X. Wang et al. / Tetrahedron Letters 53 (2012) 7–10
9
Table 3
Table 4
Scope of Cu-catalyzed sulfonamide coupling with heteroaryl halidesa
Scope of Cu-catalyzed sulfonamide coupling with aryl bromidesa
CuI (5 mol%)
CuI (5 mol %)
3
(0.5 equiv)
3
(0.5 equiv)
R1SO2NR2
Me
1
Het-X
PhSO2NH Het
+
+
2
Sulfonamide
K2CO3 (3 equiv)
MeCN/14 h
K2CO3 (3 equiv)
MeCN/25-70 ºC/4-14 h
Entry
1
Sulfonamide
Temp (°C)
Yieldb (%)
Entry
1
Het-X
Temp (°C)
Yieldb (%)
88
O
Me
Ph
S
O
O
S
O
O
S
O
O
S
NHMe
NHMe
NH2
70
70
70
97
87
85
69
N
N
Br
2
3
<5
80
2
3c
4d
70
80
80
Cl
Br
70
70
70
70
Me
t-Bu
N
N
Cl
4
5
6
<5
91
91
NH2
O
Br
Me
O
S
5
70
92
Cl
N
NH2
Br
O
O
S
O
MeO
N
N
NH
6
7
70
70
83
86
7
8
25
70
86
79
O
S
N
Br
S
O
NH
Br
N
a
b
c
Conditions: sulfonamide, 2 (1.2 equiv), CuI (5 mol %), 3 (0.5 equiv), 14 h.
Isolated yield.
2.5 equiv 2 used, 36 h, bisarylated product isolated.
36 h reaction time.
a
Conditions: 1 (250 mg), Het-X (1.2 equiv), CuI (5 mol %), 3 (0.5 equiv), K2CO3
(3 equiv), MeCN (4 mL), 25–70 °C, 4–14 h.
b
d
Isolated yield.
general alternative to complement the Pd catalyzed N-aryl
sulfonamide synthesis.15 Further mechanistic investigation is cur-
rently underway and will be reported in due course.
in a 92% yield (Table 4, entry 5). Cyclic sulfonamides such as 1,4-
butanesultam and 1,3-propanesultam were also well tolerated by
this protocol, affording an 83% and 86% yield, respectively (Table
4, entries 6 and 7).
Acknowledgments
At this stage, we are still unclear of the role of MeCN in the
Cu-catalyzed sulfonamide coupling reaction. The significant rate
enhancement in MeCN versus DMF, another commonly used sol-
vent for copper catalysis, could possibly be due to the increased
solubility of copper catalyst in the former solvent.12 To probe this
hypothesis, the copper-catalyzed reaction of 1 and 2 in two sepa-
rate solvent systems (DMF and MeCN) were evaluated separately.
The solution copper content in each reaction was quantitatively
analyzed over time by Total Reflection X-ray Fluorescence (TXRF)
analysis with an external standard. Intriguingly, almost all copper
stayed in solution in both reactions at the beginning. However, the
solution copper content in DMF was roughly unchanged through-
out the reaction time (14 h), whereas it dropped to ꢀ25% in the
reaction in MeCN, indicating there was actually less copper in solu-
tion when MeCN was used as the solvent.13 This finding argued
against the aforementioned hypothesis that the faster reaction rate
in MeCN resulted from the higher solubility of the copper cata-
lyst.14 We also conducted experiments in mixed reaction solvent
systems with different ratios of MeCN/DMF. Interestingly, the rate
enhancement effect brought by increasing concentration of MeCN
was not linear. Specifically, the Cu-catalyzed reaction of 1 and 2 in
MeCN was about 10 times faster than in a mixture of MeCN/DMF
(1:1). This result suggested that more than one MeCN molecules
could be binding to Cu in the rate limiting steps.
The authors thank Dr. Tsang-Lin Hwang and Mr. Bradley Shaw
for analytical support.
Supplementary data
Supplementary data (General procedures and spectral data.)
associated with this article can be found, in the online version, at
References and notes
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In summary, we have uncovered a copper catalyzed sulfon-
amide coupling reaction with aryl bromides to form aryl sulfon-
amide under mild conditions (25–80 °C) by using MeCN as the
solvent. The reaction protocol tolerates a broad range of substrates
including heteroaryl bromides. We believe this reaction offers a
4. For recent work on Cu-catalyzed sulfonamide and amide coupling with aryl
halides, see: (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727–7729; (b) He, H.; Wu, Y. J. Tetrahedron Lett. 2003, 44,
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