Addition of Cyanide

11 are required to obtain the high enantioselectivity. However, reactions using benzaldehyde and/or aliphatic aldehydes at room temperature were unproductive due to the rapid reverse reaction (racemisation of the products). 

In a study on the relationship between the aldehyde conversion and the enantiomeric excess of product 12, Katsuki found that the enantiomeric excess remained high (80%) until the 3-phenylpropanal substrate was completely consumed upon reacting with 1 mol% of vanadium salalen 13 at 25 After the complete conversion, the enantiomeric excess slowly 

12 in up to 95% enantiomeric excess, except when aromatic aldehydes were used as substrates (up to 29% enantiomeric excess). Acetone cyanohydrin gradually decomposed to give hydrogen cyanide when treated with complex 

13 in dichloromethane under an oig gen atmosphere. To suppress this background reaction, the mixture of complex 13 with acetone cyanohydrin was initially stirred for 6 h, followed by addition of aromatic aldehydes as substrates. As a result, the cyanation of aromatic aldehydes was complete within 10 min to give adducts 14 with 91-93% enantiomeric excess. 

The Strecker reaction is one of the most atom-economical and practical carbon-carbon bond-forming reactions for the synthesis of a-amino nitriles, which can be readily transformed to a-amino acid derivatives. As a consequence of the huge demand for optically active a-amino acids, considerable effort has been devoted to the development of catalytic and 

Addition of an alkyl nucleophile leads, due to the loss of one double bond, to a decrease of electron affinity and a concomitant negative shift of the reduction potential of about 100 to 150 mV per lost double bond. One possibility to compensate for this negative shift is the introduction of an electron-withdrawing substituent such as cyanide. Reaction of liCN or NaCN with Cjq at room temperature generates the monoadduct anion that can be quenched with various electrophiles [6]. 

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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.). 

Probably the most extensively applied masking agent is cyanide ion. In alkaline solution, cyanide forms strong cyano complexes with the following ions and masks their action toward EDTA Ag, Cd, Co(ll), Cu(ll), Fe(ll), Hg(ll), Ni, Pd(ll), Pt(ll), Tl(lll), and Zn. The alkaline earths, Mn(ll), Pb, and the rare earths are virtually unaffected hence, these latter ions may be titrated with EDTA with the former ions masked by cyanide. Iron(lll) is also masked by cyanide. However, as the hexacy-anoferrate(lll) ion oxidizes many indicators, ascorbic acid is added to form hexacyanoferrate(ll) ion. Moreover, since the addition of cyanide to an acidic solution results in the formation of deadly... 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

The same structural factors come into play in determining the position of equilibria in reversible additions to carbonyl compoimds. The best studied of such equilibrium processes is probably addition of cyanide to give cyanohydrins. 

The addition of cyanide was first examined by Kaufmann(//5-7/9), who found that aromatic iminium compounds such as quinolinium methiodide (77) added potassium cyanide to give 1,4-addition product 78. 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

Predict the product formed by nucleophilic addition of cyanide ion (CN ) to the carbonyl group of acetone, followed by protonalion to give an alcohol ... 

The cyanohydrin-forming addition of cyanide or cyanide equivalents (e.g.. cyanotrimethylsilane) to optically active a-amino aldehydes occurs diastereoselectively. 

However, only the initial formation of an imine from an aldehyde and ammonia or an amine and the subsequent proton-catalyzed addition of cyanide (path ) is in accord with the chemical... 

Addition of cyanide and ammonium ions to aldehydes or ketones,... 

Like the nitronate ion, the cyanide ion is synthetically equivalent to the aminomethyl carbanion (CH2NH2) , because of the possible reduction of - CN to the - CH2NH2 group. Consequently, the addition of cyanide ion to imines to give a-aminonitriles (Strecker-type reaction) is a viable route to 1,2-diamines. As a matter of fact, a number of diastereoselective and catalytic... 

More recently, the addition of cyanide ion, generated from TMS cyanide and cesium fluoride, to a-aziridino N-siflfinyl imines, being chiral either at the a position or at sulfur, has been examined [87] (Scheme 28). The configuration of the newly formed stereocenter was determined only by the chiral (S)-sulfinyl group. In fact, the R configuration (diastereomeric excess, de, 98%) was obtained from either the Q -(ii)-imine 186 or the a-(S)-imine 188, giving 187 and 189, respectively. Acyclic 2,3-diaminonitriles can be obtained... 

The displacement of CN by RS in surprising since C-labelled cyanide ion does not exchange with unlabelled ferricyanide . Wiberg et have shown that no exchange occurs under the conditions of the oxidation and that the effect of added cyanide is to be attributed to nucleophilic addition of cyanide to the thiol, viz. 

Diethylaluminum cyanide mediates conjugate addition of cyanide to a, (3-unsaturated oxazolines. With a chiral oxazoline, 30-50% diastereomeric excess can be achieved. Hydrolysis gives partially resolved a-substituted succinic acids. The rather low enantioselectivity presumably reflects the small size of the cyanide ion. 

A chiral aluminum-salen catalyst gives good enantioselectivity in the addition of cyanide (from TMS-CN) to unsaturated acyl imides.338... 

This method can be used in conjunction with addition of cyanide to prepare a-hydroxy aldehydes from ketones.90... 

The medicinal chemists subsequently discovered an improved route to racemic acid 9 that started with 2-bromo-2-cyclopente-l-one 11 (Scheme 7.2) [5]. Suzuki-Miyaura cross-coupling of 11 with 4-fluorophenyl boronic acid 12 provided 13 in 67% yield. Conjugate addition of cyanide furnished ketone 14 in 71% yield. Reduction of 14 with NaB H4 gave a 2.8 1 mixture of desired 15 and undesired 16 which were separated by silica gel chromatography. The observed diastereoselec-tivity with the cyano group was similar to ester 6. Hydrolysis of 15 with 5 M NaOH in MeOH gave racemic acid 9 in 91% yield, which was resolved as outlined in Scheme 7.1. 

Compounds (99) and (100) are thought to be formed by addition of cyanide ion to the ring ortho to the carbonyl, followed by protonation at oxygen, aromatization by tautomerization, hydrolysis of the nitrile, and lactonization upon acidification. The photolysis of 2-methoxyacetophenone, on the other hand, results in rearrangement to 3-methoxyacetophenone ... 

The nitroxalkylcorrinoids are easy to characterize since they are basically alkyl corrinoids. The u.v.-visible absorption spectra of the nitroxalkylcorrinoids are quite similar to other alkylcorrinoids. The nitroxalkyl cobalamin has a spectrum with Amax at 525,357, and 329nm with relative extinctions of 1.1, 1.2, and 0.65 respectively. Spectra for a number of typical alkylcobalamins have been reported by Firth et al. (121). The corresponding cobinamide has absorption maxima at 455, 428, 360, and 325 nm with relative extinctions of 1.4, 1.0, 0.61, and 0.62 respectively. Aerobic photolysis of these compounds leaves the corresponding aquocobalamin or aquocobinamide. Likewise, addition of cyanide to the nitroxalkylcobinamide in base leaves dicyano cobinamide. 

In the spectra of alkyl cobinamides two peaks have been observed at 3.89 and 4.42 which were assigned to the protons of a water molecule coordinated at the lower axial site (130). To confirm this assignment, it was found that addition of cyanide to methyl cobinamide, which displaces coordinated water, caused the peaks to disappear. Likewise, addition of excess D2O caused disappearance of the peaks through either ligand exchange or proton-deuteron exchange. 

The low solubility of AuCN(s) is thought to be a consequence of a polymeric structure based on linear chains, —Au-CN-Au-CN—, which lie parallel to one another with a close-packed arrangement of gold atoms in which each is in contact with six nearest neighbors.36 The addition of cyanide and dissolution of [Au(CN)2] is believed to take place at the chain ends. This process is enhanced by the presence of Ag2+ or other ions such as Pb2+ (see below) normally present in the gold-bearing ores. 

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. 

The application of the concept of a reactive-ion micelle is illustrated by addition of cyanide ion to N-alkylpyridinium ions (Fig. 3) and rate constants are compared in Table 4. Second-order rate constants are essentially independent of substrate hydrophobicity and are only slightly affected by added inert salts. They are also very similar to second-order rate constants in water. 

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