Palladium-catalyzed synthesis of 2-substituted benzothiazoles via a C-H functionalization/intramolecular C-S bond formation process

Article abstract of DOI:10.1021/ol802033p

(Chemical Equation Presented) Catalytic synthesis of 2-substituted benzothiazoles from thiobenzanilides was achieved in the presence of a palladium catalyst through C-H functionalization/C-S bond formation. This method features the use of a novel catalytic system consisting of 10 mol % of Pd(II), 50 mol % of Cu(I), and 2 equiv of Bu₄NBr that produced variously substituted benzothiazoles in high yields with good functional group tolerance.

Full text of DOI:10.1021/ol802033p

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5147-5150
Palladium-Catalyzed Synthesis of
2-Substituted Benzothiazoles via a C-H
Functionalization/Intramolecular C-S
Bond Formation Process
Kiyofumi Inamoto,* Chisa Hasegawa, Kou Hiroya, and Takayuki Doi*
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
inamoto@mail.pharm.tohoku.ac.jp; doi_taka@mail.pharm.tohoku.ac.jp
Received September 7, 2008
ABSTRACT
Catalytic synthesis of 2-substituted benzothiazoles from thiobenzanilides was achieved in the presence of a palladium catalyst through C-H
functionalization/C-S bond formation. This method features the use of a novel catalytic system consisting of 10 mol % of Pd(II), 50 mol %
of Cu(I), and 2 equiv of Bu4NBr that produced variously substituted benzothiazoles in high yields with good functional group tolerance.
Transition metal-catalyzed C-H functionalization has emerged,
over the past decade, as a highly attractive and powerful
strategy to construct complex molecules.1 Various catalytic
systems based on rhodium,2 ruthenium,3 and palladium4 have
been developed to effect C-C and C-heteroatom (nitrogen
and oxygen) bond formation. Copper has also been used to
catalyze this process recently.5 In this area, intermolecular
C-H functionalization has been extensively studied, while
much less attention has been paid to intramolecular func-
tionalization, which would provide more facile access to a
range of carbo- and heterocycles.2a,e,3b,4c,bb,6-8 Our group
has already developed an efficient method for indazole
synthesis through a palladium-catalyzed C-H functional-
ization/intramolecular amination sequence.6 Recently, Buch-
wald reported a new approach to benzimidazoles making use
of a copper-catalyzed intramolecular C-H amination reac-
tion.7 During the preparation of this manuscript, Nagasawa
reported the synthesis of 2-arylbenzoxazoles via intramo-
lecular C-O oxidative coupling in the presence of 20 mol
% of Cu(OTf)2.8 In this communication, we wish to describe
a novel Pd-catalyzed cyclization of thiobenzanilides through
a C-H functionalization/C-S bond formation process,
leading to a range of substituted benzothiazoles. Yields were
generally good to high in this cyclization and good functional
group tolerance (e.g., ethoxycarbonyl, cyano, etc.) was
(1) For recent reviews on transition metal-catalyzed C-H functional-
ization, see: (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(b) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (c) Herrer´ıas, C. I.;
Yao, X.; Li, Z.; Li, C.-J. Chem. ReV. 2007, 107, 2546. (d) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (e) Campos, K. R.
Chem. Soc. ReV. 2007, 36, 1069. (f) Ackermann, L. Synlett 2007, 507. (g)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(2) For selected recent examples, see (C-N bond formation): (a) Shen,
M.; Leslie, B. E.; Driver, T. G. Angew. Chem., Int. Ed. 2008, 47, 5056. (b)
Liang, C.; Collet, F.; Robert-Peillard, F.; Mu¨ller, P.; Dodd, R. H.; Dauban,
P. J. Am. Chem. Soc. 2008, 130, 343. (c) Fiori, K. W.; Du Bois, J. J. Am.
Chem. Soc. 2007, 129, 562 (C-C bond formation): (d) Umeda, N.; Tsurugi,
H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47, 4019. (e) Tsai,
A. S.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6316.
(3) For selected recent examples, see (C-N bond formation): (a) Lin,
X.; Che, C.-M.; Phillips, D. L. J. Org. Chem. 2008, 73, 529 (C-C bond
formation): (b) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008,
10, 2299. (c) Foley, N. A.; Gunnoe, T. B.; Cundari, T. R.; Boyle, P. D.;
Petersen, J. L. Angew. Chem., Int. Ed. 2008, 47, 726. (d) Matsuura, Y.;
Tamura, M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem.
Soc. 2007, 129, 9858.
10.1021/ol802033p CCC: $40.75
Published on Web 10/24/2008
2008 American Chemical Society

observed in our catalyst system. Indeed, the method devel-
oped here represents a rare example of C-S bond formation
through transition-metal-catalyzed C-H functionalization.9
Benzothiazoles are a considerably important class of
heterocycles in the medicinal area due to their broad range
of biological activities.10 Oxidative cyclization of thioben-
zanilides using various oxidants, including Jacobson’s and
Hugershoff’s methods, has been among the most widely used
routes to benzothiazoles.11,12 However, low functional group
tolerance is a major drawback of these methods as substit-
uents such as the alkoxycarbonyl group or the cyano group
seem difficult to retain intact in Jacobson’s synthesis.12c
Using stoichiometric or excess amounts of toxic reagents,
such as bromine12a or metals,12c,e may also have disadvan-
tages. Pd- or Cu-catalyzed cyclization of 2-halophenylth-
iobenzamides provide another access to benzothiazoles.13 It
is necessary to prefunctionalize starting materials in this
reaction, which significantly limits the utility and applicability
of this approach.
We began our study by examining the reaction of
thiobenzanilide 1 to 2-phenylbenzothiazole 2 in DMSO to
obtain the optimal reaction conditions (Table 1). During an
Table 1. Effect of Reaction Parameters
yielda
(%)
(4) For selected recent examples, see (C-C bond formation): (a) Shi,
B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008,
47, 4882. (b) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int.
Ed. 2008, 47, 1115. (c) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc.
2008, 130, 5636. (d) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan,
A. S. C. J. Am. Chem. Soc. 2008, 130, 3304. (e) Campeau, L.-C.; Schipper,
D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266. (f) Lebrasseur, N.;
Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (g) Zhang, Y.; Feng, J.; Li,
C.-J. J. Am. Chem. Soc. 2008, 130, 2900. (h) Larive´e, A.; Mousseau, J. J.;
Charette, A. B. J. Am. Chem. Soc. 2008, 130, 52. (i) Brasche, G.; Garc´ıa-
Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. (j) Potavathri, S.;
Dumas, A. S.; Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef,
B. Tetrahedron Lett. 2008, 49, 4050. (k) Gorelsky, S. I.; Lapointe, D.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848. (l) Chiong, H. A.; Daugulis,
O. Org. Lett. 2007, 9, 1449. (m) Chiong, H. A.; Pham, Q.-N.; Daugulis, O.
J. Am. Chem. Soc. 2007, 129, 9879. (n) Seregin, I. V.; Ryabova, V.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (o) Chuprakov, S.;
Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett. 2007, 9, 2333. (p)
Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
14570. (q) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
(r) Shabashov, D.; Daugulis, O. Org. Lett. 2006, 8, 4947. (s) Lafrance, M.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496. (t) Deprez, N. R.; Kalyani,
D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (u)
Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (v) Delcamp, J. H.;
White, M. C. J. Am. Chem. Soc. 2006, 128, 15076. (w) Campeau, L.-C.;
Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020. (x) Kalyani,
D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 7330. (y) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.,
Gevorgyan, V. Org. Lett. 2004, 6, 1159 (C-halogen bond formation): (z)
Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8,
2523(C-N bond formation): (aa) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am.
Chem. Soc. 2006, 128, 9048. (bb) Tsang, W. C. P.; Zheng, N.; Buchwald,
entry “Pd” (mol %) “Cu” (mol %) Bu4NBr cosolvent
1b Pd(OAc)2 (30) Cu(OAc)2 (100)
-
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-
+
-
+
-
+
-
-
-
-
-
-
-
-
-
-
-
16
49
56
12
47
31
13
8
2
3
4
5
6
7
8
9
Pd(OAc)2 (30) Cu(OAc)2 (100)
PdCl2 (30)
PdCl2 (30)
PdCl2 (30)
PdCl2 (30)
PdCl2 (30)
PdCl2 (30)
PdCl2 (20)
Cu(OAc)2 (100)
Cu(OTf)2 (100)
Cu(acac)2 (100)
CuF2 (100)
CuCl2 (100)
CuBr2 (100)
CuI (100)
65
65
42
10 PdCl2 (20)
11 PdCl2 (10)
12 PdCl2 (10)
13 PdCl2 (10)
14 PdCl2 (10)
15 PdCl2 (10)
16 PdCl2 (10)
CuI (50)
CuI (50)
CuI (50)
dioxane 31
o-xylene 45
2-BuOH 43
CuI (50)
CuI (50)
CuI (50)
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
48
74
79
79
53
<2
34
3
CuI (50)
17 PdCl2(cod) (10) CuI (50)
18 PdBr2 (10)
19 PdCl2 (5)
20 PdCl2 (10)
21 PdCl2 (10)
22 PdCl2 (10)
CuI (50)
CuI (50)
CuI (100)
0
0
23
24
25
0
0
0
CuI (50)
CuI (50)
0
0 (84)c
0
0 (quant)c
a Yield of isolated product from reaction on a 0.14-0.29 mmol scale.
b 39 h. c Yield of recovered starting material in parentheses.
S. L. J. Am. Chem. Soc. 2005, 127, 14560
.
(5) (C-heteroatom bond formation): (a) Zhao, B.; Du, H.; Shi, Y. J. Am.
Chem. Soc. 2008, 130, 7220. (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790 (C-C bond formation). (c)
Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (d) Phipps,
R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (e)
initial screening of the palladium/reoxidant combination, we
found that the addition of Bu4NBr considerably enhanced
this process (Table 1, entry 1 vs entry 2). Encouraged by
this result, we further examined this reaction using PdCl2 as
a palladium source. CuI proved to be best among an array
of copper salts tested (Table 1, entries 3-9). Interestingly,
the catalytic activity was maintained when the amount of
CuI was decreased to 50 mol % (Table 1, entries 10 and
11). The cosolvent effect was also investigated in the
Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968
(6) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org.
Lett. 2007, 9, 2931
(7) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932
(8) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411
.
.
.
.
(9) Very recently, we reported the Pd(II)-catalyzed one-pot conversion
of thioenols into benzo[b]thiophenes via the formation of disulfides, see:
Inamoto, K.; Arai, Y.; Hiroya, K.; Doi, T. Chem. Commun. 2008, DOI:
10.1039/<B811362A>
.
(10) For selected recent examples, see: (a) Kok, S. H. L.; Gambari, R.;
Chui, C. H.; Yuen, M. C. W.; Lin, E.; Wong, R. S. M.; Lau, F. Y.; Cheng,
G. Y. M.; Lam, W. S.; Chan, S. H.; Lam, K. H.; Cheng, C. H.; Lai, P. B. S.;
Yu, M. W. Y.; Cheung, F.; Tang, J. C. O.; Chan, A. S. C. Bioorg. Med.
Chem. 2008, 16, 3626. (b) Liu, C.; Lin, J.; Pitt, S.; Zhang, R. F.; Sack,
J. S.; Kiefer, S. E.; Kish, K.; Doweyko, A. M.; Zhang, H.; Marathe, P. H.;
Trzaskos, J.; Mckinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven, G. L.;
Leftheris, K. Bioorg. Med. Chem. Lett. 2008, 18, 1874. (c) Henriksen, G.;
Hauser, A. I.; Westwell, A. D.; Yousefi, B. H.; Schwaiger, M.; Drzezga,
(12) For selected recent examples, see: (a) Thiel, O. R.; Bernard, C.;
King, T.; Dilmeghani-Seran, M.; Bostick, T.; Larsen, R. D.; Faul, M. M. J.
Org. Chem. 2008, 73, 3508. (b) Bose, D. S.; Idrees, M.; Srikanth, B.
Synthesis 2007, 819. (c) Wang, M.; Gao, M.; Mock, B. H.; Miller, K. D.;
Sledge, G. W.; Hutchins, G. D.; Zheng, Q.-H. Bioorg. Med. Chem. 2006,
14, 8599. (d) Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71, 8261. (e)
Mu, X.-J.; Zou, J.-P.; Zeng, R.-S.; Wu, J.-C. Tetrahedron Lett. 2005, 46,
4345.
(13) (a) Vera, M. D.; Pelletier, J. C. J. Comb. Chem. 2007, 9, 569. (b)
Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (c) Joyce, L. L.;
Evindar, G.; Batey, R. A. Chem. Commun. 2004, 446. (d) Bened´ı, C.; Bravo,
F.; Uriz, P.; Ferna´ndez, E.; Claver, C.; Castillo´n, S. Tetrahedron Lett. 2003,
44, 6073.
A.; Wester, H.-J. J. Med. Chem. 2007, 50, 1087
.
(11) Metzger, J. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 6, pp
322-326.
5148
Org. Lett., Vol. 10, No. 22, 2008

Table 2. Synthesis of Variously Substituted 2-Arylbenzothiazoles
a Yield of isolated product from reaction on a 0.14 mmol scale. b A: with PdCl2, B: with PdCl2(cod), C: with PdBr2. c Formation of the corresponding
benzanilide was observed (58-76%). d Obtained as a mixture of the desired product and its dehalogenated compound (up to 11%). Yield was determined
by H NMR spectrum. e 6 h.
1
presence of 10 mol % of PdCl2 and 50 mol % of CuI (Table
1, entries 12-16). When NMP was used as a cosolvent (1:1
ratio) the process was greatly accelerated; the desired
cyclized product was obtained in 74% yield using these
conditions (Table 1, entry 16). PdCl2(cod) and PdBr2 were
found to have comparable catalytic activity (Table 1, entries
17 and 18). The combination of PdCl2 and CuI in the absence
of Bu4NBr had no catalytic activity at all (entry 20).
Essentially, no satisfactory results were obtained when only
a palladium or copper salt was used in this cyclization (Table
1, entries 21-24).14
With the optimized reaction conditions identified, the scope
of this method was investigated using variously substituted
thiobenzanilides 3 (Table 2), which were readily prepared
from condensation of the corresponding anilines and benzoyl
chlorides followed by thionation.14 As indicated in Table 2,
a range of 2-arylbenzothiazoles with both electron-donating
and electron-withdrawing groups were produced in high
yields using the optimal reaction conditions. A particularly
appealing feature of this system is its functional group
compatibility; the alkoxycarbonyl group (entry 11), the cyano
group (entries 10 and 15), and the halogen atoms including
iodine (entries 4-8 and 14) are well tolerated during the
reaction. The reactions of substrates which possess a sub-
stituent at the 3-position (3b and 3f) occurred regioselectively
at the less sterically hindered 6-position; the corresponding
benzothiazoles (4b and 4f) were obtained exclusively and
no regioisomers were observed (entries 2 and 6).
The developed method can be successfully extended to
the synthesis of 2-aminobenzothiazole. Substrate 5 thus
underwent the Pd-catalyzed cyclization to give the cyclized
product 6 in 68% yield (Scheme 1).
Although extensive studies on reaction mechanism have
not yet been carried out, a mechanism analogous to those
proposed for similar palladium-catalyzed processes might be
(14) For synthetic procedures in preparation of starting materials,
analytical data, and detailed results of screenings, see the Supporting
Information.
Org. Lett., Vol. 10, No. 22, 2008
5149

the starting materials is also highly appealing. This versatile
synthetic method is expected to find valuable application in
various areas, especially in medicinal chemistry. Our results
clearly demonstrate the potential of the catalytic approach
with palladium in the synthesis of sulfur-based heterocycles.
Further investigations to understand the precise reaction
mechanism as well as to apply this system to the construction
of other sulfur-based heterocycles are underway.
Scheme 1. Synthesis of 2-Aminobenzothiazole 6
applicable to this cyclization.4aa,bb,6 It is conceivable that
Bu4NBr, along with CuI, might be involved in the reoxidation
step of palladium(0) in the catalytic cycle.
In summary, we have achieved the catalytic C-H func-
tionalization/C-S bond formation sequence employing 10
mol % of palladium(II) catalysts in the synthesis of 2-sub-
stituted benzothiazoles. The use of Bu4NBr greatly enhanced
this transformation, which enabled this process to be
performed efficiently and quickly. In addition to the general-
ity with respect to the substrate scope, facile accessibility to
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Young Scientists (B) from the Japan Society
for the Promotion of Science (JSPS).
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic and analytical data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL802033P
5150
Org. Lett., Vol. 10, No. 22, 2008