Organic Letters
Letter
Table 3. Scope of Bromination on Pyridine N-Oxide
In conclusion, we have developed a highly regioselective and
efficient protocol for accessing a variety of 2-chloro or bromo-
3
,5-trisubstituted pyridines, which otherwise are challenging for
synthesis. The mild reaction conditions, simple setup, and high
process efficiency (high regioselectivity and yield) make this
method suitable for large-scale production.
ASSOCIATED CONTENT
Supporting Information
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S
Experimental procedures and characterization data for all
AUTHOR INFORMATION
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*
*
Present Address
†(
J.H.) Jiangshu Hengrui Medicine CO., Ltd., Chengdu R&D
Center, 88 S. Keyuan Route, B4 Suite 903, Tianfu Life Science
Park, Chengdu Hi-Tech Zone, Chengdu, Sichuan 610000,
China.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank our Amgen research colleagues Johann Chan,
Michael Bartberger, Rob Milburn, John Colyer, and Brenda
Burke for helpful discussions.
a
1
1
13
Ratio determined by 1D H and 2D NMR ( H− C HMBC and 1,1-
b
ADEQUATE). Isolated yield for both isomers.
REFERENCES
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(
1) (a) Cui, J.; Tran-Dube, M.; Shen, H.; Nambu, M.; Kung, P.;
On the basis of these experimental results, a plausible and
likely simplistic mechanism can be proposed in which the N-
oxide is first activated by oxalyl chloride and then the C2
proton in the resulting pyridinium chloride is extracted by
triethylamine to generate a highly active electrophilic species
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explain the observed regioselectivity dominated by electron-
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halogenation reagents can act as nucleophiles in the system
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(
Scheme 3). The nucleophilic reaction through a carbene
12
intermediate have been known with N-fluoropyridinium salts.
Scheme 3. Proposed Mechanism
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(
(
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(
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95 and references cited therein.
(
7
(
i
7) Base screening (Et N, Pr EtN, DBU, DABCO, 2,6-lutidine,
3 2
pyridine, K CO , Cs CO ) and solvent screening (DCM, toluene,
2
3
2
3
MeCN, CHCl , DMF, pyridine).
3
(8) A continuous flow process for the reaction and workup has been
developed to increase the manufacture throughput and reduce the
C
Org. Lett. XXXX, XXX, XXX−XXX