10.1002/adsc.201901492
Advanced Synthesis & Catalysis
intramolecular nucleophilic substitution reaction to
afford thioether 4a and intermediates 11. Finally,
intermediates 11 underwent in situ removal of HCl to
generate the 3-chlorinated indoles 3. TMSOTMS,
ethyl phenyl sulfoxide (2c), 3-chloro-1-methyl-1H-
indole (3a) and ethyl phenyl sulfide (4a) were
detected by GC-MS analysis technique (for details,
please see Supporting Information), which agreed
well with the proposed reaction mechanism
mentioned above.
In summary, we have developed a sulfoxide-
promoted chlorination of indoles and electron-rich
arenes with chlorine anion as nucleophile. The
synthetic protocol offers attractive industrial
prospects as the reaction was performed at room
temperature without the need for using metal
catalysts and inert atmosphere. This method could
tolerate a series of functional groups such as the
methoxyl, halogen, methyl, benzyl, allyl groups. In
addition, the electron-rich arenes adorned with acid
sensitive functional groups silyl ether and acetal
substituents could also execute this chlorination
reaction in good yields. Chlorination of the 1-benzyl-
1H-pyrrole with the TMSCl/sulfoxide system could
form mono-, di-, and tri-chlorinated pyrroles,
respectively. A plausible interrupted Pummerer
reaction mechanism was proposed without oxidation
of chloride anion. Furthermore, the recovered
byproduct thioether could be converted to the starting
material sulfoxide just by a simple oxidation reaction.
The further applications of this method are ongoing
in our laboratory.
[1]a) H. Zhang, L. Hong, H. Kang, R. Wang, J. Am. Chem.
Soc. 2013, 135, 14098-14101; b) M. H. Rønnest, M. S.
Raab, S. Anderhub, S. Boesen, A. Krämer, T. O.
Larsen, M. H. Clausen, J. Med. Chem. 2012, 55, 652-
660; c) G. W. Gribble, J. Chem. Educ. 2014, 81, 1441-
1449; d) M. Lang, P. Spiteller, V. Hellwig, W. Steglich,
Angew. Chem. Int. Ed. 2001, 40, 1704-1705; e) D. L.
Boger, Med. Res. Rev. 2001, 21, 356-381; f) G. W.
Gribble, Acc. Chem. Res. 1998, 31, 141-152.
[2] a) T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal,
S. W. Krska, Chem. Soc. Rev. 2016, 45, 546-576; b) B.
R. Smith, C. M. Eastman, J. T. Njardarson, J. Med.
Chem. 2014, 57, 9764-9773; c) R. Wilcken, M. O.
Zimmermann, A. Lange, A. C. Joerger, F. M. Boeckler,
J. Med. Chem. 2013, 56, 1363-1388; d) D. G. Fujimori,
C. T. Walsh, Curr. Opin. Chem. Biol. 2007, 11, 553-
560; e) A. DeLeon, N. C. Patel, M. L. Crismon, Clin.
Ther. 2004, 26, 649-666.
[3] a) P. H. Elsinga, K. Hatano, K. Ishiwata, Curr. Med.
Chem. 2006, 13, 2139-2153; b) D. J. Schlyer, Ann.
Acad. Med. Singapore 2004, 33, 146-154.
[4] a) A. M. Hiszpanski, J. D. Saathoff, L. Shaw, H. Wang,
L. Kraya, F. Lꢀttich, M. A. Brady, M. L. Chabinyc, A.
Kahn, P. Clancy, Y. L. Loo, Chem. Mater. 2015, 27,
1892-1900; b) M. L. Tang, Z. Bao, Chem. Mater. 2011,
23, 446-455.
[5] a) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016,
116, 12564-12649; b) D. S. Surry, S. L. Buchwald,
Chem. Sci. 2011, 2, 27-50; c) R. Chinchilla, C. Nájera,
Chem. Soc. Rev. 2011, 40, 5084-5121; d) K. C.
Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. Int.
Ed. 2005, 44, 4442-4489; e) A. F. Littke, G. C. Fu,
Angew. Chem. Int. Ed. 2002, 41, 4176-4211.
Experimental Section
[6] W. D. Watson, J. Org. Chem. 1985, 50, 2145-2148.
The mixture of 1-methyl-1H-indole (1a, 0.2 mmol, 1.0
equiv), an ethyl phenyl sulfoxide (2c, 0.3 mmol, 1.5 equiv)
and TMSCl (0.4 mmol, 2.0 equiv) in CH2Cl2 (1.0 mL) was
stirred at 25 °C for 20 min, then water (5 mL) and
dichloromethane (10 mL) were added. The two layers were
separated, and the aqueous phase was extracted with
dichloromethane (3 × 10 mL). The combined organic
extracts were washed by brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (100–200
mesh, elution 3% ethyl acetate in petroleum ether) to
afford the desired 3-chloro-1-methyl-1H-indole (3a) in
85% yield. Pale yellow oil, 28.1 mg; EtOAc : PE (1:30), Rf
= 0.43; 1H NMR (400 MHz, CDCl3) : 7.66 (d, J = 7.9 Hz,
1H), 7.34–7.28 (m, 2H), 7.24–7.20 (m, 1H), 7.03 (s, 1H),
3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) : 135.7, 125.6,
125.1, 122.5, 119.8, 118.2, 109.4, 104.2, 32.8; Calcd for
C9H8ClNNa [M+Na]+: 188.0237. Found: 188.0243.
[7] a) D. A. Rogers, J. M. Gallegos, M. D. Hopkins, A. A.
Lignieres, A. K. Pitzel, A. A. Lamar, Tetrahedron 2019,
75, 130498; b) R. J. Tang, T. Milcent, B. Crousse, J.
Org. Chem. 2018, 83, 930-938; c) M. A. B. Mostafa, R.
M. Bowley, D. T. Racys, M. C. Henry, A. Sutherland, J.
Org. Chem. 2017, 82, 7529-7537; d) R. Das, M. Kapur,
J Org. Chem. 2017, 82, 1114-1126; e) B. Du, X. Jiang,
P. Sun, J. Org. Chem. 2013, 78, 2786-2791; f) P. P.
Singh, T. Thatikonda, K. A. A. Kumar, S. D. Sawant, B.
Singh, A. K. Sharma, P. R. Sharma, D. Singh, R. A.
Vishwakarma, J. Org. Chem. 2012, 77, 5823-5828; g)
R. B. Bedford, M. F. Haddow, C. J. Mitchell, R. L.
Webster, Angew. Chem. Int. Ed. 2011, 50, 5524-5527;
Angew. Chem. 2011, 123, 5638-5641; h) A. Zanka, A.
Kubota, Synlett 1999, 1984-1986.
Acknowledgements
[8] a) X. Xiong, Y. Y. Yeung, Angew. Chem. Int. Ed. 2016,
55, 16101-16105; Angew. Chem. 2016, 128, 16335-
16339; b) F. Lied, A. Lerchen, T. Knecht, C. Mꢀck-
Lichtenfeld, F. Glorius, ACS Catal. 2016, 6, 7839-7843;
c) J. Yan, T. Ni, F. Yan, Tetrahedron Lett. 2015, 56,
1096-1098.
This project was funded by the Natural Science Foundation of
Shandong Province (ZR2019MB009), the Key Research and
Development Program of Shandong Province (2019GSF108089),
the National Natural Science Foundation of China (21672046,
21372054), and the Found from the Huancui District of Weihai
City.
[9] a) G. F. Mendonc, A. R. Bastos, M. Boltz, B. Louis, P.
Pale, P. M. Esteves, M. C. S. d. Mattos, Appl. Catal., A
2013, 460-461, 46-51; b) G. F. Mendonca, M. C. S. d.
References
5
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