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Facile Synthesis for Benzo-1,4-Oxazepine Derivatives by Tandem Transformation of C-N Coupling/C-H Carbonylation.

ABSTRACT: A tandem transformation of C-N coupling/C-H carbonylation has been developed for the synthesis of benzo-1,4-oxazepine pharmaceutically derivatives. Notably, this reaction was accomplished by various phenylamine with ally halides under carbon dioxide atmosphere employing 2-(2-dimethylamino-vinyl)-1H-inden-1-olcatalyzed. Furthermore, under the optimized conditions, various benzo-1,4-oxazepine derivatives were obtained in good yields. Finally, a plausible Cu^I/Cu^III mechanism of C-N coupling/C-H carbonylation transformation was proposed.

SUBMITTER: Zhao X

PROVIDER: S-EPMC6155786 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Crystal structures of methyl 3-phenyl-4,5-di-hydro-1H,3H-benzo[4,5]imidazo[2,1-c][1,4]oxazepine-4-carboxyl-ate and methyl 1-methyl-3-phenyl-4,5-di-hydro-1H,3H-benzo[4,5]imidazo[2,1-c][1,4]oxazepine-4-carboxyl-ate.

Project description:The title compounds, C19H18N2O3, (I), and C20H20N2O3, (II), differ only by a methyl substituent on the seven-membered oxazepine ring in (II). In both compounds, these rings have a twist-chair conformation. The phenyl ring makes a dihedral angle of 73.42?(10)° with the benzimidazole ring system mean plane (r.m.s. deviation = 0.015?Å) in (I) and 83.07?(7)° in (II) (r.m.s. deviation = 0.026?Å). The methyl carboxyl-ate groups are planar to within 0.031?(2) in (I) and 0.003?(2)?Å in (II). They are inclined to the phenyl and benzimidazole ring system by 33.78?(16) and 87.56?(14)°, respectively, in (I) and by 53.04?(12) and 60.22?(11)°, respectively, in (II). In the crystal of (I), mol-ecules stack in a herringbone fashion and are linked by C-H?O hydrogen bonds, forming chains along [100]. In the crystal of (II), there are no significant inter-molecular inter-actions present.

| S-EPMC4257324 | biostudies-literature

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications.

Project description:(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl 4-methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alcohols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From (31)P{(1)H}, [(18)O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO(-) and AtO(-) produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because BtO(-) is a nucleofuge, several Bt-OCH2Ar substrates have been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd ?-allyl complexes by departure of BtO(-) has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis.

| S-EPMC4168895 | biostudies-literature

Rhodium-catalyzed carbonylation of 3-acyloxy-1,4-enynes for the synthesis of cyclopentenones.

Project description:Functionalized cyclopentenones were synthesized by a Rh-catalyzed carbonylation of 3-acyloxy-1,4-enynes, derived from alkynes and α,β-unsaturated aldehydes. The reaction involved a Saucy-Marbet 1,3-acyloxy migration of propargyl esters and a [4 + 1] cycloaddition of the resulting acyloxy substituted vinylallene with CO.

| S-EPMC3306479 | biostudies-literature

Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives.

Project description:A new method for the regioselective synthesis of 2-alkoxycarbonyl- and 2-(aminocarbonyl)phenylglycinate methyl esters has been developed. The reaction of the orthopalladated complex [Pd(μ-Cl)(C(6)H(4)(CH(CO(2)Me)NMe(2))-2)](2) (1) with nucleophiles HNu under a CO atmosphere results in the selective incorporation of the C(O)Nu moiety to the phenyl ring and formation of the carbonyl species ortho-C(6)H(4)(C(O)Nu)(CH(CO(2)Me)NMe(2)) (2a-j) (Nu = OR, NHR, NR(2)). Compounds 2a-j are conformationally restricted analogues of glutamic acid and glutamine and are interesting due to their biological and pharmacological properties. The reaction of [Pd(μ-Cl)(C(6)H(4)(CH(CO(2)Me)NHTf)-2)](2) (3) with nucleophiles in a CO atmosphere results, however, in the formation of the cyclic isoindolinone or the open 2-carboxyphenylglycine methyl esters, with the reaction outcome being driven by the choice of the solvent.

| S-EPMC3510988 | biostudies-literature

Design, synthesis and biological evaluation of 2H-benzo[b][1,4] oxazine derivatives as hypoxia targeted compounds for cancer therapeutics.

Project description:A small library of 2H-benzo[b][1,4] oxazine derivative was synthesized and their biological activity was tested on HepG2 cells under normoxic and hypoxic conditions. From preliminary screening, we found compound 10 and 11 specifically inhibit hypoxic cancer cell growth IC(50) 87+/-1.8microM and IC(50) 10+/-3.7microM while sparing 'normoxic' cells IC(50) >600M and >1mM (not applicable), respectively. We tested the effect of 10 on MTT, clonogenic and hypoxia induced genes. The MTT correlates with clonogenic assays and most importantly compound 10 down regulates hypoxia induces genes (HIF-1alpha, P21 and VEGF) appropriately. We are in the process to explore the molecular mechanism of action of oxazine derivative compounds on hypoxia tumor cells.

| S-EPMC2882196 | biostudies-literature

Design, Synthesis, and Evaluation of Novel 2H-Benzo[b][1,4]thiazin-3(4H)-one Derivatives as New Acetylcholinesterase Inhibitors.

Project description:Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The AChE and BChE inhibition potentials of all compounds were evaluated by using the in vitro Ellman method. The biological evaluation showed that compounds 3i and 3j displayed significant inhibitory activity against AChE. Compounds 3i and 3j showed IC50 values of 0.027 µM and 0.025 µM against AChE, respectively. The reference drug donepezil (IC50 = 0.021 µM) also showed significant inhibition against AChE. Further docking simulation also revealed that these compounds (3i and 3j) interacted with the active site of the enzyme similarly to donepezil. The antioxidant study revealed that compounds 3i and 3j exhibited greater antioxidant effects. An in vitro blood-brain barrier permeability study showed that compounds 3i and 3j are promising compounds against AD. The cytotoxicity study of compounds 3i and 3j showed non-cytotoxic with an IC50 value of 98.29 ± 3.98 µM and 159.68 ± 5.53 µM against NIH/3T3 cells, respectively.

| S-EPMC9000418 | biostudies-literature

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions.

Project description:9-Arylbenzo[b]quinolizinium derivatives were prepared with base-free Suzuki-Miyaura coupling reactions between benzo[b]quinolizinium-9-trifluoroborate and selected benzenediazonium salts. In addition, the Sonogashira coupling reaction between 9-iodobenzo[b]quinolizinium and the arylalkyne derivatives yielded four novel 9-(arylethynyl)benzo[b]quinolizinium derivatives under relatively mild reaction conditions. The 9-(N,N-dimethylaminophenylethynyl)benzo[b]quinolizinium is only very weakly emitting, but the emission intensity increases by a factor >200 upon protonation, so that this derivative may operate as pH-sensitive light-up probe. Photometric and fluorimetric titrations of duplex and quadruplex DNA to 9-(arylethynyl)benzo[b]quinolizinium derivatives revealed a significant binding affinity of these compounds towards both DNA forms with binding constants of Kb = 0.2-2.2 × 105 M-1.

| S-EPMC6071731 | biostudies-literature

Combined chemical transformation and biological transformation of artemisinin: A facile approach to diverse artemisinin derivatives.

Project description:Introduction: Artemisinin (1) is a milestone compound in malaria treatment, and it exhibits a broad scope of bioactivities. Herein, sequential chemo-reduction and biotransformation of artemisinin were undertaken to obtain a series of artemisinin derivatives. Methods: First, 10-deoxyartemisinin (2) and 9-ene-10-deoxyartemisinin (3) were synthesized after simple handling with boron trifluoride/diethyl ether and sodium borohydride. Then, biotransformation of 10-deoxyartemisinin was conducted with Cunninghamella echinulata CGMCC 3.4879 and Cunninghamella elegans CGMCC 3.4832, and the transformed products were separated and identified. The antimalarial activity of these products was tested in vitro against Plasmodium falciparum 3D7. Results: Fifteen metabolites (4-18), including seven novel compounds, were isolated and identified after cultivation. Compounds 2, 3, 13, 15, 16, and 18 displayed moderate-to-good antimalarial activity, with a half-maximal inhibitory concentration ranging from 6 to 223 nM. Discussion: This work explored the combination of chemical and biological transformation to develop a co-environmental, efficient, and cost-efficiency synthetic methodology and applied it to synthesize novel derivatives of artemisinin. The association of the two strategies will hopefully provide an abundant source for the development of novel drugs with bioactivities.

| S-EPMC9902651 | biostudies-literature

Dearomative 1,4-difunctionalization of naphthalenes via palladium-catalyzed tandem Heck/Suzuki coupling reaction.

Project description:Dearomative functionalization reactions represent an important strategy for the synthesis of valuable three-dimensional molecules from simple planar aromatics. Naphthalene is a challenging arene towards transition-metal-catalyzed dearomative difunctionalization reactions. Reported herein is an application of naphthalene as a masked conjugated diene in a palladium-catalyzed dearomative 1,4-diarylation or 1,4-vinylarylation reaction via tandem Heck/Suzuki sequence. Three types of 1,4-dihydronaphthalene-based spirocyclic compounds are achieved in excellent regio- and diastereoselectivities. Key to this transformation is the inhibition of a few competitive side reactions, including intramolecular naphthalenyl C-H arylation, intermolecular Suzuki cross-coupling, dearomative 1,2-difunctionalization, and dearomative reductive-Heck reaction. Density functional theory (DFT) calculations imply that the facile exergonic dearomative insertion of a naphthalene double bond disrupts the sequence of direct Suzuki coupling, leading to the tandem Heck/Suzuki coupling reaction. The observed regioselectivity towards 1,4-difunctionalization is due to the steric repulsions between the introduced aryl group and the spiro-scaffold in 1,2-difunctionalization.

| S-EPMC7463262 | biostudies-literature

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates.

Project description:Herein, we present the synthesis and utilization of derivatives of 4H-benzo[b][1,4]thiazine-3-carboxylic acid. These benzothiazine compounds were assembled via the coupling of aminothiols and bromopyruvates. Oxidative dimerization of these starting materials was also observed and the corresponding benzothiazine dimers were isolated. Moreover, the coupling of benzothiazines with amino acids was realized. In doing so, an enantioselective synthesis of the nonproteinogenic amino acid 2-amino-3-propylhexanoic acid was accomplished.

| S-EPMC9475188 | biostudies-literature

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