ORGANIC LETTERS
Metal-Free Synthesis of 2‑Aminobenzothiazoles via Aerobic Oxidative Cyclization/Dehydrogenation of Cyclohexanones and Thioureas
XXXX Vol. XX, No. XX 000–000
Jinwu Zhao,†,‡ Huawen Huang,† Wanqing Wu,† Huoji Chen,† and Huanfeng Jiang*,† School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China, and School of Pharmacy, Guangdong Medical College, Songshan Lake Science and Technology Industry Park, Dongguan 523808, P. R. China
[email protected] Received March 21, 2013
ABSTRACT
A metal-free process for the synthesis of 2-aminobenzothiazoles from cyclohexanones and thioureas has been developed using catalytic iodine and molecular oxygen as the oxidant under mild conditions. Various 2-aminobenzothiazoles, 2-aminonaphtho[2,1-d]thiazoles, and 2-aminonaphtho[1,2-d]thiazoles were prepared via this method in satisfactory yields.
2-Aminobenzothiazoles are an important class of heterocycle whose diverse biological activities make them privileged scaffolds in drug discovery.1 For example, marketed Riluzole (A) is a 2-aminobenzothiazole compound employed in the treatment of amyotrophic lateral sclerosis;2 N-disubstituted 2-aminobenzothiazole (B) is used as anti-HIV agent, and N-aryl substituted 2-aminobenzothiazole (C, R116010) is serving as a potential inhibitor of retinoic acid metabolism for cancer treatment
(Figure 1).3,4 N-Alkyl substituted 2-aminobenzothiazoles might also be biologically active and of pharmaceutical value.5
†
South China University of Technology. Guangdong Medical College. (1) (a) Paget, C. J.; Kisner, K.; Stone, R. L.; DeLong, D. C. J. Med. Chem. 1969, 12, 1016. (b) Young, R. C.; Mitchell, R. C.; Brown, T. H.; Ganellin, C. R.; Griffiths, R.; Jones, M.; Rana, K. K.; Saunders, D.; Smith, I. R.; Sore, N. E.; Wilks, T. J. J. Med. Chem. 1988, 31, 656. (c) Raghavendra, N. M.; Jyothsna, A.; Rao, A. V.; Subrahmanyam, C. V. S. Bioorg. Med. Chem. Lett. 2012, 22, 820. (d) Fajkusova, D.; Pesko, M.; Keltosova, S.; Guo, J. H.; Oktabec, Z.; Vejsova, M.; Kollar, P.; Coffey, A.; Csollei, J.; Kralova, K.; Jampilek, J. Bioorg. Med. Chem. 2012, 20, 7059. (e) Gardner, C. R.; Cheung, B. B.; Koach, J.; Black, D. S.; Marshall, G. M.; Kumar, N. Bioorg. Med. Chem. 2012, 20, 6877. (2) (a) McDonnell, M. E.; Vera, M. D.; Blass, B. E.; Pelletier, J. C.; King, R. C.; Fernandez-Metzler, C.; Smith, G. R.; Wrobel, J.; Chen, S.; Wall, B. A.; Reitz, A. B. Bioorg. Med. Chem. 2012, 20, 5642. (b) Cheah, B. C.; Vucic, S.; Krishnan, A. V.; Kiernan, M. C. Curr. Med. Chem. 2010, 17, 1942. (3) Massari, S.; Daelemans, D.; Barreca, M. L.; Knezevich, A.; Sabatini, S.; Cecchetti, V.; Marcello, A.; Pannecouque, C.; Tabarrini, O. J. Med. Chem. 2010, 53, 641. ‡
Figure 1. Examples of bioactive 2-aminobenzothiazoles.
In view of the importance of 2-aminobenzothiazoles, a number of procedures have been developed to prepare this (4) (a) Van Heusden, J.; Van Ginckel, R.; Bruwiere, H.; Moelans, P.; Janssen, B.; Floren, W.; van der Leede, B. J.; van Dun, J.; Sanz, G.; Venet, M.; Dillen, L.; Van Hove, C.; Willemsens, G.; Janicot, M.; Wouters, W. Br. J. Cancer 2002, 86, 605. (b) Aelterman, W.; Lang, Y.; Willemsens, B.; Vervest, I.; Leurs, S.; De Knaep, F. Org. Process Res. Dev. 2001, 5, 467. 10.1021/ol400773k
r XXXX American Chemical Society
class of heterocyclic compound.6 An overwhelming number of these involve transition-metal catalysts, such as copper,7 palladium,8 iron,9 silver, etc.10,11 Some of these metal-based catalysts are based on noble metals and are of high cost. Moreover, transition metal catalysts may possibly leave toxic traces of metals in the products. It was reported that 2-aminobenzothiazoles could be produced by reacting isothiocyanates with o-aminothiophenols or o-iodoaniline under metal-free conditions.12,13 However, these methods suffer from limited starting materials and/or harsh reaction conditions. Therefore, the development of a new practical process for the synthesis of 2-aminobenzothiazoles under mild conditions is desirable. Recently, our group has developed a number of transition-metal-free processes to synthesize nitrogen-containing heterocyclic compounds through iodine mediated oxidative cyclization reactions.14 Herein, we disclose that cyclohexanones can react with thioureas to provide 2-aminobenzothiazoles catalyzed by iodine (Scheme 1). Moreover, the reaction utilizes molecular oxygen as an oxidant, which avoids the environmentally hazardous byproducts obtained with other oxidants.15 Our studies began by optimizing the reaction conditions on cyclohexanone and thiourea. The results are tabulated in Table 1. When this reaction was carried out in toluene at 95 °C for 24 h, using 20 mol % molecular iodine as the catalyst, in the presence of 2.0 equiv of aqueous HCl, under (5) (a) Liu, C. J.; Lin, J.; Pitt, S.; Zhang, R. F.; Sack, J. S.; Kiefer, S. E.; Kish, K.; Doweyko, A. M.; Zhang, H. J.; Marathe, P. H.; Trzaskos, J.; Mckinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven, G. L.; Leftheris, K. Bioorg. Med. Chem. Lett. 2008, 18, 1874. (b) Ouyang, L.; Huang, Y. H.; Zhao, Y. W.; He, G.; Xie, Y. M.; Liu, J.; He, J.; Liu, B.; Wei, Y. Q. Bioorg. Med. Chem. Lett. 2012, 22, 3044. (6) (a) Stewart, G. W.; Baxter, C. A.; Cleator, E.; Sheen, F. J. J. Org. Chem. 2009, 74, 3229. (b) Jordan, A. D.; Luo, C.; Reitz, A. B. J. Org. Chem. 2003, 68, 8693. (c) Neo, A. G.; Carrillo, R. M.; Marcos, C. F. Org. Biomol. Chem. 2011, 9, 4850. (d) Wang, R.; Yang, W. J.; Yue, L.; Pan, W.; Zeng, H. Y. Synlett 2012, 23, 1643. (7) (a) Ma, D. W.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y. W.; Liu, X. Q. Angew. Chem., Int. Ed. 2011, 50, 1118. (b) Rout, S. K.; Guin, S.; Nath, J.; Patel, B. K. Green Chem. 2012, 14, 2491. (c) Sun, Y. L.; Zhang, Y.; Cui, X. H.; Wang, W. Adv. Synth. Catal. 2011, 353, 1174. (d) Li, F.; Shan, H. X.; Kang, Q. K.; Chen, L. Chem. Commun. 2011, 47, 5058. (e) Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (8) (a) McGowan, M. A.; Henderson, J. L.; Buchwald, S. L. Org. Lett. 2012, 14, 1432. (b) Inamoto, K.; Hasegawa, C.; Kawasaki, J.; Hiroya, K.; Doi, T. Adv. Synth. Catal. 2010, 352, 2643. (c) Stewart, G. W.; Baxter, C. A.; Cleator, E.; Sheen, F. J. J. Org. Chem. 2009, 74, 3229. (d) Joyce, L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792. (e) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147. (f) Joyce, L. L.; Evindar, G.; Batey, R. A. Chem. Commun. 2004, 446. (9) (a) Qiu, J. W.; Zhang, X. G.; Tang, R. Y.; Zhong, P.; Li, J. H. Adv. Synth. Catal. 2009, 351, 2319. (b) Ding, Q. P.; Cao, B. P.; Liu, X. J.; Zong, Z.; Peng, Y. Y. Green Chem. 2010, 12, 1607. (10) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed 2009, 48, 9127. (11) For other metal catalysts, see: (a) Li, F.; Shan, H. X.; Chen, L.; Kang, Q. K.; Zou, P. Chem. Commun. 2012, 48, 603. (b) Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Adv. Synth. Catal. 2010, 352, 3241. (12) Zhang, X. Y.; Jia, X. F.; Wang, J. J.; Fan, X. S. Green Chem. 2011, 13, 413. (13) Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 654. (14) (a) Huang, H. W.; Ji, X. C.; Wu, W. Q.; Jiang, H. F. Adv. Synth. Catal. 2013, 355, 170. (b) Jiang, H. F.; Huang, H. W.; Cao, H.; Qi, C. Q. Org. Lett. 2010, 12, 5561. (15) For general reviews, see: (a) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105, 2329. (b) Shi, Z. Z.; Zhang, C.; Tang, C. H.; N. Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (c) Wu, W. Q.; Jiang, H. F. Acc. Chem. Res. 2012, 45, 1736. B
Scheme 1. Metal-Free Synthesis of 2-Aminobenzothiazoles from Cyclohexanones and Thioureas
1 atm of pressure of dioxygen, no desired 2-aminobenzothiazole was obtained (Table 1, entry 1). After screening common polar solvents, DMSO was found to be superior (Table 1, entries 2 4). When AcOH was used as the solvent as well as acid proton donor, 3a was obtained in 7% yield (Table 1, entry 5). Our experimental results suggested that organic strong acids were better than inorganic acids, and p-toluenesulfonic acid (PTSA) favored the transformation to the greatest extent (Table 1, entries 6 9). As shown in Table 1, the amount of acid used had a significant effect on the yield of 2-aminobenzothiazole, and finally we found that 5 equiv of PTSA gave the best results (Table 1, entries 10 12). Our investigations on reaction temperature showed that 75 °C was optimal for the process (Table 1, entries 13 and 14). When the loading of the iodine catalyst was increased from 20 to 30 mol %, the yield of 3a rose from 78% to 84% (Table 1, entry 15). Increasing the amount of the catalyst further was not beneficial (Table 1, entry 16).
Table 1. Optimization of Reaction Conditions for the Synthesis of 2-Aminobenzothiazole from Cyclohexanone and Thioureaa
entry
solvent
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15c 16d
toluene DMF DMSO H2O AcOH DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO
acid (equiv) HCl (2.0) HCl (2.0) HCl (2.0) HCl (2.0) H2SO4 (1.0) MsOH(2.0) PTSA (2.0) TfOH (2.0) PTSA (3.0) PTSA (5.0) PTSA (6.0) PTSA (5.0) PTSA (5.0) PTSA (5.0) PTSA (5.0)
temp (°C)
yieldb (%)
95 95 95 95 95 95 95 95 95 95 95 95 75 55 75 75
N. P. 15 45 N. P. 7 36 53 60 58 66 77 76 78 42 84 84
a Reaction conditions: unless otherwise noted, all reactions were performed with 1a (0.5 mmol), 2a (0.5 mmol), I2 (20 mol %), and acid (indicated amount), in a tested solvent (2 mL) at a selected temperature under O2 (1 atm) for 24 h. b Isolated yield. N. P. = no product. c 30 mol % I2 was used. d 50 mol % I2 was used.
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The scope of the protocol was further tested after the optimal reaction conditions were established. Thiourea was reacted with various cyclohexanones under the best reaction conditions, and the results are listed in Scheme 2. 4-Substituted cyclohexanones such as 4-methylcyclohexanone, 4-phenylcyclohexanone, 4-(tert-pentyl)cyclohexanone, and 4-(ethoxycarbonyl) cyclohexanone reacted smoothly to produce the desired 2-aminobenzothiazoles (3b e). The product 3e was obtained in relatively low yield for the probable reason that the ethoxycarbonyl is an electronwithdrawing group. The 2-substituted cyclohexanones, 2-methylcyclohexanone and 2-phenylcyclohexanone, also provided the target products in yields of 71% and 66% respectively (3f g). Unexpectedly, when 3-methylcyclohexanone was subjected to the reaction, the ratio of regioisomeric 5-methylbenzo[d]thiazol-2-amine and 7-methylbenzo[d]thiazol-2-amine was 93:7 as determined by GC, and the former was obtained in 43% islated yield (3h). Presumably, the regioselectivity was high because the 3-substituent of the cyclohexanone exerted steric hindrance on its neighboring R-position. The 2-tetralones, β-tetralone, 7-methoxy-2tetralone, and 6-bromo-2-tetralone also all reacted with thiourea efficiently and provided the target 2-aminonaphtho[2,1-d]thiazoles in excellent yields (3i k). To the best of our knowledge, a practical synthetic process for these 2-aminonaphtho[2,1-d]thiazoles has not been reported yet. 1-Tetralones such as β-tetralone, 6-methoxy-1-tetralone, and 4-methyl-1-tetralone were also able to undergo the transformation under the optimum reaction conditions, and 2-aminonaphtho[1,2-d]thiazoles were obtained in yields of 88%, 92%, and 89% respectively (3l n). Another cycylohexanone of notable structure, 6,7-dihydrobenzo[b]thiophen-4(5H)-one, was a good substrate for the reaction, and the desired 2-aminobenzothiazole compound was isolated in 94% yield (3o). On the whole, cyclohexanones fused with an aromatic ring gave the corresponding 2-aminobenzothiazoles in higher yield since they could enolize and participate in dehydrogenation more readily. A variety of thioureas were then probed, and the results are summarized in Scheme 3. Alkyl thioureas such as 1-methylthiourea, 1-benzylthiourea, 1-butylthiourea, and 1-phenethylthiourea all furnished the target 2-aminobenzothiazole products in good yield when they were treated with β-tetralone under the favored conditions (3p s). Aryl thioureas, 1-phenylthiourea and 1-(4-methoxyphenyl)thiourea, gave the corresponding 2-aminonaphtho[2,1-d]thiazoles in relatively lower yield compared with alkyl thioureas (3t u). 1,1-Disubstituted thioureas 1-methyl-1-phenylthiourea and piperidine-1-carbothioamide afforded the desired 2-aminonaphtho[2,1-d]thiazole in 72% and 75% yields (3v w). Substituted thioureas, such as 1-methylthiourea and 1-benzylthiourea, also reacted with R-tetralone to give N-substituted 2-aminonaphtho[1,2-d]thiazole products in satisfactory yields (3x y). Based on the experimental results mentioned above and our previous work on iodine-catalyzed oxidative cyclization reactions,14 a reasonable reaction pathway for the metal-free synthesis of 2-aminobenzothiazoles from cyclohexanones and thioureas is illustrated in Scheme 4. Org. Lett., Vol. XX, No. XX, XXXX
Scheme 2. Scope of Cyclohexanones for Metal-Free Synthesis of 2-Aminobenzothiazolesa,b
a Reactions were performed with 1 (0.5 mmol), 2a (0.5 mmol), I2 (30 mol %), and PTSA (5 equiv), in DMSO (2 mL) under O2 (1 atm) at 75 °C for 24 h. b Isolated yield.
Promoted by protonation, cyclohexanone first enolizes into I which can then undergo R-iodination to generate II. Then, the thiourea tautomer III engages in a nucleophilic substitution reaction with II to afford the R-sulfur substituted cyclohexanone IV, in which the nitrogen atom of the imine group launches an intramolecular nucleophilic attack on the carbonyl to provide V. Dehydration of V would then yield intermediate VI, which can be dehydrogenated by iodine to give the final 2-aminobenzothiazole product.16 The resultant iodide anion throughout the transformation is oxidized by oxygen under the acidic conditions to regenerate the molecular iodine. (16) Adams, C. T.; Brandenberger, S. G.; DuBois, J. B.; Mill, G. S.; Nager, M.; Richardson, D. B. J. Org. Chem. 1977, 42, 1. C
Scheme 3. Scope of Thioureas for Metal-Free Synthesis of 2-Aminobenzothiazolesa,b
Scheme 4. Possible Reaction Pathway for Metal-Free Synthesis of 2-Aminobenzothiazoles
readily available cyclohexanones and thioureas. This metal-free method offers a convenient alternative in the construction of 2-aminobenzothiazoles. Particularly, 2-aminonaphtho[2,1-d]thiazoles and 2-aminonaphtho[1,2-d]thiazoles can be produced via this protocol. This strategy also employs oxygen as a green oxidant and avoids transition metals. Acknowledgment. The authors thank the National Natural Science Foundation of China (21172076 and 20932002), the National Basic Research Program of China (973 Program) (2011CB808600), the Changjiang Scholars and Innovation Team Project of Ministry of Education, Guangdong Natural Science Foundation (10351064101000000 and S2012040007088), China Postdoctoral Science Foundation (2012T50673), and the Fundamental Research Funds for the Central Universities (2012ZP0003 and 2012ZB0011) for financial support. a Reactions were performed with 1h or 1k (0.5 mmol), 2a (0.5 mmol), I2 (30 mol %), PTSA (5 equiv), in DMSO (2 mL) under O2 (1 atm) at 75 °C for 24 h. b Isolated yield.
In conclusion, we have developed a practical procedure for the synthesis of 2-aminobenzothiazoles from
D
Supporting Information Available. Typical experimental procedure and characterization for all products. This material is available free of charge via the Internet at http://pubs.acs.org. The authors declare no competing financial interest.
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