Cyanohydrins, from aldehydes

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. ... 

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). 

The formation of unsaturated cyanohydrins (from a, -unsaturated aldehydes) is of further advantage as these products possess an additional synthetic potential. As in the saturated cyanohydrins (above in Scheme 6) they possess the same opportunities for elaboration of the hydroxyl or nitrile moiety, although the presence of the carbon-carbon double bond offers the possibility for additional transformations to be performed such as additions [108], oxidative cleavage [117,118] and epoxidation [119] (Scheme 7). Thus, these highly functionalised chiral units can be of greater importance to an organic chemist. 

Oxazoles from the condensation of equimolar amounts of aldehyde cyanohydrins and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid. 

The benzaldehydes (23-27) were chosen in order to attain similar reactivities in the cyanohydrin reactions, and thus securing sufficiently unbiased, isoenergetic dynamic systems. The rates of the individual reactions of these benzaldehydes were further investigated by H-NMR, indicahng the establishment of individual aldehyde-cyanohydrin equilibria within 30 minutes. Under these conditions, the complete dynamic cyanohydrin system generated from cyanide and benzaldehydes (23-27) then reached... 

This process presents a typical procedure applicable to preparation of cyanohydrins from ketones and aldehydes of low reactivity. l-Cyano-6-methoxy-3,4-dihydronaphthalene is useful as an intermediate for synthesis of polycyclic compounds. 

The chiral titanium reagent preparerd in situ from the chiral 1,4-diol and dichlorodiisopropoxytitanium is expected to be applicable to various reactions catalyzed by Lewis acids. We, therefore, investigated the asymmetric synthesis of cyanohydrins from aldehydes and cyanotrimethylsilane employing the chiral titanium reagent.(20)... 

The original Strecker procedure is the reaction of an aldehyde with ammonia and then with hydrogen cyanide to form the a-amino nitrile. This intermediate may also be obtained by reacting the aldehyde cyanohydrin with ammonia, but a more convenient method is to treat the aldehyde in one step with ammonium chloride and sodium cyanide. The a-amino acid is obtained when the amino nitrile is hydrolysed under either acidic or basic conditions the former are usually preferred. The preparation of a-phenylglycine (R = Ph) from benzalde-hyde is typical of the general procedure (cognate preparation in Ept 5.181). 

Oxynitrilase (Hydroxy Nitrile Lyase, HNL) Cyanohydrins from Aldehydes... 

Figure 7.8 a) Enzymatic (oxynitrilase-catalyzed) formation of cyanohydrins from aldehydes, b) Chemical hydrolysis of cyanohydrins to hydroxy acids. 

Many enzymes are both active and stable in carbon dioxide and have been used to conduct a number of reactions. Several different types of reactions have been examined, including hydrolysis (Lee et al., 1993 Randolph et al., 1985 Zheng and Tsao, 1996), oxidation (Hammond et al., 1985 Randolph et al., 1988), and esterification/transesterification (Kamihira et al., 1987 Nakamura et al., 1986 Rantakyla and Aaltonen, 1994), but there are other types of reactions that would make worthwhile investigations in carbon dioxide. These include preparation of amides, reduction of ketones, preparation of cyanohydrins from aldehydes, aldol reactions, hydroxylation reactions, and Baeyer-Villiger oxidation. 

What procedure is available for preparing an a-hydroxy acid. Answer The hydrolysis of a cyanohydrin from an aldehyde or ketone wili yield an a-hydroxy acid. 

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-... 

Reay, PP. and Gonn, E.E. (1974) The purification and properties of a uridine diphosphate glucose aldehyde cyanohydrin (3-glucosyltransferase from sorghum seedlings. Arch. Biochem. Biophys., 249, 5826-30. 

Quite often, the bisulfite product is isolated and purified before the treatment with alkali cyanide, particularly in the conversion of aromatic aldehydes since their bisulfite compounds are easily manipulated. The preparation of aromatic cyanohydrins from their bisulfite products is advantageous since benzoin formation, which is catalyzed by alkali cyanides, is largely avoided. Furthermore, because of the basic environment, hydrogen cyanide fumes are curtailed. 

Early preparations of the product from benzil, hydrogen cyanide, and hydrogen chloride (315) and by the action of hydrogen chloride on mandelonitrile (benz-aldehyde cyanohydrin) (316) were formulated by Japp and Knox (317) as 3-hydroxy-2,5-diphenylpyrazine, and a mechanism for the reaction was proposed by Ingham (318). The structure of the product, however, has been refuted by Gallagher et al. (282). 

The preparations of hydroxypyrazines by primary syntheses have been described in Chapter II, and are summarized briefly, together with further data, as follows Section II.IG, from the reaction of a, 3-dicarbonyl compounds with ammonia [282 (cf. 281, 280), 283, 285] with additional information (1042, 1043) Section II.IM, from 1,2-dicarbonyl compounds with a-amino acids (311) Section II.IN, from a-amino acids through piperazine-2,5-diones (93,95,101,282,312,313)with additional data (843) Section 11.10, from aldehyde cyanohydrins ( ) [317-319 (cf. 282)1 and Section II.IP, from o-nitromandelonitrile and ethereal hydrogen cyanide (325). The preparations from a,iJ-dicarbonyl compounds with a,/ -diamino compounds are described in Section 11.2 (60, 80, 358, 359, 361-365b, 365d, 366-375) additional data have also been reported (824, 825, 827,845,846,971, 1044, 1045) and some reaction products have been isolated as the dihydro-pyrazines (340,341,357). 

The mechanism of the benzoin condensation, as depicted in Scheme 1, suggested that anions derived from a protected aldehyde cyanohydrin should function as nucleophilic acylating reagents. The use of protected cyanohydrins as carbanion equivalents has been studied by Stork and by Hunig and has found wide applicability in chemical synthesis. Such species may serve as either acyl anion equivalents or homoenolate anions. ... 

Chiral cyanohydrins of ketones are prepared from aldehyde cyanohydrins by reaction with 18 and alkylation of the phosphoryl derivatives. ... 

Cyanohydrination. Chemoselective formation of cyanohydrins from aldehydes in the presence of ketones is achieved in water using McjSiCN as donor and 30 mol% of InFj as catalyst. 

Lipases have been used to effect the enantioselective esterification of cyanohydrins or the enantioselective hydrolysis of cyanohydrin esters. This works for aldehyde cyanohydrins. Selective (S)-cyanohydrin esterification is effected by the enzyme from Pseudomonas sp. [11], There is also an example of selective (R)-cyanohydrin esterification by Candida cylindracea lipase [12]. Effenberger has shown the feasibility of this approach in principle to produce a number of enantiopure cyanohydrins derived from aldehydes. In situ derivatization with racemization as shown in Fig. 7 is possible, resulting in theoretically 100% yield of the desired enantiomer [13]. Ketone cyanohydrins, which are tertiary alcohols, do not easily undergo this reaction. 

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