- Sustainable Route Toward N-Boc Amines: AuCl3/CuI-Catalyzed N-tert-butyloxycarbonylation of Amines at Room Temperature
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N-tert-butoxycarbonyl (N-Boc) amines are useful intermediates in synthetic/medicinal chemistry. Traditionally, they are prepared via an indirect phosgene route with poor atom economy. Herein, a step- and atom-economic synthesis of N-Boc amines from amines, t-butanol, and CO was reported at room temperature. Notably, this N-tert-butyloxycarbonylation procedure utilized ready-made substrates, commercially available AuCl3/CuI as catalysts, and O2 from air as the sole oxidant. This catalytic system provided unique selectivity for N-Boc amines in good yields. More significantly, gram-scale preparation of medicinally important N-Boc amine intermediates was successfully implement, which demonstrated a potential application prospect in industrial syntheses. Furthermore, this approach also showed good compatibility with tertiary and other useful alcohols. Investigations of the mechanisms revealed that gold catalyzed the reaction and copper acted as electron transfer mediator in the catalytic cycle.
- Cao, Yanwei,He, Lin,Huang, Yang
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- Mediator-Enabled Electrocatalysis with Ligandless Copper for Anaerobic Chan-Lam Coupling Reactions
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Simple copper salts serve as catalysts to effect C-X bond-forming reactions in some of the most utilized transformations in synthesis, including the oxidative coupling of aryl boronic acids and amines. However, these Chan-Lam coupling reactions have historically relied on chemical oxidants that limit their applicability beyond small-scale synthesis. Despite the success of replacing strong chemical oxidants with electrochemistry for a variety of metal-catalyzed processes, electrooxidative reactions with ligandless copper catalysts are plagued by slow electron-transfer kinetics, irreversible copper plating, and competitive substrate oxidation. Herein, we report the implementation of substoichiometric quantities of redox mediators to address limitations to Cu-catalyzed electrosynthesis. Mechanistic studies reveal that mediators serve multiple roles by (i) rapidly oxidizing low-valent Cu intermediates, (ii) stripping Cu metal from the cathode to regenerate the catalyst and reveal the active Pt surface for proton reduction, and (iii) providing anodic overcharge protection to prevent substrate oxidation. This strategy is applied to Chan-Lam coupling of aryl-, heteroaryl-, and alkylamines with arylboronic acids in the absence of chemical oxidants. Couplings under these electrochemical conditions occur with higher yields and shorter reaction times than conventional reactions in air and provide complementary substrate reactivity.
- Walker, Benjamin R.,Manabe, Shuhei,Brusoe, Andrew T.,Sevov, Christo S.
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supporting information
p. 6257 - 6265
(2021/05/07)
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- MONOACYLGLYCEROL LIPASE INHIBITORS
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Provided are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof: Also provided are compositions comprising compounds of formula (I). The compounds and compositions are also provided for use as medicaments, for example as medicaments useful in the treatment of a condition modulated by monoacylglycerol lipase (MAGL). Also provided are the use of compounds and compositions for the inhibition of monoacylglycerol lipase (MAGL).
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Paragraph 0109-0110; 0141; 0151-0152
(2021/09/09)
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- Highly efficient chemoselective N-tert butoxycarbonylation of aliphatic/aromatic/heterocyclic amines using diphenylglycoluril as organocatalyst
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An efficient approach for the Chemoselective N-tert-butoxycarbonylation of a variety of amines using diphenylglycoluril as organocatalyst has been described. For the first time, a plausible mechanism for the N-tert-butoxycarbonylation has been proposed using density functional theory (DFT) calculations supported by NMR studies. The reusability of the organocatalyst and observation of the desired N-Boc protected amines being formed without the formation of side products like urea, oxazolidinone, isocyanate, and N, N-di-Boc derivatives makes the present protocol desirable.
- Awasthi, Amardeep,Mukherjee, Anagh,Singh, Mandeep,Rathee, Garima,Vanka, Kumar,Chandra, Ramesh
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supporting information
(2020/05/14)
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- Copper-Catalyzed Electrophilic Amination of Alkoxyarylsilanes
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We report a copper-catalyzed amination reaction between simple alkoxyarylsilanes and N-benzoyloxyamines. Silver fluoride serves as a stoichiometric base as well as an indispensable activator that allows the catalytic process to proceed. Multiply alkoxylated arylsilanes, such as trialkoxyarylsilanes and dialkoxyarylsilanes were transformed into the corresponding tertiary anilines under mild reaction conditions.
- Hitoshio, Kenshiro,Saito, Hayate,Shimokawa, Jun,Yorimitsu, Hideki,Zhang, Qian
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supporting information
(2020/07/04)
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- Robust Buchwald-Hartwig amination enabled by ball-milling
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An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.
- Cao, Qun,Nicholson, William I.,Jones, Andrew C.,Browne, Duncan L.
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p. 1722 - 1726
(2019/02/20)
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- Selective, Catalytic, and Dual C(sp3)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions
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By using cheap and innocuous reagents, such as NaClO2, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.
- Chamorro-Arenas, Delfino,Osorio-Nieto, Urbano,Quintero, Leticia,Hernández-García, Luís,Sartillo-Piscil, Fernando
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p. 15333 - 15346
(2019/01/03)
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- Transition-Metal-Free Selective C?H Benzylation of Tertiary Arylamines by a Dearomatization-Aromatization Sequence
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Due to the significance of hybrid systems in drug discovery, there is an urgent need to assemble multiple biologically active ingredients into a single molecule. Here, we report a general transition-metal-free selective C?H benzylation of tertiary arylamines in good to excellent yields with a broad substrate scope and high functional-group tolerance under mild conditions. Besides arylamines, some other benzene derivatives also readily furnished the corresponding diaryl methane derivatives with this protocol. A series of control experiments and theoretical calculations indicated that this transition-metal-free reaction is a dearomatization-aromatization process.
- Xu, Guo-Qiang,Feng, Zhi-Tao,Xu, Ji-Tao,Wang, Zhu-Yin,Qin, Yong,Xu, Peng-Fei
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supporting information
p. 13778 - 13782
(2018/09/14)
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- Dual C(sp3)?H Bond Functionalization of N-Heterocycles through Sequential Visible-Light Photocatalyzed Dehydrogenation/[2+2] Cycloaddition Reactions
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Herein we describe a mild method for the dual C(sp3)?H bond functionalization of saturated nitrogen-containing heterocycles through a sequential visible-light photocatalyzed dehydrogenation/[2+2] cycloaddition procedure. As a complementary approach to the well-established use of iminium ion and α-amino radical intermediates, the elusive cyclic enamine intermediates were effectively generated by photoredox catalysis under mild conditions and efficiently captured by acetylene esters to form a wide array of bicyclic amino acid derivatives, thus enabling the simultaneous functionalization of two vicinal C(sp3)?H bonds.
- Xu, Guo-Qiang,Xu, Ji-Tao,Feng, Zhi-Tao,Liang, Hui,Wang, Zhu-Yin,Qin, Yong,Xu, Peng-Fei
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supporting information
p. 5110 - 5114
(2018/03/27)
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- Photocatalytic Generation of 2-Azolyl Radicals: Intermediates for the Azolylation of Arenes and Heteroarenes via C-H Functionalization
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The 2-azolyl radical, generated from 2-bromoazoles via photocatalysis, is a powerful intermediate for the intermolecular arylation of unmodified (hetero)arenes. The reaction is characterized by mild conditions, operational simplicity, tolerance toward functional and sterically demanding groups, broad scope, and anti-Minisci selectivity. A working mechanism is provided, and a low-solubility amine is essential for successful coupling. The utility of the reaction is demonstrated via late-stage functionalization of methyl estrone and application toward other bromoarenes.
- Arora, Amandeep,Weaver, Jimmie D.
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supporting information
p. 3996 - 3999
(2016/08/30)
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- Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies
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Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure-activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17-0.0072 μM against H37Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (RifR and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (RifR and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development.
- Yempalla, Kushalava Reddy,Munagala, Gurunadham,Singh, Samsher,Magotra, Asmita,Kumar, Sunil,Rajput, Vikrant Singh,Bharate, Sonali S,Tikoo, Manoj,Singh,Khan, Inshad Ali,Vishwakarma, Ram A.,Singh, Parvinder Pal
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supporting information
p. 1041 - 1046
(2015/10/20)
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- A simple, rapid, and efficient N-Boc protection of amines under ultrasound irradiation and catalyst-free conditions
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A green and simple approach for the N-Boc protection on structurally diverse amines under ultrasound irradiation is described. Selective N-Boc protection was achieved in excellent isolated yield in a short reaction time at room temperature. Mild conditions, inexpensive and an easily available reagent, and absence of any auxiliary substances are the main advantages of this procedure. Graphical abstract: [Figure not available: see fulltext.]
- Amira, Aicha,K'Tir, Hacene,Berredjem, Malika,Aouf, Nour-Eddine
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p. 509 - 515
(2014/03/21)
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- {[[K.18-Crown-6]Br3}n: A tribromide catalyst for the catalytic protection of amines and alcohols
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{[K.18-Crown-6]Br3}n, a unique tribromide-type catalyst, was utilized for the N-boc protection of amines and trimethylsilylation (TMS) and tetrahydropyranylation (THP) of alcohols. The method is general for the preparation of N-boc derivatives of aliphatic (acyclic and cyclic) and aromatic, and primary and secondary amines and also various TMS-ethers and THP-ethers. The simple separation of the catalyst from the product is one of the many advantages of this method.
- Chehardoli, Gholamabbas,Zolfigol, Mohammad Ali,Derakhshanpanah, Fateme
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p. 1730 - 1733
(2013/10/21)
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- Efficient copper-catalyzed cross-coupling of 1-Boc-piperazine with aryl iodides and its application in the synthesis of trazodone
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A convenient and practical strategy is developed for the cross-coupling of N-Boc protected piperazines with aryl iodides using CuBr/1,1′-bi-2- naphthol as the catalyst and K3PO4 as the base. The protocol affords N-arylated piperazine products in moderate to good yields under the optimized conditions. The application of this catalytic system to the synthesis of trazodone is also successfully demonstrated using commercially available substrates.
- Yong, Fui-Fong,Teo, Yong-Chua,Tan, Khee-Ngiap
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supporting information
p. 5332 - 5334
(2013/09/12)
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- Microwave assisted mild, rapid, solvent-less, and catalyst-free chemoselective N-tert-butyloxycarbonylation of amines
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Microwave assisted simple, rapid, solventless, and catalyst-free chemoselective method for the protection of amino group in aromatic, aliphatic, heterocyclic, aralkyl amines, phenyl hydrazine, and amino acid esters in good to excellent isolated yield (83-98%) in short reaction time (2-12 min) has been reported.
- Dighe, Satish N.,Jadhav, Hemant R.
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p. 5803 - 5806
(2012/10/29)
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- Synthesis and crystal structure determination of [H2-cryptand 222](Br3)2: A unique tribromide catalyst for the catalytic chemoselective N-boc protection of amines
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The organic tribromide, [H2-cryptand 222](Br3) 2 was synthesized and characterized by X-ray crystallography, and was utilized as an active catalyst for the N-boc protection of amines. The method is general for the preparation of N-boc derivatives of aliphatic (acyclic and cyclic), aromatic, primary and secondary amines. We also applied our new reaction protocols for the N-boc protection of some new amines and spectral and physical data for the obtained products are reported.
- Chehardoli, Gholamabbas,Zolfigol, Mohammad Ali,Khakyzadeh, Vahid,Golbedaghi, Reza,Hall, Nikita A.,Blackman, Allan G.
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experimental part
p. 538 - 543
(2012/01/03)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 58-59
(2011/04/14)
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- THERAPEUTICALLY ACTIVE COMPOUNDS FOR USE IN THE TREATMENT OF CANCER CHARACTERIZED AS HAVING AN IDH MUTATION
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Compounds and compositions comprising compounds useful in the treatment of cancer are described herein. The compounds and compositions can be used to modulate an isocitrate dehydrogenase (IDH) mutant (e.g., IDHIm or IDH2m) having alpha hydroxyl neoactivity
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Page/Page column 100
(2011/06/26)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.
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Page/Page column 23
(2011/01/05)
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- Umpolung amination: Nickel-catalyzed coupling reactions of N,N-dialkyl-N-chloroamines with diorganozinc reagents
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(Chemical Equation Presented) N,N-Dialkyl-N-chloroamines are an effective source of electrophilic nitrogen for nickel-catalyzed coupling with diarylzinc reagents. A variety of N-chloroamines as well as organozinc reagents react smoothly under the reaction conditions. A one-pot procedure that circumvents the need to isolate the N-chloroamines is described.
- Barker, Timothy J.,Jarvo, Elizabeth R.
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supporting information; experimental part
p. 15598 - 15599
(2010/01/29)
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- A rate enhancement of tert-butoxycarbonylation of aromatic amines with Boc2O in alcoholic solvents
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A rate enhancement of tert-butoxycarbonylation of aromatic amines by Boc2O in alcohols compared to aprotic solvents was demonstrated. Kinetic analysis by NMR suggested that the reaction in CD3OD was faster than in CDCl3 by a factor of 70. Reactions between Boc2O and various aliphatic and aromatic amines in ethanol provided the N-Boc derivatives in good to excellent yields in short reaction times.
- Vilaivan, Tirayut
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p. 6739 - 6742
(2007/10/03)
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- Molecular iodine-catalyzed facile procedure for N-Boc protection of amines
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An efficient and practical protocol for the protection of various structurally and electronically divergent aryl and aliphatic amines using (Boc)2O in the presence of a catalytic amount of molecular iodine (10 mol%) under solvent-free conditions at ambient temperature is presented.
- Varala, Ravi,Nuvula, Sreelatha,Adapa, Srinivas R.
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p. 8283 - 8286
(2007/10/03)
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- Synthesis of arylpiperazines via nucleophilic aromatic substitution of (η6-fluoroarene)tricarbonylchromium complexes
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A one-pot, high yield preparation procedure for the synthesis of arylpiperazines using a nucleophilic aromatic substitution of (η6-fluoroarene)tricarbonylchromium complexes (including those bearing electron donating groups) is described. A new, easy and fast decomplexation procedure, in DMSO as solvent, is also presented.
- Perez, Michel,Potier, Pierre,Halazy, Serge
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p. 8487 - 8488
(2007/10/03)
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