Regioselective intramolecular oxidation of unactivated C-H bonds by dioxiranes generated in situ

Full text of DOI:10.1021/ja980916u

J. Am. Chem. Soc. 1998, 120, 6611-6612
Regioselective Intramolecular Oxidation of
6611
Unactivated C-H Bonds by Dioxiranes Generated in
Situ
Figure 1. Radical oxidation.
Dan Yang,* Man-Kin Wong, Xue-Chao Wang, and
Yeung-Chiu Tang
Table 1. Oxidation of Adamantane Catalyzed by Ketonesa
Department of Chemistry
The UniVersity of Hong Kong
Pokfulam Road, Hong Kong
ketone catalyst/Oxone/NaHCO3
adamantane
8 1-adamantanol
CH3CN/H2O, rt, 2 h
ReceiVed March 18, 1998
Regioselective oxidation of unactivated C-H bonds has been
a challenging problem in organic synthesis.1,2 Intramolecular
oxidation, due to its geometric constraint, has become a very
effective approach. In particular, significant progress has been
made in remote oxidation of rigid substrates such as steroids.3,4a,b
For flexible substrates, selective oxidation of remote carbons four
bonds away from a heteroatom has been successfully achieved
by using the radical reactions that undergo intramolecular radical
1,5-hydrogen abstractions (Figure 1).4 However, for oxidation
of more remote C-H bonds in flexible molecules, there is no
general method available.5 Here we report a novel method for
selective oxidation of unactivated C-H bonds at the δ site of
ketones.
Dioxiranes, a new generation of oxidants, have excellent
reactivity toward unactivated C-H bonds under mild and neutral
conditions.6 The oxidation reaction is stereospecific and has
strong preference for tertiary C-H bonds over secondary ones.6,7
We previously reported a homogeneous solvent system that allows
dioxiranes to be generated in situ from ketones and Oxone at
neutral pH.8 This makes it possible to develop a ketone-catalyzed
intramolecular C-H bond oxidation method.
a Reaction conditions: all the oxidation reactions were carried out
at room temperature with 0.1 mmol of ketone and 0.1 mmol of
adamantane, 0.5 mmol of Oxone, 1.55 mmol of NaHCO3, 1.5 mL of
CH3CN, and 1.0 mL of aqueous Na2‚EDTA solution (4 × 10-4 M) for
1
2 h. b The product ratios were determined by H NMR.
We first examined the activities of various ketones in catalyzing
oxidation of adamantane under our in situ conditions. As shown
in Table 1, 1,1,1-trifluoroacetone and methyl pyruvate were found
Figure 2.
to exhibit higher activities than fluoroacetone and chloroacetone.
These ketone units were then attached to a series of hydrocarbon
skeletons and oxidation reactions were carried out at 10 mM
concentration (Table 2). Oxidation of linear R-keto esters 1 and
2 was found to give hemiketal 1a (70% yield) and 2a (86% yield),
respectively, as the major oxidation products in 24 h (entries 1-2,
Table 2). Despite the presence of several other secondary C-H
bonds, the δ C-H bonds were selectively oxidized. Methyl
2-oxohexanoate failed to give the desired oxidation product,
because its δ C-H bonds are primary and extremely unreactive.
In each of the branched substrates 3-8, there is one tertiary C-H
bond in addition to several secondary ones, and interestingly, only
the δ site was oxidized (entries 3-8, Table 2). Here intermo-
lecular C-H bond oxidation by dioxiranes is unlikely as the
reactions of compounds 3-5 proceeded via selective oxidation
of secondary C-H bonds despite the presence of tertiary C-H
bonds. These results indicate the predominance of stereoelec-
tronic control on the transition state for hydroxylation. Further-
more, the observed regioselectivity (i.e., δ-selectivity) is different
from that of a typical intramolecular radical reaction (i.e.,
γ-selectivity), suggesting the nonradical nature of this oxidation
reaction.9 We propose a concerted C-H bond oxidation mech-
anism (Figure 2).6b,7a,c Oxidation of a δ C-H bond generates a
δ-hydroxy ketone which cyclizes to give a hemiketal. The
hemiketal formation prevents further oxidation at the δ site.
For concerted C-H bond oxidation by dioxiranes, there are
two possible transition states (TS's), i.e., the planar TS and the
spiro TS (Figure 3).7c,10 Under a spiro TS, oxidation of the
(1) (a) Crabtree, R. H.; Habib, A. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, Chapter
1.1. (b) Breslow, R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Flemming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, Chapter 1.3.
(2) For recent reviews, see: (a) Breslow, R. Acc. Chem. Res. 1995, 28,
146. (b) Arndtsen, B. A.; Bergman, R. G.; Mobley, A.; Peterson, T. H. Acc.
Chem. Res. 1995, 28, 154. (c) Barton, D. H. R.; Doller, D. Acc. Chem. Res.
1992, 25, 504. (d) Reiser, O. Angew. Chem., Int. Ed. Engl. 1994, 33, 69.
(3) (a) Breslow, R. Acc. Chem. Res. 1980, 13, 170. (b) Breslow, R.; Zhang,
X.; Huang, Y. J. Am. Chem. Soc. 1997, 119, 4535. (c) Groves, J. T.; Neumann,
R. J. Am. Chem. Soc. 1989, 111, 2900. (d) Groves, J. T.; Neumann, R. J.
Org. Chem. 1988, 53, 3891. (e) Grieco, P. A.; Stuk, T. L. J. Am. Chem. Soc.
1990, 112, 7799. (f) Stuk, T. L.; Grieco, P. A.; Marsh, M. M. J. Org. Chem.
1991, 56, 2957. (g) Kaufman, M. D.; Grieco, P. A.; Bougie, D. W. J. Am.
Chem. Soc. 1993, 115, 11648.
(4) (a) Barton, D. H. R. Pure Appl. Chem. 1968, 16, 1. (b) Hesse, R. H.
AdV. Free-Radical Chem. 1969, 3, 83. (c) Chow, Y. L.; Danen, W. C.; Nelsen,
S. F.; Rosenblatt, D. H. Chem. ReV. 1978, 78, 243. (d) Walling, C.; Bristol,
D. J. Org. Chem. 1972, 37, 3514. (d) Turro, N. J. In Modern Molecular
Photochemistry; Benjamin/Cummings: Menlo Park, CA, 1978; p 386.
(5) (a) Wagner, P. J.; Kelso, P. A.; Kemppainen, A. E.; Zepp, R. G. J. Am.
Chem. Soc. 1972, 94, 7500. (b) Asensio, G.; Gonzalez-Nunez, M. E.;
Bernardini, C. B.; Mello, R.; Adam, W. J. Am. Chem. Soc. 1993, 115, 7250.
(6) (a) Murray, R. W.; Jeyaraman, R.; Mohan, L. J. Am. Chem. Soc. 1986,
108, 2470. (b) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am. Chem.
Soc. 1989, 111, 6749.
(7) (a) Adam, W.; Curci, R.; D’Accolti, L.; Dinoi, A.; Fusco, C.; Gasparrini,
F.; Kluge, R.; Paredes, R.; Schulz, M.; Smerz, A. K.; Veloza, L. A.; Weinkotz,
S.; Winde, R. Chem. Eur. J. 1997, 3, 105. For recent examples on oxidation
of unactivated C-H bonds by dioxiranes, see: (b) Bovicelli, P.; Lupattelli,
P.; Mincione, E.; Prencipe, T.; Curci, R. J. Org. Chem. 1992, 57, 5052. (c)
Kuck, D.; Schuster, A.; Fusco, C.; Fiorentino, M.; Curci, R. J. Am. Chem.
Soc. 1994, 116, 2375. (d) Curci, R.; Detomaso, A.; Prencipe, T.; Carpenter,
G. B. J. Am. Chem. Soc. 1994, 116, 8112. (e) Bovicelli, P.; Gambacorta, A.;
Lupattelli, P.; Mincione, E. Tetrahedron Lett. 1992, 33, 7411. (f) Bovicelli,
P.; Lupattelli, P.; Fiorini, V.; Mincione, E. Tetrahedron Lett. 1993, 34, 6103.
(8) (a) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887.
(b) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung,
K.-K. J. Am. Chem. Soc. 1996, 118, 491. (c) Yang, D.; Wang, X.-C.; Wong,
M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem. Soc. 1996, 118, 11311.
(9) As oxygen is always present under the in situ conditions, the radical
mechanism is considered unlikely. Bravo, A.; Fontana, F.; Fronza, G.; Minisci,
F.; Zhao, L. J. Org. Chem. 1998, 63, 254.
S0002-7863(98)00916-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/19/1998

6612 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Communications to the Editor
Figure 3.
Table 2. Selective Oxidation of the δ C-H Bonda
Oxone/NaHCO3
ketone
(10 mM)
8 product
CH3CN/H2O, rt, 24 h
Figure 4.
which would predict a trans/cis ratio of 4.3:1 at 20 °C. In contrast,
under a planar TS, cis-product is expected to be the major product
with a trans/cis ratio of 1:4.3. The observed trans-selectivity in
3a-5a (entries 3-5, Table 2) supports the spiro TS model.
Furthermore, oxidation of the tertiary C-H bonds in compounds
6-8 could only be possible under a spiro TS, because under a
planar TS there are severe steric interactions between the dioxirane
group and the ꢀ CH2 group (Figure 4).11
As shown in Table 2, compounds 1-8 of different substituents,
i.e., CO2CH3, CF3, CH2Cl, and CH2F, were found to give the
same δ selectivity.12 This δ-selective C-H bond oxidation
method allows incorporation of various substituents into the
tetrahydropyran products. To further demonstrate the synthetic
potential of this method, cholic acid triacetate was converted into
the trifluoromethyl ketone 9, which upon treatment with Oxone
gave selective hydroxylation at the 17-position with retention of
configuration.
In summary, we have discovered that intramolecular C-H bond
oxidation by dioxiranes is highly regioselective, and established
a spiro transition state for this reaction. Future work will be
directed at exploring the applications of this reaction in asym-
metric synthesis as well as remote functionalization of steroids.
Acknowledgment. This work was supported by the Hong Kong
Research Grants Council and The University of Hong Kong (CRCG grant
and postdoctoral fellowships to M.K.W. and X.C.W.). This paper is
dedicated to Prof. Ronald Breslow for his mentorship.
a Unless otherwise indicated, all reactions were carried out with a
1.0 × 10-2 M solution of ketone in a 1.5:1 mixture of CH3CN and
aqueous Na2‚EDTA solution (4 × 10-4 M) containing 5.0 equiv of
Oxone and 15.0 equiv of NaHCO3 for 24 h at room temperature.
b Isolated yield after flash column chromatography. c The trans/cis ratio
was determined by using NMR. d 15.5 equiv of NaHCO3. e Isolated
yield based on 55% conversion after 120 h. f The reaction time was 72
h. The product ratio (hemiketal/hydroxy ketone) was determined by
1H NMR in C6D6. g Isolated yield based on 75% conversion.
Supporting Information Available: Preparation and characterization
data of compounds 1-9; experimental details for oxidation reactions;
and characterization data of compounds 1a-9a (15 pages, print/PDF).
See any current masthead page for ordering information and Web access
instructions.
JA980916U
(11) A similar spiro transition state has been found for dioxirane epoxidation
reactions. See: (a) Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J.
Am. Chem. Soc. 1997, 119, 10147. (b) Reference 8c. (c) Tu, Y.; Wang, Z.-
X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
(12) The CH2OAc analogue of compound 4 did not undergo oxidation in
72 h at room temperature. This indicates that strong electron-withdrawing
groups at R-positions of ketones are important for their intramolecular C-H
bond oxidation.
equatorial δ C-H bond (leading to trans-product) is strain-free
whereas oxidation of the axial one (leading to cis-product) is
disfavored by one gauche-butane interaction (ca. 0.85 kcal/mol),
(10) Bach, R. D.; Andres, J. L.; Su, M. D.; McDouall, J. J. W. J. Am.
Chem. Soc. 1993, 115, 5768.