Direct oxidative C-H arylation of benzoxazoles with arylsulfonyl hydrazides promoted by palladium complexes

Article abstract of DOI:10.1055/s-0032-1317350

This study describes a direct oxidative C-2 arylation of benzoxazoles using arylsulfonyl hydrazides as the aryl sources. A simple catalyst system [Pd(OAc)₂ and Ph₃P] allows the reactions to proceed smoothly under oxidative reaction conditions. Other heteroarenes such as caffeine and benzothiazole are also applicable substrates. Notably, this catalytic system tolerates halogen substituents which provides a useful complement to the current cross-coupling reactions which use aryl halides. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317350

2714▌
LETTER
lDettierrect Oxidative C–H Arylation of Benzoxazoles with Arylsulfonyl Hydrazides
Promoted by Palladium Complexes
Oxidative C–H Arylation of Benzoxazoles using Arylsulfonyl Hydrazides
On Ying Yuen, Chau Ming So, Wing Tak Wong, Fuk Yee Kwong*
State Key Laboratory of Chirosciences, PolyU Shenzhen Research Institute (SZRI) and Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, P. R. of China
Fax +852(2364)9932; E-mail: fuk-yee.kwong@polyu.edu.hk
Received: 21.08.2012; Accepted after revision: 11.09.2012
ArZnCl) or require isolation, in general, prior to the catal-
Abstract: This study describes a direct oxidative C-2 arylation of
ysis [e.g. ArB(OH)2]. Thus, the assembling and subse-
benzoxazoles using arylsulfonyl hydrazides as the aryl sources. A
quent disposal of stoichiometric organometallic agents
are relatively not desirable. In fact, direct C–H functional-
simple catalyst system [Pd(OAc)2 and Ph3P] allows the reactions to
proceed smoothly under oxidative reaction conditions. Other
heteroarenes such as caffeine and benzothiazole are also applicable ization of heteroarenes is actually more straightforward.
substrates. Notably, this catalytic system tolerates halogen substitu-
ents which provides a useful complement to the current cross-
coupling reactions which use aryl halides.
This protocol serves as an attractive alternative to conven-
tional coupling protocols in terms of better atom econo-
my, environmental friendliness and more streamlined
chemical synthesis.3,4
Key words: palladium, arylation, arylsulfonyl chlorides, phosphine,
benzoxazoles
In continuing our research focus of applying arylsulfonyl
compounds as effective aryl sources,5 we envisioned that
arylsulfonyl hydrazides could be employed as versatile
Cross-coupling protocols have been successful in modern
arylating agents. Indeed, arylsulfonyl hydrazides are sta-
modular organic syntheses for the connection of two dif-
ble under air and can be simply prepared in one step from
ferent fragments via the formation of carbon–carbon
commonly available arylsulfonyl chlorides and hydrazine
and/or carbon–heteroatom bonds.1 To prepare useful bi-
hydrates. During the process of this work, Tian and co-
aryl motifs,2 coupling methods such as Hiyama, Kumada,
workers reported the first palladium-catalyzed Heck-type
Negishi, Stille and Suzuki–Miyaura coupling have been
reaction of alkenes with arylsulfonyl hydrazides.6 To the
found to be versatile in the past few decades.1 Even
best of our knowledge, the direct C–H arylation of benz-
though these reactions are effective, some intrinsic draw-
oxazoles remain sporadically studied.7 In fact, with re-
backs still exist in which the corresponding organometal-
spect to the reaction of olefins, the arylation of
lic nucleophiles must be prepared in situ (e.g. ArMgBr,
Pd(OAc)2 (5 mol%)
O
N
N
O
ligand (10 mol%)
+
Me
S
NHNH2
H
Me
Cu(OAc)2
dioxane, 120 °C
'under air'
O
O
ligand:
Me
Me
N
Me
N
N
Cy3P
Ph3P
(82%)
(47%)
Cy2P
Ph2P
i-Pr2P
CM-phos
(49%)
L1
(44%)
L2
(41%)
Me
Me
N
Me
N
Me
N
OMe
N
PCy2
L3
PPh2
PPh2
PPh2
L4
(44%)
PPh2-Andole phos
(52%)
L5
(57%)
(46%)
Scheme 1 A survey of ligand effect in oxidative arylation of benzoxazole
SYNLETT 2012, 23, 2714–2718
Advanced online publication: 09.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317350; Art ID: ST-2012-W0702-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative C–H Arylation of Benzoxazoles using Arylsulfonyl Hydrazides
2715
heteroarenes is known to be even more challenging be- The palladium complex associated with triphenylphos-
cause of the undesirable homocoupling outcome and de- phine gave slightly higher yield (entry 9 vs. entry 13).
composition of heteroarenes is often observed under Common inorganic/organic oxidants were also surveyed
oxidative conditions. In continuation of our research pro- (entries 1 and 14–21). Copper(II) acetate gave the best re-
gram on C-2 functionalization of benzoxazoles,8 we here- sults while BQ and O2 provided inferior product yields. In
in report our efforts in the palladium-catalyzed direct light of the successful initial results achieved, we next ex-
C–H arylation of benzoxazoles using arylsulfonyl hydra- amined the effect of phosphine ligands in this reaction
zides under oxidative reaction conditions.
(Scheme 1). Palladium(II) acetate with triphenylphos-
phine promoted the reaction and gave the highest product
yield. Yet, catalytic systems employing our previously de-
veloped tunable indolylphosphine ligands L1–L5 showed
moderate efficiency (Scheme 1).9
We initially probed the efficacy of arylsulfonyl hydrazide
as the aryl source in the direct C–H arylation of hetero-
arenes (Table 1). Benzoxazole and 4-tolylsulfonyl hydra-
zide were used as benchmark substrates. Among
commonly used solvents screened, dioxane provided the With our optimized reaction conditions in hand, we next
best results (entries 1–7). There were little differences in tested the scope of arylsulfonyl hydrazides (Table 2).10
product yield observed in the model reaction when other The coupling reaction of sterically hindered 2-tolylsulfo-
palladium precursors were investigated (entries 1 and 8–13). nyl hydrazide proceeded smoothly (entry 3). Halogen sub-
Table 1 Initial Screening of Oxidative Arylation of 4-Methylbenzenesulfonyl Hydrazide and Benzoxazolea
Pd cat. (5 mol%)
'under air'
O
S
N
O
N
O
Me
NHNH2
+
H
Me
solvent
oxidant, 120 °C
O
Entry
Pd source
Solvent
Oxidant
Yield (%)b
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
dioxane
DMF
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2H2O
Cu(acac)2
CuCl2
51
6
3
DMA
39
10
34
16
0
4
NMP
5
DMSO
toluene
H2O
6
7
8
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
48
52
47
57
46
54
36
28
0
9
10
11
12
13
14
15
16
17
18
19
20
21
Pd(acac)2
PdCl2(MeCN)2
PdCl2(PCy3)2
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CuBr2
0
Pd(OAc)2
AgOAc
0
Pd(OAc)2
BQ
0
Pd(OAc)2
K2S2O8
0
Pd(OAc)2
O2
0
a Reaction conditions: 4-tolylsulfonyl hydrazide (0.45 mmol), benzoxazole (0.3 mmol), Pd catalyst (5 mol%), solvent (3 mL) and oxidant
(0.6 mmol) were stirred at 120 °C for 18 h under air.
b Calibrated GC yields were reported using dodecane as internal standard.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2714–2718

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O. Y. Yuen et al.
LETTER
Table 2 Palladium-Catalyzed Oxidative Arylation of Benzoxazole Using Arylsulfonyl Hydrazidesa
Pd(OAc)2 (5 mol%)
Ph3P (10 mol%)
O
S
N
O
N
O
NHNH2
+
H
Cu(OAc)2
dioxane, 120 °C
'under air'
R
R
O
1
2a
3
Entry
1c
ArSO2NHNH2
Benzoxazole
Product
Yield (%)b
76
O
N
N
O
N
O
3aa
S
NHNH2
H
O
N
O
O
O
S
H
H
Me
Me
NHNH2
2
3ba
3ca
78
72
O
O
S
Me
N
O
NHNH2
N
3d
O
O
N
Me
O
N
O
N
O
N
O
H
H
H
F
F
S
NHNH2
4
3da
3ea
3fa
66
60
59
O
N
O
N
O
O
O
5c
6d
Cl
Br
S
NHNH2
NHNH2
Cl
Br
O
O
S
O
N
O
O
S
N
O
H
7
3ga
67
NHNH2
O
a Reaction conditions: arylsulfonyl hydrazide (0.45 mmol), benzoxazole (0.3 mmol), Pd(OAc)2 (5 mol%), Ph3P (10 mol%), dioxane (3 mL),
Cu(OAc)2 (0.6 mmol) were stirred for 18 h at 120 °C under air.
b Isolated yields.
c The reaction was conducted at 110 °C.
d The reaction was conducted at 100 °C.
stituents (F, Cl, Br) on the arylsulfonyl hydrazide were In addition to a variety of arylsulfonyl hydrazides exam-
found to be compatible under these reaction conditions ined, the substituted benzoxazoles were found to be feasi-
(entries 4–6). Particularly noteworthy is that the tolerance ble substrates (Table 3). Fluoro and chloro groups
of chloro and bromo groups can offer an avenue for fur- remained intact during the course of the reaction (entries
ther versatile functionalization using traditional cross- 5 and 6). Apart from benzoxazole, other heteroarenes
coupling protocols.1
were applicable. Caffeine and benzothiazole could be ap-
O
Me
Me
O
N
N
H
O
Me
N
N
Me
O
N
N
Me
Me
N
N
Pd(OAc)2 (5 mol%)
Ph3P (10 mol%)
Cu(OAc)2
O
S
Me
5: 63%
R
NHNH2
dioxane, 120 °C
'under air'
O
N
S
R
N
H
S
6a: R = H, 67% (110 °C)
6b: R = Me, 69%
Scheme 2 Palladium-catalyzed direct C–H arylation of caffeine and benzothiazole with arylsulfonyl hydrazides
Synlett 2012, 23, 2714–2718
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative C–H Arylation of Benzoxazoles using Arylsulfonyl Hydrazides
2717
Table 3 Palladium-Catalyzed Oxidative Arylation of Substituted Benzoxazoles with Arylsulfonyl Hydrazidesa
R2
Pd(OAc)2 (5 mol%)
Ph3P (10 mol%)
O
S
N
O
N
O
NHNH2
+
H
R2
R1
R1
Cu(OAc)2
dioxane, 120 °C
'under air'
O
1
2
3
Entry
1
ArSO2NHNH2
Benzoxazole
Product
Yield (%)b
70
O
S
Ph
Ph
N
N
O
3bb
3bc
Me
NHNH2
NHNH2
H
Me
Me
O
N
O
O
O
S
Me
Me
Me
Me
N
Me
H
H
2
75
72
O
O
O
Me
N
O
NHNH2
N
O
S
3c
3cc
3gc
O
Me
Me
O
N
O
Me
F
N
O
H
4
67
S
NHNH2
O
O
S
F
N
N
O
Me
Me
NHNH2
NHNH2
H
Me
5
6
3bd
3be
71
72
O
O
O
S
Cl
Cl
N
N
H
Me
O
O
O
a Reaction conditions: arylsulfonyl hydrazide (0.45 mmol), substituted benzoxazole (0.3 mmol), Pd(OAc)2 (5 mol%), Ph3P (10 mol%), dioxane
(3 mL), Cu(OAc)2 (0.6 mmol) were stirred for 18 h at 120 °C under air.
b Isolated yields.
c The reaction was conducted at 100 °C.
plied in this catalytic system (Scheme 2). Moderate-to-
good product yields were observed. In particular, the
product 5 is a useful fluorescent molecule for cell imag-
ing.11
References
(1) For selected book chapters and reviews, see: (a) Metal-
Catalyzed Cross-Coupling Reaction, 2nd ed., Vol. 1; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004. (b) Metal-Catalyzed Cross-Coupling Reaction, 2nd
ed., Vol. 2; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004. (c) Beller, M.; Bolm, C. Transition Metals
for Organic Synthesis, Building Blocks and Fine Chemicals,
2nd Ed., Vol. 1; Wiley-VCH: Weinheim, 2004. (d) Beller,
M.; Bolm, C. Transition Metals for Organic Synthesis,
Building Blocks and Fine Chemicals, 2nd Ed., Vol. 2;
Wiley-VCH: Weinheim, 2004. (e) Hassan, J.; Sévignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359. (f) Tsuji, J. Palladium Reagents and Catalysts, 2nd
ed.; Wiley: Chichester, 2004. (g) Yin, L.; Liebscher, J.
Chem. Rev. 2007, 107, 133. (h) Corbet, J.-P.; Mignani, G.
Chem. Rev. 2006, 106, 2651. (i) Roglans, A.; Pla-Quintana,
A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622.
(j) Ackermann, L. Modern Arylation Methods; Wiley-VCH:
Weinheim, 2009. (k) Kwong, F. Y.; Chan, A. S. C. Synlett
2008, 1440.
In summary, we have reported an oxidative protocol for
C-2 arylation of benzoxazoles using readily available and
easy-to-handle arylsulfonyl hydrazides as the aryl sourc-
es. Particularly noteworthy is that only a simple catalyst
system [Pd(OAc)2 and Ph3P] is required for this coupling
reaction. This methodology is a useful complement to the
current cross-coupling protocols as it tolerates halogen
substituents on both arylsulfonyl hydrazide and hetero-
arene coupling partners. Detail mechanistic study is cur-
rently under way.
Acknowledgment
We thank the Research Grants Council of Hong Kong (GRF:
PolyU5014/10P), the PolyU Development Grant (1BD07) and the
State Key Laboratory of Chirosciences (BBX-3) for financial sup-
port.
(2) For reviews concerning the applications of cross-coupling in
preparing pharmaceutically useful intermediates, see:
(a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
Int. Ed. 2005, 44, 4442. (b) Nicolaou, K. C.; Sorensen, E. J.
Classic in Total Synthesis II, More Targets, Strategies and
Methods; Wiley-VCH: Weinheim, 2003.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2714–2718

2718
O. Y. Yuen et al.
LETTER
(3) For recent reviews, see: (a) Alberico, D. M.; Scott, E.;
Lautens, M. Chem. Rev. 2007, 107, 174. (b) Daugulis, O.;
Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
(c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem. Int. Ed. 2009, 48, 5094. (d) Ackermann, L.; Vicente,
R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48, 9792.
(e) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269.
(f) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351,
673. (g) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (h) Dyker, G. Handbook of C–H Transformations;
Wiley-VCH: Weinheim, 2005.
(4) For recent notable advancements in C–H functionalization,
see: (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
(b) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(c) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science
2010, 327, 315.
(5) (a) So, C. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40, 4963.
For our recent references, see: (b) Chow, W. K.; So, C. M.;
Lau, C. P.; Kwong, F. Y. Chem.–Eur. J. 2011, 17, 6913.
(c) Wong, P. Y.; Chow, W. K.; Chung, K. H.; So, C. M.;
Lau, C. P.; Kwong, F. Y. Chem. Commun. 2011, 47, 8328.
(d) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y.
Angew. Chem. Int. Ed. 2010, 49, 8918. (e) Choy, P. Y.;
Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. Chem.–
Eur. J. 2010, 16, 9982. (f) Chow, W. K.; So, C. M.; Lau, C.
P.; Kwong, F. Y. J. Org. Chem. 2010, 75, 5109.
Japan (Nagoya University, Kyoto University and Kyushu
University).
(8) So, C. M.; Lau, C. P.; Kwong, F. Y. Chem. Eur. J. 2011, 17,
761.
(9) So, C. M.; Chow, W. K.; Choy, P. Y.; Lau, C. P.; Kwong, F.
Y. Chem.–Eur. J. 2010, 16, 7996.
(10) Representative Experimental Procedures: All reagents
were weighted in air and the reactions were performed in an
open vessel (60 mL vial equipped with an air condenser).
Pd(OAc)2 (0.0034 g, 0.015 mmol), Ph3P (Pd/L = 1:2),
arylsulfonyl hydrazides (0.45 mmol), heteroarenes (0.3
mmol) and Cu(OAc)2 (0.6 mmol) were loaded into a 60 mL
vial equipped with a Teflon-coated magnetic stir bar.
Dioxane (3 mL) was added at r.t. The vial was fitted with an
air condenser and then placed into a preheated oil bath with
the reaction temperature indicated in the table and the
reaction mixture was vigorously stirred for 18 h. After the
completion of reaction, the reaction vial was allowed to cool
to r.t. EtOAc (ca. 20 mL) and H2O (ca. 10 mL) were added.
The organic layer was subjected to GC analysis. After
analyzing the GC spectra, the crude product in the organic
layer was extracted and the vial was washed with EtOAc.
The filtrate was concentrated under reduced pressure. The
crude product was purified by flash column chromatography
on silica gel (230–400 mesh) to afford the desired product.
2-Phenylbenzoxazole (Table 2, entry1, compound 3aa):
eluent: EtOAc–hexane (1:20; Rf 0.62) was used for flash
column chromatography to provide compound 3aa (44.5
mg, 76 % yield) as a white solid. 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.40 (m, 2 H), 7.52–7.57 (m, 3 H), 7.58–
(6) (a) Yang, F.-L.; Ma, X.-T.; Tian, S.-K. Chem.–Eur. J. 2012,
18, 1582. (b) Note: We also presented a very similar Pd-
catalyzed arylation of terminal alkenes using arylsulfonyl
hydrazides in 2011, ACP-Lectureship Award, National
University of Singapore, Nanyang Technological
7.63 (m, 1 H), 7.79–7.83 (m, 1 H), 8.28–8.31 (m, 2 H). 13
C
University, A*Star Institute, 6–11th December 2011,
Singapore.
NMR (100 MHz, CDCl3): δ = 110.5, 120.0, 124.5, 125.1,
127.1, 127.6, 128.8, 131.5, 142.0, 150.7, 163.0. MS (EI): m/z
(relative intensity) = 195.0 (100) [M+], 167.0 (18), 139.0 (3),
92.0 (5), 63.0 (14).
(7) (a) During the preparation of this manuscript, one example
of arylation of benzoxazole with 4-tolylsulfonyl hydrazide
was reported: Liu, B.; Li, J.; Song, F.; You, J. Chem.–Eur. J.
2012, 18, 10830. (b) Note: We also presented arylation
examples of benzoxazoles and caffeines for this coupling
reaction using arylsulfonyl hydrazides, May 8–12, 2012 in
(11) (a) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao,
G.; You, J. Angew. Chem. Int. Ed. 2009, 48, 3296. (b) Kim,
D.; Jun, H.; Lee, H.; Hong, S.-S.; Hong, S. Org. Lett. 2010,
12, 1212.
Synlett 2012, 23, 2714–2718
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