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Synthesis of Nitriles (cyanation)

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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.

Nickel catalyzes a cyanation of unactivated secondary alkyl chlorides or bromides using less toxic Zn(CN)₂ as the cyanide source to provide a broad range of alkyl nitriles. Cyanation of primary alkyl chlorides or bromides was also achieved by reaction with Zn(CN)₂ in the presence of n-Bu₄NCl without the need for a nickel catalyst.
A. Xia, X. Xie, J. Zhao, C. Zhang, Y. Liu, Org. Lett., 2018, 20, 7735-7739.

A Ph₃P/ICH₂CH₂I-promoted dehydroxylative cyanation of alcohols avoids the use of transition metals or moisture-sensitive Lewis acids. This protocol features convenient operations, mild reaction conditions, and the use of cheap and widely available reagents.
L. Luo, J.-H. Lin, J.-C. Xiao, Y. Hu, Synthesis, 2023, 55, 1593-1596.

Nickel catalyzes a cyanation of unactivated primary and secondary alkyl mesylates with Zn(CN)₂. The reaction provides an efficient route for the synthesis of alkyl nitriles with wide substrate scope, good functional group tolerance, and compatibility with heterocyclic compounds. A gradual in situ generation of alkyl iodide as the reactive intermediate is crucial for the success of the reaction.
A. Xia, P. Lv, X. Xie, Y. Liu, Org. Lett., 2020, 22, 7842-7847.

A nickel-catalyzed deaminative cyanation of Katritzky pyridinium salts with Zn(CN)₂ enables the conversion of primary alkyl amines to alkyl nitriles in good yields. The reaction tolerates diverse functional groups and heterocycles. The conversion of 2° Katritzky pyridinium salts is accompanied with partial inversion at the stereocenter consistent with formation of an alkyl radical intermediate.
J. Xu, J. C. Twitty, M. P. Watson, Org. Lett., 2021, 23, 6242-6245.

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.

A photoelectrochemical reaction converts carboxylic acids to enantioenriched nitriles by employing cerium/copper relay catalysis with a cerium salt for catalytic decarboxylation and a chiral copper complex for stereoselective C-CN formation.
X.-L. Lai, M. Chen, Y. Wang, J. Song, H.-C. Xu, J. Am. Chem. Soc., 2022, 144, 20201-20206.

The merger of photoredox catalysis with asymmetric copper catalysis enables the synthesis of enantiomerically enriched alkyl nitriles from achiral carboxylic acids under mild reaction conditions. The reaction exhibits broad substrate scope, high yields and high enantioselectivities. Furthermore, the reaction can be scaled up to synthesize key chiral intermediates to bioactive compounds.
D. Wang, N. Zhu, P. Chen, Z. Lin, G. Liu, J. Am. Chem. Soc., 2017, 139, 15632-15635.

Oxazoles function as nitrile equivalents in a cyanide-free dual Pd/CuH-catalyzed protocol for the asymmetric Markovnikov hydrocyanation of vinyl arenes and the anti-Markovnikov hydrocyanation of terminal olefins. After an initial hydroarylation process, the oxazole substructure was deconstructed using a mild [4 + 2]/retro-[4 + 2] sequence to afford the enantioenriched nitrile product.
A. W. Schuppe, G. M. Borrajo-Calleja, S. L. Buchwald, J. Am. Chem. Soc., 2019, 141, 18668-18672.

A practical reversible transfer hydrocyanation protocol exhibits high selectivity for the thermodynamically less favorable branched isomer based on the design of a novel type of HCN donor.
B. N. Bhawal, J. C. Reisenbauer, C. Ehinger, B. Morandi, J. Am. Chem. Soc., 2020, 142, 10914-10920.

A nickel-catalyzed Markovnikov hydrocyanation of α-substituted styrenes enables the synthesis of tertiary benzylic nitriles in good yields. This Lewis-acid-free transformation features an unprecedented functional groups tolerance.
Y. Xing, R. Yu, X. Fang, Org. Lett., 2020, 22, 1008-1012.

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.

A copper-catalyzed cyanation of N-tosylhydrazones provides α-aryl nitriles in the presence of thiocyanate as a low-toxic cyanide source. The convenient method offers a broad substrate scope.
Y. Huang, Y. Yu, Z. Zhu, C. Zhu, J. Cen, X. Li, W. Wu, H. Jiang, J. Org. Chem., 2017, 82, 7621-4627.

Transfer hydrocyanation represents a clean and safe alternative to hydrocyanation processes using toxic HCN gas. An efficient and practical cooperative palladium/Lewis acid-catalyzed transfer hydrocyanation of alkenes and alkynes with 1-methylcyclohexa-2,5-diene-1-carbonitrile as a benign and readily available HCN source provides a large set of nitrile derivatives with good to excellent anti-Markovnikov selectivity.
A. Bhunia, K. Bergander, A. Studer, J. Am. Chem. Soc., 2018, 140, 15976-15984.

A nickel complex catalyzes a highly regioselective isomerization/hydrocyanation of aliphatic internal olefins to provide facile access to a wide variety of aliphatic nitriles in very good yields. Thanks to Lewis acid-free conditions, the protocol tolerates a broad range of functional groups, including secondary amines and unprotected alcohols.
J. Gao, J. Ni, R. Yu, G.-J. Cheng, X. Fang, Org. Lett., 2021, 23, 486-490.

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.

Multichiral diphosphite ligands enable a regio-, chemo-, and enantioselective nickel-catalyzed hydrocyanation of 1,3-dienes. In addition to aryl-substituted 1,3-dienes, highly challenging aliphatic 1,3-diene substrates can also be converted to the corresponding 1,2-adducts with high enantioselectivities.
R. Yu, Y. Xing, X. Fang, Org. Lett., 2021, 23, 930-935.

A (R,R)-Ph-BPE-Ni(0) complex catalyzes an enantioselective hydrocyanation of allenes to provide optically active allylic nitriles in good yield with excellent enantioselectivities.
J. Long, J. Gao, X. Fang, Org. Lett., 2020, 22, 376-380.

TADDOL-based diphosphite ligands were applied in the nickel-catalyzed asymmetric hydrocyanation of disubstituted methylenecyclopropanes to provide allylic nitriles in good yield with excellent enantioselectivities.
R. Yu, X. Fang, Org. Lett., 2020, 22, 493-496.

By using synergetic photoredox/copper catalysis, a visible-light-induced, enantioselective carbocyanation of 1,3-dienes with carboxylic acid derivatives and trimethylsilyl cyanide is achieved under mild and neutral conditions. A diverse range of chiral allyl cyanides is produced in generally good efficiency and with high enantioselectivity from bench-stable and user-safe chemicals.
F.-D. Lu, L. Q. Lu, G.-F. He, J.-C. Bai, W.-J. Xiao, J. Am. Chem. Soc., 2021, 143, 4168-4173.

A highly atom-economical strategy for a copper-catalyzed synthesis of chiral propargylic cyanides is based on a direct decarboxylation of propargylic carboxylic acids without preactivation. The reactions show excellent selectivity and functional group compatibility. Gram-scale reaction and several conversion reactions from chiral propargylic cyanide have demonstrated the synthetic value of this strategy.
G. Zhang, Y. Pei, J. Wang, X. Zhu, Z. Li, F. Zhao, F. Zhao, J. Wu, Org. Lett., 2023, 25, 5006-5010.

A dual photoredox and copper catalysis enables an asymmetric propargylic cyanation with high reaction efficiency and enantioselectivities. Whereas an organic photocatalyst serves to generate propargyl radicals and oxidize Cu(I) to Cu(II), the chiral Cu complex functions as an efficient catalyst to resemble the propargyl radical and cyanide in an enantio-controlled manner.
F.-D. Lu, D. Liu, L.-Q. Lu, Q. Yang, Q.-Q. Zhou, Y. Wei, Y. Lan, W.-J. Xiao, J. Am. Chem. Soc., 2019, 141, 6167-6172.

A site-selective cyanation of the sp² C-H bond of allenes using a copper-catalyzed radical relay affords various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. The excellent site-selectivity toward can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical.
Z. Cheng, T. Yang, C. Li, Y. Deng, F. Zhang, P. Chen, Z. Lin, S. Ma, G. Liu, J. Am. Chem. Soc., 2023, 145, 25995-26002.

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.

Electrophotochemical cerium catalysis enables a versatile redox-neutral method for the ring-opening functionalization of cycloalkanols. The reaction tolerates a broad range of functional groups. Even in the presence of chloride as a counteranion and electrolyte, this protocol selectively leads to the formation of C-CN, C-C, C-S, or C-oxime bonds instead of a C-halide bond after β-scission.
Z. Yang, D. Yang, J. Zhang, C. Tan, J. Li, S. Wang, H. Zhang, Z. Huang, A. Lei, J. Am. Chem. Soc., 2022, 144, 13006-13017.

The use of an electrophilic cyanation source enables electrocatalytic three-component acylcyanations and aminocyanations of a broad range of simple alkenes. The reaction offers high functional group tolerance and can easily be scaled up.
X. Kong, X. Chen, Y. Chen, Z.-Y. Cao, J. Org. Chem., 2022, 87, 7013-7021.

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 Lewis acidic activation of a hypervalent iodine reagent containing a transferable cyano group achieves a catalytic electrophilic cyanation of silyl enol ethers. Mechanistic studies indicate that the hypervalent iodine reagent is activated through coordination of its cyano group to B(C₆F₅)₃.
T. Nagata, H. Matsubara, K. Kiyokawa, S. Minakata, Org. Lett., 2017, 19, 4672-4675.

A reductive cyanation of tertiary alkyl bromides using an electrophilic cyanating reagent and zinc reductant provides various α-cyano ketones, esters, and carboxamides containing a nitrile-bearing all-carbon quaternary center in very good yields under mild reaction conditions.
X. Shen, G. Whang, Z. Shi, X. Tian, K. Dong, Org. Lett., 2021, 23, 2527-2532.

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.

Trifluoromethylsulfonyl-pyridinium salt (TFSP) is an efficient, solid trifluoromethylation reagent, which can be readily prepared from cheap and easily available bulk industrial feedstocks. TFSP can generate a trifluoromethyl radical under photocatalysis, that can be used for azido- or cyano-trifluoromethylation reactions of alkenes.
M. Zhang, J.-H. Lin, J.-C. Xiao, Org. Lett., 2021, 23, 6079-6083.

Base-catalyzed/mediated nucleophilic additions of TMSCN to α-(trifluoromethyl)styrenes and 2-trifluoromethyl enynes proceeded smoothly at room temperature under mild and transition-metal-free conditions without affecting the trifluoromethyl group to afford the corresponding CF₃-containing alkyl, alkynyl, and butadienyl nitriles in good yields in a highly regioselective manner.
L. Liu, L. Li, X. Wang, R. Sun, M.-D. Zhou, H. Wang, Org. Lett., 2021, 23, 5826-5830.

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.

Mn(OAc)₃-mediated phosphinoyl radical addition followed by CuCN-catalyzed cyanation enables a double-functionalization reaction of alkenes under mild conditions to afford vicinal cyanophosphinoylation products.
P.-Z. Zhang, L. Zhang, J.-A. Li, A. Shoberu, J.-P. Zou, W. Zhang, Org. Lett., 2017, 19, 5537-5540.

A palladium-catalyzed direct cyanoesterification of cyclopropenes enables a highly atom economic and diastereoselective synthesis of synthetically useful cyclopropanecarbonitriles. The reaction offers mild conditions, good functional group compatibility, and simple operation.
C. Li, R. Yu, S.-Z. Cai, X. Fang, Org. Lett., 2023, 25, 5128-5133.