Bismuth (III) Chloride Catalyzed Multicomponent Synthesis of Substituted Hexahydroimidazo[1, 2-a]Pyridines

Noah T. Haskin¹, Richard A. Guingrich¹, Allison J. Schrader¹, Matthew R. Crosse¹, Alpa Y. Dave², Eeshwaraiah Begari², Ram S. Mohan^1*

¹Laboratory for Environmentally Friendly Organic Synthesis, Department of Chemistry, Illinois Wesleyan University, Bloomington, IL, USA.
²Centre for Applied Chemistry, School of Applied Material Sciences, Central University of Gujarat, Gandhinagar, India.

DOI: 10.4236/gsc.2021.113008                

Abstract

The synthesis of nitrogen containing heterocycles is of particular interest in the pharmaceutical industry due to the range of biological activities exhibited by such compounds. Their synthesis using multicomponent reactions saves steps and minimizes waste generation. The bismuth (III) chloride multicomponent synthesis of a series of hexahydroimidazo[1, 2-a]pyridines is reported. Bismuth (III) compounds are especially attractive from a green chemistry perspective because they are remarkably nontoxic, non-corrosive and relatively inexpensive. The reported method avoids chromatography and an aqueous waste stream to afford the products in a very mass efficient manner.

Keywords

Bismuth Chloride, Green Chemistry, Heterocycles, Multicomponent Reactions

Heterocyclic rings are a common structural feature seen in many pharmaceuticals and their facile construction has been a subject of study for many decades [1] [2] . 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 [3] . 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) [4] and olprinone 3 (cardiotonic agent) [5] .

Several methods have been developed for the synthesis of a variety of imidazo[1, 2-a]pyridines [6] - [15] . 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 [16] . Another report described the synthesis and antimicrobial activities of hexahydroimidazo[1, 5-a]pyridinium bromides [17] . 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 [18] . 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 [19] . Neto and coworkers have reported a heteropolyacid containing ionic liquid-catalyzed multicomponent synthesis of hexahydroimidazo [1, 2-a]pyridine derivatives [20] . 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 [21] . 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 [22] . Due to our continued interest in developing environmentally-friendly synthesis especially using relatively nontoxic bismuth (III) compounds [23] [24] [25] [26] 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 [18] [19] 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) [27] [28] , 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 [29] . 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.

Acknowledgements

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.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

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