Cyano group aromatic substitution

Another important class of reactions involves the introduction of a cyano group by substitution in an Ar-Z precursor. In fact, novel pathways leading to aromatic nitriles-for example, photosubstitution reactions-are desirable in view of the many applications of aryl cyanides as agrochemicals and pharmaceuticals. Today, the classical copper(l)-mediated Rosenmund-von Braun and Sandmeyer reactions, from aryl halides and aryldiazonium salts respectively, have been supplanted by reactions which employ palladium- or copper-catalysis [57]. The rather common use of excess cyanide anion may lead to a deactivation of the catalyst, and affect to a remarkable extent each of the key steps of the catalytic cycle [58aj. Although the use of complex iron cyanide has been shown to offer an effective solution to this limitation [58b,c], photocyanation provides an equally useful alternative [10],... 

It has been shown that when nucleophilic aromatic photo-substitution reactions are carried out in non-deoxygenated solutions of aprotic solvents, such as DMSO and acetonitrile, destructive superoxide anions may be formed from aromatic radical anions. Such solvents are best avoided. There has been a review of mechanistic aspects of photo-substitutions of the cyano group in aromatic compounds. ... 

Aiyl fluorides and iodides cannot be prepared by direct halogenatlon. The cyano group cannot be Introduced by nucleophilic substitution of of Aromatic chlorine in chlorobenzene but cyanobenzene can be easily obtained from diazonium salt. 

F]Fluoroarylketones are easily prepared in the direct F to NO2 exchange. However, the carbonyl being less efficient than a nitro or a cyano group in promoting the aromatic nucleophific substitution, yields are generally lower than those obtained in the preparation of [ F]fiuoronitrobenzene or [ F]fluoroben-zonitrile [97,128]. 

Suzuki and co-workers achieve aromatic substitution of fluoroarenes with a variety of aldehydes in good yields [91, 92], Imidazolilydene carbene formed from 143 catalyzes the reaction between 4-methoxybenzaldehyde 22a and 4-fluoroni-trobezene 141 to provide ketone 142 in 77% yield (Scheme 20). Replacement of the nitro group with cyano or benzoyl results in low yields of the corresponding ketones. The authors propose formation of the acyl anion equivalent and subsequent addition to the aromatic ring by a Stetter-like process forming XXVIII, followed by loss of fluoride anion to form XXIX. 

Even such poor nucleophiles as tertiary aromatic amines react with 59 at elevated temperatures to give good yields of monosubstitution products such as 101 (76USP3963715). This reaction is analogous to the well-studied electrophilic substitution of a cyano group in tetracyanoethylene (102) by tertiary aromatic amines to give products 103 (63JCS4498) (Scheme 37). 

The observations that only the 3-cyano group is attacked, that only primary amine monosubstitution products undergo exchange, and that aromatic amines give only the substitution/addition products suggest that they are formed by reversible attack on an imino tautomer such as 107, which can undergo intramolecular transfer of amine, as shown in Scheme 38. 

Dichloroketene acts as a donor toward aromatic aldehyde [165], but chlorocyano-ketene behaves as an acceptor, as shown by the reactivity profile with a series of substituted benzaldehydes [97]. It must be remembered that chloro and cyano groups belong to different polarity categories, and although the fundamental donor/acceptor characters of the ketene unit do not change, the higher electrophilidty of the cyano-ketene reflects the acceptor influence by the cyano function. 

Chakrabarti and coworkers at Eli Lilly in the United Kingdom have reported the initial discovery and synthesis of olanzapine (Schemes 5 and,6). The thiophene 22 was synthesized by adding a DMF solution of malononitrile to a mixture of sulfur, propionaldehyde and triethylamine in DMF. The anion of amino thiophene 22 underwent a nucleophilic aromatic substitution with 2-fluoronitrobenzene to provide 23. The nitro group was reduced with stannous chloride and the resulting anihne cyclized with the cyano group to form amidine 24. Finally, a mixture of N-methylpiperazine and 24 were refluxed in DMSO/toluene to afford olanzapine (2). 

In aromatic compounds carbon-13 shifts are largely determined by mesomeric (resonance) and inductive effects. Field effects arising from through-space polarization of the n system by the electric field of a substituent, and the influences of steric (y) effects on the ortho carbon nuclei should also be considered. Substituted carbon (C-l) shifts are further influenced by the anisotropy effect of triple bonds (alkynyl and cyano groups) and by heavy atom shielding. 

A crude mixture of enzymes isolated from Rhodococcus sp. is used for selective hydrolysis of aromatic and aliphatic nitriles and dinitriles (117). Nitrilase accepts a wide range of substrates (Table 8). Even though many of them have low solubility in water, such as (88), the yields are in the range of 90%. Carboxylic esters are not susceptible to the hydrolysis by the enzyme so that only the cyano group of (89) is hydrolyzed. This mode of selectivity is opposite to that observed upon the chemical hydrolysis at alkaline pH, esters are more labile than nitriles. Dinitriles (90,91) can be hydrolyzed regioselectively resulting in cyanoacids in 71—91% yield. Hydrolysis of (92) proceeds via the formation of racemic amide which is then hydrolyzed to the acid in 95% ee (118). Prochiral 3-substituted glutaronitriles (93) are hydrolyzed by Phodococcus butanica in up to 71% yield with excellent selectivity (119). 

A correlation between free enthalpy of electron transfer and mode of the photoreaction was also constructed for addition of alkenes to benzonitrile. Four areas could be differentiated Full electron transfer, leading to substitution, is only observed if AG < 0 eV cycloaddition to the cyano group occurs if 0 < AG < 0.4 eV. All olefins for which AG > 0.4 eV preferentially undergo cycloaddition to the aromatic ring, ortho cycloaddition if AG < 1.7 eV and meta cycloaddition if AG > 1.7 eV. 

An overview on cycloproparenyl anions has also been reported.3 According to theoretical calculation, cyclopropabenzenyl anion is by ca 145 kJmol-1 more stable than the parent cyclopropenyl anion. It has been shown that the stability of the cyclopropabenzenyl anion could be considerably enhanced by substitution of the aromatic ring with fluorine and cyano groups, and also by a linear extension of the aromatic backbone. 

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