- Email: [email protected]
dehydration sequences
Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Iodine-promoted efficient synthesis of diheteroaryl thioethers via the integration of iodination/condensation/cyclization/dehydration sequences Wei-jian Xue, Hong-zheng Li, Kai-lu Zheng, An-xin Wu ⇑ Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 1 July 2014 Revised 26 July 2014 Accepted 9 August 2014 Available online xxxx
A novel method for the construction of diheteroaryl thioethers from aromatic methyl ketones and thiourea is described. Iodine is the unique catalyst in this protocol. The transformation is free of foul-smell thiols and transition metal. In addition, this method could synthesize two thiazole rings and a sulfur bridge in one pot. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: I2-promoted Diheteroaryl thioethers Free of foul-smell thiols Free of transition metal Thiourea
Introduction Diaryl thioethers are an important class of structural motifs present in many biologically natural products and medicinal agents (Scheme 1).1 They have also been applied in materials2 and organic reactions3 as important intermediates. Due to their potential for the treatment of many malignant diseases,4 numerous methods have been developed for the synthesis of diaryl thioethers (Scheme 2). The reaction between aryl halides or some other com-
O
S
Me COOH O
N OH HIV-1 integrase inhibitor
N
S HO
5-lipoxygenase inhibitor NH
S
S
S
N
N N N
O S
N Me
N Ph
protein tyrosine phosphatase inhibitor
pounds with thiols is a kind of widely used methods for the synthesis of diaryl thioethers.5 In addition, direct conversion of C–H bond into C–S bond is also a dramatic method, which draws lots of attention from chemists.6 Recently, Deng and Wei reported an efficient approach for the formation of diaryl thioethers from cyclohexanones under metal-free conditions7 Although many methods have been reported for the construction of diaryl thioethers, development of general methods from odorless and readily available starting materials is necessary. Based on this idea, thiourea has been used as sulfur source for the formation of thioethers in place of thiols.8 Herein, we reported a novel method for the construction of diheteroaryl thioethers, which could avoid the use of foul-smell thiols and synthesize two thiazole rings and a sulfur bridge in one pot via the integration of iodination/condensation/cyclization/dehydration sequences.
N
OMe N nicotinic acetylcholine receptor ligane
Scheme 1. Representative examples of diaryl thioethers.
⇑ Corresponding author. Tel./fax: +86 027 6786 7773. E-mail address: [email protected] (A.-x. Wu).
Results and discussion The reaction of acetophenone (1a) with thiourea (2) was selected as a model reaction for the optimization of the reaction conditions. Solvent screening reactions revealed that DMSO was the best solvent for the process in terms of the product yield. Several other solvents were also screened, but found to be unsuitable for the reaction (Table 1, entries 1–9). The reaction was also screened over different temperatures, and 40 °C was determined to be optimum (Table 1, entries 10–14). Various additives were
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Please cite this article in press as: Xue, W.-j.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.08.042
2
W.-j. Xue et al. / Tetrahedron Letters xxx (2014) xxx–xxx Previous works SH
X R1
S
TM, ligand
R1
R2 S Z
H R1
S
TM
R2
R2
R1
R2 OH
SH
O R1
R2 S
Y R1
W
H 2N
S
I 2 , Oxidant
R1
R1
R1
W
R1
S H 2N
S
Y
Strong base NH 2
This work O
R2
Metal-free
R1
R1
S
I2, DMSO NH 2
Y W
N
N S
S
H 2N
NH2
Scheme 2. Strategies for the synthesis of diaryl thioethers.
also screened in the reaction, but did not lead to a discernible increase in the product yield (Table 1, entries 15–24). The dose of iodine was also investigated, as well as the molar ratio of acetophenone (1a) to thiourea (2) (Table 1, entries 25–31). Based on the results of these screening experiments, the optimal reaction conditions were identified as 1 equiv of acetophenone (1a), 1.5 equiv of
thiourea, (2) and 1 equiv of iodine in DMSO at 40 °C (Table 1, entry 29). With the optimized conditions in hand, we proceeded to investigate the scope and generality of this procedure using a range of other aryl methyl ketones. As shown in Table 2, the reaction was successfully applied to a range of substituted aromatic ketones, with the corresponding products being formed in generally good yields (Table 2, 3a–s). Aromatic ketones bearing electron-donating groups (e.g., 4-Me, 4-OMe, 3-OMe, 4-OEt, and 2,3,4-OMe3) reacted smoothly under the optimized conditions to give the corresponding products 3b and 3g–j in good yields (78–86%, Table 2). Slightly lower yields were obtained when the optimized conditions were applied to aromatic ketones bearing electron-withdrawing halogen groups (e.g., 4-F, 4-Cl, 4-Br, and 3,4-Cl2), with the corresponding products 3c–f being obtained in moderate to good yields (70– 75%, Table 2). 4-Nitroacetophenone did not react under the optimized conditions (Table 2, 3n), which indicated that the presence of strongly electron-withdrawing groups at the para position of the aromatic ketone had an adverse impact on the reaction. The optimized conditions were tolerant of hydroxy substituents on the aromatic ketone, with the expected phenolic product 3m being obtained in 64% yield. Furthermore, the 1-naphthyl-, 2-naphthyl-, and 2-fluorine-methyl ketones (1q–s) also reacted smoothly under the optimized conditions to give the corresponding aminothiazole products (3q–s). The structure of compound 3a was confirmed by X-ray single diffraction analysis (see ESI).9 To determine the reaction mechanism, we prepared several possible intermediates and investigated their use as starting mate-
Table 1 Optimization of the reaction conditionsa Ph S
O Ph 1a
H2 N
2
Conditions
Ph S N
N S
S
NH2 H2 N
3a
NH2
Entry
I2 (equiv)
1a:2
Additive (0.25 equiv)
Solvent
Temp (°C)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1.5 1:2 1:3
TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH AlCl3 HOAc HCl CuI Na2CO3 K2CO3 Cs2CO3 DBU DABCO
MeCN THF DMF Toluene MeOH EtOH i-PrOH t-BuOH H2O DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO
40 40 40 40 40 40 40 40 40 20 40 60 80 100 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40
<5 <5 <5 <5 <5 <5 <5 <5 <5 12 40 32 25 13 38 36 15 5 29 27 17 38 35 65 0 36 50 23 80 45 40
0.3 0.5 2.0 1.0 1.0 1.0
Bold value represent the best condition of the reaction. a Reaction conditions: 1a (0.5 mmol), 2, I2 and the additive in 3 ml of solvent for 12 h. b Isolated yield.
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3
W.-j. Xue et al. / Tetrahedron Letters xxx (2014) xxx–xxx Table 2 Reaction scope of methyl ketonesa
O
R S
O R
H2 N
1
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
S
H 2N
3
H2 N
R
HN
NH2
2
NH 2
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s
80 82 72 74 75 70 85 78 86 81 76 74 64 0 75 70 80 71 63
2a
Ph
S
-H2 O
Ph
N S
Ph I
Ph
NH 2
H 2N
Ph
1aa
NH2
2
5a
3a
NH2
Scheme 4. Plausible mechanism of the present reaction.
O
O
MeO
1a
MeO
S
N NH2
NH 2
H 2N
S 4a
I2, DMSO
N
I 2, DMSO
NH2
S
S NH2
3a, 70%
Ph
Ph S
N S
NH2 3a, 0%
N
Ph
N
I
S
I 2, EtOH
NH2
NH2
NH2
o
S 4a
78 C
Ph
Ph
H2 N 1a
2
80 oC
S
S
NH2
3a, 60% Ph
N
S
S
NH2
I2 , CuO, EtOH NH2
E
N
N NH2
S
Ph S
40 o C
2
O
O
F
6a, 65% Ph
Ph
N
S
S H2 N 6a
Ph
S
NH2
Ph
NH 2
H 2N
S 5a
I
O
I 2, DMSO
N NH2
D
5a, 80% S
Ph
C
N S
40 o C
S 4a
B
N
NH2
N
Ph S
I 2, DMSO NH2
2
40 o C
NH 2 3ag, 40%
N
N
S
S NH 2
S
NH 2
NH2 3g, 10%
Ph
Ph Ph
S N
N S
NH2 3a, 20%
S
40 o C
2
OMe
S N S
NH2 NH2
Ph Ph
A
S
40 o C
NH2 2
1g
S S
I2 , DMSO
S H2 N
N
3a, 60%
NH2
N
S
S
H2 N
N S
S C
B
N
Ph
40 o C
HS
S
S N
N
- Urea
MeO
I 2, DMSO
Ph + H 2O NH2
NH2
S 4a
Ph
Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), I2 (1 mmol) in 3 ml of DMSO at 40 °C for 12 h. b Isolated yield.
S
N
I2
NH2
5a
N
S
H2 N
a
O
A
NH2
I
HN
NH 2 S
Ph
Ph
Yieldb (%)
3
Ph (1a) 4-MeC6H4 (1b) 4-FC6H4 (1c) 4-ClC6H4 (1d) 4-BrC6H4 (1e) 3,4-Cl2C6H3 (1f) 4-MeOC6H4 (1g) 3-MeOC6H4 (1h) 4-EtOC6H4 (1i) 3,4,5-(MeO)3C6H2 (1j) 3,4-OCH2OC6H3 (1k) 3,4-OCH2CH2OC6H3 (1l) 4-HOC6H4 (1m) 4-NO2C6H4 (1n) 4-PhC6H4 (1o) 2-Benzofuryl (1p) 2-Naphthyl (1q) 1-Naphthyl (1r) 2-Fluorene (1s)
SH
N S
40 oC
NH2
1aa
S
N
HN O
I
Ph
1a
R S
I2, DMSO
2
O
I2
Ph
N
N S
G
S
NH2 3a, 0%
NH2
Scheme 3. Controlled experiments to prove the mechanism.
rials in various reactions (Scheme 3). This strategy revealed that the product resulting from the iodination of acetophenone 1aa could react with thiourea (2) to give 3a in good yield when the
Scheme 5. Cross reaction between two representative substrates.
reaction was conducted in the presence of I2 in DMSO (Scheme 3A). The target molecule 3a could also be obtained from the reaction between 4a and thiourea (2) (Scheme 3B). It was not possible, however, to form 3a in the absence of thiourea (2) (Scheme 3C), which indicated that the sulfur atoms in 3 originated from thiourea (2). Further experimentation also revealed that 5a could be obtained from 4a in EtOH, and that 3a could be obtained from 5a following the addition of thiourea (2) (Scheme 3D and E). Furthermore, 5-substituted aminothiazole could be obtained from the reaction of acetophenone (1a, 2 equiv) with thiourea (2, 1 equiv) in the presence of iodine and CuO in EtOH (Scheme 3F). However, it was found that the target molecule 3a could not be obtained from 5-substituted aminothiazole (Scheme 3G). GC-MS was used to provide further evidence in support of the proposed reaction mechanism, with intermediate 4a being successfully detected in the reaction mixture (see ESI). Based on the results of our mechanistic studies, we have suggested a plausible mechanism for the current reaction using acetophenone (1a) as an example (Scheme 4). Briefly, acetophenone 1a would be converted to 1aa in the presence of I2.10 Subsequent reaction of 1aa with thiourea (2) would afford intermediate A, which would undergo an intramolecular nucleophilic addition/dehydration reaction to generate 4a. Intermediate 4a would then be converted to 5a in the presence of I2. Compound 5a would then undergo a condensation reaction with thiourea (2) to give intermediate B, which would undergo a hydrolysis reaction to form intermediate C.11 Finally, intermediate C would condense with intermediate 5a to furnish the desired product 3a. The proposed mechanism was further verified by examining the outcome of a mixed reaction between 0.5 equiv of acetophenone
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W.-j. Xue et al. / Tetrahedron Letters xxx (2014) xxx–xxx
(1a) and 0.5 equiv of 4-methyl acetophenone (1g) under the standard conditions (Scheme 5). In accordance with our proposed reaction mechanism, this reaction led to the formation of three independent molecules 3a, 3ag, and 3g. Conclusion In summary, we have developed a concise and efficient one-pot domino reaction for the synthesis of diheteroaryl thioethers from readily available aromatic methyl ketones and thiourea. The main advantage of this reaction is that it does not require the addition of foul-smell thiols and transition metals. In addition, this method could synthesize two thiazole rings and a sulfur bridge in one pot. Further studies toward the applications of this reaction will be reported in due course. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant Nos. 21032001 and 21272085). We also acknowledge the excellent doctorial dissertation cultivation Grant from Central China Normal University (2013YBYB53). Supplementary data Supplementary data (evidence in support of the hypothetic mechanism, and 1H and 13C NMR spectra and X-ray crystal data for 3a) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.042. References and notes 1. (a) Nakazawa, T.; Xu, J.; Nishikawa, T.; Oda, T.; Fujita, A.; Ukai, K.; Mangindaan, R. E. P.; Rotinsulu, H.; Kobayashi, H.; Namikoshi, M. J. Nat. Prod. 2007, 70, 439– 442; (b) Pasquini, S.; Mugnaini, C.; Tintori, C.; Botta, M.; Trejos, A.; Arvela, R. K.; Larhed, M.; Witvrouw, M.; Michiels, M.; Christ, F.; Debyser, Z.; Corelli, F. J. Med. Chem. 2008, 51, 5125–5129; (c) Alcaraz, M. L.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill, D. M.; Humphries, L. A.; Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon, R. A.; Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowan, P.; Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.; Woodland, I. A. Org. Process Res. Dev. 2005, 9, 555–569; (d) Nielsen, S. F.; Nielsen, E. O.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med. Chem. 2000, 43, 2217–2226; (e) Huang, Y.; Bae, S. A.; Zhu, Z.; Guo, N.; Roth, B. L.; Laruelle, M. J. Med. Chem. 2005, 48, 2559–2570. 2. (a) Okamoto, T.; Mitsui, C.; Yamagishi, M.; Nakahara, K.; Soeda, J.; Hirose, Y.; Miwa, K.; Sato, H.; Yamano, A.; Matsushita, T.; Uemura, T.; Takeya, J. Adv. Mater. 2013, 25, 6392–6397; (b) Takimiya, K.; Shinamura, S.; Osaka, I.; Miyazaki, E. Adv. Mater. 2011, 23, 4347–4370; (c) Anthony, J. E. Chem. Rev. 2006, 106, 5028– 5048; (d) Mori, T.; Nishimura, T.; Yamamoto, T.; Doi, I.; Miyazaki, E.; Osaka, I.; Takimiya, K. J. Am. Chem. Soc. 2013, 135, 13900–13913.
3. (a) Tsuchida, E.; Miyatake, K.; Yamamoto, K. Macromolecules 1998, 31, 6469– 6475; (b) Fujii, T.; Hao, W.; Yoshimura, T. Heteroat. Chem. 2004, 15, 246–250; (c) Stoll, A. H.; Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 606– 609. 4. (a) De Martino, G.; La Regina, G.; Coluccia, A.; Edler, M. C.; Barbera, M. C.; Brancale, A.; Wilcox, E.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2004, 47, 6120–6123; (b) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.; von Geldern, T. W.; Ormes, M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025–4040; (c) Beard, R. L.; Colon, D. F.; Song, T. K.; Davies, P. J. A.; Kochhar, D. M.; Chandraratna, R. A. S. J. Med. Chem. 1996, 39, 3556–3563. 5. For selected examples, see: (a) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205–3220; (b) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583–5586; (c) Larsson, P.; Correa, A.; Carril, M.; Norrby, P.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5691–5693; (d) Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. J. Am. Chem. Soc. 2013, 135, 9548–9552; (e) Zhao, P.; Yin, H.; Gao, H.; Xi, C. J. Org. Chem. 2013, 78, 5001–5006; (f) Wagner, A. M.; Sanford, M. S. J. Org. Chem. 2014, 79, 2263–2267; (g) Yonova, I. M.; Osborne, C. A.; Morrissette, N. S.; Jarvo, E. R. J. Org. Chem. 2014, 79, 1947–1953; (h) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697–1700; (i) Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett. 2009, 11, 5250–5253; (j) Silveira, C. C.; Mendes, S. R.; Soares, J. R.; Victoria, F. N.; Martinez, D. M.; Savegnago, L. Tetrahedron Lett. 2013, 54, 4926–4929. 6. For selected examples, see: (a) Chu, L.; Yue, X.; Qing, F. Org. Lett. 2010, 12, 1644–1647; (b) Cheng, J.; Yi, C.; Liu, T.; Lee, C. Chem. Commun. 2012, 8440– 8442; (c) Saravanan, P.; Anbarasan, P. Org. Lett. 2014, 16, 848–851; (d) Anbarasan, P.; Neumann, H.; Beller, M. Chem. Commun. 2011, 3233–3235; (e) Zou, L.; Reball, J.; Mottweiler, J.; Bolm, C. Chem. Commun. 2012, 11307–11309; (f) Dai, C.; Xu, Z.; Huang, F.; Yu, Z.; Gao, Y. J. Org. Chem. 2012, 77, 4414–4419; (g) Prasad, C. D.; Balkrishna, S. J.; Kumar, A.; Bhakuni, B. S.; Shrimali, K.; Biswas, S.; Kumar, S. J. Org. Chem. 2013, 78, 1434–1443; (h) Zhang, S.; Qian, P.; Zhang, M.; Hu, M.; Cheng, J. J. Org. Chem. 2010, 75, 6732–6735; (i) Ranjit, S.; Lee, R.; Heryadi, D.; Shen, C.; Wu, J.; Zhang, P.; Huang, K.; Liu, X. J. Org. Chem. 2011, 76, 8999–9007; (j) Ge, W.; Zhu, X.; Wei, Y. Eur. J. Org. Chem. 2013, 6015–6020. 7. (a) Liao, Y.; Jiang, P.; Chen, S.; Qi, H.; Deng, G. Green Chem. 2013, 15, 3302–3306; (b) Ge, W.; Zhu, X.; Wei, Y. Adv. Synth. Catal. 2013, 355, 3014–3021. 8. For selected examples, see: (a) Firouzabadi, H.; Iranpoor, N.; Abbasi, M. Adv. Synth. Catal. 2009, 351, 755–766; (b) Wang, L.; Zhou, W.; Chen, S.; He, M.; Chen, Q. Adv. Synth. Catal. 2012, 354, 839–845; (c) Firouzabadi, H.; Iranpoor, N.; Gholinejad, M. Adv. Synth. Catal. 2010, 352, 119–124; (d) Lu, G.; Cai, C. Adv. Synth. Catal. 2013, 355, 1271–1276; (e) Feng, J.; Lu, G.; Lv, M.; Cai, C. Asian J. Org. Chem. 2014, 3, 77–81; (f) Firouzabadi, H.; Iranpoor, N.; Abbasi, M. Tetrahedron 2009, 65, 5293–5301; (g) Azizi, N.; Yadollahy, Z.; Rahimzadeh-Oskooee, A. Tetrahedron Lett. 2014, 55, 1722–1725; (h) Woodbridge, R. G.; Dougherty, G. J. Am. Chem. Soc. 1949, 71, 1744–1745; (i) Kuhn, M.; Falk, F. C.; Paradies, J. Org. Lett. 2011, 13, 4100–4103; (j) Javadi, A.; Shockravi, A.; Kamali, M.; Rafieimanesh, A.; Malek, A. M. J. Polym. Sci. A: Polym. Chem. 2013, 51, 3505– 3515. 9. The details of the crystal data have been deposited with Cambridge Crystallographic Data Centre as Supplementary Publication, CCDC 974894. 10. (a) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Org. Lett. 2006, 8, 2245–2248; (b) Gao, M.; Yang, Y.; Wu, Y.; Deng, C.; Cao, L.; Meng, X.; Wu, A. Org. Lett. 2010, 12, 1856–1859; (c) Zhu, Y.; Gao, Q.; Lian, M.; Yuan, J.; Liu, M.; Zhao, Q.; Yang, Y.; Wu, A. Chem. Commun. 2011, 12700–12702. 11. Bierer, D. E.; Dener, J. M.; Dubenko, L. G.; Gerber, R. E.; Litvak, J.; Peterli, S.; Peterli-Roth, P.; Truong, T. V.; Mao, G.; Bauer, B. E. J. Med. Chem. 1995, 38, 2628–2648.
Please cite this article in press as: Xue, W.-j.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.08.042
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Iodine-promoted efficient synthesis of diheteroaryl thioethers via the integration of iodination/condensation/cyclization/dehydration sequences Wei-jian Xue, Hong-zheng Li, Kai-lu Zheng, An-xin Wu ⇑ Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 1 July 2014 Revised 26 July 2014 Accepted 9 August 2014 Available online xxxx
A novel method for the construction of diheteroaryl thioethers from aromatic methyl ketones and thiourea is described. Iodine is the unique catalyst in this protocol. The transformation is free of foul-smell thiols and transition metal. In addition, this method could synthesize two thiazole rings and a sulfur bridge in one pot. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: I2-promoted Diheteroaryl thioethers Free of foul-smell thiols Free of transition metal Thiourea
Introduction Diaryl thioethers are an important class of structural motifs present in many biologically natural products and medicinal agents (Scheme 1).1 They have also been applied in materials2 and organic reactions3 as important intermediates. Due to their potential for the treatment of many malignant diseases,4 numerous methods have been developed for the synthesis of diaryl thioethers (Scheme 2). The reaction between aryl halides or some other com-
O
S
Me COOH O
N OH HIV-1 integrase inhibitor
N
S HO
5-lipoxygenase inhibitor NH
S
S
S
N
N N N
O S
N Me
N Ph
protein tyrosine phosphatase inhibitor
pounds with thiols is a kind of widely used methods for the synthesis of diaryl thioethers.5 In addition, direct conversion of C–H bond into C–S bond is also a dramatic method, which draws lots of attention from chemists.6 Recently, Deng and Wei reported an efficient approach for the formation of diaryl thioethers from cyclohexanones under metal-free conditions7 Although many methods have been reported for the construction of diaryl thioethers, development of general methods from odorless and readily available starting materials is necessary. Based on this idea, thiourea has been used as sulfur source for the formation of thioethers in place of thiols.8 Herein, we reported a novel method for the construction of diheteroaryl thioethers, which could avoid the use of foul-smell thiols and synthesize two thiazole rings and a sulfur bridge in one pot via the integration of iodination/condensation/cyclization/dehydration sequences.
N
OMe N nicotinic acetylcholine receptor ligane
Scheme 1. Representative examples of diaryl thioethers.
⇑ Corresponding author. Tel./fax: +86 027 6786 7773. E-mail address: [email protected] (A.-x. Wu).
Results and discussion The reaction of acetophenone (1a) with thiourea (2) was selected as a model reaction for the optimization of the reaction conditions. Solvent screening reactions revealed that DMSO was the best solvent for the process in terms of the product yield. Several other solvents were also screened, but found to be unsuitable for the reaction (Table 1, entries 1–9). The reaction was also screened over different temperatures, and 40 °C was determined to be optimum (Table 1, entries 10–14). Various additives were
http://dx.doi.org/10.1016/j.tetlet.2014.08.042 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Xue, W.-j.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.08.042
2
W.-j. Xue et al. / Tetrahedron Letters xxx (2014) xxx–xxx Previous works SH
X R1
S
TM, ligand
R1
R2 S Z
H R1
S
TM
R2
R2
R1
R2 OH
SH
O R1
R2 S
Y R1
W
H 2N
S
I 2 , Oxidant
R1
R1
R1
W
R1
S H 2N
S
Y
Strong base NH 2
This work O
R2
Metal-free
R1
R1
S
I2, DMSO NH 2
Y W
N
N S
S
H 2N
NH2
Scheme 2. Strategies for the synthesis of diaryl thioethers.
also screened in the reaction, but did not lead to a discernible increase in the product yield (Table 1, entries 15–24). The dose of iodine was also investigated, as well as the molar ratio of acetophenone (1a) to thiourea (2) (Table 1, entries 25–31). Based on the results of these screening experiments, the optimal reaction conditions were identified as 1 equiv of acetophenone (1a), 1.5 equiv of
thiourea, (2) and 1 equiv of iodine in DMSO at 40 °C (Table 1, entry 29). With the optimized conditions in hand, we proceeded to investigate the scope and generality of this procedure using a range of other aryl methyl ketones. As shown in Table 2, the reaction was successfully applied to a range of substituted aromatic ketones, with the corresponding products being formed in generally good yields (Table 2, 3a–s). Aromatic ketones bearing electron-donating groups (e.g., 4-Me, 4-OMe, 3-OMe, 4-OEt, and 2,3,4-OMe3) reacted smoothly under the optimized conditions to give the corresponding products 3b and 3g–j in good yields (78–86%, Table 2). Slightly lower yields were obtained when the optimized conditions were applied to aromatic ketones bearing electron-withdrawing halogen groups (e.g., 4-F, 4-Cl, 4-Br, and 3,4-Cl2), with the corresponding products 3c–f being obtained in moderate to good yields (70– 75%, Table 2). 4-Nitroacetophenone did not react under the optimized conditions (Table 2, 3n), which indicated that the presence of strongly electron-withdrawing groups at the para position of the aromatic ketone had an adverse impact on the reaction. The optimized conditions were tolerant of hydroxy substituents on the aromatic ketone, with the expected phenolic product 3m being obtained in 64% yield. Furthermore, the 1-naphthyl-, 2-naphthyl-, and 2-fluorine-methyl ketones (1q–s) also reacted smoothly under the optimized conditions to give the corresponding aminothiazole products (3q–s). The structure of compound 3a was confirmed by X-ray single diffraction analysis (see ESI).9 To determine the reaction mechanism, we prepared several possible intermediates and investigated their use as starting mate-
Table 1 Optimization of the reaction conditionsa Ph S
O Ph 1a
H2 N
2
Conditions
Ph S N
N S
S
NH2 H2 N
3a
NH2
Entry
I2 (equiv)
1a:2
Additive (0.25 equiv)
Solvent
Temp (°C)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1.5 1:2 1:3
TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH AlCl3 HOAc HCl CuI Na2CO3 K2CO3 Cs2CO3 DBU DABCO
MeCN THF DMF Toluene MeOH EtOH i-PrOH t-BuOH H2O DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO
40 40 40 40 40 40 40 40 40 20 40 60 80 100 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40
<5 <5 <5 <5 <5 <5 <5 <5 <5 12 40 32 25 13 38 36 15 5 29 27 17 38 35 65 0 36 50 23 80 45 40
0.3 0.5 2.0 1.0 1.0 1.0
Bold value represent the best condition of the reaction. a Reaction conditions: 1a (0.5 mmol), 2, I2 and the additive in 3 ml of solvent for 12 h. b Isolated yield.
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W.-j. Xue et al. / Tetrahedron Letters xxx (2014) xxx–xxx Table 2 Reaction scope of methyl ketonesa
O
R S
O R
H2 N
1
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
S
H 2N
3
H2 N
R
HN
NH2
2
NH 2
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s
80 82 72 74 75 70 85 78 86 81 76 74 64 0 75 70 80 71 63
2a
Ph
S
-H2 O
Ph
N S
Ph I
Ph
NH 2
H 2N
Ph
1aa
NH2
2
5a
3a
NH2
Scheme 4. Plausible mechanism of the present reaction.
O
O
MeO
1a
MeO
S
N NH2
NH 2
H 2N
S 4a
I2, DMSO
N
I 2, DMSO
NH2
S
S NH2
3a, 70%
Ph
Ph S
N S
NH2 3a, 0%
N
Ph
N
I
S
I 2, EtOH
NH2
NH2
NH2
o
S 4a
78 C
Ph
Ph
H2 N 1a
2
80 oC
S
S
NH2
3a, 60% Ph
N
S
S
NH2
I2 , CuO, EtOH NH2
E
N
N NH2
S
Ph S
40 o C
2
O
O
F
6a, 65% Ph
Ph
N
S
S H2 N 6a
Ph
S
NH2
Ph
NH 2
H 2N
S 5a
I
O
I 2, DMSO
N NH2
D
5a, 80% S
Ph
C
N S
40 o C
S 4a
B
N
NH2
N
Ph S
I 2, DMSO NH2
2
40 o C
NH 2 3ag, 40%
N
N
S
S NH 2
S
NH 2
NH2 3g, 10%
Ph
Ph Ph
S N
N S
NH2 3a, 20%
S
40 o C
2
OMe
S N S
NH2 NH2
Ph Ph
A
S
40 o C
NH2 2
1g
S S
I2 , DMSO
S H2 N
N
3a, 60%
NH2
N
S
S
H2 N
N S
S C
B
N
Ph
40 o C
HS
S
S N
N
- Urea
MeO
I 2, DMSO
Ph + H 2O NH2
NH2
S 4a
Ph
Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), I2 (1 mmol) in 3 ml of DMSO at 40 °C for 12 h. b Isolated yield.
S
N
I2
NH2
5a
N
S
H2 N
a
O
A
NH2
I
HN
NH 2 S
Ph
Ph
Yieldb (%)
3
Ph (1a) 4-MeC6H4 (1b) 4-FC6H4 (1c) 4-ClC6H4 (1d) 4-BrC6H4 (1e) 3,4-Cl2C6H3 (1f) 4-MeOC6H4 (1g) 3-MeOC6H4 (1h) 4-EtOC6H4 (1i) 3,4,5-(MeO)3C6H2 (1j) 3,4-OCH2OC6H3 (1k) 3,4-OCH2CH2OC6H3 (1l) 4-HOC6H4 (1m) 4-NO2C6H4 (1n) 4-PhC6H4 (1o) 2-Benzofuryl (1p) 2-Naphthyl (1q) 1-Naphthyl (1r) 2-Fluorene (1s)
SH
N S
40 oC
NH2
1aa
S
N
HN O
I
Ph
1a
R S
I2, DMSO
2
O
I2
Ph
N
N S
G
S
NH2 3a, 0%
NH2
Scheme 3. Controlled experiments to prove the mechanism.
rials in various reactions (Scheme 3). This strategy revealed that the product resulting from the iodination of acetophenone 1aa could react with thiourea (2) to give 3a in good yield when the
Scheme 5. Cross reaction between two representative substrates.
reaction was conducted in the presence of I2 in DMSO (Scheme 3A). The target molecule 3a could also be obtained from the reaction between 4a and thiourea (2) (Scheme 3B). It was not possible, however, to form 3a in the absence of thiourea (2) (Scheme 3C), which indicated that the sulfur atoms in 3 originated from thiourea (2). Further experimentation also revealed that 5a could be obtained from 4a in EtOH, and that 3a could be obtained from 5a following the addition of thiourea (2) (Scheme 3D and E). Furthermore, 5-substituted aminothiazole could be obtained from the reaction of acetophenone (1a, 2 equiv) with thiourea (2, 1 equiv) in the presence of iodine and CuO in EtOH (Scheme 3F). However, it was found that the target molecule 3a could not be obtained from 5-substituted aminothiazole (Scheme 3G). GC-MS was used to provide further evidence in support of the proposed reaction mechanism, with intermediate 4a being successfully detected in the reaction mixture (see ESI). Based on the results of our mechanistic studies, we have suggested a plausible mechanism for the current reaction using acetophenone (1a) as an example (Scheme 4). Briefly, acetophenone 1a would be converted to 1aa in the presence of I2.10 Subsequent reaction of 1aa with thiourea (2) would afford intermediate A, which would undergo an intramolecular nucleophilic addition/dehydration reaction to generate 4a. Intermediate 4a would then be converted to 5a in the presence of I2. Compound 5a would then undergo a condensation reaction with thiourea (2) to give intermediate B, which would undergo a hydrolysis reaction to form intermediate C.11 Finally, intermediate C would condense with intermediate 5a to furnish the desired product 3a. The proposed mechanism was further verified by examining the outcome of a mixed reaction between 0.5 equiv of acetophenone
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W.-j. Xue et al. / Tetrahedron Letters xxx (2014) xxx–xxx
(1a) and 0.5 equiv of 4-methyl acetophenone (1g) under the standard conditions (Scheme 5). In accordance with our proposed reaction mechanism, this reaction led to the formation of three independent molecules 3a, 3ag, and 3g. Conclusion In summary, we have developed a concise and efficient one-pot domino reaction for the synthesis of diheteroaryl thioethers from readily available aromatic methyl ketones and thiourea. The main advantage of this reaction is that it does not require the addition of foul-smell thiols and transition metals. In addition, this method could synthesize two thiazole rings and a sulfur bridge in one pot. Further studies toward the applications of this reaction will be reported in due course. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant Nos. 21032001 and 21272085). We also acknowledge the excellent doctorial dissertation cultivation Grant from Central China Normal University (2013YBYB53). Supplementary data Supplementary data (evidence in support of the hypothetic mechanism, and 1H and 13C NMR spectra and X-ray crystal data for 3a) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.042. References and notes 1. (a) Nakazawa, T.; Xu, J.; Nishikawa, T.; Oda, T.; Fujita, A.; Ukai, K.; Mangindaan, R. E. P.; Rotinsulu, H.; Kobayashi, H.; Namikoshi, M. J. Nat. Prod. 2007, 70, 439– 442; (b) Pasquini, S.; Mugnaini, C.; Tintori, C.; Botta, M.; Trejos, A.; Arvela, R. K.; Larhed, M.; Witvrouw, M.; Michiels, M.; Christ, F.; Debyser, Z.; Corelli, F. J. Med. Chem. 2008, 51, 5125–5129; (c) Alcaraz, M. L.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill, D. M.; Humphries, L. A.; Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon, R. A.; Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowan, P.; Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.; Woodland, I. A. Org. Process Res. Dev. 2005, 9, 555–569; (d) Nielsen, S. F.; Nielsen, E. O.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med. Chem. 2000, 43, 2217–2226; (e) Huang, Y.; Bae, S. A.; Zhu, Z.; Guo, N.; Roth, B. L.; Laruelle, M. J. Med. Chem. 2005, 48, 2559–2570. 2. (a) Okamoto, T.; Mitsui, C.; Yamagishi, M.; Nakahara, K.; Soeda, J.; Hirose, Y.; Miwa, K.; Sato, H.; Yamano, A.; Matsushita, T.; Uemura, T.; Takeya, J. Adv. Mater. 2013, 25, 6392–6397; (b) Takimiya, K.; Shinamura, S.; Osaka, I.; Miyazaki, E. Adv. Mater. 2011, 23, 4347–4370; (c) Anthony, J. E. Chem. Rev. 2006, 106, 5028– 5048; (d) Mori, T.; Nishimura, T.; Yamamoto, T.; Doi, I.; Miyazaki, E.; Osaka, I.; Takimiya, K. J. Am. Chem. Soc. 2013, 135, 13900–13913.
3. (a) Tsuchida, E.; Miyatake, K.; Yamamoto, K. Macromolecules 1998, 31, 6469– 6475; (b) Fujii, T.; Hao, W.; Yoshimura, T. Heteroat. Chem. 2004, 15, 246–250; (c) Stoll, A. H.; Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 606– 609. 4. (a) De Martino, G.; La Regina, G.; Coluccia, A.; Edler, M. C.; Barbera, M. C.; Brancale, A.; Wilcox, E.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2004, 47, 6120–6123; (b) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.; von Geldern, T. W.; Ormes, M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025–4040; (c) Beard, R. L.; Colon, D. F.; Song, T. K.; Davies, P. J. A.; Kochhar, D. M.; Chandraratna, R. A. S. J. Med. Chem. 1996, 39, 3556–3563. 5. For selected examples, see: (a) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205–3220; (b) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583–5586; (c) Larsson, P.; Correa, A.; Carril, M.; Norrby, P.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5691–5693; (d) Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. J. Am. Chem. Soc. 2013, 135, 9548–9552; (e) Zhao, P.; Yin, H.; Gao, H.; Xi, C. J. Org. Chem. 2013, 78, 5001–5006; (f) Wagner, A. M.; Sanford, M. S. J. Org. Chem. 2014, 79, 2263–2267; (g) Yonova, I. M.; Osborne, C. A.; Morrissette, N. S.; Jarvo, E. R. J. Org. Chem. 2014, 79, 1947–1953; (h) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697–1700; (i) Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett. 2009, 11, 5250–5253; (j) Silveira, C. C.; Mendes, S. R.; Soares, J. R.; Victoria, F. N.; Martinez, D. M.; Savegnago, L. Tetrahedron Lett. 2013, 54, 4926–4929. 6. For selected examples, see: (a) Chu, L.; Yue, X.; Qing, F. Org. Lett. 2010, 12, 1644–1647; (b) Cheng, J.; Yi, C.; Liu, T.; Lee, C. Chem. Commun. 2012, 8440– 8442; (c) Saravanan, P.; Anbarasan, P. Org. Lett. 2014, 16, 848–851; (d) Anbarasan, P.; Neumann, H.; Beller, M. Chem. Commun. 2011, 3233–3235; (e) Zou, L.; Reball, J.; Mottweiler, J.; Bolm, C. Chem. Commun. 2012, 11307–11309; (f) Dai, C.; Xu, Z.; Huang, F.; Yu, Z.; Gao, Y. J. Org. Chem. 2012, 77, 4414–4419; (g) Prasad, C. D.; Balkrishna, S. J.; Kumar, A.; Bhakuni, B. S.; Shrimali, K.; Biswas, S.; Kumar, S. J. Org. Chem. 2013, 78, 1434–1443; (h) Zhang, S.; Qian, P.; Zhang, M.; Hu, M.; Cheng, J. J. Org. Chem. 2010, 75, 6732–6735; (i) Ranjit, S.; Lee, R.; Heryadi, D.; Shen, C.; Wu, J.; Zhang, P.; Huang, K.; Liu, X. J. Org. Chem. 2011, 76, 8999–9007; (j) Ge, W.; Zhu, X.; Wei, Y. Eur. J. Org. Chem. 2013, 6015–6020. 7. (a) Liao, Y.; Jiang, P.; Chen, S.; Qi, H.; Deng, G. Green Chem. 2013, 15, 3302–3306; (b) Ge, W.; Zhu, X.; Wei, Y. Adv. Synth. Catal. 2013, 355, 3014–3021. 8. For selected examples, see: (a) Firouzabadi, H.; Iranpoor, N.; Abbasi, M. Adv. Synth. Catal. 2009, 351, 755–766; (b) Wang, L.; Zhou, W.; Chen, S.; He, M.; Chen, Q. Adv. Synth. Catal. 2012, 354, 839–845; (c) Firouzabadi, H.; Iranpoor, N.; Gholinejad, M. Adv. Synth. Catal. 2010, 352, 119–124; (d) Lu, G.; Cai, C. Adv. Synth. Catal. 2013, 355, 1271–1276; (e) Feng, J.; Lu, G.; Lv, M.; Cai, C. Asian J. Org. Chem. 2014, 3, 77–81; (f) Firouzabadi, H.; Iranpoor, N.; Abbasi, M. Tetrahedron 2009, 65, 5293–5301; (g) Azizi, N.; Yadollahy, Z.; Rahimzadeh-Oskooee, A. Tetrahedron Lett. 2014, 55, 1722–1725; (h) Woodbridge, R. G.; Dougherty, G. J. Am. Chem. Soc. 1949, 71, 1744–1745; (i) Kuhn, M.; Falk, F. C.; Paradies, J. Org. Lett. 2011, 13, 4100–4103; (j) Javadi, A.; Shockravi, A.; Kamali, M.; Rafieimanesh, A.; Malek, A. M. J. Polym. Sci. A: Polym. Chem. 2013, 51, 3505– 3515. 9. The details of the crystal data have been deposited with Cambridge Crystallographic Data Centre as Supplementary Publication, CCDC 974894. 10. (a) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Org. Lett. 2006, 8, 2245–2248; (b) Gao, M.; Yang, Y.; Wu, Y.; Deng, C.; Cao, L.; Meng, X.; Wu, A. Org. Lett. 2010, 12, 1856–1859; (c) Zhu, Y.; Gao, Q.; Lian, M.; Yuan, J.; Liu, M.; Zhao, Q.; Yang, Y.; Wu, A. Chem. Commun. 2011, 12700–12702. 11. Bierer, D. E.; Dener, J. M.; Dubenko, L. G.; Gerber, R. E.; Litvak, J.; Peterli, S.; Peterli-Roth, P.; Truong, T. V.; Mao, G.; Bauer, B. E. J. Med. Chem. 1995, 38, 2628–2648.
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