Heterocyclic rings are a common structural feature seen in many pharmaceuticals and their facile construction has been a subject of study for many decades   . Nitrogen containing heterocycles in particular are among the most versatile motifs, and hence significant efforts have been directed towards developing methods for their efficient synthesis  . Of the various nitrogen containing heterocycles, bridgehead nitrogen heterocycles such as imidazo[1, 2-a]pyridines 1 are of considerable interest owing to their biological activities. The imidazo[1, 2-a]pyridine moiety is seen in drugs such as zolpidem 2 (sedative)  and olprinone 3 (cardiotonic agent)  .
Several methods have been developed for the synthesis of a variety of imidazo[1, 2-a]pyridines  -  . In contrast, until recently there have been very few reports of the synthesis and biological activities of the corresponding saturated analogs such as hexahydroimidazo[1, 2-a]pyridines. One such report detailed a series of neonicotinoids of hexahydroimidazo[1, 2-a]pyridines that were evaluated for their insecticidal activities  . Another report described the synthesis and antimicrobial activities of hexahydroimidazo[1, 5-a]pyridinium bromides  . The lack of extensive reports on the biological activities of hexahydroimidazo[1, 2-a]pyridines is due in part to the limited methods available for their facile synthesis. Wang and co-workers reported the first efficient synthesis of hexahydroimidazo[1, 2-a]pyridines via a p-toluenesulfonic acid (p-TsOH) catalyzed multicomponent reaction that utilized an aldehyde, ketone and 1,2-diaminoethane  . Li and co-workers report a similar synthesis using L-phenylalanine triflate as a catalyst, a compound that is not commercially available from a major supplier  . Neto and coworkers have reported a heteropolyacid containing ionic liquid-catalyzed multicomponent synthesis of hexahydroimidazo [1, 2-a]pyridine derivatives  . In this protocol, the heteropoly acid-ionic liquid catalyst must be synthesized. Tan and Wang have described the synthesis of hexahydroimidazo[1, 2-a]pyridines from condensation of a variety of substituted cinnamaldehydes, 1, 3-diketones and 1,2-diaminoethane catalyzed by acetic acid, which is rather corrosive  . Although a commonly used catalyst, p-toluenesulfonic acid (p-TsOH∙H2O) is somewhat toxic (LD50 = 2.48 g/kg, rat oral) and highly irritating to the skin  . Due to our continued interest in developing environmentally-friendly synthesis especially using relatively nontoxic bismuth (III) compounds     we sought to develop a bismuth (III) salt catalyzed multicomponent synthesis of hexahydroimidazo[1, 2-a]pyridines. Herein we report (Scheme 1) a bismuth (III) chloride BiCl3-catalyzed multicomponent synthesis of a series of hexahydroimidazo[1, 2-a]pyridines 6a-i starting from an aldehyde 4a-i, ketone 5a-i and 1, 2-diaminoethane in CH3OH.
Scheme 1. BiCl3-catalyzed multicomponent synthesis of hexahydro[1, 2-a]pyridines.
Table 1. BiCl3-catalyzed multicomponent synthesis of hexahydro[1, 2-a]pyridines.a
aRepresentative procedure: A solution of benzaldehyde (0.50 g, 4.71 mmol), 4-bromoacetophenone (1.87 g, 9.42 mmol), and 1, 2-diaminoethane (0.28 g, 4.71 mmol, 0.31 mL) in CH3OH (10.0 ml) was stirred at room temperature as BiCl3 (0.297 g, 0.942 mmol, 20.0 mol%) was added. The reaction mixture was then heated to 60˚C using a temperature controlled hot plate. The reaction mixture acquired a yellow color. The progress of the reaction was monitored by TLC (40:60, EtOAc/heptane). After 24 h, the reaction mixture was cooled to room temperature and methanol was removed using a rotary evaporator. The residue was then triturated with methanol (5.0 mL) and the resulting solid was collected by suction filtration to yield 2.28 g (95%) of a pale yellow solid (Table 1, entry g, product 6 g). The identity of the product was confirmed by 1H and 13C NMR spectroscopy and High Resolution Mass Spectral (HRMS) data. bProducts were characterized by comparison of their 1H and 13C NMR spectrum with literature data   and by HRMS data. cRefers to yield of isolated product deemed to be ≥98% pure by 1H and 13C NMR spectroscopy. dCrude product was triturated twice with CH3OH (5.0 ml each).
Bismuth chloride is fairly nontoxic (LD50 = 3.3 g/kg, rat oral; compare NaCl LD50 = 3.0 g/kg, rat oral)   , commercially available and relatively inexpensive. The methodology avoids an aqueous waste stream, and the product is isolated by trituration using methanol. Multicomponent reactions save steps, reduce waste, and add to the overall efficiency of the synthesis  . To discover the most efficient bismuth-based catalyst, several bismuth (III) salts (20.0 - 40.0 mol%) were screened including BiBr3, BiCl3 and Bi(OTf)3 in a variety of solvents (CH3OH, CH3CH2OH, iPrOH, CH2Cl2 and CH3CN) at reflux temperatures. No reaction was seen at room temperature. Of these BiCl3 (20.0 mol%) in CH3OH at 60˚C was found to be the optimal condition. The stereochemistry of the product was assigned by comparison of the 1H NMR spectra to literature spectra and found to be trans with respect to the aromatic ring of the aldehyde and ketone. None of the cis isomer could be detected in the 1H NMR spectrum (400 MHz in CDCl3) of any of the products. The results of this study are summarized in Table 1. While ketones with an electron withdrawing group (entries g - i) worked well, less satisfactory results were obtained with p-methylacetophenone (the product was 90% pure but could not be further purified even by multiple triturations or column chromatography).
In summary, a bismuth (III) chloride catalyzed multicomponent synthesis of hexahydroimidazo[1, 2-a]pyridines has been developed. The ease of workup, nontoxic nature of bismuth (III) compounds, and avoidance of an aqueous waste stream and chromatography are the attractive features of this method.
This material is based upon work supported by the National Science Foundation under CHE-1229133, which funded the purchase of a 400 MHz NMR spectrometer. RM would like to acknowledge an Artistic and Scholarly grant from Illinois Wesleyan University. We are also grateful to an anonymous reviewer for insightful comments.
 Taylor, A.P., Robinson, R.P., Fobian, Y.M., Blakemore, D.C., Jones, L.H. and Fadeyi, O. (2016) Modern Advances in Heterocyclic Chemistry in Drug Discovery. Organic & Biomolecular Chemistry, 14, 6611-6637.
 Kerru, N., Gummidi, L., Maddila, S., Gangu, K.K. and Jonnalagadda, S.B. (2020) A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications. Molecules, 25, 1909.
 Hanson, S.M., Morlock, E.V., Satyshur, K.A. and Czajkowski, C. (2008) Structural Requirements for Eszopiclone and Zolpidem Binding to the GABAA Receptor Are Different. Journal of Medicinal Chemistry, 51, 7243-7252.
 Enguehard-Gueiffier, C. and Gueiffier, A. (2007) Recent Progress in the Pharmacology of Imidazo[1,2-a]pyridines. Mini-Reviews in Medicinal Chemistry, 7, 888-899.
 Yan, R., Yan, H., Ma, C., et al. (2012) Cu(I)-Catalyzed Synthesis of Imidazo[1,2-a]pyridines from Aminopyridines and Nitroolefins Using Air as the Oxidant. Journal of Organic Chemistry, 77, 2024-2028.
 Stasyuk, A.J., Banasiewicz, M., Cyrański, M.K. and Gryko, D.T. (2012) Imidazo[1,2-a]pyridines Susceptible to Excited State Intramolecular Proton Transfer: One-Pot Synthesis via an Ortoleva-King Reaction. Journal of Organic Chemistry, 77, 5552-5558.
 Cai, Z., Wang, S. and Ji, S. (2013) Copper(I) Iodide/Boron Trifluoride Etherate-Cocatalyzed Aerobic Dehydrogenative Reactions Applied in the Synthesis of Substituted Heteroaromatic Imidazo[1,2-a]pyridines. Advanced Synthesis & Catalysis, 355, 2686-2692.
 Monir, K., Bagdi, A.K., Ghosh, M. and Hajra, A. (2014) Unprecedented Catalytic Activity of Fe(NO3)3·9H2O: Regioselective Synthesis of 2-Nitroimidazopyridines via Oxidative Amination. Organic Letters, 16, 4630-4633.
 Bagdi, A.K., Rahman, M., Santra, S., Majee, A. and Hajra, A. (2013) Copper-Catalyzed Synthesis of Imidazo[1,2-a]pyridines through Tandem Imine Formation-Oxidative Cyclization under Ambient Air: One-Step Synthesis of Zolimidine on a Gram-Scale. Advanced Synthesis & Catalysis, 355, 1741-1747.
 Hiebel, M., Fall, Y., Scherrmann, M. and Berteina-Raboin, S. (2014) Straightforward Synthesis of Various 2,3-Diarylimidazo[1,2-a]pyridines in PEG400 Medium through One-Pot Condensation and C-H Arylation. European Journal of Organic Chemistry, 2014, 4643-4650.
 Pan, S., Wang, G., Schinazi, R.F. and Zhao, K. (1998) Synthesis of Novel Isoxazolinyl Substituted Imidazo[1,2-a]pyridine C-Nucleoside Analogs. Tetrahedron Letters, 39, 8191-8194.
 Lhassani, M., Chavignon, O., Chezal, J., et al. (1999) Synthesis and Antiviral Activity of Imidazo[1,2-a]pyridines. European Journal of Medicinal Chemistry, 34, 271-274.
 Gudmundsson, K.S., Drach, J.C. and Townsend, L.B. (1997) Synthesis of Imidazo[1,2-a]pyridine C-Nucleosides with an Unexpected Site of Ribosylation. The Journal of Organic Chemistry, 62, 3453-3459.
 Márton-Merész, M., Zára-Kaczián, E., Boros, S. and Mátyus, P. (1997) Cyclocondensation Reaction of a 1,5-diketone with 1,2-diamines. Journal of Heterocyclic Chemistry, 34, 1033-1036.
 Shao, X., Zhang, W., Peng, Y., Li, Z., Tian, Z. and Qian, X. (2008) cis-Nitromethylene Neonicotinoids as New Nicotinic Family: Synthesis, Structural Diversity, and Insecticidal Evaluation of Hexahydroimidazo[1,2-alpha]pyridine. Bioorganic & Medicinal Chemistry Letters, 18, 6513-6516.
 Türkmen, H., Ceyhan, N., ülkü Karabay Yavasoglu, N., Ozdemir, G. and Cetinkaya, B. (2011) Synthesis and Antimicrobial Activities of Hexahydroimidazo[1,5-a]pyridinium Bromides with Varying Benzyl Substituents. European Journal of Medicinal Chemistry, 46, 2895-2900.
 Wang, R., Zhu, P., Lu, Y., Huang, F. and Hui, X. (2013) Bronsted Acid-Catalyzed Four-Component Cascade Reaction: Facile Synthesis of Hexahydroimidazo[1,2-a]pyridines. Advanced Synthesis & Catalysis, 355, 87-92.
 Jiang, J., Zhang, M., Wu, W., Lu, H., Shi, Y. and Li, J. (2018) L-Phenylalanine Triflate as Organocatalyst for Divergent Approaches to Trisubstituted Hexahydroimidazo[1,2-a]pyridine and 1,4-Diazepane Derivatives. Synlett, 29, 246-250.
 Alvim, H.G.O., Correa, J.R., Assumpcao, J.A.F., da Silva, W.A., Rodrigues, M.O., de Macedo, J.L., Fioramonte, M., Gozzo, F.C., Gatto, C.C. and Neto, B.A.D. (2018) Heteropolyacid-Containing Ionic Liquid-Catalyzed Multicomponent Synthesis of Bridgehead Nitrogen Heterocycles: Mechanisms and Mitochondrial Staining. The Journal of Organic Chemistry, 83, 4044-4053.
 Tan, H. and Wang, Y. (2020) Facile Synthesis of Novel Hexahydroimidazo[1,2-a]pyridine Derivatives by One-Pot, Multicomponent Reaction under Ambient Conditions. ACS Combinatorial Science, 22, 468-474.
 Salvador, J.A.R., Silvestre, S.M., Pinto, R.M.A., Santos, R.C. and LeRoux, C. (2012) New Applications for Bismuth(III) Salts in Organic Synthesis: From Bulk Chemicals to Steroid and Terpene Chemistry. Topics in Current Chemistry, 311, 143-178.
 Sunderhaus, J.D. and Martin, S.E. (2009) Applications of Multicomponent Reactions to the Synthesis of Diverse Heterocyclic Scaffolds. Chemistry: A European Journal, 15, 1300-1308.