Chiral catalysts trimethylsilyl cyanide

Chiral metal catalyst Trimethylsilyl cyanide Alkyl cyanoformates NaCN + anhydride All carbonyl functions accessible Expensive cyanide source, expensive and sensitive catalyst, low temperatures required (T<-20°C)... 

Cyanation of aldehydes and ketones is an important chemical process for C C bond formation." " Trimethylsilyl cyanide and/or HCN are commonly used as cyanide sources. The intrinsic toxicity and instability of these reagents are problematic in their applications. Acetyl cyanide and cyanoformates were used as cyanide sources in the enantioselective cyanation of aldehydes catalyzed by a chiral Ti complex and Lewis base (Scheme 5.31)." The Lewis base was necessary for the good yields and selectivities of these reactions. The desired products were obtained in the presence of 10mol% triethyl amine and 5mol% chiral titanium catalyst (Figure 5.14). Various aliphatic and aromatic aldehydes could be used in these reactions. 

Cyanosilylation of methyl ketones has been carried out using diphenylmethylphos-phine oxide and trimethylsilyl cyanide, generating a phosphorus isonitrile-type species, Ph2MeP(OTMS)(N=C ), as the reactive intermediate.271 A chiral oxazaborolidinium ion catalyst renders the reaction enantioselective. 

Two other types of catalysts have been investigated for the enantioselective Strecker-type reactions. Chiral N-oxide catalyst 24 has been utilized in the trimethylsilyl cyanide promoted addition to aldimines to afford the corresponding aminonitriles with enantioselectivities up to 73% ee [14]. Electron-deficient aldimines were the best substrates, but unfortunately an equimolar amount of catalyst 24 was used in these reactions. The asymmetric Strecker addition of trimethylsilyl cyanide to a ketimine with titanium-based BINOL catalyst 25 gave fast conversions to quarternary aminonitriles with enantiomeric excesses to 59%... 

Reetz et al. found that chiral 1-boracyclopentyl chloride or methoxide can be used as a catalyst in the reaction of 3-methylbutanal and trimethylsilyl cyanide (Eq. 72) [42]. Although the asymmetric induction and yield are not good, this is the first example of chiral induction by an organoborane in the hydrocyanation of aldehydes. 

The only known metal catalyst for the asymmetric catalytic Strecker reaction is the aluminum salen catalyst 465 (Sch. 65) recently reported by Sigman and Jacobsen [97]. They prepared 11 different chiral salen complexes from different transition and main group metals and screened these complexes for the addition of trimethylsilyl cyanide to imine 460 at room temperature. The aluminum catalyst 465 was optimum in terms both of asymmetric induction and rate. This constitutes the first aluminum salen complex successfully developed for an asymmetric catalytic reaction. 

A series of supported chiral VO(salen) complexes anchored on silica, single-wall carbon nanotube, achvated carbon or ionic liquids have been prepared through the simple methods based on the addition of mercapto groups to terminal C=C double bonds (Scheme 7.17) [58]. The four recoverable catalysts and the standard VO(salen) complex 37 were tested for the enantioselechve cyanosilylation of benzaldehyde using trimethylsilyl cyanide (Table 7.9). It should be noted that the ionic liquid-supported IL-VO(salen) showed the highest catalyhc achvity, though the ee-value was considerably reduced compared to the soluble 37 in [bmim][PF6] (entries 4 and 5). 

The efficiency of new unsymmetrical chiral salen ligands was examined in the asymmetric trimethylsilylcyanation of benzaldehyde. A very high level of enantioselectivity was attainable over chiral Ti(IV) salen complexes prepared from salicylaldehyde and 3,5-Di-/ert-butylsalicylaldehyde derivative as compared to the conventional salen catalyst. Enantiomeric excess of the corresponding reaction product was generally more than 70% over unsymmetric chiral salen catalysts. The chiral Titanium(IV) salen complexes immobilized on a mesoporous MCM-41 by multi grafting method showed a relatively high enantioselectivity for the addition of trimethylsilyl cyanide to the benzaldehyde. 

In 2007, Feng et al. reported an efficient self-assembled catalytic system for the addition of trimethylsilyl cyanide to imines. The combined use of cinchonine (27), achiral 3,3 -(2-naphthyl)-2,2 -biphenol (28), and titanium tetra-isopropoxide gave an efficient catalyst for aldimines and ketimines (Scheme 7.19). Cinchonine induces a chiral environment around the titanium atom by fixing a stable chiral configuration to the biphenol ligand, and also activates hydrogen cyanide, generated in situ. In addition to trimethylsilyl cyanide, safer ethyl cyanoformate can be used with similar results. 

The asymmetric 1,4-addition (Michael addition) of a cyanide ion to nitroalkenes is a potentially useful route for preparing p-amino acids via transformation of 3-nitropropanonitriles. ° In 2013, North reported the first vanadium-catalysed, enantioselective Michael addition of trimethylsilyl cyanide to aliphatic p-nitroalkenes, which provided (S)-19, as shown in Scheme 9.9. The reaction was promoted by a 3 mol% catalyst loading of chiral vanadium(v) salen complex 18 ° providing (S)-19 in 74-88% conversions with up to 89% enantiomeric excess. North proposed that the nitro group acts as a bridge for the two vanadium metals in the possible transition... 

Subsequently, the Feng group developed an enantioselective cyanosilylation of ketones by a catalytic double-activation catalyst system composed of chiral (J ,J )-salen 16-triethylaluminium complex and N-oxide 17 (Scheme 19.10). High catalytic turnovers (200 for aromatic ketones, 1000 for aliphatic ones) with high enantioselectivity (up to 94% enantiomeric excess for aromatic ketones, up to 90% enantiomeric excess for aliphatic ones) were achieved under mild reaction conditions. Based on the control experiments, a double-activation model was suggested (Scheme 19.10). The chiral aluminium complex performed as a Lewis acid to activate the ketone, whereas the N-oxide acted as a Lewis base to activate trimethylsilyl cyanide and form an isocyanide species. The activated nucleophile and ketone attracted and approached each other, and so the transition state was formed. The intramolecular transfer of cyanide to the carbonyl group gives the product cyanohydrin O-TMS ether. 

Sc(BINOL)2Li, a new chiral heterobimetallic complex, was shown to catalyze addition of a cyanide source (hydrogen cyanide (HCN) and trimethylsilyl cyanide (TMSCN)) to various imines enantioselectively [128]. Moderate to high conversions and enantiomeric excesses were obtained in this Strecker reaction using 10 mol% of the catalyst. High enantioselectivity (84% ee) and quantitative yield were also obtained by the addition of TMSCN to benzaldehyde. 

Silyl cyanides react enantioselectively with such electrophiles as aldehydes, ketones, imines, activated azines, or,/ unsaturated carbonyl compounds, epoxides, and aziridines in the presence of chiral Lewis acid catalysts to give functionalized nitriles, versatile synthetic intermediates for hydroxy carboxylic acids, amino acids, and amino alcohols (Tables 3-6, 3-7, 3-8, and 3-9, Figures 3-6, 3-7, and 3-8, and Scheme 3-154). ° Soft Lewis acid catalytst, the reaction of epoxides with trimethylsilyl cyanide often leads to isonitriles, which are derived from silylisonitrile spiecies (Schemes 3-155 and 3-156). Soft Lewis base such as phosphine oxide also catalyzes the reaction and cyanohydrin silyl ethers of high ee s are isolated. 

The addition of trimethylsilyl (TMS) cyanide to aldehydes produces TMS-protected cyanohydrins. In a recent investigation a titanium salen-type catalyst has been employed to catalyse trimethylsilylcyanide addition to benzaldehyde at ambient temperature1118]. Several other protocols have been published which also lead to optically active products. One of the more successful has been described by Abiko et al. employing a yttrium complex derived from the chiral 1,3-diketone (41)[119] as the catalyst, while Shibasaki has used BINOL, modified so as to incorporate Lewis base units adjacent to the phenol moieties, as the chiral complexing agent11201. 

The low ionic character of the aluminium-silicon bond has been cleverly utilized to develop a very mild, general and effective synthesis of acyl silanes, successful for aliphatic, aromatic, heteroaromatic, a-aUcoxy, a-amino and even a-chiral and a-cyclopropyl acyl sUanes. Acyl chlorides are treated with lithium tetrakis(trimethylsilyl)aluminium or lithium methyl tris(trimethylsilyl) aluminium in the presence of copper(I) cyanide as catalyst to give the acyl silanes in excellent yields after work-up. Later improvements include the use of 2-pyridinethiolesters in place of acyl halides, allowing preparation of acyl silanes in just a few minutes in very high yields indeed (Scheme 9) °, and the use of bis(dimethylphenylsilyl) copper lithium and a dimethylphenylsilyl zinc cuprate species as nucleophiles. 

In the synthesis of (—)-lupinine (926) by Santos et al., (lR,2S,5R)-8-phenyhnenthol was used as the chiral auxiliary in controlling the stereochemical outcome of the reaction of the piperidine-containing carbamate 1042 with the 2-silyloxyfuran 1043 (Scheme 130). With trimethylsilyl triflate as Lewis acid catalyst and butyhnethylimidazolinium tetrafluorobo-rate as additive, an 80% yield was obtained as a 9.7 1 mixture in favor of threo-product (—)-1044. After hydrogenation of the double bond, treatment of the intermediate (—)-1045 with sodium methoxide effected rearrangement to the (R,R)-(- -)-l-hydroxyquinolizidin-4-one (- -)-1046 in 93% overall yield. Mitsunobu inversion of the alcohol to the (lS)-epimer (—)-1047 followed by alane reduction of the lactam afforded the quinolizi-din-l-ol (—)-1048. A second inversion at C-1 with cyanide produced the... 

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