Background: Benzo[4,5]imidazo[1,2-a]pyridine derivatives were accessed through an efficient pseudo three component reaction between dialdehydes such as o-phthalaldehyde, glutaraldehyde, 2,3-thiophenedicarboxaldehyde and the active methylene 2-(1H-benzo[d]imidazol-2-yl)acetonitrile. The products were obtained in a one-pot manner with easy purification and further characterized by NMR, FT-IR and HRMS spectral data (Figure 1).

Keywords: MCR, pseudo 3CR, isoquinoline, benzimidazole, one-pot synthesis

Figure 1Benzo [4,5]imidazo[1,2-a]pyridine.

The benzimidazole moiety is amongst the diversely active scaffolds as antifungal, antibacterial, antiviral, anticancer and antimalarial agents.^1‒4 Therefore, developing new approaches towards the synthesis of benzimdazole fused heterocycles have always been on need.5Also, indeno and isoquinolino fused heterocycles have gained greater attention because of their medicinal and synthetic importance over years and the broad range of biological activity.^6‒8 Therefore, benzimidazole fused indene, pyridine or isoquinoline are of great interest in general and many synthetic procedures are available till date.¹ Moved by these results we desired to achieve a facile general synthetic protocol to obtain these diverse molecules. Multicomponent reaction has always proved to be a versatile tool towards the synthesis of structurally diverse and complex heterocycles in simple one pot manner.⁹ Our research group is actively engaged in developing multi-component reaction protocols for the synthesis of skeletally diverse, functionalized and biologically relevant small heterocyclic hybrids.^10‒12 We report a simple and rapid procedure for the preparation of benzo[4,5]imidazo[1,2- a]pyridines (Figure 2) with 2-(1H-benzo[d]imidazol-2-yl)acetonitrile.

Figure 2Synthesis of Benzo[4,5]imidazo[1,2-a]pyridine derivative.

We planned to perform a three component reaction with a 1,4-dielectrophilic substrate (I) and two carbon nucleophilic building blocks (II & III) to achieve the scaffold 1a (Figure 2).

Initially, a 3CR was carried out by adding sequentially

1. o-phthalaldehyde,
2. Malononitrile
3. 2-(1H-benzo[d]imidazol-2-yl)acetonitrile

In the presence of piperidine as the base in ethanol at room temperature (Figure 2). The resin like product was obtained which could not be purified and characterized. Then, the order of adding the reactants were changed to

1. o-phthalaldehyde,
2. 2-(1H-benzo[d]imidazol-2-yl) acetonitrile
3. Malononitrile (Figure 3)

A white precipitate formed in twenty minutes which was isolated by filtration, further purified and characterized by NMR to be scaffold B1 (Figure 3) as against the anticipated product A1. Then, the reaction was performed with other solvents and bases to check the feasibility, but no significant improvement in the yield was observed (Table 1). The reaction condition was optimized for ethanol as solvent and triethylamine as base (Table 1 - Entry 3).

The lack of formation of isolable product in reaction Figure 4 may be due to high reactivity of 2, with possible formation of more than one unstable product (Figure 4). However when the sequence of addition of nucleophilic reagent is reversed the reaction might follow the path 1b shown in Figure 3.

Based on the results it‘s understood that 3 didn’t take part in the reaction instead the 2 itself reacted twice to form B1. The reaction was then carried out with all other active methylene groups like 2-(benzo[d]thiazol-2-yl) acetonitrile, 2-cyanoacetamide and ethyl 2-cyanoacetate along with 2 to check the possible outcome but, only one product (B1) was observed. The experiment can be considered as a competitive experiment performed between a dialdehyde and two carbon nucleophilic species. The results observed indicate that compound (2) selectively reacts with (1). The reaction is proposed to follow the mechanism shown in (Figure 5). Feng et al.,¹³ have also proposed a similar mechanism. The initial Knoevenagel condensation of 1 with 2 and the subsequent Michael addition of another 2 to the knoevenagel condensed intermediate a give rise to Intermediate b. Further an intramolecular nucleophilic addition reaction of intermediate b would lead to c followed by tautomerisation to the desired product B1.

Encouraged by this result, we tried to explore this reaction with different diladehydes to check the feasibility of accessing skeletal diversity in one psuedo 3CR. The reaction resulted in good yield (80-89%) of the corresponding heterocyclic scaffold B1 (Figure 6). The results also support the proposed mechanism. Thus we have established a facile psuedo three component reaction protocol for accessing skeletally diverse benzo [4,5]imidazo[1,2-a]pyridine derivatives deverivatives with inherent provision for scaffold hopping.

Figure 3 Synthesis of benzo[4,5]imidazo[1,2-a]indeno[2,1-c]pyridine B1 derivative.

Figure 4 Plaussible unstable intermediates in reaction 1a.

Figure 5 Plausible mechanism for the formation of B1.

Figure 6 Compounds synthesized from 1b.

All reactions were performed under normal conditions at room temperature. All chemicals were purchased from Sigma Aldrich, Avra synthesis and were used as received. Deuterated solvents were purchased from Sigma Aldrich. IR spectra were recorded on a Perkin Elmer-FTIR spectrometer using solid samples as KBr plates. For compounds 1H NMR (400MHz, DMSO-d6) and 13C NMR (100MHz, DMSO-d6) spectra were recorded in DMSO-d6 on a Bruker 400MHz spectrometer using tetramethylsilane (TMS, δ=0) as an internal standard at room temperature. Mass spectra were recorded on Agilent 1200 LC/MS-6110 mass spectrometer (Supporting Information).

6-amino-7-(1H-benzo[d]imidazol-2-yl)-12-hydroxy-7a,12-dihydro-12aH-benzo[4,5]imidazo[1,2-a]indeno[2,1-c]pyridine-12a-carbonitrile (B1)

Into a round-bottomed flask was added 135mg (1mmol) of 1, 345.8 (2.2mmol) of 2, and trimethylamine (1mmol) in ethanol. This was stirred at room temperature for an hour. The resulting white precipitate was filtered and washed with methanol to yield 385mg (nearly 90%) of product. 1H NMR (400MHz, DMSO-d6) δ 13.08 (b, OH), 8.37 (s, NH2), 8.03 (s, 1H), 7.71 (d, 1H), 7.54 (b, 2H), 7.4-7.3 (t, dd, 4H), 7.1 (s, 4H), 6.8 (d, 1H), 6.04 (s, 1H), 5.65 (s, 1H) ppm; δ 13C NMR (100MHz, DMSO-d6) δ 153.62, 145.24, 143.02, 142.88, 142.23, 141.19, 141.14, 133.65, 131.24,129.72, 128.35, 125.48, 124.69, 123.96, 123.47, 121.63, 121.45, 120.10, 117.67, 116.99, 114.30, 110.57, 79.76, 78.77, 56.06, 48.63, 48.38,45.35,18.58 ppm. IR (KBr, ν, cm-1) 3439, 3248, 2253, 1648, 1522. HRMS (ESI) Calcd for C26H18N6O [M+H]+431.16amu, found 431.1621amu.

6-amino-5-(1H-benzo[d]imidazol-2-yl)-1-hydroxy-2,3,4,4a-tetrahydrobenzo[4,5]imidazo[2,1-a]isoquinoline-12b(1H)-carbonitrile (B2)

Into a round-bottomed flask was added glutaraldehyde 50% solution in water (1mmol), 345.8 (2.2mmol) of 2, and trimethylamine (1mmol) in ethanol. This was left to stir at room temperature for an hour. The resulting white precipitate was filtered and washed with methanol to yield 337mg (85%) of product. 1H NMR (400MHz, DMSO-d6) δ 12.5 (b, OH), 7.54 (s, 4H), 7.2-7.1 (d, t, 4H), 5.52 (b, NH2), 4.09 (b, 2H), 1.8 (dd, 2H), 1.7 (d, 1H), 1.6-1.5 (d, dd,3H), ppm; δ 13C NMR (100MHz, DMSO-d6) δ 151.56, 121.58, 117.96, 72.43, 58.36, 31.42, 19.61ppm. IR (KBr, ν, cm-1) 3431, 3186, 2254, 1525.

5-amino-4-(1H-benzo[d]imidazol-2-yl)-12-hydroxy-3b,12-dihydro-11bH-benzo[4,5]imidazo[1,2-a]thieno[3',2':3,4]cyclopenta[1,2-c]pyridine-11b-carbonitrile (B3)

Into a round-bottomed flask was added 141mg of 2,3-thiophenedicarboxaldehyde (1mmol), 345.8 (2.2mmol) of 2, and trimethylamine (1mmol) in ethanol. This was left to stir at room temperature for an hour. The resulting white precipitate was filtered and washed with methanol to yield 354mg (81 %) of product. 1H NMR (400MHz, DMSO-d6) δ 8.33 (s, 1H), 8.2 (s, 1H), 8.08 (d, 2H), 7.99 (d, 1H), 7.8(d, 2H), 7.7 (d, 1H), 7.67 (d, 1H), 7.57 (t,2H), 7.45-7.31 (m,6H), 7.22 (d, 1H) ppm; δ 13C NMR (100MHz, DMSO-d6) δ 146.35, 145.98, 142.52, 142.47, 142.18, 138.64, 136.54, 134.48, 134.11, 133.5, 133.02, 130.46, 129.97, 126.56, 123.89, 123.75, 123.52, 119.52, 117.88, 117.77, 111. 44, 111,20, 104.63, 102.99, 73.15, 72.26ppm. IR (KBr, ν, cm-1) 3115, 2226, 1610, 1584, 1539.

In conclusion, we have developed an efficient one-pot synthesis of benzo [4,5]imidazo[1,2-a]pyridine derivatives using a pseudo three-component reaction. This method we have demonstrated rapid construction of a indene fused benzo[4,5]imidazo[1,2-a]pyridine and hydroisoquinoline fused benzimidazole derivatives in good yields from simple dialdehydes and 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in EtOH under normal conditions in the presence of trimethylamine as a base. Thus we have established a facile psuedo three component reaction protocol for accessing skeletally diverse benzo [4,5]imidazo[1,2-a]pyridine derivatives deverivatives with inherent provision for scaffold hopping.

Dr. G. Vasuki thank DST-SERB (SB/S1/OC-37/2014), Govt. of India, for financial support, and TSK thank CSIR for JRF and SRF (File No. 09/559(102)/2012-EMR- I). Authors also thank Central Instrumentation Facility (CIF), Pondicherry University, for high-resolution NMR and the Department of Chemistry for ESI-HRMS and single-crystal XRD.

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