- Evaluation of Cyclic Amides as Activating Groups in N-C Bond Cross-Coupling: Discovery of N-Acyl-δ-valerolactams as Effective Twisted Amide Precursors for Cross-Coupling Reactions
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The development of efficient methods for facilitating N-C(O) bond activation in amides is an important objective in organic synthesis that permits the manipulation of the traditionally unreactive amide bonds. Herein, we report a comparative evaluation of a series of cyclic amides as activating groups in amide N-C(O) bond cross-coupling. Evaluation of N-acyl-imides, N-acyl-lactams, and N-acyl-oxazolidinones bearing five- and six-membered rings using Pd(II)-NHC and Pd-phosphine systems reveals the relative reactivity order of N-activating groups in Suzuki-Miyaura cross-coupling. The reactivity of activated phenolic esters and thioesters is evaluated for comparison in O-C(O) and S-C(O) cross-coupling under the same reaction conditions. Most notably, the study reveals N-acyl-δ-valerolactams as a highly effective class of mono-N-acyl-activated amide precursors in cross-coupling. The X-ray structure of the model N-acyl-δ-valerolactam is characterized by an additive Winkler-Dunitz distortion parameter ?(τ+χN) of 54.0°, placing this amide in a medium distortion range of twisted amides. Computational studies provide insight into the structural and energetic parameters of the amide bond, including amidic resonance, N/O-protonation aptitude, and the rotational barrier around the N-C(O) axis. This class of N-acyl-lactams will be a valuable addition to the growing portfolio of amide electrophiles for cross-coupling reactions by acyl-metal intermediates.
- Bisz, Elwira,Chen, Hao,Dziuk, B?a?ej,Ejsmont, Krzysztof,Lalancette, Roger,Pyle, Daniel J.,Rahman, Md. Mahbubur,Szostak, Michal,Szostak, Roman,Wang, Qi
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p. 10455 - 10466
(2021/07/31)
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- Chemoselective Synthesis of Aryl Ketones from Amides and Grignard Reagents via C(O)-N Bond Cleavage under Catalyst-Free Conditions
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Conversion of a wide range of N-Boc amides to aryl ketones was achieved with Grignard reagents via chemoselective C(O)-N bond cleavage. The reactions proceeded under catalyst-free conditions with different aryl, alkyl, and alkynyl Grignard reagents. α-Ketoamide was successfully converted to aryl diketones, while α,β-unsaturated amide underwent 1,4-addition followed by C(O)-N bond cleavage to provide diaryl propiophenones. N-Boc amides displayed higher reactivity than Weinreb amides with Grignard reagents. A broad substrate scope, excellent yields, and quick conversion are important features of this methodology.
- Sureshbabu, Popuri,Azeez, Sadaf,Muniyappan, Nalluchamy,Sabiah, Shahulhameed,Kandasamy, Jeyakumar
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p. 11823 - 11838
(2019/10/02)
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- Synthesis, spectroscopic characterization and antimicrobial activities of benzoxazolone derivatives
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Background: Pathogenic microbial diseases are now the key virulence in our daily life. Significant research has been carried out in order to trigger the bacterial infections. Amongst the organic molecules, oxazolone and derivatives were found to have excellent bioactivities including antimicrobial activities. Methods: By keeping in mind the considerable antimicrobial activities of class benzoxazolones, a series of benzoxazolone derivatives 3-16 have been synthesized. Out of which five compounds 10, 11, 14, 15, and 16 were new synthetic derivatives whereas compounds 9, 12, and 13 were already known compounds. These compounds have been synthesized by refluxing of amino phenol and 1,1-carbonyldiimidazole1 (CHN)CO) (CDI) in a dry THF and then treated with commercially available acid chloride. The structures of the compounds were elucidated on the basis of 1H-NMR, EIMS and elemental analysis. All the compounds were screened for their antibacterial activities and tested by agar well diffusion method. Results: Compounds 14 and 16 showed good activity against S. aureus. Compound 5 showed good while 14 and 16 were found to be most active against E. coli using cefuroxime as a standard. Antifungal activities were carried out by using standard drug nystatin and compounds 4, 5, 9, 11 and compound 12 was found to be active against C. albicans. Compounds 4, 5, 9 and compound 10 showed good activities while 7, 11, and compound 13 showed excellent activities against Chrysosporium sp. Compounds 6, 7 and compound 12 were found to be most active against A. Niger and A. flavus, respectively. Conclusion: A number of derivatives were identified to have potent antimicrobial activities and may serve as lead compounds for future research.
- Siddiqui, Nida I.,Versiani, Muhammad A.,Jawaid, Khurshid,Shafique, Maryam,Hameed, Abdul,Ambreen, Nida,Karim, Aneela,Khan, Khalid M.
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p. 384 - 390
(2017/06/20)
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- Discovery of potent IDO1 inhibitors derived from tryptophan using scaffold-hopping and structure-based design approaches
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Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e, 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells. Treatment with these three compounds promoted the proliferation of T lymphocyte and led to the dramatic decrease of regulatory T cells in the B16F1 cells and na?ve T cells co-culture system. Subsequent spectroscopic experiments suggested that these benzoxazolinones formed a coordinate bond with the heme iron to stabilize the complex. This study suggested that the benzoxazolinone was an interesting scaffold for discovering novel IDO1 inhibitors, and these compounds are attractive candidates for further development.
- Zou, Yi,Wang, Yan,Wang, Fang,Luo, Minghao,Li, Yuezhen,Liu, Wen,Huang, Zhangjian,Zhang, Yihua,Guo, Wenjie,Xu, Qiang,Lai, Yisheng
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p. 199 - 211
(2017/07/03)
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- Benzo five-membered heterocyclic IDO1 (indoleamine 2,3-dioxygenase 1) inhibitor, preparation method thereof and application
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The invention belongs to the field of medicines, and particularly relates to a benzo five-membered heterocyclic compound or pharmaceutically acceptable salt of the compound, a preparation method of the compound and an application of the compound serving as an IDO1 (indoleamine 2,3-dioxygenase 1) inhibitor. Experimental results indicate that the compound has a remarkable inhibiting effect on activity of IDO1, T cell proliferation can be effectively promoted, differentiation of initial T cells into regulatory T cells is inhibited, IDO1-mediated immune inhibition is reversed, and the compound can be used for treating related diseases with pathological features of an IDO1-mediated kynurenine metabolic pathway, wherein the related diseases include cancer, virus infection, neurodegenerative diseases, cataract, organ transplant rejection, depression and autoimmune diseases.
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Paragraph 0169; 0170; 0171; 0172; 0173; 0174; 0175; 0176
(2017/07/22)
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- Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies
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Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.
- Bach, Anders,Pizzirani, Daniela,Realini, Natalia,Vozella, Valentina,Russo, Debora,Penna, Ilaria,Melzig, Laurin,Scarpelli, Rita,Piomelli, Daniele
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supporting information
p. 9258 - 9272
(2015/12/23)
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- Design and synthesis of 3-acyl-2(3H)-benzoxazolone and 3-acyl-2(3H)- benzothiazolone derivatives
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A simpler and efficient "green" method using solid sodium hydroxide in a solvent mixture of acetone/water was found to catalyze N-acylation of 2(3H)-benzoxazolones and 2(3H)-benzothiazolones for facile and rapid synthesis of N-acyl derivatives in excellent yields. This method was applied to the synthesis of a series of 132 compounds employing a variety of acyl chlorides. Graphical abstract: [Figure not available: see fulltext.]
- Guenadil, Faouzi,Aichaoui, Hocine,Kapanda, Coco N.,Lambert, Didier M.,McCurdy, Christopher R.,Poupaert, Jacques H.
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experimental part
p. 67 - 80
(2011/09/20)
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- Electrogenerated N-heterocyclic carbenes: N-functionalization of benzoxazolones
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A simple electrochemical procedure for the N-acylation and N-alkylation of benzoxazol-2(3H)-ones has been set up via electrolysis of an ionic liquid containing a benzoxazolone followed by addition of saturated or unsaturated anhydrides or alkyl halides. The electrochemically induced N-functionalization of benzoxazol-2(3H)-ones works very well in all tested ionic liquids, avoiding the use of volatile organic solvents. The N-acyl and N-alkyl derivatives of benzoxazol-2(3H)-ones were isolated in good to excellent yields; moreover, the ionic liquid has been reused fivefold maintaining the high yield of the products.
- Chiarotto,Feroci,Orsini,Sotgiu,Inesi
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experimental part
p. 3704 - 3710
(2009/09/05)
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- Efficient and selective deprotection method for N-protected 2(3H)-benzoxazolones and 2(3H)-benzothiazolones
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Cyclic carbamate flanked with heterocyclic or aliphatic moieties are frequently used in medicinal chemistry. The synthesis of derivatives bearing a free NH often requires the use of a protection method. A literature search reveals very few protection/deprotection methods for cyclic carbamates. In this paper, we described different methods applicable to 2(3H)-benzoxazolone and 2(3H)-benzothiazolone. Graphical abstract
- Carato, Pascal,Yous, Sa?d,Sellier, Didier,Poupaert, Jacques H.,Lebegue, Nicolas,Berthelot, Pascal
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p. 10321 - 10324
(2007/10/03)
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- Unsymmetrical Diarylketones from Electron-rich Heterocyclic Arenes
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AlCl3-mediated chlorocarbonylation of a first arene by oxalyl chloride followed by in situ Friedel-Crafts acylation of a second electron-rich arene expeditiously provides, in a one-pot procedure, either symmetrical or unsymmetrical benzophenones with yields ranging from 17-52%. Best results are obtained when the more activated substrate is used as the second arene. Another advantage is that the resultant benzophenone precipitates from the reaction mixture allowing facile workup.
- Poupaert, Jacques H.,Depreux, Patrick,McCurdy, Christopher R.
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p. 823 - 830
(2007/10/03)
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- 'Fries like' rearrangement: A novel and efficient method for the synthesis of 6-acyl-2(3H)-benzoxazolones and 6-acyl-2(3H)-benzothiazolones
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6-Acyl-2(3H)-benzoxazolone and 6-acyl-2(3H)-benzothiazolone derivatives have particularly interesting anti-inflammatory, antiepileptic, analgesic and antiviral properties. In this study, we report an original method of acylation on the 6-position of 2(3H)-banzoxazolone and 2(3H)benzothiazolone which consists in a two-step procedure involving migration of the acyl group from the N-position to the 6-position of the hetexocycle, at 165 °C and catalyzed by AlCl3. This new procedure was found to be more efficient with regard to the consumption of AICI3 and the yield (76-90%) than other acylation methods previously described.
- Ucar, Huseyin,Van Derpoorten, Kim,Depovere, Paul,Lesieur, Daniel,Isa, Majed,Masereel, Bernard,Delarge, Jacques,Poupaert, Jacques H.
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p. 1763 - 1772
(2007/10/03)
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- Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)- benzothiazolone derivatives
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A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were synthesized and evaluated for anticonvulsant activity. The compounds were assayed, intraperitoneally in mice and per os in rats, against seizures induced by maximal electroshock (MES) and pentylene-tetrazole (scMet). Neurologic deficity was evaluated by the rotarod test. The compounds were prepared to determine the relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives' structures and anticonvulsant activity. Several of these compounds showed significant anticonvulsant activity. Compounds 43 and 45 were the most active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6 mg/kg, respectively. Compound 45 displayed good protection against MES-induced seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a protective index (PI = TD50/ED50) of 1 receptors with nanomolar affinities.
- Ucar, Huseyin,Van Derpoorten, Kim,Cacciaguerra, Silvia,Spampinato, Santi,Stables, James P.,Depovere, Paul,Isa, Majed,Masereel, Bernard,Delarge, Jacques,Poupaert, Jacques H.
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p. 1138 - 1145
(2007/10/03)
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- ACYLATION OF 2,3-DIHYDROBENZOXAZOL-2-ONE IN A TWO STEPS METHOD INVOLVING AN ACYL MIGRATION
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A new method of acylation of 2,3-dihydrobenzoxazol-2-one 1 is proposed in a two-steps procedure involving an acyl migration.
- Cotelle, Nicole,Cotelle, Philippe,Lesieur, Daniel
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p. 3259 - 3266
(2007/10/02)
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- The N-Phosphobiotin Route: a Possible New Pathway for Biotin Coenzyme
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The formation of N-acylureas from N-phosphorylated ureas under very mild conditions is presented as a possible route to the formation of carboxybiotin from biotin in biotin-mediated enzymatic carboxylations in which an N-phosphobiotin is the activated form.The detailed mechanistic pathway for the model reaction indicates that an intermediate acylphosphate is formed, the rate-determining step being a nucleophilic attack of the ureido anion or its enol on this acylphosphate.In no case was an O-phosphorylated intermediate (of the phosphobiotin type) involved.
- Blonski, Casimir,Belghith, Hachemi,Klaebe, Alain,Perie, Jean-Jacques
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p. 1369 - 1374
(2007/10/02)
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- 3,3'-(Phenylphosphinylidene)bis and 3,3'-(Phenylphosphinylidene)bis. New Activating Agents
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New activating agents, 3,3'-(phenylphophinylidene)bis (4) and 3,3'-(phenylphosphinylidene)bis (5), were readily prepared by the reaction of phenylphosphonic dichloride (3) with 2(3H)-benzoxazolone (1) and 2(3H)-benzothiazolone (2) respectively in the presence of triethylamine at room temperature.The new activating agents 4 and 5 were found to be useful for the preparation of amides, esters, and dipeptides under mild conditions.Furthemore, the direct polycondensation of isophthalic acid with aromatic diamines using the activating agent 4 in the presence of pyridine proceeded fast at room temperature to produce polyamides with inherent viscosities up to 0.80 dL/g.
- Ueda, Mitsuru,Mochizuki, Amane,Hiratsuka, Ichiro,Oikawa, Hideaki
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p. 3291 - 3297
(2007/10/02)
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- MODELS OF BIOTIN COENZYME REACTIONS ACTIVATED THROUGH PHOSPHORYLATION
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The reactivity of models of enzymatic carboxylation reactions mediated by biotin coenzyme is presented; a possible role of the requiered ATP molecule for these reactions was investigated.Several models of biotin activated through phosphorylation - according to the O-phosphobiotin model - are described and their reactivity towards carboxylating agents discussed.Models also exhibit phosphoryl transfer propeties which may mimic known ATP synthesis from ADP, catalyzed by biotin carboxylases.Possible involvement of the same O-phosphobiotin structure is considered.
- Blonski, C.,Etemad-Moghadam, G.,Gasc, M. B.,Klaebe, A.,Perie, J. J.
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p. 361 - 364
(2007/10/02)
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