Categories: C-C Bond Formation > Nitrogen-containing molecules >
Synthesis of Nitriles (Cyanomethylation)
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Recent Literature
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.
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.
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.
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.