LETTER
Efficient and Scalable Synthesis of Pyridine Sulfonamides
1119
Table 2 Transformation of Halopyridines into Sulfonamidesa
(continued)
PrMgCl selectively afforded the desired product by the
same reaction sequence (entry 7).14 Fluorine-substituted
sulfonamide 7k was also obtained in moderate yield be-
cause nucleophilic substitution of Et2NH with a fluoro
group in the amidation step proceeded to some extent (en-
try 11). We also examined the transformations with func-
tionalized pyridine derivatives other than halogen-
substituted pyridines. A methoxy group was tolerated af-
fording the desired product (entry 12), but an ester group
did not survive the standard conditions, as methyl 5-bro-
mopyridine-2-carboxylate did not afford the desired prod-
uct at all. Under the same reaction conditions bicyclic
heteroaromatic compounds, 4-bromoisoquinoline (3m)
and 3-bromoquinoline (3n) were also efficiently convert-
ed into the corresponding sulfonamide (entries 13 and 14).
SO2Cl2
n-Bu3MgLi
Ar
X
Ar
M
3
Et2NH
Ar SO2NEt2
Ar SO2Cl
7
5
Entry Halopyridine
Product
Yield (%)b
63
N
Cl
N
Cl
10
SO2NEt2
N
Br
3j
7j
F
F
N
In summary, we have developed an efficient synthetic
procedure for large-scale preparation of 6-bromopyridine-
2-sulfonyl chlorides. This method was proved to be appli-
cable to the synthesis of functionalized sulfonyl chlorides
and sulfonamides which are versatile intermediates for
drug discovery.
11d
12
53e
80
SO2NEt2
Br
3k
7k
MeO
MeO
N
N
Br
SO2NEt2
3l
7l
Supporting Information for this article is available online at
N
N
13
14
52
46
Br
SO2NEt2
Acknowledgment
3m
3n
7m
7n
We thank colleagues in process chemistry group (Masao Tsukazaki,
Nobuaki Kimura, Sunao Takeda, Junichi Shiina, Minoru Yamawaki)
for the support for large-scale synthesis and editing services of
Chugai Pharmaceutical Co., Ltd for assistance with English usage.
N
N
SO2NEt2
Br
a Reaction conditions: halopyridine (0.8 mmol), n-Bu3MgLi (0.32
mmol), in THF (0.76 mL) at -10 °C, then SO2Cl2 (1.2 mmol) at
-10 °C and Et2NH (0.414 mL, 4.0 mmol) at 10 °C.
b Isolated yield.
References and Notes
(1) (a) Pu, Y.-M.; Christensen, A.; Ku, Y.-Y. Tetrahedron Lett.
2010, 51, 418. (b) Wang, C.; Hamilton, C.; Meister, P.;
Menning, C. Org. Process Res. Dev. 2007, 11, 52.
(c) Dudutiene, V.; Baranauskiene Matulis, D. Bioorg. Med.
Chem. Lett. 2007, 17, 3335. (d) Allison, B. D.; Phuong, V.
K.; McAtee, L. C.; Rosen, M.; Morton, M.; Prendergast, C.;
Barrett, T.; Lagaud, G.; Freedman, J.; Li, L.; Wu, X.;
Venkatesan, H.; Pippel, M.; Woods, C.; Rizzolio, M. C.;
Hack, M.; Hoey, K.; Deng, X.; King, C.; Shanley, N. P.;
Rabinowitz, M. H. J. Med. Chem. 2006, 49, 6371.
(e) Hogan, P. J.; Cox, B. G. Org. Process Res. Dev. 2009, 13,
875.
(2) Yoshino, H.; Sato, H.; Shiraishi, T.; Tachibana, K.; Emura,
T.; Honma, A.; Ishikura, N.; Tsunenari, T.; Watanabe, M.;
Nishimoto, A.; Nakamura, R.; Nakagawa, T.; Ohta, M.;
Takata, N.; Furumoto, K.; Kimura, K.; Kawata, H. Bioorg.
Med. Chem. 2010, 18, 8150.
(3) (a) Park, Y. J.; Shin, H. H.; Kim, Y. H. Chem. Lett. 1992, 21,
1483. (b) Prakash, G. K. S.; Mathew, T.; Panja, C.; Olah,
G. A. J. Org. Chem. 2007, 72, 5847. (c) Bahrami, K.;
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(4) Hamada, T.; Yonemitsu, O. Synthesis 1986, 852.
(5) Pandya, R.; Murashima, T.; Tedeschi, L.; Barrett, A. G. M.
J. Org. Chem. 2003, 68, 8274.
c i-PrMgCl (0.96 mmol) was used for halogen–metal exchange at 10 °C.
d Et2NH was added at -10 °C.
e 2-Diethylamino-5-pyridinesulfonamide was isolated in 5.3% yield.
In the reaction of monobromopyridines, each regioisomer
afforded the pyridine sulfonamides in good yield
(Table 2, entries 1–3). In the case of 3-bromopyridine
(3c), since the use of n-Bu3MgLi afforded non-transfer-
able precipitate of the metalated pyridine, i-PrMgCl was
used for halogen–metal exchange giving the sulfonamide
7c as a major product by the usual chlorosulfonylation and
amidation sequence (entry 2). Various dibromopyridines
reacted in the same manner via monoselective halogen–
metal exchange affording the bromo-substituted sulfona-
mides in good yield, which are versatile intermediates for
further modification (entries 4–6).8 In the case of 2,5-di-
bromopyridine (3f), halogen–metal exchange occurred
regioselectively8 giving the corresponding sulfonamide,
whereas the regioisomer of 7f was selectively synthesized
by 2-iodo-5-bromopyridine (3g). Although chemoselec-
tive halogen–metal exchange of 2-iodo-5-bromopyridine
(3g) with n-Bu3MgLi was not performed, the use of i-
(6) (a) Bhattacharya, S. N.; Eaborn, C.; Walton, D. R. M.
J. Chem. Soc. C 1968, 1265. (b) Gilbert, E. E. Synthesis
1969, 3.
Synlett 2011, No. 8, 1117–1120 © Thieme Stuttgart · New York