- 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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- Palladium-Catalyzed Suzuki Coupling of N-Acyloxazolidinones via Selective Cleavage of C–N Bonds
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By implementing a palladium-catalyzed Suzuki coupling reaction of N-acyloxazolidinones with arylboronic acid, we herein report on the preparation of substituted diaryl ketones via selective cleavage of exocyclic C–N Bonds. The reaction was carried out under mild reaction conditions with excellent functional group compatibility in good yields (up to 93 %).
- Jian, Junsheng,He, Zhanyu,Zhang, Yuqi,Liu, Tingting,Liu, Lizhen,Wang, Zijia,Wang, Hui,Wang, Sanyong,Zeng, Zhuo
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supporting information
p. 4176 - 4180
(2020/07/13)
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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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- CuCl/TMEDA/nor-AZADO-catalyzed aerobic oxidative acylation of amides with alcohols to produce imides
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Although aerobic oxidative acylation of amides with alcohols would be a good complement to classical synthetic methods for imides (e.g., acylation of amides with activated forms of carboxylic acids), to date, there have been no reports on oxidative acylation to produce imides. In this study, we successfully developed, for the first time, an efficient method for the synthesis of imides through aerobic oxidative acylation of amides with alcohols by employing a CuCl/TMEDA/nor-AZADO catalyst system (TMEDA = teramethylethylendiamine; nor-AZADO = 9-azanoradamantane N-oxyl). The proposed acylation proceeds through the following sequential reactions: aerobic oxidation of alcohols to aldehydes, nucleophilic addition of amides to the aldehydes to form hemiamidal intermediates, and aerobic oxidation of the hemiamidal intermediates to give the corresponding imides. This catalytic system utilizes O2 as the terminal oxidant and produces water as the sole by-product. An important point for realizing this efficient acylation system is the utilization of a TMEDA ligand, which, to the best of our knowledge, has not been employed in previously reported Cu/ligand/N-oxyl systems. Based on experimental evidence, we consider that plausible roles of TMEDA involve the promotion of both hemiamidal oxidation and regeneration of an active CuII-OH species from a CuI species. Here promotion of hemiamidal oxidation is particularly important. Employing the proposed system, various types of structurally diverse imides could be synthesized from various combinations of alcohols and amides, and gram-scale acylation was also successful. In addition, the proposed system was further applicable to the synthesis of α-ketocarbonyl compounds (i.e., α-ketoimides, α-ketoamides, and α-ketoesters) from 1,2-diols and nucleophiles (i.e., amides, amines, and alcohols).
- Kataoka, Kengo,Wachi, Keiju,Jin, Xiongjie,Suzuki, Kosuke,Sasano, Yusuke,Iwabuchi, Yoshiharu,Hasegawa, Jun-Ya,Mizuno, Noritaka,Yamaguchi, Kazuya
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p. 4756 - 4768
(2018/06/07)
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- Design, synthesis, and biological evaluation of oxazolidone derivatives as highly potent N-acylethanolamine acid amidase (NAAA) inhibitors
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N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that catalyzes the hydrolysis of endogenous fatty acid ethanolamides (FAEs), such as N-palmitoylethanolamide (PEA). PEA exhibits anti-inflammatory and analgesic activities by engaging peroxisome proliferator-activated receptor α (PPAR-α). Preventing PEA degradation by inhibition of NAAA has been proposed as a novel strategy for the treatment of inflammation and pain. In the present study, we reported the discovery of the oxazolidone derivative as a novel scaffold for NAAA inhibitors, and studied the structure-activity relationship (SAR) by modification of the side chain and terminal lipophilic substituents. The results showed that the link chain length of C5, straight and saturated linkages were the preferred shape patterns for NAAA inhibition. Several nanomolar NAAA inhibitors were described, including 2f, 3h, 3i and 3j with IC50 values of 270 nM, 150 nM, 100 nM and 190 nM, respectively. Enzymatic degradation studies suggested that 2f inhibited NAAA in a selective, noncompetitive and reversible pattern. Moreover, 2f showed high anti-inflammatory and analgesic activities after systemic and oral administration.
- Ren, Jie,Li, Yuhang,Ke, Hongwei,Li, Yanting,Yang, Longhe,Yu, Helin,Huang, Rui,Lu, Canzhong,Qiu, Yan
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p. 12455 - 12463
(2017/03/11)
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- Palladium-Catalyzed Aerobic Oxidative Dehydrogenation of Cyclohexenes to Substituted Arene Derivatives
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A palladium(II) catalyst system has been identified for aerobic dehydrogenation of substituted cyclohexenes to the corresponding arene derivatives. Use of sodium anthraquinone-2-sulfonate (AMS) as a cocatalyst enhances the product yields. A wide range of functional groups are tolerated in the reactions, and the scope and limitations of the method are described. The catalytic dehydrogenation of cyclohexenes is showcased in an efficient route to a phthalimide-based TRPA1 activity modulator.
- Iosub, Andrei V.,Stahl, Shannon S.
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p. 3454 - 3457
(2015/03/30)
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- REACTIVE OXYGEN SPECIES-BASED PRODRUGS
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Provided herein are ROS-sensitive prodrug compositions and methods of treating ROS-associated diseases by administering the ROS-sensitive prodrug compositions.
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Paragraph 0275; 0276; 0280
(2015/02/05)
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- Exploring hydrogen peroxide responsive thiazolidinone-based prodrugs
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A novel approach for developing prodrugs based on masked carboxylic acids is described. Rather than using conventional esterase-based activation, thiazolidinone protecting groups have been identified that can reveal carboxylic acid groups upon activation by hydrogen peroxide. This may prove valuable in the continuing development of prodrug strategies that rely on reactive oxygen species (ROS) as a trigger. This journal is
- Perez, Christian,Monserrat, Jean-Philippe,Chen, Yao,Cohen, Seth M.
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supporting information
p. 7116 - 7119
(2015/04/27)
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- Palladium-catalyzed fluorocarbonylation using N-formylsaccharin as CO source: General access to carboxylic acid derivatives
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N-Formylsaccharin, an easily accessible crystalline compound, has been employed as an efficient CO source in Pd-catalyzed fluorocarbonylation of aryl halides to afford the corresponding acyl fluorides in high yields. The reactions use a near-stoichiometric amount of the CO source (1.2 equiv) and tolerate diverse functional groups. The acyl fluorides obtained could be readily transformed into various carboxylic acid derivatives such as carboxylic acid, esters, thioesters, and amides in a one-pot procedure.
- Ueda, Tsuyoshi,Konishi, Hideyuki,Manabe, Kei
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p. 5370 - 5373
(2013/11/06)
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- Chemoselective N-acylation of indoles and oxazolidinones with carbonylazoles
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Unique reactivity: In the presence of more reactive amine and alcohol functional groups and of carboxylic acids, the chemoselective N-acylation of indoles (see scheme) and oxazolidinones is achieved by taking advantage of the unique reactivity of carbonylazole acylating agents with catalytic amounts of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Copyright
- Heller, Stephen T.,Schultz, Erica E.,Sarpong, Richmond
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supporting information; experimental part
p. 8304 - 8308
(2012/09/08)
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- Rhodium/copper-catalyzed annulation of benzimides with internal alkynes: Indenone synthesis through sequential C-H and C-N cleavage
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Doubled up: A rhodium(III)/copper(II) system co-catalyzes the annulation of benzimides with internal alkynes for the synthesis of indenones (see scheme; Cp=C5Me5). The reaction involves an uncommon nucleophilic addition of a transition-metal-carbon bond to an imide moiety. This novel reaction provides a facile route to synthesize indenones from readily available benzimides and internal alkynes. Copyright
- Li, Bi-Jie,Wang, Hao-Yuan,Zhu, Qi-Lei,Shi, Zhang-Jie
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supporting information; experimental part
p. 3948 - 3952
(2012/05/20)
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- Short communication: Silica sulfuric acid: A versatile and reusable heterogeneous catalyst for the synthesis of N-ACYL carbamates and oxazolidinones under solvent-free conditions
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Silica sulfuric acid catalyzes efficiently the reaction of carbamates and oxazolidinones with anhydrides under solvent-free conditions. All the reactions were done at room temperature and the N-acyl carbamates and oxazolidinones were obtained with high yi
- Wu, Liqiang,Yang, Xiaojuan,Yan, Fulin
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experimental part
p. 151 - 155
(2012/05/20)
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- Synthesis of N-Acyl carbamates and oxazolidinones using HClO 4-SiO2 as catalyst under solvent-free conditions
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Silica supported perchloric acid catalyzes efficiently the reaction of carbamates and oxazolidinones with anhydrides in the presence of silica sulfuric acid under solvent-free conditions. All the reactions were done at room temperature and the N-acyl carb
- Yang, Li Juan,Yang, Yuping,Dong, Ruoyi
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experimental part
p. 1085 - 1087
(2011/12/16)
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- Facile formation of N-acyl-oxazolidinone derivatives using acid fluorides
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A mild method is presented for the formation of N-acylated oxazolidinones that employs acid fluorides and mild bases, such as iPr 2NEt and NEt3. Optimized reaction conditions for two types of substrates have been developed utilizing either the oxazolidinone itself or the corresponding in situ generated O-silyloxazolidinones resulting in the formation of the desired N-acylated products in high yields of up to 98%.
- Schindler, Corinna S.,Forster, Patrik M.,Carreira, Erick M.
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supporting information; scheme or table
p. 4102 - 4105
(2010/11/19)
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- Spiro-fysed 2-alkoxy-2-amino-Δ3-1,3,4-oxadiazolines. Synthesis and thermolysis to corresponding aminooxycarbenes
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Δ3-1,3,4-Oxadiazolines spiro-fused at C2 to C2 to oxazolidines (12) or to C2 of tetrahydro-1,3-oxazines (13) were synthesized. The oxadiazolines undergo thermolysis in benzene at 90°C with first-order rate constants of (1.6-50) × 10-5 s-1. The dependence of these rate constants on the nature of the substituents present on the oxadiazoline ring is consistent with a mechanism involving a carbonyl ylide intermediate. Substituents on N of the oxazolidine or tetrahydro-1,3-oxazine moieties play a major role in determining the fragmentation pathways. Oxadiazolines with N-carbonyl groups (12c-j, 13d,e) afford essentially quantitative yields of the corresponding aminooxycarbenes, while other fragmentation reactions compete with carbene generation in the case of oxadiazolines with N-methyl (12b, 13c) or N-sulfonyl (12k) groups.
- Couture, Philippe,Warkentin, John
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p. 1264 - 1280
(2007/10/03)
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- α,α,α-Trichloromethylcarbonyl Compounds as Acylating Reagents of Amides
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Various α,α,α-trichloromethylcarbonyl compounds, namely chloral, trichloroacetone, trichloracetophenone and benzyltrichloromethyl acetate are used in alkaline medium as acylating reagents for primary and secondary amides.
- Atanassova, I.A.,Petrov, J.S.,Ognjanova, V.H.,Mollov, N.M.
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p. 2083 - 2090
(2007/10/02)
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- Formation of N-Tributylstannyl Heterocycle from Bis(tributyltin) Oxide and ω-Haloalkyl Isocyanate. One-Pot Convenient Synthesis of 2-Oxazolidinones and Tetrahydro-2H-1,3-oxazin-2-one
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Novel types of compounds, N-tributylstannyl-2-oxazolidinone (4a) and tetrahydro-2H-1,3-oxazin-2-one (4b), are formed from the adduct of (n-Bu3Sn)2O (1) with ω-haloalkyl isocyanate (2), and the subsequent coupling reaction with alkyl halides gives a variety of N-substituted 2-oxazolidinones and tetrahydro-2-oxazinones in a one-pot procedure.Both the cyclization and the coupling reaction proceed quantitatively in the presence of HMPA which enhances the reactivity of the Sn-heteroatom bond by coordination.
- Shibata, Ikuya,Nakamura, Kenji,Baba, Akio,Matsuda, Haruo
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p. 853 - 859
(2007/10/02)
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- The Use of 2-Oxazolidinone as a Latent Aziridine Equivalent. I. A Facile Method for the Preparation of 2-Substituted Oxazolines
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Ring-opening reaction of 2-oxazolidinone with acid chlorides followed by treatment with aqueous sodium hydroxide yields 2-substituted oxazolines.
- Poindexter, Graham S.
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p. 1431 - 1433
(2007/10/02)
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- REGENTS AND SYNTHETIC METHODS. 16. AMINOLYSIS OF N-ACYL-2-PHENYLIMINOOXAZOLIDINE. A NEW SYNTHESIS OF AMIDES
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N-Acyl-2-phenyliminooxazolidines 7 were easily prepared and treated with several amines at room temperature, yielding amides 9 in very high yields.Possible mechanisms for this transformation are briefly discussed.
- Ganboa, Inaki,Palomo, Claudio
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p. 167 - 170
(2007/10/02)
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- A Novel Synthesis of 2-Substituted Oxazolines
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Thermal rearrangement of N-acyl-2-oxazolidones in the presence of calcium oxide has been shown to provide a new entry into 2-substituted oxazolines.
- Mundy, Bradford P.,Kim, Youseung
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p. 1221 - 1222
(2007/10/02)
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- 3-Alkylsilyl-2-oxazolidonone compounds and synthesis thereof
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Silylating agents, such as 3-alkylsilyl-2-oxazolidinones, are useful for the preparation of penicillins and cephalosporins at low temperatures and in a short time. The process for preparing these compounds comprises reacting 2-oxazolidinone or 5-methyl-2-oxazolidinone with trimethylchlorosilane, dimethylchlorosilane or triethylchlorosilane, in the presence of an organic tertiary base acting as a hydrogen chloride removal agent.
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