Cyanation cyanohydrin synthesis

Aldehydes, ketones, and acetals react with allyltrimethylsilane in the presence of a catalytic amount of BiX3 (X = C1, Br, OTf) to give homoallyl alcohols or homoallyl alkyl ethers (Equation (52)).91-93 The BiX3-catalyzed allylation of aldehydes and sequential intramolecular etherification of the resulting homoallylic silyl ethers are involved in the stereoselective synthesis of polysubstituted tetrahydropyrans (Equation (53)).94,95 Similarly, these Lewis acids catalyze the cyanation of aldehydes and ketones with cyanotrimethylsilane. When a chiral bismuth(m) catalyst is used in the cyanation, cyanohydrines are obtained in up to 72% ee (Equation (54)). a-Aminonitriles are prepared directly from aldehydes, amines, and cyanotrimethysilane by the BiCl3-catalyzed Strecker-type reaction. 

The allylation and cyanation of aldehydes and ketones are mediated by BiCl3 and BiBr3 [174, 175]. When a chiral bismuth(lll) catalyst is used for cyanation, cyanohydrins are obtained in up to 72% ee (Scheme 14.85) [175]. The Bi(OTf)3-promoted intramolecular Sakurai cyclization of homoallylic alcohols is involved as a key step in the stereoselective synthesis of polysubstituted tetrahydropyrans (Scheme 14.86) [176]. In the presence of the BiCl3-xMl binary catalyst, allyltrimethylsilane [177] and silyl enolates [178] are acylated to give aUyl ketones and /l-dikelories, respectively. 

The double process of cyanation/transcyanation of co-bromoaldehydes and racemic cyanohydrins as a source of HCN is a really interesting process (Scheme 10.25). Thus, using this reaction it is possible to obtain optically active (S)-ketone- and (R)-aldehyde-cyanohydrins in one pot [55], The reaction is carried out in diisopropyl ether using a crude extract of almond containing (R)-oxynitrilase as biocatalyst. The optically active (a-bromocyanohydrins prepared by this method is used as starting materials for the synthesis of valuable compounds such as... 

Relatively few of the enzymatic methods applicable to the preparation of secondary cyanohydrins have been adapted successfully to the synthesis of optically pure tertiary cyanohydrins [1,3,4]. Similarly, progress in asymmetric hydro-cyanation of ketones with synthetic catalysts lagged far behind advances in aldehyde cyanation. This situation has changed fairly dramatically over the past... 

This reaction can be extended to synthesis of alternating polyol chains found in polyene macrolide antibiotics. Thus reaction of the dibromide 5 with 2 equiv. of the cyanohydrin anion of 6 provides, after reductive cyanation, the protected polyol 7 in good yield. 

Inagaki M, Hatanaka A, Mimura M, Hiratake J, Nishioka T, Oda J (1992) One-pot synthesis of optically active cyanohydrin acetates from aldehydes via quinidine-catalyzed transhydro-cyanation coupled with lipase-catalyzed kinetic resolution in organic solvent. Bull Chem Soc Jpn 65 111-120... 

Asymmetric cyanation of aldehydes is important in organic synthesis. Mukaiyama and Minowa have developed a new chiral Lewis acid catalyst which is readily prepared from l,l -dimethylstannocene, triflic acid, and (+)-cinchonine [49]. In the presence of this Lewis acid reaction of TMSCN with aldehydes proceed smoothly at -78 °C in dichloromethane to give the corresponding cyanohydrin trimethylsilyl ether in high yield with good to excellent ee. In this reaction the products are isolated as trimethylsilyl ethers and the reaction proceeds smoothly in the presence of 30 mol % tin(II) Lewis acid (Eq. 31). The catalyst, Sn(II) monoalkoxymonotriflate, is assumed to be regenerated from the initially produced Sn(II) alkoxide and trimethylsilyl triflate. 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

Thus, the preparation of the optically active cyanohydrins and aminonitriles has been a major topic of interest in the field of asymmetric synthesis. However, a practical method for cyanation was not reported until the early 1980 s, except for the use of an enzyme, oxynitrilase a flavoprotein isolated from seeds and blossoms of various Prunaceae species, which catalyzes the addition of hydro-... 

Since the toxicity and volatility of HCN are high, these facts limit its extensive and practical application in organic synthesis. In this respect, a number of cyanating agents have been developed to avoid the use of toxic HCN, such as TMSCN [76], (Et0)2P(0)CN [77], Et AlCN [78], BUjSnCN [79], MeCOCN [80], K [Ee-(CN)g] [81], and acetone cyanohydrin [82]. Although TMSCN has been the most widely used in the Strecker reaction, this often requires a Brpnsted or Lewis acids or bases as catalysts [83]. 

Due to the high price of trimethylsilyl cyanide, access to alternative cyanation reagents is desirable. In this regard, cyanoformate esters (CNCO2R) have been employed, providing direct access to O-alkojycarbonyl-functionalised cyanohydrins, which are stable and not easily hydrolysed by moisture in air. Moreover, they are useful synthetic intermediates and can be applied in the synthesis of a-amino alcohols and (3-substituted unsaturated nitriles from O-carbonylated allylic cyanohydrins. ... 

Optically active cyanohydrins can be easily transformed to P-hydroxy amines, a-hydroxy and a-amino carboxylic acids, which represent versatile intermediates for the synthesis of biologically important compounds, including insecticides and medicines [189, 190]. Asymmetric cyanation of carbonyl compounds catalyzed by chiral metal complexes, particularly titanium compounds, has provided one of the most convenient protocols to the access of these type of compounds. The first example of catalytic asymmetric cyanation of aliphatic aldehydes was realized in Reetz s group using BINOL-Ti complex as the catalyst to give the cyanohydrins in up to 82% ee [104] (Scheme 14.85). 

In the cyanation of carbonyl compounds, the common practice is the use of TMSCN or hydrogen cyanide (HCN) as the nucleophile. Unfortunately, TMSCN is expensive and HCN is extremely toxic. Development of the method for asymmetric synthesis of cyanohydrin derivatives from carbonyl compounds using inexpensive and nonvolatile cyanide source would be highly advantageous. Belokon and North... 

Asymmetric phase-transfer catalytic addition of cyanide to C=N, C=0, and C=C bonds has been recently explored, which has been demonstrated to be an efficient method toward the synthesis of a series of substituted chiral nitriles. In this context, Maraoka and coworkers disclosed an enantioselective Strecker reaction of aldimines by using aqueous KCN [140]. In this system, the chiral quaternary ammonium salts (R)-36e bearing a tetranaphthyl backbone were found to be remarkably efficient catalysts (Scheme 12.25). Subsequently, this phase-transfer-catalyzed asymmetric Strecker reaction was further elaborated by use of a-amidosulfones as precursor of N-arylsulfonyl imines. Interestingly, the reaction could be conducted with a slight excess of potassium cyanide [141] or acetone cyanohydrin [40] as cyanide source, and good to high enantioselectivities were observed. In contrast, the asymmetric phase-transfer-catalytic cyanation of aldehydes led to the cyanation products with only moderate enantioselectivity [142]. 

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