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Synthesis of Nitriles


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A solvent-free [Cp*IrCl2]2-catalyzed reaction of substituted acetonitriles with primary alcohols delivered monosubstituted aryl/heteroaryl acetonitriles in excellent yield. This process can be achieved by conventional or microwave heating.
C. Löfberg, R. Grigg, M. A. Whittaker, A. Keep, A. Derrick, J. Org. Chem., 2006, 71, 8023-8027.

A one-pot protocol for the cyanomethylation of aryl halides through a palladium-catalyzed reaction with isoxazole-4-boronic acid pinacol ester proceeds through Suzuki coupling, base-induced fragmentation, and deformylation. Under optimized conditions (PdCl2dppf, KF, DMSO/H2O, 130 °C) a broad spectrum of aryl bromides could be converted into arylacetonitriles in good yields.
J. Velcicky, A. Soicke, R. Steiner, H.-G. Schmalz, J. Am. Chem. Soc., 2011, 133, 6948-6951.

A palladium-catalyzed α-arylation of nitriles was developed by exploring the structure and reactivity of arylpalladium cyanoalkyl complexes. The high yields and short reaction times observed for BINAP-ligated complexes suggested that BINAP-ligated palladium catalysts might be appropriate for the arylation of nitriles. Initial results on a palladium-catalyzed process for the direct coupling of aryl bromides and primary, benzylic, and secondary nitrile anions to form α-aryl nitriles in good yields are reported.
D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 9330-9331.

TMPZnCl·LiCl as a kinetically highly active base enables a Pd-catalyzed α-arylation of nitriles and esters under mild conditions. Remarkably, even a regioselective γ-arylation or a γ-alkenylation of α,β- or β,γ-unsaturated nitriles can be observed.
S. Duez, S. Bernhardt, J. Heppekausen, F. F. Fleming, P. Knochel, Org. Lett., 2011, 13, 1690-1693.

α-Cyanohydrin triflates undergo Pd-catalyzed cross-coupling with aryl and vinyl boronic acids under mild conditions. Coupling proceeds with complete inversion of configuration at the stereogenic carbon. The resultant nitrile can be easily converted into a variety of alternative functional groups of value in organic synthesis and thus a high level of molecular diversity can be achieved.
A. He, J. R. Falck, J. Am. Chem. Soc., 2010, 132, 2524-2525.

α-Halonitriles react with alkyllithium, organomagnesium, and lithium dimethylcuprate reagents generating reactive, metalated nitriles. The rapid halogen-metal exchange with alkyllithium and Grignard reagents allows Barbier-type reactions with various electrophiles.
F. F. Fleming, Z. Zhang, W. Liu, P. Knochel, J. Org. Chem., 2005, 70, 2200-2005.

α-Cyano aldehydes undergo selective transition-metal-catalyzed allylation to provide α-allylated nitriles. The transformation leads to linear allylated nitriles with palladium catalysts whereas an iridium catalyst provides branched substitution products. TBD-catalyzed retro-Claisen cleavage is leveraged to attain selective monoallylation.
T. Maji, J. A. Tung, Org. Lett., 2014, 16, 5072-5075.

A low loading of a proazaphosphatrane compound efficiently catalyzes the reaction of trimethylsilylacetonitrile (TMSAN) with aldehydes for the synthesis of β-hydroxynitriles under mild reaction conditions. Various functional groups were tolerated, and good to excellent yields were obtained.
K. Wadhwa, J. G. Verkade, J. Org. Chem., 2009, 74, 5683-5686.

3-Oxo-3-(hetero)arylpropanenitriles can be synthesized via a carbonylative palladium-catalyzed α-arylation of tert-butyl 2-cyanoacetates with (hetero)aryl bromides followed by an acid-mediated decarboxylation step. Through the combination of only a stoichiometric loading of carbon monoxide and mild basic reaction conditions for the deprotonation step, an excellent functional group tolerance was ensured.
M. T. Jensen, M. Juhl, D. U. Nielsen, M. F. Jacobsen, A. T. Lindhardt, T. Skrydstrup, J. Org. Chem., 2016, 81, 1358-1366.

A green, practical, convenient, and cheap copper-catalyzed oxidative coupling of aromatic alcohols and acetonitrile to β-ketonitriles involves a C-C coupling with loss of two hydrogen atoms from the corresponding two carbons, using oxygen as the terminal oxidant.
J. Shen, D. Yang, Y. Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C. Chu, R. Liu, Org. Lett., 2014, 16, 350-353.

A general method for the direct α-arylation of nitriles with aryl chlorides was developed. With a catalytic system generated from palladium and a commercially available ligand, it is now possible to effect direct α-arylation using a wide variety of starting materials.
J. You, J. G. Verkade, Angew. Chem., 2003, 115, 5205-5207.

In the “deacylative allylation”, the coupling partners, ketone pronucleophiles and readily available allylic alcohols undergo in situ retro-Claisen activation to generate an allylic acetate and a carbanion. In the presence of palladium, these reactive intermediates undergo catalytic coupling to form a new C-C bond.
A. J. Grenning, J. A. Tunge, J. Am. Chem. Soc., 2011, 133, 14785-14794.

An efficient method enables the synthesis of α-cyanomethyl-β-dicarbonyls in good yields from MeCN and simple 1,3-dicarbonyls. A radical mechanism is proposed.
C. Wang, Y. Li, M. Gong, Q. Wu, J. Zhang, J. K. Kim, M. Huang, Y. Wu, Org. Lett., 2016, 18, 4151-4153.

Knoevenagel condensation followed by hydrogenation with triethylamine-formic acid in the presence of a ruthenium-amido complex allowed an α-alkylation of various nitriles with carbonyl compounds in good yields. The reaction tolerated various functional groups, including nitro and chloro groups, and a furan ring.
H. Sun, D. Ye, H. Jiang, K. Chen, H. Liu, Synthesis, 2010, 2577-2582.

Benzylic, allylic, and aliphatic alcohols without β-branching have been converted to nitriles with two more carbon atoms than present in the substrate by treatment with an excess of (cyanomethyl)trimethylphosphonium iodide and subsequent in situ hydrolysis of the intermediate C-alkylated (cyanomethyl)phosphonium salts.
F. Zaragoza, J. Org. Chem, 2002, 67, 4963-4964.

A palladium-catalyzed double isocyanide insertion and elimination enables an efficient one-pot synthesis of α-iminonitriles from readily available aryl halides without using hypertoxic cyanides and excess oxidants. Furthermore, the utility of this reaction was demonstrated by a rapid total synthesis of a quinoxaline.
Z.-B. Chen, Y. Zhang, Q. Yuan, F.-L. Zhang, Y.-M. Zhu, J.-K. Shen, J. Org. Chem., 2016, 81, 1610-1616.