Synthesis and Chemical Reactivity of New Azaenamines Incorporated the 4,5,6,7-Tetrahydrobenzo[b]thiophene Moiety: 3+3 Atom Combination

Abstract

Novel azaenamines incorporating a tetrahydrothiophene moiety were prepared. Michael addition of an azaenamine with a,bunsaturated nitriles took place to give [1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine (thia-triaza-benzo[a]fluorene) derivatives. The condensation with malononitrile resulted in the formation of a [1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carbonitrile. The azaenamine also reacted with aldehydes and piperidine to give Mannich products.Compounds containing the tetrahydrobenzothiophene (THBT) moiety are selective HCV polymerase inhibitors, 1 selective versus human DNA polymerase and calf thymus. 1 These compounds also have diverse pharmacological activities including antibacterial, 2 immunodulatory, 3 anti-inflammatory, 4 antidiabetic, antiplatelet activating factor, 5 and antiviral activity. 6,7 In continuation of our interest in azaenamine chemistry, [8][9][10][11][12] we report here a new synthesis of azaenamines containing the 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and -carboxamide moieties. Also we report the chemical reactivity of the synthesized azaenamines. Thus, it has been found that coupling acetoacetic acid with the 3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-diazonium chloride (3a) and the 3-carboxamide 3b afforded the corresponding pyruvaldehyde-1-arylhydrazones 5a and 5b in 73% and 68% yields, respectively. Although, the appearance of NH at very low field implies the presence of an azaenamine in the syn-form 6, in related work we obtained an X-ray crystal structure for an azaenamine analogue that indicated that it exists in the antiform 5. 10 The low field hydrazone NH at d = 12 is not, thus, due to deshielding by hydrogen bonding as we believed, but most likely results from the delocalization of the nitrogen lone pair [cf. Scheme 1 structure 5(II)]. It is clear that azaenamines can be seen as bidentate ligands since they have two nucleophilic and two electrophilic centers. Due to an interest in developing syntheses for biologically interesting fused pyridazines 8,12,13 herein, we report an efficient route for the Michael addition reaction of azaenamines 5 to a,b-unsaturated nitriles. As stated above, the CH group of the azaenamine is quite nucleophilic as a result of the hydrazone lone pair delocalization. Thus, in a preliminary study, we found that reacting compound 5a with ethyl 2-cyano-3-phenylacrylate (7a) afforded a product for which several isomeric structures seemed possible. Structures involving addition on the acyl methyl group was readily ruled out on the basis of the 1 H NMR spectrum, which revealed a methyl signal at d = 2.36. Acyclic structures were also excluded based on 1 H NMR spectra analysis, which showed in addition to the methyl signal, a singlet signal at d = 5.09 for H4 of the pyridazine and a broad signal at d = 11.19 for the NH group. The resulting product was assigned the tetracyclic structure 10 based on mass spectroscopy and NMR analysis, which revealed the absence of an OEt group on the thiophene ring. IR and 13 C NMR...

Facile Synthesis of 3‐Amino‐2,5‐dihydropyridazines and 4‐Deazatoxoflavin Analogues via [3 + 3] Atom Combination: Approaches to Pyridazine Incorporating Pyrazole Moiety

“…In continuation to our investigations in the chemistry of azaenamines and the development of new pyridazine derivatives , the Michael addition reaction of pyruvaldehyde‐1‐arylhydrazones 1a , 1b towards (4‐pyrazolylmethylene)malononitrile derivatives 2a , 2b , 2c was studied (Scheme ). The reactions are carried out in boiling dioxane in presence of catalytic amount of piperidine for 3 h. The yields of the products are given in Table .…”

“…, method A) includes the cycloaddition of diazomethane to cyclopropene derivatives, while the other (Fig. , method B) utilizes the Michael addition of azaenamine derivatives to varieties of α , β ‐unsaturated nitrile .…”

Microwave Assisted Green Multicomponent Synthesis of Novel bis(2‐Amino‐tetrahydro‐4H‐chromene‐3‐carbonitrile) Derivatives Using Chitosan as Eco‐friendly Basic Catalyst

“…In connection with these findings, and in continuation of previous studies on Michael addition reactions for carrying out carbon‐carbon forming reactions under both homogeneous and heterogeneous catalysis , the present study aimed at synthesis of novel bis(4 H ‐benzo[ b ]pyrans) by a multicomponent reaction using chitosan as eco‐friendly basic catalyst and under microwave irradiation as an efficient energetic heating source.…”

Chemistry of 2-Arylhydrazonals

“…Arylhydrazonals also attack 2-cyclohexenone (80) to assemble tetrahydrocinnolin-5(1H)-one derivatives 83 75 that are formed via the intermediacy of 81 and 82. Attempts to isolate the Baylis-Hillman adducts 81 and 82 failed (Scheme 29 and Table 10).…”