Cyanohydrins of aldehydes

In 1971 Stork and Maldonado214 showed that anions derived from 0-pro tec ted cyanohydrins of aldehydes could be efficiently metallated and the resultant anions could serve as synthetically useful acyl anion equivalents. Other develop-... 

The synthesis of a drug using a dithian as an acyl anion equivalent Dithioacetal monoxides Protected Cyanohydrins of Aldehydes... 

Cyclopropanone and cyclobutanone cyanohydrins. Stork has extended his synthesis of ketones from protected cyanohydrins of aldehydes (equation I) to a synthesis of cyclic ketones, in particular, cyclopropanone and cyclobu-... 

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). ... 

Stork has demonstrated that the readily available protected cyanohydrins of aldehydes are useful acyl carbanion equivalents, and has now applied these in the preparation of small rings. Treatment of the ethoxyethyl-protected cyanohydrin of 4-chlorobutyraldehyde (17) with sodium hexamethyldisilazide gives the cyclo-butanone cyanohydrin derivative (18) in high yield. The cyanohydrin derivative is easily hydrolysed to the ketone, or may be reduced with lithium aluminium hydride to the P-amino-ether (19), which is also a useful synthetic intermediate. 

Nitriles contain the —C=N functional group We have already discussed the two mam procedures by which they are prepared namely the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins Table 20 6 reviews aspects of these reactions Neither of the reactions m Table 20 6 is suitable for aryl nitriles (ArC=N) these compounds are readily prepared by a reaction to be dis cussed m Chapter 22... 

Preparation. The general preparation of y acids is by the hydrolysis of an a-halo acid or by the acid hydrolysis of the cyanohydrins of an aldehyde or a ketone. 

A cyanohydrin is an organic compound that contains both a cyanide and a hydroxy group on an aUphatic section of the molecule. Cyanohydrias are usually a-hydroxy nitriles which are the products of base-cataly2ed addition of hydrogen cyanide to the carbonyl group of aldehydes and ketones. The lUPAC name for cyanohydrias is based on the a-hydroxy nitrile name. Common names of cyanohydrias are derived from the aldehyde or ketoae from which they are formed (Table 1). 

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

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves and by the addition of hydrogen cyanide to silyl enol ethers. Silylated cyanohydrins have proved to be quite useful in a variety of synthetic transformations, including the regiospecific protection of p-quinones, as intermediates in an efficient synthesis of a-aminomethyl alcohols, and for the preparation of ketone cyanohydrins themselves.The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as... 

Cyanohydrin trimethylsilyl ethers are generally useful as precursors of ctir-bonyl anion equivalents and as protected forms of aldehydes. Direct conversion of p-anisaldehyde into 0-TRIMETHYLSILYL-4-METH0XYMANDEL0-NITRILE employs a convenient in situ generation of trimethylsilyl cyanide from chlorotnmethylsilane A general synthesis of allemc esters is a variant of the Wittig reaction. Ethyl (triphenylphosphoranylidene)acetate converts pro-pionyl chloride into ETHYL 2,3-PENTADlENOATE. 

Cyanohydrin formation (Section 17.7) Hydrogen cyanide adds to the carbonyl group of aldehydes and ketones. 

The Fisher oxazole synthesis involves condensation of equimolar amounts of aldehyde cyanohydrins (1) and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid. ... 

In a German patent issued in 1929, Bergs described a synthesis of some 5-substituted hydantoins by treatment of aldehydes or ketones (1) with potassium cyanide, ammonium carbonate, and carbon dioxide under several atmospheres of pressure at 80°C. In 1934, Bucherer et al. isolated a hydantoin derivative as a by-product in their preparation of cyanohydrin from cyclohexanone. They subsequently discovered that hydantoins could also be formed from the reaction of cyanohydrins (e.g. 3) and ammonium carbonate at room temperature or 60-70°C either in water or in benzene. The use of carbon dioxide under pressure was not necessary for the reaction to take place. Bucherer and Lieb later found that the reaction proceeded in 50% aqueous ethanol in excellent yields for ketones and good yields for aldehydes. ... 

A general property of aldehydes and ketones is that when heated with hydrocyanic acid, additive compounds, termed nitriles or cyanohydrins, are produced, according to the general equations—... 

The reaction is an important step in a method for the oxidative decyanation of nitriles containing an a hydrogen. The nitrile is first converted to the a-hydro-peroxy nitrile by treatment with base at — 78°C followed by O2. The hydroperoxy nitrile is then reduced to the cyanohydrin, which is cleaved (the reverse of 16-51) to the corresponding ketone. The method is not successful for the preparation of aldehydes (R =H). 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

Similar reactions were undertaken by Choi et al. in the presence of a new family of A -sulfonylated p-amino alcohols possessing two stereocentres as the chiral ligands. In using the chiral sulfonylated p-amino alcohol ligand depicted in Scheme 10.41, the asymmetric addition of McsSiCN to a wide range of aldehydes afforded the corresponding cyanohydrins in both excellent yields and enantioselectivities of up to 96% ee. 

The reaction of aldehydes with MnOz in the presence of cyanide ion in an alcoholic solvent is a convenient method of converting aldehydes directly to esters.214 This reaction involves the cyanohydrin as an intermediate. The initial oxidation product is an acyl cyanide, which is solvolyzed under these reaction conditions. 

Indeed the only conversion where biocatalysis should be seriously considered is the transformation of aldehydes into optically active cyanohydrins1 2. For example, the conversion of aryl aldehydes into the appropriate (R)-cyanohydrins using almond meal may be accomplished in quantitative yield and gives products... 

Complexation of an amino acid derivative with a transition metal to provide a cyanation catalyst has been the subject of investigation for some years. It has been shown that the complex formed on reaction of titanium(IV) ethoxide with the imine (40) produces a catalyst which adds the elements of HCN to a variety of aldehydes to furnish the ( R)-cyanohydrins with high enantioselectivity[117]. Other imines of this general type provide the enantiomeric cyanohydrins from the same range of substrates11171. 

The production of optically active cyanohydrins, with nitrile and alcohol functional groups that can each be readily derivatized, is an increasingly significant organic synthesis method. Hydroxynitrile lyase (HNL) enzymes have been shown to be very effective biocatalysts for the formation of these compounds from a variety of aldehyde and aliphatic ketone starting materials.Recent work has also expanded the application of HNLs to the asymmetric production of cyanohydrins from aromatic ketones. In particular, commercially available preparations of these enzymes have been utilized for high ee (5)-cyanohydrin synthesis from phenylacetones with a variety of different aromatic substitutions (Figure 8.1). 

In order to generate the dynamic cyanohydrin systems, several cyanide sources can be used, for example, cyanide salts, TMSCN, and cyanohydrin adducts such as acetone cyanohydrin. The latter method represents a means to form cyanohydrin DCLs under mild conditions, where acetone cyanohydrin is treated with amine base to release the cyanide ion together with acetone in organic solvents. The resulting cyanide ion then reacts with the set of aldehydes (or ketones), giving rise to the corresponding cyanohydrin adducts... 

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