Organic Letters
Letter
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Scheme 8. Co-Catalyzed Cross-Coupling between Halides
and Cyclobutylmagnesium Bromide
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In summary, we developed a flexible, efficient, and cost-
effective cross-coupling allowing the introduction of cyclo-
propyl, cyclobutyl, and alkenyl moieties on both primary and
secondary alkyl iodides. The reaction tolerated an array of
functional groups and was applied to the functionalization of
N-heterocycles, which are valuable scaffolds in pharmaceutical
industry. To the best of our knowledge, this is the first general
cross-coupling of cyclopropyl and cyclobutyl magnesium
bromides with alkyl iodides including secondary iodides. In
addition, alkenyl Grignard reagents are also suitable partners
resulting in the corresponding alkenes that can be transformed
into polysubstituted cyclopropanes. The formation of radical
intermediates could be hypothesized and could explain the
diastereoconvergence of the coupling. This cross-coupling
appears as a promising method for the late-stage introduction
of cyclopropyl or cyclobutyl rings and could thus become an
attractive tool for the design and synthesis of bioactive
molecules for medicinal chemists.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Wu, Y. Tetrahedron 2012, 68, 900. (d) Gu
Jacobi von Wangelin, A. J. Adv. Synth. Catal. 2013, 355, 2197.
(e) Vila, C.; Giannerini, M.; Hornillos, V.; Fananas-Mastral, M.;
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lak, S.; Gieshoff, T. N.;
The Supporting Information is available free of charge on the
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Experimental procedures and spectral data for all new
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Coniglio, S.; Colagioia, S.; Beccari, A. R.; Bizzarri, C.; Cavicchia, M.
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AUTHOR INFORMATION
Corresponding Authors
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ORCID
́
Notes
(12) (a) Chen, H.; Deng, M.-Z. J. Chem. Soc., Perkin Trans. 2000, 1,
1609. (b) Chen, H.; Deng, M.-Z. J. Org. Chem. 2000, 65, 4444.
(c) Colombel, V.; Rombouts, F.; Oehlrich, D.; Molander, G. A. J. Org.
Chem. 2012, 77, 2966.
(13) de Lang, R.-J.; Brandsma, L. Synth. Commun. 1998, 28, 225.
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Mino, K.; Walport, L.; Ohkubo, R.; Kawamura, A.; Yonezawa, M.;
Tsukada, Y.; Tumber, A.; Nakagawa, H.; Hasegawa, M.; Sasaki, R.;
Mizukami, T.; Schofield, C. J.; Miyata, N. J. Med. Chem. 2013, 56,
7222. (c) Lu, J.-Y.; Du, Y.; Zhao, B.; Lu, J. Tetrahedron 2016, 72, 161.
(d) Wey, H. G.; Betz, P.; Butenschoen, H. Chem. Ber. 1991, 124, 465.
(15) Jia, Z.; Liu, Q.; Peng, X.-S.; Wong, H. N. C. Nat. Commun.
2016, 7, 10614.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Sanofi for financial support (C.A.).
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Org. Lett. XXXX, XXX, XXX−XXX