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Journal of the American Chemical Society
equiv), THF (0.1 M), 100 °C, 16 h, N2; cOxidation step: KHCO3
Ala Bunescu: 0000-0002-3880-8182
1
2
3
4
5
6
7
8
(4.0 equiv), KF(4.0 equiv), 50% aqueous H2O2(10 equiv), MeOH,
Trevor W. Butcher: 0000-0001-5006-692X
d
60 °C, 2h; Isolated yield for the 1,2 diols over the three steps
1
eYield for the oxasilolane determined by H NMR spectroscopy
Funding Sources
f
using CH2Br2 as internal standard; The starting dihydro-α-ionone
was purchased as the mixture of cyclohex-2-ene and cyclohex-3-
ene derivative in 4:1 ratio.
This work was supported by the NIH (GM 115812) and The
Dow Chemical Company.
Natural products containing tertiary alcohols underwent the
sequence with a trifluoromethyl substituent containing remov-
able directing group. The developed strategy led to hydroxyla-
tion of the primary β C–H bonds of (+)-cedrol (5ah), ledol
(5ag), (-)-α-bisabolol (5af) and α-terpinol (5ae) to form the
coresponding 1,2-diols. The diols were isolated in 21-36%
yield over the three-step sequence. Although occurring in
modest yield this sequence leads to the formation of readily
isolable amounts of the modified products. The initial intro-
duction of the directing group (TFAA, pyridine, DCM) did not
require isolation by column chromatography.
ACKNOWLEDGMENT
We thank the NIH (GM 115812) and The Dow Chemical
Company for support of this work. AB thanks the Swiss Na-
tional Science Foundation for a postdoctoral fellowship. TWB
gratefully acknowledges the National Science Foundation for
a predoctoral fellowship.
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The complementarity of our developed method to function-
alize alcohols is well illustrated in the case of (+)-cedrol (5ah),
a sesquiterpenoid used in the perfume industry extracted from
Texas cedarwood oil. Direct chemical or microbial16 oxidation
of cedrol has been studied extensively. Generally, the oxida-
tion reactions of cedrol with m-chlorobenzoic acid and ruthe-
nium or iron catalysts lead to the introduction of a hydroxyl
group at the tertiary C(2) carbon (5ak).17 The oxidation of
cedrol with the “Gif IV system” resulted in the introduction of
ketone functionality at the C(10) position (5ai).18 Finally,
methods based on the generation of oxygen-centered radicals,
followed by 1,5-hydrogen atom transfer, lead to etherification
of the distal methyl group (C(14) position, 5aj).19 None of the
developed methods have led to the selective oxidation of pri-
mary C–H bonds located β to the alcohol. Thus, the method
we report offers new opportunities for selective alcohol oxida-
tion.
Conclusion.
We have developed an Ir-catalyzed functionalization of C–
H bonds located β to hydroxyl functionality by incorporating
traceless perfluorinated ester directing groups. Diethyl silane
plays a dual role in the overall process, acting as the reductant
for the hydrosilylation of the ester and as the reagent for si-
lylation of the C–H bond, in this case to obtain six-membered
dioxasilinanes. The silicon-containing intermediates undergo
oxidation to 1,2-diols, leading to a net alcohol directed β-
C(sp3)–H hydroxylation. The iridium catalysts react preferen-
tially with primary β-C(sp3)–H bonds over secondary, benzylic
or tertiary C–H bonds, leading to a selectivity that comple-
ments the selectivity of previously developed oxidation meth-
ods. Thus, this functionalization of an alkyl C–H bond enrich-
es the currently-available toolbox of C–H bond functionaliza-
tion reaction suitable for diversification of complex structures.
ASSOCIATED CONTENT
Supporting Information
Experimental details, synthetic procedures and spectral data.
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Soc. 2016, 138, 7982-7991.
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12842-12845; (b) Piou, T.; Bunescu, A.; Wang, Q.; Neuville, L.;
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AUTHOR INFORMATION
Corresponding Author
*jhartwig@berkeley.edu
ORCID
John F. Hartwig: 0000-0002-4157-468X.
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