Nitriles, addition reactions

A few 6- and 8-cyanopurines have been prepared and undergo characteristic nitrile addition reactions rather readily. Thus, alkaline hydrolysis produces carboxamides, then carboxylic acids, alcoholysis leads to imidates, ammonolysis to amidines, hydrazinolysis to amidhydrazines, hydroxylamine to amidoximes, and hydrogen sulfide to thioamides. Acid hydrolysis tends to give the decarboxylated acid derivative. Reduction either by sodium-ethanol or, preferably, by catalytic hydrogenation affords aminoalkylpurines and addition of Grignard reagents produces, in the first place, acylpurines. As with aldehydes, most of the compounds examined have been relatively non-polar derivatives. Table 28 lists some reactions and relevant literature. 

Likewise, intermolecular reactions are possible and lead to coupling products which correspond retrosynthetically to the addition of an acyl anion synthon to a ketone. The presence of a proton-donor cosolvent is crucial, otherwise j8-hydroxy nitriles are formed preferentially. The nitrile addition reaction proceeds with good stereoselectivity, e.g. preferentially one diastereoisomer is formed from the electro-reductive addition of acetonitrile (which can advantageously be used as solvent) to dihydrocarvone. 

However, the term saturated is often applied to compounds containing double or triple bonds which do not easily undergo addition reactions. Thus ethanoic acid is termed a saturated carboxylic acid and acetonitrile a saturated nitrile, whereas a Schiff base is considered to be unsaturated. 

Additions. The addition reactions of ammonia and amines to the cyanamide nitrile group have been thoroughly studied (15). For optimum conditions, the reaction should be carried out ia an aqueous medium at about 140°C. Gradual addition of the cyanamide to the amine salt minimises dimerization. 

The greatest attention is at present paid to the second variant which forms the 1—5 and 3—4 bonds, i.e., the addition reaction of nitrile... 

The conversion of a nitrile R —CN into a ketone R —CO—R demonstrates that polarized multiple bonds other than C=0 also react with Grignard reagents, and that such reactions are synthetically useful. Esters 22 and acid chlorides can react subsequently with two equivalents of RMgX the initially formed tetravalent product from the first addition reaction can decompose to a ketone that is still reactive, and reacts with a second RMgX. The final product 23 then contains two substituents R, coming from the Grignard reagent ... 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

Just as the Kiliani-Fischer synthesis lengthens an aldose chain by one carbon, the Wohl degradation shortens an aldose chain by one carbon. The Wohl degradation is almost the exact opposite of the Kiliani-Fischer sequence. That is, the aldose aldehyde carbonyl group is first converted into a nitrile, and the resulting cyanohydrin loses HCN under basic conditions—the reverse of a nucleophilic addition reaction. 

Mixing trichlorosilane, acetonitrile and diphenylsulphoxide, carried out at 10°C, detonated. This accident was put down to the exothermic addition reaction of the silicon-hydrogen bond on the carbon-nitrogen triple bond of nitrile. Other interpretations are possible for instance, the effect of traces of hydrogen chloride formed by the hydrolysis of chlorosilane on acetonitrile. 

In contrast to the related organoboranes, which are mostly used in the addition to non-polar carbon-carbon multiple bonds, aluminum hydrides have found their widest use in organic synthesis in the addition reaction to polar carbon-carbon and carbon-heteroatom multiple bonds including carbonyl, nitrile and imino groups as well as their a,(J-unsaturated analogs. Although these reduction reactions are also sometimes referred as hydroalumination reactions in the Hterature, they are outside the scope of this review. 

The addition reaction of enolates and enols with carbonyl compounds is of broad scope and of great synthetic importance. Essentially all of the stabilized carbanions mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the carbanions of nitriles and nitro compounds, as well as phosphoms- and sulfur-stabilized carbanions and ylides undergo this reaction. In the next section we emphasize the fundamental regiochemical and stereochemical aspects of the reactions of ketones and aldehydes. 

Anions derived from nitriles can act as nucleophiles in conjugate addition reactions. A range of substituted phenylacetonitriles undergoes conjugate addition to 4-phenylbut-3-en-2-one. 

Silyl esters of trivalent phosphorus acids have been used successfully in conjugate addition reactions using acrylates,393 395 nitriles,394 amides,396 397 ketones and aldehydes,398-404 and nitro compounds.387... 

S-Nucleophiles are very reactive in 1,3-addition reactions with nitrile oxides. A series of a-glucosinolates 27 (R = CR1=NOH R1 =Ph, CH2PI1, CH2CH2PI1, ( )-CH=CHPh, 3-indolylmethyl) was prepared by addition reactions of thiol 27 (R = H) with nitrile oxides (123). The indolyl-substituted glucosinolate was then converted to a-glucobrassicin 28. 

An expedient and fully stereocontrolled synthesis of epothilones A (435, R = H) and B (435, R = Me) has been realized (473, 474). The routes described, involve an extensive study of nitrile oxide cycloadditions, as substitutes for aldol addition reactions, leading to the realization of a highly convergent synthesis, based on the Kanemasa hydroxyl-directed nitrile oxide cycloaddition. 

Only few examples are known for an addition reaction of trialkylboranes across a nitrile group according to Eq. (35) 2> (but c.f. Sect. Ill, Eq. (11)). The low reaction temperature required for this process is quite surprising. 

In the course of investigation into new C-C bond formation processes, Hiyama has developed an efficient nickel-catalyzed arylcyanation of alkynes.67 The addition reaction of an aryl-CN bond to alkyne affords aryl-substituted alkene nitrile in good yield. Good regioselectivity is reported in the case of unsymmetrical alkynes with two sterically different substituents. 

Closely related to the reaction of allylzirconocene derivatives with aldehydes are various carbonyl addition reactions of 1,3-dienezirconocene complexes [119], including additions to even ketones, esters, and nitriles (Scheme 1.29). 

In addition, Hegedus and co-workers extended this chemistry to the /V-alkylation of 1-lithioindole with alkenes (PdC MeCN /THF/HMPA/EtsN/then H2) to afford A/-alkylindoles in 28-68% yields [411], Moreover, a similar reaction of N-allylindole 343 with nitriles leads either to 344a, 344b, or 344c depending on how the intermediate Pd-alkyl (or acyl) complexes are treated [431]. The formation of these pyrazino[ 1,2-a]indoles is similar to a nitrile-Ritter reaction. 

In many of its reactions hydrocyanic acid behaves as the nitrile of formic add H.CN. Many facts, in particular its great chemical and pharmacological similarity to the isonitriles >C = NR suggest another constitution, namely, that of carbimide >C =NH with bivalent carbon. The addition reactions of the nitriles (see above), which reactions are also characteristic of hydrocyanic acid, can equally well be explained on the basis of this second structural formula. In the nitrile form it is at the triple bond between carbon and nitrogen that addition takes place. In the methylene form this occurs at the two free valencies of the bivalent carbon atom, e.g. ... 

Conversely, activated methylene compounds undergo an addition reaction across the C=N bond of imines. For example, benzylic ketones react with benzylidene anilines to from P-aminoketones [35], whereas the analogous reaction of diphenyl-methylene-protected a-amino esters, and nitriles, produces a disastereomeric mixture of the A-protected a,p-diamino esters, and nitriles [36, 37]. 

Similar waves in the cathodic polarogram were observed by Donnet and Henrich 58) using oxidized carbon black. The wave disappeared after treatment with isobutyronitrile. It was assumed that isobutyro-nitrile gives an addition reaction with quinones. No reaction with this reagent was observed after reduction with hydrogen iodide, after treatment with aniline, or after treatment with diazomethane. The latter finding confirms the assumption by Studebaker et al. 38) that diazomethane is added to the quinones in the carbon black surface. 

Addition reactions of CF3SCI to olefins and nitriles were intensively studied. It has been shown that these reactions have to be either initiated with UV light or carried out in a strongly polar solvent. 

Group-transfer polymerizations make use of a silicon-mediated Michael addition reaction. They allow the synthesis of isolatable, well-characterized living polymers whose reactive end groups can be converted into other functional groups. It allows the polymerization of alpha, beta-unsaturated esters, ketones, amides, or nitriles through the use of silyl ketenes in the presence of suitable nucleophilic catalysts such as soluble Lewis acids, fluorides, cyanides, azides, and bifluorides, HF. ... 

Scheme 2.4. Addition Reactions of Carbanions Derived from Esters, Carboxylic Acids, Amides, and Nitriles... 

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