One-pot synthesis of chiral β-hydroxysulfones from alkynes: Via aerobic oxysulfonylation and asymmetric reduction in MeOH/H2O

Article abstract of DOI:10.1039/c8gc03671c

A highly enantioselective synthesis of β-hydroxysulfones from inexpensive and readily available terminal alkynes and sodium sulfinates via a consecutive one-pot reaction in an aqueous medium under mild conditions is described. The intermediates, β-keto sulfones, generated from an aerobic oxysulfonylation of terminal alkynes and sodium sulfinates catalyzed by an iron salt in MeOH/H₂O (v : v = 3 : 1) at 50 °C, were subsequently reduced by a Ru-catalyzed asymmetric transfer hydrogenation with HCOONa as a hydrogen source. A variety of chiral β-hydroxysulfones were obtained in good yields and up to 99.9% ee values. This one-pot process could be easily scaled up for gram-scale synthesis.

Full text of DOI:10.1039/c8gc03671c

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DOI: 10.1039/C8GC03671C
Green Chemistry
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One-pot synthesis of chiral β-hydroxysulfones from alkynes via
aerobic oxysulfonylation and asymmetric reduction in MeOH/H2O
Received 00th January 20xx,
Accepted 00th January 20xx
Peng Cui, Qixing Liu, Juan Wang, Huan Liu, Haifeng Zhou*
DOI: 10.1039/x0xx00000x
A highly enantioselective synthesis of β-hydroxysulfones from inexpensive and readily available terminal alkynes and
sodium sulfinates via a consecutive one-pot reaction in an aqueous medium under mild conditions is described. The
intermediates, β-keto sulfones, generated from an aerobic oxysulfonylation of terminal alkynes and sodium sulfinates
catalyzed by an iron salt in MeOH/H2O (v:v = 3:1) at 50 ℃, were subsequently reduced by a Ru-catalyzed asymmetric
transfer hydrogenation with HCOONa as a hydrogen source. A variety of chiral β-hydroxysulfones were obtained in good
yields and up to 99.9% ee values. This one-pot process could be easily scaled up for gram-scale synthesis.
www.rsc.org/
simple and readily available materials under mild conditions is
highly desired. Very recently, a one-pot synthesis of chiral β-
Introduction
One-pot multi-step transformation is an environmentally friendly
process for the preparation of complex and high-value organic
compounds from simple, inexpensive and commercially available
raw materials.1 By this method, the desired products could be
obtained without isolation and purification of the intermediates,
minimizing production cycle and cost, saving time and resource,
as well as decreasing waste. Thus, the increasing demands for
green and sustainable synthetic process have promoted the
development of one-pot synthesis.
hydroxysulfones from α-bromoketones and sodium sulfinates has
been realized.8
Direct transformation of alkynes into alcohols is of great
significance due to the readily available starting materials as well
as the valuable products. For example, the alkynes can be
converted into alcohols by hydroboration reaction.9 In general,
the one-pot synthesis of alcohols from alkynes is still challenging
due to the incompatibility problems of the reaction conditions in
multi-step process.10 In 2013, Xiao and co-workers reported a
one-pot transformation of terminal alkynes into chiral alcohols by
hydration/asymmetric transfer hydrogenation process for the
first time.11 After that, several similar examples using bimetallic
complexes as catalysts have also been realized.12 However, the
one-pot multi-component synthesis of functionalized chiral
alcohols from alkynes is still undeveloped. Lately, our group has
developed a simple process for the one-pot transformation of
alkynes into chiral alcohols via TfOH-catalyzed hydration and Ru-
catalyzed asymmetric reduction.13 To continue our interest in
asymmetric difunctionalization of alkynes, we report a one-pot
muti-component synthesis of chiral β-hydroxysulfones from
readily available terminal alkynes and sodium sulfinates via
aerobic oxysulfonylation and consecutive asymmetric transfer
hydrogenation in an aqueous medium under mild conditions
(Scheme 1).
Chiral β-hydroxysulfones are useful synthons in organic
synthesis due to the diversification of the molecular structures
without racemisation, such as further functionalization of the α-
carbon, removal of the sulfonyl group.2 Furthermore, they have
also been used in the preparation of pharmaceutical molecules
and biologically active compounds.3 Several methods have been
developed for their preparation. Initially, the enantiomerically
enriched β-hydroxysulfones were provided by dynamic kinetic
resolution.4 Subsequently, the enantioselective borane reduction
of β-keto sulfones5 and asymmetric conjugate boration of α,β-
unsaturated sulfones6 have also been developed. Recently, the
asymmetric
hydrogenation7
and
asymmetric
transfer
hydrogenation4a have been applied to the enantioselective
reduction of β-keto sulfones. Although the above progresses
have been made, some drawbacks like high pressure conditions
and the use of sensitive chiral diphosphine ligands restrain their
practical application. Moreover, the β-keto sulfones are
commercially unavailable, which need to be synthesized in
advance. Therefore, the development of environmentally friendly
process for the preparation of chiral β-hydroxysulfones from
OH
O
S
one-pot two-step
MeOH/H2O
Ar
+
RSO2Na
Ar
R
O
O
O
S
FeCl3, O2 (air)
(S,S)-5a
Ar
R
O
HCOONa
Research Center of Green Pharmaceutical Technology and Process, Hubei Key
Laboratory of Natural Products Research and Development, College of Biological
and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002,
China.
without isolation
Scheme1. One-pot synthesis of chiral β-hydroxysulfones
E-mail: zhouhf@ctgu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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With the optimized aerobic oxysulfonylatViioewnArtriceleaOctniloinne
Results and discussion
conditions in hand, the consecutive asyDmOmI:e1t0r.i1c03r9e/dCu8cGtCio0n36w71aCs
investigated. The reaction of phenylacetylene (1a) and sodium
benzenesulfinate (2a) was chosed as a model reaction, and the
results were summarized in Table 2. When the aerobic
oxysulfonylation of 1a was completed, 2.5 mol % of chiral
ruthenium complex (S,S)-5a and 10 equivalents of HCOONa were
added to the reaction solution, then degassed three times, the
subsequent asymmetric transfer hydrogenation was carried out
at 50 ℃ for 12 h under nitrogen atmosphere. To our delight, the
aerobic oxysulfonylation and asymmetric transfer hydrogenation
are compatible in one-pot process, giving the (S)-1-phenyl-2-
(phenylsulfonyl)ethanol (4a) in 82% yield and 99.6% ee (entry 1).
Next, other chiral ruthenium complexes 5b‒5f, rhodium complex
5g, and iridium complex 5h were also screened (entries 2‒8). It
was found that (S,S)-5a provided the best results in terms of
yields and ee values. When FeCl3 was replaced by FeCl2 or FeBr3,
the same ee values but lower yields were obtained (entries 9‒10).
In order to achieve one-pot synthesis of chiral β-
hydroxysulfones from readily available alkynes and sodium
sulfinates, the key to success is to develop a compatible catalytic
system for aerobic oxysulfonylation and consecutive asymmetric
transfer hydrogenation process. Therefore, the study was begun
by developing simple conditions for aerobic oxysulfonylation of
alkynes. In 2013, Lei and co-workers reported a dioxygen-
triggered oxidative radical reaction to prepare β-keto sulfones
from terminal alkynes and excess amount of unstable, air
sensitive and commercial unavailable sulfinic acids, which is not
suitable for the sequential asymmetric reduciton.14 Subsequently,
an aerobic oxysulfonylation of alkynes with sodium sulfinates in
the presence of FeCl3/K2S2O8 to prepare β-keto sulfones was
developed by Yadav’s group.15 However, the oxidative conditions
involving K2S2O8 are incompatible with the subsequent reduction
conditions. Accordingly, the reaction conditions for the aerobic
oxysulfonylation of alkynes were optimized based on the above
15
two reports.14,
As shown in Table 1, the reaction of
Table 2. Optimization the conditions for the one-pot process a
phenylacetylene (1a) and sodium benzenesulfinate (2a) in the
presence of 20 mol % FeCl3 and 20 mol % pyridine in H2O at 25 ℃
for 16 h under air atmosphere delivered β-keto sulfone 3a in 65%
yield (entry 1). The yield of 3a remained almost unchanged if Et3N
was used instead of pyridine or in the absence of base (entries 2
and 3). Next, other parameters like temperature, solvent, and
iron salt were also screened. It was found that the yield of 3a was
increased to 79% at elevated temperature (entry 4). When a
mixture of MeOH/H2O was used as a solvent, the yields were
enhanced apparently. And the optimal ratio of MeOH/H2O is 3:1
(v/v), giving 3a in 93% yield (entries 5‒8). The other iron salts like
FeCl2 and FeBr3 provided parallel results (entries 8 and 9). No
desired product 3a was observed in the absence of iron salt
(entry 10). The optimal and simple reaction conditions for the
aerobic oxysulfonylation of alkynes were set as: 20 mol % FeCl3,
MeOH/H2O (v/v = 3:1), 50 oC, 16 h, under air atmosphere.
1. FeCl3 (20 mol %)
O
OH
O2 (air), MeOH/H2O
50 oC, 16 h
S
+
PhSO2Na
O
2. Cat. (2.5 mol %)
[H] source (10 equiv)
50 oC, 12 h
4a
2a
1a
Ts
N
SO2R
Ts
N
M
Ru
Ru
N
Cl
H2N
Cl
Cl
H2N
Ph
H2N
Ph
Ph
Ph
Ph
5g
Ph
(S,S)- : M = Rh
5b
(S,S)- : R = 4-CH3C6H4
5c
(S,S)- : R = 4-CF3C6H4
5a
(S,S)-
5h
(S,S)- : M = Ir
5d
(S,S)- : R = 3-CF3C6H4
5e
(S,S)- : R = 2-CF3C6H4
5f
(S,S)- : R = 3,4,5-FC6H2
Entry
Cat.
[H] Source
Yield (%)
Ee (%)
Table 1. Optimization the conditions for aerobic oxysulfonylation
1
2
3
4
5
6
7
8
9b
10c
11d
12d
13e
(S,S)-5a
(S,S)-5b
(S,S)-5c
(S,S)-5d
(S,S)-5e
(S,S)-5f
(S,S)-5g
(S,S)-5h
(S,S)-5a
(S,S)-5a
(S,S)-5a
(S,S)-5a
(S,S)-5a
HCOONa
HCOONa
HCOONa
HCOONa
HCOONa
HCOONa
HCOONa
HCOONa
HCOONa
82
73
62
51
47
39
53
43
72
71
<10
<10
56
99.6
89.5
83.2
63.4
39.2
29.6
65.6
89.4
99.5
99.3
94.7
79.1
89.3
O
O
S
iron salt
O2 (air)
+
PhSO2Na
O
2a
3a
1a
Tem.
(℃)
25
Iron salt
(20 mol %)
Additive
(20 mol %)
Solvent
(v/v)
Yield
(%)
Entry
1
2
3
4
5
6
7
8
9
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
FeBr3
--
pyridine
H2O
H2O
H2O
H2O
65
69
64
79
93
87
82
89
91
0
Et3N
--
--
--
--
--
--
--
--
25
25
50
50
50
50
50
50
50
HCOONa
HCOOH/Et3N (5:2)
HCOOH/Et3N (1.1:1)
HCOONa
MeOH/H2O (3:1)
MeOH/H2O (1:1)
MeOH/H2O (1:3)
MeOH/H2O (3:1)
MeOH/H2O (3:1)
MeOH/H2O (3:1)
aReaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), FeCl3 (20
mol %), MeOH/H2O (v/v = 3:1, 4 mL), under air atmosphere, 50 ℃,
16 h; then catalyst (2.5 mol %) and hydrogen source (10 equiv)
were added, degassed, 50 ℃, 12 h, under nitrogen atmosphere,
10
b
isolated yields, the ee values were determined by HPLC; FeCl2
c
d
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), iron salt (20
mol %), additive (20 mol %), solvent (4 mL), 16 h, under air
atmosphere, isolated yields.
(20 mol %) was used; FeBr3 (20 mol %) was used; The data in
the bracket are molar ratio; eH2O was used as a solvent.
Switching the hydrogen source from HCOONa to a mixture of
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HCOOH-Et3N (molar ratio = 5:2 or 1.1:1) provided 4a with less
than 10% yields (entries 11‒12). If neat water was used as a
solvent for the one-pot reaction, inferior results were provided
(entry 13). Finally, the reaction condiDtiOonI:s10i.n103e9n/Ctr8yGC103w67e1rCe
determined as the best one.
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Table 3. One-pot synthesis of chiral β-hydroxysulfones
FeCl3 (20 mol %)
O2 (air)
5a
(S,S)- (2.5 mol %)
OH
O
S
HCOONa (10 equiv)
Ar
+ RSO2Na
2
Ar
R
MeOH/H2O (v/v = 3:1)
MeOH/H2O (v/v = 3:1)
O
℃
50 , 12 h, N2
℃
50 , 16 h
1
4
Yield Ee (%
Yield Ee
(%) (%)
Entry
1
Alkyne 1
Sulfinate 2
Product 4
Entry Alkyne 1
Sulfinate 2
Product 4
(%)
)
OH
O
S
OH
O
S
PhSO2Na
PhSO2Na
O
O
82
99.6
12
13
57 99.5
47 95.1
N
N
2a
2a
1a
1l
4l
4a
F
OH
O
S
F
OH
O
S
PhSO2Na
PhSO2Na
O
O
2
3
79
74
99.8
97.1
N
S
2a
2a
N
1m
1n
4m
4b
1b
OH
O
S
OH
O
S
PhSO2Na
O
PhSO2Na
O
14
2a
56 99.6
S
2a
F
F
4n
1c
4c
OH
O
S
OH
O
S
SO2Na
O
PhSO2Na
O
4
5
6
71
72
77
97.5
97.8
99.0
15
16
17
72 95.7
77 95.5
69 99.2
H3C
CH3
2a
OCH3
OCH3
2b
1a
1a
1e
4o
1d
4d
OH
O
S
OH
O
S
SO2Na
PhSO2Na
O
O
Cl
Br
Cl
2a
Br
2c
1e
4p
4e
OH
O
S
OH
O
SO2Na
O
S
PhSO2Na
O
O2N
H3C
Br
Br
O2N
Br
CH3
2a
2b
4q
1f
4f
OH
O
S
OH
O
SO2Na
S
PhSO2Na
O
O
7
8
69
79
74
72
71
99.3
99.6
99.5
99.4
99.9
18
19
20
21
71 99.5
67 99.3
64 97.1
17 71.2
Cl
H3CO
H3CO
Br
Cl
2a
2c
1g
1e
1g
4r
OH
4g
OH
O
S
O
S
SO2Na
PhSO2Na
O
O
H3C
H3CO
H3CO
H3CO
H3C
H3CO
CH3
H3C
2a
2b
4s
OH
1h
1i
4h
OH
O
S
O
SO2Na
S
PhSO2Na
O
O
9
C2H5
Cl
H3CO
Cl
C2H5
2a
1g
1g
2c
4t
4i
OH
O
S
OH
O
S
CF3
PhSO2Na
CF3SO2Na
O
O
10
11
n-C3H7
n-C3H7
H3CO
2a
2d
1j
4j
OH
4u
O
S
PhSO2Na
O
Ph
Ph
2a
1k
4k
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), FeCl3 (20 mol %), MeOH/H2O (v/v = 3:1, 4 mL), under air atmosphere, 50 ℃, 16 h; then (S,S)-
5a (2.5 mol %) and HCOONa (10 equiv) were added, degassed, N2, 50 ℃, 12 h, isolated yields, the ee values were determined by HPLC.
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With the optimized reaction conditions in hand, the scope of
rotation was measured on a MCP-500. Melting point were
DOI: 10.1039/C8GC03671C
the one-pot synthesis of chiral β-hydroxysulfones was investigated.
As shown in Table 3, it was found that the reactions of sodium
benzenesulfinate (2a) and phenylacetylenes bearing substitutents
at 2’-, or 3’-, or 4’-position, regardless of the electron-withdrawing
(F, Br, NO2) or -donating (CH3O, CH3, C2H5, C3H7, Ph) ones, gave the
corresponding chiral β-hydroxysulfones 4a‒4k in 69‒82% yields
and 97.1‒99.9% ee values (entries 1‒11). Furthermore, the
reactions of 2a with heteroaryl alkynes, such as 2-ethynylpyridine
(1l), 3-ethynylpyridine (1m), and 2-ethynylthiophene (1n),
proceeded successfully as well. The corresponding products 4l‒4n
were obtained with excellent ee values and moderate yields
(entries 12‒14). The other sodium aryl sulfinates like sodium 4-
methylbenzenesulfinate (2b) and sodium 4-chlorobenzenesufinate
(2c) were also successfully applied in this one-pot process with
alkynes 1a, 1e, and 1g respectively, providing the corresponding β-
hydroxysulfones 4o‒4t in 64‒77% yields and 95.5‒99.5% ee values
(entries 15‒20). By contrast, the sodium alkyl sulfinate 2d
provided the β-hydroxysulfone 4u in only 17% yield and 71.2% ee
value (entry 21).
determined using X-4 made by Peking Taike Apparatus Co. Ltd.
HPLC analysis was conducted on a Waters 2489 Series instrument
with chiral column OJ-H, AD-H, AS-H and OD-H. HRMS spectra
were acquired using an Agilent 6210 ESI/TOF mass spectrometer.
Aerobic oxysulfonylation of phenylacetylene (1a)
Phenylacetylene 1a (0.2 mmol, 21 mg), sodium benzenesulfinate
2a (0.3 mmol, 49 mg), and FeCl3 (0.04 mmol, 6.5 mg) were put into
a 10 mL of glass tube, then a mixture of MeOH/H2O (4 mL, v/v =
3/1) was added. The mixture was stirred at 50 ℃ for 16 h under air
atmosphere. After the reaction was complete, 5.0 mL of H2O was
added, the mixture was extracted with ethyl acetate (3 × 10 mL).
The combined organic layer was dried over Na2SO4 and
evaporated in vacuo. The residue was purified by silica gel column
chromatography to give the product 3a (48 mg, 93% yield).
General procedure for the one-pot synthesis of chiral β-
hydroxysulfones 4
The corresponding alkyne 1 (0.2 mmol), sodium sulfinate 2 (0.3
mmol), and FeCl3 (0.04 mmol, 6.5 mg) were put into a 10 mL of
glass tube, then a mixture of MeOH/H2O (4 mL, v/v = 3/1) was
added. The mixture was stirred at 50℃ for 16 h under air
atmosphere. After the aerobic oxysulfonylation of alkyne 1 was
complete monitored by TLC, (S,S)-5a (0.005 mmol, 3.2 mg) and
HCOONa (2 mmol, 136 mg) were added, and then degassed 3
times, the mixture was stirred at 50 ℃ for 12 h under nitrogen
atmosphere. After the reaction was complete, 5.0 mL of H2O was
added, the mixture was extracted with ethyl acetate (3 × 10 mL).
The combined organic layer was dried over Na2SO4 and
evaporated in vacuo. The residue was purified by silica gel column
chromatography to give the corresponding chiral β-
hydroxysulfone 4.
To further demonstrate the practicality of this one-pot process,
a gram-scale reaction of phenylacetylene (1a; 1.02 g) and sodium
benzenesulfinate (2a; 1.97 g) was carried out, the product (S)-1-
phenyl-2-(phenylsulfonyl)ethanol (4a) was isolated in 78% yield
(2.04 g) and 98.7% ee with 2 mol % of (S,S)-5a as a catalyst and 5
equivalents of HCOONa as a hydrogen source (Scheme 2).
Scheme 2. Gram-scale synthesis of 4a
OH
O
S
One-pot process
+
PhSO2Na
O
1a
: 1.02 g
10 mmol
2a
: 1.97 g
12 mmol
4a
: 2.04 g
78% yield, 98.7% ee
Reaction conditions: phenylacetylene (1a; 1.02 g, 10 mmol), sodium
benzenesulfinate (2a; 1.97 g, 12 mmol), FeCl3 (2 mmol, 0.324 g),
MeOH/H2O (v/v = 3:1, 20 mL), under air atmosphere, 50 ℃, 16 h;
then (S,S)-5a (0.20 mmol, 131 mg), HCOONa (50 mmol, 3.4 g) were
added, degassed, under nitrogen atmosphere, 50 ℃, 12 h, isolated
yield.
Gram-scale synthesis of chiral β-hydroxysulfone 4a
Phenylacetylene 1a (10 mmol, 1.02 g), sodium benzenesulfinate
2a (12 mmol, 1.97 g), and FeCl3 (2 mmol, 324 mg) were put into a
50 mL of glass tube, then a mixture of MeOH/H2O (20mL, v/v = 3/1)
was added. After the aerobic oxysulfonylation of alkyne 1a was
complete monitored by TLC, (S,S)-5a (0.2 mmol, 131 mg) and
HCOONa (50 mmol, 3.4 g) were added, and then degassed 3 times,
the mixture was stirred at 50 ℃ for 12 h under nitrogen
atmosphere. After the reaction was complete, 20 mL of H2O was
added, the mixture was extracted with ethyl acetate (3 × 20 mL).
The combined organic layer was dried over Na2SO4 and
evaporated in vacuo. The residue was purified by silica gel column
chromatography to give chiral β-hydroxysulfone 4a (2.04 g, 78%
yield, 98.7% ee).
Conclusions
We have developed a novel, simple and compatible one-pot
synthesis of chiral β-hydroxysulfones from readily available
terminal alkynes and sodium sulfinates in an aqueous medium
under mild conditions. A variety of β-hydroxysulfones was
obtained in good yields and up to 99.9% ee values. Moreover, the
practical potential of this one-pot process was also demonstrated
by a gram-scale synthesis.
Acknowledgements
Experimental Section
We are grateful for financial support from Hubei Key Laboratory
of Natural Products Research and Development, China Three
Gorges University (NPRD 2018007), and a joint research fund from
Yichang Humanwell Pharmaceutical Co., Ltd. (SDHZ2017032).
General information
Unless otherwise noted, all reagents, catalysts and solvents were
purchased from commercial suppliers and used without further
purification. Column chromatography was performed with silica
gel (200-300 mesh). NMR spectra were recorded on Bruker
ADVANCE III (400 MHz) spectrometers. CDCl3 was the solvent used
for the NMR analysis with tetramethylsilane as the internal
standard. Chemical shifts were reported up field to TMS (0.00 ppm)
Notes and references
1 Selected reviews, see: (a) L. Albrecht, H. Jiang, K. A. Jorgensen,
Angew. Chem. Int. Ed., 2011, 50, 8492; (b) M. J. Climent, A.
1
for H NMR and relative to CDCl3 (77.0 ppm) for 13C NMR. Optical
4 | Green Chem., 2018, 00, 1-3
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DOI: 10.1039/C8GC03671C
One-pot synthesis of chiral β-hydroxysulfones from alkynes via
aerobic oxysulfonylation and asymmetric reduction in MeOH/H2O
Peng Cui, Qixing Liu, Juan Wang, Huan Liu, Haifeng Zhou*
OH
O
S
Ar
one-pot two-step
+
Ar
R
an aqueous medium
O
RSO2Na
aerobic
oxysulfonylation
asymmetric
reduction
O
O
S
Ar
R
O
21 examples
up to 99.9% ee
without isolation
gram-scale synthesis
A highly enantioselective synthesis of β-hydroxysulfones from inexpensive and
readily available alkynes via a consecutive one-pot reaction in MeOH/H2O under mild
conditions is described.