Table 2 (continued )
Entry
21
Product
Yield (%)b
72
22
23
a
75
56
Scheme 2 Possible catalytic cycle.
Reaction conditions: ortho-aminobenzenethiol (1.1 mmol), aryl
ortho-dihalide (1 mmol), CuI (0.3 mmol), K2CO3 (5 mmol), DMSO
the CuI-catalyzed cascade C–S and C–N coupling of 2-amino-
benzenethiol and 2-bromoiodobenzene is proposed (Scheme 2).
Due to the stronger acidity of the proton on the thio group of
2-aminobenzenethiol than that of the amino group, 2-aminobenz-
enethiol is turned into potassium 2-aminobenzenethiolate by
K2CO3, which promptly reacts with CuI to form more stable
copper(I) 2-aminobenzenethiolate complex 4 (Scheme 2) When
copper(I) 2-aminobenzenethiolate complex 4 encounters 2-bromo-
iodobenezene, oxidative addition occurs and Cu(III) species 5 is
formed. And then Cu(III) species 5 proceeds through reductive
elimination, and a new C–S bond is formed and Cu(I) species 6 is
produced. K2CO3 strips a proton from the amino group of Cu(I)
species 6 with difficulty, and then the second oxidative addition of
the catalytic cycle occurs slowly to give Cu(III) species 7, which is the
rate determining step. Finally, Cu(III) species 7 facilely undergoes
reductive elimination to afford phenothiazine and restore CuI.
We thank the Sci-Tech Bureau of Sichuan (2011HH0016),
Opening Fund of State Key Lab of Geohazard Prevention and
Geoenvironment Protection (SKLGP2012K005) and Cultivating
Program for Excellent Innovation Team of Chengdu University
of Technology (HY0084) for financial support.
b
(5 ml), at 120 1C for 48 h unless otherwise stated. Isolated yield.
Cs2CO3 (5 mmol) was used as the base. Ten times the amounts of the
reagents of entry 19 were used, i.e. 2-bromoiodobenzene (10 mmol).
c
d
performance (Table 2, entries 7 and 8 vs. 2). It should be
emphasized that regioselective substituted phenothiazines
were obtained and no other isomer was observed, which
obeyed a rule that the more active thio group reacts with the
more active aryl bromides or iodides, and the less active amino
group reacts with the less active aryl halides.
ortho-Bromochlorobenzenes with an electron-withdrawing
group commonly demonstrated better coupling performance as
well as excellent regioselectivity (Table 2, entries 9 to 11 vs. 2).
Even aryl ortho-dichloride 3-nitro-1,2-dichlorobenzene carried
out the cascade coupling (entry 12). 1,2,4,5-Tetrabromobenzene
was coupled with 2-aminobenzenethiol to give 2,3-dibromo-
10H-phenothiazine with fair yield due to the multi active points
of 1,2,4,5-tetrabromobenzene (entry 13).
Substituted 2-aminobenzenethiols with electron-withdrawing
groups, such as chloro, trifluoromethyl, accomplished CuI-
catalyzed cascade C–S and C–N coupling with various aryl
ortho-dihalides tested to afford substituted phenothiazines with
moderate to high yields (Table 2, entries 14 to 19). 2-Chloro
phenothiazine, the shared intermediate of two typical antipsy
chotics chlorpromazine and prochlorperazine, was obtained with
good yields (entries 14 to 17). The shared intermediate of another
two typical antipsychotics, fluphenazine and trifluoperazine,
2-trifluoromethyl-10H-phenothiazine was obtained with excellent
yield when 2-bromoiodobenzene was used (entries 18 and 19).
Furthermore, the reaction could be scaled up to the gram-scale
under the same conditions (entry 20).
Notes and references
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R. M. Jefferson, J. Med. Chem., 1992, 35, 716.
2 M. Mayer, P. T. Lang, S. Gerber, P. B. Madrid, I. G. Pinto,
R. K. Guy and T. L. James, Chem. Biol., 2006, 13, 993.
3 N. Sharma, R. Gupta, M. Kumar and R. R. Gupta, J. Fluorine
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4 (a) M. Sailer, A. W. Franz and T. J. J. Muller, Chem.–Eur. J., 2008,
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J. Am. Chem. Soc., 2003, 125, 12631.
Cross coupling of substituted aryl ortho-dihalides and substituted
2-aminobenezenethiol afforded substituted phenothiazine with
good yield (entry 21). Excitingly, substituted heteroaryl ortho-
dihalides accomplished CuI-catalyzed cascade coupling with
2-aminobenzenethiols (Table 2, entries 22 and 23).
5 T. Dahl, C. W. Tornøe, B. Bang-Andersen, P. Nielsen and
M. Jørgensen, Angew. Chem., Int. Ed., 2008, 47, 1726.
6 D. Ma, Q. Geng, H. Zhang and Y. Jiang, Angew. Chem., Int. Ed.,
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7 (a) Y. Liu and J. P. Wan, Org. Biomol. Chem., 2011, 9, 6873;
(b) A. Minatti and S. L. Buchwald, Org. Lett., 2008, 10, 2721.
8 A. J. Lin and S. Kasina, J. Heterocycl. Chem., 1981, 18, 759.
9 J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire,
Chem. Rev., 2002, 102, 1359.
10 D. S. Surry and S. L. Buchwald, Chem. Sci., 2010, 1, 13.
11 D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41, 1450.
12 M. Cortes-Salva, C. Garvin and J. C. Antilla, J. Org. Chem., 2011,
76, 1456.
13 (a) A. Casitas, A. E. King, T. Parella, M. Costas, S. S. Stahl and
X. Ribas, Chem. Sci., 2010, 1, 326; (b) R. Giri and J. F. Hartwig,
J. Am. Chem. Soc., 2010, 132, 15860.
The mechanisms of Ullmann type reactions were extensively
studied,13 and the Cu(III) intermediates were already isolated.
A typical improved Ullmann type reaction ordinarily has a
copper catalyst with a bidentate ligand, so our ligand-free
CuI-catalyzed cascade C–S and C–N coupling reaction is
somewhat different from the reported Ullmann type reactions.
We think that perhaps one of two substrates ortho-aminobenzene-
thiol acts as the ligand of copper. A possible catalytic cycle of
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5367–5369 5369