Organic Letters
Letter
various 4-bromopyridines regardless of their electronic proper-
ties and substitution patterns were suitable substrates, leading
to α-arylation products such as 3ab, 3ac, and 3ae in good
yields. Pleasingly, heteroaryl products with multiple heter-
oatoms on the ring such as pyrazine (3ah, 3ak), pyrimidine
(3ai, 3aj), pyrazole (3al), isoxazole (3am), and isothiazole
(3an) were all formed in moderate to high yields (43−91%).
To demonstrate the synthetic practicality of this method, the
preparation of several α-heteroaryl propionic acids was studied.
A derivative of NSAID-type drugs, e.g., compound 4, was
prepared from tert-butyl ester 3r in 89% yield by treatment
with TFA.9 Likewise, compound 5 was obtained from 3x in
88% yield under similar reaction conditions (Scheme 4).
To explore an enantioselective version of this transformation
(Scheme 5), a chiral P,PO ligand L16 was subjected to a
gram-scale reaction between 3-bromopyridine (1a) and silyl
ketene acetal (2). The desired product was afforded in 93%
yield with 50% ee. Although the enantiomeric excess was only
moderate, this showcases the potential to further explore an
enantioselective variant of this transformation.
In summary, we have established a practical and efficient
synthesis of α-heteroaryl propionic esters by palladium-
catalyzed intermolecular α-heteroarylation. A wide range of
α-heteroaryl propionic esters with various electronic properties
and functionalities were obtained from simple starting
materials in moderate to excellent yields. This work further
demonstrates that the employment of the bulky P,PO ligand
can provide exceptional ability in tolerating heterocycles. The
facile access to a wide range of structurally diverse α-heteroaryl
propionic esters which are difficult to prepare otherwise should
promote their applications in drug discovery and biomedical
research.
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China
Aaron C. Smith − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States;
Daniel W. Widlicka − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States;
Simon Berritt − Pfizer Worldwide Research and Development,
Groton, Connecticut 06340, United States; orcid.org/
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Strategic Priority Research Program of
the Chinese Academy of Sciences (XDB20000000), CAS
(QYZDY-SSW-SLH029), the NSFC (21725205, 21432007,
21572246), STCSM-18520712200, and the K.C. Wong
Education Foundation.
REFERENCES
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2001, 2, 37−51. (b) Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.;
(c) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas,
383−394.
(2) (a) Nguyen, L. A.; He, H.; Pham-Huy, C. Chiral drugs: an
overview. Int. J. Biomed Sci. 2006, 2, 85−100. (b) Porta, R.; Benaglia,
124, 3500−3501. (f) García-Fortanet, J.; Buchwald, S. L. Asymmetric
Chem., Int. Ed. 2008, 47, 8108−8111. (g) Allen, A. E.; MacMillan, D.
2011, 133, 4260−4263. (h) Skucas, E.; MacMillan, D. W. C.
2012, 134, 9090−9093. (i) Bigot, A.; Williamson, A. E.; Gaunt, M. J.
ASSOCIATED CONTENT
* Supporting Information
■
sı
. The Supporting Information is available free of charge at
Experimental procedures; NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Caroline A. Blakemore − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States;
Wenjun Tang − School of Chemistry and Material Sciences,
Hangzhou Institute for Advanced Study, University of
Chinese Academy of Sciences, Hangzhou 310024, China;
State Key Laboratory of Bio-Organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China; orcid.org/
Authors
Bowen Li − School of Chemistry and Material Sciences,
Hangzhou Institute for Advanced Study, University of
Chinese Academy of Sciences, Hangzhou 310024, China;
State Key Laboratory of Bio-Organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
(3) (a) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. Palladium-
Conditions. J. Am. Chem. Soc. 2003, 125, 11176−11177. (b) Hama,
Chem. 2013, 78, 8250−8266.
Bangke Luo − State Key Laboratory of Bio-Organic and
Natural Products Chemistry, Shanghai Institute of Organic
6442
Org. Lett. 2021, 23, 6439−6443