Palladium-catalyzed C-H cyclization in water: A milder route to 2-arylbenzothiazoles

Article abstract of DOI:10.1055/s-0031-1291164

Water was successfully employed as a reaction medium in palladium-catalyzed C-H cyclization of thiobenzanilides. Reactions efficiently proceeded under considerably mild conditions such as 40 °C in water, providing a more practical, greener method for the synthesis of 2-arylbenzothiazoles. For some substrates, the addition of an amphiphilic surfactant greatly enhanced the process. The method represents a rare example of palladium-catalyzed C-H functionalization processes performed in water. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291164

1678▌
LETTER
letter
Palladium-Catalyzed C–H Cyclization in Water: A Milder Route to 2-Aryl-
benzothiazoles
Palladium-Catalyzed C–H Cyclization in Water
Kiyofumi Inamoto,* Kanako Nozawa, Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Fax +81(22)7955917; E-mail: inamoto@m.tohoku.ac.jp; E-mail: ykondo@m.tohoku.ac.jp
Received: 29.02.2012; Accepted after revision: 19.04.2012
an amphiphilic surfactant greatly enhanced the cycliza-
Abstract: Water was successfully employed as a reaction medium
tion process.6 Compared to the previously reported meth-
in palladium-catalyzed C–H cyclization of thiobenzanilides. Reac-
ods,4 the reactions efficiently proceeded under
considerably milder conditions (40 °C vs. 100–120 °C) in
tions efficiently proceeded under considerably mild conditions such
as 40 °C in water, providing a more practical, greener method for
the synthesis of 2-arylbenzothiazoles. For some substrates, the ad- water, thus resulting in a more practical, greener synthesis
of benzothiazoles.7–9
dition of an amphiphilic surfactant greatly enhanced the process.
The method represents a rare example of palladium-catalyzed C–H
functionalization processes performed in water.
Table 1 Effect of Reaction Parametersa
Key words: palladium, catalysis, heterocycles, water, C–H func-
tionalization
H
N
"Pd" cat. (x mol%)
Base (1 equiv)
Ph
N
Ph
S
H2O, 40 °C, 24 h
O2 (1 atm)
S
2a
H
The use of water as a solvent for organic synthesis has re-
cently attracted considerable attention because it offers a
range of advantages such as inexpensiveness, wide avail-
ability, nontoxicity, and nonflammability, thus providing
highly economic and sustainable synthetic routes.1 While
its use is sometimes hampered by the insolubility of the
polar organic molecules, the addition of an amphiphilic
surfactant, forming micelles, has been known to have a
positive effect for the reactions conducted in water, result-
ing from hydrophobic and concentration effects in the mi-
croheterogeneous two-phase system.2
1a
Entry Pd catalyst (mol%)
Base
Yield (%)b
1
2
PdCl2 (10)
CsF
0
0
PdCl2 (10) + TMEDA (10)
PdCl2 (10) + bipyridyl (10)
PdCl2 (10) + proline (10)
PEPPSI-IPr (10)
CsF
3
CsF
0
4
CsF
0
5
CsF
0
6
PdCl2 (10) + t-Bu3P·HBF4 (10)
PdCl2 (10) + DPEPhos (10)
PdCl2 (10) + Ph3P (20)
CsF
0
Considerable progress has been made in the development
of novel transformations via transition-metal-catalyzed
C–H functionalization recently. A wide range of catalytic
systems, which successfully effect carbon–carbon and
carbon–heteroatom bond-forming reactions, have so far
been developed.3 Very recently, our group reported a
versatile synthetic method for preparing 2-arylbenzo-
thiazoles involving a palladium-catalyzed C–H function-
alization–intramolecular C–S formation process.4 Indeed,
this represents a rare example of C–S formation through
transition-metal-catalyzed C–H functionalization.5 Al-
though variously substituted 2-arylbenzothiazoles can be
obtained by using the method, the process requires harsh
reaction conditions in terms of high temperatures (100–
120 °C); therefore, the development of a milder approach
for synthesizing benzothiazoles is still of considerable im-
portance from a point of view of applicability.
7
CsF
0
8
CsF
14
54
21
53
54
63
63
55
47
83
64
13
9
PdCl2 (10) + P(2-Tol)3 (20)
PdCl2 (10) + P(2-Tol)3 (20)
PdCl2 (10) + P(2-Tol)3 (20)
PdCl2 (10) + P(2-Tol)3 (20)
PdCl2 (10) + P(2-Tol)3 (20)
PdBr2 (10) + P(2-Tol)3 (20)
Pd(OAc)2 (10) + P(2-Tol)3 (20)
Pd(acac)2 (10) + P(2-Tol)3 (20)
Pd2(dba)3 (5) + P(2-Tol)3 (20)
Pd2(dba)3 (5) + P(2-Tol)3 (20)
Pd2(dba)3 (5) + P(2-Tol)3 (20)
CsF
10
11
12
13
14
15
16
17
18c
19d
KF
NaOMe
K2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Herein, we describe our finding that palladium-catalyzed
C–H cyclization of thiobenzanilides can be successfully
performed in water by carefully tuning the catalytic sys-
tem. For some substrates, it was found that the addition of
a Reaction was run on a 0.15 mmol scale in H2O (3 mL).
b Isolated yield.
c Under an air atmosphere.
d Performed at r.t.
SYNLETT 2012, 23, 1678–1682
Advanced online publication: 13.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291164; Art ID: ST-2012-U0182-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed C–H Cyclization in Water
1679
We began our investigation using thiobenzanilide (1a) to electron-withdrawing group afforded the cyclized prod-
identify the optimal reaction conditions that would pro- ucts 2e–n,q–s generally in lower yields (Table 2, entries
duce the desired product 2a in water (Table 1). On the ba- 5–14 and 17–19, conditions A). However, further exami-
sis of our recent report,4b the reaction of 1a in water was nation of the reaction conditions revealed that the addition
first carried out in the presence of 10 mol% of PdCl2 and of a surfactant such as Triton X-100 greatly enhances the
one equivalent of CsF at 40 °C under an O2 atmosphere. process (Table 2, entries 5–14 and 17–19, conditions B).10
However, no desired benzothiazole 2a was obtained (Ta- In this benzothiazole synthesis, yields are generally high
ble 1, entry 1). Thus, the effect of a ligand was next eval- and are comparable to those from previously established
uated (Table 1, entries 2–9). A range of ligands, including methods.4 Good functional-group compatibility (e.g., cy-
diamines, amino acids, NHC, and phosphines, were test- ano, alkoxycarbonyl) is also observed. It is particularly
ed, and it was found that 2a was obtained only when a noteworthy that the whole range of halogen atoms, includ-
monodentate arylphosphine was employed for the process ing iodine, can be incorporated (Table 2, entries 9–13).
(Table 1, entries 8 and 9). Among them, P(2-Tol)3 gave Moreover, substrates possessing a heteroaromatic ring
the best result, giving rise to 2a in 54% yield (Table 1, en- system (1t and 1u) were found to be suitable for the pro-
try 9). A subsequent screening of base (Table 1, entries cess although the yields were moderate (Table 2, entries
10–13) revealed that the use of Rb2CO3 gave a slightly 20 and 21).11
better result (Table 1, entry 13). Examination of the opti-
In conclusion, we have demonstrated that the Pd-cata-
mal palladium source (Table 1, entries 14–17) resulted in
lyzed C–H cyclization of thiobenzanilides can be success-
the finding that the use of Pd(0) such as Pd2(dba)3 provid-
fully performed in water. For reactions of some substrates,
ed 2a in high yield (Table 1, entry 17). The reaction car-
the addition of an amphiphilic surfactant greatly improved
ried out under an air atmosphere gave a somewhat lower
the yields. Variously substituted 2-arylbenzothiazoles
yield, suggesting that O2 efficiently worked as an oxidant
were efficiently obtained generally in high yields under
for the process (Table 1, entry 18). Unfortunately, the re-
considerably mild conditions (40 °C) in water, which
action performed at room temperature resulted in a forma-
compares favorably with the previously reported methods
tion of 2a only in 13% yield (Table 1, entry 19).
(100–120 °C in high-boiling solvents such as DMSO and
The scope of the catalytic conditions developed above NMP).4 Indeed, this method represents a rare example of
was next evaluated using variously substituted thiobenza- Pd-catalyzed C–H functionalization processes in water.7
nilides (Table 2). Whereas substrates 1b–d,o,p, which Further investigations into the use of water as a reaction
contain an electron-donating methoxy or methyl group on medium in other Pd-catalyzed C–H functionalization pro-
the benzene ring, showed good reactivity (Table 2, entries cesses are under way.
2–4, 15, and 16), the reactions of substrates possessing an
Table 2 Substrate Scope of the Processa
Pd2(dba)3 (5 mol%)
P(2-Tol)3 (20 mol%)
Rb2CO3 (1 equiv)
H
N
Ar2
N
Ar1
Ar2
Ar1
S
H2O
[Triton X-100 (30 mol%)]
40 °C, 24 h
S
H
1
2
O2 (1 atm)
Entry Substrate
1
Product
2
Yield (%)b
Yield (%)b
for conditions Ac
for conditions Bc
H
N
S
N
1
1a
2a
83
–
S
H
N
S
H
N
2
3
1b
1c
2b
2c
80
90
–
–
MeO
MeO
S
H
MeO
MeO
H
N
N
S
S
H
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1678–1682

1680
K. Inamoto et al.
LETTER
Table 2 Substrate Scope of the Processa (continued)
Pd2(dba)3 (5 mol%)
P(2-Tol)3 (20 mol%)
Rb2CO3 (1 equiv)
H
N
Ar2
N
Ar1
Ar2
Ar1
S
H2O
[Triton X-100 (30 mol%)]
40 °C, 24 h
S
H
1
2
O2 (1 atm)
Entry Substrate
1
Product
2
Yield (%)b
Yield (%)b
for conditions Bc
for conditions Ac
H
N
N
S
4
1d
2d
quant.
–
S
H
512
N
S
H
N
1e
1f
2e
2f
10
18
21
15
55
30
27
14
62
77
74
61
84
83
82
86
70
75
O2N
S
H
O2N
H
N
N
6
7
8
9
S
NC
NC
S
H
NC
NC
H
N
N
S
1g
1h
1i
2g
2h
2i
S
H
N
S
H
N
EtO2C
S
H
EtO2C
N
H
N
S
Cl
S
H
Cl
N
S
H
N
10
1j
2j
Br
Br
S
H
Br
Br
H
N
N
S
11
12
13
1k
1l
2k
2l
S
H
N
H
N
S
I
S
I
H
F
F
H
N
N
S
1m
2m
S
H
Synlett 2012, 23, 1678–1682
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed C–H Cyclization in Water
1681
Table 2 Substrate Scope of the Processa (continued)
Pd2(dba)3 (5 mol%)
P(2-Tol)3 (20 mol%)
Rb2CO3 (1 equiv)
H
N
Ar2
N
Ar1
Ar2
Ar1
S
H2O
[Triton X-100 (30 mol%)]
40 °C, 24 h
S
H
1
2
O2 (1 atm)
Entry Substrate
1
Product
2
Yield (%)b
Yield (%)b
for conditions Bc
for conditions Ac
Ph
Ph
H
N
N
S
14
1n
2n
62
87
S
H
OMe
N
S
H
N
OMe
15
16
17
1o
1p
1q
2o
2p
2q
76
86
38
–
S
S
H
N
S
H
N
–
OMe
CN
OMe
H
N
S
H
N
CN
Cl
68
S
S
H
Cl
N
S
H
N
18
1r
2r
59
64
H
OMe
N
S
H
N
OMe
19
20
21
1s
1t
2s
2t
19
17
29
70
44
69
NC
N
S
H
NC
N
H
N
N
S
S
H
H
N
N
S
1u
2u
S
S
S
H
a Reaction was run on a 0.15 mmol scale in H2O (3 mL).
b Isolated yield.
c Conditions A: without Triton X-100; conditions B: with Triton X-100.
Acknowledgment
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
This work was partly supported by a Grant-in-Aid for Scientific Re-
search (B) (No. 23390002), a Grant-in-Aid for Challenging Explo-
ratory Research (No. 23659001), and a Grant-in-Aid for Young
Scientists (B) (No. 23790002) from Japan Society for the Promoti-
on of Science.
experimental procedures and spectroscopic data.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1678–1682

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K. Inamoto et al.
LETTER
(g) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.;
References and Notes
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Chem. Commun. 2011, 47, 11775.
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(2) For reviews on the use of amphiphilic surfactants for organic
synthesis, see: (a) Dwars, T.; Paetzold, E.; Oehme, G.
Angew. Chem. Int. Ed. 2005, 44, 7174. (b) Lipshutz, B. H.;
Ghorai, S. Aldirichimica Acta 2008, 41, 59.
(3) For selected recent reviews on transition-metal-catalyzed C–
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J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (b) Baudoin,
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Shi, Z.-J. Chem. Commun. 2010, 46, 677.
(7) Only a few examples of Pd-catalyzed C–H functionalization
processes using water as a reaction medium have so far been
reported, see: (a) Turner, G. L.; Morris, J. A.; Greaney, M.
F. Angew. Chem. Int. Ed. 2007, 46, 7996. (b) Nishitaka, T.;
Lipshutz, B. H. Org. Lett. 2010, 12, 1972. (c) Ref. 6a.
(8) Several processes involving Ru-catalyzed C–H
functionalization in water have recently been reported, see:
(a) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf,
P. H. Angew. Chem. Int. Ed. 2010, 49, 6629. (b) Ackermann,
L.; Fenner, S. Org. Lett. 2011, 13, 6548. (c) Ackermann, L.;
Wang, L.; Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14,
728. (d) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14,
764.
(9) Pd-catalyzed C–H functionalization processes performed
under mild conditions such as room temperature still remain
an important challenge, see: Haffemayer, B.; Gulias, M.;
Gaunt, M. J. Chem. Sci. 2011, 2, 312; and references cited
therein.
(4) (a) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org.
Lett. 2008, 10, 5147. (b) Inamoto, K.; Hasegawa, C.;
Kawasaki, J.; Hiroya, K.; Doi, T. Adv. Synth. Catal. 2010,
352, 2643.
(10) Use of other surfactants such as SDS, TPGS, PTS, Brij 30,
and Brij S-100 led to somewhat decreased yields.
(5) For other examples of C–S formation via transition-metal-
catalyzed or -mediated C–H functionalization, see:
(a) Inamoto, K.; Arai, Y.; Hiroya, K.; Doi, T. Chem.
Commun. 2008, 5529. (b) Zhao, X.; Dimitrijević, E.; Dong,
V. M. J. Am. Chem. Soc. 2009, 131, 3466. (c) Fukuzawa,
S.-i.; Shimizu, E.; Atsumi, Y.; Haga, M.; Ogata, K.
Tetrahedron Lett. 2009, 50, 2374. (d) Joyce, L. L.; Batey,
R. A. Org. Lett. 2009, 11, 2792. (e) Chu, L.; Yue, X.; Qing,
F.-L. Org. Lett. 2010, 12, 1644. (f) Zhang, S.; Qian, P.;
Zhang, M.; Hu, M.; Cheng, J. J. Org. Chem. 2010, 75, 6732.
(g) Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu, P. M.;
Mahon, M. F.; Kociok-Köhn, G.; Whittlesey, M. K.; Frost,
C. G. J. Am. Chem. Soc. 2011, 133, 19298. (h) For selected
recent examples for the synthesis of 2-arylbenzothiazoles
from thiobenzanilides, see: Bose, D. S.; Idrees, M. J. Org.
Chem. 2006, 71, 8261. (i) See also: Bose, D. S.; Idrees, M.;
Srikanth, B. Synthesis 2007, 819. (j) See also: Moghaddam,
F. M.; Zargarani, D. J. Sulfur Chem. 2009, 30, 507. (k) See
further: Wang, H.; Wang, L.; Shang, J.; Li, X.; Wang, H.;
Gui, J.; Lei, A. Chem. Commun. 2012, 48, 76.
(6) For selected recent reports on the use of amphiphilic
surfactants in transition-metal-catalyzed processes, see:
(a) Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Angew.
Chem. Int. Ed. 2010, 49, 781. (b) Krasovskiy, A.; Duplais,
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Masini, T.; Nucara, L.; Bellina, F.; Rossi, R. Adv. Synth.
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12, 790. (f) Cicco, S. R.; Farnola, G. M.; Martinelli, C.;
Naso, F.; Tiecco, M. Eur. J. Org. Chem. 2010, 2275.
(11) (a) As preliminary mechanistic studies, reactions using the
isotopically labeled substrates were carried out, which
resulted in the observation of KIEs (kinetic isotope effects)
of 2.3–2.7. For details, see Supporting Information. (b) For
C–S bond-forming reductive elimination from Pd(IV)
complexes, see: Zhao, X.; Dong, V. M. Angew. Chem. Int.
Ed. 2011, 50, 932.
(12) Representative Procedure for the Synthesis of 2-
Arylbenzothiazoles (Table 2, Entry 5, Conditions B)
Under an O2 atmosphere, a mixture of N-(4-nitrophenyl)-
thiobenzamide (1e, 37.2 mg, 0.14 mmol), Pd2(dba)3 (7.4 mg,
0.0081 mmol), tris(2-methylphenyl)phosphine (9.6 mg, 0.32
mmol), Rb2CO3 (36.2 mg, 0.16 mmol), and Triton X-100
(29.7 mg, 0.048 mmol) in H2O (3 mL) was stirred for 24 h at
40 °C. The reaction mixture was diluted with sat. aq NH4Cl
(5 mL) and extracted with CHCl3 (3 × 30 mL), and then the
combined organic layer was dried over Na2SO4. The solvent
was removed under a reduced pressure, and the residue was
purified by SiO2 column chromatography (eluent; 1%
EtOAc in hexane) to give 6-nitro-2-phenylbenzothiazole
(2e, 28.3 mg, 77%). Recrystallization from EtOAc–hexane
gave pale orange prisms, mp 191–192 °C. 1H NMR (400
MHz, CDCl3/TMS): δ = 7.50–7.56 (m, 3 H), 8.09–8.12 (m,
3 H), 8.34 (dd, 1 H, J = 9.0, 2.3 Hz), 8.81 (d, 1 H, J = 2.3 Hz)
ppm. 13C{1H} NMR (100 MHz, CDCl3/TMS): δ = 118.1,
121.8, 123.2, 127.8, 129.2, 132.1, 132.6, 135.2, 144.8,
157.7, 173.6 ppm. LRMS (EI): m/z = 256 [M+]. HRMS:
m/z calcd for C13H8N2O2S: 256.0307; found: 256.0287. IR
(neat): 1518, 1333 cm–1.
Synlett 2012, 23, 1678–1682
© Georg Thieme Verlag Stuttgart · New York

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