basic phosphine oxide induces cyanide addition by nucleophihc activation (Scheme 10.240). This catalytic asymmetric cyanosilylation has been used for the total synthesis of epothilones [652]. 

A sugar-based catalyst for catalytic asymmetric cyanosilylation has been developed. This catalyst, 248, is derived from tri-O-acetyl-D-glucal via the intermediates shown in Scheme 39. It incorporates a Lewis acidic and a Lewis basic site within the molecule, and it was found that the conformational constraint induced by the phenyl group was necessary for good enantioselectivity. Treatment of benzaldehyde and TmsCN with catalytic quantities of 248 gave after acid hydrolysis the cyanohydrin 249 in 80% ee, and several other aldehydes behaved similarly. 

An unsymmetrical salen ligand bearing a Lewis base catalyses Ti(OPr-i)4-promoted addition of TMSCN to benzaldehyde with as little as 0.05 mol% loading, quantitative conversion is achieved in 10 min at ambient temperature. Another salen catalyst - a bifunctional salen-phosphine oxide-Ti(IV) combination - promotes enantioselective cyanosilylation of aldehydes. Fine tweaking of the structure of another series of bifunctional chiral salen-Ti(IV) complexes allows the enantioselectivity to be reversed. Biaryl-bridged salen-titanium complexes are also highly efficient catalysts, one example giving 87% ee at room temperature. ... 

Recently, hydrocyanation and cyanosilylation reactions with other type of chiral aluminum complexes were reported. In 1999, Shibasaki and Kanai reported enantioselective cyanosilylation of aldehydes catalyzed by Lewis acid-Lewis base bifunctional catalyst (64a) [56, 57]. In this catalyst, aluminum center works as a Lewis acid to activate the carbonyl group, and the oxygen atom of the phosphine oxide works as a Lewis base to activate TMSCN. Asymmetric induction was explained by the proposed transition state model having the external phosphine oxide coordination to aluminum center, thus giving rise to pentavalent aluminum... 

In 2005, thiourea catalyst 7 was proved to be an efHcient and recyclable catalyst for the cyanosilylation of various ketones 6 (Table 30.2) [8]. In the reaction with 5 mol% catalyst 7, TMSCN, and an alcoholic additive, aryl-alkyl (entries 1, 3-5), alkenyl-alkyl (entries 10, 11) ketones, and cyclic ketones (entry 12) afforded adducts in high yields (91-98%) and high enantiopurities (86-98% ee). Yields for heteroaromatic analogues were lower (81-88%) but with high enantioselectivities (97-98% ee) (entries 6, 7). The substrate scope could be also extended to aldehydes... 

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