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Green Chemistry
under HCl conditions, indicating that a bromide anion is
necessary and sufficient for this conversion. Indeed, much
lower yields were observed under TBAI or TBACl conditions,
and the hydrolyzed compound 11 was obtained as the major
product (Scheme 6). The last substitution reaction would be
very unfavorable for TBAI as iodoformate is less reactive than
bromoformate. For TBACl, although the last step is more favor-
able, the first step is less favorable, as chloride is less nucleo-
philic than bromide. Second, 3a was obtained in only 15%
yield by using 4-methylphenyl disulfide as the thiolation
source, which further proves the necessity of the acid–base
reaction in pathway 3, requiring the participation of the thiol
hydrogen.
3 For reviews, see: (a) C. Shen, P. Zhang, Q. Sun, S. Bai,
T. S. A. Hor and X. Liu, Chem. Soc. Rev., 2015, 44, 291–314;
(b) S. Liang, S. Shaaban, N.-W. Liu, K. Hofman and
G. Manolikakes, in Advances in Organometallic Chemistry, ed.
P. J. Pérez, Academic Press, 2018, ch. 3, vol. 69, pp. 135–207.
4 (a) R. A. Daines, P. A. Chambers, J. J. Foley, D. E. Griswold,
W. D. Kingsbury, L. D. Martin, D. B. Schmidt, K. K. C. Sham
and H. M. Sarau, J. Med. Chem., 1996, 39, 3837–3841;
(b) J. J. Li, L. G. Hamann, Z. Ruan, C. B. Cooper, S. C. Wu,
L. M. Simpkins, H. Wang, A. Nayeem and S. R. Krystek,
US20060235028A1, 2006; (c) F. Haviv, R. W. DeNet,
R. J. Michaels, J. D. Ratajczyk, G. W. Carter and P. R. Young,
J. Med. Chem., 1983, 26, 218–222; (d) H. Schickaneder,
H. Engler and I. Szelenyi, J. Med. Chem., 1987, 30, 547–551.
5 (a) P. Lindberg, A. Braendstroem, B. Wallmark,
H. Mattsson, L. Rikner and K. J. Hoffmann, Med. Res. Rev.,
1990, 10, 1–54; (b) C. I. Carswell and K. L. Goa, Drugs, 2001,
61, 2327–2356.
6 (a) S. Rádl, O. Klecán and J. Havlíček, J. Heterocycl. Chem.,
2006, 43, 1447–1453; (b) P. R. Reddy, V. Himabindu,
L. Jaydeepkumar, G. M. Reddy, J. V. Kumar and
G. M. Reddy, Org. Process Res. Dev., 2009, 13, 896–899;
(c) B. Kohl, E. Sturm, J. Senn-Bilfinger, W. A. Simon,
U. Krueger, H. Schaefer, G. Rainer, V. Figala, K. Klemm,
et al., J. Med. Chem., 1992, 35, 1049–1057; (d) S. Souda,
N. Ueda, S. Miyazawa, K. Tagami, S. Nomoto, M. Okita,
N. Shimomura, T. Kaneko, M. Fujimoto, et al.,
EP268956A2, 1988; (e) R. L. M. Broeckx, D. De Smaele and
S. M. H. Leurs, WO2003008406A1, 2003.
Conclusions
In summary, we have disclosed the first protocol for the thiola-
tion of the unactivated methyl C(sp3)–H bond in 2-picolines.
The protocol comprises a one-pot, two-step reaction through a
TFAA-mediated [3,3]-sigmatropic rearrangement of pyridine
N-oxides and TBAB-catalyzed direct conversion of trifluoroace-
tates into thioethers under metal- and base-free conditions.
The present method is mild, scalable, highly regioselective,
and step- and atom-economical. The TBAB catalyst is not
required for those highly electron-rich 2-picoline N-oxides. On
the other hand, the method doesn’t work well for electron-
poor N-oxides or alkylthiols. Furthermore, the method has
been successfully applied to the synthesis of omeprazole
sulfide and rabeprazole sulfide, which are the advanced inter-
mediates of two on-market hot drugs.
7 R. A. Sheldon, Green Chem., 2017, 19, 18–43.
8 (a) D. Wei, W. Song, D. Gao, L. Dong, Z. Jia, L. Wang,
W. Wang, C. Yang, Y. Wang and C. Liu, CN106674198A,
2017; (b) K. M. Joseph and I. Larraza-Sanchez, Tetrahedron
Lett., 2011, 52, 13–16.
Conflicts of interest
9 (a) D. Wang, Y. Wang, J. Zhao, M. Shen, J. Hu, Z. Liu,
L. Li, F. Xue and P. Yu, Org. Lett., 2017, 19, 984–987;
(b) D. Wang, H. Feng, L. Li, Z. Liu, Z. Yan and P. Yu,
J. Org. Chem., 2017, 82, 11275–11287; (c) D. Wang,
M. Shen, Y. Wang, J. Hu, J. Zhao and P. Yu, Asian J. Org.
Chem., 2018, 7, 879–882; (d) D. Wang, J. Hu, J. Zhao,
M. Shen, Y. Wang and P. Yu, Tetrahedron, 2018, 74, 4100–
4110.
10 C.-S. Wang, T. Roisnel, P. H. Dixneuf and J.-F. Soulé, Org.
Lett., 2017, 19, 6720–6723.
11 Y. Yang, C. Qu, X. Chen, K. Sun, L. Qu, W. Bi, H. Hu, R. Li,
C. Jing, D. Wei, S. Wei, Y. Sun, H. Liu and Y. Zhao, Org.
Lett., 2017, 19, 5864–5867.
There are no conflicts to declare.
Acknowledgements
Financial support by the Foundation of Tianjin Educational
Committee (no. 2017KJ008) is greatly acknowledged. The
authors are thankful to the Research Center of Modern
Analytical Technology, Tianjin University of Science and
Technology for NMR measurements and high resolution mass
analysis.
12 C.-S. Wang, P. H. Dixneuf and J.-F. Soulé, Org. Biomol.
Chem., 2018, 16, 4954–4957.
Notes and references
1 (a) H. Hagiwara, K. Kobayashi, S. Miya, T. Hoshi, T. Suzuki, 13 X. Wang, R. Qiu, C. Yan, V. P. Reddy, L. Zhu, X. Xu and
M. Ando, T. Okamoto, M. Kobayashi, I. Yamamoto, S.-F. Yin, Org. Lett., 2015, 17, 1970–1973.
S. Ohtsubo, M. Kato and H. Uda, J. Org. Chem., 2002, 67, 14 S.-r. Guo, Y.-q. Yuan and J.-n. Xiang, Org. Lett., 2013, 15,
5969–5976; (b) J. Bonjoch, J. Catena and N. Valls, J. Org.
Chem., 1996, 61, 7106–7115.
2 K. L. Dunbar, D. H. Scharf, A. Litomska and C. Hertweck,
Chem. Rev., 2017, 117, 5521–5577.
4654–4657.
15 D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy,
S. Abou-Shehada and P. J. Dunn, Green Chem., 2016, 18,
288–296.
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