Table
reactions
3
Cu(I)-catalyzed heteroaryl bromide–chloride exchange
a
b
Time (h) Yield (%)
Entry Bromide 3 Chloride product 4
c
1
2
3a
3b
20
20
93
52
d
Scheme 2 Proposed mechanism.
e
3
4
5
3c
3d
3e
96
96
24
81
75
70
intermediate B. The halogen exchange reaction between B and
Me NCl would occur to generate intermediate C, which would
4
e
subsequently undergo reductive elimination reaction to produce
aryl chloride 2 and regenerate Cu(I) catalyst A.
In conclusion, a new method for the direct conversion of
aryl and heteroaryl bromides into the corresponding chlorides
has been achieved using copper catalysis. The new method
represents a significant improvement over previous methods: the
c
89
6
7
a
3f
36
10
4
reaction conditions are mild, the chlorine source (Me NCl) is cheap
3g
98
and readily available, and the substrate scope is broad. In addition,
the new method has good functional group tolerance. To the best
of our knowledge, this catalytic heteroaryl bromide–chloride
exchange is the first example reported on such reactions.
We are grateful to the National Natural Science Foundation
of China (No. 21073025 and 21072023) for their financial support.
Reaction conditions: heteroaryl bromide (3a–3g, 0.5 mmol), Me
2.0 equiv.), Cu O (10 mol%), L6 (20 mol%), and EtOH (3 mL) in a
sealed tube at 110 1C for the period indicated in the table. Isolated
yield. GC yield due to product volatility. C–N coupling product 5
e
was isolated in 11% yield (for the structure of 5, see ESI). 4.0 equiv.
4
NCl
(
2
b
c
d
4
Me NCl was used.
Notes and references
2
4
-bromopyridine (3a) with Me NCl proceeded smoothly to
1
(a) For a book, see: Metal Catalyzed Cross Coupling Reactions,
ed. F. Dieterich and P. J. Stang, Wiley-VCH, New York, 1998. For
selected reviews, see: (b) F. Bellina and R. Rossi, Chem. Rev., 2010,
110, 1082; (c) G. C. Fu, Acc. Chem. Res., 2008, 41, 1555; (d) A. F. Littke
and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 4176.
For selected reviews, see: (a) J. Magano and J. R. Dunetz, Chem.
Rev., 2011, 111, 2177; (b) G. Evano, N. Blanchard and M. Toumi,
Chem. Rev., 2008, 108, 3054.
Of the top 10 products by U.S. spending of 2011 in the U.S., three
were aryl chlorides, accounting for a combined sales revenue of
$16.6 billion. IMS Health Inc. 2011 U.S. Spending Information:
www.imshealth.com (accessed 04/06/2012).
(a) Y. Lai, L. Ma, W. Huang, X. Yu, Y. Zhang, H. Ji and J. Tian,
Bioorg. Med. Chem. Lett., 2010, 20, 7349; (b) M. K. Gurjar, A. M.
S. Murugaiah and D. S. Reddy, Org. Process Res. Dev., 2003,
7, 309. For selected patents, see: (c) Shashiprabha, K. Shridhara,
M. Debkiron, B. Padmashree, K. R. Sundarraja and
K. Nagarajan, WO2009116085, 2009; (d) C. Burgarolas Montero,
J. Puig Serrano, C. Agnalot Aguilar and J. Bosch Illado,
WO2006034964, 2006; (e) B. B. Molloy, US3882236, 1975.
produce the desired product, 2-chloropyridine (4a), in 93%
yield (entry 1). 2-Chloro-5-nitropyridine (4b) was obtained
along with C–N coupling product 5 in 52% and 11% yields,
respectively, by reacting 2-bromo-5-nitropyridine (3b) with
2
3
Me NCl (entry 2). This result indicated that the electron-
4
deficient heteroaryl bromide could undergo a Cu(I)-catalyzed
C–N coupling reaction. Similar to the reaction of dibromo-
substituted aryl bromide 1j described earlier, the reactions of
1,5-dibromopyridine (3c) and 2,6-dibromopyridine (3d) needed a
4
long reaction time (96 h) to complete (entries 3 and 4). The
desired products 4c and 4d were obtained in 81% and 75%
yields, respectively. The reaction of 2-pyridinyl bromide 3e
bearing an electron-donating group MeO on the 6-position
also proceeded smoothly to produce the corresponding chlori-
nated product 4e in a satisfactory yield (entry 5, 70% yield).
Compared with 2-bromopyridine (3a), 3-bromopyridine (3f)
exhibited relatively low reactivity in this type of halogen
exchange reaction. 3-Chloropyridine (4f) was obtained in
5 (a) Y. Matsubara, S. Hirakawa, Y. Yamaguchi and Z.-i. Yoshida,
Angew. Chem., Int. Ed., 2011, 50, 7670; (b) G. Sivaprasad,
R. Rajesh and P. T. Perumal, Tetrahedron Lett., 2006, 47, 1783;
c) S. Suri, G. S. Sarin and M. Mahendru, WO2006021974, 2006.
6 For a review, see: (a) T. D. Sheppard, Org. Biomol. Chem., 2009,
, 1043; (b) W. B. Hardy and R. B. Fortenbaugh, J. Am. Chem.
(
8
9% yield (entry 6). Finally, the reaction of 2-bromoquinoline
3g) was investigated under the same conditions. The Cu(I)-
catalyzed halogen exchange reaction of 3g with Me NCl
proceeded quickly to produce the corresponding product,
7
(
Soc., 1958, 80, 1716.
(a) R. Cramer and D. R. Coulson, J. Org. Chem., 1975, 40, 2267;
(b) S. H. Yang, C. S. Li and C. H. Cheng, J. Org. Chem., 1987,
52, 691.
4
7
2
-chloroquinoline (4g), in 98% yield (entry 7).
8
9
H. Wu and J. Hynes Jr., Org. Lett., 2010, 12, 1192.
J. M. Murphy, X. Liao and J. F. Hartwig, J. Am. Chem. Soc., 2007,
The plausible mechanism for the Cu(I)-catalyzed halogen
exchange reaction is shown in Scheme 2. The interaction
129, 15434.
10 R. H. Szumigala Jr., P. N. Devine, D. R. Gauthier Jr. and
R. P. Volante, J. Org. Chem., 2004, 69, 566.
between L-proline and Cu O would generate a Cu(I) complex A.
2
The oxidative addition of 1 to Cu(I) species A would produce
9
470 Chem. Commun., 2012, 48, 9468–9470
This journal is c The Royal Society of Chemistry 2012