Organic Letters
Letter
distributions observed with trans-4, trans-5, trans-6, and trans-7,
indicative of strong tertiary axial C−H bond deactivation,
coupled to the selective tertiary equatorial C−H bond oxidation
of the corresponding cis isomers, point toward torsional effects as
a determinant contributor in governing the functionalization
selectivity of cyclohexane derivatives. Interestingly, an increase in
steric hindrance of the ring substituent, i.e., on going from
isopropyl to tert-butyl (trans-8), results in a drastic change in site-
selectivity. The presence of the bulky tert-butyl group at C-4
strongly deactivates the C−H bonds at C-3, directing oxidation
at C-2. The 2-keto amide product was obtained in modest to
good isolated yield and er both for the pivalamide and acetamide
derivatives (8a and 9a). Furthermore, the use of the electron-
withdrawing trifluoromethyl group as in trans-10 also directs
oxidation toward C-2, presumably by electronic deactivation of
the proximal position (C-3), providing the corresponding 2-keto
amide-product 10a with modest yield and er (17% yield, 70:30
er, Scheme 5). We notice that this result is in full agreement with
those recently obtained for the C−H bond oxidation reactions of
monosubstituted cyclohexanes catalyzed by manganese catalyst,
where the presence of an EWG substituent strongly affects the
interaction of the substrate with an electrophilic oxidizing
species.17
In summary, we have shown that C−H bond oxidation
directed by torsional effects can be successfully employed to
selectively oxidize cis-1,4-, trans-1,3-, and cis-1,2-cyclohexanedia-
mides over the corresponding diastereoisomers. As a conse-
quence, competitive oxidation of cis−trans mixtures of 4-
substituted N-cyclohexylamides leads to quantitative conversion
of the cis-isomers, allowing isolation of the trans-isomers in good
to excellent yield, which can in turn be converted into densely
functionalized oxidation products with excellent site-selectivity
and good enantioselectivity. Overall, the current report discloses
kinetic resolution in C−H bond oxidation of cyclohexane
derivatives as a novel tool for organic synthesis, and exemplifies a
rapid building up on chemical complexity and functionality on
the basis of site selective and enantioselective aliphatic C−H
bond oxidation guided by torsional effects.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
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AUTHOR INFORMATION
Corresponding Authors
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ORCID
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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M.C. acknowledges the MINECO of Spain (CTQ2015-70795-
P) and the Catalan DIUE (2017 SGR 264 ICREA Academia
award).
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Org. Lett. XXXX, XXX, XXX−XXX