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

Abstract

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...

More Sustainable Approaches for the Synthesis of N-Based Heterocycles

“…For the synthesis of pyrazolone derivatives, β-keto esters can be made to react with a hydrazine under microwave irradiation up to 3 min resulting in the desired product in good to excellent yields (86−94%). However when 2 equiv of the β-keto ester are used, 1 H ,6 H -pyrano[2,3 c ]pyrazol-6-one derivatives are obtained in excellent yields (86−95%). , By reaction of hydrazines with 3-dimethylamino acrylates under solvent-free conditions (under conventional heating or microwave irradiation), 1,2-dihydropyrazol-3-ones can be obtained in good yields through an aza-annulation reaction (Scheme ) . Chromones can also be attached to a pyrazolinone through condensation of this heterocycle with chromone aldehyde derivatives under MWI in the presence or absence of alumina as inorganic support .…”

“…390,391 By reaction of hydrazines with 3-dimethylamino acrylates under solvent-free conditions (under conventional heating or microwave irradiation), 1,2-dihydropyrazol-3-ones can be obtained in good yields through an aza-annulation reaction (Scheme 81). 392 Chromones can also be attached to a pyrazolinone through condensation of this heterocycle with chromone aldehyde derivatives under MWI in the presence or absence of alumina as inorganic support. 393 Through the solid-state reaction of an aldehyde, indole, and 1-phenyl-3methyl-5-pyrazolones in the presence of a catalytic amount of molecular iodine (10 mol %), 4-[(indol-3-yl)-arylmethyl]-1-phenyl-3-methyl-5-pyrazolones can be obtained in good yields (72-93%) after 2 h at room temperature, making this a suitable reaction for the introduction of a new substituent in the 4-position of the pyrazolone moiety.…”

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

“…In previous work, we used 5 as an ambident synthon in a regioselective azaannulation with isocyanate for the preparation of 1-oxo-1,2-dihydropyrimido[1,6-a]benzimidazole-4-carboxylates using solvent-free conditions under microwave irradiation [19]. This solvent-free aza-annulation was also extended to mono N-substituted hydrazines in the synthesis of new 4-(1Hbenzimidazol-2-yl)-1,2-dihydro-(3H)-pyrazol-3-ones [20]. Based on these results, we decided to examine the reactivity of 5 with mono N-substituted diamines 11 in solution phase under microwave because microwave-assisted organic synthesis (MAOS) [21] has shown to dramatically reduce reaction times and improve product yields and ratios.…”

Microwaves in Heterocyclic Chemistry

“…b-Hydrazinoacrylates derived from benzimidazole, benzoxazole and benzothiazole are readily prepared in good yields by transamination of the corresponding 3-dimethylamino acrylates with a variety of hydrazines [96] (Scheme 8.70). These hydrazino acrylates can then be cyclized to the corresponding 1,2-dihydropyrazol-3-ones either under the action of irradiation or by heating conventionally.…”