Cyanohydrins, preparation

DiaminO 4,4-dimethyl-l,3,5-thiadiazine hydrobromide was isolated as by-product (418). Benzene sulfonates of cyanohydrin prepared from sodium cyanide and an halobenzoaldehyde, when treated with thiourea or its derivatives, afford 2,4-diamino-5-(p-halogenophenyl)-thiazole benzene sulfonates (447). Similarly, cyanoamido thiocarbamates obtained from cyanamide and isothiocyanates yield substituted 2,4-diaminothiazoles (598). 

Protected cyanohydrins may be employed as acyl anion equivalents in 1,4-additions in the presence of HMPA129. For instance cyanohydrins prepared from arylaldehydes add in a 1,4-fashion under thermodynamic control (THF or THF/HMPA) to cyclohexenone, isophorone and decalone systems in the latter case c/.s-octahydro-2(l/f)-naphthalenones are exclusively obtained 130-131. 

Bitter almonds contain amygdalin, which is the P-D-glucoside of prunasin, so it hydrolyses sequentially to the same products. Cassava, which is used in many parts of the world as a food plant, contains linamarin, which is the P-D-glucoside of acetone cyanohydrin. Preparation of the starchy tuberous roots of cassava for food involves prolonged hydrolysis and boiling to release and drive off the HCN before they are suitable for consumption. 

The efficiency of the amination methodology of enolates with 0-phoshinylhydroxyl-amine-type reagents was further demonstrated by Boche and Schrodt in the high-yield amination of 0-(trimethylsilyl)cyanohydrin anions with 4c (Scheme 44)". 0-(Trimethyl-silyl)cyanohydrins prepared by treatment of aryl, hetaryl and conjugated aldehydes with trimethylsilyl cyanide were lithiated to the eniminates. This is a practical method that enables the easy conversion of aldehydes to iV,Ai-dimethylamides under mild conditions. 

Scheme 6.84 Typical silylated cyanohydrins prepared from various ketones under asymmetric 72-catalysis (cyanosilylation).

Scheme 6.95 TMS-protected cyanohydrins prepared from the cyanosilylation of aidehydes in the presence of atropoisomeric thiourea catalyst (aR/aR)-(R,R)-ZZ. Desilylation and acetylation to the respective more stable acetates.

F. Effenberger, T. Ziegler, and S. Foerster, Enzyme-catalyzed cyanohydrin preparation in organic solvents, Angew. Chem. 1987, 99, 491-492. 

In summary, much information has been gathered by different methods, but there is still room for improvement of the substrate spectrum of the diketopiperazine catalyst 1 and for detailed understanding of the mechanism - and thus predictability - of this fairly complex heterogeneous catalyst system. Nevertheless, enantiomerically pure cyanohydrins - prepared with the aid of 1 - have already been used for synthesis of several natural product (and other) target molecules... 

Hydrolysis of the nitrile group in a cyanohydrin, prepared by addition of HCN to an aldehyde or a ketone (Section 17-11), is a general route to 2-hydroxycarboxylic acids, which possess antiseptic properties. 

The NHase and amidase were largely nonselective for cyanohydrins and the corresponding 2-hydroxy amides, respectively, but they were suitable for the hydrolysis of enantiopure cyanohydrins prepared from aldehydes and HCN by oxynitrilases [89, 90]. The cascade of NHase and amidase, in which the latter enzyme catalyzed an acyl transfer reaction, was suitable for the preparation of... 

Recovery yield of crude cyanohydrin, preparative scale. 

U8 C, (-l-)-or (-)- m.p. 133X. Occurs combined in the glucoside amygdalin. Prepared by hydrolysis of mandelonitrile (ben-zaldehyde cyanohydrin). It is administered in large doses in the treatment of urinary infections. 

CHi=CMeCOOH. Colourless prisms m.p. 15-16 C, b.p. 160-5 C. Manufactured by treating propanone cyanohydrin with dilute sulphuric acid. Polymerizes when distilled or when heated with hydrochloric acid under pressure, see acrylic acid polymers. Used in the preparation of synthetic acrylate resins the methyl and ethyl esters form important glass-like polymers. 

Mandelic acid. This preparation is an example of the synthesis of an a-hydroxy acid by the cyanohydrin method. To avoid the use of the very volatile and extremely poisonous hquid hydrogen cyanide, the cyanohydrin (mandelonitrile) is prepared by treatment of the so um bisulphite addition compound of benzaldehj de (not isolated) with sodium cyanide ... 

The addition of hydrogen cyanide is catalyzed by cyanide ion but HCN is too weak an acid to provide enough C=N for the reaction to proceed at a reasonable rate Cyanohydrins are therefore normally prepared by adding an acid to a solution containing the carbonyl compound and sodium or potassium cyanide This procedure ensures that free cyanide ion is always present m amounts sufficient to increase the rate of the reaction... 

Nitrile groups m cyanohydrins are hydrolyzed under conditions similar to those of alkyl cyanides Cyanohydrin formation followed by hydrolysis provides a route to the preparation of a hydroxy carboxylic acids... 

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... 

Section 20 18 Nitnles are prepared by nucleophilic substitution (8 2) of alkyl halides with cyanide ion by converting aldehydes or ketones to cyanohydrins (Table 20 6) or by dehydration of amides... 

Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

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. 

High yields of optically active cyanohydrins have been prepared from hydrogen cyanide and carbonyl compounds using an enzyme as catalyst. Reduction of these optically active cyanohydrins with lithium aluminum hydride in ether affords the corresponding substituted, optically active ethanolamine (5) (see Alkanolamines). 

Nitrilotriacetonitrile [628-87-5], N(CH2CN)2, a precursor to nitrilotriacetic acid [139-13-9], N(CH2COOH)2, can be prepared from the reaction of formaldehyde cyanohydrin with ammonia (26). Formaldehyde cyanohydrin is also used as an intermediate in pharmaceutical production. Commercial formaldehyde cyanohydrin is available as a 70% aqueous solution stabiLhed by phosphoric acid. 

Like the formation of a-cyanohydrins, this reaction is catalyzed by bases or cyanide ion, but unlike the a-cyanohydrin case this reaction is not reversible, and under certain conditions it can proceed with violence. Ethylene cyanohydrin can also be prepared by the reaction of ethylene chlorohydrin and alkaH cyanides (39). 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

R3SiCl, KCN, Znl2, CH3CN, 86-98% yield. This method was used to prepare the r-BuPH2, /-BuMe2Si, and /-Pr3Si cyanohydrins. 

The ethoxyethyl cyanohydrin was prepared (NaCN, HCl, THF, 0°, 75% yield, followed by EtOCH=CH2, HCl, 50% yield) to convert an aldehyde ultimately to a protected ketone. It was cleaved by hydrolysis (0.01 N HCl, MeOH, 25°, followed by NaOH, 0°, 85% yield). ... 

The tetrahydropyranyl cyanohydrin was prepared from a steroid cyanohydrin (di-hydropyran, TsOH, reflux, 1.5 h) and cleaved by hydrolysis (cat, coned. HCl, acetone, reflux, 15 min, followed by aq. pyridine, reflux, 1 h)."... 

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... 

The in situ cyanosilylation of p-an1saldehyde is only one example of the reaction which can be applied to aldehydes and ketones in general. - The simplicity of this one-pot procedure coupled with the use of inexpensive reagents are important advantages over previous methods. The silylated cyanohydrins shown in the Table were prepared under conditions similar to those described here. Enolizable ketones and aldehydes have a tendency to produce silyl enol ethers as by-products in addition to the desired cyanohydrins. The... 

Semicarbazones can be prepared from 17-ketones by the conventional procedure. The formation of 17-cyanohydrins by exchange with acetone cyanohydrin and the use of this protective group has been already discussed (see section II-A-2). ... 

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