Hydroxy nitriles from ketones

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). 

The cyanohydrin synthesis of a-hydroxy acids is very often carried out without isolation or purification of the cyanohydrins. The various techniques for the preparation of the cyanohydrins are discussed elsewhere (method 390). Hydrolysis to the a-hydroxy acids is usually effected by heating with concentrated hydrochloric acid. Excellent directions are given for mandelic acid (52% over-all from benzaldehyde), a-methyl-a-hydroxybutyric acid (65% from methyl ethyl ketone), and eighteen dialkyl- and alkylphenyl-glycolic acids (60-80%). Sodium hydroxide solution is used in the preparation of /S-hydroxypropionic acid from the /S-hydroxy nitrile (80%). ... 

Likewise, intermolecular reactions are possible and lead to coupling products which correspond retrosynthetically to the addition of an acyl anion synthon to a ketone. The presence of a proton-donor cosolvent is crucial, otherwise j8-hydroxy nitriles are formed preferentially. The nitrile addition reaction proceeds with good stereoselectivity, e.g. preferentially one diastereoisomer is formed from the electro-reductive addition of acetonitrile (which can advantageously be used as solvent) to dihydrocarvone. 

The hydroxy acids obtained from aldehydes will contain the group,. —CH(OH) —COOH, and are thus secondary alcohols while those obtained from ketones will contain the group, =C(OH) —COOH, and are tertiary alcohols. These reactions are of especial importance in connection with the poly-hydroxy aldehydes and ketones, which, as we shall find, are the sugars. The cyan hydrines, or hydroxy acid nitriles, which are the intermediate products in these reactions, are not isolated as such, the reaction being completed without interruption. 

From To — Akanes CycJoaikanes Akenes Akynes Aryls Halogen compounds Alcohols Phenols Ethers, Quinones B, 5 and Si compounds P and BI compounds Nttro. Nitroso, Azo. Azoxy, Hydrazo Azides Amines Organometahic compounds Adehydes Ketones Acids. AnHyd rides. Esters Amides, Amidines. Nitriles Hydroxy-aldehydes or -ketones. Sugars. Hydroxy acids Ammo acids. Peptides Heterocycles Nucleosides Miscellaneous, including heterocycles... 

New routes to bases of the emetine type have been developed. In one, ( )-protoemetine (118) has been prepared by the reduction of the jS-hydroxy-nitrile (117) with lithium di-isobutylaluminium hydride, (117) being obtained from the known ketone (116) by a Reformatsky-type reaction. 

Hydroxy-ester enolates are oxidized by iodine at — 78°C to give the least hindered oxiran. Thus, by generating the /3-hydroxy-ester from a ketone and acetate enolates, the overall conversion represents a stereoselective Darzens condensation. Glycidic esters can also be obtained from the corresponding nitriles via iminoether derivatives prepared by alkoxide-catalysed addition of alcohols to the nitrile group. 

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.). 

The reaLUons of phenyltetrafluorophosphorane with numerous silylated secondary or tertiary a- or (1-hydroxy esters, ketones, nitriles, ethers, nitro, and trichloromethyl derivatives have been investigated, the corresponding a or p fluoro derivatives are obtained in yields varying from reasonable to nearly quantitative [24, 25, 26, 27 The application of phenyltetrafluorophosphorane for fliiorination of silyloxy steroids has also been reported [28]... 

The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane, provides 9,ll-ethano-13,15-isoxazolinoprostanoids, PGH analogs, with alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (461). Chemical transformations of 9,11-ethano-13,15-isoxazolinoprostanoids furnish prostanoids with bifunctional fragments of P-hydroxyketone and a-aminoalcohol in the oo-chain. The reaction of P-hydroxy ketones with methanesulfonyl chloride gives rise to prostanoids with an enone component in the oo-chain. 9,ll-Ethano-16-thiaprostanoids have been prepared, for the first time, by nucleophilic addition of thiols to the polarized double bond in the oo-chain. The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane provides 9,ll-ethano-13,15-isoxazolinoprostanoids with an alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (462). 

Chiral cyanohydrins are versatile intermediates in the synthesis of a-hydroxy acids, /3-amino alcohols, amino nitriles, a-hydroxy ketones and aziridines. For the synthesis of enantiopure cyanohydrins, the use of hydroxynitrile lyases is currently the most effective approach.Application of an organic-solvent-free system allows thermodynamically hindered substrates to be converted with moderate to excellent yields. With the use of the highly selective hydroxynitrile lyase from Manihot esculenta, the syntheses of several acetophenone cyanohydrins with excellent enantioselectivities were developed (Figure 8.2). (5)-Acetophenone cyanohydrin was synthesized on a preparative scale. ... 

Add 0.4 g of powdered, anhydrous zinc chloride to a solution of 1.1 g of anhydrous phloroglucinol in 25 ml of sodium-dried ether, and introduce the nitrile (0.01 mol) dissolved in 5 ml of dry ether. Pass a steady stream of dry hydrogen chloride through the solution for 25-30 minutes it becomes turbid after 2-3 minutes but the turbidity subsequently disappears. Decant the supernatant liquid, dissolve the residual oil or crystals in 25 ml of water and shake the aqueous solution with two 20 ml portions of ether. Concentrate the aqueous layer to about 10-12 ml. The hydroxy ketone separates upon cooling recrystallise it from hot water and dry in the air. The hydrate is thus produced. 

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