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Synthesis of Nitriles (cyanation)


Name Reactions

Kolbe Nitrile Synthesis

Van Leusen Reaction

Recent Literature

Nucleophilic fluorination using CsF or alkali metal fluorides was completed in short reaction time in the presence of [bmim][BF4] affording the desired products without any byproducts. Facile nucleophilic substitutions such as halogenations, acetoxylation, nitrilation, and alkoxylations in the presence of ionic liquids provided the desired products in good yields.
D. W. Kim, C. E. Song, D. Y. Chi, J. Org. Chem., 2003, 68, 4281-4285.

In the presence of inexpensive CuI and a readily available light source (UVC compact fluorescent light bulb), a wide array of secondary alkyl halides undergo cyanation in good yield.
T. S. Ratani, S. Bachman, G. C. Fu, J. C. Peters, J. Am. Chem. Soc., 2015, 137, 13902-13907.

Tosylmethyl isocyanide allows an efficient conversion of ketones into nitriles by adding one carbon unit to a ketone without formation of an α-hydroxy group. The synthesis of nitriles is applicable to a broad range of ketones.
O. H. Oldenziel, D. Van Leusen, A. M. Van Leusen, J. Org. Chem., 1977, 42, 3114-3118.

Indium(III)-catalyzed reductive iodination or bromination of carboxylic acids enables a one-pot preparation of alkyl cyanides from carboxylic acids via alkyl iodides or alkyl bromides.
T. Moriya, K. Shoji, S. Yoneda, R. Ikeda, T. Konakahara, N. Sakai, Synthesis, 2013, 45, 3233-3238.

Hydroboration with catecholborane, followed by treatment with easily available reagents such as alkenyl sulfones or alkynyl phenyl sulfones in the presence of a radical initiator, represents an effective and simple one-pot procedure for direct vinylation, formylation, and cyanation.
A.-P. Schaffner, V. Darmency, P. Renaud, Angew. Chem. Int. Ed., 2006, 45, 5847-5849.

A direct cyanation of benzylic alcohols with TMSCN under the catalysis of 5-10 mol % of InBr3 allows the synthesis of the corresponding nitriles in short reaction time with good yields.
G. Chen, Z. Wang, J. Wu, K. Ding, Org. Lett., 2008, 10, 4573-4576.

A copper-catalyzed reaction of terminal alkynes with cyanogen iodide (ICN) produces alkynyl cyanides in the presence of of tetramethylpiperidine as a sterically congested base. Some control experiments revealed that the reaction involves the noncatalyzed formation of alkynyl iodides followed by copper-catalyzed cyanation of the iodides without the formation of copper(I) acetylide.
K. Okamoto, M. Watanabe, N. Sakata, M. Murai, K. Ohe, Org. Lett., 2013, 15, 5810-5813.

A facile and efficient 1,4-addition of Me3SiCN to enones has been achieved with perfect regioselectivity using Cs2CO3 as catalyst in the presence of H2O as an additive. β-Cyanoketones are obtained in excellent yields within one to five hours. Both aromatic and aliphatic enones are suitable substrates.
J. Yang, Y. Shen, F.-X. Chen, Synthesis, 2010, 1325-1333.

An efficient 1,4-addition of TMSCN to aromatic enones has been achieved in excellent yields in the presence of CsF as catalyst and H2O as an additive in refluxing dioxane.
J. Yang, Y. Wang, S. Wu, F.-X. Chen, Synlett, 2009, 3365-3367.

Gd(OTf)3 as co-catalyst dramatically accelerated a Ni-catalyzed conjugate addition of cyanide to enones. The substrate scope of the reaction is broad, including cyclic, linear, branched, and aromatic enones. Gadolinium triflate is supposed to facilitate the oxidative addition of Ni(0) to enones, which constitutes a key step in the catalytic cycle.
Y. Tanaka, M. Kanai, M. Shibasaki, Synlett, 2008, 2295-2298.

A selective conjugate hydrocyanation of aromatic enones by a one-pot, two-step procedure takes place in the presence of potassium hexacyanoferrate(II) as an original eco-friendly cyanide source, potassium hydroxide as a base, and benzoyl chloride as a promoter. This protocol has the advantages of a nontoxic cyanide source, high yield, and simple workup procedure.
Z. Li, C. Liu, Y. Zhang, R. Li, B. Ma, J. Yang, Synlett, 2012, 23, 2567-2571.

A procedure for a Cu-catalyzed hydrocyanation of α-aryl diazoesters using acetone cyanohydrin as a source of hydrogen cyanide is significantly accelerated by addition of trimethylsilyl cyanide (TMSCN) presumably by delivering free cyanide ion in situ. This method provides various types of α-aryl cyanoacetates in good yields under mild conditions.
E. J. Park, S. Lee, S. Chang, J. Org. Chem., 2010, 75, 2760-2762.

A (Salen)Al-Cl complex catalyzes the asymmetric conjugate addition of hydrogen cyanide to α,β-unsaturated imides in high yields and enantioselectivities. The cyanide adducts can readily be converted into a variety of useful chiral building blocks, including α-substituted-β-amino acids.
G. M. Sammis, E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125, 4442-4443.

A clean and efficient method for the oxidative transformations of primary carboxamides to one-carbon dehomologated nitriles using the combination of o-iodoxybenzoic acid and tetraethylammonium bromide exhibits a broad scope and is expected to be of great utility in organic synthesis.
D. S. Bhalarao, U. S. Mahajan, K. H. Chaudhari, K. G. Akamanchi, J. Org. Chem., 2007, 72, 662-665.

An indium triiodide catalyzed deoxygenative functionalization of N-sulfonyl amides with silyl cyanide or silyl enolates in the presence of hydrosilanes gives α-cyanoamines and β-aminocarboxyl compounds, respectively.
Y. Inamoto, Y. Kaga, Y. Nishimoto, M. Yasuda, A. Baba, Org. Lett., 2013, 15, 3448-3451.

In the presence of oxygen and a small amount of AIBN as radical initiator, primary amines are oxidatively coupled to imines and tertiary amines are cyanated to α-aminonitriles. These metal-free aerobic oxidative coupling reactions may find applications in a wide range of green oxidation chemistry.
L. Liu, Z. Wang, X. Fu, C.-H. Yan, Org. Lett., 2012, 14, 5692-5695.

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.

A copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes provides various CF3-containing alkylnitriles with excellent enantiomeric excess. The reaction is initiated by a SET process between activated Togni’s CF3+ reagent and a Cu(I) catalyst. The released CF3 radical readily added to styrene to provide a benzylic radical, which is then trapped by a chiral Cu(II) cyanide species.
F. Wang, D. Wang, X. Wan, L. Wu, P. Chen, G. Liu, J. Am. Chem. Soc., 2016, 138, 15547-15550.

A highly practical copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes provides a general and straightforward way to synthesize various useful CF3-containing nitriles, which can be used for the preparation of pharmaceutically and agrochemically important compounds.
Y.-T. He, L.-H. Li, Y.-F. Yang, Z.-Z. Zhou, H.-L. Hua, X.-Y. Liu, Y.-M. Liang, Org. Lett., 2014, 16, 270-273.

A highly regioselective cyanotrifluoromethylation of electron-deficient styrenes with a trifluoromethylated hypervalent iodine reagent proceeds under mild conditions in the presence of a bulky phosphine and CuCN. The process involves the consecutive formation of two C-C bonds in a single addition reaction. In the presence of a p-methoxy substituent in the styrene, oxytrifluoromethylation occurs instead of the cyanotrifluoromethylation.
N. O. Ilchenko, P. G. Janson, K. J. Szabó, J. Org. Chem., 2013, 78, 11087-11091.