Addition of Cyanide Ion

Cyanide ion acts as a carbon nucleophile in the conjugate addition reaction. The pK of HCN is 9.3, so addition in hydroxylic solvents is feasible. An alcoholic solution of potassium or sodium cyanide is suitable for simple compounds. 

Cyanide addition has also been done under Lewis acid catalysis. Triethylaluminum-hydrogen cyanide and diethylaluminum cyanide are useful reagents for conjugate 

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 

Reactions of Carbon Nucleophiles with Carbonyl Compounds 

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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 ... 

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... 

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 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. 

Oxynitrilases, isolated from either almond [(J )-specific]2° or a microorganism [( -specific],21 catalyze the enantioselective addition of cyanide ion to a range of aromatic or aliphatic aldehydes, providing cyanohydrins with ee values of up to 99%. 

A simple tandem Michael addition of cyanide ion with alkylation on Jt-deficient alkenes has been effected on diethyl l -methylpropylidenecyanoacetates and benzyl-idenemalonates using benzyltriethylammonium chloride to yield 2-alkyl-2,3-dicyanopropanoates and the analogous 2-ethoxycarbony derivatives [44]. 

Addition of cyanide ion to a carbonyl compound leads to a cyanohydrin, a process with many applications including the synthesis of amino adds via an aminonitrile. The dired reaction between an aldehyde, KCN and NH4CI in acetonitrile leads to a mixture... 

Interestingly, the trans enones 91 and 92 (R=H or CHj) have their ring A essentially conformationally rigid. Consequently, the addition of cyanide ion from the a face, occurring via a chair-like transition state (93 - 94) should be preferred over that on the B face which can take place only via a boat-like transition state (93->95). Agami, Fadlallah and Levisalles (35) have recently observed that in strictly kinetically controlled conditions, only the axial cyano isomer resulting from an attack on the a face was observed with the trans enones 91 and 92. 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

Strecker addition (cyanide addition to an iminium ion). The major problem here is that the reaction is more complicated, involving pre-equilibrium formation of the iminium ion and then C-C bond formation. The ratedetermining step is taken to be the addition of cyanide ion to an iminium ion. There are not many cases where the rate and equilibrium constants for the rate-determining step are known. For these few cases the rate constants could be calculated by NBT as shown in Table 12. 

There is no reason to confine these ideas to six-membered rings. Flexibility, which allows antiperiplanar configuration to be achieved in the transition state, is a crucial factor governing the reactivity of any ketone. To check this idea, we have studied the addition of cyanide ion to cyclopentanone and 3-pentanone.78 Cyclopentanone can be... 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

IR-spectra of pseudostrychnine in the solid phase and in solution indicate that it exists almost entirely in the carbinolamine form CXCVI. Two other forms might be expected to exist in equilibrium with CXCVI in solution the immonium form CXCVII, produced by proton-catalyzed loss of the hydroxyl group, is totally excluded on steric grounds the keto-amine form CXVIII, on the other hand, almost certainly exists in equilibrium with CXCVI in solution, but in concentrations which escape detection by physical methods. Its presence is deduced from some of the chemical reactions of pseudostrychnine. The easy formation of O-alkyl ethers (125) by interaction with methanol or ethanol even at room temperature almost certainly involves nucleophilic attack of the alcohol molecule on the carbonyl carbon in CXCVIII or in the O-protonated form CXCIX (R = H) to yield a hemiacetal as a first step likewise, the formation of 16-cyanostrychnine (XXV CN instead of OH) must involve addition of cyanide ion to CXCVIII, and the reaction with... 

Halide and Azide Anions. These also open the epoxide re-gioselectively at the C-3 position. Addition of Li2CuBr4 results in bromide addition at the C-3 position of rac-(l), forming 3-bromo-1,2-propane 1-0-tosylate in 70-76% yield in THF or acetonitrile at It, or 1,3-dibromo-2-propanol in 82% yield in refluxing acetonitrile. Hydrofluorination takes place with KHF2 under solid-liquid phase transfer conditions, but the yield of fluorohydrin is very low (eq 3). Azidotrimethylsilane adds in the presence of a Lewis acid catalyst (eq 3). Addition of cyanide ion is achieved by using Diethylaluminum Cyanide in toluene. ... 

The nucleophilic addition of cyanide ions to the electrochemically generated iminium cation is a synthetically very useful reaction and has been studied for a variety of symmetric and unsymmetric ions (Table 10) [266]. 

Cyanohydrin Formation. The rate-determining step in the formation of cyanohydrins is the addition of cyanide ion to the carbonyl group. The mechanism of the reaction can be illustrated by the following equations ... 

Two more complicated ring-contraction reactions, both yielding 4-amino-3-oxothiadiazoline 1,1-dioxides, are known. Disselnkoetter reported (71GEP1961864) that the reaction of 1,4,3,5-oxathiadiazine 127 with hydrogen cyanide produced imino derivatives 128, which were easily hydrolyzed to the corresponding oxo derivatives 89b by acid treatment (Scheme 49). The course of the reaction may involve addition of cyanide ion, decarboxylation of the resulting carbamic acid, and a nucleophilic attack at the carbonitrile group, as shown in Scheme 49. 

Danion, D., and Carrie, R., Nucleophilic addition of cyanide ion to a-cyanovinylphosphonic esters. Synthesis and physicochemical properties of 1,2-dicyanoethylphosphonic esters. Bull. Soc. Chim. Pr., 1538, 1974. 

El tsov and co-workers (85JOU596) (Scheme 67) have proposed a mechanism for the reaction of 4-[(dimethylamino)methylidene]-pyrazol-3-one 248 with cyanide ion in the presence of dimethylacetamide followed by the addition of carbon dioxide and then acidification that gives cyano(3-oxopyrazol-4-ylidene)acetic acid 252. Addition of cyanide ion to the a,jS-unsaturated functionality of 248 affords 249 which eliminates dimethylamine to give 250. Proton abstraction from 250 gives the pyrazol-3-one salt 251, which is converted into the acid 252 by bubbling in carbon dioxide and then acidifying. The progress of the reaction up to intermediate 251 was monitored by UV and IR spectroscopy. 

Extension of the carbon chain of an aldose from the carbonyl by one unit at a time can be carried out fairly readily by the Kiliani reaction. A cyanhydrin is formed by addition of cyanide ion, followed by reduction and hydrolysis (in either order) historically, the sugar was unprotected, and the cyanohydrin was hydrolysed to the sugar lactone, and then reduced with sodium amalgam (Figure 1.4). Because a new asymmetric centre is formed, two epimeric sugars result (epimers are diastereomers that differ in the configuration of only one carbon). 

Oxynitrilase enzymes from various plants catalyse the addition of cyanide ion to aldehydes to give the cyanohydrins present in many plants. Amygdalin, the cyanohydrin of a trisaccharide, is perhaps the most notorious of these as it releases HCN from oil of bitter almonds and has been responsible for the death of people drinking old samples of the liqueur noyeau.37... 

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