Reaction with cyanohydrins

Table 11.10 Asymmetric catalytic Strecker reaction with cyanohydrin under PTC conditions.

Reaction of cyanohydrins with absolute ethanol in the presence of HCl yields the ethyl esters of a-hydroxy acids (3). A/-substituted amides can be synthesized by heating a cyanohydrin and an amine in water. Thus formaldehyde cyanohydrin and P-hydroxyethylamine lead to A/- (P-hydroxyethyl)hydroxyacetamide (4). 

A" -3-Ketones do not undergo the exchange reaction with acetone cyanohydrin, although the formation of a 3-cyaiiohydrin has been reported by reaction with hydrocyanic acid. ... 

The reaction of 17-keto steroids with hydrogen cyanide (or acetone cyanohydrin) to form a mixture of the 17-cyano-17-hydroxy compounds, followed by dehydration and reaction with methyl Grignard reagent, is one of the earliest methods for the conversion of androstanes to pregnanes. 

The enhanced reactivity of fluoroalkyl ketones is also manifested in the failure to stop the reaction with hydrogen cyanide at the stage of cyanohydrins Instead, oxazohdinones or dioxolanones are formed (equation 11) If, however, the reaction IS conducted under basic conditions with sodium bisulfite and sodium cyanide, the desired cyanohydrin can be prepared [ll ... 

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. ... 

Reaction of cyanohydrin 4 with ammonia leads to formation of a-amino nitrile 2, which can easily be hydrolyzed to give the corresponding a-amino acid 3 ... 

Aldehydes and unhindered ketones undergo a nucleophilic addition reaction with HCN to yield cyanohydrins, RCH(OH)C=N. Studies carried out in the early 1900s by Arthur Eapworth showed that cyanohydrin formation is reversible and base-catalyzed. Reaction occurs slowly when pure HCN is used but rapidly when a small amount of base is added to generate the nucleophilic cyanide ion, CN. Alternatively, a small amount of KCN can be added to HCN to catalyze the reaction. Addition of CN- takes place by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN-. 

Detailed preparation from LiCN (from LiH and acetone cyanohydrin) and TMSC1, followed by its reaction with p-bcnzoquinone in the presence of 18-Crown-6 and KCN. 

The hydrolysis of nitriles to carboxylic acids is one of the best methods for the preparation of these compounds. Nearly all nitriles give the reaction, with either acidic or basic catalysts. Hydrolysis of cyanohydrins, RCH(OH)CN, is usually carried out under acidic conditions, because basic solutions cause competing reversion of the cyanohydrin to the aldehyde and CN . However, cyanohydrins have been hydrolyzed under basic conditions with borax or alkaline borates. ... 

Cyanide and thiocyanate anions in aqueous solution can be determined as cyanogen bromide after reaction with bromine [686]. The thiocyanate anion can be quantitatively determined in the presence of cyanide by adding an excess of formaldehyde solution to the sample, which converts the cyanide ion to the unreactive cyanohydrin. The detection limits for the cyanide and thiocyanate anions were less than 0.01 ppm with an electron-capture detector. Iodine in acid solution reacts with acetone to form monoiodoacetone, which can be detected at high sensitivity with an electron-capture detector [687]. The reaction is specific for iodine, iodide being determined after oxidation with iodate. The nitrate anion can be determined in aqueous solution after conversion to nitrobenzene by reaction with benzene in the presence of sulfuric acid [688,689]. The detection limit for the nitrate anion was less than 0.1 ppm. The nitrite anion can be determined after oxidation to nitrate with potassium permanganate. Nitrite can be determined directly by alkylation with an alkaline solution of pentafluorobenzyl bromide [690]. The yield of derivative was about 80t.with a detection limit of 0.46 ng in 0.1 ml of aqueous sample. Pentafluorobenzyl p-toluenesulfonate has been used to derivatize carboxylate and phenolate anions and to simultaneously derivatize bromide, iodide, cyanide, thiocyanate, nitrite, nitrate and sulfide in a two-phase system using tetrapentylammonium cWoride as a phase transfer catalyst [691]. Detection limits wer Hi the ppm range. 

Attack by eCN is slow (rate-limiting), while proton transfer from HCN or a protic solvent, e.g. HzO, is rapid. The effect of the structure of the carbonyl compound on the position of equilibrium in cyanohydrin formation has already been referred to (p. 206) it is a preparative proposition with aldehydes, and with simple aliphatic and cyclic ketones, but is poor for ArCOR, and does not take place at all with ArCOAr. With ArCHO the benzoin reaction (p. 231) may compete with cyanohydrin formation with C=C—C=0, 1,4-addition may compete (cf. p. 200). 

Those carbonyl compounds for which the equilibrium with HCN does not lie over in favour of cyanohydrin formation may often be converted satisfactorily into a derivative of the cyanohydrin through reaction with Me3SiCN ... 

This reaction of aromatic aldehydes, ArCHO, resembles the Cannizzaro reaction in that the initial attack [rapid and reversible—step (1)] is by an anion—this time eCN—on the carbonyl carbon atom of one molecule, the donor (125) but instead of hydride transfer (cf. Cannizzaro, p. 216) it is now carbanion addition by (127) to the carbonyl carbon atom of the second molecule of ArCHO, the acceptor (128), that occurs. This, in common with cyanohydrin formation (p. 212) was one of the earliest reactions to have its pathway established— correctly —in 1903. The rate law commonly observed is, as might be expected,... 

The reaction of a nitrile with a Reformatsky reagent is known as the Blaise reaction and when applied to (9-trimethylsilyl cyanohydrins leads to the formation of tetronic acids with high ee [79]. By working-up the Blaise reaction with ammonium chloride it is possible to isolate... 

The synthesis of the furan-imidazole derivatives, shown in Scheme 2, were also described by Wang et al. [34]. Reaction of 4-(dimethylamino)benzalde-hyde (20) with trimethylsilylcyanide (TMS)-CN in the presence of Znl2 produced the TMS cyanohydrin 21. Compound 21 was treated with LDA followed by the addition of 3,4,5-trimethoxybenzaldehyde to give the benzoin intermediate 22. Oxidation with CUSO4 in aqueous pyridine, followed by reaction with 3-furaldehyde in acetic acid, produced the substituted imidazole 23. 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

The endo-spiro-OZT could be prepared through a reaction sequence similar to that applied for the exo-epimer, with spiro-aziridine intermediates replacing the key spiro-epoxides (Scheme 18). Cyanohydrin formation from ketones was tried under kinetic or thermodynamic conditions, and only reaction with the d-gluco derived keto sugar offered efficient stereoselectivity, while no selectivity was observed for reaction with the keto sugar obtained from protected D-fructose. The (R) -cyanohydrin was prepared in excellent yield under kinetic conditions (KCN, NaHC03, 0 °C, 10 min) a modified thermodynamic procedure was applied to produce the (S)-epimer in 85% yield (Scheme 18). 

The ACH process has recently been improved, as stated by Mitsubishi Gas. Acetone-cyanohydrin is first hydrolized to 2-hydroxyisobutylamide with an Mn02 catalyst the amide is then reacted with methylformiate to produce the methyl ester of 2-hydroxyisobutyric acid, with coproduction of formamide (this reaction is catalyzed by Na methoxide). The ester is finally dehydrated with an Na-Y zeolite to methylmethacrylate. Formamide is converted to cyanhydric acid, which is used to produce acetone-cyanohydrin by reaction with acetone. The process is very elegant, since it avoids the coproduction of ammonium bisulphate, and there is no net income of HCN. Problems may derive from the many synthetic steps involved, and from the high energy consumption. 

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