N-Heterocyclic Carbene-Catalyzed Asymmetric Benzoin Reaction in Water

Article abstract of DOI:10.1021/acs.joc.8b00481

A chiral N-heterocyclic carbene-catalyzed benzoin condensation reaction in water has been developed, affording α-hydroxy ketones in good to high yields and high enantioselectivities. Water was proposed as a proton shuttle in the aqueous asymmetric condens

Full text of DOI:10.1021/acs.joc.8b00481

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NHC-Catalyzed Asymmetric Benzoin Reaction in Water
Jun Yan, Rong Sun, Kuangxi Shi, Kai Li, Limin Yang, and Guofu Zhong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00481 • Publication Date (Web): 11 Jun 2018
Downloaded from http://pubs.acs.org on June 11, 2018
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NHC-Catalyzed Asymmetric Benzoin Reaction in Water
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Jun Yan, Rong Sun, Kuangxi Shi, Kai Li, Limin Yang,* and Guofu Zhong*
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College of Materials, Chemistry & Chemical Engineering, Hangzhou Normal University, Hangzhou
310036, China
Supporting Information
ABSTRACT: A chiral NHCꢀcatalyzed benzoin condensation reaction in water was developed, thereby
affording αꢀhydroxy ketones in good to high yields and high enantioselectivities. Water was proposed
as a proton shuttle in the aqueous asymmetric condensation reaction.
In nature, the largest number of biochemical reactions are enzymatic catalytic ones, which are
complex, highly efficient and highly selective reactions occurring in aqueous conditions. One of the
most wellꢀknown biotransformations is the nucleophilic acylation reaction catalyzed by transketolase
enzyme1 in the presence of coenzyme thiamine (vitamin B1).2 Until 1943, Ugai proposed that the
coenzyme thiamine was actually a natural thiazolium salt used as a catalyst in the acylation reaction,
the soꢀcalled benzoin reaction.3 To organic chemists, one of the important research aims is to develop
synthetic reactions that mimic enzymatic processes such as this enzymatic system.4 Consequently,
significant developments in the last decade have been made in enabling organic reactions in aqueous
media with the application of chiral organocatalysts, such as aldol condensations, Michael reactions
and Mannich reactions.5 Aqueous reactions have various advantages for instance: reduced pollution,
lower cost and simpler processing compared to reactions carried out in organic solvents. Furthermore,
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water is widespread and extremely attractive as a renewable green medium for organic synthesis.
NꢀHeterocyclic carbenes (NHCs), with their special electronic characteristics, not only serve as
excellent ligands in organometallic catalysis,6 but also act as organocatalysts.7 Over the past decade,
NHCs have received significant interest in organocatalyzed reactions due to their special electronic
characteristics.8 Making use of intriguing organocatalytic activation of NHC for new bondꢀformation
opens up a new avenue for the synthesis of target molecules. For example, the traditional a1ꢀd1
umpolung (benzoin condensation and Stetter reaction)9 and a3ꢀd3 umpolung (homoenolate
cycloaddition10) approaches have been wellꢀdocumented. We have disclosed a series of chiral
NHCꢀcatalyzed reactions11 and our ongoing interest on this topic prompted us to go back to investigate
the wellꢀknown, direct and useful benzoin condensation reaction in water with a chiral environment.
Many reports on carrying out NHCꢀcatalyzed reactions have been prepared, due to their ability to
produce acyl anion equivalents.12 The benzoin condensation catalyzed by NHCs has been intensively
investigated. Since the first asymmetric benzoin condensation reactions reported by Sheehan and
Hunneman,13 there have been further reports on this topic.14 Furthermore, benzoin condensation
reactions have been carried out in aqueous media.15 However, to the best of our knowledge,
NHCꢀcatalyzed asymmetric benzoin condensation reactions in water have never been investigated or
successfully achieved. Herein, we report a NHCꢀcatalyzed asymmetric benzoin condensation reaction
catalyzed by a pentafluorophenyl substituted triazolium salt in water to afford αꢀhydroxy ketones in
good to high yields and high enantioselectivities.
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To investigate this chiral benzoin condensation reaction, we first surveyed the simple substrate
benzaldehyde (1a) in the presence of different catalysts and bases with water as the solvent. The
screening of different chiral triazolium catalysts was carried out and the results are summarized in
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Table 1. When catalyst A (with Mes), with K2CO3 as base in water was used, the reaction could
proceed smoothly and afforded the desired product αꢀhydroxycarbonyl, albeit with moderate yield
(65%) and low enantioselectivity (55:45 er) (entry 1). When a catalyst with a strong electron
withdrawing group (4ꢀCF3) or a strong electron donating group (4ꢀMeO) on a phenyl ring was used,
only a trace amount of the desired product was obtained. To our delight, when catalyst D was used, a
significantly better result was obtained (80% yield, 90:10 er, Table 1, entry 4). Subsequent screening of
catalyst indicated that catalyst E was the best catalyst, which led to the desired product in higher yield
and enantioselectivity (entry 6). The screening of different bases revealed that organic bases were
deemed to be unsuitable for the reaction as they led to only a trace amount of the desired product. This
is likely because of the very low solubility of the organic bases in water. Accordingly, Na2CO3 was
found to be the best base. When DCM was employed as the solvent, the yield decreased dramatically to
40%. Furthermore, a mixed solvent of water and DCM in a 1:3 or 3:1 ratio led to only a trace amount
of the desired product (Table 1, entries 17 and 18), while brine promoted the reaction and afforded a
higher yield of 85% (entry 15) and no change in the enantioselectivity was observed.
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Table 1. Optimization of Reaction Conditionsa
reaction
time (h)
yieldb
(%)
entry
1
cat.
A
base
solvent
H2O
erc
K2CO3
8
65
55:45
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B
C
D
E
E
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
H2O
H2O
H2O
H2O
H2O
24
24
8
trace
trace
80
n.d.
n.d.
90:10
92:8
93:7
8
65
75
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H2O
H2O
H2O
H2O
H2O
7
E
E
E
E
E
CS2CO3
Et3N
7
50
92:8
n.d.
8
24
24
9
trace
trace
63
9
DIPEA
AcONa
AcOK
n.d.
10
11
93:7
92:8
61
9
H2O
H2O
H2O
12
13
14
E
E
E
KOH
10
10
10
7
52
46
64
90:10
91:9
NaOH
K3PO4
89:11
15
16
17
E
E
E
Na2CO3 Brine
Na2CO3 DCM
85
93:7
91:9
n.d.
40
24
Na2CO3 DCM/H2O
(1:3)
trace
24
24
18
E
Na2CO3 DCM/H2O
(3:1)
trace
n.d.
a Unless otherwise specified, the reaction was performed by using 0.2 mmol aldehyde in water (2.0 mL) at rt, and the racemic
version was catalyzed by cat. F. b Yields of isolated products. c er values determined by HPLC analysis on Chiralcel column (see
the Experimental Section).
With the optimal reaction conditions established, we evaluated the substrate scope (Table 2) of this
NHCꢀcatalyzed asymmetric benzoin condensation reaction in water. The reaction proceeded smoothly
for a broad spectrum of substituted benzaldehydes to afford the desired products in good yields and
high enantioselectivities. Both electronꢀdonating and electronꢀwithdrawing substituents on the phenyl
group were tolerated. The reaction proceeded smoothly for substituted benzaldehydes bearing
electronꢀwithdrawing group on phenyl ring (2b, 2c and 2e). Similarly, electronꢀdonating substituents
were also tolerated, with 4ꢀmethyl and 4ꢀethyl substituted benzaldehydes giving the highest
enantioselectivities (94:6 er) with good yields (2f and 2h). When a substrate with a bulkier group was
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used, the desired product was provided with a lower enantioselectivity and lower yield (2k). The
position of the substituent on phenyl ring seemed to have little influence on the reaction outcomes (2c,
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2d, 2f and 2g). Replacing the phenyl group with a heteroaryl, such as furanꢀ2ꢀyl, thiopheneꢀ2ꢀyl, did
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Table 2. Substrate Scope of the Asymmetric Condensation Reaction in Water
O
O
10 mol% cat. E
R
Na2CO3 (0.5 eqiuv)
H
R
R
2
H2O (2.0 mL)
OH
1
2
F
Cl
O
O
O
OH
OH
OH
F
2b, 28% yield, 90:10 er
Cl
2a, 75% yield, 93:7 er
2c, 78% yield, 89:11 er
Cl
O
O
Br
O
OH
OH
OH
Br
Cl
2f, 71% yield, 94:6 er
2e, 80% yield, 90:10 er
2d, 77% yield, 85:15 er
O
O
O
OH
OH
OH
2g, 79% yield, 93:7 er
2i, 80% yield, 91:9 er
2h, 64% yield, 94:6 er
O
O
OH
OH
2j, 56% yield, 84:16 er
2k, 59% yield, 80:20 er
O
O
O
O
S
S
O
S
S
HO
HO
2l, 52% yield, 90:10 er
HO
2n, 57% yield, 84:16 er
2m, 55% yield, 90:10 er
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not change the reaction result in terms of yields and enantioselectivities (2m and 2n). A thiopheneꢀ3ꢀyl
heteroaryl was also well tolerated, giving the yield and enantioselectivity (2l) similar to those of
thiopheneꢀ2ꢀyl aldehyde (2m). The absolute configuration of the benzoin condensation products was
confirmed to be S (with exception of 2m for R) by comparison with the optical rotation data reported in
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the literature.17
Figure 1. Proposed Mechanism and Water Was Proposed as a Proton Shuttle
To understand the asymmetric benzoin condensation reaction in aqueous conditions, we proposed a
mechanism (Figure 1). In which, the addition of NHC to benzaldehyde (1a) provides a zwitterion of
triazolium salt adduct I. The proton transfer from carbon to oxygen leads to the formation of an
enolꢀtype Breslow intermediate II. The Breslow intermediate II is actually an acylation reagent, which
reacts with another benzaldehyde 1a to provide an intermediate III. Water was deemed to be a proton
shuttle in a 1,4ꢀH shift process by simultaneously providing one proton to the oxygen and obtaining
another from the hydroxyl group to give an intermediate IV. This is followed by the regeneration of the
NHC catalyst and elimination of the benzoin product 2a. As such, when dichloromethane was
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employed as a solvent, a low yield of 40% was obtained in contrast to a higher yield of 75% when the
reaction was carried out in water. Furthermore, when brine was selected as the solvent, the reaction
could be accelerated slightly in 85% yield, thereby indicating the presence of a hydrophobic effect.16
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In conclusion, an asymmetric benzoin condensation reaction of benzaldehydes in water has been
developed. This transformation provides rapid access to optically enriched αꢀhydroxy carbonyl
products that are found common in bioactive compounds. Water was proposed as a proton shuttle in the
aqueous asymmetric condensation reaction.
Experimental Section
1H and 13C NMR spectra were measured at 500 and 125 MHz, respectively. The solvent used for
NMR spectroscopy was CDCl3, using tetramethylsilane as the internal reference. HRMS (Quadrupole,
ESI, m/z) was determined by an HRMS/MS instrument. Analytical grade solvents for the column
chromatography were used after distillation, and commercially available reagents were used as
received.
To a 10 mL vial was added 2.0 mL water, aldehyde (21.2 mg, 0.20 mmol, 1.0 equiv), cat. E (9.3 mg,
0.02 mmol, 10 mol%) and Na2CO3 (10.5 mg, 0.10 mmol, 0.5 equiv). Then the resulting solution was
stirred under at room temperature, until complete disappearance of the starting material monitored by
TLC. The reaction mixture was concentrated under reduced pressure and the residue was subjected to
column chromatography using EtOAc/PE = 1:15 as eluent to afford the desired product 2.
(S)-2-hydroxy-1,2-diphenylethan-1-one (2a).17a White solid, 75% yield (15.9 mg), reaction time 8 h.
1H NMR (500 MHz, CDCl3) δ 7.91 (dd, J = 8.4, 1.3 Hz, 2H), 7.54 – 7.49 (m, 1H), 7.39 (t, J = 7.8 Hz,
2H), 7.35 – 7.29 (m, 4H), 7.29 – 7.26 (m, 1H), 5.95 (d, J = 6.1 Hz, 1H), 4.55 (d, J = 6.1 Hz, 1H). 13C
NMR (125 MHz, CDCl3) δ 199.3, 139.3, 134.6, 133.8, 129.5, 129.5, 129.0, 128.9, 128.1, 76.6. HRMS
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m/z calculated for C14H11O2 [MꢀH]ꢀ: 211.0765, found: 211.0758. HPLC: Chiralcel OD
(nꢀhexane/iꢀPrOH, 90/10, flow rate 0.7 mL/min, λ= 254 nm), tR (major) = 18.2 min, tR (minor) = 13.3
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min; 93:7 er, [α]D = +94.5 (c = 0.50, CHCl3); lit17a: > 99.5:0.5 er, [α]D22 = +123.3 (c = 1.51, MeOH)
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for (S)ꢀ2a. Melting point: 116 ꢀ 117 °C.
(S)-1,2-bis(4-fluorophenyl)-2-hydroxyethan-1-one (2b).17b White solid, 28% yield (6.5 mg), reaction
time 19 h. 1H NMR (500 MHz, CDCl3) δ 7.99 – 7.81 (m, 2H), 7.35 – 7.26 (m, 2H), 7.14 – 6.94 (m, 4H),
5.90 (s, 1H), 4.51 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 197.5, 15.8 (d, J = 422.1 Hz), 163.8 (d, J =
413.3 Hz), 135.2 (d, J = 2.5 Hz), 133.1 (d, J = 3.8 Hz), 132.2 (d, J = 8.8 Hz), 130.0 (d, J = 2.5 Hz),
129.9 (d, J = 8.8 Hz), 116.52 (d, J = 42.84 Hz), 116.5, 75.7. HRMS m/z calculated for C14H9F2O2
[MꢀH]ꢀ: 247.0576, found: 247.0579. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 90/10, flow rate 1 mL/min,
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λ= 254 nm), tR (major) = 9.4 min, tR (minor) = 7.9 min; 90:10 er, [α]D = +56.8 (c = 0.50, CHCl3);
lit17b: 92:8 er, [α]D26 = +98.3 (c = 0.6, CHCl3) for (S)ꢀ2b. Melting point: 78 ꢀ 79 °C.
17b
(S)-1,2-bis(4-chlorophenyl)-2-hydroxyethan-1-one (2c).
White solid, 78% yield (21.9 mg),
reaction time 6 h. 1H NMR (500 MHz, CDCl3) δ 7.85 – 7.79 (m, 2H), 7.42 – 7.35 (m, 2H), 7.33 – 7.28
(m, 2H), 7.26 – 7.23 (m, 2H), 5.88 (d, J = 5.9 Hz, 1H), 4.48 (d, J = 5.9 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 197.8, 141.1, 137.5, 135.1, 131.9, 130.8, 129.8, 129.6, 129.4, 75.8. HRMS m/z calculated for
C14H9Cl2O2 [MꢀH]ꢀ: 278.9985, found: 278.9991. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 90/10, flow
rate 1.0 mL/min, λ= 254 nm), tR (major) = 9.2 min, tR (minor) = 7.6 min; 89:11 er. [α]D25 = +44.0 (c =
0.50, CHCl3); lit17b: 87:13 er [α]D25 = +34.3 (c = 0.28, MeOH) for (S)ꢀ2c. Melting point: 84 ꢀ 85 °C.
17a
(S)-1,2-bis(3-chlorophenyl)-2-hydroxyethan-1-one (2d).
White solid, 77% yield (21.6 mg),
reaction time 6 h. 1H NMR (500 MHz, CDCl3) δ 7.90 (t, J = 1.9 Hz, 1H), 7.74 (dt, J = 7.8, 1.4 Hz, 1H),
7.52 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.32 (q, J = 1.4 Hz, 1H), 7.28 – 7.26 (m,
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2H), 7.20 (dq, J = 5.3, 1.7 Hz, 1H), 5.88 (d, J = 6.0 Hz, 1H), 4.45 (d, J = 6.1 Hz, 1H). 13C NMR (125
MHz, CDCl3) δ 197.7, 140.6, 135.6, 135.5, 135.1, 134.5, 130.9, 130.5, 129.4, 129.4, 128.2, 127.5,
126.2, 76.0. HRMS m/z calculated for C14H9Cl2O2 [MꢀH]ꢀ: 278.9985, found: 278.9988. HPLC:
Chiralcel IC (nꢀhexane/iꢀPrOH, 95/5, flow rate 1.0 mL/min, λ= 254 nm), tR (major) = 15.4 min, tR
(minor) = 12.7 min; 85:15 er, [α]D25 = +29.8 (c = 0.50, CHCl3); lit17a: 93:7 er, [α]D25 = +93.4 (c = 1.82,
CHCl3) for (S)ꢀ2d. Melting point: 78 ꢀ 79 °C.
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(S)-1,2-bis(4-bromophenyl)-2-hydroxyethan-1-one (2e).17b White solid, 80% yield (29.4 mg),
reaction time 6 h. 1H NMR (500 MHz, CDCl3) δ 7.79 – 7.69 (m, 2H), 7.59 – 7.51 (m, 2H), 7.49 – 7.42
(m, 2H), 7.21 – 7.14 (m, 2H), 5.85 (s, 1H), 4.47 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 198.0, 138.0,
132.8, 132.6, 132.3, 130.8, 129.9, 129.7, 123.3, 75.9. HRMS m/z calculated for C14H9Br2O2 [MꢀH]ꢀ:
366.8975, found: 366.8977. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 90/10, flow rate 1.0 mL/min, λ=
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254 nm), tR (major) =9.9 min, tR (minor) = 8.1 min; 90:10 er, [α]D = +31.64 (c = 0.50, CHCl3); lit17b
:
93:7 er, [α]D25 = +14.2 (c = 0.50, CHCl3) for (S)ꢀ2e. Melting point: 93 ꢀ 94 °C.
(S)-2-hydroxy-1,2-di-p-tolylethan-1-one (2f).17b White solid, 71% yield (17.1 mg), reaction time 10 h.
1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.19 (dd, J = 14.7, 8.0 Hz, 4H), 7.11 (d, J = 7.8
Hz, 2H), 5.89 (d, J = 6.1 Hz, 1H), 4.53 (d, J = 6.1 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 198.9, 145.2, 138.7, 136.7, 131.3, 130.1, 129.7, 129.6, 128.0, 76.1, 22.1, 21.5. HRMS
m/z calculated for C16H15O2 [MꢀH]ꢀ: 239.1078, found: 239.1070. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH,
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90/10, flow rate 1.0 mL/min, λ= 254 nm), tR(major) = 20.6 min, tR (minor) = 16.8 min; 94:6 er, [α]D
=
+31.6 (c = 0.5, CHCl3); lit17b: 95.5:4.5 er, [α]D25 = +81.0 (c = 0.3, CHCl3) for (S)ꢀ2f. Melting point: 85 ꢀ
86 °C.
(S)-2-hydroxy-1,2-di-m-tolylethan-1-one (2g).17a White solid, 79% yield (19.0 mg), reaction time 10
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h. 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.28 –
7.24 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 6.7 Hz, 2H), 7.07 (d, J = 7.5 Hz, 1H), 5.90 (d, J =
6.1 Hz, 1H), 4.52 (d, J = 6.1 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 199.5,
139.3, 139.2, 138.9, 135.0, 133.8, 129.9, 129.7, 129.3, 128.8, 128.6, 126.8, 125.3, 76.5, 21.7, 21.7.
HRMS m/z calculated for C16H15O2 [MꢀH]ꢀ: 239.1078, found: 239.1089. HPLC: Chiralcel IC
(nꢀhexane/iꢀPrOH, 90/10, flow rate 1.0 mL/min, λ= 254 nm), tR (major) = 16.3 min, tR (minor) = 13.9
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min; 93:7 er, [α]D = +70.4 (c = 0.50, CHCl3); lit17a: 98:2 er, [α]D = +95.6 (c = 1.03, MeOH) for
(S)ꢀ2g. Melting point: 73 ꢀ 74 °C.
(S)-1,2-bis(4-ethylphenyl)-2-hydroxyethan-1-one (2h). White solid, 64% yield (17.2 mg), reaction
time 10 h. 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.23 (dd, J = 16.0, 8.1 Hz, 4H), 7.15
(d, J = 8.0 Hz, 2H), 5.90 (d, J = 6.2 Hz, 1H), 4.53 (d, J = 6.2 Hz, 1H), 2.65 (q, J = 7.6 Hz, 2H), 2.59 (q,
J = 7.6 Hz, 2H), 1.23 – 1.16 (m, 6H). 13C NMR (125 MHz, CDCl3) δ 198.9, 151.3, 144.6, 136.9, 131.5,
129.8, 129.0, 128.5, 128.0, 76.2, 29.3, 28.9, 15.7, 15.3. HRMS m/z calculated for C18H19O2 [MꢀH]ꢀ:
267.1391, found: 267.1381. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 90/10, flow rate 1.0 mL/min, λ=
254 nm), tR (major) = 19.9 min, tR (minor) = 16.9 min; 94:6 er, [α]D25 = +68.9 (c = 0.50, CHCl3); lit17a
97:3 er, [α]D22 = +58.8 (c = 1.47, MeOH) for (S)ꢀ2h. Melting point: 88 ꢀ 89 °C.
:
(S)-2-hydroxy-1,2-bis(4-isopropylphenyl)ethan-1-one (2i).17c White solid, 80% yield (23.7 mg),
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reaction time 12 h. H NMR (500 MHz, CDCl3) δ 7.91 – 7.81 (m, 2H), 7.27 – 7.23 (m, 4H), 7.18 (d, J
= 8.2 Hz, 2H), 5.90 (d, J = 6.2 Hz, 1H), 4.52 (d, J = 6.2 Hz, 1H), 2.87 (dh, J = 27.7, 6.9 Hz, 2H), 1.24 –
1.16 (m, 12H). 13C NMR (125 MHz, CDCl3) δ 198.8, 155.9, 149.6, 137.0, 131.6, 129.8, 128.0, 127.6,
127.2, 76.1, 34.6, 34.1, 24.2, 24.2, 23.9, 23.8. HRMS m/z calculated for C20H23O2 [MꢀH]ꢀ: 295.1693,
found: 295.1706. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 95/5, flow rate 1.0 mL/min, λ= 254 nm), tR
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(major) = 25.6 min, tR (minor) = 20.8 min; 91:9 er, [α]D25 = +20.2 (c = 0.50, CHCl3). Melting point: 91
ꢀ 92 °C.
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(S)-2-hydroxy-1,2-bis(4-isobutylphenyl)ethan-1-one (2j). White solid, 56% yield (18.2 mg), reaction
time 12 h. 1H NMR (500 MHz, CDCl3) δ 7.87 – 7.78 (m, 2H), 7.26 – 7.22 (m, 2H), 7.18 – 7.13 (m, 2H),
7.11 – 7.06 (m, 2H), 5.89 (d, J = 6.1 Hz, 1H), 4.54 (d, J = 6.2 Hz, 1H), 2.47 (d, J = 7.2 Hz, 2H), 2.41 (d,
J = 7.2 Hz, 2H), 1.76 – 1.89 (m, 2H), 0.86 (dd, J = 8.4, 6.6 Hz, 12H). 13C NMR (125 MHz, CDCl3) δ
198.9, 148.9, 142.5, 136.9, 131.6, 130.2, 129.7, 129.5, 127.9, 76.2, 45.8, 45.4, 30.5, 30.3, 22.7, 22.7.
HRMS m/z calculated for C22H27O2 [MꢀH]ꢀ: 323.2017, found: 323.2034. HPLC: Chiralcel IC
(nꢀhexane/iꢀPrOH, 95/5, flow rate 1.0 mL/min, λ= 254 nm), tR (major) = 14.1 min, tR (minor) = 11.7
min; 84:16 er. [α]D25 = +29.8 (c = 0.50, CHCl3). Melting point: 94 ꢀ 95 °C.
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(S)-1,2-bis(4-(tert-butyl)phenyl)-2-hydroxyethan-1-one (2k).17a White solid, 59% yield (19.1 mg),
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reaction time 12 h. H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H),
7.34 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 5.91 (d, J = 5.0 Hz, 1H), 4.51 (d, J = 6.2 Hz, 1H),
1.29 (s, 9H), 1.27 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 198.7, 158.1, 151.8, 136.6, 131.2, 129.6,
127.7, 126.4, 126.0, 76.0, 35.6, 34.9, 31.6, 31.3. HRMS m/z calculated forC22H27O2 [MꢀH]ꢀ: 323.2017,
found: 323.2043. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 95/5, flow rate 1.0 mL/min, λ= 254 nm), tR
25
(major) = 15.2 min, tR (minor) = 12.2 min; 80:20 er, [α]D = +45.6 (c = 0.50, CHCl3); lit17a: 98:2 er,
[α]D25 = +54.8 (c = 2.37, CHCl3) for (S)ꢀ2k. Melting point: 111 ꢀ 112 °C.
(S)-2-hydroxy-1,2-di(thiophen-3-yl)ethan-1-one (2l).17d White solid, 52% yield (11.6 mg) , reaction
time 14 h. 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J = 3.0, 1.3 Hz, 1H), 7.52 (dd, J = 5.2, 1.3 Hz, 1H),
7.33 (dd, J = 3.0, 1.3 Hz, 1H), 7.29 (ddd, J = 5.1, 2.9, 0.9 Hz, 2H), 7.00 (dd, J = 5.0, 1.4 Hz, 1H), 5.84
(d, J = 6.0 Hz, 1H), 4.34 (d, J = 6.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 191.4, 138.9, 136.9, 133.2,
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126.2, 126.1, 125.6, 125.2, 123.2, 71.4. HRMS m/z calculated for C10H7O2S2 [MꢀH]ꢀ: 222.9893, found:
222.9894. HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 90/10, flow rate 1.0 mL/min, λ= 254 nm), tR (major)
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= 21.5 min, tR (minor) = 16.9 min; 90:10 er. [α]D = +67.84 (c = 0.50, CHCl3); lit17d: > 99.5:0.5 er,
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[α]D25 = ꢀ103.96 (c = 0.005, CHCl3) for (R)ꢀ2l. Melting point: 103 ꢀ 104 °C.
(R)-2-hydroxy-1,2-di(thiophen-2-yl)ethan-1-one (2m).17e White solid, 55% yield (12.3 mg), reaction
time 14 h. 1H NMR (500 MHz, CDCl3) δ 7.75 (dd, J = 3.9, 1.1 Hz, 1H), 7.70 (dd, J = 4.9, 1.1 Hz, 1H),
7.30 (dd, J = 5.1, 1.2 Hz, 1H), 7.13 – 7.06 (m, 2H), 6.97 (dd, J = 5.1, 3.5 Hz, 1H), 6.03 (d, J = 6.4 Hz,
1H), 4.35 (d, J = 6.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 190.3, 142.4, 139.6, 135.7, 134.6, 128.7,
127.6, 127.3, 127.2, 72.0. HRMS m/z calculated for C10H7O2S2 [MꢀH]ꢀ: 222.9893, found: 222.9911.
HPLC: Chiralcel IC (nꢀhexane/iꢀPrOH, 90/10, flow rate 1.0 mL/min, λ= 254 nm), tR (major) = 22.2
25
min, tR (minor) = 19.7 min; 90:10 er, [α]D = +22.8 (c = 0.50, CHCl3); lit17e: 97.5:2.5 er for (S)ꢀ2m,
[α]D25 = ꢀ380 (c = 0.1, CHCl3). Melting point: 114 ꢀ 115 °C.
(S)-1,2-di(furan-2-yl)-2-hydroxyethan-1-one (2n).17d White solid, 57% yield (11.0 mg), reaction time
12 h. 1H NMR (500 MHz, CDCl3) δ 7.65 – 7.58 (m, 1H), 7.37 (dd, J = 1.9, 0.9 Hz, 1H), 7.25 (d, J = 3.9
Hz, 1H), 6.54 (dd, J = 3.7, 1.7 Hz, 1H), 6.40 (d, J = 3.3 Hz, 1H), 6.35 (dd, J = 3.3, 1.8 Hz, 1H), 5.80 (s,
1H), 4.18 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 184.7, 151.6, 150.0, 148.1, 143.5, 120.5, 113.0, 111.1,
109.5, 69.6. HRMS m/z calculated for C10H7O4 [MꢀH]ꢀ: 191.0350; found: 191.0347. HPLC: Chiralcel
IA (nꢀhexane/iꢀPrOH, 90/10, flow rate 1.0 mL/min, λ= 254 nm), tR (major) = 16.6 min, tR (minor) =
25
25
20.1 min; 84:16 er, [α]D = +38.7 (c = 0.5, CHCl3); lit17d: 98.5:1.5 er, [α]D = ꢀ110.8 (c = 0.0066,
CHCl3) for Rꢀ2n. Melting point: 99 ꢀ 100 °C.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website.
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Copies of 1H NMR, 13C NMR and HPLC spectra for all the products (2aꢀ2n) (PDF).
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■AUTHOR INFORMATION
Corresponding Author
*Email: myang@hznu.edu.cn.
*Email: zgf@hznu.edu.cn.
ORCID
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Limin Yang: 0000ꢀ0003ꢀ1021ꢀ3942
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the NSFC (21373073, 21302032 and 21672048) and the PCSIRT (IRT 1231) for support.
G.Z. appreciated a Qianjiang Scholar from Zhejiang Province in China. L.Y. thanks financial support
from the Pandeng Plan Foundation of Hangzhou Normal University for Youth Scholars of Materials,
Chemistry and Chemical Engeering.
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