Cyanide source

A short synthesis of 6-cyano-l,2,3,4-tetrahydroisoquinoline used an improved method of aryl triflate cyanation that employs zincfll) cyanide as the cyanide source <95SC(25)3255>. 

The catalysts bearing a cyclohexylamine moiety combined with a bulky sal-icylidene compound linked via one thiourea function to a terf-leucine ben-zylamide (Scheme 38, Ri = Bn, R2 = H) was the most efficient. The test was performed in solution at - 78 °C, with HCN as the cyanide source. Excellent results were obtained 78% isolated yield with 91% ee for the optimised substrate and 70-86% ee for other imine derivatives (65-92% isolated yield) [148,152-157]. 

This scheme shows that cyanide sourced from smoking or otherwise (see 6.3.7) may determine the metabolism of chrysotherapeutic agents. [Au(CN)2] anions bind to serum albumin predominantly by the formation of adducts without the displacement of cyanide [94]. The ions bind tightly to albumin independent of the oxidative state of Cys-34. The equilibrium constant values for [Au(CN)2] binding to serum albumin are similar to values for other gold complexes that bind to albumin. This indicates that albumin can act as a carrier for transporting [Au(CN)2] in the bloodstream. 

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. 

Enantiomeric or specific synthesis of cyanohydrin is influenced by the reaction medium, cyanide source, water content, buffer pH, enzyme, and temperature during the HNL-catalyzed reaction. To maximize the enantiomeric excess of the cyanohydrin product, care must be taken to minimize the parallel chemical (nonenzymatic) condensation and racemi-zation of products. 

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]. 

An improvement of the palladium-catalyzed cyanation of aryl bromides, in which zinc cyanide was used as the cyanide source, was reported in the middle of the nineties [49], Typically, the conversion from halide to nitrile takes at least 5 h by this route and the subsequent cycloaddition to the tetrazole is known to require even longer reaction times. 

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... 

Lundgren, S. Wingstrand, E. Penhoat, M. Moberg, C. Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide and cyanoformate as cyanide sources. J. Am. Chem. Soc. 2005,127, 11592-11593. 

Prather, B. Berketneyer, R. Cyanide sources in petroleum refineries. Proceedings, 30th Purdue Industrial Waste Conference, West Lafayette, IN, 1975. 

Cyanation of aldehydes and ketones is an important chemical process for C C bond formation." " Trimethylsilyl cyanide and/or HCN are commonly used as cyanide sources. The intrinsic toxicity and instability of these reagents are problematic in their applications. Acetyl cyanide and cyanoformates were used as cyanide sources in the enantioselective cyanation of aldehydes catalyzed by a chiral Ti complex and Lewis base (Scheme 5.31)." The Lewis base was necessary for the good yields and selectivities of these reactions. The desired products were obtained in the presence of 10mol% triethyl amine and 5mol% chiral titanium catalyst (Figure 5.14). Various aliphatic and aromatic aldehydes could be used in these reactions. 

When ethyl cyanoformate was used as the cyanide source and a heterobimetallic YLi3(binaphthoxide) complex (YLB) (Figure 5.15) was used as catalyst, asymmetric cyanoethoxycarbonylations of aldehydes were achieved in high yields and enantioselectivities in the presence of three achiral additives water, tris(2,6-... 

In addition to metal catalysts, organocatalysts could also be used in asymmetric cyanation reactions. Chiral Lewis bases, modified cinchona alkaloids, catalyzed asymmetric cyanation of ketones by using ethyl cyanoformate as the cyanide source (Scheme 5.34)." Similar to metal-catalyzed reactions, ethyl cyanoformate was first activated by chiral Lewis bases to form active nucleophiles. Various acyclic and cyclic dialkyl ketones were transformed into the desired products. Because of using... 

First published in 1850 [1], the Strecker reaction (Scheme 21) is a convenient tool for the synthesis of a-amino acids. Originally it was reported as a condensation of an aldehyde, ammonia and a cyanide source in buffered aqueous medium to form an a-amino nitrile, which is then hydrolysed to an a-amino acid [47, 48]. 

Various adaptations of the original procedure have been reported over the years, with variations in catalysts and conditions [7, 8, 52]. However, most of these procedures still encounter a range of shortcomings the need for elevated reaction temperatures, extended reaction times, expensive homogeneous catalysts or an excess of the cyanide source, variable yields and most notably competing cyanohydrin formation that can occur (Scheme 22) [48]. This problem is usually bypassed. 

In a first series of trials, trimethylsUyl cyanide (TMSCN) was used as the cyanide source and polymer-supported (ethylenediaminetetraacetic acid) ruthenium(lll) chloride as the Lewis acid catalyst (Scheme 23). After the optimisation of the conditions on a model reaction, a small library of compounds was produced, proving the concept by obtaining 100% yields in 2.5 h reaction time. Using flow rates of... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Scheme 6.2 Cyanation of nitrones utilizing TMSCN as cyanide source and catalyst 9 yields in parentheses refer to uncatalyzed reactions.

Scheme 6.14 Product range of the 9-catalyzed acetyl cyanation reaction of aldimines with acetyl cyanide as the cyanide source.

List and co-workers reported the 47-catalyzed (lmol% loading) asymmetric acetylcyanation of N-benzyl-protected aliphatic and aromatic aldimines by using commercially available liquid acetyl cyanide as the cyanide source instead of HCN [161]. Under optimized reaction parameters (toluene, -40 °C) the procedure resulted in the desired N-protected a-amino nitriles 1-5 in yields ranging from 62... 

Scheme 6.47 Strecker products obtained from the 47-catalyzed asymmetric acetylcyanation using acetyl cyanide as cyanide source.

N-Oxide Substituent (mol) Acyl halide (mol) Cyanide source (mol) Conditions % Yield of products 2-CN 4-CN 6-CN Ref. ... 

Schneider, J., V. Burger, and F. Arnold, Methyl Cyanide and Hydrogen Cyanide Measurements in the Lower Stratosphere Implications for Methyl Cyanide Sources and Sinks, . /. Geophys. Res., 102, 25501-25506 (1997). 

The Gotor group succeeded in using almond meal for the enantioselective cleavage of ketone cyanohydrins, which served additionally as the cyanide source in the subsequent asymmetric addition of HCN to co-bromoaldehydes in one pot (Figure 9.4) [53]. 

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 Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

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]. 

Baxendale et al. (2008) reported a bifurcated approach to the synthesis of thiazoles and imidazoles by coupling a glass microreactor and a packed-bed reactor to achieve a base-mediated condensation reaction. As Scheme 32 illustrates, reactions focused on the use of ethyl isocyanoacetate 123, as the cyanide source, with variations made via the isothiocyanate reagent, as illustrated in Table 13. 

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