Stereoselective synthesis of (2E) 3‐amino‐2‐(1H‐benzimidazol‐2‐yl)acrylate and symmetric bisacrylates by transamination reactions

Brugidou, Richard; Bazureau, Jean Pierre; Hamelin, J.; Dahmani, Zohra; Rahmouni, Mustapha

doi:10.1002/(sici)1098-1071(1999)10:6<446::aid-hc2>3.3.co;2-5

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“…Introduction of a 4-amino-quinolyl fragment to benzimidazole at the C-4 position in compound VI exhibited inhibitory activity against VEGFR-2 (IC 50 = 30 nM) associated to anticancer activity against MCF-7 cancer cells (IC 50 = 1.3 µM) [10]. Stimulated by these pharmaceutical applications for benzimidazole scaffold bearing specific groups as bioactive compounds against a variety of cancer cell lines, our goal was to explore the construction of stereocontrolled !-amino benzimidazole acrylates [11] Our retrosynthetic strategy towards new N-functionalized !-amino benzimidazole acrylate derivatives shows two possible routes. Route A is based on a transamination reaction between !dimethylamino benzimidazole acrylates (building block A) and a mono N-substituted diamine.…”

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confidence: 99%

A practical multi-step synthesis of ethyl N-functionalized $$\varvec{\upbeta }$$ β -amino benzimidazole acrylate derivatives as promising cytotoxic agents

et al. 2018

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A series of 16 new ethyl [Formula: see text]-amino benzimidazole acrylate derivatives 12(a-p) with a (2E)-s-cis/trans conformation and bearing two points of diversity was designed and synthesized by using a multi-step strategy (reductive amination, deprotection in acidic media and transamination) in moderate to good yields from ethyl 3-dimethylamino-2-(1H-benzimidazol-2-yl)acrylate (5) and monosubstituted N-Boc diamines (7a,7b) as starting building blocks. Products 12 were evaluated for their in vitro cytotoxic potential against six selected human cell lines (Huh7-D12, Caco2, MDA-MB231, HCT116, PC3 and NCI-H727). Compounds 12a, 12e and 12l exhibited selective and micromolar antitumor activities against Huh7-D12 and Caco2 cell lines.

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Section: Introductionmentioning

confidence: 99%

A practical multi-step synthesis of ethyl N-functionalized $$\varvec{\upbeta }$$ β -amino benzimidazole acrylate derivatives as promising cytotoxic agents

et al. 2018

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“…Benzimidazoles 1 and pyrazol-3-ones 2 are used extensively in medicinal chemistry. In the course of our work on the synthesis of a-hetero-b-amino acrylates 3 as potential chemotherapeutic agents, we have previously obtained a series of a-benzimidazoleand a-benzoxazole-b-amino acrylates with in-vitro antitumoral activities. 4 To investigate how the substitution pattern affects the pharmacological profile on this type of molecule, we wished to prepare a series of new a-hetero acrylates with a hydrazino group at b-position.…”

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Eco-Friendly Transamination and Aza-Annulation Reactions: Solvent-Free Synthesis of New α-Hetero-β-Hydrazino Acrylates and 1,2-Dihydropyrazol-3-ones

Meddad¹,

Rahmouni²,

Derdour³

et al. 2001

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Ethyl 3-dimethylamino acrylates 1a-c have been used as starting materials to develop an efficient and mild solvent-free preparation of new ethyl b-hydrazino acrylates 3a-h and 1,2-dihydropyrazol-3-ones 4a-c in good yields from a variety of hydrazines 2a-d by transamination and aza-annulation reactions under microwave irradiations.Benzimidazoles 1 and pyrazol-3-ones 2 are used extensively in medicinal chemistry. In the course of our work on the synthesis of a-hetero-b-amino acrylates 3 as potential chemotherapeutic agents, we have previously obtained a series of a-benzimidazole-and a-benzoxazole-b-amino acrylates with in-vitro antitumoral activities. 4 To investigate how the substitution pattern affects the pharmacological profile on this type of molecule, we wished to prepare a series of new a-hetero acrylates with a hydrazino group at b-position.Encouraged by the primary results, 4 we have continued to explore the reactivity of 3-dimethylamino acrylates 5 1a-c derived from benzimidazole, benzoxazole and benzothiazole, respectively, with a range of hydrazines 2a-d in transamination reactions 6 under solvent free conditions (Scheme) and subsequently report here our results. SchemeThe starting 3-dimethylamino acrylates 1a-c were readily obtained in large scale as previously described using solvent-free conditions assisted by focused microwave irradiations. 7 Synthesis of compounds 3a-h was easily achieved according to the solvent-free technique. 8 Several experiments for compounds 3a, b, 3d-f were performed, at various irradiations times and powers, in order to find the most adequate conditions for the reaction in the focused microwave oven (Synthewave ® 402). In a typical procedure, 3-dimethylamino acrylate 1 was mixed with hydrazine 2 in a microwave reactor (Ø = 4 cm). Then, the mixture was immediately submitted to microwave irradiation at the suitable temperature (Table 1) during 30 minutes. This reaction was monitored by 1 H NMR spectroscopy. For compounds 3c, 3g and 3h the reactions were performed under nitrogen in a thermostated oil bath at the appropriate temperature. The expected compounds 3a-h were purified by recrystallization or by flash chromatography on silica gel.The results, summarized in Table 1, show that the a-hetero-b-hydrazino acrylates 3a-h were obtained in yields ranging from 71 to 95%. The assigned structures of these new b-hydrazino acrylates 3a-h were substantiated by the 1 H, 13 C NMR and MS analyses. Characteristic features of the 13 C NMR spectra of acrylates 3a-h are both the upfield shift of C-2 (3a : d C-2 = 84.94) which indicates a high electron density and the downfield shift of C-3 (3a: d C-3 = 152.15) as a consequence of a "push-pull" effect. 9During the course of our work, we have also found that reactions of N-methylhydrazine (2a) or N-phenylhydrazine (2c) with 3-dimethylamino acrylates 1a and 1b without solvent afforded directly the respective 1,2-dihydropyrazol-3-ones 10 4a-c in good yields (Table 2). In this process, the mechanism is an aza-annulation after the successive los...

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Stereoselective synthesis of (2E) 3‐amino‐2‐(1H‐benzimidazol‐2‐yl)acrylate and symmetric bisacrylates by transamination reactions

Cited by 2 publications

References 0 publications

A practical multi-step synthesis of ethyl N-functionalized $$\varvec{\upbeta }$$ β -amino benzimidazole acrylate derivatives as promising cytotoxic agents

A practical multi-step synthesis of ethyl N-functionalized $$\varvec{\upbeta }$$ β -amino benzimidazole acrylate derivatives as promising cytotoxic agents

Eco-Friendly Transamination and Aza-Annulation Reactions: Solvent-Free Synthesis of New α-Hetero-β-Hydrazino Acrylates and 1,2-Dihydropyrazol-3-ones

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