- Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines
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α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenrichedN-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.
- Cheng, Jiang-Tao,Dong, Xiao-Yang,Gu, Qiang-Shuai,Li, Zhong-Liang,Liu, Juan,Liu, Xin-Yuan,Luan, Cheng,Wang, Fu-Li,Wang, Li-Lei,Yang, Ning-Yuan,Zhang, Yu-Feng
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supporting information
p. 15413 - 15419
(2021/09/30)
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- Comparative conventional and microwave assisted synthesis of heterocyclic oxadiazole analogues having enzymatic inhibition potential
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A comparative microwave assisted and conventional synthetic strategies were applied to synthesize heterocyclic 1,3,4-oxadiazole analogues as active anti-enzymatic agents. Green synthesis of compound 1 was achieved by stirring 4-methoxybenzenesulfonyl chloride (a) and ethyl piperidine-4-carboxylate (b). Compound 1 was converted into respective hydrazide (2) by hydrazine and then into 1,3,4-oxadiazole (3) by CS2 on reflux. The electrophiles, N-alkyl/aralkyl/aryl-2-bromopropanamides (6a–p) were synthesized and converted to N-alkyl/aralkyl/aryl-2-propanamide derivatives (7a–p) by reaction with 3 under green chemistry. Microwave assisted method was found to be effective relative to conventional method. 13C-NMR, 1H-NMR and IR techniques were availed to corroborate structures of synthesized compounds and then subjected to screening against lipoxygenase (LOX), α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. A number of compounds presented better potential against these enzymes. The most active compounds against LOX and α-glucosidase enzymes were subjected to molecular docking study to explore their interactions with the active sites of the enzymes.
- Javid, Jamila,Aziz-ur-Rehman,Abbasi, Muhammad A.,Siddiqui, Sabahat Z.,Iqbal, Javed,Virk, Naeem A.,Rasool, Shahid,Ali, Hira A.,Ashraf, Muhammad,Shahid, Wardah,Hussain, Safdar,Ali Shah, Syed A.
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- Visible-Light-Driven Aryl Migration and Cyclization of α-Azido Amides
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This paper reports two new visible-light-promoted radical reactions of α-azido amides. By catalysis of [Ir(ppy)2(dtbbpy)]PF6 with i-Pr2NEt as the reducing agent, N-aryl α-azido tertiary amides were first converted to the corresponding aminyl radicals through reduction of the azido group; the aminyl radicals then underwent N-to-N aryl migration to give α-anilinyl-functionalized amides. α-Azido secondary amides, on the other hand, reacted with the solvent ethanol and i-Pr2NEt to afford the imidazolinone products.
- Liang, Siyu,Wei, Kaijie,Lin, Yajun,Liu, Tuming,Wei, Dian,Han, Bing,Yu, Wei
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supporting information
p. 4527 - 4531
(2021/06/28)
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- Unbalanced-Ion-Pair-Catalyzed Nucleophilic Fluorination Using Potassium Fluoride
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An unbalanced ion pair promoter (e.g., tetrabutylammonium sulfate), consisting of a bulky and charge-delocalized cation and a small and charge-localized anion, greatly accelerates nucleophilic fluorinations using easy handling KF. We also successfully converted an inexpensive and commercially available ion-exchange resin to the polymer-supported ion pair promoter (A26–SO42–), which could be reused after filtration. Moreover, A26–SO42– can be used in continuous flow conditions. In our conditions, water is well-tolerated.
- Hammond, Gerald B.,Li, Wangbing,Lu, Zhichao,Xu, Bo
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supporting information
p. 9640 - 9644
(2021/12/14)
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- Enantioselective Palladium-Catalyzed Cross-Coupling of α-Bromo Carboxamides and Aryl Boronic Acids
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We herein report an enantioselective palladium-catalyzed cross-coupling between α-bromo carboxamides and aryl boronic acids, generating a series of chiral α-aryl carboxamides in good yields and excellent enantioselectivities. The development of a chiral P,P=O ligand was critical in overcoming the second transmetalation issue and allows the first asymmetric palladium-catalyzed coupling of α-bromo carbonyl compounds.
- Li, Bowen,Li, Tiejun,Aliyu, Muinat A.,Li, Zhen Hua,Tang, Wenjun
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supporting information
p. 11355 - 11359
(2019/07/12)
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- Switchable Smiles Rearrangement for Enantioselective O-Aryl Amination
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Asymmetric assembly of atropisomeric anilines from abundant and readily available precursors is one of the most challenging but valuable processes in organic synthesis. The use of highly efficient Smiles rearrangement to accomplish switchable enantioselec
- Chang, Xihao,Zhang, Qinglin,Guo, Chang
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supporting information
p. 4915 - 4918
(2019/06/27)
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- A novel five-step synthetic route to 1,3,4-oxadiazole derivatives with potent α-glucosidase inhibitory potential and their in silico studies
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A series of new N-aryl/aralkyl derivatives of 2-methyl-2-{5-(4-chlorophenyl)-1,3,4-oxadiazole-2ylthiol}acetamide were synthesized by successive conversions of 4-chlorobenzoic acid (a) into ethyl 4-chlorobenzoate (1), 4-chlorobenzoylhydrazide (2) and 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol (3), respectively. The required array of compounds (6a–n) was obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a–n) in the presence of DMF (N,N-dimethylformamide) and sodium hydroxide at room temperature. The structural determination of these compounds was done by infrared, 1H-NMR (nuclear magnetic resonance), 13C-NMR, electron ionization mass spectrometry, and high-resolution electron ionization mass spectrometry analyses. All compounds were evaluated for their α-glucosidase inhibitory potential. Compounds 6a, 6c–e, 6g, and 6i were found to be promising inhibitors of α-glucosidase with IC50 values of 81.72 ± 1.18, 52.73 ± 1.16, 62.62 ± 1.15, 56.34 ± 1.17, 86.35 ± 1.17, 52.63 ± 1.16 μM, respectively. Molecular modeling and ADME (absorption, distribution, metabolism, excretion) predictions supported the findings. The current synthesized library of compounds was achieved by utilizing very common raw materials in such a way that the synthesized compounds may prove to be promising drug leads.
- Iftikhar, Muhammad,Shahnawaz,Saleem, Muhammad,Riaz, Naheed,Aziz-ur-Rehman,Ahmed, Ishtiaq,Rahman, Jameel,Ashraf, Muhammad,Sharif, Muhammad S.,Khan, Shafi U.,Htar, Thet T.
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- Microwave-assisted synthesis of triazole derivatives conjugated with piperidine as new anti-enzymatic agents
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The current study was aimed for the study of piperidine-based triazole compounds for their biological potential against various enzymes. A novel library of compounds, 9a-r, having piperidine, 1,2,4-triazole, and propanamides was synthesized through consecutive steps including the formation of sulfonamide, hydrazide, 1,2,4-triazole, and thio-ether. Initially, 4-methoxybenzenesulfonyl chloride (1) and ethyl isonipecotate (2) were utilized to develop ethyl 1-(4-methoxyphenylsulfonyl)-4-piperidinecarboxylate (3). The product 3 was converted into respective hydrazide (4) which was further cyclized into 1,2,4-triazole (5) nucleus. A series of propanamides, 8a-r, were synthesized from different amines, 6a-r. These electrophiles, 8a-r, were reacted with compound 5 under conventional and microwave-assisted protocols to acquire the library of hybrids, 9a-r. The structural confirmations were availed by 1H-NMR, 13C-NMR, and IR techniques. The whole series was evaluated for biological potential against acetylcholinesterase (AChE) and α-glucosidase enzymes. The biological evaluation ranges low to high in potential for different compounds based on the structural variations of synthesized compounds. Almost all the compounds remained active against both the enzymes except a few ones. The bovine serum albumin (BSA) binding study demonstrated the flow of drug in the body, and the docking study explained the interactions responsible for active behavior of synthesized compounds.
- Abbasi, Muhammad A.,Ali Shah, Syed A.,Htar, Thet T.,Iqbal, Javed,Khalid, Hira,Khan, Shafi U.,Laulloo, Sabina J.,Rasool, Shahid,Rehman, Aziz-ur-,Siddiqui, Sabahat Z.,Virk, Naeem A.
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- A transition metal-free approach to a regioselective total synthesis of the natural product derivative 6-methylellipticine, a potent anticancer agent
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A transition metal-free and regioselective total synthesis of 6-methylellipticine, a potent anticancer agent, was developed. This synthetic approach mainly involved two key reactions: a direct amination of multi-functional phenol via an alkylation-Smiles
- Lin, Song-Bo,Wang, Wan-Wan,Meng, Jin-Peng,Li, Xi-Wang,Wu, Jun,Sun, Xiao-Ling
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supporting information
(2019/11/26)
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- Copper-Catalyzed Cross-Coupling of Secondary α-Haloamides with Terminal Alkynes: Access to Diverse 2,3-Allenamides
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A copper-catalyzed C(sp)?C(sp3) cross-coupling of terminal alkynes with readily available secondary α-haloamides for the efficient synthesis of 2,3-allenamides is realized. The methodology is characterized by its wide substrate scope, which makes it an important complement to traditional methods for synthesizing allenes. A mechanism involving an alkynylcopper species is proposed. (Figure presented.).
- Lv, Yunhe,Pu, Weiya,Zhu, Xueli,Zhao, Tiantian,Lin, Feifei
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supporting information
p. 1397 - 1401
(2018/02/19)
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- Synthesis and Antimicrobial Activity of 2-(4-(Hydroxyalkyl)-1H-1,2,3-triazol-1-yl)-N-substituted propanamides
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A series of 21 2-(4-(hydroxyalkyl)-1H-1,2,3-triazol-1-yl)-N-substituted propanamides (1,4-disubstituted 1,2,3-triazoles having amide linkage and hydroxyl group) have been synthesized from click reaction between terminal alkyne and 2-azido-N-substituted propanamide (generated in situ from reaction of 2-bromo-N-substituted propanamide and sodium azide) and characterized by FTIR, 1H NMR, 13C NMR spectroscopy, and HRMS. All the newly synthesized triazoles were tested in vitro for antimicrobial activity against four bacterial cultures – Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Staphylococcus aureus – and two fungal cultures – Candida albicans and Aspergillus niger. The synthesized 1,4-disubstituted 1,2,3-triazoles displayed moderate to good antimicrobial potential against the tested strains.
- Kaushik,Luxmi, Raj
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p. 3618 - 3625
(2017/11/21)
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- Facile expeditious one-pot synthesis and antifungal evaluation of disubstituted 1,2,3-triazole with two amide linkages
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A library of twenty five amide linked 1,4-disubstituted 1,2,3-triazoles have been prepared through a facile expeditious synthetic protocol involving Cu(I) mediated cyclization of N-(2-methylbut-3-yn-2-yl)aromatic amides and in situ generated 2-azido-N-substituted propanamides. Structures of newly synthesized compounds (5a–5y) were confirmed by analytical techniques, such as FTIR, 1H NMR, 13C NMR, and HRMS. In vitro antifungal activity was also examined against two fungal strains Candida albicans and Aspergillus niger by serial dilution method. The compounds 5 m and 5w exhibited appreciable potent activity.
- Kaushik,Luxmi, Raj
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supporting information
p. 2225 - 2231
(2017/11/15)
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- Direct amination of phenols under metal-free conditions
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Herein, we disclose the metal-free synthesis of arylamines via the direct amination of phenols using aminating reagents. This reaction procedure uses easy accessible aminating reagents and provides a versatile synthetic route to a broad range of arylamines with various functionalities in good to excellent yield. By using a two-step route of amination and oxidative coupling reaction, we synthesized three naturally occurring carbazole alkaloids: murrayafoline A, mukonine, and clausenine from two commercially available phenols. Georg Thieme Verlag Stuttgart · New York.
- Yu, Jianzhong,Wang, Yongtao,Zhang, Peizhi,Wu, Jun
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supporting information
p. 1448 - 1454
(2013/07/26)
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- Design and synthesis of new 8-anilide theophylline derivatives as bronchodilators and antibacterial agents
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Theophylline derivatives have long been recognized as potent bronchodilators for the relief of acute asthma. Recently, it was found that bacterial infection has a role in asthma pathogenesis. The present work involves the design and synthesis of 8-substituted theophylline derivatives as bronchodilators and antibacterial agents. The chemical structures of these compounds were elucidated by IR, 1H-NMR, mass spectrometry, and elemental analyses. The bronchodilator activity was evaluated using acetylcholine-induced bronchospasm in guinea pigs, and most of the compounds showed significant anti-bronchoconstrictive activity in comparison with standard aminophylline. In addition, the antibacterial activity of all the target compounds was investigated in vitro against Gram-positive and Gram-negative bacteria using ampicillin as a reference drug. Results showed that some of the tested compounds possessed significant antibacterial activity. A pharmacophore model was computed to obtain useful insight into the essential structural features of bronchodilator activity. A structure activity relationship was also discussed.
- Hayallah, Alaa M.,Talhouni, Ahmad A.,Abdel Alim, Abdel Alim M.
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p. 1355 - 1368
(2013/01/15)
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- Process for the preparation of α-aminoacylanilides
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A novel process for the preparation of α-aminoacylanilides comprises the treatment of the corresponding α-haloacylanilides with a solution of ammonium carbamate in aqueous ammonia. The process is especially useful in the preparation of certain active cardiac antiarrhythmic agents, such as tocainide.
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- Aminothiazole Derivatives. II. A Facile Synthesis of Condensed 4-Aminothiazole Derivatives using α-Bromolactams and Thioamides
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The reaction of an α-bromolactam with a thioamide was found to give a cyclic 4-aminothiazole derivative.Novel heterocyclic compounds such as 4,5,6,7-tetrahydrothiazolopyridines 10, 5,6,7,8-tetrahydro-4H-thiazoloazepines 11, 4,5,6,7,8,9-hexahydrothiazoloazocine 12 and 9,10-dihydro-4H-thiazolobenzazepines 18 were thus prepared and the utility of this method in the construction of 4-aminothiazole-containing compounds was suggested.
- Uchikawa, Osamu,Aono, Tetsuya
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p. 1545 - 1552
(2007/10/02)
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- Convenient Syntheses of Cyclic Carboxamides from α,β,γ,δ and ε-halocarboxamides under Phase Transfer Conditions
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Piperazine-2,5-diones (2) were prepared by N-alkylation between two molecules of α-halocarboxamides (1) in the presence of a phase transfer catalyst in yields of 64-88percent. β,γ,δ and ε-Lactams (6,9 and 13) were similarly synthesized by intramolecular N-alkylation of the corresponding halocarboxamides (5, 8 and 12) under phase transfer conditions in 53-99percent yields.Keywords--piperazine-2,5-dione; β-lactam; γ, δ, and ε lactams; bis-β-lactam; phase transfer catalyst; intramolecular N-alkylation
- Okawara, Tadashi,Matsuda, Takashi,Furukawa, Mitsuru
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p. 1225 - 1233
(2007/10/02)
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