Asymmetric α-hydroxylation of β-dicarbonyl compounds by C-2′ modified cinchonine-derived phase-transfer catalysts in batch and flow microreactors

Article abstract of DOI:10.1080/00397911.2020.1781183

The asymmetric α-hydroxylation of β-dicarbonyl compounds was catalyzed by C-2′-modified cinchonine-derived phase-transfer catalysts. Excellent yields (up to 95%) and good enantioselectivities (up to 89% ee) were obtained. The reaction was carried out in a flow microreactor and similar results were obtained (up to 93% yield, 84% ee), the residence time was shortened from 24 h in batch to 2 h.

Full text of DOI:10.1080/00397911.2020.1781183

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Asymmetric α-hydroxylation of β-dicarbonyl
compounds by C-2′ modified cinchonine-derived
phase-transfer catalysts in batch and flow
microreactors
Xiao-Fei Tang, Jing-Nan Zhao, Yu-Feng Wu, Ze-Hao Zheng, Cun-Fei Ma, Zong-
Yi Yu, Lei Yun, Guang-Zhi Liu & Qing-Wei Meng
To cite this article: Xiao-Fei Tang, Jing-Nan Zhao, Yu-Feng Wu, Ze-Hao Zheng, Cun-Fei Ma,
Zong-Yi Yu, Lei Yun, Guang-Zhi Liu & Qing-Wei Meng (2020): Asymmetric α-hydroxylation of β-
dicarbonyl compounds by C-2′ modified cinchonine-derived phase-transfer catalysts in batch and
flow microreactors, Synthetic Communications, DOI: 10.1080/00397911.2020.1781183
To link to this article: https://doi.org/10.1080/00397911.2020.1781183
Published online: 24 Jun 2020.
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https://doi.org/10.1080/00397911.2020.1781183
Asymmetric a-hydroxylation of b-dicarbonyl compounds by
C-20 modified cinchonine-derived phase-transfer catalysts in
batch and flow microreactors
Xiao-Fei Tanga,b, Jing-Nan Zhaoa, Yu-Feng Wua, Ze-Hao Zhenga, Cun-Fei Maa,
Zong-Yi Yua, Lei Yuna, Guang-Zhi Liua, and Qing-Wei Menga
aState Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of
b
Technology, Dalian, P.R. China; Xi’an Modern Chemistry Research Institute, Xi’an, Shaanxi, P.R. China
ABSTRACT
ARTICLE HISTORY
Received 30 September 2019
The asymmetric a-hydroxylation of b-dicarbonyl compounds was cat-
alyzed by C-20-modified cinchonine-derived phase-transfer catalysts.
Excellent yields (up to 95%) and good enantioselectivities (up to
89% ee) were obtained. The reaction was carried out in a flow micro-
reactor and similar results were obtained (up to 93% yield, 84% ee),
the residence time was shortened from 24 h in batch to 2 h.
KEYWORDS
Asymmetric; microreac-
tor; oxidation
GRAPHICAL ABSTRACT
Introduction
In recent decades, microreactors have been widely applied in the synthesis of fine chem-
icals and pharmaceuticals.[1] Microreactors are considered to have advantages in
improving safety, heat/mass transfer efficiency, and automation.[2] However, the
reported reactions using microreactors are still mainly used for the synthesis of achiral
compounds.[3,4] There are only a few examples of microreactors being used to achieve a
homogeneous asymmetric reaction in only one fluid phase,[5,6] such as the Aldol reac-
tion and Michael addition reaction.[7,8] Because of its mass transferability, microreactors
have already been applied to the gas–liquid and liquid–liquid catalytic reactions.[9,10]
Until 2004, de Bellefon’s group reported the heterogeneous gas–liquid asymmetric
hydrogenation catalyzed by the chiral rhodium-based catalysts in the microreactors.[11]
Then, Newton and Ley reported the asymmetric hydrogenation catalyzed by the chiral
iridium- and rhodium-based catalysts in a tube-in-tube gas–liquid flow reactor.[12]
a-Hydroxy-b-dicarbonyl compounds are important structural cores in various natural
products and pharmaceuticals.[13] In particular, they have been used as the key
CONTACT Qing-Wei Meng
mengqw@dlut.edu.cn
State Key Laboratory of Fine Chemicals, School of Chemical
Engineering, Dalian University of Technology, Dalian, P.R. China.
ß 2020 Taylor & Francis Group, LLC

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X.-F. TANG ET AL.
Scheme 1. The PTCs used for a-hydroxylation.
intermediate in the synthesis of the insecticide, indoxacarb. Although we have reported
asymmetric photooxygenation of b-dicarbonyl compounds in the flow photomicroreac-
tors,[14] the photomicroreacotors are very expensive. Therefore, we hope to use peroxide
as an oxidant to achieve this asymmetric oxidation reaction in the flow microreactors.
According to Deng’s method,[15] we synthesized a series of C-20-modified cinchonine-
derived PTCs by the Suzuki–Miyaura coupling reaction. Furthermore, we hope to use
these PTCs to achieve asymmetric a-hydroxylation of b-dicarbonyl compounds in a
microreactor. This not only expands the application of C-20-modified cinchonine-
derived PTCs, but also realizes heterogeneous liquid-liquid asymmetric oxidation by
flow microreactors.
Results and discussion
According to the previous work,[15,16] we synthesized a series of C-20-modified cinchon-
ine-derived PTCs as shown in Scheme 1, and the catalysts and reaction conditions were
the screened further. Firstly, the reaction was carried out with C-20-substituted phenyl
catalyst PTC-1, product 2a obtained in 93% yield and 81% ee (Table 1, entry 1). The
electron-withdrawing substituted catalyst PTC-2 gave the product 2a with similar yield
and enantioselectivity (Table 1, entry 2). However, with the electron-donating substi-
tuted catalyst PTC-3, 2a was obtained in 84% yield with 73% ee (Table 1, entry 3). The
1-naphthalenyl-substituted catalyst PTC-4 and 9-phenanthrenyl-substituted catalyst
PTC-5 afforded 2a with good yields and enantioselectivities (89–95% yield, 79–82% ee,
Table 1, entries 4-5). Catalyst PTC-5 achieved a better enantioselectivity than the others.
Then, a benzyl substituent PTCs were examined. It was found that 3,5-iodo groups in
the benzylic position PTC-8 resulted in a higher enantioselectivity than 3,5-fluoro,
3,5-chloro, 3,5-bromo and 3,5-phenyl groups (95% yield and 85% ee, Table 1, entries
5–9). The reaction conditions were investigated. The reaction performed in m-xylene
provided the product 2a in 96% yield with 86% ee (Table 1, entry 10). Performing the
reaction at –15ꢀC could improve the enantioselectivity (95% yield and 88% ee, Table 1,
entry 11). Finally, the enantioselectivity could be further improved by decreasing the
substrate concentration (Table 1, entry 12).
Having established the optimal reaction conditions, the scope of substrates were
examined (Table 2). The nonsubstituted indanone 1-adamantyl ester 1a was obtained
with best result (95% yield, 89% ee, Table 2, 2a). Substitutes of 1-indanone-derived
1-adamantly b-keto esters were investigated initially. The aromatic rings of indanone
were substituted by electron-withdrawing groups (–F, –Cl, –Br), the desired products
2b-2d were obtained in excellent yields (86–94%) and good enantioselectivities (83–85%
ee). The electron-donating (–CH3, –OCH3) substrates provided the corresponding

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Table 1. Screening of PTCs of a-hydroxylation of b-keto ester 1a.a
Entry
Cat.
Solvent
T/oC
Yield/%b
ee/%c
1
2
3
4
5
6
7
8
PTC-1
PTC-2
PTC-3
PTC-4
PTC-5
PTC-6
PTC-7
PTC-8
PTC-9
PTC-8
PTC-8
PTC-8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
m-Xylene
m-Xylene
m-Xylene
–5
–5
–5
–5
–5
–5
–5
–5
–5
93
93
84
89
95
86
93
95
90
96
95
95
81
80
73
79
82
69
75
85
82
86
88
89
9
10
11
12d
–5
–15
–15
aUnless otherwise specified, the reaction was performed with b-keto ester 1a (31.0 mg, 0.1 mmol), 1.5 equiv. cumene
hydroperoxide (CHP), 5 mol% catalyst, 4 mL PhCH3, 2 mL 50% K2HPO4 at –5 ꢀC.
bIsolated yields.
cDetermined by HPLC analysis (Chiralcel AD-H) with hexane/2-propanol (80:20) as the eluent.
d8 mL m-xylene.
Table 2. Substrate scopea.
aGeneral Conditions: substrate 1 (0.1 mmol), 1.5 equiv CHP and 5 mol% PTC-8 in 8 mL m-xylene, and 2 mL 50% K2HPO4
at –15 ꢀC for 24 h. All yields were isolated yields, and enantiomeric excess was determined by chiral HPLC.

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X.-F. TANG ET AL.
Scheme 2. Plausible transition state.
products 2e–2g in 87–93% yields with 68–74% ee. Next, the ester group on 1-indanone
derivatives was investigated. The 2-adamantyl ester product 2h was produced in excel-
lent yield and good enantioselectivity (93% yield, 86% ee). The product 2i was obtained
in satisfactory yield and enantioselectivity (83% yield, 87% ee). The substrates 1j–1k
with electron-donating groups in 5- and 6-substituted of indanone gave the correspond-
ing products 2j–2k with good yields and moderate enantioselectivities (82% yield,
64–79% ee). The methyl ester product 2l was obtained in 71% yield with 28% ee prob-
ably because of the steric hindrance. Finally, the scope of the b-keto amides was exam-
ined. The 5-position of indanone substituted by bromo and chloro groups could be
successfully transformed into the desired products 2m and 2n with good yields
(85–86%) and enantioselectivities (69–84% ee). Meanwhile, the product 2o was obtained
in 81% yield with 44% ee. Substrate 1p with methyl and phenyl in the N-position trans-
formed into the corresponding product 2p in 84% yield and only 22% ee. The enantio-
selectivity of b-keto amide was decreased with the increased amount of substituents.
Therefore, a plausible transition state was proposed in Scheme 2. The substrate formed
an enolate anion under basic conditions. Then, three different types of interactions
could exist: (1) an ion-pair interaction between the anion of the substrate and the cation
of the PTC; (2) hydrogen bonding between the carbonyl group of the substrate and the
C-9 hydroxy group of the PTCs; (3) hydrogen bonding between the H (–OOH) of CHP
and the O (ester group) or N (amide group) of the substrate. With the increase of the
substituents of b-keto amide, the hydrogen bond stability between the CHP and sub-
strates decreases, which leads to the enantioselectivity of the products decreasing.
Next, we attempted to transfer this reaction in flow micoreactors as shown in
Figure 1 (Corning Advanced Flow Reactor). Due to the limitations of the microreactor
material (glass reactor), reaction conditions were not exactly the same as in batch. The
organic phase was prepared by dissolving substrates 1a (0.1 mmol), PTC-8 (5 mol%)
and CHP (1.5 equiv) in m-xylene (8 mL). The aqueous phase was a K2HPO4 solution
(10% K2HPO4). The organic phase and aqueous phase were introduced through pump
1 and pump 2 at a flow rate of 1.5 mL/min. The product 2a was obtained in 93% yield
with 78% ee at 0 ꢀC (Table 3, entry 1). At the same time, the residence time was drastic-
ally shortened from 24 h in the batch to 2 h in the flow microreactors. Using toluene as

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Figure 1. Schematic representation of microreactor for asymmetric oxidation of b-dicar-
bonyl compounds.
Table 3. Optimization of the reaction conditions for a-hydroxylation of b-keto ester 1a in the flow
microreactors.a
Entry
Base
Solvent
m-Xylene
T/ꢀC
Yield/%b
ee/%c
1
2
3
4
5
6
10% K2HPO4
10% K2HPO4
1% K2HPO4
1% Cs2CO3
1% Cs2CO3
1% Cs2CO3
1% Cs2CO3
3.3% Cs2CO3
3.3% Cs2CO3
0
0
0
92
93
87
91
93
94
93
95
24
78
80
80
82
81
81
84
83
83
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0
10
20
0
0
0
7d
8e
9e,f
apump 1: substrate 1a (0.1 mmol), 5 mol% PTC-8 and 1.5 equiv CHP in 8 mL m-xylene, 1.5 mL/min; pump 2: 10%
K2HPO4 aq.1.5 mL/min.
bIsolated yields.
cDetermined by HPLC analysis (Chiralcel AD-H) with hexane/2-propanol (80:20) as the eluent.
d10 mol% PTC-8.
eb-Keto ester 1a (31.0 mg, 0.1 mmol), 10 mol% PTC-8 and 1.5 equiv. CHP in 4 mL PhCH3, 2 equiv. Cs2CO3 in 2 mL H2O
(ꢁ3.3% Cs2CO3) at 0 ꢀC in batch.
fReaction time 2 h.
solvent in microreactors, the enantioselectivity was increased to 80% ee (Table 3, entry
2). Then, the basic solution, reaction temperature and catalyst loading were screened
(Table 3, entries 3–7). The product 2a was obtained from higher enantioselectivity with
1% Cs2CO3 aqueous solution (Table 3, entries 3–4). By performing the reaction at 10 or
20 ꢀC, the stereoselectivity was decreases slightly (Table 3, entries 5–6). By increasing

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X.-F. TANG ET AL.
Table 4. Substrate scope in the flow microreactors.a
apump1: substrate 1 (0.1 mmol), 10 mol% PTC-8 and 1.5 equiv CHP in 8 mL PhCH3, 1.5 mL/min; pump2: 1% Cs2CO3 aq.
1.5 mL/min. All yields were isolated yields, and enantiomeric excess was determined by chiral HPLC.
the PTC-8 loading to 10 mol%, product 2a was obtained in 93% yield with 84% ee
(Table 3, entry 7). Comparing entry 7 and entry 8 in Table 3, the product 2a was
obtained with 93% yield and 84% ee in the microreactors, and 95% yield and 83% ee in
batch. From here, the enantioselectivity was increased and the reaction time was shorted
from 24 h to 2 h in the microreactors. When the reaction time was 2 h, the product 2a
was obtained in only 24% yield and 83% ee in batch (Table 3, entry 9). Hence, the opti-
mum conditions for the asymmetric oxidation of b-dicarbonyl compounds were identi-
fied as follows: 0.1 mmol substrate 2, 10 mol% PTC-8 and 1.5 equiv CHP in 8 mL
toluene, and 1% Cs2CO3 aqueous solution at 0 ꢀC, and the flow rates of organic phase
and aqueous phase were 1.5 mL/min. After that, the substrate scope was investigated
(Table 4). For substrates 1b–1d, 1h and 1i were transformed into the corresponding
products (2b–2d, 2h and 2i) in excellent yields (83–93%) and good enantioselectivities
(78–84% ee). Meanwhile, the reaction residence time was greatly shortened from 24 h in
batch to 2 h in the flow microreactor.
Conclusion
The asymmetric oxidation of b-dicarbonyl compounds catalyzed by the C-20-modified
cinchonine-derived PTCs and the corresponding products were obtained in excellent
yields and enantioselectivities. At the same time, the flow microreactors had been used
to achieve a heterogeneous liquid–liquid asymmetric oxidation reaction. Good yields
and enantioselectivities were obtained and the residence time could be greatly shortened

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7
by flow microreactors. We will further expand the application of C-20-cinchonine-
derived PTCs and flow microreactors to other asymmetric reactions.
Experimental part
Analytical TLC was visualized with UV light at 254 nm. Thin-layer chromatography was
carried out on TLC aluminum sheets with silica gel 60F254. Purification of reaction
products was carried out with chromatography on silica gel 60 (200–300 mesh). Melting
points were determined with a hot plate apparatus. Optical rotations were measured on
1
a digital polarimeter with a sodium lamp at 20 ꢀC (10 cm cell, c given in g/100 mL). H
NMR (400 MHz MHz) spectra was obtained at 25 ꢀC; 13C NMR (101 MHz) were
recorded on a VARIAN INOVA-400M and AVANCE II 400 spectrometer at 25 ꢀC.
Chemical shifts are reported as d (ppm) values relative to TMS as internal standard and
coupling constants (J) in Hz. High-resolution mass spectrometry data were obtained
with UPLC/Q-Tof Mass Spectrometer and were determined by electrospray ionization
(ESI). The enantiomeric excess (ee) were determined by HPLC. HPLC analyses were
performed on equipped with Diacel Chiralpak AD-H, OD-H and AS-H chiral column
(0.46 cm ꢂ 25 cm), using mixtures of n-hexane/isopropyl alcohol as mobile phase, at
25 ꢀC with an injection volume of 20 lL at a flow rate of 1 mL/min.
General procedure for the asymmetric a-hydroxylation of
b-dicarbonyl compounds
Substrate 1 (0.1 mmol), PTC-8 (5 mol %), CHP (1.5 equiv) and 50% K2HPO4 aq. (2 mL)
were added to a test tube equipped with a stirring bar and dissolved in m-xylene (8 mL)
at –15 ꢀC. After completion of the reaction (confirmed by TLC), the mixture was
diluted with EtOAc (50 mL), washed with water (3 ꢂ 20 mL), dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate ¼ 10/1, 5/1) to afford the prod-
uct 2a–2p. The ee of the product was determined by chiral HPLC.
Funding
This work was supported by the National Natural Science Foundation of China (Nos. 21476041,
U1608224, 61633006), and the State Key Laboratory of Fine Chemicals.
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