- Organocatalytic Desymmetrisation of Fittig's Lactones: Deuterium as a Reporter Tag for Hidden Racemisation
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Highly enantioselective desymmetrisation of Fittig's lactones with alcohols is promoted by bifunctional cinchona squaramides. The reactions were carried out with monodeuterated methanol to detect possible hidden racemisation of the stereogenic centre. Current evidence suggests that racemisation was not a relevant process for most substrates; partial erosion of enantioselectivity was only detected with ortho -substituted aryl derivates. The resultant glutaric acid derivatives possess a scaffold that is common in natural products and the compounds are also useful chiral building blocks for further synthetic endeavours.
- Spránitz, Péter,Soregi, Petra,Botlik, Bence Béla,Berta, Máté,Soós, Tibor
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p. 1263 - 1272
(2019/02/26)
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- PPh3/Selectfluor-Mediated Transformation of Carboxylic Acids into Acid Anhydrides and Acyl Fluorides and Its Application in Amide and Ester Synthesis
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By taking the advantage of PPh3/Selectfluor system, carboxylic acids are efficiently converted into the pivotal intermediates acyloxyphosphonium ions that can selectively react with a second carboxylic acid or fluoride to in situ yield the corresponding acid anhydrides or acyl fluorides. The developed protocol features commercially availabile reagents, no involvement of base, room temperature conditions, and simple experimental procedure. Additionally, various amides or esters are readily achieved, respectively, with the addition of amines or alcohols.
- Yang, Zhen,Chen, Siwei,Yang, Fang,Zhang, Chenxi,Dou, You,Zhou, Qiuju,Yan, Yizhe,Tang, Lin
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p. 5998 - 6002
(2019/08/21)
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- Synthesis, molecular docking, and pharmacological evaluation of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide derivatives as selective COX-2 inhibitors and anti-inflammatory agents
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A series of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide derivatives (3am) was synthesized and evaluated for their in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC50 50 values in the range of 0.06–0.71 μM. The in vivo anti-inflammatory activity of these six compounds (3a, 3b, 3d, 3g, 3j, and 3k) was assessed by the carrageenan-induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti-inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX-2, to understand the binding mechanism of these inhibitors to the active site of COX-2.
- Kaur, Avneet,Pathak, Dharam P.,Sharma, Vidushi,Wakode, Sharad
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- Synthesis, biological evaluation and docking study of a new series of di-substituted benzoxazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents
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A new series of substituted-N-(3,4-dimethoxyphenyl)-benzoxazole derivatives 13a–13p was synthesized and evaluated in vitro for their COX (I and II) inhibitory activity, in vivo anti-inflammatory and ulcerogenic potential. Compounds 13d, 13h, 13k, 13l and 13n exhibited significant COX-2 inhibitory activity and selectivity towards COX-2 over COX-1. These selected compounds were screened for their in vivo anti-inflammatory activity by carrageenan induced rat paw edema method. Among these compounds, 13d was the most promising analogs of the series with percent inhibition of 84.09 and IC50 value of 0.04 μM and 1.02 μM (COX-2 and COX-1) respectively. Furthermore, ulcerogenic study was performed and tested compounds (13d, 13h, 13k, 13l) demonstrated a significant gastric tolerance than ibuprofen. Molecular docking study was also performed with resolved crystal structure of COX-2 to understand the binding mechanisms of newly synthesized inhibitors in the active site of COX-2 enzyme and the results were found to be concordant with the biological evaluation studies of the compounds. These newly synthesized inhibitors also showed acceptable pharmacokinetic profile in the in silico ADME/T analyses.
- Kaur, Avneet,Pathak, Dharam P.,Sharma, Vidushi,Wakode, Sharad
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p. 891 - 902
(2018/01/22)
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- Synthesis, biological evaluation and docking study of N-(2-(3,4,5-trimethoxybenzyl)benzoxazole-5-yl) benzamide derivatives as selective COX-2 inhibitor and anti-inflammatory agents
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A series of N-(2-(3,4,5-trimethoxybenzyl)-benzoxazole-5-yl)benzamide derivatives (3a–3n) was synthesized and evaluated for its in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC50 50 in the range of 0.14–0.69 μM. In vivo anti-inflammatory activity of these six compounds (3b, 3d, 3e, 3h, 3l and 3m) was assessed by carrageenan induced rat paw edema method. The compound 3b (79.54%), 3l (75.00%), 3m (72.72%) and 3d (68.18%) exhibited significant anti-inflammatory activity than standard drug ibuprofen (65.90%). Ulcerogenic activity with histopathological studies was performed, and the screened compounds demonstrated significant gastric tolerance than ibuprofen. Molecular Docking study was also performed with resolved crystal structure of COX-2 to understand the interacting mechanisms of newly synthesized inhibitors with the active site of COX-2 enzyme and the results were found to be in line with the biological evaluation studies of the compounds.
- Kaur, Avneet,Pathak, Dharam P.,Sharma, Vidushi,Narasimhan, Balasubramanian,Sharma, Prateek,Mathur, Rajani,Wakode, Sharad
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p. 191 - 202
(2018/08/23)
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- Synthesis, cyclooxygenase-2 inhibition, anti-inflammatory evaluation and docking study of substituted-n-(3,4,5-trimethoxyphenyl)-benzo[d]oxazole derivatives
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Background: Non-steroidal anti-inflammatory drugs are widely used for many years, but the chronic use of NSAID’s leads to gastric side effects, ulceration and kidney problems. These side effects are due to non-selective inhibition of COX-2 along with COX-1. Therefore, it is imperative to develop novel and selective COX-2 inhibitors. Objective: In this paper wehave synthesized a series of novel hybrids comprising of substituted-N-(3,4,5-trimethoxyphenyl)-benzo[d]oxazole derivatives and screened for the treatment of inflammation. Methods: The structures of the obtained compounds were elucidated by elemental and spectral analysis (ATR-FTIR,1 H NMR,13 C NMR, Mass spectroscopy). All of the compounds were evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activity by in vitro enzymatic assay. The compound which showed COX-2 activity (3a-3e, 3g – 3h, 3k, 3m and 3o) was further screened for in vivo anti-inflammatory activity and ulcerogenic liability. Molecular docking study was also performed with resolved crystal structure of COX-2 to understand the binding mechanism of newly synthesized inhibitors in the active site of COX-2enzyme. Results: The in vitro COX-1 and COX-2 inhibitory studies showed that the synthesized compounds potentially inhibited COX-2 (IC50 = 0.04 – 26.41 μM range) over COX-1 (IC50 = 0.98 – 33.33 μM range). The in vivo studies predicted that compounds 3c (70.9%, 0.6±0.22), 3m (68.1%, 1.9±0.41) and 3o (70.4%, 1.7±0.27) produced more efficacy against carrageenan induced paw edema and less ulcerogenic effect, as compared to standard ibuprofen (65.9%, 2.2±0.44). The results of docking studies were found to be concordant with the biological evaluation studies of the prepared compound. Conclusion: Among all the tested compounds, 2-Chloro-N-(2-(3,4,5-trimethoxyphenyl)-benzo[d]oxazol-5-yl)-benzamide (3c) was the most potent anti-inflammatory agent and has less ulcerogenic potential. This series of compound can be explored more for development of safer and more active anti-inflammatory agents.
- Kaur, Avneet,Wakode, Sharad,Pathak, Dharam P.,Sharma, Vidushi,Shakya, Ashok K.
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p. 660 - 673
(2018/11/06)
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- TBHP/ n -Bu 4 PBr-Promoted Oxidative Cross-Dehydrogenative Coupling of Aryl Methanols: A Facile Synthesis of Symmetrical Carboxylic Anhydride Derivatives
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A transition-metal-free oxidative cross-dehydrogenative coupling reaction has been developed for the preparation of symmetrical carboxylic anhydrides through self-coupling dual C-O bond formations of aryl methanols. In the presence of a catalytic amount of tetrabutylphosphonium bromide (TBPB) as transfer agent and aqueous tert -butyl hydroperoxide (TBHP) as oxidant and reactant, methylene groups of aryl methanols were efficiently oxidized to C=O and coupled with the peroxide oxygen from TBHP to form a diverse array of symmetrical carboxylic anhydride derivatives.
- Adib, Mehdi,Pashazadeh, Rahim
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supporting information
p. 136 - 140
(2017/12/27)
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- Cu-MOF: An efficient heterogeneous catalyst for the synthesis of symmetric anhydrides: Via the C-H bond activation of aldehydes
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In this paper, an efficient and straightforward synthetic approach for the preparation of a number of symmetric carboxylic anhydrides was reported using Cu2(BDC)2(DABCO) as an efficient heterogeneous catalyst via the C-H bond activation of aldehydes with excellent yields and simple work up. This C-H bond activation reaction appears simple and convenient, has a wide substrate scope and makes use of cheap, abundant, and easily available reagents. The Cu-MOF catalyst was recycled and reused four times without any loss of catalytic activity.
- Ahmadzadeh, Zahra,Mokhtari, Javad,Rouhani, Morteza
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p. 24203 - 24208
(2018/07/25)
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- Anhydrides from aldehydes or alcohols via oxidative cross-coupling
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A novel type of metal-free oxidative cross-coupling for the synthesis of symmetrical and mixed anhydrides from aldehydes or benzylic alcohols has been developed. The aldehydes or alcohols were converted in situ into their corresponding acyl chlorides, which were then reacted with an array of carboxylic acids. The methodology has a general applicability, and was successfully employed to prepare either aromatic or aliphatic symmetrical anhydrides and mixed anhydrides, which are very unstable compounds.
- Gaspa, Silvia,Amura, Ida,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 931 - 939
(2017/02/10)
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- An investigation on practical synthesis of carboxylic acid derivatives using p-toluenesulfonyl chloride
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Carboxylic acid derivatives are well recognized as important class of reagents frequently used in the preparation of a variety of fine or special chemicals such as amides, esters, peptides, drugs, and dyes. Although several methods were developed for the preparation of these compounds, many of them present difficulties, including low yield, high reaction temperature, harsh reaction conditions, tedious work-up, and incompatibility with scale-up. Methods: The synthesis of carboxylic anhydrides is developed through the reaction of carboxylic acids with TsCl in the presence of K2CO3 and acetonitrile as a solvent under ultrasound irradiation and conventional conditions. In addition, one-pot synthesis of acyl azides was carried out in the presence of produced carboxylic anhydrides and the addition of sodium azide under identical condition. Results: A series of carboxylic anhydrides and acyl azides were synthesized using TsCl under ultrasound irradiation and conventional stirring with simple procedure, mild reaction conditions, high yields, and scale-up ability without any restriction. In most cases, the reaction under ultrasound irradiation was better in both yields and the reaction times compared to the conventional method. Conclusion: A convenient method has been developed for the preparation of carboxylic anhydrides and acyl azides under ultrasound irradiation and conventional stirring. The present method is practical and a highly effective alternative for previous reports. The major advantages of this method are: (i) simplicity of the procedure (ii) high yields and high purity of product (iii) scale-up capacity without considerable limitation in conventional system. Under ultrasound irradiation short reaction times as compared to conventional method are observed; yields are comparable to or better than conventional method.
- Eskandari, Parvin,Kazemi, Foad
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p. 431 - 439
(2017/07/24)
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- Metal-free oxidative self-coupling of aldehydes or alcohols to symmetric carboxylic anhydrides
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A metal-free synthesis of symmetrical anhydrides has been developed starting from aldehydes, both aliphatic and aromatic or primary benzylic alcohols. The reaction occurs at room temperature and makes use of trichloroisocyanuric acid (TCCA) as an oxidant providing the desired carboxylic anhydrides in satisfactory yields.
- Gaspa, Silvia,Porcheddu, Andrea,De Luca, Lidia
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supporting information
p. 2533 - 2536
(2017/06/13)
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- Acid anhydrides and the unexpected N,N-diethylamides derived from the reaction of carboxylic acids with Ph3P/I2/Et3N
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The formation of acid anhydrides from the phosphorous-mediated activation of carboxylic acids was investigated. Under various systems, activation of benzoic acid in the presence of base led to the formation of benzoic anhydride at different rates depending on the reactivity of the reagents. Using the Ph3P-I2/Et3N combination, most aryl acids were converted into the corresponding anhydrides in high yields within 5-10 min. However, for nitro-substituted derivatives, unexpectedly, N,N-diethylamides were isolated without anhydride formation. These results indicated the pronounced effect of substituents in governing these potential side reactions which can significantly affect the yields of acylation reactions promoted by phosphonium species.
- Phakhodee, Wong,Duangkamol, Chuthamat,Wangngae, Sirilak,Pattarawarapan, Mookda
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supporting information
p. 325 - 328
(2016/01/12)
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- Metal-free cross-dehydrogenative coupling of aryl aldehydes to give symmetrical carboxylic anhydrides promoted by the TBHP/nBu4PBr system
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A novel, efficient, and metal-free dual C–O bond formation reaction for the synthesis of carboxylic anhydrides from aryl aldehydes via cross-dehydrogenative coupling is described. Heating a mixture of aromatic aldehydes and an aqueous solution of tert-butyl hydroperoxide as oxidant in the presence of catalytic nBu4PBr in chlorobenzene at 80?°C for 3?h afforded the corresponding carboxylic anhydrides in good to excellent yields.
- Adib, Mehdi,Pashazadeh, Rahim,Rajai-Daryasarei, Saideh,Mirzaei, Peiman,Jamal Addin Gohari, Seyed
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supporting information
p. 3071 - 3074
(2016/07/06)
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- Oxidative self-coupling of aldehydes in the presence of CuCl2/TBHP system: Direct access to symmetrical anhydrides
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A simple synthesis of symmetrical anhydrides has been developed. Using tert-butylhydroperoxide (TBHP) as the oxidant and copper(II) chloride as the catalyst in acetonitrile, various aromatic and heteroaromatic aldehydes were reacted to provide symmetrical anhydrides in modest to good yields.
- Saberi, Dariush,Shojaeyan, Fatemeh,Niknam, Khodabakhsh
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p. 566 - 569
(2016/01/20)
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- Synthesis of acylsilanes by copper(I)-catalyzed addition of silicon nucleophiles onto acid derivatives
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The transition metal-catalyzed transfer of silicon nucleophiles onto various electrophiles has recently gained considerable attention, due to the now readily available silicon pro-nucleophiles such as silylboronates. Our interest lies in the addition of such species to acid derivatives for the generation of acylsilanes. We report herein an efficient method to synthesize these compounds, starting from easy-to-form anhydrides, with very good yields. Copyright
- Cirriez, Virginie,Rasson, Corentin,Riant, Olivier
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supporting information
p. 3137 - 3140
(2013/12/04)
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- Carboxylic acid anhydrides via Pd-catalyzed carbonylation of aryl halides at atmospheric CO pressure
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A convenient method has been developed, which allows for the direct transformation of aryl iodides into the corresponding carboxylic acid anhydrides via Pd-catalyzed carbonylation under atmospheric CO pressure. The Royal Society of Chemistry 2012.
- Li, Yang,Xue, Dong,Wang, Chao,Liu, Zhao-Tie,Xiao, Jianliang
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supporting information; experimental part
p. 1320 - 1322
(2012/02/04)
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- Substrate activity screening: A fragment-based method for the rapid identification of nonpeptidic protease inhibitors
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A new fragment-based method for the rapid development of novel and distinct classes of nonpeptidic protease inhibitors, Substrate Activity Screening (SAS), is described. This method consists of three steps: (1) a library of N-acyl aminocoumarins with diverse, low molecular weight N-acyl groups is screened to identify protease substrates using a simple fluorescence-based assay, (2) the identified N-acyl aminocoumarin substrates are optimized by rapid analogue synthesis and evaluation, and (3) the optimized substrates are converted to inhibitors by direct replacement of the aminocoumarin with known mechanism-based pharmacophores. The SAS method was successfully applied to the cysteine protease cathepsin S, which is implicated in autoimmune diseases. Multiple distinct classes of nonpeptidic substrates were identified upon screening an N-acyl aminocoumarin library. Two of the nonpeptidic substrate classes were optimized to substrates with >8000-fold improvements in cleavage efficiency for each class. Select nonpeptidic substrates were then directly converted to low molecular weight, novel aldehyde inhibitors with nanomolar affinity to cathepsin S. This study demonstrates the unique characteristics and merits of this first substrate-based method for the rapid identification and optimization of weak fragments and provides the framework for the development of completely nonpeptidic inhibitors to many different proteases.
- Wood, Warren J. L.,Patterson, Andrew W.,Tsuruoka, Hiroyuki,Jain, Rishi K.,Ellman, Jonathan A.
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p. 15521 - 15527
(2007/10/03)
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- Synthesis of unsymmetrical ketones by palladium-catalyzed cross-coupling reaction of carboxylic anhydrides with organoboron compounds
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On the basis of fundamental studies on oxidative addition of carboxylic anhydrides to zerovalent palladium complexes to yield acyl(carboxylato)bis(tertiary phosphine)palladium(II) complexes and their reactions with organoboronic acids to yield ketones, a novel catalytic process has been developed. This converts carboxylic anhydrides and organoboron compounds into ketones catalyzed by palladium complexes under mild conditions. The process provides a general, versatile, synthetic method to produce various symmetrical and unsymmetrical ketones with aromatic, aliphatic, and heterocyclic groups. The catalytic cycle is proposed to comprise (a) oxidative addition of a carboxylic anhydride to produce an acyl(carboxylato)palladium intermediate, (b) transmetallation with an organoboron compound to give an acyl(organo)palladium intermediate, and (c) its reductive elimination to yield a ketone. Not only homogeneous catalyst systems but also heterogeneous systems were found to give ketones under mild conditions.
- Kakino, Ryuki,Yasumi, Sayaka,Shimizu, Isao,Yamamoto, Akio
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p. 137 - 148
(2007/10/03)
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- Palladium-promoted One-step Synthesis of Aromatic Acid Anhydrides from Aromatic Compounds with Carbon Monoxide
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The one-step synthesis of aromatic acid anhydrides from aromatic compounds such as benzene, toluene, anisole, chlorobenzene, furan, and thiophen has been carried out using carbon monoxide, 1,2-dibromoethane, and palladium acetate
- Fujiwara, Yuzo,Kawata, Itaru,Kawauchi, Tomio,Taniguchi, Hiroshi
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p. 132 - 133
(2007/10/02)
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- Reaction of Diazonium Salts with Transition Metals. 6. Preparation of Mixed Acid Anhydrides from Arenediazonium Salts and Sodium Carboxylates under Palladium(0) Catalysis
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The palladium(0)-catalyzed reaction of arenediazonium tetrafluoroborates with carbon monoxide and sodium carboxylates in acetonitrile at 25 deg C gave mixed acid anhydrides, ArCOOCOR (Ar = 3-Me-Ph, 4-Me-Ph, 2-MeO-Ph, 4-Br-Ph, 4-I-Ph, 3-NO2-Ph, 4-NO2-Ph, and Ph; R = H, Me, Et, t-Bu, and Ph) in good yields.Homoaromatic acid anhydrides, (ArCO)2O, were obtained by heating of ArCOOCOMe at 100-120 deg C under vacuum.ArCOOCO-t-Bu can be utilized to obtain the corresponding arenecarboxamides by the reaction with some amines.
- Kikukawa, Kiyoshi,Kono, Kiyoshi,Nagira, Kazuhiko,Wada, Fumio,Matsuda, Tsutomu
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p. 4413 - 4416
(2007/10/02)
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