A substitution/dynamic kinetic resolution - Asymmetric transfer hydrogenation tandem process for preparation of stereocenters Β-hydroxy sulfones

Article abstract of DOI:10.1016/j.mcat.2018.04.019

A noval method for the synthesis of optically active β-hydroxy sulfones was developed. Through a substitution/dynamic kinetic resolution-asymmetric transfer hydrogenation, the presented method was based on one-pot enantioselective organic transformations of α-bromoindenones and sodium arylsulfinate. The protocol employed RuCl₂[(S,S)-TsDPEN](mesitylene) as a catalyst, and sodium formate as a hydrogen source, affording various optically pure vicinal stereocenters β-hydroxy sulfones in high yields with excellent enantioselectivities (up to 99%) and diastereomeric ratios (up to 99:1) under mild reaction conditions.

Full text of DOI:10.1016/j.mcat.2018.04.019

MolecularCatalysis452(2018)271–276
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
A substitution/dynamic kinetic resolution – Asymmetric transfer
hydrogenation tandem process for preparation of stereocenters β-hydroxy
sulfones
Xiaoying Hu, Kun Zhang, Fengwei Chang, Rui Liu⁎, Guohua Liu, Tanyu Cheng⁎
Key Laboratory of Resource Chemistry of Ministry of Education, Key Laboratory of Rare Earth Functional Materials, Department of Chemistry, Shanghai Normal
University, No. 100 Guilin Road, Shanghai 200234, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A noval method for the synthesis of optically active β-hydroxy sulfones was developed. Through a substitution/
dynamic kinetic resolution–asymmetric transfer hydrogenation, the presented method was based on one-pot
enantioselective organic transformations of α–bromoindenones and sodium arylsulfinate. The protocol em-
ployed RuCl2[(S,S)–TsDPEN](mesitylene) as a catalyst, and sodium formate as a hydrogen source, affording
various optically pure vicinal stereocenters β-hydroxy sulfones in high yields with excellent enantioselectivities
(up to 99%) and diastereomeric ratios (up to 99:1) under mild reaction conditions.
Asymmetric transfer hydrogenation
Dynamic kinetic resolution
β-Hydroxy sulfones
α–Bromoindenones
Tandem process
1. Introduction
DKR–ATH method was use in our procedure to obtain an efficient or-
ganic transformations of β–substituted ketones into 1,3–position ste-
reocenters phthalides [23]. By screening a series of N–(4–methyl)ben-
One–pot multi–step organic transformations, such as tandem reaction
and sequential reaction, were particularly attractive due to atom economy
and minimum workload. Another notable advantage of this reaction was the
reduction of environmental pollution and cost [1–10]. Therefore, the
synthesis of optically pure molecules via multi–step organic transformations
was becoming popular in preparation of biologically active compounds
[11–14]. It was well-known that optically pure cyclic β-hydroxy sulfones
with two contiguous chiral centers can be converted into plenty types of
biologically active molecules in medicinal chemistry [15–20]. The con-
struction of these β-hydroxy sulfones has been used in many reactions,
which in general consists of two steps, i.e. substitution and reduction (re-
ported in Scheme 1). In particular, the enantioselective synthesis of these
vicinal cyclic β-hydroxy sulfones and derivatives with two contiguous chiral
centers were used in a dynamic kinetic resolution via asymmetric transfer
hydrogenation (DKR–ATH) strategy [21,22]. Zhang’s group [21] used RuCl
[TsDPEN](p-cymene) as a catalyst and HCOOH–Et3N as a hydrogen source
to in a DKR–ATH organic transformations of four cyclic β-keto sulfones. In
Wang’s group, asymmetric hydrogenation method was applied to realize
DKR–ATH organic transformations of a cyclic β-keto sulfone [22]. Despite
of significant efforts made in the preparation of optically active cyclic β-
hydroxy sulfones, the direct construction of 1,2–position stereocenters cyclic
β-hydroxy sulfones through a multi–step enantioselective organic transfor-
mations with a tandem process has not been fully explored yet.
zenesulfonylated
1,2–diphenylethylenediamine
(TsDPEN)–based
η6–areneRu complexes and η5–Cp*M complexes (Cp* = penta-
methylcyclopentadiene) [29–31], η6–mesityleneRuTsDPEN complex
could behave efficiently as an optimal catalyst in substitution/
DKR–ATH tandem process, furnishing optically pure 1,2–position ste-
reocenters β-hydroxy sulfones with high yields, enantioselectivities
(92–99% ee) and diastereomeric ratios (up to 99:1) under mild reaction
conditions (shown in Scheme 1).
2. Experimental
2.1. Chemicals and instruments
At the outset of our research, the α–bromoindenones and 2-bromo-
3,4-dihydronaphthalen-1(2H)-one were prepared according to the
published procedures [32]. All other chemicals and solvents were of
analytic grade and used as received except as specified. NMR spectra
were measured on a Bruker DRX-400 spectrometer. HRMS data were
recorded on a GC–TOF instrument by the ESI technique. Then, analy-
tical HPLC was carried out with a Waters® Chromatography setup
consisting of: Waters® 717plus Autosampler, Waters® 1525 Binary HPLC
Pump, and Waters® 2478 Dual
antiomeric excesses (ee) were determined by using a Daicel Chiralpak®
λ Absorbance Detector. The en-
To explore various asymmetric transfer hydrogenation [23–28], a
⁎
Corresponding authors.
E-mail addresses: rliu@shnu.edu.cn (R. Liu), tycheng@shnu.edu.cn (T. Cheng).
https://doi.org/10.1016/j.mcat.2018.04.019
Received 27 January 2018; Received in revised form 26 March 2018; Accepted 19 April 2018
2468-8231/©2018ElsevierB.V.Allrightsreserved.

X. Hu et al.
MolecularCatalysis452(2018)271–276
Scheme 1. One–pot Two–step Enantioselective Organic Transformations of α–bromoindenones to Chiral β-Hydroxy Sulfones.
column AD-H or Daicel Chiralcel® column OJ-H with the above HPLC
setup.
(1R,2S)-2-(mesitylsulfonyl)-2,3-dihydro-1H-inden-1-ol
(3d):
white solid; 29 mg, 93% yield; 99% ee, 99:1 dr; 1H NMR (400 MHz,
CDCl3) δ 7.48–7.39 (m, 1H), 7.38–7.24 (m, 3H), 7.03 (s, 2H), 5.42 (d,
J = 5.4 Hz, 1H), 4.07–3.96 (m, 1H), 3.76 (dd, J = 15.7, 9.3 Hz, 1H),
3.40 (s, 1H), 3.07 (dd, J = 15.7, 7.8 Hz, 1H), 2.74 (s, 6H), 2.35 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 144.2, 143.1, 140.8, 140.3, 135.3,
132.7, 129.0, 127.6, 125.2, 125.1, 74.7, 67.2, 31.1, 23.2, 21.1; HRMS
(ESI) m/z [M+Na]+ calcd for C18H20NaO3S 339.1025, found
339.1029; [α]2D5 = +11.289 (c = 0.552, CHCl3). HPLC (AD-H, elute:
Hexane/i-PrOH = 90/10, detector: 254 nm, flow rate: 1.0 mL/min,
25 °C), t1 = 17.0 min, t2 = 19.6 min (major).
2.2. Typical procedure for tandem enantioselective transformations of
indenoes into chiral β-hydroxy sulfones
During the process, the catalyst (2.0 μmol, 5 mol%),
α–bromoindanones (0.10 mmol), sodium arylsulfinate (0.40 mmol),
HCOONa (1.0 mmol, 10 equiv) were added sequentially in H2O/i-PrOH
(4.0 mL, v/v = 1/3). The mixture was then stirred at 60 °C for 5 h.
During this period, the reaction was monitored constantly by TLC. After
completion of the reaction, the aqueous solution was extracted with
ethyl ether (3 × 3.0 mL). The combined ethyl ether extracts were wa-
shed with NaHCO3 and brine, and then dehydrated with Na2SO4.
After evaporation of ethyl ether, the residue was purified by silica
gel flash column chromatography to afford the desired product. The ee
values were determined by a HPLC analysis using a UV–vis detector
(254 nm) and a Daicel chiralcel column (Ф 0.46 × 25 cm), and the dr
values were determined by NMR.
(1R,2S)-2-((4-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-1-
ol (3e): white solid; 28 mg, 96% yield; 99% ee, 99:1 dr; 1H NMR
(400 MHz, CDCl3) δ 8.12–8.01 (m, 2H), 7.44–7.36 (m, 1H), 7.36–7.19
(m, 5H), 5.31 (d, J = 5.9 Hz, 1H), 4.02–3.92 (m, 1H), 3.69 (dd,
J = 16.2, 8.7 Hz, 1H), 3.23 (dd, J = 16.2, 8.1 Hz, 1H), 3.13 (s, 1H); 13
C
NMR (100 MHz, DMSO-d6) δ 166.3 (d, J = 252 Hz), 143.6, 140.2,
136.8, 132.5 (d, J = 9.8 Hz), 128.9, 127.5, 125.0 (d, J = 4 Hz), 116.4
(d, J = 23 Hz), 73.8, 67.3, 31.6; 19F NMR (376 MHz, CDCl3)
δ
−103.04. HRMS (ESI) m/z [M+Na]+ calcd for C15H13FNaO3S
315.0462, found 345.0464; [α]2D5 = +8.897 (c = 0.220, CHCl3). HPLC
(AD-H, elute: Hexane/i-PrOH = 90/10, detector: 254 nm, flow rate:
1.0 mL/min, 25 °C), t1 = 20.6 min, (major) t2 = 32.2 min.
(1R,2S)-2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-ol
(3a).
white solid; 26 mg, 95% yield; 99% ee, 99:1 dr; 1H NMR (400 MHz,
CDCl3) δ 8.08–7.98 (m, 2H), 7.74–7.65 (m, 1H), 7.64–7.56 (m, 2H),
7.43–7.37 (m, 1H), 7.34–7.22 (m, 3H), 5.36–5.28 (m, 1H), 4.02–3.92
(m, 1H), 3.71 (dd, J = 16.1, 8.9 Hz, 1H), 3.27–3.14 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 143.9, 140.8, 140.5, 134.1, 129.6, 129.2, 129.1,
127.7, 125.3, 125.2, 74.1, 67.3, 31.9; HRMS (ESI) m/z [M+Na]+ calcd
(1R,2S)-2-((4-chlorophenyl)sulfonyl)-2,3-dihydro-1H-inden-1-
ol (3f): white solid; 29 mg, 95% yield; 98% ee, 99:1 dr; 1H NMR
(400 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H),
7.41 (d, J = 6.7 Hz, 1H), 7.36–7.19 (m, 3H), 5.32 (d, J = 5.9 Hz, 1H),
4.04–3.90 (m, 1H), 3.71 (dd, J = 16.2, 8.8 Hz, 1H), 3.25 (dd, J = 16.3,
8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.8, 140.4, 139.5, 139.2,
131.20 (d, J = 32.3 Hz), 129.6, 129.1, 127.7, 125.23 (d, J = 4.5 Hz),
74.0, 67.5, 31.7; HRMS (ESI) m/z [M+Na]+ calcd for C15H13ClNaO3S
331.0166, found 331.0169; [α]2D5 = +5.742 (c = 0.320, CHCl3). HPLC
(OJ-H, elute: Hexane/i-PrOH = 90/10, detector: 254 nm, flow rate:
1.0 mL/min, 25 °C), t1 = 20.6 min, t2 = 27.1 min (major).
(1R,2S)-2-((4-bromophenyl)sulfonyl)-2,3-dihydro-1H-inden-1-
ol (3 g). white solid; 34 mg, 96% yield; 99% ee, 99:1 dr; 1H NMR
(400 MHz, CDCl3) δ 7.91 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H),
7.40 (d, J = 6.8 Hz, 1H), 7.36–7.18 (m, 3H), 5.35–5.27 (m, 1H),
4.03–3.91 (m, 1H), 3.69 (dd, J = 16.2, 8.8 Hz, 1H), 3.23 (dd, J = 16.2,
8.1 Hz, 1H), 3.02 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 143.8, 140.4,
140.0, 132.6, 131.4, 130.0, 129.2, 129.1, 128.3, 127.7, 74.1, 67.4,
31.8; HRMS (ESI) m/z [M+Na]+ calcd for C15H13BrNaO3S 374.9661,
found 374.9665; [α]2D5 = +1.664 (c = 0.120, CHCl3). HPLC (OJ-H,
elute: Hexane/i-PrOH = 90/10, detector: 254 nm, flow rate: 1.0 mL/
min, 25 °C), t1 = 22.7 min (major), t2 = 30.1 min.
for
C
15H14NaO3S 297.0556, found 297.0552; [α]2D5 = +14.163
(c = 0.220, CHCl3). HPLC (AD-H, elute: Hexane/i-PrOH = 90/10, de-
tector: 254 nm, flow rate: 1.0 mL/min, 25 °C), t1 = 54.6 min (major),
t2 = 68.4 min.
(1R,2S)-2-tosyl-2,3-dihydro-1H-inden-1-ol (3b). white solid;
27 mg, 94% yield; 99% ee, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ 7.92
(d, J = 8.3 Hz, 2H), 7.45–7.35 (m, 3H), 7.35–7.18 (m, 3H), 5.30 (d,
J = 5.8 Hz, 1H), 4.00–3.89 (m, 1H), 3.70 (dd, J = 16.1, 9.0 Hz, 1H),
3.19 (dd, J = 16.1, 8.1 Hz, 2H), 2.48 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 144.5, 144.0, 140.6, 138.0, 130.0, 129.3, 129.1, 127.7, 125.3,
125.2, 74.1, 67.3, 31.9, 21.7; HRMS (ESI) m/z [M+Na]+ calcd for
C
16H16NaO3S 311.0712, found 311.0725; [α]2D5 = +13.784 (c = 0.284,
CHCl3). HPLC (AD-H, elute: Hexane/i-PrOH = 90/10, detector:
254 nm, flow rate: 1.0 mL/min, 25 °C), t1 = 23.8 min (major),
t2 = 29.1 min.
(1R,2S)-2-((4-(tert-butyl)phenyl)sulfonyl)-2,3-dihydro-1H-
inden-1-ol (3c). white solid; 31 mg, 94% yield; 92% ee, 95:5 dr; 1H
NMR (400 MHz, DMSO-d6)
δ 7.88 (d, J = 8.5 Hz, 2H), 7.63 (d,
J = 8.6 Hz, 2H), 7.30–7.15 (m, 4H), 5.60 (d, J = 7.1 Hz, 1H), 5.14 (dd,
J = 7.1, 5.9 Hz, 1H), 4.25–4.14 (m, 1H), 3.41 (dd, J = 15.8, 8.7 Hz,
1H), 3.04 (dd, J = 15.8, 8.0 Hz, 1H), 1.32 (s, 9H); 13C NMR (100 MHz,
DMSO-d6) δ 157.0, 144.0, 140.5, 138.0, 129.2, 129.1, 127.7, 126.4,
125.3, 125.2, 74.1, 67.4, 35.6, 31.9, 31.5; HRMS (ESI) m/z [M+Na]+
calcd for C19H22NaO3S 353.1182, found 353.1185; [α]2D5 = +13.381
(c = 0.406, CHCl3). HPLC (AD-H, elute: Hexane/i-PrOH = 90/10, de-
tector: 254 nm, flow rate: 1.0 mL/min, 25 °C), t1 = 13.5 min,
t2 = 15.9 min (major).
(1R,2S)-2-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-
1H-inden-1-ol (3 h). white solid; 31 mg, 92% yield; 94% ee, 99:1 dr; 1H
NMR (400 MHz, DMSO-d6)
δ 8.17 (d, J = 8.2 Hz, 2H), 8.00 (d,
J = 8.2 Hz, 2H), 7.29–7.15 (m, 4H), 5.69 (d, J = 7.1 Hz, 1H), 5.16 (dd,
J = 7.1, 6.0 Hz, 1H), 4.44–4.32 (m, 1H), 3.45 (dd, J = 15.9, 8.1 Hz,
1H), 3.13 (dd, J = 15.9, 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
144.4, 143.5, 140.1, 133.4 (q, J = 32 Hz), 130.2, 129.0, 127.5, 126.4
(q, J = 3.7 Hz), 125.0, 124.0 (q, J = 275 Hz), 73.8, 67.2, 31.4; 19F NMR
272

X. Hu et al.
MolecularCatalysis452(2018)271–276
Table 1
Screening the chiral catalyst for the DKR–ATH of 2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-one.a
entry
catalyst
yield (%)b
ee (%)c
drc
1
2
3
4
5
6
7
8
9
A
B
C
D
E
F
G
H
I
99
95
95
95
90
97
trace
95
95
99
99
99
99
99
99
–
99:1
98:2
98:2
99:1
99:1
99:1
–
−57
−84
1:99
1:99
a
Reaction conditions: 2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-one (0.10 mmol), HCOONa (1.0 mmol), solvent (4 mL).
Isolated yield.
Determined by chiral HPLC.
b
c
(376 MHz, CDCl3) δ −63.22. HRMS (ESI) m/z [M+Na]+ calcd for
16H13F3NaO3S 365.0430, found 365.0433; [α]2D5 = −4.872 (c = 0.328,
4.02–3.94 (m, 1H), 3.70 (dd, J = 16.4, 8.6 Hz, 1H), 3.31 (d, J = 6.8 Hz,
1H), 3.19 (dd, J = 16.4, 8.1 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ
143.4, 143.3, 140.6, 134.2, 130.6, 129.6, 129.2, 128.2, 127.2, 122.1,
73.6, 67.2, 31.7; HRMS (ESI) m/z [M+Na]+ calcd for C15H13BrNaO3S
374.9661, found 374.9661; [α]2D5 = +19.582 (c = 0.408, CHCl3). HPLC
(OJ-H, elute: Hexane/i-PrOH = 97/3, detector: 254 nm, flow rate:
1.0 mL/min, 25 °C), t1 = 103.4 min (major), t2 = 126.2 min.
(1R,2S)-5-chloro-2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-ol
(3l). white solid; 29 mg, 94% yield; 99% ee, 99:1 dr; 1H NMR (400 MHz,
CDCl3) δ 8.06–8.00 (m, 2H), 7.75–7.67 (m, 1H), 7.64–7.57 (m, 2H),
7.32 (d, J = 8.0 Hz, 1H), 7.27–7.20 (m, 2H), 5.31 (d, J = 5.9 Hz, 1H),
4.04–3.90 (m, 1H), 3.68 (dd, J = 16.3, 8.7 Hz, 1H), 3.17 (dd, J = 16.4,
8.1 Hz, 1H), 2.82 (br, 1H). 13C NMR (100 MHz, DMSO-d6) δ 143.0,
142.9, 140.6, 134.2, 133.5, 129.6, 129.2, 127.8, 126.8, 125.2, 73.5,
67.3, 31.7; HRMS (ESI) m/z [M+Na]+ calcd for C15H13ClNaO3S
331.0166, found 331.0169; [α]2D5 = +21.381 (c = 0.454, CHCl3). HPLC
(OJ-H, elute: Hexane/i-PrOH = 93/7, detector: 254 nm, flow rate:
1.0 mL/min, 25 °C), t1 = 81.2 min (major).
(1R,2S)-6-methoxy-2-(phenylsulfonyl)-2,3-dihydro-1H-inden-
1-ol (3m). white solid; 30 mg, 97% yield; 99% ee, 99:1 dr; 1H NMR
(400 MHz, CDCl3) δ 8.00–7.88 (m, 2H), 7.64–7.56 (m, 1H), 7.56–7.45
(m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 6.76 (dd,
J = 8.3, 2.5 Hz, 1H), 5.24–5.09 (m, 1H), 3.94–3.85 (m, 1H), 3.70 (s,
3H), 3.53 (dd, J = 15.8, 8.6 Hz, 1H), 3.21 (d, J = 7.2 Hz, 1H), 3.03 (dd,
J = 15.8, 8.1 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 159.4, 145.3,
140.9, 134.0, 132.2, 129.5, 129.2, 125.9, 115.5, 110.1, 74.2, 67.8,
55.7, 31.1; HRMS (ESI) m/z [M+Na]+ calcd for C16H16NaO4S
327.0622, found 327.0665; [α]2D5 = +21.148 (c = 0.204, CHCl3). HPLC
(OJ-H, elute: Hexane/i-PrOH = 97/3, detector: 254 nm, flow rate:
1.0 mL/min, 25 °C), t1 = 47.5 min (major).
C
CHCl3)·HPLC (AD-H, elute: Hexane/i-PrOH = 90/10, detector: 254 nm,
flow rate: 1.0 mL/min, 25 °C), t1 = 14.0 min, t2 = 18.4 min (major).
(1R,2S)-2-((2-fluorophenyl)sulfonyl)-2,3-dihydro-1H-inden-1-
ol (3i). white solid; 27 mg, 91% yield; 99% ee, 99:1 dr; 1H NMR
(400 MHz, CDCl3) δ 8.07–7.98 (m, 1H), 7.76–7.65 (m, 1H), 7.46–7.22
(m, 6H), 5.41 (d, J = 6.0 Hz, 1H), 4.39–4.24 (m, 1H), 3.81 (dd,
J = 16.3, 8.4 Hz, 1H), 3.27 (dd, J = 16.3, 8.3 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 159.5 (d, J = 256 Hz), 143.8, 140.1, 137.0 (d,
J = 8 Hz), 131.6, 128.7 (d, J = 15 Hz), 127.7, 125.6, 125.1 (d,
J = 10 Hz), 117.8 (d, J = 22 Hz), 74.4, 67.5, 31.4; 19F NMR (376 MHz,
CDCl3) δ −109.43. HRMS (ESI) m/z [M+Na]+ calcd for C15H13FNaO3S
315.0462, found 315.0463; [α]2D5 = −8.459 (c = 0.340, CHCl3). HPLC
(OJ-H, elute: Hexane/i-PrOH = 90/10, detector: 254 nm, flow rate:
1.0 mL/min, 25 °C), t1 = 28.3 min (major), t2 = 31.2 min.
(1R,2S)-2-(naphthalen-2-ylsulfonyl)-2,3-dihydro-1H-inden-1-ol
(3j). white solid; 29 mg, 89% yield; 99% ee, 99:1 dr; 1H NMR (400 MHz,
CDCl3) δ 8.62 (s, 1H), 8.11–7.92 (m, 4H), 7.78–7.62 (m, 2H), 7.41 (d,
J = 7.0 Hz, 1H), 7.36–7.18 (m, 3H), 5.35 (d, J = 5.7 Hz, 1H), 4.13–4.00
(m, 1H), 3.78 (dd, J = 16.1, 9.0 Hz, 1H), 3.23 (dd, J = 16.1, 8.0 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 143.9, 140.5, 138.0, 135.4,
132.3, 130.7, 130.1, 129.8, 129.5, 129.1, 128.5, 128.2, 127.7, 125.3,
125.2, 124.3, 74.2, 67.4, 31.9; HRMS (ESI) m/z [M+Na]+ calcd for
C19H16NaO3S 347.0712, found 347.0715; [α]2D5 = +7.452 (c = 0.520,
CHCl3). HPLC (OJ-H, elute: Hexane/i-PrOH = 85/15, detector: 254 nm,
flow rate: 1.0 mL/min, 25 °C), t1 = 18.1 min (major), t2 = 21.8 min.
(1R,2S)-5-bromo-2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-ol
(3k). white solid; 34 mg, 95% yield; 99% ee, 99:1 dr; 1H NMR
(400 MHz, CDCl3) δ 8.07–7.99 (m, 2H), 7.75–7.67 (m, 1H), 7.66–7.57
(m, 2H), 7.45–7.37 (m, 2H), 7.31–7.24 (m, 1H), 5.34–5.26 (m, 1H),
(1R,2S)-2-(phenylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol
273

X. Hu et al.
MolecularCatalysis452(2018)271–276
Table 2
Optimization of reaction conditions for the DKR–ATH of 2-(phenylsulfonyl)-
2,3-dihydro-1H-inden-1-one.a
entry
solvent
temp. (°C)
time (h)
yield (%)b
ee (%)c
99
drc
1
2
3
4
5
6
H2O/i-PrOH
(1:3)
H2O/i-PrOH
(1:1)
H2O/EtOH
(1:3)
H2O/MeOH
(1:3)
H2O/DMF
(1:3)
H2O/DMSO
(1:3)
60
60
60
60
60
60
5
98
99:1
86:14
71:29
93:7
98:2
ND
5
93
99
6
95
99
6
85
98
12
12
95
99
< 10
ND
7
8
H2O
H2O/CH2Cl2
(1:3)
60
40
6
12
83
97
97
94
97:3
99:1
9
H2O/DCE
(1:3)
H2O/i-PrOH
(1:3)
H2O/i-PrOH
(1:3)
H2O/i-PrOH
(1:3)
60
r.t.
40
70
12
12
7
95
98
98
98
98
99
99
99
99:1
99:1
99:1
96:4
10
11
12
Fig. 1. Time course of the transformation of α–bromoindanone and sodium
benzenesulfinate
to
(1R,2S)–2–(phenylsulfonyl)–2,3–dihydro–1H–indenol
(Reactions were performed with 5.0 mol% of catalyst A, 0.1 mmol of
α–bromoindanone and 4 equivalent of sodium benzenesulfinate, 10 equivalent
of HCOONa in H2O/i-PrOH (4.0 mL, v/v, 3:1) at 60 °C.
4
a
Reaction conditions: catalyst A (2.0 μmol), 2-(phenylsulfonyl)-2,3-dihydro-
1H-inden-1-one (0.10 mmol), HCOONa (1.0 mmol), 4.0 mL of solvent.
most considerable objective. Therefore, the reaction conditions for the
ATH process were optimized firstly. Based on our previous work [33],
the chiral catalysts were screened in the co-solvent of H2O/i-PrOH (1/3,
v/v). As shown in Table 1, most of tested catalysts except G provided
corresponding product with high yields. Low ee (57% and 84%) values
were obtained with H and I as the catalyst (entry 8 and 9, Table 1).
Excellent diastereomeric selectivities were observed with each catalyst
(A-I). In this work, A was chosen as the catalyst for the present one-pot
transformation approach. With the best ruthenium catalyst in hand,
further study focuses on the optimization of the asymmetric transfer
hydrogenation of 2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-one in the
presence of catalyst A, and the results were displayed in Table 2. After
getting good result in the solvent of H2O/i-PrOH (1/3, v/v), this
transformation in H2O/i-PrOH (1:1) was also testified. Corresponding
product was obtained with high yield, excellent enantioselectivities
(99% ee) and medium diastereoselectivity (dr 86:14, entry 2, Table 2).
Two other alcohols (methanol and ethanol) with water were also used
as the reaction solvent. A little lower diastereoselectivity (dr value
b
Isolated yield.
Determined by HPLC.
c
(3n). white solid; 27 mg, 94% yield; 99% ee, 99:1 dr; 1H NMR
(400 MHz, CDCl3) δ 8.04–7.97 (m, 2H), 7.77–7.68 (m, 1H), 7.68–7.58
(m, 2H), 7.31–7.10 (m, 4H), 5.11–5.04 (m, 1H), 3.40–3.21 (m, 2H),
3.15–3.05 (m, 1H), 2.92–2.76 (m, 1H), 2.56–2.39 (m, 1H), 2.33–2.20
(m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 139.8, 138.5, 135.7, 134.2,
130.6, 129.7, 129.5, 129.1, 128.5, 65.8, 65.3, 28.6, 18.0; HRMS (ESI)
m/z [M+Na]+ calcd for C16H16NaO3S 311.0712, found 311.0715;
[α]2D5 = −8.171 (c = 0.132, CHCl3). HPLC (OJ-H, elute: Hexane/i-
PrOH = 80/20, detector: 254 nm, flow rate: 1.0 mL/min, 25 °C),
t1 = 18.1 min (major), t2 = 25.3 min.
3. Results and discussion
In this one-pot organic transformation, enantioselectivity was the
Table 3
Screening the chiral catalyst for the asymmetric transfer hydrogenation of 2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-one.a
entry
2a
yield (%)b
ee (%)c
drc
1
2
3
4
2 eq
3 eq
4 eq
5 eq
67
83
93
95
99
99
99
99
99:1
99:1
99:1
93:7
a
Reaction conditions: catalyst A (2.0 μmol), α–bromoindanone (0.10 mmol), sodium benzenesulfinate, HCOONa (1.0 mmol), H2O/i-PrOH (4.0 mL, v/v, 3:1).
b
c
Isolated yield.
Determined by chiral HPLC.
274

X. Hu et al.
MolecularCatalysis452(2018)271–276
Table 4
The Substitution/DKR–ATH One-pot Enantioselective Tandem Reaction of α–Bromoindanones and Sodium Arylsulfinate.a
entry
3
n
R
Ar
yield (%)b
ee (%)c
drc
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
1
1
1
1
1
1
1
1
1
1
1
1
1
2
H
H
H
H
H
H
H
H
Ph
93
94
94
93
96
95
96
92
91
89
95
94
97
94
99
99
92
99
99
98
99
94
99
99
99
99
99
99
99:1
99:1
95:5
99:1
99:1
99:1
99:1
91:9
99:1
99:1
99:1
99:1
99:1
99:1
4–MePh
4–tBuPh
2,4,6–Me3Ph
4–FPh
4–ClPh
4–BrPh
4–CF3Ph
2–FPh
2–naphthyl
Ph
9
H
H
10
11
12
13
14
5–Br
5–Cl
6–MeO
H
Ph
Ph
Ph
a
Reaction conditions: catalyst A (2.0 μmol), α–bromoindanone (0.10 mmol), sodium benzenesulfinate (0.40 mmol), HCOONa (1.0 mmol), H2O/i-PrOH (4.0 mL, v/
v, 3:1), reaction temperature: 60 °C.
b
Isolated yield.
Determined by HPLC (See ESI).
c
Scheme 2. Proposed catalytic mechanism and (b) the X–Ray Structure of 3a.
71:29) and yield (85%) were obtained in H2O/EtOH (1:3) and H2O/
MeOH (1:3), respectively (entries 3 and 4, Table 2). More reaction time
was needed to complete the transformation in the co-solvent of polar
aprotic solvents (DMF and DMSO) and water (entries 5 and 6, Table 2).
Only 83% yield was observed when the reaction was carried out in
water (entry 7, Table 2). Longer reaction time was needed in two-phase
system (entries 8 and 9, Table 2). Moreover, through the further opti-
mization of the reaction temperature, It was found that lower reaction
temperature reduced reaction rate (entries 10 and 11, Table 2), while
the enhanced temperature reduced the diastereoselectivity (entry 12,
Table 2). In combination with the results from the above studies, the
asymmetric transfer hydrogenation was optimized and carried out in
the presence of catalyst A in H2O/i-PrOH (1/3, v/v) at 60 °C with
HCOONa as hydrogen source.
Having established the efficient DKR-ATH of 2-(phenylsulfonyl)-2,3-
dihydro-1H-inden-1-one, the substitution/DKR–ATH one-pot en-
antioselective tandem reaction was further investigated. It was found
that the increased amount of sodium benzenesulfinate enhanced the
275

X. Hu et al.
MolecularCatalysis452(2018)271–276
total yields (Table 3). However, diastereoselectivity started decreasing
when 5 equivalent sodium benzenesulfinate was added (entry 4,
Table 3). Therefore, 4 equivalent sodium benzenesulfinate was chosen
for the one-pot reaction.
absolute stereochemistry of 3a could be determined as (1R,2S)–isomer
configuration, confirming the product’s absolute stereochemistry that
are accorded with to the reported configuration [37].
It was worth mentioning that such a clean substitution/DKR–ATH re-
action of α–bromoindanone and sodium benzenesulfinate catalyzed by A
could reach its catalytic completion within 5 h, which was the same with
single step of ATH. This finding suggested the tandem behaviour in this
substitution/DKR–ATH one-pot enantioselective reaction was better than
that in two step reaction. In order to explore the nature of this tandem
4. Conclusion
In conclusions, through the use of RuCl[(S,S)–TsDPEN)](mesity-
lene) as a catalyst, an efficient substitution/DKR–ATH one-pot en-
antioselective tandem reaction of α–bromoindanones and arylsulfinate
was presented. This reaction was carried out in a co-solvent of H2O/i-
PrOH (1/3, v/v) at 60 °C using HCOONa as a hydrogen source, af-
fording various optically active 1,2–position stereocenters β-hydroxy
sulfones in high yields with excellent enantioselectivities and diaster-
eomeric ratios from a variety of α–bromoindanones.
reaction,
the
time
course
of
one–pot
transformation
of
2–(phenylsulfonyl)–2,3–dihydro–1H–indenone and sodium benzenesulfi-
nate to (1R,2S)–2–(phenylsulfonyl)–2,3–dihydro–1H–indenol was in-
vestigated. As shown in Fig. 1, it was found that the substitution processes at
first with the 2–bromoindenone (1a) decreases sharply, which was faster as
seen by the formation of 2–(phenylsulfonyl)–2,3–dihydro–1H–indenone
(1aa) in a maximum yield of 35%. Subsequently, the DKR–ATH of
2–(phenylsulfonyl)–2,3–dihydro–1H–indenone occurs quickly at the point
where the maximum amount of 1aa has been produced, providing the
target product of (1R,2S)–2–(phenylsulfonyl)–2,3–dihydro–1H–indenol
(3a). It was found that almost no 1ab was detected during the reaction,
which means the reaction was a tandem reaction.
Acknowledgements
We are grateful to the National Nature Science Foundation of China
(21672149 and 21402120), the Shanghai Science and Technologies
Development Fund (13ZR1458700), the Shanghai Municipal Education
Commission (13CG48) and the Ministry of Education of China
(PCSIRT_IRT_16R49).
After obtaining an efficient substitution/DKR–ATH one-pot en-
antioselective tandem reaction of α–bromoindanone and sodium ben-
zenesulfinate, a series of α–bromoindenones and sodium arylsulfinate
were further investigated to verify its general applicability in this
tandem process. As shown in Table 4, various 2–bromoindenones and
arylsulfinate could be transferred smoothly into optically pure
1,2–position stereocenters β-hydroxy sulfones in high yields with ex-
cellent enantioselectivities and diastereomeric ratios under the optimal
reaction conditions. Also, it was found that the structures and electronic
properties of substituents in the Ar group did not affect significantly
their enantioselectivities, where both electron–withdrawing and elec-
tron–donating substituents connecting with Ar group were equally ef-
ficient on the basis of the catlaytic results (entries 2–10). Similarly, the
structures and electronic properties of substituents in the aromatic ring
at R1 group did also not affect significantly their enantioselectivities as
observed (entries 11–13). Besides the one–pot organic transformations
of the α–bromoindanones described in Table 4, this substitution/
DKR–ATH was also applied to the other kinds of tandem reaction.
Taking 2-bromo-3,4-dihydronaphthalen-1(2H)-one as an example, the
substitution/DKR–ATH one-pot enantioselective tandem reaction of 2-
bromo-3,4-dihydronaphthalen-1(2H)-one and sodium benzenesulfinate
also gave the chiral product of (1R,2S)-2-(phenylsulfonyl)-1,2,3,4-tet-
rahydronaphthalenol in 94% yield with 99% ee and 99:1 dr under the
same reaction conditions (entry 14).
The ATH proceeds in aqueous solution have been reported [34,35]
and the proposed catalytic cycle was shown in Scheme 2. The catalyst
precursor A was actived by HCOONa, which was proved by Noyori,
Ikariya and co-workers [29]. Then the active catalyst combines with the
substrate 1aa and transfers hydrogen to it. As shown in Scheme 2, (S,S)-
TsDPENRu-H-mesitylene, active catalyst, prefer combining with (S)-
1aa rather than (R)-1aa. A diastereomeric transition state models was
proposed, TSSS (favorable transition state) and TSSR (unfavorable
transition state), for KR–ATH of 1a with the active catalyst A in Scheme
2. Notably, the unfavorable transition state (TSSR) was attributed to the
steric hindrance between the Ph group in TsDPEN molecule and the Ph
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.mcat.2018.04.019.
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groups in −SO2Ph moiety, whereas the favorable transition state (TSSS
)
has not the steric hindrance to afford the major enantiomer product 3a
that are similar to that reported by Bhanage’s group [36]. In addition,
(R)-1aa could be converted into (S)-1aa via enolization process, which
provides the possibility of DKR. To determine chiral product’s absolute
stereochemistry, compound 3a was investigated by a X–ray crystal-
lographic analysis. As shown in Scheme 2, it was found that the
276