Cyanohydrin ether alkylation

Cyclic cyanohydrin ethers, 6-alkyl-2,2-dimethyl-l,3-dioxane-4-carbonitriles 1, are easily available from silylated aldols. Deprotonation of 1 and subsequent alkylation gives, v+ -4,6-disubsti-tuted 2,2-dimethyl-l,3-dioxane-4-carbonitriles 2 in good yields in a highly diastereoselective reaction48. Primary bromoalkanes and oxiranes have been used as alkylating reagents. Reduction of the alkylation products 2 afforded the protected, vj. -l,3-diols 3 with complete retention of configuration (see Section D.2.I.). 

Heteroatom-stabilized Carbanions. Heteroatom-stabilized and allylic carbanions serve as homoenolate anions and acyl anion equivalents, e.g. a-anions of protected cyanohydrins of aldehydes and Q ,/3-unsaturated aldehydes are intermediates in general syntheses of ketones and Q ,/3-unsaturated ketones (eq 36). Allylic anions of cyanohydrin ethers may be a-alkylated (eq 37) or, if warmed to —25°C, may undergo 1,3-silyl migration to cyanoenolates which may be trapped with TMSCl. Metalated Q -aminonitriles of aldehydes are used for the synthesis of ketones and enamines (eq 38). Similarly, allylic anions from 2-morpholino-3-alkenenitriles undergo predominantly a-C-alkyl-ation to give, after hydrolysis, a,/3-unsaturated ketones (eq 39). ... 

Higher substituted cyanohydrines e.g. 303 for insecticidally inactive esters may be obtained by a-alkylation of cyanohydrine ethers 302 [656] (Reaction scheme 214). 

Butadienyl sulphoxides act as excellent Michael acceptors for nucleophilic acylating agents, particularly lithiated cyanohydrin ethers." The resulting allylic anions may be alkylated, and simple hydrolyses complete an efficient synthesis of dienones [equation (30)]. 

This form of protection is advantageous for aldehydes, because the trimethylsilyl cyanohydrin ethers of aldehydes present a reactive hydrogen atom on the a carbon. This hydrogen can be replaced with lithium, after which the compound may be converted to a ketone by reaction with an alkyl halide, or it may be converted to an a-hydroxyketone by reaction with another aldehyde or ketone (Scheme 4.4) ... 

Conversion of aldehydes to ketones via cyanohydrin derivatives (ethers) by alkylation or Michael addition also used with sdyl ethers, dialtylamlnonitnies (see also Stetter reaction). 

Scheme 9). Although cyanohydrin acetonide 64 could conceivably have been used, the silyl ether 75 was chosen. This compound is readily available from (l)-malic acid, and can undergo electrophilic activation under far more mild conditions than compound 64. Alkylation of the 1,3-diol synthon 75 with bromide 76 created the C11-C26 framework of roflamycoin, in 85% yield. A two-step conversion of the terminal siloxy group to the primary iodide (78) proceeded in 80% overall yield. 

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. 

OL-Keto esters. The cyanohydrin silyl ether < 1) of methyl glyoxylate (4, 542-543 5, 720) can be converted by alkylation of the anion into the enol acetate (2) of a-keto esters. 

A recent variation of this strategy is due to Ziegler, who used TMS ethers of cyanohydrins of (x, -unsaturated aldehydes as substrates. Alkylation with an allylic halide, such as crotyl bromide in equation... 

Acid-catalyzed addition of aliphatic, aromatic or heteroaromatic cyanohydrins to ethyl vinyl ether, n-butyl vinyl ether or dihydro-4//-pyran provides base stable, protected cyanohydrin derivatives. Phase transfer catalyzed alkylation of aliphatic cyanohydrins with allylic bromides gave a-substituted a-allyl-oxyacetonitrile. Carbonyl compounds react wiA cyanide under phase transfer catalysis to give cyanohydrin anions, which are trapped by an acyl chloride or ethyl chloroformate to give acyl- or alkoxycarbonyl-protected cyanohydrins respectively. The reduction of the carbonyl group of an acyl cyanide by NaBH4 under phase transfer conditions followed by esterification serves as an alternative route to aldehyde-derived cyanohydrin esters. ... 

Masked formyl cyanides such as cyanohydrin alkyl ethers of formyl cyanide are also applicable to the aldol reaction. Palladium complexes, especially Pd2(dba)3-CHCl3, show high catalytic activities for the additions to aldehydes (Eq. 66) [136]. 

Dehydration over catalytic surfaces produces ethers. Substitution of alkyl hydrogen atoms may occur in alcohols without affecting the hydroxyl functional group, resulting in formation of products such as chlorohy-drins and cyanohydrins. 

A number of methods for the generation of acyl anion equivalents from aldehydes have been developed. Related to the benzoin condensation, aldehyde cyanohydrins, protected as their ether derivatives, are readily transformed into anions by treatment with lithium diisopropylamide (LDA). Reaction with an alkyl halide gives the protected cyanohydrin of a ketone from which the ketone is liberated easily. Reaction with an aldehyde or ketone leads to the formation of an a-hydroxy ketone (1.109). ... 

KHMDS has been used to effect a-deprotonation of O-sUyl protected cyanohydrins derived from 2-/7-tolylsulfinyl henzalde-hyde followed by trapping of the C-nucleophile with diverse C-electrophiles, providing a powerful alternative approach to cyanohydrins of ketones. The remote 1,4-asymmetric induction was equally effective for either epimer (diastereomer) of the 0-TIPS protected cyanohydrin, and an equimolar mixture of the two epimers was employed. Both KHMDS and LHMDS bases provided the substituted cyanohydrins from reactions with highly reactive electrophiles (ClCOOMe and ClCOMe) in excellent yields and diastereoselectivities (dr > 98 2) (eq 65). The deprotonation induced by KHMDS led to more reactive nucleophiles, shortening the reaction times. Notably, in alkylations of Eschen-moser s salt, and benzyl and allyl bromides, the application of LHMDS instead of KHMDS improved the diastereoselectivity. The stereoselectivity of the alkylations mediated by KHMDS could be increased by the inclusion of the 18-crown-6 ether... 

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