Photo-organocatalytic enantioselective α-hydroxylation of β-keto esters and β-keto amides with oxygen under phase transfer catalysis

Article abstract of DOI:10.1039/c6gc01245k

An efficient and enantioselective photo-organocatalytic α-hydroxylation of β-dicarbonyl compounds using molecular oxygen was extended. This simple catalytic procedure is applicable to a range of β-keto esters and β-keto amides (30 examples) with a new series of C-2′-substituted phase transfer catalysts in good enantiopurity (up to 90% ee) and yield (up to 99%). Moreover, the reaction was successfully scaled up to gram quantity without any loss of enantioselectivity.

Full text of DOI:10.1039/c6gc01245k

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Photo-organocatalytic enantioselective α-hydroxylation of β-keto
esters and β-keto amides with oxygen under phase transfer
catalysis
Yakun Wang,a,b Zehao Zheng,a Mingming Lian,c Hang Yin,a Jingnan
Zhao,a Qingwei Meng*a and Zhanxian Gaoa
An efficient and enantioselective photo-organocatalytic α-hydroxylation of β-dicarbonyl compounds using molecular
oxygen was extended. This simple catalytic procedure is applicable to a range of β-keto esters and β-keto amides (30
examples) with a new series of C-2′-substituted phase transfer catalysts in good enantiopurity (up to 90% ee) and yield (up
to 99%). Moreover, the reaction was successfully scaled up to gram quantity without any loss of enantioselectivity.
Introduction
dicarbonyl compounds is a significant transformation. Davis
first reported the enantioselective ɑ-hydroxylation of β-keto
Over the past several decades, visible light has been
recognized as type of environmentally friendly and
esters using stoichiometric amounts of chiral oxaziridine in
1981.13
Asymmetric catalysis by chiral
a
sustainable energy.1 Moreover, enormous research interest in
visible-light-driven catalytic asymmetric chemistry has been
shown in recent years.2-4 Among the photo-chemical reactions,
photo-oxygenation is a novel oxidation method. Furthermore,
molecular oxygen in air is considered a green oxidant, but it is
usually torpid. However, molecular oxygen can be transferred
from its non-excited triplet state (3O2) to its more reactive
singlet state (1O2) by photosensitization. The application for
visible-light-activated asymmetric catalysis with oxygen is a
challenge. In 2004, Córdova and his co-workers first reported
enantioselective photo-oxygenation of aldehydes and ketones
using singlet molecular oxygen as the oxidant and amino acids
metal complexes and organocatalysts were then developed
rapidly.14-15 In regard to organocatalytic approaches, chiral
phosphoric acids, 15b lappaconitine15c and S-timolol analogues,
15d
chiral guanidines15h, i and cinchona alkaloids15a, o have been
reported as efficient catalysts. However, most of these
reactions require oxidants such as organic peroxide,
oxaziridine, dimethyldioxirane or nitrosobenzene. Considering
economical as well as environmental viewpoints, the use of
molecular oxygen as the oxidant would undoubtedly make it
an ideal candidate in organic synthesis,16 especially in the field
of asymmetric catalysis.17
as chiral organocatalysts.5 Our group independently reported Results and Discussion
an enantioselective α-hydroxylation of β-keto esters with
Currently, phase-transfer catalysis has been recognized as an
molecular oxygen by a chiral phase transfer catalyst.6 The
limited success in photo-oxygenation urges us to extend its use
in oxidation reactions.
effective and sustainable method for organic synthesis. The
enantioselective phase-transfer reactions have been
developed rapidly, and the research area has become
The optically active ɑ-hydroxy β-dicarbonyl compounds attractive in the pursuit of green and sustainable chemistry.18
represent a functional and common structural motif in a Based on our previous research, an efficient and
variety of natural products and pharmaceuticals.7 These enantioselective phase-transfer catalyzed photo-oxygenation
compounds have been used for the synthesis of bioactive of
products, such as Ginkgolide B,8 Kjellmanianone,9 Hamigeran but the enantioselectivity is moderate and the substrate scope
A10 and Doxycycline.11 Furthermore, they have been used as an is limited to the -keto esters derived from indanone6. Here,
β-keto esters has been developed under mild conditions,
β
important intermediate in the synthesis of the insecticide we have developed a series of new phase-transfer catalysts
indoxacarb.12 Therefore, asymmetric ɑ-hydroxylation of β- (PTC’s) derived from cinchona alkaloids and attempted the
reaction of 1-indanone-derived β-keto ester 1a (0.1 mmol) in
toluene, treated with
a PTC (10 mol%, 0.01 mmol),
aState Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and
Technology, Dalian University of Technology, Dalian 116024, P. R. China
No. 2 Linggong Road, Ganjingzi District, Dalian, Liaoning
tetraphenylporphine (TPP, 1 mol%, 0.001 mmol), and K2HPO4
(50% aq.) in air for enantioselective αꢀhydroxylation. First, the
use of the simplest PTC 3a provided 2a with 38% ee after two
hours (Table 1, entry 1). Next, we prepared a series of phase-
Province 116012, P. R. China Fax +86(411)84986201; E-mail: mengqw@dlut.edu.cn
b School of Pharmacy, Xinxiang Medical College, Xinxiang, Henan,
P. R.China
cDepartment of Pharmaceutics, Daqing Campus, Harbin Medical University.
No. 1 Xinyang Road, Gaoxin District, Daqing, Heilongjiang163319, P. R. China
transfer catalysts via modification of the C-9 and C-6
′ group.
PTC 3b with a methoxyl group at C-6′ position led to lower
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enantioselectivity and conversion (Table 1, entry 2). To our
disappointment, PTC 3c, which has two hydroxy groups at C-9
and C-6’ positions, showed poor results (Table 1, entry 3). PTC
3d was then introduced with a bulky 1-adamantyl group at C-9
Entry
Cat.
t [h]
Con [%]b
ee [%]c
1
2
3a
3b
3c
3d
3e
3f
2
3
90
80
38
31
20
35
21
43
51
68
32
85
58
86
78
80
84
80
-
position, but the ee value was slightly lower than that of 3a
,
which supported the assumption that the free hydroxy group
at the C-9 position was responsible for inducing high
enantioselctivity in the reaction process (Table 1, entry 4).
3
6
40
4
2
>95
>95
>95
>99
>95
81
5
1
Recently, doubly quaternized cinchona-alkaloid based phase-
transfer catalysts were developed.18 We obtained the PTC 3e
using the method mentioned above. Although the reaction
time was shortened, the enantioselectivity of 2a was poor
(Table 1, entry 5). We were therefore interested in the
structural modification at C-2’ position,19 and 3f and 3g were
synthesized. They had been modified with a bromo atom and
phenyl at C-2’ position, respectively. We were pleased to see
that their respective values of enantiomeric excess were
increased to 43% and 51% (Table 1, entries 6,7). These results
revealed that the stereocontrol was sensitive to structural
6
1
7
3g
3h
3i
1
8
1
9
2
10
11
12
13
14
15
16
17
3j
0.5
1
>99
>99
>99
95
3k
3l
0.3
0.5
0.5
0.5
0.5
4
3m
3n
3o
3p
3q
>99
>99
>99
Trace
modifications at the C-2′ position of the quinoline ring. Next,
3h and 3i were introduced. Interestingly, 3h containing 3,5-
bromo groups in the benzyl position, worked well and gave
enantioselectivity of 68% ee. Nevertheless, 3i containing
a Unless otherwise specified, β-keto ester 1a (31.0 mg, 0.1 mmol), catalyst (0.01
mmol, 10 mol%), and TPP (0.6 mg, 0.001 mmol) were added to a test tube
equipped with a stirring bar and dissolved in toluene (10 mL). Then, 50% K2HPO4
(4 mL) was added. The mixture was stirred in air with exposure to a 100-
W halogen lamp at 15 oC until the reaction was completed. b Determined by HPLC
Scheme 1. Cinchona alkaloid derivatives employed for the α-
hydroxylation reaction.
c
analysis with hexane/2-propanol (80:20) as the eluent (Kromasil, SiO2, 5 m).
Determined by HPLC analysis (Chiralcel AD-H) with hexane/2-propanol (80:20) as
the eluent.
An n-Bu group at C-2’ position was also introduced: 3k
provided 2a with only 58% ee (Table 1, entry 11). Importantly,
3l which has a 4-CF3-C6H4 group, afforded even higher activity
and enantioselectivity (>99% conversion, 86% ee) (Table 1,
entry 12). We next focused on the substituent group in the
benzyl position. Unfortunately, 3,5-trifluoromethyl, 3,5-fluoro,
3,5-chloro, and 3,5-iodo groups in the benzyl position showed
slightly lower ee values compared with the 3,5-bromo groups
(Table 1, entries 13-16). Only a trace of 2a was formed using
3,5-phenyl groups gave 2a in only 32% ee (Table 1, entries 8, 9).
These examples indicated that the enantioselective control in
the benzyl position was possibly due to the electronic tuning.
Addition of large steric hindrance groups, such as phenyl in the
benzyl position, seems to have little influence on the
enantioselectivity. We next examined catalyst 3j, which was
benzyltrimethylammonium bromide (BTMAB)
(3q) as the
quaternary ammonium salt (Table 1, entry 17), which
confirmed that the structural characteristics of the phase-
transfer catalysts were responsible for both the catalytic
activity and the enantioselectivity observed for the ɑ-
hydroxylation.
designed to have not only a phenyl group at C-2′ position but
also 3,5-bromo groups in the benzyl position. Gratifyingly, 3j
afforded 2a with 85% ee and almost quantitative conversion in
30 min (Table 1, entry 10).
After a suitable catalyst 3I had been identified, further
reaction optimization was undertaken. Table 2 summarizes the
effect of several parameters on this reaction. First, we found
that the enantioselectivity of the reaction could be increased
from 81% to 86% ee when the substrate concentration was
reduced from 0.02 M to 0.01 M (Table 2, entries 1, 2).
However, further reduction in the reactant concentration (0.01
M to 0.005 M) resulted in no significant improvement for the
Table 1. Screening of cinchona alkaloid derivatives for α-
hydroxylation of β-keto ester.a
2 | J. Name., 2012, 00, 1-3
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ee value (Table 2, entry 3). The effect of using different light sources was evaluated. Similar enantioselectivities with
Table 2. Optimization of the reaction conditions for α-hydroxylation of β-keto ester with catalyst 3I.a
Entry
Sub
(mmol)
0.1
Light source
Solvent
PTC 3I
base
Sensitizer
T
Reaction
time
Con
[%]b
97d
98d
93d
ee
[%]c
86
81
85
83
83
85
86
77
86
Nd
89
(mol%)
[oC]
15
15
15
15
15
15
15
15
15
15
15
1
2
3
4
5
6
7
8
9
100-W halogen lamp
100-W halogen lamp
100-W halogen lamp
7-W LED blue lamp
3-W LED blue lamp
3-W LED red lamp
3-W LED yellow lamp
3-W LED purple lamp
Sunlight
PhMe
PhMe
5
5
5
5
5
5
5
5
5
5
5
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
TPP (1 mol%)
20 min
15 min
40 min
40 min
30 min
10 min
10 min
30 min
10 min
360 min
10 min
0.2
0.05
0.1
PhMe
PhMe
>99
>99
>99
>99
>99
>99
Trace
>99
0.1
PhMe
0.1
PhMe
0.1
PhMe
0.1
PhMe
0.1
PhMe
10
0.1
Darkness
PhMe
11
12
13
14
15
16
17
18e
19
20
21
0.1
3-W LED yellow lamp
PhMe/CHCl3
=8:2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
3-W LED yellow lamp
PhMe/CHCl3
=8:2
5
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
25%K2HPO4
30%K2CO3
Rose bengal
(1 mol%)
[Ru(bpy)3]Cl2
(1 mol%)
I2
15
15
15
15
15
15
15
15
0
20 min
60 min
360 min
30 min
60 min
10 min
30 min
>99
Trace
15
87
Nd
41
90
89
84
PhMe/CHCl3
=8:2
5
PhMe/CHCl3
=8:2
5
(1 mol%)
TPP
PhMe/CHCl3
=8:2
5
>99
>99
>99
>99
(0.05 mol%)
TPP
PhMe/CHCl3
=8:2
5
(0.05 mol%)
TPP
PhMe/CHCl3
=8:2
5
(0.05 mol%)
TPP
PhMe/CHCl3
=8:2
2.5
0.5
2.5
2.5
50%K2HPO4
50%K2HPO4
50%K2HPO4
50%K2HPO4
90
(87)e
(0.05 mol%)
TPP
(15 min)e (>99)e
PhMe/CHCl3
=8:2
360 min
60 min
30 min
80
85
(0.05 mol%)
TPP
PhMe/CHCl3
=8:2
>99
>99
88
89
(0.05 mol%)
TPP
PhMe/CHCl3
35
=8:2
(0.05 mol%)
b
a Unless otherwise specified, the reaction was performed with 0.1 mmol 1a by using the same conditions described in Table 1. Determined by HPLC analysis with
hexane/2-propanol (80:20) as the eluent (Kromasil, SiO2). c Determined by HPLC analysis (Chiralcel AD-H) with hexane/2-propanol (80:20) as the eluent. d Isolated yield
eUsing pure oxygen gas as the oxidant.
complete conversion in a short time (40 min) were obtained completed in only 10 minutes without evident loss of
when a 7-W LED blue lamp was used (Table 2, entry 4). We enantioselectivity (Table 2, entries 6, 7). However, the purple
think the reaction activity was possibly due to the wavelength of and blue lamps showed obviously poor results (Table 2, entries
the light rather than the wattage. Next, we tested 3-W LED 5, 8). It is worth mentioning that the reaction also proceeded
lamps of different wavelength, such as blue, red, yellow and well in the sunlight and gave the corresponding product 2a in
purple. To our delight, the yellow lamp and red lamp showed almost quantitative yield (without any impurities by HPLC)
high activity for the ɑ-hydroxylation, and the reaction was with 86% ee after approximately 10 min (Table 2, entry 9).
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Conversely
，nearly no reaction happened in the darkness
OMe
H
(Table 2, entry 10). The ee value was improved to 89% when
we used PhMe/CHCl3 =8:2 as the component solvent (Table 2,
entry 11). Other sensitizers such as Rose Bengal, [Ru(bpy)3]Cl2
and I2 were also tested. It was found that rose bengal showed
considerable reactivity, whereas [Ru(bpy)3]Cl2 and I2 showed poor
results. The reason for the significant differences in reactivity
among these sensitizers may have been that the two different
photo-oxygenation reaction mechanisms. In this reaction system,
singlet oxygen (1O2), activated by energy-transfer sensitization, is
more suitable than electron-transfer (ET) sensitization. Thus, TPP
(tetraphenylporphine) was selected as the best sensitizer for
this reaction (Table 2, entries 12-14). Further study showed
that the sensitizer (TPP) loading could be decreased to as low
as 0.05 mol%, while maintaining a comparable reaction
conversion and achieving a higher ee value (90%) (Table 2,
entry 15). We also tested other bases. The use of 25% K2HPO4
led to a slightly long reaction time compared with 50% K2HPO4.
The 30% K2CO3 was also tested and led to lower ee, although
the reaction time was shortened (Table 2, entries 16, 17). The
use of pure oxygen will obviously lead to a faster reaction rate.
Under the standard conditions, 1a was nicely converted into
2a in 15 minutes, but the ee value was decreased to 87%
accordingly (Table 2, entry 18). Considering economy,
practicability and enantioselectivity, we still choose air as the
most suitable oxidant. As a testament to the remarkable
reactivity of this new class of catalysts, the loading of catalyst
3I in this α-hydroxylation was reduced to as low as 0.5 mol%
while still achieving 80% conversion in 6 h at 15 oC, with no
apparent decrease in enantioselectivity (85% ee) (Table 2,
entry 19). Finally we investigate the effect of temperature on
reaction. Whether at 0 oC or 35 oC, the enantioselectivity of 2a
was maintained (Table 2, entries 20, 21).
11
12
1k
1l
1
1
2Ad
0.5
0.5
97
96
81
78
tert-
amyl
H
13
14
1m
1n
1
1
3-ethyl
amyl
H
0.5
0.5
99
97
70
69
3-ethyl
amyl
5-Cl
H
15
16
1o
1p
1
1
t-Bu
t-Bu
0.5
1
97
92
76
72
5,6-di-
OMe
17
18
19
1q
1r
1s
1
1
2
i-Pr
Me
1Ad
H
H
H
0.5
0.5
6
96
65
98
62
85
67
(1)d
1
(92)d
89
(74)d
68
20d
21d
22d
1t
2
2
2
2
1Ad
1Ad
1Ad
1Ad
7-Br
1u
1v
1w
5,7-di-Br
7-OMe
6-OMe
1
70
71
1
93
80
23d
1
87
74
a
The reaction was conducted with substrate (0.1 mmol) in the presence
mixture containing
of PTC 3l (2.5 mol%) and TPP (0.05 mol%) in
a
PhCH3/CHCl3=8:2 (10 mL) and K2HPO4 (4 mL, 50% aq.) at room temperature, with
b
exposure to a 3-W LED yellow lamp for the given reaction period. Yield of
c
isolated product. The enantiomeric excess was determined by HPLC analysis of
the product using a chiral column (DAICEL Chiralcel OD-H, AD-H, or AS-H) with
n-hexane/2-propanol as the eluent (see the supporting information for
details). d Using K2CO3 (4 mL, 30% aq.) as an inorganic base, TPP: 0.5 mol% .
With the optimized conditions in hand, we explored the
substrate scope of the α-hydroxylation reaction shown in Table 3. A
series of 1-indanone-derived adamantly β-keto esters were first
investigated. Esters with a variety of substituents on the aromatic
rings, such as methyl, methoxy, chloro, and bromo groups, were
nicely converted into the corresponding products 2a - 2j in good
yields (88–98%) with 82–90% ee (Table 3, entries 1-10). Then, we
investigated the effect of the ester group on the 1-indanone
derivatives. We observed that the enantioselectivities
were influenced by the size of substitution in the
ester group. For example, 1o, which contains a bulky tert-butyl
ester group, provided the α-hydroxylation product with 76% ee
(Table 3, entry 15), whereas the β-indanone methyl ester 1r
afforded the corresponding product with 62% ee (Table 3, entry 18).
Next, we explored the α-hydroxylation of 1-tetralone-derived
adamantly β-keto ester 1s. The reaction with 50% K2HPO4 led to a
long reaction time (6 hours), producing 2s in 85% yield with 67% ee.
We then used a stronger inorganic base: 30% K2CO3 instead of
50%K2HPO4. We can clearly see that the reaction time was
shortened to 1 hour and that the ee value was improved to 74%. In
consideration of the enantioselectivity and the reactivity, we chose
30% K2CO3 as the inorganic base (Table 3, entry 19). Different
substituents such as methoxy and bromo groups were investigated.
Table 3. Substrate scope in the asymmetric α-hydroxylation
of β-keto esters.a
Entr Sub
y
n
R1
R2
t [h]
Yield
(%)b
98
ee
(%)c
90
87
83
89
85
85
82
84
85
88
1
1a
1b
1c
1d
1e
1f
1
1
1
1
1
1
1
1
1
1
1Ad
1Ad
1Ad
1Ad
1Ad
1Ad
1Ad
1Ad
1Ad
1Ad
H
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
2
5-Cl
97
3
5-Br
96
4
4-Br
88
5
6-Br
92
6
6-F
89
7
1g
1h
1i
6-Me
4-OMe
6-OMe
5,6-di-
97
8
93
9
0.5
1
98
10
1j
97
4 | J. Name., 2012, 00, 1-3
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Under mild conditions, 2t–2w were all easily obtained with up to was treated with PTC 3l (2.5 mol%) and tetraphenylporphine
80% ee (Table 3, entries 20-23).
(TPP, 0.1 mol%) on a gram-quantity scale in toluene (500 mL) and
an aqueous solution containing 50% K2HPO4 (200 mL) under mild
conditions. The reactor was exposed to a 100-W halogen lamp in air
room temperature. After 3 hours, the reaction was completed and
the α-hydroxylation product was obtained by chromatography in
98% yield and 90% ee (Scheme 2). It is worth mentioning that the
catalyst 3l can be recovered by chromatography in 85% yield. The
recovered catalyst was reused in the model reaction (Table
3, entry 1), giving almost identical yields and enantioselectivities.
Table 4. Substrate scope in the asymmetric α-hydroxylation
of β-keto amides.a
Entr Sub
y
n
NR1
R2
t [h]
Yield
(%)b
92
ee
(%)c
39
5
Scheme 2. Scaled-up version of the reaction
1
4a
4b
4c
4d
4e
4f
1
1
1
1
1
2
2
H
0.5
0.5
0.5
4
HN
2
H
99
HN
HN
N
3
5-Br
H
94
52
66
63
25
Nd
4d
5d
6d
73
N
H
4
71
Next, we proposed
a plausible mechanism for this photo-
H
1
84
HN
N
organocatalytic α-hydroxylation of β-dicarbonyl compounds. The
molecular oxygen in air was easily transferred from its non-excited
triplet state (3O2) to its more reactive singlet state (1O2) by
photosensitization with light. Then, deprotonation of 1 quickly
occurred in the presence of base. The enolate-PTC complex could
have formed and reacted with the active singlet molecular oxygen
(1O2), thereby resulting in the formation of α-hydroperoxide
intermediate 3. Bruice have indicated that the relative reaction
rates of ROOHs correlate satisfactorily with the pKa values of the
corresponding ROHs21. The α-hydroperoxide intermediate 3 which
contains two electron-withdrawing carbonyl groups at the α-
position seemed to be a stronger oxidant than traditional hydrogen
peroxide. The very active hydroperoxide intermediate could be
rapidly converted into the final α-hydroxylation product 2 in the
second step.
7e
4g
H
4
Trace
a
The reaction was conducted with substrate (0.1 mmol) in the presence
of PTC 3l (2.5 mol%) and TPP (0.5 mol%) in a mixture containing PhCH3/CHCl3=8:2
(10 mL) and K2HPO4 (4 mL, 50% aq.) at room temperature, with exposure to a 3-
W LED yellow lamp for the given reaction period. b Yield of isolated product. c The
enantiomeric excess was determined by HPLC analysis of the product using a
chiral column (DAICEL Chiralcel OD-H or AD-H or AS-H) with
n-hexane/2-propanol as the eluent (see the supporting information for
d
e
details). Using K2CO3 (4 mL, 30% aq.) as an inorganic base. Using NaOH (30%
aq.) as an inorganic base, TPP:1 mol%.
Compared with the β-keto esters, the α-hydroxylation of β-keto
amides has been much less explored,14h,15k,15o even though the
amido groups are useful for their easy manipulation20. Thus, after
investigation of the β-keto esters, the scope of β-keto amides was
examined. Under the standard conditions, we found that 4a was
nicely converted into 5a in 92% yield with moderate
enantioselectivity (Table 4, entry 1). Compounds 4b, with H and
isopropyl in N-position, afforded 5b in near racemisation(Table 4,
entry 2). 4c, which bears a Br-atom at 5-position, afforded 5c with
52% ee (Table 4, entry 3). Next we found the enantioselectivity of
β-keto amides was related to the N-substituent group. 4d with
methyl and phenyl in N-position afforded 5d with 66% ee, though
with the reaction time extended to 4 hours (Table 4, entry 4). 5e
was obtained in 71% yield with 63% ee (Table 4, entry 5). The 1-
tetralone-derived β-keto amide 4f provided 5f with 25% ee (Table 4,
entry 6). Unfortunately, the β-keto amide 4g showed low reaction
activity even though 30% NaOH was used (Table 4, entry 7). Overall,
this method showed good substrate suitability of β-keto esters and
β-keto amides using an operationally simple and economical
method.
Scheme 3. Plausible mechanism
A plausible transition state, depicted in Scheme 4, was proposed.
Three different types of interactions could exist: 1) an ion-pair
interaction between the substrate and the PTC; 2) hydrogen
bonding between the C-9 hydroxy group and the ester group; and
3) two π-π stacking interactions between the PTC and the substrate.
This activation model may explain the structure-function
relationship between the PTC and the substrate, as mentioned
above. For example, when PTC 3h was used, the reaction was
completed in 60 min and the ee value of 2a was 68% (Table 1, entry
The absolute configurations of α-hydroxy β-keto esters 2a, 2o, and
2r were determined to be S, by comparison of their optical
rotations with literature data.15o,15l
To test the scale-up potential of our methodology, a 1.55 g
sample (50 mmol) of 1-adamantyl (1-Ad) indanone carboxylate 1a
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55.97, 54.31, 37.03, 26.34, 23.06, 20.47. HRMS calcd. for
[C33H30F3N2OBr3-Br]+ requires m/z 685.0677, found m/z 685.0655.
8). However, when PTC 3l was introduced, the ee value of 2a was
improved to 86% and the reaction time was shortened to 20 min
(Table 1, entry 12). These results indicated that adding another π-π
stacking interaction between the benzene ring of the substrate and
the phenyl group in the C-2′ position was important for the higher
activity and enantioselectivity of the α-hydroxylation.
General procedure for α-hydroxylation of β-keto esters and
β-keto amides
The reaction was conducted with substrate (0.1 mmol) in the
presence of PTC 3 l (2.5 mol%) and tetraphenylporphine (TPP) (0.05
mol% or 0.5 mol%) in a mixture containing PhCH3/CHCl3=8:2 (10
mL) and 50% K2HPO4 (4 mL) or 30% K2CO3 (4 mL) at room
temperature, with exposure to a 3-W LED yellow lamp for the given
reaction period. After the reaction was completed (confirmed by
TLC analysis), the mixture was diluted with EtOAc (50 mL), washed
with water (3× 20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography to give the desired product. The ee of the product
was determined by chiral HPLC.
Scheme 4. Plausible transition state
Acknowledgements
We would likely to thank the National Natural Science Foundationof
Conclusions
China (No. 21176041 ， No. 21476041
) and the State Key
Laboratory of Fine Chemicals for their support.
An efficient and enantioselective phase-transfer catalyzed photo-
oxygenation of β-keto esters and β-keto amides was extended
under mild conditions. A series of new C-2′-substituted phase
transfer catalysts were identified and demonstrated to be effective
catalysts for α-hydroxylation. A wide range of α-hydroxy β-keto
esters and β-keto amides can be obtained with excellent yields and
enantiopurity under mild conditions with relatively low catalyst and
photosensitizer loadings. Further research of expanding the
applications of C-2′-substituted phase transfer catalysts and other
asymmetric photo-oxygenation reactions are currently underway.
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