Arylations of Nitriles

Alkyl nitriles have a relatively high pfQ value compared with that of ketones, for example, and therefore stronger bases are required for their deprotonation. As a 

In 2003, Verkade disclosed details of the arylation of nitriles using his TAP ligands and NaHMDS as base in toluene, and also observed diarylations when using acetonitrile [235]. 

Klapars and Waldman, of the Merck research group, reported a transition metal-free a-arylation of aliphatic nitriles with heteroaryl halides using KHMDS or NaHMDS as bases in a toluene/THF mixture at 0-25 °C. However, this protocol was strictly limited to the conversion of electronically activated heteroaryl halides [236]. 

Based on the observation that a-arylated ketones were obtained as byproducts in the arylation of amines containing carbonyl functionalities, the main potential of this methodology was soon acknowledged and, consequently, it was developed into a very powerftil synthetic took 

Perhaps the most encouraging factor regarding the processes described in this chapter is that, even after more than 100 years of synthetic organic chemistry, fundamental organic methodologies can still be discovered and developed into synthetic tools with far-reaching impact  

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You, J. and Verkade, J.G. (2003) P( BuNCH2CH2)3N an efficient ligand for the direct a-arylation of nitriles with aryl bromides. The Journal of Organic Chemistry, 68, 8003-8007. 

Finally, the a-arylation of nitrile derivatives was also reported using NaHMDS (eq 15). ... 

In general, in contrast to high reactivity of malononitrile for arylation, mononitriles are less acidic than ketones and hence less reactive. Hartwig reported, however, that a-arylation of nitriles is possible by using BINAP or P(r-Bu)3 as a ligand. Diarylation of butyronitrile and acetonitrile occurred to give 87a and 87b... 

Tobisu, M., Kita, Y, Ano, Y, Chatani, N. (2008). Rhodium-catalyzed silylation and intramolecular arylation of nitriles via the silicon-assisted cleavage of carbon-cyano bonds. Journal of the American Chemical Society, 130,15982-15989. 

Although LHMDS was also used with methyl isobutyrate, better yields were obtained for the same reaction with r-butyl propionate and NaHMDS at room temperature. The a-arylation with t-butyl propionate and LHMDS proceeds only at a higher temperature (80 °C). It was shown later that LiNCy2 could also be very effective for this reaction. More sensitive substrates, such as a-imino esters, required the use of milder base as decomposition was observed with LHMDS. Finally, a-arylation of nitrile derivatives was also reported using LHMDS (eq 24). ... 

The synthesis of a-aryl activated derivatives has been approached via a Pd-catalyzed reaction. The enolate form of the activated nucleophile may act as a transmetallating agent, which may, therefore, react with a Pd intermediate resulting from the oxidative addition of aryl halides. Arylation of di-teri-butyl malonate was described in the presence of Pd(dba)2 catalyst the reaction also was possible with dimer 1 (eq 86). Aryl bromides and ethyl cyanoacetate also can participate in such reactions. Other ligands than P(f-Bu)3 were efficient for these couplings. The bicyclic triaminophosphine, P(i-BuNCH2CH2)3N, served as a versatile ligand for the Pd-catalyzed a-arylation of nitriles with aryl bromides. 

By the hydrolysis of nitriles. The nitriles may be easily prepared either from amines by the Sandmeyer reaction (Section IV,66) or by the action of cuprous cyanide upon aryl halides (compare Section IV,163). Benzyl cyanide... 

Sandmeyer reaction (Section 22 17) Reaction of an aryl dia zonium ion with CuCl CuBr or CuCN to give respec tively an aryl chloride aryl bromide or aryl cyanide (nitrile)... 

A series of 3-imino-2-aryl-l-azetines has been prepared by cycloaddition of nitrile ylides to isocyanides. Thus generation of the nitrile ylides (215) in the presence of cyclohexyl isocyanide gives the 3-cycIohexyIimino-2-aryI-l-azetines (205). Similar 1-azetines are formed by interception of nitrile ylides with a-methylbenzyl isocyanide (72AG(E)47) cf. Section 5.09.4.2.2). 

A multitude of 1,4-dicarbonyls (1) undergo the Paal-Knorr reaction with and ranging from H to alkyl, aryl, carbonyl, nitrile, and phosphonate, while R and R vary between H, alkyl, aryl, trialkylsilyl, and O-alkyl. Protic acid catalysts are typically used with sulfuric, hydrochloric, and p-toluenesulfonic acids the most popular. Conversion to the furan takes place either at room temperature or upon heating with reaction times varying from five minutes to 24 hours and yields ranging from 17-100%. 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

These compds are also formed during the prepn of nitriles, by heating aryl or arylalkyl halides, or alkyl sulfuric or phosphoric esters, or arylsulfonic esters with K or Na cyanide in ale... 

In Section 8.2.3.2, we discussed arylation of enolates and enolate equivalents using palladium catalysts. Related palladium-phosphine combinations are very effective catalysts for aromatic nucleophilic substitution reactions. For example, conversion of aryl iodides to nitriles can be done under mild conditions with Pd(PPh3)4 as a catalyst. 

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