Cyanohydrins from cyanide + ketones

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. ... 

Cyanohydrins from the attack of cyanide on aldehydes and ketones... 

Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and agrochemical industries [2-9]. Consequently their enantioselective synthesis has attracted considerable attention (Scheme 5.1). Their preparation by the addition of HCN to an aldehyde or a ketone is 100% atom efficient. It is, however, an equilibrium reaction. The racemic addition of HCN is base-catalyzed, thus the enantioselective, enzymatic cyanide addition should be performed under mildly acidic conditions to suppress the undesired background reaction. While the formation of cyanohydrins from aldehydes proceeds readily, the equilibrium for ketones lies on the side of the starting materials. The latter reaction can therefore only be performed successfully by either bio- or chemo-cat-... 

The second example is the familiar one of cyanohydrin formation from a ketone. The reaction is indeed reversible but in basic solution the cyanide anion is more stable than the oxyanion in the product and the carbonyl group is very stable too. In acidic solution (at pHs less than about 12) the oxyanion will be protonated and the reaction driven over to the right. 

TrialkylsUyl cyanides, which also possess sp C—Si bonds, react with carbonyls. Znh, " AlCb, TMSOTf, LnCb (Ln = La, Ce, Sm), etc., are employed as the promoter, and cyanohydrin silyl ethers are obtained in high yields even from hindered ketones (equation 12). The products are converted to various synthetically important intermediates such as cyanohydrins, a,p-unsaturated nitriles or amino alcohols. 

Methyl nitroacetate sodium cyanide Epimeric cyanohydrins from ketones Carbohydrate derivs. 

The reaction can also be carried out on trimethylsilyl ethers of cyanohydrins, which can be obtained from the ketone and trimethylsilyl cyanide. The cyano ether is reduced to the aminomethylcarbinol by LiAlH4 ... 

A new two-step procedure for the preparation of cyanohydrins from ketones is particularly useful for the synthesis of highly hindered cyanohydrins [equation (38)]. Note that potassium cyanide and trimethylsilyl chloride can be used in place of trimethylsilyl cyanide in the above reaction. ... 

The most common example of the addition of hydrogen cyanide to a double bond is the formation of cyanohydrins from aldehydes and ketones with this reagent. The addition of hydrogen cyanide to olefins and acetylenes is important industrially but requires special equipment and precautions. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Cyanohydrins (qv) are formed by the reaction of glucose and similar compounds with hydrogen cyanide. The corresponding aminonitrile from methyl isobutyl ketone can be formed with ammonia and hydrogen cyanide. 

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). 

Ethylene Cyanohydrin. This cyanohydrin, also known as hydracrylonitnle or glycocyanohydrin [109-78-4] is a straw-colored Hquid miscible with water, acetone, methyl ethyl ketone, and ethanol, and is insoluble in benzene, carbon disulfide, and carbon tetrachloride. Ethylene cyanohydrin differs from the other cyanohydrins discussed here in that it is a P-cyanohydrin. It is formed by the reaction of ethylene oxide with hydrogen cyanide. 

Cyanohydrins are prepared from unsubstituted 20-ketones by the exchange procedure but not in the presence of a diluent. A 17a-hydroxyl group inhibits the exchange reaction but 20-ketones react with potassium cyanide even in the presence of Ha-bromo or 21-acetoxy substituents. 

The formation of adducts of enamines with acidic carbon compounds has been achieved with acetylenes (518) and hydrogen cyanide (509,519,520) (used as the acetone cyanohydrin). In these reactions an initial imonium salt formation can be assumed. The addition of malonic ester to an enamine furnishes the condensation product, also obtained from the parent ketone (350,521). 

Problem 19.5 Treatment of an aldehyde or ketone with cyanide ion (- C=N), followed by protonation of the tetrahedral alkoxide ion intermediate, gives a c)>anohyi1rin. Show the structure of the cyanohydrin obtained from cyclohexanone. 

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