ZnI2-Catalyzed Synthesis of Benzo[d]imidazo[2,1-b]thiazole

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FeCl3/ZnI2‑Catalyzed Synthesis of Benzo[d]imidazo[2,1‑b]thiazole through Aerobic Oxidative Cyclization between 2‑Aminobenzothiazole and Ketone Subhajit Mishra, Kamarul Monir, Shubhanjan Mitra, and Alakananda Hajra* Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India S Supporting Information *

ABSTRACT: The FeCl3/ZnI2-catalyzed aerobic oxidative cyclization between 2-aminobenzothiazole and ketone/chalcone for the synthesis of benzo[d]imidazo[2,1-b]thiazole is described. A variety of fused benzoimidazothiazole derivatives are obtained by this protocol.

S

we need of a direct and practical method for the preparation of these heterocycles from basic chemicals. The direct oxidative C−H bond functionalization offers an excellent route to form C−C and C-heteroatom bonds avoiding the prefunctionalization of the reactants.9 As a consequence much attention has been drawn on the oxidative C−H bond functionalization for the construction of various heterocycles from the readily available reactants. Based on our experiences on the synthesis of imidazopyridines,10 we envisaged that the benzo[d]imidazo[2,1-b]thiazole could be directly synthesized from 2-aminobenzothiazole and ketone via oxidative amination. So far there is no such direct oxidative method for the synthesis of this moiety from methyl ketones which are more easily available compared to the α-halo/tosyloxy ketones. Herein we report the synthesis of benzo[d]imidazo[2,1-b]thiazole derivatives from ketones via FeCl3/ZnI2-catalyzed oxidative C−H functionalization under aerobic conditions (Scheme 1). Optimization of the reaction conditions was carried out by taking 2-aminobenzothiazole (1a) and acetophenone (2a) as the model substrates. Initially the reaction was carried out employing a combination of FeCl3 (20 mol %) and ZnI2 (10 mol %) in acetonitrile under refluxing conditions, and to our delight, the desired product was obtained in 10% yield (Table 1, entry 1). Other common solvents like 1,2-dichloroethane, 1,2-dichlorobenzene (DCB), DMF, DMSO, DMAc, and NMP were also screened (Table 1, entries 2−7). 1,2-DCB was found to be the most effective solvent. We also investigated the catalytic activity of other iron salts such as FeBr3 and Fe(NO3)3.9H2O. However, lower yields were obtained (Table 1, entries 8 and 9). No product was obtained either in absence of the FeCl3 or ZnI2 (Table 1, entries 10 and 11). Thus, a combination of both the catalysts is necessary for the reaction.

ulfur-containing heterocyclic compounds are frequently found in naturally occurring compounds and generally show various biological activities.1 Benzo[d]imidazo[2,1-b]thiazole is one of the important fused bicyclic sulfur containing heterocycles and also an important chemical building block in synthetic organic and biological chemistry (Figure 1). Various

Figure 1. Biologically active benzo[d]imidazo[2,1-b]thiazole derivatives.

benzo[d]imidazo[2,1-b]thiazoles have been used as antitumor agents (I and II), antimicrobial agents, antibacterial agents, and antiallergic agents.2−5 These derivatives are also found to be particular kinase inhibitors and receptors (III) and employed for PET imaging of Alzheimer’s patients brains (IV) as well as β-amyloid plaques.6,7 Despite of having such important biological activities, only a few methods have been developed so far for the synthesis of this scaffold.8 The conventional approach for the construction of benzo[d]imidazo[2,1-b]thiazole moiety is the condensation of 2-aminobenzothiazole with α-halo/tosyloxy ketone. However, the utilization of prefunctionalized as well as commercially less available starting materials still limits the application of these procedures. Thus, © XXXX American Chemical Society

Received: September 30, 2014

A

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product was obtained by carrying out the reaction employing 20 mol % of FeCl3 and 10 mol % of ZnI2 in 1,2-DCB at 110 °C for 15 h (Table 1, entry 3). With the optimal reaction conditions in hand, we investigated the scope of the reaction (Scheme 2). First,

Scheme 1. Synthesis of Benzo[d]imidazo[2,1-b]thiazoles

Scheme 2. Substrate Scopea,b

Table 1. Optimization of the Reaction Conditionsa

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

catalyst (mol %) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeBr3 (20) Fe(NO3)3·9H2O (20) FeCl3 (20) Cu(OAc)2.H2O (20) 99.99% FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (20) FeCl3 (10) FeCl3 (5)

additive (mol %) ZnI2 ZnI2 ZnI2 ZnI2 ZnI2 ZnI2 ZnI2 ZnI2 ZnI2

(10) (10) (10) (10) (10) (10) (10) (10) (10)

ZnI2 (10) ZnI2 (10) ZnI2 (10) ZnCl2 (10) KI (10) NaI (10) TBAI (10) I2 (10) HI (10) ZnI2 (5) ZnI2 (2)

solvent c

CH3CN 1,2-DCEc 1,2-DCB DMF DMSO DMAc NMP 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB 1,2-DCB

yieldb (%) 10 24 88 21 20 10 17 72 60

15 86 trace 48 43 41 32 44 45 28

a

Reaction conditions: 0.6 mmol of 1 and 0.5 mmol of 2 in the presence of FeCl3 (20 mol %) and ZnI2 (10 mol %) in 1,2-DCB at 110 °C for 15 h in air. bIsolated yields.

different substituted 2-aminobenzothiazoles were employed under the optimized reaction conditions. Satisfactorily, 2aminobenzothiazoles bearing electron-donating as well as electron-withdrawing substituents afforded the corresponding benzo[d]imidazo[2,1-b]thiazoles with high yields (3aa, 3bb, 3ca, and 3da). We then studied the scope and limitation of this protocol by varying a wide range of aromatic, heteroaromatic, and aliphatic ketones. Both the electron-donating and electronwithdrawing groups like −Me, −OMe, −Cl, −Br, −I, and −NO2 on the aromatic ring were compatible with this transformation, and the corresponding benzo[d]imidazo[2,1b]thiazole derivatives were obtained in good to excellent yields (3ab, 3ac, 3ad, 3ae, 3ag, 3ah, and 3bo). The halogencontaining benzo[d]imidazo[2,1-b]thiazoles could be further functionalized by the traditional cross-coupling reaction. The CF3-containing acetophenone also afforded the product with good yield (3af). 2-Phenylacetophenone gave the 2,3diphenylbenzo[d]imidazo[2,1-b]thiazole in good yield under the optimized reaction conditions (3ai). The heteroaryl ketones like 2-acetylfuran and 2-acetylthiophene also proceeded well under the present reaction conditions (3aj, 3ak, and 3al). The o-allyl group containing acetophenone afforded the

a Reaction conditions: 0.6 mmol of 1a and 0.5 mmol of 2a in the presence of catalyst and additive in solvent (2 mL) at 110 °C for 15 h in air. bIsolated yields. cReaction was carried out under refluxing conditions.

The use of Cu(OAc)2·H2O instead of FeCl3 only afforded 15% of the desired product (Table 1, entry 12). Furthermore, the reaction was carried out employing analytically pure (>99.99%) FeCl3 (20 mol %) and ZnI2 (10 mol %). A similar result (86% yield) was obtained which proves that contamination of copper does not act as the catalyst in the present methodology (Table 1, entry 13). ZnCl2 instead of ZnI2 diminished the formation of desired product (Table 1, entry 14). It is notable to observe that other iodide sources such as NaI, KI, TBAI, HI, and I2 were examined and found to be less effective compared to ZnI2 (Table 1, entries 15−19). Use of I2 produces a mixture of undesired products. The decrease of catalyst loading of FeCl3/ ZnI2 decreased the yield of the product significantly (Table 1, entries 20−21). Thus, the optimized yield of the desired B

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corresponding product without affecting the allyl group (3am). Furthermore, cyclohexyl methyl ketone, acetophenone, and trifluoroacetophenone were also found to be suitable for this transformation (3an, 3as, and 3at). Sterically hindered orthosubstituted acetophones furnished the desired products in moderate to good yields (3bo, 3ap, and 3aq). 1-Acetonaphthone also reacted well under the present reaction conditions (3ar). However, the present methodology is not applicable for methyl pyruvate, propiophenone, and isobutyl methyl ketone. Next, we checked the feasibility of chalcone derivatives as the coupling partner with 2-aminobenzothiazole under the optimized reaction conditions for the synthesis of highly substituted benzo[d]imidazo[2,1-b]thiazoles, which are difficult to prepare through conventional methods (Scheme 3). To our

Scheme 4. Controlled Experiments

Scheme 3. Synthesis of 2-Aroylbenzo[d]imidazo[2,1b]thiazoles

Scheme 5. Plausible Mechanism

delight, the 2-aroylbenzo[d]imidazo[2,1-b]thiazoles were obtained in high yields under oxygen atmosphere (5aa, 5ab, 5ac, 5ad). To the best of our knowledge this is the first reported method for the synthesis of these aroyl substituted derivatives. Some controlled experiments were carried out to understand the probable mechanistic path of this oxidative cyclization (Scheme 4). Only a trace amount of the desired product was obtained under argon atmosphere, which indicates that the presence of oxygen is required to fulfill the catalytic cycle (Scheme 4, eq A). When the reaction was carried out in the presence of AgOAc, a much lower yield was obtained (Scheme 4, eq B). From this observation, it seems that the in situ generated iodine from the iodide source acts as the catalyst in this reaction. However, the utilization of molecular iodine resulted only 15% yield (Scheme 4, eq C). CuI is not effective in this reaction, as it only produces 10% of the desired product (Scheme 4, eq D). The combination of FeCl3 (20 mol %) and CuI (10 mol %) is also not an effective catalyst for this transformation. ZnI2 acts as an effective iodide source for this reaction. From these controlled experiments and the literature reports, the probable mechanism of the reaction is represented in Scheme 5. The Ortoleva−King reaction promoted by Lewis acid is the key step for this reaction.11 The first step is the generation of iodine by the oxidation of iodide anion with aerobic oxygen in the presence of FeCl3. In the next step, acetophenone reacts with this in situ generated iodine to produce the α-iodoketone (A). The 2-aminobenzothiazole

reacts with this α-iodoketone (A) to form the intermediate B. The subsequent intramolecular cyclization of the intermediate B affords the 2-phenylbenzo[d]imidazo[2,1-b]thiazole. On the basis of the experimental results, it seems that FeCl3 plays a crucial role in aerial oxidation of iodide anion to iodine and might help in the cyclization step as well. In the case of chalcones, the reaction possibly proceeds through the formation of iodonium intermediate. This intermediate on sequential nucleophilic substitutions and aerobic oxidation affords the 2-aroylbenzo[d]imidazo[2,1-b]thiazoles. In summary, we have demonstrated FeCl3/ZnI2-catalyzed direct synthesis of benzo[d]imidazo[2,1-b]thiazole derivatives through aerobic oxidative amination. The versatile method shows broad functional group tolerance and is applicable to a wide range of readily accessible ketones. This catalytic combination is also effective for the construction of 2aroylbenzo[d]imidazo[2,1-b]thiazoles. The reaction probably proceeds through in situ formation of α-iodo ketone followed by intramolecular cyclization. We believe this operationally simple protocol will find important applications in organic, medicinal, and material chemistry. C

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(9) (a) Louillat, M.-L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901. (b) Shi, Z. Z.; Zhang, C.; Tang, C. H.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (d) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105, 2329. (e) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (f) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (10) (a) Monir, K.; Bagdi, A. K.; Ghosh, M.; Hajra, A. Org. Lett. 2014, 16, 4630. (b) Santra, S.; Mitra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. Tetrahedron Lett. 2014, 55, 5151. (c) Monir, K.; Bagdi, A. K.; Mishra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2014, 356, 1105. (d) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013, 355, 1741. (e) Santra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013, 355, 1065. (11) (a) Stasyuk, A. J.; Banasiewicz, M.; Cyrański, M. K.; Gryko, D. T. J. Org. Chem. 2012, 77, 5552. (b) Zhang, Y.; Chen, Z.; Wu, W.; Zhang, Y.; Su, W. J. Org. Chem. 2013, 78, 12494.

ASSOCIATED CONTENT

S Supporting Information *

Additional data, spectral data of all compounds, and scanned spectra of new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.H. acknowledges financial support from CSIR, New Delhi (Grant No. 02(0168)/13/EMR-II). S.M. thanks UGC, and K.M. thanks CSIR (SPM) for their fellowship.

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REFERENCES

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