Cyanohydrin from carbonyl compounds

Cyanohydrins from carbonyl compounds and hydrogen cyanide (9.10)... 

Cyano groups are readily introduced via the formation of cyanohydrins from carbonyl compounds. However, the nitrile group of a cyanohydrin has quite a different electronic environment from that in... 

The formation of hydantoin (2) from carbonyl compound 1 with potassium cyanide and ammonium carbonate or from cyanohydrin 3 and ammonium carbonate is referred to as... 

Formation of hydantoins from carbonyl compounds with potassium cyanide (KCN) and ammonium carbonate [(NH4)2C03] or from cyanohydrins and ammonium carbonate. It belongs to the category of multiple component reaction (MCR). 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

The synthesis of a-hydroxy acids from carbonyl compounds by way of the cyanohydrin was an early discovery in organic chemistry. In 1867 Simpson and Gautier, working in Wurtz laboratory, described the cyanohydrin from acetaldehyde and hydrocyanic acid, and its conversion to racemic lactic acid by strong hydrochloric acid. 

If one of the heteroatoms is present as an OH group then only one nucleophile is involved and molecules such as cyanohydrins (7) are obviously made from carbonyl compounds and HCN. Hence hydroxy amine (8), needed for a ring expansion (see Chapter 30), can be made by reduction of (9) (see Chapter 8) and hence from cyclohexanone. 

Cyanohydrins are usually prepared from carbonyl compounds and a cyanide source. Initially performed with volatile and very toxic hydrogen cyanide, the reaction is now carried out with safer cyanide agents, such as acetone cyanohydrin, acyl cyanides, cyanoformates or the most used trimethylsilyl cyanide. In terms of atom economy, this reaction is 100% atom efficient and is widely used despite the toxicity of the reagents. The asymmetric reaction can now be efficiently catalysed by a variety of chiral Lewis acids, and a recent review presents in detail the work realised in this field, with a large description of titanium-based catal)dic systems. 

Preparation of hydantoin from carbonyl compounds by reaction with potassium cyanide and ammonium carbonate, or from the corresponding cyanohydrin and ammonium carbonate ... 

In the cyanation of carbonyl compounds, the common practice is the use of TMSCN or hydrogen cyanide (HCN) as the nucleophile. Unfortunately, TMSCN is expensive and HCN is extremely toxic. Development of the method for asymmetric synthesis of cyanohydrin derivatives from carbonyl compounds using inexpensive and nonvolatile cyanide source would be highly advantageous. Belokon and North... 

Trimethylsilyl cyanohydrin ethers are obtained from carbonyl compounds and cyanotrimethylsilane (Scheme 4.3) ... 

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). 

Table 3. Equilibrium Constants for Formation of Cyanohydrins from Hydrogen Cyanide Plus Carbonyl Compounds ...

Production of cyanohydrins is accompHshed through the base-cataly2ed combination of hydrogen cyanide and the carbonyl compound in a solvent, usually the cyanohydrin itself (17). The reaction is carried out at high dilution of the feeds, at 10—15°C, and pH 6.5—7.5. The product is continuously removed from the reaction 2one, cooled to push the equilibrium toward cyanohydrin formation, and then stabili2ed with mineral acid. Purification is usually effected by distillation. 

Racemic hydantoins result from the reaction of carbonyl compounds with potassium cyanide and ammonium carbonate or the reaction of the corresponding cyanohydrins with ammonium carbonate (Bucherer-Bergs reaction). Hydantoins racemize readily under basic conditions or in the presence of hydantoin racemase, thus allowing DKR (Figure 6.43). Hydantoinases (EC 3.5.2.2), either isolated enzymes or whole microorganisms, catalyze the hydrolysis of five-substituted... 

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). 

Carbonyl compounds (5 g) were taken in appropriate solvent (DIPE, TBME or DBE, 50 mL) saturated with 5 mL of citrate buffer (pH 4.0). A solution of partially purified (/f)-HNL from kernels of P. mume (50 U mmol of substrate) followed by acetone-cyanohydrin (1.5 equiv) was added to the reaction mixture. 

We have found a new (/ )-hydroxynitrile lyase from Japanese apricot (P. mume). The new enzyme accepts a broad array of substrates, ranging from aromatic, heteroaromatic, bicyclic to aliphatic carbonyl compounds, and yields the corresponding cyanohydrins with excellent enantioselection. 

It will destabilise the carbonyl compound a lot, and have very little effect on the product it will therefore push the equilibrium over to the cyanohydrin side. Consider cyanohydrin formation from ... 

Since tJtiis reaction is an equilibrium, the amount of cyanohydrin formed from any given carbonyl compound will depend on the relative stabilities of the carbonyl compound itself and the product. There can be many substituents X on a carbonyl compound R.CO.X, such as Cl, Me, NH2, Ph, OEt, H. Some have inductive effects, some conjugate with the carbonyl group. Some stabilise RCOX making it less reactive. Others activate it towards nucleophilic attack. Arrange the compounds RCOX, where X can be the substituents listed above, into an order of reactivity towards a nucleophile. 

Cyanohydrins should be stabilized with acid to pH 3-4 to prevent decomposition 10 hydrogen cyanide and carbonyl compound. When cyanohydrins are shipped, steel drums, carboys, tank cars, and barges are used. In general, cyanohydrins are combustible liquids and many decompose upon heating. They should be stored in a cool, dry place, preferably outside and separated from other storage. Containers should be protected against physical damage. 

Cyanation of carbonyl compounds has one of the richest histories of any transformation in the field of asymmetric catalysis, and intensive research efforts have continued unabated since the editorial deadline for the first edition of Comprehensive Asymmetric Catalysis in 1998. This chapter will summarize all efforts in this area from 1998 to date, highlighting the most important catalytic systems from a synthetic and/or mechanistic standpoint. Significant advances in both the cyanation of aldehydes (formation of secondary cyanohydrins Section 28.2.1) and the cyanation of ketones (formation of tertiary cyanohydrins Section 28.2.2) will be addressed [1,2]. 

In asymmetric syntheses, the bulky (i-Pr)3Si group can direct 1,2-addition of phosphite 92 to (S j-triisopropylsilyloxy lactaldehyde (93) to afford adduct 94 preferentially along with the by-product 95 (equation 42)157. The stereochemical outcome results from the bulk of the (i-Pr)3Si protecting group9. Furthermore, the steric congestion in allylic cyanohydrin trimethylsilyl and ferf-butyldimethylsilyl ethers influences their regioselective 1,2- and 1,4-additions to carbonyl compounds under basic conditions158. 

Fig. 9.9. Formation of cyanohydrin or a-aminonitrile from a carbonyl compound, ammonium chloride and sodium cyanide a matter of reaction time. The formation of the cyanohydrin proceeds fast and reversibly, that of a-aminonitrile slowly and irreversibly.

The duration of the reaction time alone determines whether carbonyl compounds, sodium cyanide and ammonium chloride will generate a cyanohydrin (Figure 9.9, top) or an a-aminonitrile (Figure 9.9, bottom). We are already familiar with the first reaction pattern from the initial reaction of the three-step Kiliani-Fischer synthesis of aldoses (Figure 7.15). The second reaction pattern initiates the Strecker synthesis of a-amino acids, which is completed by a total hydrolysis of the C=N group, as in the Bucherer modification discussed elsewhere (Figure 7.11). 

Htinig and coworkers found that carbanion 290 which is derived from O-trimethylsilyl-cyanohydrin reacted with carbonyl compounds to afford the corresponding a-siloxyketones through a 1,4-silyl migration (equation 181)440-442. 

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