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Brønsted acid promoted addition–cyclization and C–C bond cleavage: a convenient synthesis of 2-amino-5-aroylmethylthiazoles derivatives† Fan Ni, Yan Yang, Wen-Ming Shu, Jun-Rui Ma and An-Xin Wu* A Brønsted acid promoted C–C bond cleavage method for the synthesis of novel 2-amino-5-aroylmethylthiazole derivatives has been directly developed from 1,4-enediones and thioureas through self-
Received 19th July 2014, Accepted 1st October 2014
sequenced thio-Michael-addition, intramolecular selective cyclization, dehydration/aromatization, and C–C bond cleavage reactions. It is noteworthy that this reaction has significant advantages in simple
DOI: 10.1039/c4ob01519c
reagents, under environmentally benign conditions and with excellent yields. This highly efficient method
www.rsc.org/obc
is also a highly attractive alternative for the preparation of PLTP, CETP inhibitors and novel biheterocycles.
C–C bond cleavage(activation) has formed a novel chapter in organic synthesis, and provided a great opportunity for synthetic chemists to design highly efficient transformations from inert starting materials.1 To control this great challenge for C–C bond cleavage, efficient strategies were proposed in the past decade.2 In recent years, the carbonyl group has been considered an ideal group for assisting the cleavage of C–C bonds3 through a chelation effect,4 ring strain release,5 “retro” processes,6 aromatization,7 rearrangement8 and others. Increased efforts have been made for the development of metal-catalyzed cleavage; however, it is particularly of interest to obtain C–C bond cleavage by metal-free strategies.9 In this paper, an effective Brønsted acid promoted C–C bond cleavage method is developed for the synthesis of 2-amino-5-aroylmethylthiazole derivatives. 2-Aminothiazoles are commonly present in numerous medicinally and biologically relevant compounds,10 which have been extensively applied in the treatment of cancer, osteoporosis, allergies, hypertension and HIV infections. It is noteworthy that 2-amino-5-aroylmethylthiazoles have shown significant potential in kinase inhibition, immune-stimulant, as well as showing anti-inflammatory properties;11 however, limited methods are available for their synthesis. Therefore, it
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan Hubei 430079, China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures and compound characterisation data, including X-ray crystal structures of 3ah. CCDC 1013833. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01519c
9466 | Org. Biomol. Chem., 2014, 12, 9466–9470
is desirable to develop an efficient method for their synthesis from readily available starting materials. Inspired by previous excellent work for the cleavage of C–C bonds and the significance of developing novel synthetic methods for 2-aminothiazoles, a Brønsted acid promoted process was proposed for the construction of 2-amino-5-aroylmethylthiazoles from 1,4-enediones and thioureas via domino thio-Michaeladdition, intramolecular selective cyclization, and dehydration/ aromatization and C–C bond cleavage reactions (Scheme 1).
Scheme 1
Proposed reaction pathway.
To explore the feasibility of the proposed strategy, we commenced our study with 1,4-enedione 1a and thiourea 2a as model substrates to optimize the reaction conditions. When the reaction was conducted in EtOH at reflux, the desired product 3aa was obtained in 7% yield (Table 1, entry 1). Then, various Brønsted and Lewis acids were screened (entries 2–13), and concentrated hydrochloric acid was identified as the
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Table 1
Optimization of the reaction conditionsa
Entry
Additive (equivalence)
Solvent
Temp (°C)
Yieldb (%)
1c 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
— HCl (1.0) H2SO4 (1.0) CH3SO3H (1.0) CF3COOH (1.0) TsOH·H2O (1.0) AlCl3 (0.2) ZnCl2 (0.2) FeCl3 (0.2) Sc(OTf)3 (0.2) Zn(OTf)2 (0.2) Cu(OTf)2 (0.2) InCl3 (0.2) HCl (1.2) HCl (1.5) HCl (1.7) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5)
EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH DMSO DMF CH3CN CH2Cl2 EtOAc Acetone EtOH EtOH EtOH
Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux 80 80 Reflux Reflux Reflux Reflux 60 40 20
7 85 83 82 67 84 20 7 81 12 17 29 34 87 89 89 52 81 44 Trace 57 78 78 54 Trace
Table 2
Scope of the reactiona,b
a Unless noted otherwise, the reactions were performed with 1a (0.30 mmol), 2a (0.30 mmol) in 3.0 mL of solvent for 3 h. b Isolated yield. c Without additive.
optimal catalyst. Subsequently, screening demonstrated that an increase in the acid dosage to the equivalence of 1.5 provided us with the most satisfactory result (entries 14–16). Different solvents were also screened, but no better results were obtained (entries 17–22). When the reaction was conducted at lower temperature, only decreased yields were obtained (entries 24–25). On the basis of these results, the optimal conditions were determined as 1,4-enedione 1a (1.0 mmol), thiourea 2a (1.0 mmol) and concentrated hydrochloric acid (1.5 mmol) in EtOH at reflux for 3 h. Then, with the optimized conditions in hand, the scope of the substrates was explored. On the basis of our previous study, diversely substituted 1,4-enediones 1 were prepared via the cross-coupling reaction of 1,3-dicarbonyl compounds and arylmethylketones.12 As shown in Table 2, the scope of the reaction was first examined for R1 substituents. Pleasingly, the reaction efficiently proceeded to afford the desired products with electron-neutral groups (84–92%, 3aa–3ac) and electrondonating substituents (81–95%, 3ad–3ai). Various halogenated R1 substituents were found compatible with this reaction to afford the desired products (78–90%, 3aj–3ap). Moreover, substrates with sterically hindered R1 substituents and heteroaryl substituents provided the corresponding products in good yields under the optimal conditions (77–90%, 3aq–3at). Notably, the alkyl R1 substituent (Me) was also suitable for the
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a Unless noted otherwise, the reactions were performed with 1 (1.0 mmol), 2 (1.0 mmol) and conc. HCl (1.5 mmol) in 5 mL EtOH at reflux. b Isolated yield.
transformation and the desired product was obtained in a promising yield (93%, 3au). Encouraged by these results, the scope of R2 substituents were further explored. With the p-methoxylphenyl group as R2 the reaction proceeded smoothly and gave the desired product (82%, 3av). To our satisfaction, the desired product was also obtained in excellent yield when a phenyl group was used as R3 (93%, 3ba). Fortunately, the structure of 3ah was unambiguously confirmed by X-ray diffraction(see ESI†).13 Interestingly, the application of 1w as a substrate provided the product 3aa in 89% yield by the selective cleavage of the
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Table 3
Organic & Biomolecular Chemistry Control experimentsa,b
a The reaction was performed using 1 (1.0 mmol), 2a (1.0 mmol) and conc. HCl (1.5 mmol) in 5 mL EtOH at reflux. b Isolated yields. c The reaction was performed using 1a (1.0 mmol), 2a (1.0 mmol) and CH3SO3H (1.5 mmol) in 5 mL EtOH at reflux. EtOH was redistilled. d The reaction was performed using 1a (1.0 mmol), 2a (1.0 mmol) and CH3SO3H (1.5 mmol) in 5 mL EtOH at reflux. 5 equivalents of water were added before the start of the reaction. EtOH was redistilled.
acetyl group (Table 3a). However, the use of 1x under the standard conditions led to product 4aa in 52% yield, and the C–C bond cleavage product was not observed (Table 3b). This was attributed to the influence of the strong and stable intramolecular O–H⋯O hydrogen bond.14 Then, in order to explore the important role of water in this transformation, the following control experiments were conducted. Product 3aa could only be obtained in 33% yield with the catalysis of CH3SO3H in the absence of moisture (Table 3c). The addition of 5 equivalents of water led to a significant increase in the yield of 3aa (Table 3d). In accordance with the aforementioned results and previous studies,6b a possible reaction mechanism is proposed in Scheme 2 with the reaction of 1,4-enedione 1a and thiourea 2a as an example, as shown in Scheme 2. Initially, thiourea 2a reacted with 1a via a thiol–aza-Michael addition to afford intermediate B, which could then undergo selective intramolecular cyclization and dehydration to afford the intermediate C. Finally, a Brønsted acid catalyzed C–C bond cleavage reaction took place and released benzoic acid in the presence of H2O to afford the product 3aa. The domino reaction was applied for the synthesis of pharmaceutical and novel molecules to highlight its potential utility. In the initial application, the pharmaceutically important compound 5 was synthesized in only two steps (Scheme 3b), which can provide inhibitory qualities towards the PLTP and CETP of blood plasma.15 This route has shown significant advantages over previous methods (Scheme 3a). Furthermore, 2-amino-5-aroylmethylthiazoles were also utilized for the construction of novel biheterocycles (Scheme 4). The treatment of 3a with o-phenylenediamine or thiourea in methanol with CuO and I2 as catalysts can lead to biheterocycles 6 and 7 in nearly quantitative yields, respectively.
9468 | Org. Biomol. Chem., 2014, 12, 9466–9470
Scheme 2
Proposed mechanism.
Scheme 3 Application to the process for the synthesis of PLTP and CETP inhibitors.
In conclusion, a conc. HCl promoted domino synthesis of 2-amino-5-aroylmethylthiazoles has been developed directly from 1,4-enediones and thioureas. This domino process integrated the following distinct transformations: thio-Michaeladdition, intramolecular cyclization, dehydration/aromatization, and C–C bond cleavage reactions. Especially, the Brønsted acid promoted C–C bond cleavage reaction provided significant advantages because of its environmentally benign properties, easily available substrates, high reaction efficiency and metal-free reaction conditions. Notably, 2-amino-5-aroylmethylthiazole can also be used for the synthesis of important pharmaceutical molecules and novel biheterocycles.
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7
Scheme 4 Further derivation of 2-amino-5-aroylmethylthiazoles to novel biheterocycles.
We are grateful to the National Natural Science Foundation of China (grant 21032001 and 21272085). We also thank Dr Chuanqi Zhou for his help in performing HRMS analysis and Dr Xianggao Meng for performing X-ray diffraction analysis.
8
9
Notes and references 1 (a) C.-H. Jun, Chem. Soc. Rev., 2004, 33, 610–618; (b) M. Rubin, M. Rubina and V. Gevorgyan, Chem. Rev., 2007, 107, 3117–3179; (c) B. Rybtchinski and D. Milstein, Angew. Chem., Int. Ed., 1999, 38, 870–883; (d) A. Dermenci, J. W. Coe and G.-B. Dong, Org. Chem. Front., 2014, 1, 567– 581; (e) F. Chen, T. Wang and N. Jiao, Chem. Rev., 2014, 114, 8613–8661. 2 (a) A. M. Dreis and C. J. Douglas, J. Am. Chem. Soc., 2009, 131, 412–413; (b) A. J. Grenning and J. A. Tunge, J. Am. Chem. Soc., 2011, 133, 14785–14794; (c) H. Li, Y. Li, X.-S. Zhang, K. Chen, X. Wang and Z.-J. Shi, J. Am. Chem. Soc., 2011, 133, 15244–15247; (d) E. Doni, B. Mondal, S. O’Sullivan, T. Tuttle and J. A. Murphy, J. Am. Chem. Soc., 2013, 135, 10934–10937. 3 (a) C. He, S. Guo, L. Huang and A.-W. Lei, J. Am. Chem. Soc., 2010, 132, 8273–8275; (b) á. Gutiérrez-Bonet, A. FloresGaspar and R. Martin, J. Am. Chem. Soc., 2013, 135, 12576– 12579; (c) C. Zhang, P. Feng and N. Jiao, J. Am. Chem. Soc., 2013, 135, 15257–15262; (d) L.-Z. Gao, B. C. Kang and D. H. Ryu, J. Am. Chem. Soc., 2013, 135, 14556–14559; (e) N. Ishida, W. Ikemoto and M. Murakami, J. Am. Chem. Soc., 2014, 136, 5912–5915; (f) H.-R. Li, W.-J. Li, W.-P. Liu, Z.-H. He and Z.-P. Li, Angew. Chem., Int. Ed., 2011, 50, 2975–2978. 4 (a) J. W. Suggs and C.-H. Jun, J. Am. Chem. Soc., 1986, 108, 4679–4681; (b) C. M. Rathbun and J. B. Johnson, J. Am. Chem. Soc., 2011, 133, 2031–2033; (c) J.-J. Wang, W.-Q. Chen, S.-J. Zuo, L. Liu, X.-R. Zhang and J.-H. Wang, Angew. Chem., Int. Ed., 2012, 51, 12334–12338. 5 (a) M. Murakami, K. Takahashi, H. Amii and Y. Ito, J. Am. Chem. Soc., 1997, 119, 9307–9308; (b) T. Xu, H. M. Ko,
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N. A. Savage and G.-B. Dong, J. Am. Chem. Soc., 2012, 134, 20005–20008; (c) L.-T. Liu, N. Ishida and M. Murakami, Angew. Chem., Int. Ed., 2012, 51, 2485–2488; (d) P. Kumar and J. Louie, Org. Lett., 2012, 14, 2026–2029. (a) A. J. Grenning and J. A. Tunge, J. Am. Chem. Soc., 2011, 133, 14785–14794; (b) A. Kawata, K. Takata, Y. Kuninobu and K. Takai, Angew. Chem., Int. Ed., 2007, 46, 7793–7795; (c) K. M. Steward and J. S. Johnson, Org. Lett., 2011, 13, 2426–2429. (a) M. S. Mayo, X.-Q. Yu, X.-Y. Zhou, X.-J. Feng, Y. Yamamoto and M. Bao, Org. Lett., 2014, 16, 764–767; (b) Y.-L. Zhao, C.-H. Di, S.-D. Liu, J. Meng and Q. Liu, Adv. Synth. Catal., 2012, 354, 3545–3550; (c) M.-C. Jiang and C.-P. Chuang, J. Org. Chem., 2000, 65, 5409–5012; (d) Y. Chen, Y.-J. Wang, Z.-M. Sun and D.-W. Ma, Org. Lett., 2008, 10, 625–628. (a) Z.-Y. Ge, X.-D. Fei, T. Tang, Y.-M. Zhu and J.-K. Shen, J. Org. Chem., 2012, 77, 5736–5743; (b) A. Maji, S. Rana, Akanksha and D. Maiti, Angew. Chem., Int. Ed., 2014, 53, 2428–2432; (c) H. Yoshida, Y. Ito, Y. Yoshikawa, J. Ohshita and K. Takaki, Chem. Commun., 2011, 47, 8664–8666. (a) H. Liu, C. Dong, Z.-G. Zhang, P.-Y. Wu and X.-F. Jiang, Angew. Chem., Int. Ed., 2012, 51, 12570–12574; (b) Q.-H. Gao, Y.-P. Zhu, M. Lian, M.-C. Liu, J.-J. Yuan, G.-D. Yin and A.-X. Wu, J. Org. Chem., 2012, 77, 9865–9870; (c) N. Zhang and J. Vozzolo, J. Org. Chem., 2002, 67, 1703– 1704. For the selected methods for the synthesis of 2-aminothiazoles. (a) A. Hantzsch and J. H. Weber, Chem. Ber., 1887, 20, 3118–3132; (b) P. T. S. Lau and T. E. Gompf, J. Org. Chem., 1970, 35, 4103–4108; (c) S. Hibi, Y. Okamoto, K. Tagami, H. Numata, N. Kobayashi, M. Shinoda, T. Kawahara, M. Murakami, K. Oketani, T. Inoue, H. Shibata and I. Yamatsu, J. Med. Chem., 1994, 37, 3062–3070; (d) R. Joachim, Tetrahedron, 2000, 56, 3161–3165; (e) M. Ochiai, Y. Nishi, S. Hashimoto, Y. Tsuchimoto and D.-W. Chen, J. Org. Chem., 2003, 68, 7887–7888; (f) Y.-P. Zhu, J.-J. Yuan, Q. Zhao, M. Lian, Q.-H. Gao, M.-C. Liu, Y. Yang and A.-X. Wu, Tetrahedron, 2012, 68, 173–178. For the importance of 2-aminothiazoles, (g) L. A. Solt, N. Kumar, P. Nuhant, Y.-J. Wang, J. L. Lauer, J. Liu, M. A. Istrate, T. M. Kamenecka, W. R. Roush, D. Vidović, S. C. Schürer, J.-H. Xu, G. Wagoner, P. D. Drew, P. R. Griffin and T. P. Burris, Nature, 2011, 472, 491–494; (h) J. Das, P. Chen, D. Norris, R. Padmanabha, J. Lin, R. V. Moquin, Z.-Q. Shen, L. S. Cook, A. M. Doweyko, S. Pitt, S.-H. Pang, D.-R. Shen, Q. Fang, H. F. Fex, K. W. McIntyre, D. J. Shuster, K. M. Gillooly, K. Behnia, G. L. Schieven, J. Wityak and J. C. Barrish, J. Med. Chem., 2006, 49, 6819–6832; (i) Y. Katsura, T. Tomishi, Y. Inoue, K. Sakane, Y. Matsumoto, C. Morinaga, H. Ishikawa and H. Takasugi, J. Med. Chem., 2000, 43, 3315–3321. (a) F. Jung, G. Pasquet, C. L. Brempt, J.-J. Lohmann, N. Warin, F. Renaud, H. Germain, C. Savi, N. Roberts, T. Johnson, C. Dousson, G. Hill, A. Mortlock, N. Heron,
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13 CCDC 1013833 (3ah) contains the supplementary crystallographic data for this paper. 14 (a) V. Bertolasi, V. Ferretti, P. Gilli, X.-Q. Yao and C.-J. Li, New J. Chem., 2008, 32, 694–704; (b) J. Emsley, L. Ma, P. A. Bates, M. Motevalli and M. B. Hursthouse, J. Chem. Soc., Perkin Trans. 2, 1989, 527–533. 15 S. Li, C.-B. Guo, X.-C. Jiang, J.-H. Xiao and W. Zhong, WO 2008/006257 A1, 2008.
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R. Wilkinson, S. Wedge, S. Heaton, R. Odedra, N. Keen, S. Green, E. Brown, K. Thompson and S. Brightwell, J. Med. Chem., 2006, 49, 955–970; (b) S. H. Kowalczyk-Bronisz and J. G, Arch. Imuunol., Ther. Exp., 1978, 26, 921–929; (c) K. Hirai and H. Sugimoto, Chem. Pharm. Bull., 1977, 25, 2292–2299. 12 M. Gao, Y. Yang, Y.-D. Wu, C. Deng, L.-P. Cao, X.-G. Meng and A.-X. Wu, Org. Lett., 2010, 12, 1856–1859.
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9470 | Org. Biomol. Chem., 2014, 12, 9466–9470
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Brønsted acid promoted addition–cyclization and C–C bond cleavage: a convenient synthesis of 2-amino-5-aroylmethylthiazoles derivatives† Fan Ni, Yan Yang, Wen-Ming Shu, Jun-Rui Ma and An-Xin Wu* A Brønsted acid promoted C–C bond cleavage method for the synthesis of novel 2-amino-5-aroylmethylthiazole derivatives has been directly developed from 1,4-enediones and thioureas through self-
Received 19th July 2014, Accepted 1st October 2014
sequenced thio-Michael-addition, intramolecular selective cyclization, dehydration/aromatization, and C–C bond cleavage reactions. It is noteworthy that this reaction has significant advantages in simple
DOI: 10.1039/c4ob01519c
reagents, under environmentally benign conditions and with excellent yields. This highly efficient method
www.rsc.org/obc
is also a highly attractive alternative for the preparation of PLTP, CETP inhibitors and novel biheterocycles.
C–C bond cleavage(activation) has formed a novel chapter in organic synthesis, and provided a great opportunity for synthetic chemists to design highly efficient transformations from inert starting materials.1 To control this great challenge for C–C bond cleavage, efficient strategies were proposed in the past decade.2 In recent years, the carbonyl group has been considered an ideal group for assisting the cleavage of C–C bonds3 through a chelation effect,4 ring strain release,5 “retro” processes,6 aromatization,7 rearrangement8 and others. Increased efforts have been made for the development of metal-catalyzed cleavage; however, it is particularly of interest to obtain C–C bond cleavage by metal-free strategies.9 In this paper, an effective Brønsted acid promoted C–C bond cleavage method is developed for the synthesis of 2-amino-5-aroylmethylthiazole derivatives. 2-Aminothiazoles are commonly present in numerous medicinally and biologically relevant compounds,10 which have been extensively applied in the treatment of cancer, osteoporosis, allergies, hypertension and HIV infections. It is noteworthy that 2-amino-5-aroylmethylthiazoles have shown significant potential in kinase inhibition, immune-stimulant, as well as showing anti-inflammatory properties;11 however, limited methods are available for their synthesis. Therefore, it
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan Hubei 430079, China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures and compound characterisation data, including X-ray crystal structures of 3ah. CCDC 1013833. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01519c
9466 | Org. Biomol. Chem., 2014, 12, 9466–9470
is desirable to develop an efficient method for their synthesis from readily available starting materials. Inspired by previous excellent work for the cleavage of C–C bonds and the significance of developing novel synthetic methods for 2-aminothiazoles, a Brønsted acid promoted process was proposed for the construction of 2-amino-5-aroylmethylthiazoles from 1,4-enediones and thioureas via domino thio-Michaeladdition, intramolecular selective cyclization, and dehydration/ aromatization and C–C bond cleavage reactions (Scheme 1).
Scheme 1
Proposed reaction pathway.
To explore the feasibility of the proposed strategy, we commenced our study with 1,4-enedione 1a and thiourea 2a as model substrates to optimize the reaction conditions. When the reaction was conducted in EtOH at reflux, the desired product 3aa was obtained in 7% yield (Table 1, entry 1). Then, various Brønsted and Lewis acids were screened (entries 2–13), and concentrated hydrochloric acid was identified as the
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Table 1
Optimization of the reaction conditionsa
Entry
Additive (equivalence)
Solvent
Temp (°C)
Yieldb (%)
1c 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
— HCl (1.0) H2SO4 (1.0) CH3SO3H (1.0) CF3COOH (1.0) TsOH·H2O (1.0) AlCl3 (0.2) ZnCl2 (0.2) FeCl3 (0.2) Sc(OTf)3 (0.2) Zn(OTf)2 (0.2) Cu(OTf)2 (0.2) InCl3 (0.2) HCl (1.2) HCl (1.5) HCl (1.7) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5) HCl (1.5)
EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH DMSO DMF CH3CN CH2Cl2 EtOAc Acetone EtOH EtOH EtOH
Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux 80 80 Reflux Reflux Reflux Reflux 60 40 20
7 85 83 82 67 84 20 7 81 12 17 29 34 87 89 89 52 81 44 Trace 57 78 78 54 Trace
Table 2
Scope of the reactiona,b
a Unless noted otherwise, the reactions were performed with 1a (0.30 mmol), 2a (0.30 mmol) in 3.0 mL of solvent for 3 h. b Isolated yield. c Without additive.
optimal catalyst. Subsequently, screening demonstrated that an increase in the acid dosage to the equivalence of 1.5 provided us with the most satisfactory result (entries 14–16). Different solvents were also screened, but no better results were obtained (entries 17–22). When the reaction was conducted at lower temperature, only decreased yields were obtained (entries 24–25). On the basis of these results, the optimal conditions were determined as 1,4-enedione 1a (1.0 mmol), thiourea 2a (1.0 mmol) and concentrated hydrochloric acid (1.5 mmol) in EtOH at reflux for 3 h. Then, with the optimized conditions in hand, the scope of the substrates was explored. On the basis of our previous study, diversely substituted 1,4-enediones 1 were prepared via the cross-coupling reaction of 1,3-dicarbonyl compounds and arylmethylketones.12 As shown in Table 2, the scope of the reaction was first examined for R1 substituents. Pleasingly, the reaction efficiently proceeded to afford the desired products with electron-neutral groups (84–92%, 3aa–3ac) and electrondonating substituents (81–95%, 3ad–3ai). Various halogenated R1 substituents were found compatible with this reaction to afford the desired products (78–90%, 3aj–3ap). Moreover, substrates with sterically hindered R1 substituents and heteroaryl substituents provided the corresponding products in good yields under the optimal conditions (77–90%, 3aq–3at). Notably, the alkyl R1 substituent (Me) was also suitable for the
This journal is © The Royal Society of Chemistry 2014
a Unless noted otherwise, the reactions were performed with 1 (1.0 mmol), 2 (1.0 mmol) and conc. HCl (1.5 mmol) in 5 mL EtOH at reflux. b Isolated yield.
transformation and the desired product was obtained in a promising yield (93%, 3au). Encouraged by these results, the scope of R2 substituents were further explored. With the p-methoxylphenyl group as R2 the reaction proceeded smoothly and gave the desired product (82%, 3av). To our satisfaction, the desired product was also obtained in excellent yield when a phenyl group was used as R3 (93%, 3ba). Fortunately, the structure of 3ah was unambiguously confirmed by X-ray diffraction(see ESI†).13 Interestingly, the application of 1w as a substrate provided the product 3aa in 89% yield by the selective cleavage of the
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Table 3
Organic & Biomolecular Chemistry Control experimentsa,b
a The reaction was performed using 1 (1.0 mmol), 2a (1.0 mmol) and conc. HCl (1.5 mmol) in 5 mL EtOH at reflux. b Isolated yields. c The reaction was performed using 1a (1.0 mmol), 2a (1.0 mmol) and CH3SO3H (1.5 mmol) in 5 mL EtOH at reflux. EtOH was redistilled. d The reaction was performed using 1a (1.0 mmol), 2a (1.0 mmol) and CH3SO3H (1.5 mmol) in 5 mL EtOH at reflux. 5 equivalents of water were added before the start of the reaction. EtOH was redistilled.
acetyl group (Table 3a). However, the use of 1x under the standard conditions led to product 4aa in 52% yield, and the C–C bond cleavage product was not observed (Table 3b). This was attributed to the influence of the strong and stable intramolecular O–H⋯O hydrogen bond.14 Then, in order to explore the important role of water in this transformation, the following control experiments were conducted. Product 3aa could only be obtained in 33% yield with the catalysis of CH3SO3H in the absence of moisture (Table 3c). The addition of 5 equivalents of water led to a significant increase in the yield of 3aa (Table 3d). In accordance with the aforementioned results and previous studies,6b a possible reaction mechanism is proposed in Scheme 2 with the reaction of 1,4-enedione 1a and thiourea 2a as an example, as shown in Scheme 2. Initially, thiourea 2a reacted with 1a via a thiol–aza-Michael addition to afford intermediate B, which could then undergo selective intramolecular cyclization and dehydration to afford the intermediate C. Finally, a Brønsted acid catalyzed C–C bond cleavage reaction took place and released benzoic acid in the presence of H2O to afford the product 3aa. The domino reaction was applied for the synthesis of pharmaceutical and novel molecules to highlight its potential utility. In the initial application, the pharmaceutically important compound 5 was synthesized in only two steps (Scheme 3b), which can provide inhibitory qualities towards the PLTP and CETP of blood plasma.15 This route has shown significant advantages over previous methods (Scheme 3a). Furthermore, 2-amino-5-aroylmethylthiazoles were also utilized for the construction of novel biheterocycles (Scheme 4). The treatment of 3a with o-phenylenediamine or thiourea in methanol with CuO and I2 as catalysts can lead to biheterocycles 6 and 7 in nearly quantitative yields, respectively.
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Scheme 2
Proposed mechanism.
Scheme 3 Application to the process for the synthesis of PLTP and CETP inhibitors.
In conclusion, a conc. HCl promoted domino synthesis of 2-amino-5-aroylmethylthiazoles has been developed directly from 1,4-enediones and thioureas. This domino process integrated the following distinct transformations: thio-Michaeladdition, intramolecular cyclization, dehydration/aromatization, and C–C bond cleavage reactions. Especially, the Brønsted acid promoted C–C bond cleavage reaction provided significant advantages because of its environmentally benign properties, easily available substrates, high reaction efficiency and metal-free reaction conditions. Notably, 2-amino-5-aroylmethylthiazole can also be used for the synthesis of important pharmaceutical molecules and novel biheterocycles.
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Scheme 4 Further derivation of 2-amino-5-aroylmethylthiazoles to novel biheterocycles.
We are grateful to the National Natural Science Foundation of China (grant 21032001 and 21272085). We also thank Dr Chuanqi Zhou for his help in performing HRMS analysis and Dr Xianggao Meng for performing X-ray diffraction analysis.
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