Organic Letters
Letter
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accomplished to provide pentasubstituted benzaldehyde 5,
which is not easy to access by other means. Compound 5
represents a key synthetic intermediate to construct diverse
important natural products and drug molecules, such as fungal
metabolite terreinol, polyketide kendomycin, chlorizidine,
chlorofusin, and sclerotiorin.18 On the other hand, ortho-
chlorination of imidazolecarbaldehyde 6 provided 7, which can
be readily converted to angiotensin II receptor antagonist
losartan.19 Finally, an enlarged 10 mmol scale reaction was
performed to demonstrate the practicality of the current
methodology, generating the desired product 2f without any
evident erosion of efficiency. Furthermore, a series of bioactive
heterocycles were synthesized through diverse late-stage trans-
In summary, an unprecedented MonoTDG strategy was
successfully developed for Pd-catalyzed direct ortho-C(sp2)−H
methoxylation and chlorination of benzaldehydes. Moderate to
excellent yields were obtained for a broad substrate scope under
mild conditions. On the basis of the X-ray structure of binuclear
cyclopalladium intermediate, a plausible mechanism was
proposed. This new MonoTDG strategy provided an alternative
approach for C−H activation and opened the door for
discovering of new reactivities and activation modes. Detailed
mechanistic studies and new applications of this TDG strategy
are underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Experimental details and spectra including fluorescence
profiles and NMR spectra (PDF)
Accession Codes
(14) (a) Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927. For
̈
selected examples, see: (b) Chen, G.; Gong, W.; Zhuang, Z.; Andra, M.
CCDC 1886914 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q.
Science 2016, 353, 1023. (c) Wang, P.; Farmer, M. E.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2017, 56, 5125. (d) Chen, Y.-Q.; Wang, Z.; Wu, Y.;
Wisniewski, S. R.; Qiao, J. X.; Ewing, W. R.; Eastgate, M. D.; Yu, J.-Q. J.
Am. Chem. Soc. 2018, 140, 17884. (e) Cabrera, P. J.; Lee, M.; Sanford,
M. S. J. Am. Chem. Soc. 2018, 140, 5599−5606.
(15) (a) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. (b) Deprez,
N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234.
(16) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc.
2012, 134, 11948−948.
AUTHOR INFORMATION
■
Corresponding Author
ORCID
(17) (a) Ryabov, A. D. Inorg. Chem. 1987, 26, 1252. (b) Powers, D. C.;
Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
17050.
Author Contributions
§F.L. and Y.Z. contributed equally.
(18) (a) Zhu, J.; Germain, A. R.; Porco, J. A. Angew. Chem., Int. Ed.
2004, 43, 1239. (b) Williams, D. R.; Shamim, K. Org. Lett. 2005, 7, 4161.
(c) Wei, W.-G.; Zhang, Y.-X.; Yao, Z.-J. Tetrahedron 2005, 61, 11882.
(d) Clark, R. C.; Lee, S. Y.; Boger, D. L. J. Am. Chem. Soc. 2008, 130,
12355. (e) Lin, L.; Mulholland, N.; Wu, Q.-Y.; Beattie, D.; Huang, S.-
W.; Irwin, D.; Clough, J.; Gu, Y.-C.; Yang, G.-F. J. Agric. Food Chem.
2012, 60, 4480. (f) Mahajan, J. P.; Mhaske, S. B. Org. Lett. 2017, 19,
2774.
Notes
The authors declare no competing financial interest.
(19) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A.
L.; Pierce, M. E.; Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler, R.
R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. J. Med. Chem.
1991, 34, 2525.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 21602089).
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