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Synthesis of Nitriles
The use of an O-protected oxime rather than an explosive O-protected hydroxylamine enables a safe, Brønsted acid-catalyzed synthesis of nitriles via O-protected aldoximes through transoximation. The reaction could be performed on a 1 g scale.
K. Hyodo, K. Togashi, N. Oishi, G. Hasegawa, K. Uchida, Org. Lett., 2017, 19, 3005-3008.
The Schmidt reaction of aldehydes with NaN3 furnishes the corresponding nitriles in near quantitative yields in the presence of TfOH and tolerates various electron-withdrawing and electron-donating substituents. Formanilides, common side products, are not observed. The reaction is easily scalable, high yielding, and nearly instantaneous.
B. V. Rokade, J. R. Prabhu, J. Org. Chem., 2012, 77, 5364-5370.
The use of inorganic reagents (NH2OH/Na2CO3/SO2F2) in DMSO enables a simple and practical transformation of readily available, inexpensive, and abundant aldehydes to highly valuable nitriles in a pot, atom, and step-economical manner without transition metals. The reaction offers a wide substrate scope and great functional group tolerability.
W.-Y. Fang, H.-L. Qin, J. Org. Chem., 2019, 84, 5803-5812.
Participation of 'activated DMSO' in the one-pot transformation of aldehydes to nitriles allows the generation of a wide range of aromatic, heterocyclic, and aliphatic nitriles with water as the only byproduct. A straightforward and practical procedure is demonstrated on a multigram scale.
J. K. Augustine, A. Bombrun, R. N. Atta, Synlett, 2011, 2223-2227.
A deep eutectic mixture of choline chloride and urea (1:2) is an efficient and ecofriendly catalyst for the one-pot synthesis of nitriles from aldehydes under solvent-free conditions under both conventional and microwave irradiation. Nitriles were obtained in good to excellent yields.
U. B. Patil, S. S. Shendage, J. M. Nagarkar, Synthesis, 2013, 45, 3295-3299.
In the presence of a catalytic amount of 4-AcNH-TEMPO, NaNO2, and HNO3, benzaldehydes underwent condensation with NH4OAc and a subsequent aerobic oxidation to produce nitriles selectively under O2. Aerobic oxidative conversion of a primary alcohol is also achieved.
J.-H. Noh, J. Kim, J. Org. Chem., 2015, 80, 11624-11628.
A copper-promoted C≡N triple bond cleavage of coordinated cyanide anion under a dioxygen atmosphere enables a nitrogen transfer to various aldehydes via a single electron-transfer process. This protocol provides a new cleavage pattern for the cyanide ion and maybe a more useful synthetic pathway to nitriles from aldehydes.
Q. Wu, Y. Luo, A. Lei, J. You, J. Am. Chem. Soc., 2016, 138, 2885-2888.
A mild, aerobic, catalytic synthesis of nitriles directly from alcohols and aqueous ammonia proceeds via a dehydrogenation cascade mediated by catalytic CuI, bpy, and TEMPO in the presence of oxygen. The substrate scope includes various functionalized aromatic and aliphatic alcohols. This protocol also enabled a one-pot synthesis of various biaryl heterocycles directly from commercially available alcohols.
W. Yin, C. Wang, H. Huang, Org. Lett., 2013, 15, 1850-1853.
A direct conversion of a wide range of aliphatic, benzylic, heteroaromatic, allylic, and propargyl alcohols into nitriles with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), iodosobenzene diacetate, and ammonium acetate as a nitrogen source proceeds through an oxidation-imination-aldimine oxidation sequence in situ. Highly chemoselective ammoxidation of primary alcohols in the presence of secondary alcohols was also achieved.
J.-M. Vatèle, Synlett, 2014, 25, 1275-1278.
Various alcohols were efficiently converted into the corresponding nitriles at room temperature by treatment with tert-butyl hypochlorite, diiodine, or 1,3-diiodo-5,5-dimethylhydantoin (DIH) in the presence of TEMPO, followed by treatment with diiodine and aqueous ammonia. The nitriles were obtained in good yields and high purities by a simple extraction of the reaction mixture with chloroform and subsequent removal of the solvent.
H. Shimojo, K. Moriyama, H. Togo, Synthesis, 2013, 45, 2155-2156.
An efficient one-pot conversion of various alcohols, aldehydes and primary amines into the corresponding nitriles in excellent yields was easily achieved by the use of trichloroisocyanuric acid (TCCA) as an oxidant in aqueous ammonia. Also, various benzylic halides were smoothly and directly converted into the corresponding aromatic nitriles in high yields under the same conditions.
H. Veisi, Synthesis, 2010, 2631-2635.
A facile nickel-catalyzed oxidation of primary alcohols with tetrabutylammonium peroxydisulfate in the presence of ammonium hydrogen carbonate under basic aqueous conditions provides access to various aliphatic, aromatic and heterocyclic nitriles in excellent yields with very high purity.
F.-E. Chen, Y.-Y. Li, M. Xu, H.-Q. Jia, Synthesis, 2002, 1804-1806.
A scalable cyanation of gem-difluoroalkenes to (hetero)arylacetonitrile derivatives offers mild reaction conditions, excellent yields, wide substrate scope, and broad functional group tolerance. Significantly, the use of aqueous ammonia entirely avoids toxic cyanating reagents or metal catalysis and enables a green synthesis of arylacetonitriles.
J.-Q. Zhang, J. Liu, D. Hu, J. Song, G. Zhu, H. Ren, Org. Lett., 2022, 24, 786-790.
Heterogeneous nitrogen-doped carbon-incarcerated iron/copper bimetallic nanoparticle (NP) catalysts showed a high activity for aerobic ammoxidation of alcohols to nitriles.
T. Yasukawa, X. Yang, S. Kobayashi, J. Org. Chem., 2020, 85, 7543-7548.
A ruthenium(II) complex bearing a naphthyridine-functionalized pyrazole ligand catalyzes an oxidant-free and acceptorless selective double dehydrogenation of primary amines to provide nitriles at moderate temperature.
I. Dutta, S. Yadav, A. Sarbajna, S. De, M. Hölscher, W. Leitner, J. K. Bera, J. Am. Chem. Soc., 2018, 140, 8662-8666.
An in situ formed complex of commercially available dichloro(1,5-cyclooctadiene) ruthenium(II) and simple hexamethylenetetramine catalyzes acceptorless dehydrogenative oxidation of primary amines into nitriles in good yields. The synthetic protocol is highly selective and produces hydrogen as the sole byproduct.
M. Kannan, S. Muthaiah, Synlett, 2020, 31, 1073-1076.
The reagents poly(N,N'-dichloro-N-ethylbenzene-1,3-disulfonamide) (PCBS) and N,N,N',N'-tetrachlorobenzene-1,3-disulfonamide (TCBDA) allow the preparation of N,N-dichloroamines, nitriles, and aldehydes from primary amines. A direct oxidative conversion of primary alcohols into nitriles was successfully carried out in aqueous ammonia.
R. Ghorbani-Vaghei, H. Veisi, Synthesis, 2009, 945-950.
Various primary alcohols, and primary, secondary, and tertiary amines were efficiently converted into the corresponding nitriles in good yields by oxidation with 1,3-diiodo-5,5-dimethylhydantoin (DIH) in aqueous ammonia at 60 °C.
S. Iida, H. Togo, Synlett, 2007, 407-410.
A tandem TBAB-catalyzed substitution and a subsequent novel oxidative rearrangement allow the synthesis of aryl or alkenyl nitriles from benzyl and allyl halides. The broad reaction scope and the mild conditions may make these methods of use in organic synthesis.
W. Zhou, J. Xu, L. Zhang, N. Jiao, Org. Lett., 2010, 12, 2888-2891.
An efficient and highly selective method for the oxidative conversion of primary amines to the corresponding nitriles using trichloroisocyanuric acid in the presence of catalytic TEMPO provides a new entry to the synthesis of various aliphatic, aromatic and heterocyclic nitriles in excellent yield.
F.-E. Chen, Y.-Y. Kuang, H.-F. Dai, L. Lu, M. Huo, Synthesis, 2003, 2629-2631.
Ruthenium supported on alumina acts as an efficient heterogeneous catalyst for the oxidation of non-activated as well as activated amines to the corresponding nitriles or imines with 1 atm of dioxygen or air.
K. Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed., 2003, 42, 1480-1483.
A simple base-promoted intramolecular nucleophilic aromatic substitution of N-[(2-nitrophenyl)sulfonyl]benzamides provides nitriles in very good yields under redox-neutral conditions and avoids the use of toxic cyanide species and transition metals. This process shows broad scope and tolerates various functional groups.
M. Abe, S. Nitta, E. Miura, T. Kimachi, K. Inamoto, J. Org. Chem., 2022, 87, 4460-4467.
[RuCl2(p-cymene)]2 catalyzes a highly efficient dehydration of aldoximes in the presence of molecular sieves under essentially neutral and mild conditions to provide various types of cyano compounds in very good yields.
S. H. Yang, S. Chang, Org. Lett., 2001, 3, 4209-4211.
A traceless directing group strategy enables a nickel-catalyzed transformation of alkene-tethered oxime ethers to nitriles. A series of alkene-tethered oxime ethers derived from benzaldehyde and cinnamyl aldehyde derivatives were converted into the corresponding benzonitriles and cinnamonitriles in good yields.
Y. Takahashi, H. Tsuji, M. Kawatsurna, J. Org. Chem., 2020, 85, 2654-2665.
In the presence of an easily prepared supported ruthenium hydroxide catalyst, Ru(OH)x/Al2O3, various primary azides including benzylic, allylic, and aliphatic ones could be converted into the corresponding nitriles in good yields. The Ru(OH)x/Al2O3 catalyst could be further employed for synthesis of amides in water from benzylic or aliphatic primary azides.
J. He, K. Yamaguchi, N. Mizuno, J. Org. Chem., 2011, 76, 4552-4553.
A transition-metal-free deacylative C(sp3)-C(sp2) bond cleavage enables a practical oxidative amination of ketones and aldehydes to nitriles using cheap and commercially abundant NaNO2 as the oxidant and the nitrogen source. Various nitriles bearing aryl, heteroaryl, alkyl, and alkenyl groups could be smoothly obtained from ketones and aldehydes in high yields.
J.-J. Ge, C.-Z. Yao, M.-M. Wang, H.-X. Zheng, Y.-B. Kang, Y. Li, Org. Lett., 2016, 18, 228-231.
A metal-free C≡C bond cleavage of terminal alkynes in the presence of tBuONO as a powerful nitrogenating agent provides a vast range of nitriles containing aryl, heteroaryl, and natural product derivatives.
U. Dutta, D. W. Lupton, D. Maiti, Org. Lett., 2016, 18, 860-863.
A metal-free PhI(OAc)2 mediated nitrogenation of alkenes via C=C bond cleavage using inorganic ammonia salt as nitrogen source under mild conditions affords nitriles in good yields. The method offers mild reaction conditions, operational simplicity, and use of an ammonium salt as nitrogen source. A plausible reaction mechanism is proposed.
J.-H. Xu, Q. Jiang, C.-C. Guo, J. Org. Chem., 2013, 78, 11881-11882.
The combination of TpRh(C2H4)2 and P(2-furyl)3 catalyzes the reaction of tertiary alkyl-substituted alkynes with tert-butylhydrazine providing 3,3,3-trisubstituted propionitrile derivatives. This reaction system is also applicable to 1,1-disubstituted propargyl alcohols and amines to afford the corresponding β-cyanohydrins and β-amino nitriles, respectively.
Y. Fukumoto, Y. Tamura, Y. Iyori, N. Chatani, J. Org. Chem., 2016, 81, 3161-3167.
A direct conversion of various benzylic alkyl halides and primary alkyl halides into corresponding nitriles was efficiently and simply carried out in aqueous ammonia in the presence of molecular iodine as oxidant.
S. Iida, H. Togo, Synlett, 2008, 1639-1642.
Among the reported examples of new reactivity of the hypervalent iodine reagent DMP (Dess-Martin periodinane) are the one-step oxidation of secondary amides to imides and N-acyl vinylogous carbamates or ureas and the direct oxidation of benzylic and related primary amines to the corresponding nitriles.
K. C. Nicolaou, C. J. N. Mathison, Angew. Chem. Int. Ed., 2005, 44, 5992-5997.
The use of oxalyl chloride with a catalytic amount of dimethyl sulfoxide in the presence of Et3N enables the preparation of nitriles from primary amides or aldoximes within 1 h at room temperature. A diverse range of nitriles were obtained in good to excellent yields, including aromatic, heteroaromatic, cyclic, and acyclic aliphatic compounds.
R. Ding, Y. Liu, M. Han, W. Jiao, J. Li, H. Tian, B. Sun, J. Org. Chem., 2018, 83, 12939-12944.
A dehydration reaction of aldoximes and amides for the synthesis of nitriles using XtalFluor-E proceeds rapidly at room temperature in an environmentally benign solvent with only a slight excess of the dehydrating agent. A broad scope of nitriles can be prepared, including chiral products without racemization.
M. Keita, M. Vandamme, J.-F. Paquin, Synthesis, 2015, 47, 3758-3766.
The use of SO2F2 as a reagent enables a rapid, simple and mild dehydration of aldoximes to give the corresponding nitriles. A variety of (hetero)arene, alkene, alkyne and aliphatic aldoximes can be converted to nitriles in excellent yields with great functional group compatibilities in acetonitrile under ambient conditions. An eco-friendly protocol with aqueous methanol as solvent is also described.
Y. Zhao, G. Mei, H. Wang, G. Zhang, C. Ding, Synlett, 2019, 30, 1484-1488.
A palladium(II)-catalyzed reaction of a broad range of primary amides provides nitriles in the presence of Selectfluor. This efficient and chemoselective reaction tolerates steric bulk and electronic modification.
M. H. Al-Huniti, J. Rivera-Chávez, K. L. Colón, J. L. Stanley, J. E. Burdette, C. J. Pearce, N. H. Oberlies, M. P. Croatt, Org. Lett., 2018, 20, 6046-6050.
A highly expedient catalytic Appel-type dehydration of amides to nitriles in the presence of oxalyl chloride and triethylamine along with triphenylphosphine oxide as a catalyst is usually complete in less than 10 min. The reaction tolerates aromatic, heteroaromatic, and aliphatic amides, including derivatives of α-hydroxy and α-amino acids.
S. A. Shipilovskikh, V. Yu. Vaganov, E. I. Denisova, A. E. Rubtsov, A. V. Malkov, Org. Lett., 2018, 20, 728-731.
A copper-hydride-catalyzed silylative dehydration of primary amides is an economical approach to the synthesis of nitriles. The reaction avoids a typically challenging 1,2-siloxane elimination step, proceeds at ambient temperature, and tolerates a variety of metal-, acid-, or base-sensitive functional groups.
R. Y. Liu, M. Bae, S. L. Buchwald, J. Am. Chem. Soc., 2018, 140, 1627-1631.
A convenient protocol for the catalytic dehydration of aromatic and aliphatic amides using silanes in the presence of catalytic amounts of fluoride allows the synthesis of a wide range of aliphatic and aromatic nitriles with high selectivity under mild conditions.
S. Zhou, K. Junge, D. Addis, S. Das, M. Beller, Org. Lett., 2009, 11, 2461-2464.
Propylphosphonic anhydride (T3P) is an efficient reagent for the transformation of aromatic, heteroaromatic, and aliphatic aldehydes to respective nitriles in excellent yields. This procedure offers simple and one-pot access to nitriles and highlights the synthetic utility of T3P as a versatile reagent in organic chemistry.
J. K. Augustine, R. N. Atta, B. K. Ramappa, C. Boodappa, Synlett, 2009, 3378-3382.
An ethyl dichlorophosphate/DBU-mediated dehydration of aldoxime intermediates from aldehydes enables a new and efficient one-pot conversion of various aldehydes into the corresponding nitriles under mild reaction conditions.
J.-L. Zhu, F.-Y. Lee, J.-D. Wu, C.-W. Kuo, K.-S. Shia, Synlett, 2007, 1317-1319.
Areneselenenic acids (ArSeOH), that are readily generated from diaryl diselenides and H2O2 by in situ oxidation, are effective and recycable catalysts for dehydration of aldoximes. The catalysts enable a practical and scalable preparation of useful organonitriles under mild conditions.
L. Yu, H. Li, X. Zhang, J. Ye, J. Liu, Q. Xu, M. Lautens, Org. Lett., 2014, 16, 1346-1349.
PhSe(O)OH is a good pre-catalyst for aldoxime dehydrations in open air. Compared with the previously reported (PhSe)2-H2O2 system, it is more stable and milder and tolerates more functional groups. The presence of air is the key factor to maintain enough concentration of PhSeOH, which should be the real catalytic species.
X. Zhang, J. Sun, Y. Ding, L. Yu, Org. Lett., 2015, 17, 5840-5842.
Different ketoximes, which are prepared from the corresponding ketones, undergo the Beckmann rearrangement at room temperature in excellent yields upon treatment with 2,4,6-trichloro[1,3,5]triazine in N,N-dimethylformamide. Nitriles are obtained from aldoximes using the same procedure.
L. De Luca, G. Giacomelli, A. Porcheddu, J. Org. Chem., 2002, 67, 6272-6274.
Adsorbed [RuCl2(p-cymene)]2 on activated carbon is an efficient, environmentally attractive and highly selective catalyst for use in aerobic oxidations, hydrolytic oxidations and dehydrations. The heterogeneous catalyst was recovered quantitatively by simple filtration and could be reused with minimal loss of activity.
E. Choi, C. Lee, Y. Na, S. Chang, Org. Lett., 2002, 4, 2369-2371.
An inexpensive homogeneous iron catalyst enables a direct approach to alkenyl nitriles from allylarenes or alkenes. Three C-H bond cleavages occur under the mild conditions during this process, involving the cleavage of the allyl C(sp3)-H bond as the rate-determining step.
C. Qin, N. Jiao, J. Am. Chem. Soc., 2010, 132, 15893-15895.
Using NaNO2 as the nitrogen source and Fe(OTf)3 as a promoter at 50°C, a series of arylacetic acids provides aromatic nitriles in good yields. The reaction is compatible with a broad range of functional groups.
Z. Shen, W. Liu, X. Tian, Z. Zhao, Y.-L. Ren, Synlett, 2020, 31, 1805-1808.
A hypervalent iodine reagent, (diacetoxyiodo)benzene, and catalytic amount of sodium azide in acetonitrile enable an oxidative decarboxylation of 2-aryl carboxylic acids into the corresponding aldehydes, ketones, and nitriles in good yields at room temperature. The advantages of this protocol are short reaction times and mild reaction conditions.
V. N. Telvekar, K. A. Sasane, Synlett, 2010, 2778-2779.
An efficient catalytic and highly enantioselective protonation of silyl ketene imines is catalyzed by the chiral phosphoric acids TRIP or STRIP in the presence of a stoichiometric amount of methanol as the proton source and silyl acceptor. Various substituted racemic silyl ketene imines have been transformed into highly enantioenriched nitriles.
J. Guin, G. Varseev, B. List, J. Am. Chem. Soc., 2013, 135, 2100-2103.
Various ketoximes undergo the Beckmann rearrangement when heated with 0.5 molar equiv. of chloral (hydrate) in the absence of solvents and acids. Yields of the corresponding amides were excellent after a simple work-up. Aromatic aldoximes were dehydrated to the corresponding nitriles in excellent yields under similar conditions.
S. Chandrasekhar, K. Gopalaiah, Tetrahedron Lett., 2003, 44, 755-756.
A convenient, environmentally friendly method for the synthesis of optically active aldoximes and nitriles starting from chiral nitroalkanes was developed.
C. Czekelius, E. M. Carreira, Angew. Chem. Int. Ed., 2005, 44, 612-615.
Palladium-catalyzed dehydration of primary amides to nitriles efficiently proceeds under mild, aqueous conditions in the presence of dichloroacetonitrile as a water acceptor. Dichloroacetonitrile preferentially reacts with amides over other polar functional groups with the aid of the Pd catalyst.
H. Okabe, A. Naraoka, T. Isogawa, S. Oishi, H. Naka, Org. Lett., 2019, 21, 4767-4770.
4,5-Dioxo-imidazolinium cation activation of 1-acyl-1-carbamoyl oximes provides cyanoformamides with very good yields in short reaction times. This method of activation offers high reactivity, exhibits a high functional group compatibility with mild conditions, and could be scaled up easily.
Y. Gao, J. Zhang, Z. Li, T. Guo, Y. Zhu, Z. Yao, B. Liu, Y. Li, L. Guo, J. Org. Chem., 2020, 85, 1087-1096.
A facile and efficient one-pot reaction enables the synthesis of cyanoformamides from readily available 1-acyl-1-carbamoyl oximes in the presence of phosphoryltrichloride under mild conditions in very good yields.
J. Yang, D. Xiang, R. Zhang, Y. Liang, D. Dong, Org. Lett., 2015, 17, 809-811.
A convenient reaction of isoxazoles with an electrophilic fluorinating agent (Selectfluor) provides tertiary fluorinated carbonyl compounds under mild reaction conditions and with good functional group tolerance. Diverse transformations of the resulting α-fluorocyanoketones furnish a broad range of fluorinated compounds.
M. Komatsuda, H. Ohki, H. Kondo Jr., A. Suto, J. Yamaguchi, Org. Lett., 2022, 24, 3270-3274.
A Ni-catalyzed decarbonylative cyanation of acyl chlorides with trimethylsilyl cyanide is applicable to the synthesis of an array of nitrile compounds bearing a wide range of functional groups under neutral conditions.
Z. Wang, X. Wang, Y. Ura, Y. Nishihara, Org. Lett., 2019, 21, 6690-6694.