Palladium-copper-catalyzed desulfitative amination of benzo[d]oxazole C-H bond

Article abstract of DOI:10.1016/j.tetlet.2012.09.044

An efficient palladium-copper-catalyzed direct C-H amination of substituted benzoxazoles with various sulfamoyl chlorides as nitrogen group sources has been developed. The system does not need a strong base and tolerates a series of functional groups, such as chloro, methyl, and nitro groups, providing the amination products in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.09.044

Tetrahedron Letters 53 (2012) 6297–6299
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Tetrahedron Letters
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Palladium-copper-catalyzed desulfitative amination of benzo[d]oxazole
C–H bond
⇑
Shuyou Chen, Kui Zheng, Fan Chen
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2012
Revised 3 September 2012
Accepted 11 September 2012
Available online 19 September 2012
An efficient palladium-copper-catalyzed direct C–H amination of substituted benzoxazoles with various
sulfamoyl chlorides as nitrogen group sources has been developed. The system does not need a strong
base and tolerates a series of functional groups, such as chloro, methyl, and nitro groups, providing the
amination products in moderate to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium-copper-catalyzed
Amination
Benzo[d]oxazole
C–H activation
The transition-metal-catalyzed amination reaction of azoles is a
highly important transformation in synthetic chemistry since these
amination products are widely employed in biological, pharmaceu-
tical, and material sciences.1 In the past decades, remarkable re-
sults have been obtained in hydroamination,2 allylic amination,3
and oxidative amidation4 of double or triple bonds. The palla-
dium-catalyzed Buchwald–Hartwig coupling,5 copper-catalyzed
Ullmann and Goldberg couplings6 and copper-promoted Chan–
Lam coupling7 are all powerful tools to fulfill these transforma-
tions. However, two functionalized precursors are required for
the aforementioned transformation. To circumvent this drawback,
the direct amination of heteroarenes C–H is undoubtedly the most
straightforward strategy on such transformations.8 As far as the
nitrogen group sources are concerned, primary and secondary
amines,9 chloroamines,10 and amides11 have been successfully in-
stalled into the corresponding substrates via C–H activation. De-
spite the remarkable success that has been achieved, to the best
of our knowledge, the desulfination of sulfamoyl chloride in the di-
rect amination reaction via C–H bond cleavage followed by C–N
bond formation has never been reported. Herein, we report the
aerobic oxidative amination of azoles with sulfamoyl chlorides as
nitrogen sources.
oxidant, affording N,N-dimethylbenzo[d]oxazol-2-amine (3aa) in
34% yield (entry 1, Table 1). A series of palladium catalysts were
screened, such as Pd2(dba)3, PdCl2(CH3CN)2, PdCl2 (entries 2–6,
Table 1), and bipyPdCl2 was found to be the best. Copper salts were
crucial for the amination reaction. After a range of copper salts
screened, CuCN was superior to others, such as Cu(OAc)2, CuCl,
CuI (entries 7–9, Table 1). The yield dramatically decreased to
10% without CuCN (entry 10, Table 1). Whereas CuCN was en-
hanced to 1.0 equiv, the yield did not improve significantly (entry
5, Table 1). We next examined the effect of oxidants on this reac-
tion (entries 15 and 16, Table 1), and K2Cr2O7 was the best. The
base played an important role in the amination reaction and
K2CO3 was superior to other bases (entries 5, 11–13, Table 1).
The solvent had a significant impact on the reaction, replacing of
PhCl with DMSO, 1,4-dioxane, or CH3CN, the reaction became slug-
gish and provided poor conversions (entries 17–19, Table 1). To our
delight, when 4 Å molecular sieves were added to the reaction
mixture, the desired product 3aa was obtained in 85% yield (entry
5, Table 1).
Further experiments showed that various substituted benzox-
azoles allowed the direct amination reaction under the optimum
reaction conditions (Table 2). Both electron-rich and electron-poor
substituted benzoxazoles were successfully converted to the corre-
sponding cross-coupling products in moderate to good yields. The
procedure was a little sensitive to the electron-nature of the sub-
stituents on the aromatic ring of the benzoxazoles. For example,
except for 3ca, electron-withdrawing groups gave a slightly higher
yield than electron-donating groups (3da, 3la vs 3ba, 3ea, and 3fa,
Table 2). Notably, the p-methoxyphenyl, p-trifluoromethylphenyl,
p-methoxycarbonylphenyl, and p-methylphenyl on benzoxazoles
During the optimization of the reaction conditions, this amina-
tion reaction was performed using benzoxazole (1a) and dim-
ethylsulfamoyl chloride (2a) as substrates as summarized in
Table 1. Initially, the reaction was performed in dry PhCl at
150 °C in the presence of Pd(O2CCF3)2/CuCN with K2Cr2O7 as the
⇑
Corresponding author.
E-mail address: fanchen@wzu.edu.cn (F. Chen).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.044

6298
S. Chen et al. / Tetrahedron Letters 53 (2012) 6297–6299
Table 1
Optimization of reaction conditionsa
O
S
O
2a
O
N
O
N
Pd source, Cu source
+
N
Cl
N
base, oxidant, solvent
150 oC
1a
3aa
Entry
Pd source
Cu source
Base
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(O2CCF3)2
Pd2(dba)3
PdCI2(CH3CN)2
PdCI2
BipyPdCI2
—
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
BipyPdCI2
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
Cu(OAc)2
CuCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
t-BuOK
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
K2Cr2O7
BQ
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
34
42
75
50
76 (85)c (76)d
66
60
62
42
10
60
18
65
<5
53
50
40
32
58
9
Cul
—
10
11
12
13
14
15
16
17
18
19
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
DDQ
—
K2Cr2O7
K2Cr2O7
K2Cr2O7
DMSO
1,4-Dioxane
CH3CN
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Pd source (10 mol %), Cu source (20 mol %), base (0.4 mmol), and oxidant (0.2 mmol), in dry PhCl (2 mL), air, 150 °C,
sealed tube, 24 h.
b
Isolated yield.
4 Å molecular sieves (50 mg).
CuCN (1.0 equiv).
c
d
Table 2
Palladium-copper-catalyzed direct amination of benzoxazole with dimethylsulfamoyl
chloridea
Table 3
Palladium-copper-catalyzed direct amination of benzoxazole with sulfamoyl chloride a
O
S
O
2a
O
N
BipyPdCl2, CuCN
O
R2
R2
R1
O
S
O
O
N
BipyPdCl2, CuCN
O
N
Cl
R
+
R
N
+
K2CO3, K2Cr2O7
PhCl, 150 oC
N
Cl
N
N
K2CO3, K2Cr2O7
PhCl, 150 oC
R1
N
1a- 1l
O
3aa-3la
3ab-3ae
1a
O
2b-2e
O
N
N
N
O
N
N
O
N
3ba, 60%
3aa, 85%
N
N
O
O
N
N
N
3ab, 61%
3ac, 52%
N
N
3da, 76%
O
Cl
O2N
t-Bu
O
N
N
O
3ca, 62%
C
N
O
N
O
N
N
N
3ad, 33%
3ae, 0%
3ea, 68%
3fa, 70%
O
N
O
N
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), BipyPdCl2 (10 mol %), CuCN
N
N
(20 mol %), K2CO3 (0.4 mmol) and K2Cr2O7 (0.2 mmol), in dry PhCl (2 mL), air,
150 °C, sealed tube, 24 h, 4 Å MS (50 mg).
O
F3C
3ga, 91%
3ha, 86%
O
O
N
N
N
N
were all well tolerated under these reaction conditions and the
desired products were obtained in good yields (3ga–3ja, Table 2).
The p-acetylphenyl on benzoxazole which had an electron-
withdrawing group only provided the product in 48% yield (3ka,
Table 2). It was regrettable that benzothiazole, benzofuran and
N-methylindole did not work under the optimum reaction
conditions.
O
O
3ja, 83%
O
3ia, 88%
3ka, 48%
O
N
O
N
N
N
O
O
Next, some sulfamoyl chlorides were tested for the direct ami-
nation of benzoxazole (Table 3). Sulfamoyl chloride including mor-
3la, 80%
a
pholine-4-sulfonyl chloride, pyrrolidine-
piperidine- -sulfonyl chloride were tolerated under the optimal
reaction conditions, and the desired products were obtained in
1-sulfonyl chloride, and
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), BipyPdCl2 (10 mol %), CuCN
(20 mol %), K2CO3 (0.4 mmol) and K2Cr2O7 (0.2 mmol), in dry PhCl (2 mL), air,
150 °C, sealed tube, 24 h, 4 Å MS (50 mg).
1

S. Chen et al. / Tetrahedron Letters 53 (2012) 6297–6299
6299
N
N
O
References and notes
NR1R2
O
Cu(I)
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Scheme 1. Plausible mechanism.
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moderate yields (3ab–3ad, Table 3). Unfortunately, no desired
product was obtained when chlorosulfonyl isocyanate was em-
ployed under the reaction conditions, which may be caused by
the SO2 extrusion from chlorosulfonyl isocyanate unsuccessfully
(3ae, Table 3).
Based upon the previous literature, a plausible mechanism was
outlined in Scheme 1. A Pd(IV/II) catalytic cycle may be involved in
this transformation. Firstly, the cupration of benzoxazole took
place to form Cu(I) species A.12 Meanwhile, the oxidative addition
of sulfamoyl chloride of Pd(II) formed a Pd(II) species B. Secondly,
the transmetallation of Cu(I) to Pd formed the new Pd(IV) species
C. The intermediate C released SO2 to yield intermediate D.13
Finally, the reductive elimination of intermediate D released the
aminated product, along with the Pd(II) to enter the catalytic cycle.
However, we could not thoroughly rule out the possibility of a
Pd(0)/Pd(II) mechanism.14
10. Selected recent literatures: (a) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Org.
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Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656.
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R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13, 359; (b) Xiao, B.; Gong, T.-J.; Xu, J.;
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J.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2011, 47, 3652; (d) Li, J.-J.; Mei, T.-S.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452; (e) Tan, Y.; Hartwig, J. F. J. Am. Chem.
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Zhang, Y.; Wang, J.-B. J. Am. Chem. Soc. 2011, 133, 3296.
In summary, an efficient and palladium-copper-catalyzed direct
C–H amination of substituted benzoxazoles with sulfamoyl chlo-
rides as nitrogen group sources has been developed in moderate
to excellent yields. The reaction provides a novel methodology
allowing for a wide functional group tolerance. Further studies
aimed at obtaining a better understanding of the reaction mecha-
nism and at expanding the substrate scope of the reaction are
underway.
13. (a) Zhao, X.-D.; Dimitrijevic´, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466;
(b) Zhao, X.-D.; Dong, V. M. Angew. Chem., Int. Ed. 2011, 50, 932.
14. Some recent papers about desulfitative arylation of azoles via Pd(0)/Pd(II)
mechanism: (a) Chen, R.; Liu, S.; Liu, X.; Yang, L.; Deng, G.-J. Org. Biomol. Chem.
2011, 9, 7675; (b) Liu, B.; Guo, Q.; Cheng, Y.; Lan, J.; You, J. Chem. Eur. J. 2011,
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Wan, B. Org. Biomol. Chem. 2012, 10, 7479.
Acknowledgments
We thank the Natural Science Foundation of China (No.
21272178) and the Natural Science Foundation of Zhejiang Prov-
ince (LY12B02010) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
044.