An efficient synthesis of new imidazo[1,2-a]pyridine-6-carbohydrazide and pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives via a five-component cascade reaction

A highly efficient and straightforward synthesis of N-fused heterocyclic compounds including N′-(1-(4-nitrophenyl)ethylidene)imidazo[1,2-a]pyridine-6-carbohydrazide and N′-(1-(4-nitrophenyl)ethylidene)pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives is successfully achieved via a five-component cascade reaction utilizing cyanoacetohydrazide, 4-nitroacetophenone, 1,1-bis(methylthio)-2-nitroethylene and various diamines in a mixture of water and ethanol. The new efficient domino protocol involving a sequence of N,N-acetal formation, Knoevenagel condensation, Michael reaction, imine–enamine tautomerization and N-cyclization as key steps. The merit of this catalyst free approach is highlighted by its easily available starting materials, operational simplicity, clean reaction profile, the use of environmentally benign solvents and tolerance of a wide variety of functional groups.


Introduction
Imidazopyridines have displayed a broad spectrum of pharmacological and biological activities. 1 Among the diverse derivatives of imidazopyridine, the imidazo[1,2-a]pyridine skeleton is probably the most important structure due to its vital role as a key construction in drugs and biologically active compounds with properties such as anti-inammatory, 2,3 antiviral, 4-6 antifungal, 7-9 anticancer, 10 anxiolytic, 11 anti-ulcer, 12 and antiprotozoal. 13 They can be found in marketed drugs such as the clinical anti-ulcer compound zolpidem and alpidem, 14 olprinone, 15 zolimidine, 16 necopidem and saripidem 17 (Fig. 1).
The design of reactions with minimized number of steps is one of the purpose of modern synthesis. One approach to achieve this goal includes the development of multicomponent methods. Multicomponent reactions (MCRs) offer a wide range of probabilities for the fast generation of functionalized molecules in a single step with high atom economy, minimum time and cost and straight forward experimental procedures. 25 These benets are highlights for multicomponent cascade reactions, which involve in situ production of an intermediate with a reactive site for subsequent transformations. 26 By now, various synthetic approaches have been reported to synthesize imidazo [1,2-a]pyridines. The common reactions were the cyclocondensations of 2-aminopyridines with a-halocarbonyl compounds, 27 1,3-dicarbonyl compounds, 28 nitroolens or alkynes. 29 Condensation of 2-aminopyridines, aldehydes and isonitriles or alkynes in a one-pot process, was also a convenient method for the synthesis of imidazo [1,2-a] pyridines. 30 Furthermore, over the past decade, a number of methods have been described to synthesize pyrido [1,2-a] pyrimidines by focusing on traditional two-component condensation of 2-aminopyridines with a variety of bifunctional electrophiles. [31][32][33] In recent years some other new synthetic approaches have been developed for the synthesis of tetrahydroimidazo [1,2-a] pyridines and tetrahydro-1H-pyrido[1,2-a]pyrimidine using heterocyclic ketene aminals (HKAs). [34][35][36][37][38] Heterocyclic ketene aminals (HKAs) are efficient synthons for the synthesis of heterocyclic compounds. Reactions of cyclic ketene aminals with a variety of bis-electrophilic compounds have so far been applied to construct veand six-membered fused heterocyclic structures. 39 In the process of our efforts to synthesize the new heterocyclic compounds using cyanoacetohydrazide, we report herein an efficient one-pot ve-component synthesis of novel imidazo [1,2-a]pyridine-6-carbohydrazides and 1H-pyrido[1,2-a] pyrimidine-7-carbohydrazides via in situ preparation of nitroketene aminals. To the best of our knowledge, there is no report on the synthesis of these structures.
The experimental results showed when ethanol was used as solvent without any catalyst at reux conditions, the yield of desired product was 60% (Table 1, entry 1). With piperidine as catalyst, the reaction efficiency did not change signicantly (entry 2). With p-TSA and acetic acid, the product did not form (entry 3, 4). The use of water or acetonitrile instead of ethanol did not result in the desired product (entry 5, 8), but when the mixture of water and ethanol was used (overall 1 : 2, v/v), the efficiency increased slightly (entry 6). By changing the ratio of solvents (1 : 3, v/v) at reux conditions the ve-component product 6c was obtained in a yield of 87% within 5 hours (entry 7).
The reactions were completed aer 4-7 h overall to afford corresponding heterocyclic systems in good to high yields (73-90%). The results are summarized in Table 2.

Effect of substituents
From the observation of reaction times in Table 2, it was found that with aldehydes containing an electron-withdrawing group on para position of ring (nitro and halogens), the reaction rate is the highest and with methoxy group, the rate is the lowest. This reaction was performed with other derivatives of diamines (1,4-diaminobutane and 1,2-diaminocyclohexane) under the same conditions, which did not result in the product. Also the reaction with ortho derivatives of benzaldehyde (2chloro and 2-nitro) did not produce the desired product. Other derivatives of acetophenone (4-chloro, 4-bromo and 4-methoxyacetophenone) were also used which resulted no product formation.
In addition, the reaction with aliphatic ketones instead of 4nitroacetophenone and aliphatic aldehydes instead of aromatic aldehydes did not lead to the desired products.
It should be noted that these reactions involve two-, threeand four-component impurities. In fact, the most important side product was a four-component structure without participation of 4-nitroacetophenone that was previously synthesized using two equivalents of aldehyde. 34 To achieve the pure product, it was necessary to complete the reaction of cyanoacetohydrazide and 4-nitroacetophenone in a mixture of water and ethanol at reux conditions in sufficient time (3 hours), then ketene aminal solution and aromatic aldehyde were added at the same time.

Structure determination
The structures of compounds 6a-q were deduced from their IR, 1 H NMR, 13 C NMR spectroscopic and Mass spectrometric data (see the ESI †).
The formation of suggested products 6a-q is clearly veried by the 1 H and 13 C NMR spectra of the crude products. As a representative case the key signals of 1 H and 13 Fig. 2.
The 1 H NMR spectrum of 6a showed two NH groups at d 9.16 and 9.43 ppm. The protons of 4-nitrobenzene ring were seen at d 7.96 and 8.20 ppm as two doublet signals and the protons of 3chlorobenzene ring were observed at d 6.92-7.31 ppm. The NH 2 group appeared at d 8.21 ppm. The proton of CH at pyridine ring was seen at d 5.49 ppm. Two protons of two methylene groups appeared at d 3.81 and 4.05 ppm. The signal at d 2.14 ppm was related to methyl group.
The 1 H-decoupled 13 C NMR spectrum of 6a indicated 20 distinct resonances in accordance to desired structure. The characteristic signals of four aliphatic carbons (CH 3 , CH and two CH 2 groups) were seen at d 13.9, 38.2, 43.6 and 44.7 ppm respectively. Two signals at d 80.0 and 107.4 ppm were related to C]C-CO and C-NO 2 respectively. The carbonyl group appeared at d 165.78 ppm (Fig. 2).
The mass spectrum of 6a displayed the molecular-ion peak at m/z 497 in agreement with the proposed structure. The IR spectrum of this compound showed absorption bands at 3486, 3400, 3327 cm À1 due to NH and NH 2 groups, stretching vibration of aliphatic C-H bands at 2909, and strong absorption of carbonyl group at 1658 and C-N band at 1254 cm À1 . Two absorption bands due to nitro group appeared at 1519 and 1375 cm À1 .

Mechanism
A general reasonable mechanism for the formation of imidazo

Materials
All commercially available reagents and other solvents were purchased from Aldrich and Merck chemical Co. and used without further purication. The NMR spectra were recorded with a Bruker DRX-300 AVANCE instrument (300 MHz for 1 H and 75.4 MHz for 13    added to this mixture simultaneously. The progress of the reaction was monitored by TLC using ethyl acetate/n-hexane (1 : 1). Aer completion of the reaction, the precipitated product was collected by ltration and washed with warm ethanol to give the pure products 6a-q in 73-90% yield.