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Synthesis of α-Aminonitriles

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S-oxidation of potassium thiocyanate releases cyanide units that can be trapped in the presence of co-oxidized tertiary amines to form α-amino nitriles. These cyanations work in aqueous solutions without catalyst and without toxic byproducts.
A. Wagner, A. R. Ofial, J. Org. Chem., 2015, 80, 2848-2854.

A transition-metal-free α-cyanation of easy accessible N-fluorotosylsulfonamides provides α-amino nitriles through elimination of HF. More than 50 substrate examples, including difficult-to-access all-alkyl α-tertiary scaffolds, prove a wide functional group tolerance. The method also offers gram-scalability and late-stage modification of natural compounds.
S. Shi, X. Yang, M. Tang, J. Hu, T.-P. Loh, Org. Lett., 2021, 23, 4018-4022.

A mild protocol for the α-C-H cyanation of tertiary aliphatic, benzylic, and aniline-type substrates and complex substrates tolerates a broad range of fuctional groups, including various heterocycles and ketones, amides, olefins, and alkynes. The presented catalyst system especially tolerates functional groups that typically react with free radicals, suggesting an alternative reaction pathway.
O. Yilmaz, C. Dengiz, M. H. Emmert, J. Org. Chem., 2021, 86, 2489-2498.

RuCl₃-catalyzed oxidative cyanation of tertiary amines with sodium cyanide under molecular oxygen at 60°C gives the corresponding α-aminonitriles in excellent yields. This reaction is clean and should be an environmentally benign and useful process.
S.-I. Murahashi, N. Komiya, H. Terai, T. Nakae, J. Am. Chem. Soc., 2003, 125, 15312-15313.

In situ generation of N-unsubstituted ketimines enables a one-pot catalytic synthesis of α-tetrasubstituted amino acids. Because of the irreversible formation of N-unsubstituted ketimines, the yields were higher than those generated under the conventional one-pot reaction conditions.
Y. Kondo, Y. Hirazawa, T. Kadota, K. Yamada, K. Morisaki, H. Morimoto, T. Ohshima, Org. Lett., 2022, 24, 6594-6598.

4-CN-pyridine is an effective cyanation reagent under catalyst-free, paired electrochemical reaction conditions. Mechanistic studies support a nucleophilic reaction pathway, and the cyanation protocol can be applied to diverse substrates including N,N-dialkyl anilines, indole derivatives and amino acids (via decarboxylative cyanation).
G. S. Kumar, P. S. Shinde, H. Chen, K. Muralirajan, R. Kancherla, M. Rueping, Org. Lett., 2022, 24, 6357-6363.

A highly efficient, direct C(sp³)-H cyanation under mild photocatalytic conditions offers excellent functional group tolerance. Notably, complex natural products and bioactive compounds were efficiently cyanated.
K. Kim, S. Lee, S. H. Hong, Org. Lett., 2021, 23, 5501-5505.

A novel, simple and efficient one-pot synthesis of α-aminonitriles has been achieved by a three-component condensation of carbonyl compounds, amines and trimethylsilyl cyanide in the presence of (bromodimethyl)sulfonium bromide as a catalyst at room temperature.
B. Das, R. Ramu, B. Ravikanth, K. Ravinder Reddy, Synthesis, 2006, 1419-1422.

An environmentally benign and highly efficient, biomimetic procedure for the nucleophilic addition of trimethylsilyl cyanide to imines (Strecker reaction) using β-cyclodextrin as a catalyst and water as solvent afforded α-aminonitriles in quantitative yields. The catalyst can be recycled a number of times without loss in activity.
K. Surendra, N. S. Krishnaveni, A. Mahesh, K. R. Rao, J. Org. Chem., 2006, 71, 2532-2534.

A very fast, simple one-step, environmentally friendly procedure for the synthesis of α-aminonitriles in high yields from aldehydes, using trimethylsilyl cyanide in the absence of solvent, gives almost quantitative yields of the corresponding α-aminonitriles. However, only cyclic ketones afford the corresponding α-aminonitriles in excellent chemical yields.
A. Baeza, C. Nájera, J. M. Sansano, Synthesis, 2007, 1230-1234.

A simple and efficient one-pot, three-component Strecker reaction of aldehydes and ketones with aliphatic or aromatic amines and trimethylsilyl cyanide in the presence of a palladium Lewis acid catalyst allows the synthesis of α-aminonitriles in good yields at room temperature.
J. Jarusiewicz, Y. Choe, K. Soo. Yoo, C. P. Park, K. W. Jung, J. Org. Chem., 2009, 74, 2873-2876.

After an iridium-catalyzed reduction of secondary amides, the resulting imines can undergo the Strecker reaction, the Mannich reaction, allylation, and [3 + 2]-cycloaddition. The method shows high chemoselectivity in the presence of other functional groups such as methyl ester.
Y. Takahashi, R. Yoshii, T. Sato, N. Chida, Org. Lett., 2018, 20, 5705-5708.

A highly enantioselective cyanation of imines at room temperature in the presence of 5 mol% of a partially hydrolyzed titanium alkoxide (PHTA) precatalyst together with a readily available N-salicyl-β-aminoalcohol ligand gives aminonitriles with up to 98% ee and quantitative yields in 15 min of reaction time. Various N-protecting groups are tolerated.
A. M. Seayad, B. Ramalingam, K. Yushinaga, T. Nagata, C. L. L. Chai, Org. Lett., 2010, 12, 264-267.

A simple, mild, catalyst-free, and efficacious KOtBu-mediated reductive cyanation reaction of tertiary amides provides a series of α-aminonitriles in good yields under hydrosilylation conditions with good functional group tolerance. The reaction works well with readily available amide substrates, cheap KOtBu, and a commercially available hydrosilane (EtO)₃SiH and the workup is convenient.
L . Liu, Y. Liu, X. Shen, X. Zhang, S. Deng, Y. Chen, J. Org. Chem., 2022, 87, 6321-6329.

An efficient, safe, and environmentally friendly TBHP-mediated rearrangement of aryl/alkylidene malononitrile with anilines produces in situ HCN as the cyanide source for the synthesis of substituted α-aminonitriles and α-aminoamides in very good yields. This method features good functional group tolerance, and the in situ-generated HCN bypasses the use of an external cyanide source.
S. P. Bhoite, A. H. Bansode, G. Suryavanshi, J. Org. Chem., 2020, 85, 14858-14865.

An indium-catalyzed three-component coupling reaction of alkynes, amines, and trimethylsilyl cyanide provides quaternary α-aminonitrile derivatives via hydroamination of the alkyne and a subsequent nucleophilic addition of Me₃SiCN.
Y. Hamachi, M. Katano, Y. Ogiwara, N. Sakai, Org. Lett., 2016, 18, 1634-1637.

An aluminum complex was found to be high yielding and enantioselective for the addition of cyanide to aldimines and ketimines. The present catalyst provides uniformly high enantioselectivity for aromatic, heteroaromatic, and aliphatic aldimines and ketimines using ethyl cyanoformate as the cyanide source.
J. P. Abell, H. Yamamoto, J. Am. Chem. Soc., 2009, 131, 15118-15119.

An N-heterocyclic carbene as a nucleophilic organocatalyst allows the cyanation of ketones and ketimines with TMSCN in good yields under mild reaction conditions.
Y. Fukuda, K. Kondo, T. Aoyama, Synthesis, 2006, 2649-2652.

Aryl imines, formed in situ from aldehydes and amines undergo mild nucleophilic addition with trimethylsilyl cyanide on the surface of montmorillonite KSF clay to afford the corresponding α-aminonitriles in excellent yields. The solid acid can be recovered and recycled in subsequent reactions with a gradual decrease of activity.
J. S. Yadav, B. V. S. Reddy, B. Eeshwaraiah, M. Srinivas, Tetrahedron, 2004, 60, 1767-1771.

Related

An oxidative Strecker reaction of aldehydes, amines, and TMSCN in a biphasic solvent system in the presence of Oxone, TBAB and sodium bicarbonate affords α-iminonitriles in good yields. This three component reaction is applicable to a wide range of aldehydes and amines.
J.-B. Gualtierotti, X. Schumacher, Q. Wang, J. Zhu, Synthesis, 2013, 45, 1380-1386.