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Synthesis of Nitriles (Cyanomethylation)


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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 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 homogeneous nonprecious manganese catalyst enables a general and chemoselective catalytic alkylation of nitriles with naturally abundant alcohols. The reaction tolerates a wide range of functional groups and heterocyclic moieties and provides useful cyanoalkylated products with water as the only side product.
J. C. Borgh, M. A. Tran, J. Sklyaruk, M. Rueping, O. El-Sepelgy, J. Org. Chem., 2019, 84, 7927-7935.

A well-defined molecular homogeneous cobalt complex catalyzes an α-alkylation of nitriles with primary alcohols in very good yields. Remarkably, this transformation is environmentally friendly and atom economical with water as the only byproduct.
K. Paudell, S. Xu, K. Ding, J. Org. Chem., 2020, 85, 14980-14988.

An iron(0) catalyst system achieves chemoselectivity between borrowing hydrogen and dehydrogenative coupling protocols by simply changing the base. A broad range of nitriles and alcohols, including benzylic, linear aliphatic, cycloaliphatic, heterocyclic, and allylic alcohols, were selectively and efficiently converted to the corresponding α-alkylation or α-olefination products.
R. R. Putta, S. Chun, S. B. Lee, J. Hong, S. H. Choi, D.-C. Oh, S. Hong, J. Org. Chem., 2022, 87, 16378-16389.

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.

Practical and mild electrochemical cyanations and cyanomethylations of trimethylammonium salts with tosyl cyanide or azido allyl alcohol as the cyanation or cyanomethylation reagents offer high functional group compatibility and can be applied for the cyanation of natural product derivatives. The method avoids the use of an external stoichiometric reducing agent or a sacrificial anode.
X. Kong, Y. Wang, Y. Chen, X. Chen, L. Lin, Z.-Y. Cao, Org. Chem. Front., 2022, 9, 1288-1294.

The use of trimethylamine-borane facilitates a six-electron reduction of CO2 for a highly selective monomethylation of 2-arylacetonitrile derivatives. Various 2-arylpropionitriles were obtained in good yields.
X. Zhang, S. Wang, C. Xi, J. Org. Chem., 2019, 84, 9744-9749.

A cyanomethyl radical species generated from a cyanomethylphosphonium ylide by irradiation with visible light in the presence of an iridium complex, a thiol, and ascorbic acid enables an efficient 1,2-hydro(cyanomethylation) of alkenes. The cyanomethyl radical species adds across the C=C double bond to form an elongated alkyl radical species that accepts a hydrogen atom from the thiol.
T. Miura, D. Moriyama, Y. Funakoshi, M. Murakami, Synlett, 2019, 30, 511-514.

t-BuOK catalyzes the addition of ketones or imines to styrenes in very good yield in NMP or in DMSO at room temperature.
A. L. Rodriquez, T. Bunlaksananusorn, P. Knochel, Org. Lett., 2000, 2, 3285-3287.

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.

A Rh/silane-cocatalyzed regio- and enantioselective allylic cyanomethylation with inert acetonitrile directly provides mono- and bis-allylation products by adjusting the size of substituents on the silane, ligands, and temperature. Addition of a catalytic amount neutral silane reagent as an acetonitrile anion carrier is essential for the success of this reaction.
M. Sun, L. Wei, C. Li, J. Am. Chem. Soc., 2023, 145, 3897-3902.

A Rh/silane-cocatalyzed regio- and enantioselective allylic cyanomethylation with inert acetonitrile directly provides mono- and bis-allylation products by adjusting the size of substituents on the silane, ligands, and temperature. Addition of a catalytic amount neutral silane reagent as an acetonitrile anion carrier is essential for the success of this reaction.
M. Sun, L. Wei, C. Li, J. Am. Chem. Soc., 2023, 145, 3897-3902.

Iodine promotes a metal-free Csp2-Csp3 coupling between olefins and AIBN or ACCN to provide allyl nitriles with N2 as the only byproduct. More than 30 examples of desired products including aromatic and aliphatic nitriles have been synthesized in very good yields.
Z.-z. Cao, Z. Nie, T. Yang, M. Su, H. Li, W.-p. Luo, Q. Liu, C.-C. Guo, J. Org. Chem., 2020, 85, 3287-3296.

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 convenient and general atom transfer radical addition (ATRA) of simple nitriles, ketones, and esters to alkynes provides a wide range of β,γ-unsaturated nitriles, ketones, and esters.
Y. Xiao, Z.-Q. Liu, Org. Lett., 2019, 21, 8810-8813.

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.

An efficient and convenient NHC (N-heterocyclic carbene)-catalyzed radical coupling reaction between aldehydes and azobis(isobutyronitrile) (AIBN) provides β-ketonitriles containing a quaternary carbon center in very good yields. This protocol offers broad substrate scope and good functional group tolerance under metal-free and mild reaction conditions.
J.-M. Wang, T. Chen, C.-S. Yao, K. Zhang, Org. Lett., 2023, 25, 3325-3329.

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.

An intermolecular addition of malononitrile and related pronucleophiles to several 1,3-disubstituted acyclic 1,3-dienes in the presence of a Pd-PHOX catalyst provides products with quaternary stereogenic centers in good yield, excellent er, and in most cases as a single regioisomer. The products undergo oxidative functionalization to afford β,γ-unsaturated carboxylic acid derivatives.
N. J. Adamson, S. Park, P. Zhou, A. L. Nguyen, S. J. Malcolmson, Org. Lett., 2020, 22, 2017-2021.

A cobalt-catalyzed enantioselective allylic alkylation of malononitriles with allylic carbonates provides chiral γ,δ-unsaturated malononitriles with >20:1 branched/linear regioselectivity and up to 99% enantiomeric excess under mild reaction conditions. The ligand is essential to realize the high reactivity in the carbon-carbon bond formation process.
S. Ghorai, S. U. Rehman, W.-B. Xu, W.-Y. Huang, C. Li, Org. Lett., 2020, 22, 3519-3523.

Copper-catalyzed carboamination of alkenes enables an efficient synthesis of γ-amino butyric acid (GABA) derivatives from alkenes. In this difunctionalization reaction, acetonitrile serves as the source of the carbon and nitrogen functionalities. A copper-catalyzed radical-polar crossover mechanism is proposed.
N. Zhu, T. Wang, L. Ge, Y. Li, X. Zhang, H. Bao, Org. Lett., 2017, 19, 4718-4721.

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.

An ultrasound-promoted three-component reaction provides C3-cyanomethylated imidazo[1,2-a]pyridines under catalyst-free, oxidant-free, and mild conditions. A series of C3-cyanomethylated imidazo[1,2-a]pyridines were rapidly prepared with satisfactory yields and good functional group compatibility.
. Zhang, Y. Zhang, J. Zhang, Q. Wu, H. Yang, Synlett, 2022, 33, 264-268.