Selective oxidation of unactivated C-H bonds by supramolecular control

Article abstract of DOI:10.1039/c2ob07069c

Efficient methods for dioxirane-based selective C-H bond oxidation by supramolecular control in H₂O have been developed. With β-cyclodextrin as the supramolecular host, site-selective oxidation of the terminal over the internal tertiary C-H bond of 3,7-dimethyloctyl esters 3a-c was achieved. In addition, β-cyclodextrin selectively enhanced the C-H bond oxidation of cumene in a mixture of cumene and ethyl benzene in H₂O. Through ¹H NMR studies, the selectivity in C-H bond oxidation could be attributed to the inclusion complex formation between β-cyclodextrin and the substrates. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob07069c

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PAPER
Selective oxidation of unactivated C–H bonds by supramolecular control†
Yat-Sing Fung, Siu-Cheong Yan and Man-Kin Wong*
Received 10th December 2011, Accepted 22nd February 2012
DOI: 10.1039/c2ob07069c
Efficient methods for dioxirane-based selective C–H bond oxidation by supramolecular control in H2O
have been developed. With β-cyclodextrin as the supramolecular host, site-selective oxidation of the
terminal over the internal tertiary C–H bond of 3,7-dimethyloctyl esters 3a–c was achieved. In addition,
β-cyclodextrin selectively enhanced the C–H bond oxidation of cumene in a mixture of cumene and ethyl
benzene in H2O. Through 1H NMR studies, the selectivity in C–H bond oxidation could be attributed to
the inclusion complex formation between β-cyclodextrin and the substrates.
Introduction
Selective C–H bond oxidation is a great challenge in organic
synthesis.1 By selective oxidation of C–H bonds, functional
groups can be strategically incorporated at the desired positions
of hydrocarbons, providing an efficient method for the synthesis
of structurally diverse organic molecules.2 Over the decades, sig-
Fig. 1 General structure of cyclodextrins.
nificant advancements have been made in selective C–H bond
oxidation based on electronic,3 steric,4 and substrate-based
target site to the reaction centre has been widely investigated.
Breslow and Dong reported pioneering work on selective C–H
bond oxidations of steroids using cyclodextrin-attached metallo-
directing5 factors. However, these approaches are limited by the
inherent structural properties of the substrates. Thus, it remains a
great interest to develop new strategies for selective C–H bond
porphyrins as catalysts.7d However, selective C–H bond oxidation
oxidation to cater for a wide diversity of substrates.
by obstructing the approach of non-target C–H bonds to the reac-
Supramolecular host–guest chemistry provides a promising
tion centre using cyclodextrins remains largely unexplored.8
means to achieve selectivity in a wide range of organic reac-
Dioxiranes are powerful oxidants which can be generated
tions.6 In general, supramolecular hosts function in two ways for
in situ from ketones and Oxone for oxidation of organic com-
selectivity enhancement in organic reactions. One way is by
positioning the target sites of the substrates close to the reaction
pounds,9 including C–H bond oxidation.10,11 In 2003, we
employed cyclodextrin-ketoester as a supramolecular catalyst for
centre, and hence the target sites are preferentially reacted.
stereoselective alkene epoxidation.12 Bols and co-workers devel-
Another way is by obstructing the approach of the non-target
oped cyclodextrin ketones for organic oxidations.13
sites of the substrates to the reaction centre through inclusion
In this work, we report efficient methods for selective C–H
bond oxidation by a supramolecular approach. Cyclodextrins
were chosen as the supramolecular host, and dioxiranes gener-
ated in situ were used as the oxidant. Selective C–H bond oxi-
dation was achieved by obstructing the approach of dioxiranes to
the C–H bond with higher induced steric hindrance through
inclusion complex formation with cyclodextrins. As a result, the
unbound C–H bonds far away from cyclodextrins would be pre-
complex formation. As a result, the selectivity of reaction at the
target sites would be enhanced.
Cyclodextrins (CDs) are water-soluble supramolecular com-
pounds with hydrophobic cavity and hydrophilic surface (Fig. 1)
which have been extensively employed as ideal hosts in supra-
molecular catalysis.7 For C–H bond oxidation by cyclodextrin-
based catalysts, the selectivity enhancement by directing the
ferentially oxidized.
State Key Laboratory of Chirosciences and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Hong Kong, China. E-mail: bcmkwong@
Results and discussion
inet.polyu.edu.hk; Fax: +(852)2364 9932; Tel: +(852)3400 8701
†Electronic supplementary information (ESI) available: Data for optim-
ization of adamantane oxidation and selective C–H bond oxidations of
Optimization of reaction conditions for C–H bond oxidation by
dioxiranes generated in situ
3a–d; LC-MS spectra of β-CD; NMR spectra; GC calibration curve; GC
temperature program and GC chromatograms. See DOI: 10.1039/
c2ob07069c
To increase the efficiency of C–H bond oxidation by dioxiranes
generated in situ from ketones and Oxone, reaction temperature,
3122 | Org. Biomol. Chem., 2012, 10, 3122–3130
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Table 1 Studies on activities of ketones towards C–H bond oxidation
of adamantane (1)a
Scheme 1 Oxidation of 3,7-dimethyloctyl esters.
Entry
1
Ketone
1 : 2a : 2a′b
Conv. (%)
93
Table 2 Studies on the effect of β-CD on site-selective C–H bond
oxidation of 3aa
7 : 50 : 43
2
3
14 : 71 : 15
43 : 52 : 5
86
57
4
5
24 : 66 : 10
52 : 43 : 5
76
48
H2O
(mL)
CH3CN
(mL)
Conv.b
(%)
Yieldc
(%)
Entry
β-CD
4a : 4a′d
1
2
3
4
1.1 equiv
—
1.1 equiv
—
10
4
4
—
6
6
40
35
34
4
71
96
75
34
20 : 1
7 : 1
7 : 1
5 : 1
10
—
6
61 : 35 : 4
39
a Reactions were conducted with 3a (0.2 mmol), 1,1,1-trifluoroacetone
(0.2 mmol) at room temperature with Oxone (0.5 mmol × 8) and
NaHCO3 (1.55 mmol × 8) for 8 h. b Conversion was calculated from the
amount of substrate recovered by flash column chromatography. c Yield
based on conversion. d Determined by 1H NMR.
7
8
22 : 61 : 17
60 : 40 : 0
78
40
Design of substrates for site-selective C–H bond oxidation
a Reactions were conducted with 1 (0.1 mmol) and ketone (0.1 mmol) in
H2O (1 mL) and CH3CN (1.5 mL) at room temperature with Oxone
(0.5 mmol × 3) and NaHCO3 (1.55 mmol × 3) added at 0 h, 2 h and 4 h
(total reaction time: 6 h). b Determined by 1H NMR analysis of the
crude reaction mixture.
To investigate the effect of cyclodextrins on the site-selectivity
of C–H bond oxidation, 3,7-dimethyloctyl esters with two ter-
tiary C–H bonds located at the terminal and internal positions
were chosen as the substrate (Scheme 1). Owing to the electronic
effect, 7-hydroxy-3,7-dimethyloctyl esters are expected to be the
major product through oxidation at the terminal C–H bond.3b
choice of base, and amounts of Oxone, base, and ketones have
been optimized using adamantane (1) as the substrate (see ESI†).
It was noted that the conversion of C–H bond oxidation could be
enhanced by portion-wise additions of Oxone and base. Based
on the optimized reaction conditions, the activities of a variety of
ketones towards C–H bond oxidation were examined.
Effect of β-CD on site-selective C–H bond oxidation of 3a
β-Cyclodextrin (β-CD) was chosen for studying the effect of
cyclodextrins on site-selective C–H bond oxidation with 3,7-
dimethyloctyl benzoate (3a) as the substrate. The reaction was
conducted with 3a (0.2 mmol), 1,1,1-trifluoroacetone
(0.2 mmol) and β-CD (0.22 mmol, 1.1 equiv) in the presence of
Oxone (0.5 mmol × 8) and NaHCO3 (1.55 mmol × 8) in H2O
(10 mL) at room temperature for 8 h (Table 2, entry 1). 4a and
4a′ were obtained in 71% yield based on 40% conversion with a
product ratio of 20 : 1. We have studied the effect of the equival-
ent of β-CD (Table S6 in ESI†). With 0.1 and 0.5 equiv of
β-CD, lower conversion (23–32%), yield (40–50%), and selec-
tivity (∼7 : 1) were obtained. Increasing the amount of β-CD to
2, 5, and 10 equiv led to enhanced selectivity of 25 : 1, 29 : 1,
and 30 : 1 yet with reduced yield. Monitored by LC-MS, no sig-
nificant change on β-CD was observed during the course of the
reaction (see ESI†). A comparable conversion (35%) and yield
(96%) was obtained for oxidation conducted in H2O (4 mL) and
CH3CN (6 mL) without β-CD. However, the ratio of 4a to 4a′
As shown in Table 1, the C–H bond oxidation of adamantane
(1) (0.1 mmol) was conducted with ketone (0.1 mmol), Oxone
(0.5 mmol × 3), and NaHCO3 (1.55 mmol × 3) in H2O (1 mL)
and CH3CN (1.5 mL) at room temperature for 6 h. It was found
that 1,1,1-trifluoroacetone exhibited the highest activity towards
adamantane oxidation (entry 1), and it converted 93% of 1 to 2a
and 2a′. This would be attributed to the strong electron-with-
drawing trifluoromethyl group. Methyl pyruvate with an elec-
tron-withdrawing ester group also gave high conversion of
adamantane oxidation (entry 2, 86%). Yet, ketones with a phenyl
group (entries 3–6) gave lower conversion (39–76%). Despite
their possession of the electron-withdrawing trifluoromethyl
group, the lower conversion would be due to the unfavorable
steric effect of the phenyl ring. Cyclic ketones14 (entries 7
and 8) gave moderate to good conversion (78% and 40%,
respectively).
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Fig. 2 Partial 1H NMR spectra of a mixture of 3a and β-CD in D2O
(signals of β-CD). Ratios of 3a : β-CD: (a) 0 : 10, (b) 1 : 9, (c) 2 : 8, (d)
3 : 7, (e) 4 : 6, (f) 5 : 5, (g) 6 : 4, (h) 7 : 3.
Fig. 3 1H NMR titration curve for 3a and β-CD.
Table 3 Effect of substituents and α-, β- and γ-CDs on site-selective
C–H bond oxidation of 3a–da
was only 7 : 1, which is consistent with the literature reports
based on the electronic effect of the substrates.3b A control
experiment was performed in H2O (10 mL) without β-CD (entry
4). Only poor conversion could be obtained (34% yield based on
4% conversion), probably due to the low solubility of 3a in
H2O.
These findings indicated that β-CD could provide enhanced
site-selectivity for C–H bond oxidation (20 : 1 vs. 7 : 1), probably
by obstructing the approach of dioxirane to the internal C–H
bond of 3a through inclusion complex formation in H2O. More-
over, β-CD could act as a reaction vessel to give comparable
conversion and yield of C–H bond oxidation as that of the reac-
tion performed in a mixture of H2O and CH3CN, by assisting
the dispersion of 3a in H2O.
Entry Substrate
CD
Conv.c (%)
Yieldd (%)
4a–d : 4a′–d′e
1
3a
3a
3a
3a
α
β
γ
—
6
55
71
81
96
6 : 1
20 : 1
7 : 1
2
40
17
35
3
4b
7 : 1
5
6
3b
3b
3b
3b
α
β
γ
—
34
40
28
52
23
40
22
56
11 : 1
12 : 1
5 : 1
1H NMR titration for binding of 3a to β-CD
7
8b
7 : 1
We studied the inclusion complex formation between β-CD and
1
3a by H NMR titration.15 The inclusion complexation between
9
3c
3c
3c
3c
α
β
γ
—
41
61
45
54
18
20
19
39
3 : 1
12 : 1
4 : 1
1
β-CD and 3a was confirmed by H NMR titration (Fig. 2). The
10
11
12b
signals of H3 and H5 were shifted upfield significantly when the
amount of 3a presented in the aqueous solution of β-CD
increased, whereas the signals of H2 and H4 remained
unchanged. This reflects the fact that 3a interacts with the
protons inside β-CD.
4 : 1
13
14
15
16b
3d
3d
3d
3d
α
β
γ
—
64
68
73
54
5
n.d.
24
39
61
5 : 1
10 : 1
4 : 1
A
1H NMR titration curve was obtained by plotting the
a Unless otherwise indicated, reactions were conducted with substrate
(0.2 mmol), 1,1,1-trifluoroacetone (0.2 mmol) and α-, β- or γ-CD
(0.22 mmol) in H2O (10 mL) at room temperature with Oxone
(0.5 mmol × 8) and NaHCO3 (1.55 mmol × 8) for 8 h. b The reaction
was carried out in H2O (4 mL) and CH3CN (6 mL). c Conversion was
calculated from the amount of substrate recovered by flash column
chromatography. d Yield based on conversion. e Determined by 1H
NMR.
change of chemical shift of H3 against the ratio of 3a to β-CD
(Fig. 3). The stoichiometry for the inclusion complex formation
was 1 : 1, determined by extrapolating the curve. The association
constant of the inclusion complex was 210 M−1, determined by
Scott’s method.16
Effect of different substituents on the site-selectivity of C–H
bond oxidation of 3a–d in the presence of cyclodextrins
enhancement of the site-selectivity of C–H bond oxidations of
3a, 3b, and 3c (entries 2, 6 and 10), as compared to the oxi-
dations performed in H2O (4 mL) and CH3CN (6 mL) without
β-CD (entries 4, 8 and 12) i.e., 4a : 4a′ (20 : 1 vs. 7 : 1); 4b : 4b′
(12 : 1 vs. 7 : 1); 4c : 4c′ (12 : 1 vs. 4 : 1). The site-selectivity
obtained in the presence of β-CD was two-to-three fold higher
than that controlled by the inherent electronic effect of the
Upon confirmation of the inclusion complex formation between
3,7-dimethyloctyl benzoate (3a) and β-CD, the effect of cyclo-
dextrins on the C–H bond oxidations of 4-tert-butylbenzoate 3b,
pivalate 3c, and acetate 3d were studied. The results are summar-
ized in Table 3.
In the presence of β-CD, 3a–d (Table 3, entries 2, 6, 10 and
14) were oxidized to 4a–d and 4a′–d′. β-CD in H2O gave
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Fig. 4 Partial contour plot of 600 MHz 2D ROESY spectrum for
binding of 4a (phenyl ring moiety) to β-CD in D2O.
Fig. 5 Partial contour plot of 600 MHz 2D ROESY spectrum for
binding of 4a (3,7-dimethyloctyl carbon chain) to β-CD in D2O.
substrates.3b,f For 3d, the site-selectivity of the C–H bond oxi-
dation was enhanced by γ-CD (entry 15, 4d : 4d′ = 10 : 1) rather
than β-CD (entry 14, 4d : 4d′ = 5 : 1). In the presence of α-CD
or γ-CD, the oxidation of 3a–c generally gave poor conversion
and yield, and the site-selectivity was not enhanced.
The stoichiometries of the inclusion complexes of 3a–c and
β-CD were found to be 1 : 1 with similar association constants
(3a: 210 M−1; 3b: 220 M−1; 3c: 325 M−1). In this regard, the
difference in site-selectivity (20 : 1 vs. 12 : 1) for 3a and 3b–c
could not be accounted for by the stoichiometries and the associ-
ation constants of 3a–c and β-CD. We decided to study the
binding geometry of 3a–c to β-CD by 2D ROESY experiments15
in order to provide hints on the different site-selectivities.
However, owing to the low solubility of 3a–c in D2O,
attempts to perform 2D ROESY experiments for the inclusion
complexes between 3a–c and β-CD were not successful (the
signals of 3a–c in 2D ROESY spectra are too weak in D2O).
Therefore, we performed the 2D ROESY experiment for the
binding of 4a (as a model of 3a).
Fig. 6 Proposed binding geometry for the inclusion of 3a in β-CD.
Studies on the binding geometries between 4a to β-CD through
2D ROESYexperiments
The 2D ROESY spectrum for the binding of 4a and β-CD
showed that H3, H5, and H6 of β-CD have NOE correlation
signals with the phenyl ring (Fig. 4) and the 3,7-dimethyloctyl
carbon chain (Fig. 5) of 4a.
The NOE correlation signals of the phenyl ring of 4a with H3,
H5, and H6 of β-CD (Fig. 4) suggested that the phenyl ring
binds to the cavity of β-CD. The absence of the NOE signals of
the p-H of 4a indicated that the phenyl ring is deeply included in
the cavity of β-CD. Apart from this, the NOE correlation signals
of the 3,7-dimethyloctyl carbon chain of 4a with H3, H5, and
H6 of β-CD (Fig. 5) revealed that the 3,7-dimethyloctyl carbon
chain of 4a would also bind into the cavity of β-CD.
Thus, based on the 2D ROESY spectrum of the inclusion
complex of 4a and β-CD, β-CD would bind to 3a with two poss-
ible binding modes. It is proposed that β-CD would affect the
site-selectivity through binding to the phenyl substituent of the
3a (Fig. 6, Binding mode A), and no C–H bond oxidation is
expected to occur when β-CD binds to the 3,7-dimethyloctyl
carbon chain of 3a (Fig. 6, Binding mode B).
Fig. 7 5a–c as model compounds of 3a–c for 2D ROESY
experiments.
Studies on the binding geometries between model compounds of
3a–c to β-CD through 2D ROESYexperiments
After establishment of the two possible binding geometries of 3a
to β-CD, the effect of different substituents on the binding geo-
metries was studied. In this part, methyl benzoate (5a), methyl
4-tert-butylbenzoate (5b), and methyl pivalate (5c) were chosen
as the model compounds of 3a, 3b, and 3c, respectively (Fig. 7).
From the 2D ROESY spectra for the binding of 5a–c to β-CD
(see ESI†), it was found that 5a–c would bind into the β-CD
cavity with different depth (Fig. 8). 5a was deeply included into
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As shown in Table 3, α-CD and γ-CD could not give enhance-
ment of the site-selectivity of C–H bond oxidation of 3a–c. It
may be because the size of the cavity of α-CD did not fit the
substrates; and the structure of γ-CD was too flexible to bind
with the substrates (the changes of the chemical shift of H3 and
H5 of γ-CD induced by the inclusion complexation between
γ-CD and the substrates were very small, see ESI†). Apart from
the site-selectivity, the low yields and conversions obtained with
α-CD or γ-CD could be due to the undesirable binding.
Fig. 8 Proposed binding geometries of 5a–c to β-CD.
Effect of CDs on the site-selectivity of C–H bond oxidation of 3d
Unlike the results obtained from 3a–c, β-CD did not improve the
site-selectivity of C–H bond oxidation of 3d. The stoichiometry
of the inclusion complex of 3d to β-CD was found to be 2 : 1 by
1H NMR titration. The 2D ROESY experiment for the binding of
3d to β-CD has been conducted (see ESI†). The results showed
that β-CD bound to the 3,7-dimethyloctyl carbon chain of 3d.
Thus, no C–H bond oxidation of 3d would occur based on this
binding mode. The C–H bond oxidation of 3d was likely to
occur with poor site-selectivity in aqueous medium (Table 3,
entry 14). Interestingly, γ-CD gave a two-fold improvement on
the site-selectivity of C–H bond oxidation of 3d (Table 3, entry
15). The stoichiometry of the inclusion complex of 3d to γ-CD
1
was found to be 1 : 1 by H NMR titration. However, it was not
possible to study the binding geometry of 3d to γ-CD due to the
weak NOE signal between 3d and γ-CD.
Fig. 9 Schematic diagrams for site-selective C–H bond oxidation of
3a–c.
Selective C–H bond oxidation of hydrocarbon mixtures by
supramolecular approach
the β-CD cavity. For 5b, only the tert-butyl moiety and a half of
the phenyl ring were included into the β-CD cavity. The tert-
butyl moiety of 5c was included close to the secondary face of
β-CD.
As β-CD gave an enhancement of the conversion and site-selec-
tivity of C–H bond oxidation, it was interesting to study the
selectivity in C–H bond oxidation of hydrocarbon mixtures by
supramolecular approach. In this regard, cumene (6a) and ethyl
benzene (6b) were used as the substrates.
The oxidation of 6a in the presence of β-CD gave cumyl
alcohol (7a) in 32% yield with 38% recovery of 6a (Table 4,
entry 1). However, no 7a was obtained with only 3% recovery of
6a in the absence of β-CD (entry 2). It is known that 6a has low
solubility in H2O and would evaporate during the course of reac-
tion. Comparing the findings in entries 1 and 2, it was suggested
that β-CD could enhance the reaction yield by acting as a reac-
tion vessel and minimizing the evaporation of volatile 6a
through inclusion complex formation.17 In H2O (4 mL) and
CH3CN (6 mL), 7a in 4% yield with 63% recovery of 6a was
obtained (entry 3). The poor oxidation efficiency of 6a would be
due to the biphasic separation of H2O and CH3CN during the
reaction.
β-CD exhibited a similar effect on the oxidation of 6b to
afford 7b in 15% yield with 65% recovery of 6b (entry 4).
Without β-CD, no oxidation of 6b occurred and only 3% of 4b
was recovered (entry 5). The oxidation of 6b in H2O (4 mL) and
CH3CN (6 mL) gave 7b in 4% yield with 73% recovery of 6b
(entry 6).
Proposed relationship between binding geometries and
site-selective C–H bond oxidation of 3a–c
Based on the 2D ROESY studies of binding geometries of 5a–c
to β-CD, it is expected that the different binding geometries of
the substituents to β-CD could affect the site-selectivity (Fig. 9).
A deep inclusion of the phenyl ring of 3a into the β-CD
cavity leading to significant steric hindrance induced by the
β-CD could effectively obstruct the approach of dioxirane to the
internal tertiary C–H bond of 3a, resulting in the highest site-
selectivity in C–H bond oxidation (4a : 4a′ = 20 : 1). In the case
of 3b, the inclusion of the tert-butyl moiety and only half of the
phenyl ring into the β-CD cavity led to a longer distance
between the internal tertiary C–H bond and the β-CD. The
reduced steric hindrance induced by β-CD on the internal tertiary
C–H bond gave lower site-selectivity in C–H bond oxidation
(4b : 4b′ = 12 : 1). The tert-butyl group of 3c was in close proxi-
mity to H3 located at the rim of β-CD and not as deeply included
as the phenyl group of 3a. Thus, β-CD provides less effective
obstruction to the approach of dioxirane to the internal tertiary
C–H bond, leading to the lower site-selectivity in the C–H bond
oxidation (4c : 4c′ = 12 : 1).
In a mixture of 6a and 6b, the oxidation of 6a was selectively
enhanced in the presence of β-CD. With β-CD, 7a (23% yield;
50% recovery) and 7b (3% yield; 59% recovery) were obtained
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Table 4 Effect of β-CD on dioxirane-based oxidation of 6a, 6b, and their mixture
Entry
Substrate
Conditions
Product
Yieldd (%) (Recovery of starting materials (%))
1
2
3
H2O + β-CDa
H2Ob
32 (38)
0 (3)
4 (63)
H2O + CH3CNc
4
5
6
H2O + β-CDa
H2Ob
15 (65)
0 (3)
4 (73)
H2O + CH3CNc
7
8
H2O + β-CDa
7a: 23 (50); 7b: 3 (59)
7a: 9 (71); 7b: 4 (59)
H2O + CH3CNc
a The reaction was conducted by stirring substrate (0.2 mmol), 1,1,1-trifluoroacetone (0.2 mmol) and β-CD (0.22 mmol) in H2O (10 mL) at room
temperature with Oxone (0.5 mmol × 8) and NaHCO3 (1.55 mmol × 8) for 8 h. b The reaction was performed in H2O (10 mL) without β-CD. c The
reaction was performed in H2O (4 mL) and CH3CN (6 mL) without β-CD. d Obtained by GC analysis of crude reaction mixture using authentic
standards.
(entry 7). The experiment conducted in H2O–CH3CN gave 7a
(9% yield; 71% recovery) and 7b (4% yield; 70% recovery)
without notable selectivity. It should be pointed out that the
binding constant of 6a to β-CD (1.2 × 103 M−1) is about four-
fold higher than that of 6b to β-CD (3.3 × 102 M−1).18 Thus, the
preferential binding of 6a to β-CD would probably lead to an
enhanced oxidation efficiency of 6a over 6b.
film thickness). The carrier gas was nitrogen at 12 psi. The
running mode was splitless. The sample injection was done by
auto-sampler. 1 μL of solution was injected for each run.
General procedure for C–H bond oxidation of adamantane
(Table 1)
To a stirring solution of adamantane (1) (0.1 mmol) in a mixture
of H2O (1 mL) and CH3CN (1.5 mL), 1,1,1-trifluoroacetone
(0.1 mmol) was added, followed by 3 additions of Oxone
(0.5 mmol × 3) and NaHCO3 (1.55 mmol × 3) at 0 h, 2 h and
4 h. After an additional stirring of 2 h, H2O (4 mL) was added,
and the resulting mixture was extracted with ethyl acetate
(10 mL × 3). The combined organic extract was dried over anhy-
drous Na2SO4 and filtered, and the organic solvent evaporated
under reduced pressure. The residue was analyzed by 1H NMR.
Conclusions
In summary, we have developed efficient methods for C–H bond
oxidation by dioxiranes generated in situ in aqueous medium.
With portion-wise additions of Oxone and NaHCO3, the conver-
sion and yield would be increased. Site-selective C–H bond oxi-
dation of aliphatic esters was achieved by obstructing the
approach of dioxiranes to the C–H bond with higher steric hin-
drance induced through inclusion complexation with β-CD in
H2O. In addition, using β-CD, cumene was preferentially oxi-
dized in a mixture of cumene and ethyl benzene.
Preparation of 3a–d
To 0.1 mmol of DMAP in 5 mL of distilled dichloromethane
under nitrogen atmosphere, 1 mmol of 3,7-dimethyl 1-octanol
was added, followed by addition of 5 mmol of triethylamine and
dropwise addition of 1.2 mmol of acyl chloride (For preparation
of 3d, 1.2 mmol of acetic anhydride was used instead of acyl
chloride). After stirring the reaction mixture overnight under
nitrogen atmosphere, the reaction was quenched by addition of
10 mL of H2O. The resulting solution was extracted with 10 mL
of dichloromethane. The organic extract was then washed with
10 mL of 3.7% hydrochloric acid, 10 mL of saturated sodium
bicarbonate solution and 10 mL of brine, followed by drying
with anhydrous Na2SO4. The organic solvent was filtered and
evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel using ethyl acetate–
hexane as eluent.
Experimental
General information
Reagents and solvents purchased from commercial sources were
used without further purification. Flash column chromatography
was performed using silica gel 60 (230-400 mesh ASTM) with
ethyl acetate–n-hexane as eluent. 1H NMR and 13C NMR
spectra were recorded on Varian AS-500 spectrometer. Chemical
shifts (ppm) were referred to TMS (internal standard). The 2D
ROESY spectra were recorded using Brucker Avance III 600. IR
spectra were reported with a Thermo Scientific Nicolet 380
FT-IR spectrometer. Mass spectra were measured using a Q-TOF
2TM mass spectrometer with an ESI source (Waters-Micromass,
Manchester, UK). Gas chromatography experiments were carried
out with gas chromatograph system (Hewlett Packard 5890
series II) equipped with a flame ionization detector operated at
280 °C. The injector temperature was set to be 250 °C. The
column used was HP-5 column (30 m × 0.32 mm × 0.25 μm
3,7-Dimethyloctyl benzoate (3a).3a Colorless liquid; analytical
TLC (silica gel 60) (2% EtOAc in hexane), Rf = 0.5; δH
(500 MHz; CDCl3) 8.04 (d, J = 7.0 Hz, 2H), 7.54 (t, J = 7.0 Hz,
1H), 7.43 (t, J = 8.2 Hz, 2H), 4.40–4.32 (m, 2H), 1.85–1.77
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1
(m, 1H), 1.70–1.48 (m, 3H), 1.38–1.12 (m, 6H), 0.96 (d, J = 6.6
Hz, 3H), 0.87 (d, J = 6.8 Hz, 6H); δC (125 MHz, CDCl3) 166.7,
132.9, 130.8, 129.7, 128.5, 63.7, 39.4, 37.4, 35.8, 30.2, 28.2,
24.9, 22.8, 19.8.
curve of H NMR titration was obtained by plotting the change
of chemical shift of H3 against the mole ratio of substrate to
cyclodextrin.
3,7-Dimethyloctyl 4-tert-butylbenzoate (3b). Colorless liquid;
yield: 97% (0.308 g, 0.97 mmol); analytical TLC (silica gel 60)
(2% EtOAc in n-hexane), Rf = 0.45; δH (500 MHz, CDCl3)
7.98–7.96 (d, 2H), 7.46–7.44 (d, 2H), 4.38–4.30 (m, 2H),
1.83–1.76 (m, 1H), 1.67–1.60 (m, 1H), 1.59–1.49 (m, 1H),
1.38–1.22 (m, 12H), 1.18–1.13 (m, 3H), 0.96–0.95 (d, 3H),
0.87–0.86 (d, 6H); δC (125 MHz, CDCl3) δ 166.8, 156.54,
129.63, 128.02, 125.46, 63.52, 39.45, 37.41, 35.88, 35.24,
31.35, 30.22, 28.17, 24.88, 22.92, 22.83, 19.85; IR (KBr): =
2956, 2869, 1721, 1276, 855, 755, 708 cm−1; HRMS (ESI) m/z
for C21H34O2Na [M + Na]+ calcd: 341.2457, found: 341.2466.
General procedure for site-selective C–H bond oxidation of
3,7-dimethyloctyl esters 3a–d with cyclodextrins (Table 3)
To a mixture of 3,7-dimethyloctyl ester (0.2 mmol) and cyclo-
dextrin (0.22 mmol), H2O (10 mL) was added, followed by
addition of 1,1,1-trifluoroacetone (0.2 mmol). Then, the reaction
mixture was treated with 8 additions of Oxone (0.5 mmol × 8)
and NaHCO3 (1.55 mmol × 8) at an interval of 1 h. After stirring
for a total of 8 h at room temperature, the resulting mixture was
extracted with ethyl acetate (20 mL × 3). The combined organic
extract was dried over anhydrous Na2SO4 and filtered, and the
organic solvent was evaporated under reduced pressure. The
residue was then dissolved in CDCl3 for analysis of the product
3,7-Dimethyloctyl pivalate (3c).20 Colorless liquid; analytical
TLC (silica gel 60) (2% EtOAc in n-hexane), Rf = 0.55; δH
(500 MHz, CDCl3) 4.15–4.04 (m, 2H), 1.59–1.49 (m, 2H),
1.47–1.38 (m, 1H), 1.36–1.25 (m, 3H), 1.19 (s, 9H), 1.17–1.11
(m, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 6H); δC
(125 MHz, CDCl3) 178.7, 63.0, 39.3, 38.8, 37.3, 35.7, 30.0,
28.1, 27.3, 24.8, 22.8, 22.7, 19.7.
1
ratio by H NMR spectroscopy. The yield and conversion were
obtained by flash column chromatography of the residue.
7-Hydroxy-3,7-dimethyloctyl
benzoate
(4a).3a Colorless
liquid; analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf
= 0.35; δH (500 MHz, CDCl3) 8.04 (d, J = 7.1 Hz, 2H), 7.55 (t,
J = 7.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 4.40–4.31 (m, 2H),
1.85–1.79 (m, 1H), 1.71–1.55 (m, 3H), 1.48–1.32 (m, 5H), 1.21
(s, 6H), 0.973 (d, J = 6.6 Hz, 3H); δC (125 MHz, CDCl3) 166.7,
132.8, 130.5, 129.5, 128.3, 70.9, 63.5, 44.1, 37.4, 35.6, 30.1,
29.2, 29.2, 21.6, 19.6; MS (ESI) m/z 301 [M + Na]+.
3,7-Dimethyloctyl acetate (3d).3f Colorless liquid; analytical
TLC (silica gel 60) (2% EtOAc in n-hexane), Rf = 0.6; δH
(500 MHz, CDCl3) 4.15–4.04 (m, 2H), 2.03 (s, 3H), 1.70–1.09
(m, 10H), 0.90 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 7.1 Hz, 6H); δC
(125 MHz, CDCl3) 171.0, 63.0, 39.3, 37.2, 35.6, 29.9, 28.0,
24.7, 22.7, 22.6, 21.0, 19.6.
3-Hydroxy-3,7-dimethyloctyl
benzoate
(4a′).19 Colorless
liquid; analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf
= 0.45; δH (500 MHz, CDCl3) 8.03 (d, J = 7.1 Hz, 2H), 7.56 (t,
J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 4.50 (t, J = 6.9 Hz,
2H), 2.01–1.92 (m, 2H), 1.57–1.50 (m, 3H), 1.40–1.33 (m, 2H),
1.27 (s, 3H), 1.20–1.15 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H); δC
(125 MHz, CDCl3) 166.9, 133.1, 130.5, 129.7, 128.6, 72.2,
62.0, 43.1, 40.0, 39.7, 28.2, 27.4, 22.8, 22.8, 22.0; MS (ESI)
m/z 301 [M + Na]+.
Procedure for site-selective C–H bond oxidation of 3a with β-CD
(Table 2, entry 1)
To a mixture of 3a (0.2 mmol) and β-CD (0.22 mmol), H2O
(10 mL) was added, followed by the addition of 1,1,1-trifluoro-
acetone (0.2 mmol). Then, the reaction mixture was treated with
8 additions of Oxone (0.5 mmol × 8) and NaHCO3 (1.55 mmol
× 8) at an interval of 1 h. After stirring for a total of 8 h at room
temperature, the resulting mixture was extracted with ethyl
acetate (20 mL × 3). The combined organic extract was dried
over anhydrous Na2SO4 and filtered, and the organic solvent was
evaporated under reduced pressure. The residue was then dis-
7-Hydroxy-3,7-dimethyloctyl 4-tert-butylbenzoate (4b). Color-
less liquid; analytical TLC (silica gel 60) (20% EtOAc in
hexane), Rf = 0.48; δH (500 MHz, CDCl3) 7.97 (d, J = 8.5 Hz,
2H), 7.45 (d, J = 8.8 Hz, 2H), 4.39–4.31 (m, 2H), 1.84–1.78 (m,
1H), 1.71–1.62 (m, 1H), 1.61–1.54 (m, 1H), 1.47–1.32 (m,
15H), 1.27–1.22 (m, 1H), 1.21 (s, 6H), 0.97 (d, J = 6.8 Hz, 3H);
δC (125 MHz, CDCl3) 166.7, 156.4, 129.4, 127.7, 125.3, 70.9,
63.3, 44.1, 37.4, 35.6, 31.1, 30.0, 29.3, 29.2, 21.6, 19.6; IR
1
solved in CDCl3 for analysis of the product ratio by H NMR
spectroscopy. The yield and conversion were obtained by flash
column chromatography of the residue.
(KBr): = 3449, 2966, 2870, 1720, 1278, 855, 776, 708 cm−1
;
MS (ESI) m/z 335 [M + H]+; HRMS (ESI) m/z for C21H35O3
Experimental procedures for 1H NMR titration experiment
[M + H]+ calcd: 335.2586, found: 335.2598.
To the solutions of β-cyclodextrin of different concentrations in
D2O (0.5 mL) in NMR tubes at room temperature, different
volumes of the solution of substrates in D6-acetone (0.5 M) were
added (the ratio of β-cyclodextrin to substrate = 0 : 10, 1 : 9,
2 : 8, 3 : 7, 4 : 6, 5 : 5, 5.5 : 4.5, 6 : 4, 6.7 : 3.3, 7 : 3). The result-
3-Hydroxy-3,7-dimethyloctyl 4-tert-butylbenzoate (4b′). Color-
less liquid; analytical TLC (silica gel 60) (20% EtOAc in
hexane), Rf = 0.52; δH (500 MHz, CDCl3) 7.95 (d, J = 8.3 Hz,
2H), 7.45 (d, J = 8.1 Hz, 2H), 4.48 (t, J = 6.8 Hz, 2H),
2.00–1.91 (m, 2H), 1.64–1.48 (m, 5H), 1.35–1.32 (m, 12H),
1.27 (s, 3H), 0.86 (d, J = 6.6 Hz, 6H); δC (125 MHz, CDCl3)
166.8, 156.8, 129.6, 127.7, 125.6, 72.2, 61.8, 43.1, 40.1, 39.7,
35.3, 31.3, 28.2, 27.4, 22.8, 22.8, 22.0; MS (ESI) m/z 335
1
ing solutions were analyzed by H NMR spectrometer immedi-
ately after being shaken vigorously with cover. Using the
chemical shift of H4 as internal reference (as the chemical shift
of H4 is least affected during inclusion complex formation), the
3128 | Org. Biomol. Chem., 2012, 10, 3122–3130
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[M + H]+; HRMS (ESI) m/z for C21H35O3 [M + H]+ calcd:
335.2586, found: 335.2573.
Notes and references
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7-Hydroxy-3,7-dimethyloctyl pivalate (4c).20 Colorless liquid;
analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =
0.38; δH (500 MHz, CDCl3) 4.15–4.04 (m, 2H), 1.72–1.63 (m,
1H), 1.61–1.53 (m, 1H), 1.49–1.29 (m, 7H), 1.22 (s, 6H), 1.20
(s, 9H), 0.92 (d, J = 6.6 Hz, 3H); δC (125 MHz, CDCl3) 178.7,
70.9, 62.9, 44.1, 38.7, 37.4, 35.5, 29.9, 29.3, 29.2, 27.2, 21.7,
19.5; MS (ESI) m/z 281 [M + Na]+.
3-Hydroxy-3,7-dimethyloctyl pivalate (4c′). Colorless liquid;
analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =
0.48; δH (500 MHz, CDCl3) 4.23 (t, J = 6.6 Hz, 2H), 1.87–1.77
(m, 2H), 1.59–1.50 (m, 2H), 1.49–1.44 (m, 2H), 1.38–1.31 (m,
3H), 1.22 (s, 3H), 1.20 (s, 9H), 0.88 (d, J = 8.1 Hz, 6H); δC
(125 MHz, CDCl3) 178.7, 72.2, 61.5, 43.0, 40.0, 39.7, 38.9,
28.2, 27.4, 27.2, 22.8, 22.8, 21.9; MS (ESI) m/z 281 [M + Na]+;
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7-Hydroxy-3,7-dimethyloctyl acetate (4d).3b Colorless liquid;
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0.20; δH (500 MHz, CDCl3) 4.24 (t, J = 7Hz, 2H), 2.05 (s, 3H),
1.87–1.77 (m, 2H), 1.60–1.15 (m, 7H), 1.21 (s, 3H), 0.88 (d, J =
6.6 Hz, 6H); δC (125 MHz, CDCl3) 171.0, 71.9, 61.3, 42.8,
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General procedure for C–H bond oxidation of 6a or 6b with
β-CD (Table 4)
To a mixture of substrate (0.2 mmol) and β-CD (0.22 mmol),
H2O (10 mL) was added, followed by addition of 1,1,1-trifluoro-
acetone (0.2 mmol). Then, the mixture was treated with 8
additions of Oxone (0.5 mmol × 8) and NaHCO3 (1.55 mmol ×
8) at an interval of 1 h. After stirring for 8 h at room temperature,
the resulting mixture was extracted with ethyl acetate (10 mL ×
3). The combined organic extract was dried over anhydrous
Na2SO4 and filtered. Then, 0.4 mL of the extract was mixed
with a hexane solution of n-decane as internal standard, and
made up to 0.9 mL solution by n-hexane in a 1.5 mL vial for
GC analysis.
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Council (PolyU 7052/07p) and The Hong Kong Polytechnic
University (A-PK37, PolyU Departmental General Research
Funds, Competitive Research Grants for Newly Recruited Junior
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