- Metal-Free Deoxygenation of Chiral Nitroalkanes: An Easy Entry to α-Substituted Enantiomerically Enriched Nitriles
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A metal-free, mild and chemodivergent transformation involving nitroalkanes has been developed. Under optimized reaction conditions, in the presence of trichlorosilane and a tertiary amine, aliphatic nitroalkanes were selectively converted into amines or nitriles. Furthermore, when chiral β-substituted nitro compounds were reacted, the stereochemical integrity of the stereocenter was maintained and α-functionalized nitriles were obtained with no loss of enantiomeric excess. The methodology was successfully applied to the synthesis of chiral β-cyano esters, α-aryl alkylnitriles, and TBS-protected cyanohydrins, including direct precursors of four active pharmaceutical ingredients (ibuprofen, tembamide, aegeline and denopamine).
- Pirola, Margherita,Faverio, Chiara,Orlandi, Manuel,Benaglia, Maurizio
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supporting information
p. 10247 - 10250
(2021/06/18)
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- METHOD FOR MANUFACTURING AROMATIC NITRILE COMPOUND
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The present invention provides a method for industrially producing a highly pure aromatic nitrile compound and a highly pure aromatic carboxylic acid compound safely and highly efficiently at low costs. Compound (2) is subjected to Willgerodt reaction in the presence of an additive as necessary, and the obtained amide compound (3) is hydrolyzed and neutralized to give carboxylic acid compound (4). Carboxylic acid compound (4) is reacted with a halogenating agent in the presence of a catalyst as necessary in an organic solvent, and further reacted with an amidating agent, and the obtained amide compound (5) or (6) is reacted with a dehydrating agent to give nitrile compound (1). Alternatively, carboxylic acid compound (4) is reacted with a halogenating agent and a compound represented by the formula R6SO2R7 in the presence of a catalyst as necessary in an organic solvent to give nitrile compound (1). Np is a naphthyl group optionally having substituent(s), R5 is an alkylene group having 1-3 carbon atoms, and other symbols are as described in the DESCRIPTION.
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- Assembly of α-(Hetero)aryl Nitriles via Copper-Catalyzed Coupling Reactions with (Hetero)aryl Chlorides and Bromides
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α-(Hetero)aryl nitriles are important structural motifs for pharmaceutical design. The known methods for direct synthesis of these compounds via coupling with (hetero)aryl halides suffer from narrow reaction scope. Herein, we report that the combination of copper salts and oxalic diamides enables the coupling of a variety of (hetero)aryl halides (Cl, Br) and ethyl cyanoacetate under mild conditions, affording α-(hetero)arylacetonitriles via one-pot decarboxylation. Additionally, the CuBr/oxalic diamide catalyzed coupling of (hetero)aryl bromides with α-alkyl-substituted ethyl cyanoacetates proceeds smoothly at 60 °C, leading to the formation of α-alkyl (hetero)arylacetonitriles after decarboxylation. The method features a general substrate scope and is compatible with various functionalities and heteroaryls.
- Chen, Ying,Xu, Lanting,Jiang, Yongwen,Ma, Dawei
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supporting information
p. 7082 - 7086
(2021/02/26)
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- Divergent synthesis of isonitriles and nitriles by palladium- catalyzed benzylic substitution with TMSCN
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Ligand-controlled palladium-catalyzed divergent synthesis of isonitriles and nitriles from benzylic carbonates and TMSCN has been developed. The BINAP- or DPEphos-ligated palladium catalyst selectively provides the corresponding benzylic isonitriles, wher
- Hirano, Koji,Miura, Masahiro,Asai, Kento
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p. 12703 - 12714
(2020/11/09)
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- Nickel-Catalyzed Cyanation of Benzylic and Allylic Pivalate Esters
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A nickel-catalyzed cyanation reaction of benzylic and allylic pivalate esters is reported using an air-stable Ni(II) precatalyst and substoichiometric quantities of Zn(CN)2. Alkene additives were found to inhibit catalysis, suggesting that avoiding β-hydride elimination side reactions is essential for productive catalysis. An enantioenriched allylic ester undergoes enantiospecific cross-coupling to produce an enantioenriched allylic nitrile. This method was applied to an efficient synthesis of (±)-naproxen from commercially available starting materials.
- Michel, Nicholas W. M.,Jeanneret, Alexandria D. M.,Kim, Hyehwang,Rousseaux, Sophie A. L.
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p. 11860 - 11872
(2018/10/02)
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- New [4]helicene derivatives: Synthesis, characterization and photophysical properties
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The design and synthesis of new [4]helicene derivatives were carried out by incorporating well-defined electron donor and acceptor groups at selected positions of the aromatic nuclei, aiming to use them in optical applications. Helicenes have been obtained in good overall yields through a five-step sequence involving mild experimental conditions and easy purification. Photophysical properties of these tetracyclic systems have been evaluated by UV–visible absorption and fluorescence spectroscopies and an emission in the visible region was observed.
- Hafedh, Nesrine,Aloui, Faouzi,Raouafi, Sondes,Dorcet, Vincent,Hassine, Béchir Ben
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p. 310 - 316
(2018/05/04)
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- Copper-Catalyzed Cyanation of N-Tosylhydrazones with Thiocyanate Salt as the "cN" Source
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A novel protocol for the synthesis of α-aryl nitriles has been successfully achieved via a copper-catalyzed cyanation of N-tosylhydrazones employing thiocyanate as the source of cyanide. The features of this method include a convenient operation, readily available substrates, low-toxicity thiocyanate salts, and a broad substrate scope.
- Huang, Yubing,Yu, Yue,Zhu, Zhongzhi,Zhu, Chuanle,Cen, Jinghe,Li, Xianwei,Wu, Wanqing,Jiang, Huanfeng
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p. 7621 - 7627
(2017/07/26)
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- One-Pot Preparation of C1-Homologated Aliphatic Nitriles from Aldehydes through a Wittig Reaction under Metal-Cyanide-Free Conditions
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A one-pot protocol to obtain C1-homologated aliphatic nitriles was achieved by treating aromatic and aliphatic aldehydes with the (methoxymethyl)triphenylphosphonium ylide followed by hydrolysis of the resulting methyl vinyl ethers with pTsOH (Ts = para-toluenesulfonyl) and treatment with molecular iodine and aqueous ammonia under metal cyanide free conditions. Neopentyl-type nitriles, which could not be obtained by conventional methods that involved conversion of the neopentyl alcohol into a tosylate and treatment with metal cyanide, were successfully obtained by using the present method.
- Ezawa, Masatoshi,Togo, Hideo
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p. 2379 - 2384
(2017/05/01)
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- Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: Evidence for naphthalene as a DNA intercalator
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N-Acyloxy-N-alkoxyamides are direct-acting mutagens in S. typhimurium TA100 with a linear dependence upon log P that maximises at log P0 = 6.4. Eight N-acyloxy-N-alkoxyamides (2-9) bearing a naphthalene group on any of the three side-chains and with log P0 6.4 have been demonstrated to be significantly and uniformly more mutagenic towards S. typhimurium TA100 than 50 mutagens without naphthalene. The activity enhancement of 2-9 is likely due to intercalative binding of naphthalene to bacterial DNA as a number are also active in TA98, a frame-shift strain of S. typhimurium, which is modified by intercalators. DNA damage profiles for naphthalene-bearing mutagens confirm enhanced reactivity with DNA when naphthalene is incorporated and a different binding mode when compared to mutagens without naphthalene. The effect is independent of whether the naphthalene is attached to an electron-donating alkyl or electron-withdrawing acyl group, alkyl tether length or, in the case of 6 and 7, the point of attachment to naphthalene. A new quantitative structure activity relationship has been constructed for all 58 congeners incorporating log P and an indicator variable, I, for the presence (I = 1) or absence (I = 0) of naphthalene and from which the activity enhancing effect of a naphthalene has been quantified at between three and four log P units. Contrary to conventional views, simple naphthalene groups could target molecules to DNA through intercalation.
- Banks, Tony M.,Clay, Samuel F.,Glover, Stephen A.,Schumacher, Rhiannon R.
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supporting information
p. 3699 - 3714
(2016/05/09)
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- Two-step cyanomethylation protocol: Convenient access to functionalized aryl- and heteroarylacetonitriles
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A two-step protocol has been developed for the introduction of cyanomethylene groups to metalated aromatics through the intermediacy of substituted isoxazoles. A palladium-mediated cross-coupling reaction was used to introduce the isoxazole unit, followed by release of the cyanomethylene function under thermal or microwave-assisted conditions. The intermediate isoxazoles were shown to be amenable to further functionalization prior to deprotection of the sensitive cyanomethylene motif, allowing access to a wide range of aryl- and heteroaryl-substituted acetonitrile building blocks.
- Lindsay-Scott, Peter J.,Clarke, Aimee,Richardson, Jeffery
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supporting information
p. 476 - 479
(2015/03/05)
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- Synthesis of α-aryl esters and nitriles: Deaminative coupling of α-aminoesters and α-aminoacetonitriles with arylboronic acids
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Transition-metal-free synthesis of α-aryl esters and nitriles using arylboronic acids with α-aminoesters and α-aminoacetonitriles, respectively, as the starting materials has been developed. The reaction represents a rare case of converting C(sp3)-N bonds into C(sp3)-C(sp2) bonds. The reaction conditions are mild, demonstrate good functional-group tolerance, and can be scaled up. Touch base: A transition-metal-free protocol for the synthesis of α-aryl esters and nitriles by deaminative coupling is presented. Strong bases and transition-metal catalysts are not needed. The new synthetic method uses readily available starting materials and demonstrates wide substrate scope.
- Wu, Guojiao,Deng, Yifan,Wu, Chaoqiang,Zhang, Yan,Wang, Jianbo
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supporting information
p. 10510 - 10514
(2016/02/18)
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- Synthesis of α-Aryl nitriles through palladium-catalyzed decarboxylative coupling of cyanoacetate salts with aryl halides and triflates
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Worth its salt: The palladium-catalyzed decarboxylative coupling of the cyanoacetate salt as well as its mono- and disubstituted derivatives with aryl chlorides, bromides, and triflates is described (see scheme). This reaction is potentially useful for the preparation of a diverse array of α-aryl nitriles and has good functional group tolerance. S-Phos=2-(2,6- dimethoxybiphenyl)dicyclohexylphosphine), Xant-Phos=4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene. Copyright
- Shang, Rui,Ji, Dong-Sheng,Chu, Ling,Fu, Yao,Liu, Lei
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supporting information; experimental part
p. 4470 - 4474
(2011/06/24)
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- Palladium-catalyzed cyanomethylation of aryl halides through domino Suzuki coupling-isoxazole fragmentation
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A one-pot protocol for the cyanomethylation of aryl halides through a palladium-catalyzed reaction with isoxazole-4-boronic acid pinacol ester was developed. Mechanistically, the reaction proceeds through (1) Suzuki coupling, (2) base-induced fragmentation, and (3) deformylation as shown by characterization of all postulated intermediates. Under optimized conditions (PdCl2dppf, KF, DMSO/H2O, 130 °C) a broad spectrum of aryl bromides could be converted into arylacetonitriles with up to 88% yield.
- Velcicky, Juraj,Soicke, Arne,Steiner, Roland,Schmalz, Hans-Guenther
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supporting information; experimental part
p. 6948 - 6951
(2011/06/19)
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- Versatile and fluoride-free cyanation of alkyl halides and sulfonates with trimethylsilyl cyanide
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Cyanation of biphenyl-4-ylmethyl methanesulfonate with trimethylsilyl cyanide using fluoride-free inorganic salts, such as Cs2CO 3, K2CO3, and LiOH·H2O, as additives in MeCN quantitatively gave biphenyl-4-ylacetonitrile. This methodology was applied to various alkyl halides to give the corresponding nitrile compounds in good to excellent yields. Of note, 4-(hydroxymethyl) benzyliodide O-protected by the silyl group was converted into phenylacetonitrile derivative in 99% yield without desilylation. Georg Thieme Verlag Stuttgart.
- Yabe, Osamu,Mizufune, Hideya,Ikemoto, Tomomi
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experimental part
p. 1291 - 1294
(2009/10/23)
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- Controlled conversion of phenylacetic acids to phenylacetonitriles or benzonitriles using bis(2-methoxyethyl)aminosulfur trifluoride
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A mild, efficient, and practical method for the one-step synthesis of benzonitriles from phenylacetic acids using bis(2-methoxyethyl)aminosulfur trifluoride is described. The reaction was easily extended to the synthesis of the corresponding phenylacetonitriles by inclusion of triethylphosphine.
- Kangani, Cyrous O.,Day, Billy W.,Kelley, David E.
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p. 914 - 918
(2008/09/17)
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- Synthesis of 7-cyano- and 7-acetamido-indoles via cyanocarbonation/hydrogenation of 7-formyl indole
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A procedure for the synthesis of 7-cyano and 7-acetamido indoles via cyanocarbonation/hydrogenation of 7-formyl indole is presented. The process can be efficiently scaled up to provide multigram quantities of the desired compounds in good yield. A small survey of substrate scope indicates that the reaction may prove generally useful for the synthesis of aryl acetonitriles.
- Kolis, Stanley P.,Clayton, Marcella T.,Grutsch, John L.,Faul, Margaret M.
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p. 5707 - 5710
(2007/10/03)
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- Fragmentation of anion radicals with elimination of aryloxy groups
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4-Vinylbenzyl phenyl ether, 4-phenylbenzyl phenyl ether, 1- and 2-naphthylmethyl phenyl ethers react with sodium thiophenolate under photochemical stimulation with replacement of the phenoxy group. The composition of reaction products and relation of reactivity to the structure of substrates is consistent with anion-radical mechanism. The corresponding methoxy and cyano derivatives do not undergo the reaction.
- Dneprovskii,Fedosov
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p. 1438 - 1443
(2007/10/03)
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- Preparation of nitriles from carboxylic acids: A new, synthetically useful example of the Smiles rearrangement
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Reaction of 2,4-dinitrobenzenesulfonamide with acyl chlorides in the presence of excess triethylamine produces the corresponding nitrile in good to fair yields. Mechanistic studies indicate that the reaction proceeds via a Smiles rearrangement of the initially formed N-(2,4- dinitrobenzenesulfonyl)amide to form the nitrile, 2,4-dinitrophenol and sulfur dioxide.
- Huber, Vincent J.,Bartsch, Richard A.
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p. 9281 - 9288
(2007/10/03)
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- Water-soluble calixarenes as new inverse phase-transfer catalysts. Nucleophilic substitution of alkyl and arylalkyl halides in aqueous media
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The water-soluble calix[n]arenes 1n (n = 4, 6 and 8) containing trimethylammoniomethyl groups act as efficient inverse phase-transfer catalysts in the nucleophilic substitution reaction of alkyl and arylalkyl halides with nucleophiles in water.
- Shimizu, Shoichi,Kito, Katsuyuki,Sasaki, Yasuyuki,Hirai, Choichiro
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p. 1629 - 1630
(2007/10/03)
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- A new synthesis of nitriles from N-methoxy imidoyl bromides by photolysis
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N-Methoxy imidoyl bromides are synthesized in one-pot from the carboxylic acids with methoxyamine and triphenylphosphine-tetrabromomethane. Photolysis of them leads to formation of the corresponding nitriles in high yield without affecting functional groups sensitive to ordinary dehydrating and halogenating reagents.
- Kikugawa,Fu,Sakamoto
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p. 1061 - 1069
(2007/10/02)
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- Enzymes in organic synthesis 51. Probing the dimensions of the large hydrophobic pocket of the active site of pig liver esterase
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The dimensions of the large hydrophobic pocket (H(L)) of the active site model of pig liver esterase (PLE) were probed using a series of aliphatic and phenylic malonates. Results from the hydrolyses of these new unnatural substrates permitted the extension of the H(L) pocket to give the new dimensions of 6.2 x 2.3 x 3.9 A for a total volume of ~56 A3.
- Provencher,Wynn,Jones,Krawczyk
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p. 2025 - 2026
(2007/10/02)
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- Degradation of 3-aryl-2-hydroxyiminopropionic acids into arylacetonitriles using 1,1'-carbonyldiimidazole or 2,2'-oxalyldi(o-sulfobenzimide)
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1,1'-Carbonyldiimidazole (1) is a useful reagent for the preparation of arylacetonitriles (9) from 3-aryl-2-hydroxyiminopropionic acids (8), and 2,2'-oxalyldi (o-sulfobenzimide) (2) can also be used for this purpose under essentially neutral conditions.
- Kitagawa,Kawaguchi,Inoue,Katayama
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p. 3030 - 3033
(2007/10/02)
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- Photochemical Aromatic Cyanomethylation
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Cyanomethylation is accomplished by the photolysis of chloroacetonitrile in the presence of aromatics by way of electron transfer followed by radical coupling.
- Lapin, Stephen,Kurz, Michael E.
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p. 817 - 818
(2007/10/02)
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