Communications
We next explored the possibility of employing aryl
of the other existing methods for producing substituted
benzothiazoles and in many cases would have definite
advantages in terms of the scope and the conditions of the
reaction. Thus, it can find numerous applications in organic
synthesis. Additionally, the successful application of metal
sulfides as coupling partners will stimulate studies on metal-
catalyzed S-arylation by employing these inexpensive
reagents.
bromides as substrates and found that their reaction with
K2S under our standard conditions is sluggish. However, when
the reaction temperature was raised to 1408C, a satisfactory
conversion was achieved to give benzothiazoles in moderate
to good yields (Table 4). Notably, a 2,4,6-trisubstituted
benzothiazole was obtained in 66% yield from N-(2-bromo-
4,6-dimethylphenyl)acetamide (Table 4, entry 5), thus further
demonstrating the enormous potential of our method for the
assembly of polysubstituted benzothiazoles.
Experimental Section
Typical procedure: A mixture of CuI (19 mg, 0.1 mmol), o-iodoben-
zamide (1 mmol), and Na2S·9H2O (or K2S) (3 mmol) in DMF (2 mL)
was stirred at 808C for 12 h. The reaction mixture was cooled to RT
and then 0.8 mL of conc. HCl was added and the reaction mixture
stirred for 5–10 h. After adding 10 mL saturated aq. NaHCO3, it was
extracted with ethyl acetate and then purified by silica gel chroma-
tography to furnish the desired product.
Table 4: Assembly of substituted benzothiazoles from aryl bromides.[a]
Entry
R
X (for 8)
Product
Yield [%][b]
1
2
3
4
5
6
Ph
H
H
8 f
88
78
66
41
86
63
4-NH2-3-MeC6H3
Me
Me
Ph
8ad
8ae
8x
8af
8m
Received: January 26, 2009
Published online: May 7, 2009
4,6-dimethyl
5-methoxy
6-fluoro
H
Keywords: biological activity · catalysis · cross-coupling ·
.
2-pyridinyl
heterocycles · sulfur
[a] Reaction conditions: 9 (1 mmol), K2S (3 mmol), CuI (0.1 mmol),
DMF (2 mL), 1408C, 12 h, then added 0.8 mL of 12n HCl, RT, 5–10 h.
[b] Yield of isolated product.
[1] B. L. Mylari, E. R. Larson, T. A. Beyer, W. J. Zembrowski, C. E.
Aldinger, M. F. Dee, T. W. Siegel, D. H. Singleton, J. Med. Chem.
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Surowy, O. F. E. Kouhen, S. W. Muchmore, J. D. Brioni, A. O.
Although a detailed mechanistic investigation of this
process awaits additional experimentation, a tentative pro-
posal is outlined in Scheme 1. After an oxidative addition of
[3] M. C. Van Zandt, M. L. Jones, D. E. Gunn, L. S. Geraci, J. H.
Jones, D. R. Sawicki, J. Sredy, J. L. Jacot, A. T. DiCioccio, T.
[4] C. G. Mortimer, G. Wells, J.-P. Crochard, E. L. Stone, T. D.
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[6] D. O. Koltun, T. A. Maequart, K. D. Shenk, E. Elzein, Y. Li, M.
Nguyen, S. Kerwar, D. Zeng, N. Chu, D. Soohoo, J. Hao, V. Y.
Maydanik, D. A. Lustig, K.-J. Ng, H. Fraser, J. A. Zablocki,
Scheme 1. Putative catalytic cycle for the S arylation.
[10] J. Suh, S. H. Yoo, M. G. Kim, K. Jeong, J. Y. Ahn, M.-S. Kim, P. S.
Chae, T. Y. Lee, J. Lee, J. Lee, Y. A. Jang, E. H. Ko, Angew.
[11] V. O. Rodionov, S. I. Presolski, S. Gardinier, Y.-H. Lim, M. G.
CuI to the aryl halide to form complex A, a ligand exchange
with sodium sulfide might provide complex B, which could
then undergo reductive elimination to give intermediate C
and regenerate CuI. The intramolecular condensation of C
would furnish benzothiazoles 8. The formation of C was
confirmed by isolation of 10 (26% yield, together with some
unidentified side products) after trapping the coupling
mixture with iodomethane. Additionally, it was found that
the amido group was essential for the coupling step,
presumably because of an ortho-substituent effect directed
by this group[23] or the capability for subsequent condensation.
In conclusion, we have developed a novel method for the
synthesis of substituted benzothiazoles, which relies on an
unprecedented CuI-catalyzed coupling reaction of aryl hal-
ides with metal sulfides. This approach can compliment many
[12] S. Rudrawar, A. Kondaskar, A. K. Chakraborti, Synthesis 2005,
2521, and references therein.
F. Bravo, P. Uriz, E. Fernꢂndez, C. Claver, S. Castillꢃn,
Tetrahedron Lett. 2003, 44, 6073.
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 4222 –4225