Synthesis of IBT Scaffolds Experiment

Published Date: 28 Nov 2017

Chapter III: Section A Present work

PRESENT WORK

Over the years, multi component reactions (MCRs) or three component coupling reactions have gained much attention in synthetic as well as medicinal chemistry to generate structural diversity for drug discovery programs.³¹ MCR is a process in which at least three simple building blocks are combined together in one pot to provide diversity oriented product with minimum of synthetic time and effort. The imidazo [2,1-b] benzothiazole (IBT) motif is an important pharmacophore and is known to exhibit significant biological activities such as antimicrobial, antitumor, antituberculosis, and anti-inflammatory etc.,^13-30

Consequently, different methods^23-26 have been developed for the synthesis of IBT scaffolds. Of these, the MCR of 2-aminobenzothiazole, aldehyde, and alkyne is one of the most attractive methods for the synthesis of 2-aryl imidazo[1,2-a]benzothiazoles. To the best of our cognition, there is only one report^14c for synthesis of the title compounds till date which is a multi step procedure. In prolongation of our involvement in exploring the synthesis³² of biologically active scaffolds, we herein describe a three-component, one-pot synthesis of IBTs using a catalytic amount of La(OTf)₃ and CuI in acetonitrile.

Accordingly, we first treated 2-aminobenzothiazole (1a) and benzaldehyde (31a) with ethylpropiolate (32) in acetonitrile in the presence of 10 mol % La(OTf)₃ and CuI. The reaction proceeded well at r. t. and made the desired IBT 33a in 86% yield (Scheme 10).

Scheme 10

Formation of 33a confirmed by its spectral analysis, ¹H NMR of IBT 33a shows a characteristic methylene protons at δ 4.16 (s, 2H) as a singlet, doublets at δ 7.78 (d, J = 7.9 Hz, 1H) and 7.70 (d, J = 8.3 Hz, 1H) belongs to benzothiazole ring (ortho-hydrogens w.r.t sulphur and nitrogen) in the fused system. Another doublet at δ 7.68 (d, J = 7.9 Hz, 2H) belongs to ortho-hydrogens of phenyl ring at C-2 position and peaks for remaining aromatic protons observed at δ 7.42 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H) and 7.01 (t, J = 7.9 Hz, 2H). Ethyl ester protons resonated at δ 4.26 (q, J = 6.8 Hz, 2H) and 1.27 (t, J = 8.1 Hz, 3H) belongs to OCH₂CH₃ and OCH₂CH₃ respectively. In ¹³C NMR, presence of a peak at δ 171.1 resembling ester (-C=O) functionality, a peak at δ 61.1 belongs to CH₃–CH₂-O-COAr, and remaining aromatic carbons resonated at their expected chemical shift values. The new absorption maximum at 1735 cm^-1 in IR spectrum also supports the presence of ester (-C=O). Finally, ESI-MS also supports the IBT 33a showing a peak with m/z 337 for its molecular ion.

Plausible mechanism

Scheme 11 Plausible mechanism for CuI-La(OTf)₃ catalyzed multi-component reaction

In accordance with the mechanism described by Mishra et al.³³ The reaction may proceed in one of the two paths mentioned above. In path-I, benzaldehyde was first reacted with 2-aminobenzothiazole in the presence of La(OTf)_3, and the resulting imine further reacted with ethyl propiolate to form desired imidzobenzothiazole 33a via initial formation of propargylamine I. Tautomerization of propargylamine I followed by 5-exo-dig cyclization formed intermediate III, which finally isomerized to product 33a.

Optimization study

Table 1 Screening of the catalyst for three component reaction

Initially, we screened the reaction between 2-aminobenzothiazole 1a benzaldehyde 31a and ethylpropiolate 32 as starting materials using different catalysts to optimize the reaction conditions (Table 1). The desired product yielded in 65% when 10 mol % of CuI used in CH₃CN. Further optimization was performed to improve the yield of the product. The best result was obtained when La(OTf)₃ was used with high yield, low reaction time and optimal temperature. However, in the absence of the catalyst the reaction proceeds with low yield even after longer reaction time (24 h). Our attempts to optimize the conditions for the synthesis of the 2-aryl imidazo[2,1-b]benzothiazoles 33a-o are summarized in Table 1.

To check the generality and scope of the present protocol (Table 1), variety of benzaldehydes containing electron withdrawing or electron donating substituents were reacted under these conditions with 2-aminobenzothiazole, which affords corresponding IBT (Scheme 12).

Scheme 12

To explore the limitations of this reaction, we extended it to various para-substituted benzaldehydes with 6-methyl-2-aminobenzothiazole. As can be seen in Table 2, the yield of products seems to be affected by the nature of substituents and their positions on the benzothiazole as well as benzaldehydes. The yields decreased when electron-withdrawing substituents were present on reactants (scheme 13).

Scheme 13

The compounds 33f-j were characterized by ¹H NMR, ¹³C NMR, IR and ESI-MS, the results are shown in the experimental section. For an instance, spectral analysis of 33h explained here. ¹H NMR of IBT 33h shows a characteristic methylene protons at δ 4.27 (s, 2H), and methyl protons at 2.35 (s, 3H), methoxy protons at 3.86 (s, 3H), and hydrogen adjacent to sulphur attached carbon resonated at 7.71 (s, 1H) as a singlets, doublets at δ 7.64 (d, J = 7.9 Hz, 1H), and 7.35 (d, J = 7.1 Hz, 1H) belongs to benzothiazole ring (ortho- and meta- hydrogens w.r.t nitrogen) in the fused system. Another two doublets appeared at δ 7.55 (d, J = 7.8 Hz, 2H), and 7.01 (d, J = 7.6 Hz, 2H) belongs to methoxy substituted phenyl ring, whereas ethyl ester protons resonated at δ 4.15 (q, J = 8.1 Hz, 2H), and 1.27 (t, J = 8.2 Hz, 3H) belongs to OCH₂CH₃ and OCH₂CH₃ respectively. In ¹³C NMR, the presence of a peak at δ 169.1 resembling ester (-C=O) functionality, a peak resonated at 160.8ppm belongs to –Ome attached carbon on phenyl ring, where as a peak at δ 61.2 belongs to CH₃–CH₂-O-COAr, and remaining aromatic carbons resonated at their expected chemical shift values. The new absorption maximum of 1738 and 1210 cm^-1 in IR spectrum also supports the presence of ester (-C=O). Finally, ESI-MS also supports the IBT 33h showing a peak with m/z 381 for its molecular ion.

Furthermore, a variety of aromatic aldehydes such as p-methyl-, p-methoxy-, p-nitro and p-cyano benzaldehyde participated well in this MCR with 6-nitro-2-aminobenzothiazole and gave excellent yields.

The synthesized compounds 33k-o were characterized by ¹H NMR, ¹³C NMR, IR and ESI-MS, the results are shown in the experimental section. For example, the spectral analysis of IBT 33n was explained here. ¹H NMR of IBT 33n shows a characteristic methylene protons at δ 4.19 (s, 2H), and hydrogen adjacent to sulphur attached carbon and –NO₂ group resonated at 8.55 (s, 1H) as a singlets, doublet at δ 8.01 (d, J = 7.7 Hz, 2H) belongs to meta-hydrogens of nitro-substituted phenyl ring and a multiplet appeared between 8.40-8.50 (m, 3H) belongs to a hydrogen of benzothiazole ring merged with ortho-hydrogens of nitro-substituted phenyl ring, whereas ethyl ester protons resonated at δ 4.11 (q, J = 8.0 Hz, 2H), and 1.21 (t, J = 8.2 Hz, 3H) belongs to OCH₂CH₃ and OCH₂CH₃ respectively. In ¹³C NMR, the presence of a peak at δ 169.1 resembling ester (-C=O) functionality, peaks resonated at 147.8, 144.7 ppm belongs to –NO₂ attached carbons, where as a peak at δ 61.5 belongs to CH₃–CH₂-O-COAr, and remaining aromatic carbons resonated at their expected chemical shift values. The new absorption maximum of 1735 cm^-1 in IR spectrum also supports the presence of ester (-C=O), bands at 1536 and 1365 cm^-1 resemble the –NO₂ group. Finally, ESI-MS also supports the IBT 33a showing a peak with m/z 427 for its molecular ion.

The imidazobenzothiazole derivatives was synthesized by La(OTf)₃-CuI catalytic combination in good to excellent yields as shown in Table 2.

Table 2 The new ethyl 2-(2-arylimidazo[2,1-b][1,3]-benzothiazol-1-yl)acetates 33a-o

Conclusion

In summary, a novel method for the synthesis of ethyl 2-(2-arylimidazo[2,1-b][1,3]-benzothiazol-1-yl) acetates was demonstrated from bezaldehyde, ethylpropiolate, and 2-aminobenzothiazole in the presence of La(OTf)₃-CuI catalyst in good to excellent yields. This reaction took place under mild conditions and it tolerates a wider range of functionalities. Therefore this methodology offers an alternative to multi step reactions.