Synthesis of 5-amino-N′-(9H-fluoren-9-ylidene)-8-nitro-7-aryl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbohydrazide derivatives based on heterocyclic ketene aminals

A new class of tetrahydroimidazo[1,2-a]pyridine derivatives has been successfully prepared via a five-component domino reaction using cyanoacetohydrazide, 9-fluorenone, aromatic aldehydes, 1,1-bis(methylthio)-2-nitroethene and ethylenediamine in ethanol at reflux. The new efficient cascade approach involves a sequence of N,N-acetal formation, Knoevenagel condensation, Michael addition, imine–enamine tautomerization and N-cyclization as key steps. The merit of this protocol is highlighted by its available and economical starting compounds, operational simplicity, clean reaction profile and tolerance of a wide diversity of functional groups.


Introduction
Imidazopyridines have shown a broad spectrum of pharmacological and biological activities. 1 Among the various derivatives, the imidazo[1,2-a]pyridine framework is likely the most important construction due to its vital role as a key structure in drugs and biologically active compounds with properties such as anti-inammatory, 2,3 antiviral, 4-6 antiulcer agents, 7,8 antifungal, 9 anticancer, 10 anxiolytic, 11 anti-ulcer, 12 and antiprotozoal. 13 They are included in marketed drugs such as the clinical anti-ulcer compound zolpidem and alpidem, 14 olprinone, 15 zolimidine, 16 necopidem and saripidem, 17 soraprazan and minodronic acid 18 (Fig. 1).
The design of reactions that minimize the number of synthetic steps for the rapid formation of functionalized molecules is one of the goals of modern synthesis. One way to achieve this purpose involves the development of multicomponent processes. Multicomponent reactions (MCRs) present a wide range of possibilities for the construction of complex molecules in a single step. The benets of this approach include minimum time, labor and cost, high atom economy, and straight experimental procedures. 19 These advantages are highlights for multicomponent cascade reactions, which contain in situ production of an intermediate with a reactive site for subsequent variations. 20 By now, various synthetic methods have been developed to prepare imidazo[1,2-a]pyridines. The common strategies were the cyclocondensations of 2-aminopyridines with a-halocarbonyl compounds, 21 1,3-dicarbonyl compounds, 22 nitro-olens or alkynes. 23 Besides, the condensation of 2aminopyridines, aldehydes and isonitriles or alkynes in a onepot process was also an efficient method for the synthesis of imidazo[1,2-a]pyridines. 24 There are still many efforts to the development of new methods for the synthesis of imidazo[1,2-a]pyridine derivatives with a variety of substituents at two rings. Some other novel synthetic approaches have been established in recent years for the synthesis of tetrahydroimidazo[1,2-a]pyridines by heterocyclic ketene aminals (HKAs). [25][26][27][28][29] Heterocyclic ketene aminals (HKAs) have been proven to be efficient synthons in the synthesis of heterocyclic systems. During the past few years, reactions of cyclic ketene aminals with a variety of biselectrophilic compounds have been applied to make veand six-membered fused heterocycles. 30 As a part of our current studies on synthesis of novel heterocyclic compounds using cyanoacetohydrazide, we describe herein an efficient one-pot ve-component synthesis of novel imidazo[1,2-a]pyridine-6-carbohydrazides via in situ preparation of nitroketene aminal. These structures are completely new and there is no report on their synthesis.

Optimization of the conditions
Initially, to identify the optimum reaction condition, 4-uorobenzaldehyde was used as model substrate (since 4-uorobenzaldehyde has clear reaction with obvious TLC at appropriate R f value). At rst, ethanol was used as solvent without any catalyst at reux conditions and it was observed the desired product was not formed ( Table 1, entry 1). The use of piperidine catalyst resulted in a yield of 40% in the product (entry 2). In order to improve yield, two other types of catalysts were used. With p-TSA, the ve-component product did not form, and with acetic acid in a mixture of water and ethanol the efficiency did not change signicantly (entry 3 and 5). The use of water and ethanol or water or acetonitrile without any catalyst resulted in no product formation (entry 4, 7 and 8). It was found that the reaction proceeded with high yield to formation of 5amino-N 0 -(9H-uoren-9-ylidene)-7-(4-uorophenyl)-8-nitro-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbohydrazide 6a when ethanol was used as solvent and acetic acid was applied as catalyst at reux conditions (entry 6).
It should be noted that initially a two-component reaction of cyanoacetohydrazide and 9-uorenone is performed in the presence of acetic acid and then, without separating the product, aldehyde and ketene aminal are added.
The reactions were completed aer 8-12 h overall to afford corresponding heterocyclic systems 6a-k in good to high yields (65-87%). The results are summarized in Table 2.

Effect of substituents
This reaction was performed with other derivatives of diamines (1,3-diaminopropane, 1,4-diaminobutane and 1,2-diaminocyclohexane) under the same conditions, which did not result in the desired product. Also the reaction with ortho derivatives of benzaldehyde (2-chloro and 2-nitro) did not  produce the product, probably due to steric effects. For aldehydes with 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. It was found that the most important side product in these reactions was a four-component structure that was previously synthesized using two equivalents of aldehyde which will be further explained in the Mechanism section.

Structure determination
The structures of compounds 6a-k were deduced from their IR, 1 H NMR, 13 C NMR spectroscopic and mass spectrometric data (see the ESI †).
The 1 H NMR spectrum of 6a showed two NH groups at d 9.43 and 10.36 ppm. The NH 2 group appeared at d 8.34 ppm. The protons of three aromatic rings were seen at d 6.99-7.84 ppm. The proton of CH at pyridine ring was observed at d 5.76 ppm. Two protons of two methylene groups appeared at d 3.75-3.86 and 4.04-4.07 ppm. The 1 H-decoupled 13 C NMR spectrum of 6a displayed 25 distinct signals in accordance to desired structure. The characteristic signals of three aliphatic carbons (CH and two CH 2 groups) were observed at d 36.6, 43.6 and 44.8 ppm respectively. Two signals at d 79.9 and 108.1 ppm were related to C]C-CO and C-NO 2 respectively. The carbonyl group appeared at d 166.7 ppm (Fig. 2).
The mass spectrum of 6a displayed a molecular-ion peak at m/z 496 in agreement with the proposed product. The IR spectrum of this compound showed absorption bands at 3431, 3344, 3272 due to NH and NH 2 groups, stretching vibration of aliphatic C-H bands at 2920, strong absorption of carbonyl group at 1654, stretching vibration of C]C of aromatic ring at 1445 and C-N stretching band at 1259 cm À1 . Two absorption bands due to nitro group appeared at 1363 and 1528 cm À1 .