Acetone cyanide source

A variety of reaction conditions have been developed for nucleophilic ring opening by cyanide.123 Heating an epoxide with acetone cyanohydrin (which serves as the cyanide source) and triethylamine leads to ring opening at the less-substituted position. 

HCN is the most preferred cyanide source in cyanohydrin synthesis. Besides HCN, several different cyanide sources, like potassium cyanide, are being used in biotransformation. Alternative methods for the safe handling of cyanides on a laboratory scale are, for instance, to use cyanide salts in solution. These solutions can be acidified and used as the aqueous layer in two-phase systems or the HCN can be extracted into the organic layer with the desired solvent for reactions in an organic phase. After the reaction, excess cyanide can readily be destroyed with iron(II) sulfate, or iron(III) chloride or bleach. Cyanide can also be presented in the form of organic cyano, such as acetone cyanohydrin [46] or cyanoformates. However, as claimed by Effenberger, some results could not be reproduced [47]. 

In order to generate the dynamic cyanohydrin systems, several cyanide sources can be used, for example, cyanide salts, TMSCN, and cyanohydrin adducts such as acetone cyanohydrin. The latter method represents a means to form cyanohydrin DCLs under mild conditions, where acetone cyanohydrin is treated with amine base to release the cyanide ion together with acetone in organic solvents. The resulting cyanide ion then reacts with the set of aldehydes (or ketones), giving rise to the corresponding cyanohydrin adducts... 

The conversion of co-hydroxyalkanals to the corresponding cyanohydrins in moderate enantioselectivities could also be accomplished by transhydrocyanation with acetone cyanohydrin as the cyanide source. These substrates are considered difficult because of their high solubility in water. Through the employment of an almond meal preparation in a micro-aqueous organic reaction system, the ee-values could be significantly improved [54]. 

As well as almond meal, Sorghum bicolor shoots have also found application in the synthesis of aromatic cyanohydrins [55]. The enantiomeric purity obtained in transhydrocyanation experiments with acetone cyanohydrin as the cyanide source suffers from the high water content (>14% v/v) necessary for the decomposition of acetone cyanohydrin. In contrast, the application of HCN allows the use of low amounts of water (2% v/v), leading to yields and optical purities comparable with those obtained by the isolated enzymes. 

Initial preparative work with oxynitrilases in neutral aqueous solution [517, 518] was hampered by the fact that under these reaction conditions the enzymatic addition has to compete with a spontaneous chemical reaction which limits enantioselectivity. Major improvements in optical purity of cyanohydrins were achieved by conducting the addition under acidic conditions to suppress the uncatalyzed side reaction [519], or by switching to a water immiscible organic solvent as the reaction medium [520], preferably diisopropyl ether. For the latter case, the enzymes are readily immobilized by physical adsorption onto cellulose. A continuous process has been developed for chiral cyanohydrin synthesis using an enzyme membrane reactor [61]. Acetone cyanhydrin can replace the highly toxic hydrocyanic acid as the cyanide source [521], Inexpensive defatted almond meal has been found to be a convenient substitute for the purified (R)-oxynitrilase without sacrificing enantioselectivity [522-524], Similarly, lyophilized and powered Sorghum bicolor shoots have been successfully tested as an alternative source for the purified (S)-oxynitrilase [525],... 

The search for other amino acid-based catalysts for asymmetric hydrocyanation identified the imidazolidinedione (hydantoin) 3 [49] and the e-caprolactam 4 [21]. Ten different substituents on the imide nitrogen atom of 3 were examined in the preparation, from 3-phenoxybenzaldehyde, of (S)-2-hydroxy-2-(3-phenoxy-phenyl)acetonitrile, an important building block for optically active pyrethroid insecticides. The N-benzyl imide 3 finally proved best, affording the desired cyanohydrin almost quantitatively, albeit with only 37% enantiomeric excess [49]. Interestingly, the catalyst 3 is active only when dissolved homogeneously in the reaction medium (as opposed to the heterogeneous catalyst 1) [49]. With the lysine derivative 4 the cyanohydrin of cyclohexane carbaldehyde was obtained with an enantiomeric excess of 65% by use of acetone cyanohydrin as the cyanide source [21]. 

To prepare dynamic cyanohydrin systems under mild conditions, a range of aldehyde compounds and cyanide sources was evaluated. As a result, benzaldehydes 23A-E were selected due to their diverse substitution patterns and their inability to generate any side reactions. Even though there are many cyanide sources, acetone cyanohydrin 24 was chosen as cyanide source in presence of triethylamine base, resulting in smooth cyanide release. Dynamic cyanohydrin systems (CDS-3) were thus generated from one equivalent of each benzaldehyde 23A-E and acetone cyanohydrin 24 in chloroform- at room temperature (Scheme 10). One equivalent of triethylamine was added to accelerate the reversible cyanohydrin reactions and this amount was satisfactory to force the dynamic system to reach equilibrium even at low temperature. 

The cyanation of aldehydes with commercially available acetone cyanohydrin as cyanide source also appears feasible. For example, treatment of 2,2-dichlorodecanal (20) with acetone cyanohydrin under the influence of aluminum reagent 26a or 26b afforded the corresponding cyanohydrin 30 in high yield (Sch. 14) [34]. 

Recently, the group of Herrera, Bernardi, and Ricci realized the enantioselective synthesis of protected a-amino nitriles from the corresponding a-amino sulfones 137, which act as effective precursors for the in situ generation of imines, by the use of acetone cyanohydrin (138) as a cyanide source using quinine-derived PTC 136 [64]. The aminonitriles 139 were produced with broad generality in 50-88% ee (Scheme 8.53). However, a similar protocol using KCN and TMSCN resulted in a lower ee value. 

The transcyanation (exactly termed transhydrocyanation ) of aromatic and aliphatic aldehydes with acetone cyanohydrin, catalyzed by (R)-oxynitrilase to give cyanohydrins (see Fig. 14.7-2.), was first performed in Tallahassee 771. This innovative method avoids the use of free HCN as the cyanide source and is mostly accompanied... 

Transhydrocyanation for HCN generation. An alternative method of employing organic solvents that allows the safe use of HCN is transhydrocyanation [72, 73, 77-79, ii6, ii7] An example 0f cyanohydrin formation using acetone cyanohydrin as the cyanide source is given in the following procedure 771. 

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. 

Recently, atom-economical cyanation process under catalyst-free conditions has been developed using acetone cyanohydrin [84] in water, as an example of mild and alternative cyanide source (Scheme 10.30) [85]. 

SCHEME 10.30 Strecker reaction using acetone cyanohydrin as cyanide source. 

However, sinks are not necessarily the same as electrophiles. The sink is always an atom that can accept a negative charge and still be relatively stable. To explain what is meant by this, consider the nucleophilic attack of cyanide on the carbonyl of acetone. The source for the first arrow is the lone pair of electrons on the carbon of cyanide, and the sink is the par-... 

In order to minimise these deactivation pathways and maximise catalytic turnover, it was found that a slow, controlled addition of the cyanating agent was beneficial. The dosage of solid cyanide sources can be difficult to control. To address this issue, Beller et al. pioneered the use of acetone cyanohydrin (145) as the cyanide source (Scheme 7.3) in the palladium-catalysed cyanation of aryl hahdes [49]. 

A similar concept of was pursued by the Ricci group [45], The hydrocyanation of ahphatic N-Boc a-amido sulfones 80 was accompHshed with the cinchona-derived quaternary ammonium salt 82 (Scheme 30.19). Here, acetone cyanohydrin 81 was employed as cyanide source that is cheap, has good solubility in organic solvents, and is available on a large scale. (S)-Configurated primary, secondary, and tertiary aliphatic N-Boc a-amino nitriles 83 were obtained in high yields (85-95%), but enantioselectivities were lower (50-88% ee) in comparison to Ooi s protocol [43, 44]. 

Asymmetric phase-transfer catalytic addition of cyanide to C=N, C=0, and C=C bonds has been recently explored, which has been demonstrated to be an efficient method toward the synthesis of a series of substituted chiral nitriles. In this context, Maraoka and coworkers disclosed an enantioselective Strecker reaction of aldimines by using aqueous KCN [140]. In this system, the chiral quaternary ammonium salts (R)-36e bearing a tetranaphthyl backbone were found to be remarkably efficient catalysts (Scheme 12.25). Subsequently, this phase-transfer-catalyzed asymmetric Strecker reaction was further elaborated by use of a-amidosulfones as precursor of N-arylsulfonyl imines. Interestingly, the reaction could be conducted with a slight excess of potassium cyanide [141] or acetone cyanohydrin [40] as cyanide source, and good to high enantioselectivities were observed. In contrast, the asymmetric phase-transfer-catalytic cyanation of aldehydes led to the cyanation products with only moderate enantioselectivity [142]. 

Acetone cyanhydrin has been used as a convenient source of cyanide ion for the preparation of alkyl cyanides (6.1.1.E) [21]. Moderate yields (50-77%) have been achieved using tetra-n-butylammonium cyanide or hydroxide as the base. 

Catalyst of the Cyanation Reaction. The reaction was studied in the presence of Ni(0) complexes or aryl(chloro)nickel complexes. For a clearer interpretation the corresponding results are considered separately. A variant of the process consisting in the use of acetone cyanohydrin as source of cyanide ions is also reported. 

By using this source of cyanide ions the reaction occurred in a variety of solvents and at very mild conditions. For example in acetone it was possible to observe a rapid reaction even at 30 °C. A strong base, such as triethylamine, was necessary to induce the formation of cyanide ion (15). In the presence of weak bases such as pyridine, cyanation does not occur under the same reaction conditions. Ortho substituted aryl halides were... 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

Generally benzoins are generated by the action of sodium cyanide or potassium cyanide on aromatic aldehydes in aqueous ethanol via cyanohydrin intermediates. Benzoins may also be prepared in good yields by treating aromatic aldehydes with potassium cyanide in the presence of crown ethers in water or aptotic solvents. Other sources for cyanide in this type of condensation are tetrabutylammonium cyanide, polymer-supported cyanide and acetone cyanohydrin with KaCOs. Similarly, addition of aromatic ddehydes to a,3-unsaturated ketones can be accomplished by means of cyanide catalysis in DMF.7... 

Acetone cyanohydrin 97 was used as a cyanide ion source by Herrera and Ricci to accomplish the phase-transfer enantioselective cyanation of in situ-generated... 

To avoid handling of hydrogen cyanide directly, cyanohydrins have been employed as a source of HCN under reaction conditions. See, for example, a disclosure of this technique employing acetone cyanohydrin and either nickel, palladium, copper or cobalt catalysts W. C. Drinkard, Jr., U.S. Pat. 3,655,723 (1972) Chem. Abstr., 77, 4986p (1972). 

Holzinger, R., C. Warneke, A. Hansel, A. Jordan, W. Lindinger, D.H. Scharffe, G. Schade, and P. J. Crutzen, Biomass burning as a source of formaldehyde, acetaldehyde, methanol, acetone, acetonitrile, and hydrogen cyanide. Geophys Res Lett 26, 1161,... 

Most methyl methacrylate (MMA) is made by the acetone cyanohydrin process. Developed in the 1930s for the production of MMA from acetone, hydrogen cyanide, sulfuric acid, and methanol, it has been improved over the years, but problems inherent in the basic process persist. For example, production of large quantities of ammonium bisulfate by-product and sulfuric acid sludge, as well as difficulty in obtaining low cost sources of... 

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