One-pot synthesis of β-hydroxysulfones and its application in the preparation of anticancer drug bicalutamide

Article abstract of DOI:10.1021/acs.joc.7b01371

An efficient one-pot multistep strategy has been developed, comprising auto-oxidative difunctionalization of alkenes, oxidation of sulfides, and a further reduction of peroxides for the synthesis of complex β-hydroxysulfone derivatives from phenthiols and alkenes. This method has several advantageous characteristics, including readily available substrates, low-cost and environmental benign reagents, nontoxic and renewable solvents, and mild reaction conditions. The application of this transformation to the multigram-scale preparation of the anticancer drug bicalutamide is accomplished.

Full text of DOI:10.1021/acs.joc.7b01371

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Note
One-Pot Synthesis of #-Hydroxysulfones and its Application
in the Preparation of Anti-cancer Drug Bicalutamide
Yajun Wang, Wei Jiang, and Congde Huo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01371 • Publication Date (Web): 06 Sep 2017
Downloaded from http://pubs.acs.org on September 7, 2017
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OneꢀPot Synthesis of βꢀHydroxysulfones and its
Application in the Preparation of Antiꢀcancer Drug
Bicalutamide
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Yajun Wang, Wei Jiang, Congde Huo*
Key Laboratory of EcoꢀEnvironmentꢀRelated Polymer Materials Ministry of Education; College
of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu
730070, China.
KEYWORDS: oneꢀpot, βꢀhydroxysulfone, bicalutamide, phenthiol, alkene
ABSTRACT: An efficient oneꢀpot multiꢀstep strategy has been developed, comprising autoꢀ
oxidative difunctionalization of alkenes, oxidation of sulfides, and a further reduction of
peroxides for the synthesis of complex βꢀhydroxysulfone derivatives from phenthiols and
alkenes. This method has several advantageous characteristics, including readily available
substrates, lowꢀcost and environmental benign reagents, nonꢀtoxic and renewable solvent and
mild reaction conditions. The application of this transformation to the multiꢀgram scale
preparation of antiꢀcancer drug bicalutamide is accomplished.
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Oneꢀpot multiꢀstep synthesis is an environmentally and economically friendly methodology for
the construction of complex and highꢀvalue compounds.1 Through this strategy, the products are
obtained without the separation and purification of intermediates, which minimizes production
cycles and cost, and saves time and resources. Thus, the increasing demands for green and
sustainable synthetic processes promote the development of the sequential oneꢀpot synthesis.
Oxidation reactions are of great importance in nature and play an important role in organic
synthesis. Following the principle of sustainable chemistry, O2 is an environmentally benign
oxidant and also an ideal oxygen source for the functionalization of organic molecules, and it has
received considerable attention in modern oxidation chemistry.2 Recently, autoꢀoxidation
involved transformations have captured growing attention from organic chemists and interesting
progress has been made.3
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Oxone is a commercially available triple salt (2:1:1 molar mixed of KHSO5, KHSO4, and
K2SO4), wherein the active oxidizing reagent is KHSO5.4 It is a white crystalline solid, which is
stable and easy to handle. In addition, it is incredibly cheap, which can compare with H2O2 and
bleach. More importantly, based on animal studies, it has a low order of toxicity when taken
internally. And the byproducts associated with oxone are generally recognized as safe.4a
Solvents are used in large quantities in the chemical industry nowadays，which define a major
part of the environmental performance of a process and also impact on cost, safety and health
issues.5 Therefore, the use of less toxic solvents is encouraged. Ethanol is considered as a green
bioꢀsolvent because it can be produced by fermentation of sugarꢀcontaining feeds, starchy feed
materials or lignocellulosic materials which are renewable resources.6
The synthesis of sulfurꢀcontaining compounds continues to be an active and challenging field
of organic chemistry.7 In particular,
βꢀhydroxysulfones are important structural motifs in
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pharmaceutical molecules and key building blocks in organic synthesis.8 Thus, the development
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of synthetic approaches for the preparation of structurally diverse βꢀhydroxysulfones is a field of
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constant interest. Traditionally,
sulfinate salts, the reduction of
β
ꢀhydroxysulfones are prepared by the opening of epoxides with
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β
ꢀoxosulfones, or the hydroxylation of α,βꢀunsaturated sulfones.9
However, these methods always produce large amounts of byproducts or require multiple steps.
Since 2013, addition of sodium sulfinates or sulfinic acids to alkenes has become a
straightforward method to construct this kind of molecules.10 But this method still has some
drawbacks: 1, the commercially available substrates are very limited. Sulfinic acids are
commercially unavailable (unstable, air sensitive) and only few sodium sulfinates are
commercially available. 2, stoichiometric amount of triphenylphosphine (PPh3) is often required
for the reduction of peroxides. Removal of the byproduct triphenylphosphine oxide (Ph3PO) is a
classical problem, always requiring tedious chromatography.11 Therefore, the development of
environmentally benign processes to access
chemicals is still highly desired.
βꢀhydroxysulfones from simple and readily available
Herein, we report the oneꢀpot synthesis of
βꢀhydroxysulfones from phenthiols and alkenes.
This new methodology of green chemistry has several advantages: wide availability of substrates,
cheap and environmental benign reagents, the use of ethanol as the sole solvent, reactions at
room temperature or under slightly heated.
At the outset, pꢀtoluenethiol (1a) and styrene (2a) were selected as the model substrates to
optimize the reaction conditions, including the reagents, solvents, and the reaction temperature.
To our delight, the oneꢀpot reaction of styrene with pꢀtoluenethiol in the presence of O2 in
ethanol as solvent at room temperature followed by addition of oxone or mCPBA as oxidant and
then workedꢀup with NaBH4 gave the desired
β
ꢀhydroxysulfone product (3aa) in excellent yield
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(Scheme 1, entries 1, 2). The structure of 3aa was confirmed using single crystal Xꢀray
diffraction as shown in Scheme 5.12 Treatment of styrene and pꢀtoluenethiol with other oxidants
such as K2S2O8, H2O2 and CH3CO3H provided no desired product (Scheme 1, entries 3ꢀ5).
Considering the environmentally safe and benign nature of Oxone, it was chosen for the further
reaction conditions screening. The reductant played a key role in the present reaction too
(Scheme 1, entries 6ꢀ11). NaBH4 was the most effective one among the tested reducing agents.
Different solvents were then evaluated, and the results showed that the reaction proceeded
optimally in ethanol (Scheme 1, entries 12ꢀ18). Screening of temperature suggested that 30oC
was the best choice for the transformation (Scheme 1, entries 19ꢀ21). Increasing the temperature
resulted in slightly lower yields. After various reaction parameters were optimized, the best
results were found to be O2 (balloon), oxone (1.1 equiv), and NaBH4 (1.1 equiv) at 30oC in
EtOH. Under these reaction conditions, a 97% yield of 3aa was obtained after 17 h (Scheme 1,
entry 19).
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Scheme 1, Screening of Reaction Conditions a
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a Standard reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), O2 (balloon), oxone (0.55 mmol),
NaBH4 (0.55 mmol), EtOH (5 mL), 30oC. b Isolated yield. c Reaction time: step 1: 5 h; step 2: 12
h; step 3: 0.1 h.
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Scheme 2 Reactions of thiophenols 1a-i with styrenes 2a-l.a, b, c
a Standard reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), O2 (balloon), oxone (0.55 mmol),
b
NaBH4 (0.55 mmol), EtOH (5 mL), 30oC. Reaction time: step 1: 4ꢀ14 h; step 2: 12 h; step 3:
c
0.1ꢀ0.5 h. Isolated yield.
Scheme 3 Reactions of thiophenols 1a-i with α,βꢀunsaturated esters/amides 2m-q. a, b, c
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a Standard reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), O2 (balloon), oxone (0.55 mmol),
b
NaBH4 (0.55 mmol), EtOH (5 mL), 30oC. Reaction time: step 1: 4ꢀ17 h; step 2: 12 h; step 3:
c
0.1ꢀ0.5 h. Isolated yield. d Reduction step is not needed.
Having optimized conditions in hand, we pursued for the exploration of substrate scope.
Phenthiols bearing either electronꢀdonating groups or electronꢀwithdrawing groups could furnish
the desired
βꢀhydroxysulfones in high yields (Scheme 2, 3aa–3ha). And the corresponding
product 3ia could be achieved in 52% yield using 2ꢀnaphthalenethiol as the substrate. On the
other hand, reacting pꢀtoluenethiol with different aryl olefins with electron donating groups or
electron withdrawing groups at the paraꢀ, metaꢀ, and orthoꢀpositions of the aryl ring all provided
corresponding products in high yields (Scheme 2, 3aa–3aj). The reactions are tolerant to fluoro,
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chloro and bromo substituents on the aromatic ring of styrenes and phenthiols, and the
corresponding target products were obtained in good to high yields (Scheme 2, 3da–3fa, 3ae-
3ai). Styrene having strong electron withdrawing group such as NO2 works smoothly to afford
the corresponding product 3aj in 76% yield. Moreover, αꢀMethylstyrene gave 85% yield of the
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corresponding tertiary βꢀhydroxysulfone 3ak .
To develop a more general and useful method, we shifted to investigate other alkene partners.
Acrylic esters and amides were selected as next research subjects due to its potential for the
synthesis of bioactive molecules. As shown in Scheme 3, again, reacting different phenthiols
bearing either electronꢀdonating groups or electronꢀwithdrawing groups with methyl
methacrylate all gave the corresponding products in good to high yields (Scheme 3, 3am–3im).
And various α,βꢀunsaturated esters and amides were effective as substrates in this system too
(Scheme 3, 3aa–3aq).
To demonstrate the practicality of this transformation, a multiꢀgramꢀscale reaction was
performed between commercially available thiophenol 1d and α,βꢀunsaturated amide 2q to
synthesize the antiꢀcancer drug bicalutamide.13 The corresponding pharmaceutical molecule 3dq
was prepared in 68% yield (2.92 g) in one pot manner (Scheme 4).
Scheme 4. Gram scale synthesis of bicalutamide in oneꢀpot manner.
To have a better understanding of this transformation, intermediate B (βꢀhydroperoxysulfone,
see: scheme 5) was isolated from the reaction mixture of 1a and 2a before NaBH4 was added.
The structure of intermediate B was identified by HRMS, HNMR and 13CNMR spectroscopy
1
and was confirmed using single crystal Xꢀray diffraction.14 Tetramethylpiperidinꢀ1ꢀoxyl
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(TEMPO), a well known radical scavenger, was added in the reaction of 1a with 2a. No desired
product was observed in the reaction. However, 2,2,6,6ꢀtetramethylꢀ1ꢀ((phenylthio)oxy)ꢀ
piperidine formed from the reaction of TEMPO and thiophenyl radical was isolated in low yield.
This result suggests that the reaction includes a radical process and is initiated by a thiyl radical
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which generated by autoꢀoxidation. On the basis of above evidence and previous work,3b
tentative mechanism for this oneꢀpot reaction of thiophenols with olefins is shown in Scheme 5.
ꢀHydroperoxysulfide intermediate was first formed through an autoꢀoxidative
difunctionalization reaction of 1a and 2a. Intermediate A was then oxidized by oxone to generate
ꢀhydroperoxysulfone intermediate B. Finally, a reductive workup by NaBH4 resulted in the
desired product βꢀhydroxysulfone 3aa.
Scheme 5. Reaction mechanism
a
β
A
β
In summary, a mild transformation for the oneꢀpot synthesis of substituted
is described. Reaction proceeds via formation of ꢀhydroperoxysulfides as versatile intermediate,
which obtained through an autoꢀoxidative difunctionalization reaction of alkenes and thiols.
Hydroperoxysulfides were then transformed to ꢀhydroperoxysulfones using oxone as a
βꢀhydroxysulfones
β
β
ꢀ
β
sustainable oxidant.
β
ꢀHydroperoxysulfones were sequentially reduced by NaBH4 to provide the
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desired
β
ꢀhydroxysulfones in high yields. All steps were carried out in oneꢀpot manner to provide
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the desired products in an efficient way. The reactions were carried out using less hazardous
ethanol as solvent under mild reaction conditions. This oneꢀpot sequential approach should
reduce the cost and waste associated with pharmaceutical synthesis.
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Experimental Section
OneꢀPot Synthesis of βꢀHydroxysulfones: Thiophenols (1, 0.5 mmol) and alkenes (2, 0.5 mmol)
o
were dissolved in ethanol (5 mL) at 30 C. The reactions were performed under oxygen
atmosphere (balloon) until substrates disappeared. Oxone (0.55 mmol) was then added. The
reactions were completed in 12 hours as monitored by TLC. Thereafter NaBH4 (0.55 mmol) was
added to the reaction mixtures, which were stirred for a few minutes. The products were isolated
by silica gel column chromatography using petroleum ether/ethyl acetate (v/v 10:1 to 3:1).
Gram scale synthesis of bicalutamide: Thiophenol 1d (1.63 ml) and alkene 2q (2.58 g) were
o
dissolved in ethanol (100 mL) at 45 C. The reaction was performed under oxygen atmosphere
(balloon) until substrates disappeared. Oxone (0.55 mmol) was then added. The reaction was
completed in 28 hours as monitored by TLC. The product 3dq were isolated by silica gel column
chromatography using petroleum ether/ethyl acetate (v/v 4:1).
Characterization of the products
1-phenyl-2-tosylethanol
（ 3aa） The desired pure product was obtained in 97% yield (134.4 mg)
as a white solid, mp 74ꢀ75 °C. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.37 (d, J
= 8.2 Hz, 2H), 7.33 – 7.25 (m, 5H), 5.24 (d, J = 10.0 Hz, 1H), 3.74 (s, 1H), 3.47 (dd, J = 14.4,
10.1 Hz, 1H), 3.31 (dd, J = 14.5, 1.7 Hz, 1H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
145.2, 140.8, 136.2, 130.1, 128.7, 128.3, 128.0, 125.7, 68.5, 64.0, 21.7. HRMS (ESI) exact mass
calcd for C15H16NaO3S [M+Na] m/z 299.0718, found 299.0712.
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2-((4-isopropylphenyl)sulfonyl)-1-phenylethanol (3ba) The desired pure product was obtained
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in 93% yield (141.5 mg) as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz,
2H), 7.43 (d, J = 8.3 Hz, 2H), 7.34 – 7.24 (m, 5H), 5.28 (d, J=10.0 Hz, 1H), 3.76 (s, 1H), 3.48
(dd, J=14.3 Hz, 10.1 Hz, 1H), 3.34 (dd, J = 14.4, 1.6 Hz, 1H), 3.06 – 2.96 (m, 1H), 1.29 (d, J =
6.9 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 155.9, 140.7, 136.4, 128.7, 128.3, 128.1, 127.6,
125.7, 68.4, 64.0, 34.3, 23.6. HRMS (ESI) exact mass calcd for C17H20NaO3S [M+Na] m/z
327.1031, found 327.1027.
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2-((4-methoxyphenyl)sulfonyl)-1-phenylethanol (3ca) The desired pure product was obtained
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in 77% yield (112.6 mg) as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz,
2H), 7.33 – 7.23 (m, 5H), 7.02 (d, J = 8.9 Hz, 2H), 5.23 (d, J = 10.1 Hz, 1H), 3.88 (s, 3H), 3.77
(d, J = 2.0 Hz, 1H), 3.46 (dd, J = 14.2, 10.2 Hz, 1H), 3.30 (d, J = 14.4 Hz, 1H). 13C NMR (151
MHz, CDCl3) δ 164.0, 140.8, 130.6, 130.2, 128.7, 128.3, 125.7, 114.7, 68.5, 64.2, 55.8. HRMS
(ESI) exact mass calcd for C15H16NaO4S [M+Na] m/z 315.0667, found 315.0666.
2-((4-fluorophenyl)sulfonyl)-1-phenylethanol (3da) The desired pure product was obtained in
1
81% yield (113.5 mg) as a colorless oil. H NMR (600 MHz, CDCl3) δ 8.00 – 7.93 (m, 2H), 7.35
– 7.22 (m, 7H), 5.28 (d, J = 9.9 Hz, 1H), 3.54 – 3.49 (m, 2H), 3.34 (dd, J = 14.5, 1.4 Hz, 1H).
13C NMR (151 MHz, CDCl3) δ 166.8, 165.1, 140.6, 135.4, 131.0, 130.9, 128.8, 128.4, 125.6,
116.8, 116.7, 68.6, 64.1. HRMS (ESI) exact mass calcd for C14H13FNaO3S [M+Na] m/z
303.0467, found 303.0470.
2-((4-chlorophenyl)sulfonyl)-1-phenylethanol (3ea) The desired pure product was obtained in
1
77% yield (114.2 mg) as a white solid, mp 106ꢀ108 °C. H NMR (600 MHz, CDCl3) δ 7.89 (d, J
= 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.35 – 7.27 (m, 5H), 5.28 (d, J = 10.0 Hz, 1H), 3.52 (dd,
J = 14.5, 10.0 Hz, 1H), 3.44 (d, J = 2.3 Hz, 1H), 3.34 (dd, J = 14.5, 1.7 Hz, 1H). 13C NMR (151
MHz, CDCl3) δ 140.9, 140.5, 137.8, 129.7, 129.5, 128.8, 128.5, 125.6, 68.6, 64.0. HRMS (ESI)
exact mass calcd for C14H13ClNaO3S [M+Na] m/z 319.0172, found 319.0171.
2-((4-bromophenyl)sulfonyl)-1-phenylethanol (3fa) The desired pure product was obtained in
1
80% yield (136.5 mg) as a white solid, mp 121ꢀ122 °C. H NMR (600 MHz, CDCl3) δ 7.81 (d, J
= 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.31 – 7.27 (m, 3H), 5.28 (d, J =
10.0 Hz, 1H), 3.52 (dd, J = 14.5, 10.0 Hz, 1H), 3.43 (d, J = 2.2 Hz, 1H), 3.34 (dd, J = 14.5, 1.8
Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 140.5, 138.4, 132.7, 129.6, 129.5, 128.8, 128.5, 125.6,
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68.6, 64.0. HRMS (ESI) exact mass calcd for C14H13BrNaO3S [M+Na] m/z 362.9667, found
362.9672.
1-phenyl-2-(phenylsulfonyl)ethanol (3ga) The desired pure product was obtained in 74% yield
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(97.4 mg) as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 7.4 Hz, 2H), 7.69 (t, J =
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7.5 Hz, 1H), 7.60 (t, J = 7.7 Hz, 2H), 7.36 – 7.26 (m, 5H), 5.28 (d, J = 10.1 Hz, 1H), 3.66 (s, 1H),
3.51 (dd, J = 14.4, 10.2 Hz, 1H), 3.35 (d, J = 14.4 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ
140.6, 139.2, 134.1, 129.5, 128.8, 128.4, 128.0, 125.6, 68.5, 64.0. HRMS (ESI) exact mass calcd
for C14H14NaO3S [M+Na] m/z 285.0561, found 285.0554.
1-phenyl-2-(m-tolylsulfonyl)ethanol (3ha) The desired pure product was obtained in 82% yield
(113.3 mg) as a colorless oil. 1H NMR (600 MHz, CDCl3) δ 7.77 – 7.73 (m, 2H), 7.50 – 7.44 (m,
2H), 7.34 – 7.25 (m, 5H), 5.27 (d, J = 10.0 Hz, 1H), 3.74 (s, 1H), 3.49 (dd, J = 14.4, 10.1 Hz,
1H), 3.34 (dd, J = 14.4, 1.6 Hz, 1H), 2.45 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 140.6, 139.8,
139.0, 134.9, 129.3, 128.7, 128.3, 128.2, 125.7, 125.1, 68.4, 63.9, 21.3. HRMS (ESI) exact
mass calcd for C15H16NaO3S [M+Na] m/z 299.0718, found 299.0723.
2-(naphthalen-2-ylsulfonyl)-1-phenylethanol (3ia) The desired pure product was obtained in
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52% yield (81.2 mg) as a white solid, mp 124ꢀ126 °C. H NMR (600 MHz, CDCl3) δ 8.54 (s,
1H), 8.05 – 7.99(m, 2H), 7.95 (d, J = 8.1 Hz, 1H), 7.91 (dd, J = 8.6, 1.8 Hz, 1H), 7.72 – 7.68 (m,
1H), 7.68 – 7.64 (m, 1H), 7.31 – 7.27 (m, 4H), 7.26 – 7.23 (m, 1H), 5.31 (d, J = 10.1 Hz, 1H),
3.72 (d, J = 2.0 Hz, 1H), 3.58 (dd, J = 14.5, 10.1 Hz, 1H), 3.43 (dd, J = 14.5, 1.7 Hz, 1H). 13C
NMR (151 MHz, CDCl3) δ 140.6, 135.9, 135.4, 132.1, 130.0, 129.9, 129.6, 129.5, 128.7, 128.3,
128.0, 127.9, 125.6, 122.4, 68.5, 64.0. HRMS (ESI) exact mass calcd for C18H16NaO3S [M+Na]
m/z 335.0718, found 335.0723.
1-(p-tolyl)-2-tosylethanol (3ab) The desired pure product was obtained in 95% yield (138.0 mg)
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as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 7.9 Hz,
2H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 5.20 (d, J = 10.1 Hz, 1H), 3.66 (s, 1H),
3.47 (dd, J = 14.4, 10.1 Hz, 1H), 3.30 (dd, J = 14.4, 1.4 Hz, 1H), 2.46 (s, 3H), 2.31 (s, 3H). 13C
NMR (151 MHz, CDCl3) δ 145.2, 138.1, 137.8, 136.2, 130.1, 129.4, 128.0, 125.6, 68.3, 64.0,
21.7, 21.1. HRMS (ESI) exact mass calcd for C16H18NaO3S [M+Na] m/z 313.0874, found
313.0867.
1-(4-(tert-butyl)phenyl)-2-tosylethanol (3ac) The desired pure product was obtained in 94%
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yield (156.3 mg) as a white solid, mp 108ꢀ110 °C. H NMR (600 MHz, CDCl3) δ 7.82 (d, J =
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8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 5.23 (d,
J = 10.0 Hz, 1H), 3.66 (s, 1H), 3.50 (dd, J=14.5, 1.8 Hz, 1H), 3.34 (dd, J = 14.5, 1.8 Hz, 1H),
2.46 (s, 3H), 1.28 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 151.3, 145.1, 137.8, 137.7, 136.3,
130.0, 128.0, 125.6, 125.4, 68.3, 63.9, 34.5, 31.3, 21.7. HRMS (ESI) exact mass calcd for
C19H24NaO3S [M+Na] m/z 355.1344, found 355.1338.
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1-(4-methoxyphenyl)-2-tosylethanol (3ad) The desired pure product was obtained in 70% yield
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(107.2 mg) as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 7.4 Hz, 2H), 7.37 (d, J
= 7.8 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 7.9 Hz, 2H), 5.19 (d, J = 10.0 Hz, 1H), 3.76
(s, 3H), 3.67 (s, 1H), 3.47 (dd, J = 14.4, 10.1 Hz, 1H), 3.29 (dd, J = 14.4, 1.6 Hz, 1H), 2.46 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 159.5, 145.2, 136.2, 132.9, 130.1, 128.0, 127.0, 114.1, 68.1,
64.0, 55.3, 21.7. HRMS (ESI) exact mass calcd for C16H18NaO4S [M+Na] m/z 329.0824, found
329.0828.
1-(4-fluorophenyl)-2-tosylethanol (3ae) The desired pure product was obtained in 80% yield
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(117.7 mg) as a white solid, mp 93ꢀ95 °C. H NMR (600 MHz, CDCl3) δ 7.84 – 7.81 (m, 2H),
7.38 (d, J = 7.6 Hz, 2H), 7.29 – 7.24 (m, 2H), 7.02 – 6.96 (m, 2H), 5.24 (d, J = 10.1 Hz, 1H),
3.82 (s, 1H), 3.44 (dd, J = 14.4, 10.1 Hz, 1H), 3.28 (dd, J = 14.4, 1.6 Hz, 1H), 2.46 (s, 3H). 13C
NMR (151 MHz, CDCl3) δ 163.3, 161.7, 145.4, 136.5, 136.5, 136.1, 130.1, 128.0, 127.5, 127.4,
115.7, 115.7, 115.5, 67.9, 64.0, 21.7. HRMS (ESI) exact mass calcd for C15H15FNaO3S [M+Na]
m/z 317.0624, found 317.0630.
1-(4-bromophenyl)-2-tosylethanol (3af) The desired pure product was obtained in 60% yield
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(106.6 mg) as a white solid, mp 110ꢀ112 °C. H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz,
2H), 7.43 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.21 (d, J=10.0
Hz, 1H), 3.84 (s, 1H), 3.43 (dd, J = 14.4, 10.0 Hz, 1H), 3.28 (dd, J = 14.4, 1.8 Hz, 1H), 2.46 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 145.4, 139.7, 136.0, 131.8, 130.1, 128.0, 127.4, 122.1, 68.0,
63.8, 21.7. HRMS (ESI) exact mass calcd for C15H15BrNaO3S [M+Na] m/z 376.9823, found
376.9814.
1-(4-chlorophenyl)-2-tosylethanol (3ag) The desired pure product was obtained in 79% yield
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(122.8 mg) as a white solid, mp 98ꢀ99 °C. H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz,
2H), 7.38 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 5.23 (d, J = 10.0
Hz, 1H), 3.83 (s, 1H), 3.42 (dd, J = 14.4, 10.0 Hz, 1H), 3.28 (dd, J = 14.4, 1.7 Hz, 1H), 2.46 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 145.4, 139.2, 136.0, 134.0, 130.1, 128.9, 128.0, 127.1, 67.8,
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63.8, 21.7. HRMS (ESI) exact mass calcd for C15H15ClNaO3S [M+Na] m/z 333.0328, found
333.0336.
1-(3-chlorophenyl)-2-tosylethanol (3ah) The desired pure product was obtained in 74% yield
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(115.1 mg) as a white solid, mp 102ꢀ104 °C. H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 7.3 Hz,
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2H), 7.38 (d, J = 7.7 Hz, 2H), 7.29 (s, 1H), 7.25 – 7.22 (m, 2H), 7.18 – 7.14 (m, 1H), 5.22 (d, J =
10.0 Hz, 1H), 3.84 (s, 1H), 3.43 (dd, J = 14.4, 10.0 Hz, 1H), 3.30 (dd, J = 14.4, 1.4 Hz, 1H), 2.46
(s, 3H). 13C NMR (151 MHz, CDCl3) δ 145.4, 142.7, 136.0, 134.6, 130.1, 130.0, 128.4, 128.0,
125.9, 123.8, 67.9, 63.8, 21.7. HRMS (ESI) exact mass calcd for C15H15ClNaO3S [M+Na] m/z
333.0328, found 333.0323.
1-(2-chlorophenyl)-2-tosylethanol (3ai) The desired pure product was obtained in 76% yield
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(118.0 mg) as a white solid, mp 116ꢀ118 °C. H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 8.1 Hz,
2H), 7.67 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.26 ꢀ 7.20 (m,
2H), 5.42 (d, J = 10.0 Hz, 1H), 4.01 (s, 1H), 3.50 (d, J = 14.5 Hz, 1H), 3.27 (dd, J = 14.6, 10.0
Hz, 1H), 2.47 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 145.3, 137.8, 135.6, 130.9, 130.1, 129.4,
129.2, 128.2, 127.4, 127.2, 65.5, 61.8, 21.7. HRMS (ESI) exact mass calcd for C15H15ClNaO3S
[M+Na] m/z 333.0328, found 333.0332.
1-(4-nitrophenyl)-2-tosylethanol (3aj) The desired pure product was obtained in 76% yield
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(122.0 mg) as a white solid, mp 131ꢀ133 °C. H NMR (600 MHz, CDCl3) 8.17 (d, J = 8.8 Hz,
2H), 7.83 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 5.39 (d, J = 9.4
Hz, 1H), 4.04 (s, 1H), 3.43 (dd, J = 14.3, 10.0 Hz, 1H), 3.32 (dd, J = 14.3, 1.8 Hz, 1H), 2.47 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 147.7, 147.7, 145.7, 135.8, 130.3, 128.0, 126.6, 123.9, 67.7,
63.6, 21.7. HRMS (ESI) exact mass calcd for C15H15NNaO5S [M+Na] m/z 344.0569, found
344.0577.
2-phenyl-1-tosylpropan-2-ol (3ak) The desired pure product was obtained in 85% yield (123.4
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mg) as a white solid, mp 83ꢀ85 °C. H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H), 7.30
ꢀ 7.27 (m,2H), 7.21 – 7.13 (m, 5H), 4.63 (s, 1H), 3.69 (d, J = 14.7 Hz, 1H), 3.59 (d, J = 14.7
Hz, 1H), 2.38 (s, 3H), 1.70 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 144.5, 137.4, 129.7, 128.2,
127.5, 127.1, 124.6, 73.1, 66.7, 30.7, 21.5. HRMS (ESI) exact mass calcd for C16H18NaO3S
[M+Na] m/z 313.0874, found 313.0869.
2-tosyl-2,3-dihydro-1H-inden-1-ol (3al) The desired pure product was obtained in 90% yield
(130.0 mg) as a white solid, mp 138ꢀ140 °C. 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz,
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2H), 7.40 (d, J = 8.1 Hz, 2H), 7.39 – 7.36 (m, 1H), 7.28 – 7.24 (m, 3H), 7.15 (d, J = 6.5 Hz, 2H),
5.79 – 5.75 (m, 1H), 3.87 – 3.82 (m, 1H), 3.28 (dd, J = 15.9, 9.3 Hz, 1H), 3.13 (dd, J = 15.9, 8.8
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Hz, 1H), 2.75 (d, J = 4.7 Hz, 1H), 2.47 (s, 3H). C NMR (151 MHz, CDCl3) δ 145.2, 141.2,
137.7, 135.3, 130.1, 129.0, 128.5, 127.7, 124.5, 124.4, 75.5, 72.9, 31.7, 21.7. HRMS (ESI) exact
mass calcd for C16H16NaO3S [M+Na] m/z 311.0718, found 311.0723.
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methyl 2-hydroxy-2-methyl-3-tosylpropanoate (3am) The desired pure product was obtained in
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75% yield (101.5 mg) as a white solid, mp 65ꢀ67 °C. H NMR (600 MHz, CDCl3) δ 7.76 (d, J =
8.2 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 3.78 (s, 3H), 3.76 (s, 1H), 3.73 (d, J = 14.6 Hz, 1H), 3.52
(d, J = 14.6 Hz, 1H), 2.43 (s, 3H), 1.44 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 174.4, 144.8,
137.6, 129.7, 128.1, 72.3, 63.9, 53.3, 27.2, 21.6. HRMS (ESI) exact mass calcd for C12H16NaO5S
[M+Na] m/z 295.0616, found 295.0609.
methyl 2-hydroxy-3-((4-isopropylphenyl)sulfonyl)-2-methylpropanoate (3bm) The desired pure
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product was obtained in 90% yield (135.2 mg) as a white solid, mp 83ꢀ84 °C. H NMR (600
MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 3.80 (s, 1H), 3.77 (s, 3H), 3.74
(d, J = 14.6 Hz, 1H), 3.53 (d, J = 14.6 Hz, 1H), 3.03 – 2.95 (m, 1H), 1.45 (s, 3H), 1.27 (d, J = 6.9
Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 174.3, 155.5, 137.8, 128.2, 127.3, 72.3, 63.9, 53.3, 34.3,
27.2, 23.6. HRMS (ESI) exact mass calcd for C14H20NaO5S [M+Na] m/z 323.0929, found
323.0937.
methyl 2-hydroxy-3-((4-methoxyphenyl)sulfonyl)-2-methylpropanoate (3cm) The desired pure
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product was obtained in 60% yield (86.5 mg) as a colorless oil. H NMR (400 MHz, CDCl3) δ
7.83 – 7.79 (m, 2H), 7.02 – 6.98 (m, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.77 (s, 1H), 3.73 (d, J =
14.7 Hz, 1H), 3.50 (d, J = 14.6 Hz, 1H), 1.44 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.4,
163.8, 132.0, 130.3, 114.3, 72.4, 64.0, 55.7, 53.3, 27.2. HRMS (ESI) exact mass calcd for
C12H16NaO6S [M+Na] m/z 311.0565, found 311.0558.
methyl 3-((4-fluorophenyl)sulfonyl)-2-hydroxy-2-methylpropanoate (3dm) The desired pure
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product was obtained in 80% yield (110.5 mg) as a white solid, mp 65ꢀ67 °C. H NMR (400
MHz, CDCl3) δ 7.94 – 7.88 (m, 2H), 7.24 – 7.18 (m, 2H), 3.83 (s, 3H), 3.76 (d, J = 14.7 Hz, 1H),
3.66 (s, 1H), 3.55 (d, J = 14.8 Hz, 1H), 1.44 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.5,
166.7, 165.0, 136.7, 136.7, 131.1, 131.1, 116.4, 116.3, 72.3, 63.9, 53.5, 27.3. HRMS (ESI) exact
mass calcd for C11H13FNaO5S [M+Na] m/z 299.0365, found 299.0375.
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methyl 3-((4-chlorophenyl)sulfonyl)-2-hydroxy-2-methylpropanoate (3em) The desired pure
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product was obtained in 78% yield (114.0 mg) as a white solid, mp 106ꢀ108 °C. H NMR (400
MHz, CDCl3) δ 7.86 – 7.82 (m, 2H), 7.55 – 7.50 (m, 2H), 3.85 (s, 3H), 3.77 (d, J = 14.8 Hz, 1H),
3.63 (s, 1H), 3.56 (d, J = 14.8 Hz, 1H), 1.45 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.5,
140.5, 139.1, 129.7, 129.4, 72.3, 63.8, 53.5, 27.3. HRMS (ESI) exact mass calcd for
C11H13ClNaO5S [M+Na] m/z 315.0070, found 315.0069.
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methyl 3-((4-bromophenyl)sulfonyl)-2-hydroxy-2-methylpropanoate (3fm) The desired pure
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product was obtained in 81% yield (136.6 mg) as a white solid, mp 118ꢀ120 °C. H NMR (400
MHz, CDCl3) δ 7.78 – 7.74 (m, 2H), 7.71 – 7.68 (m, 2H), 3.84 (s, 3H), 3.76 (d, J = 14.7 Hz, 1H),
3.62 (s, 1H), 3.55 (d, J = 14.8 Hz, 1H), 1.45 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.5,
139.7, 132.4, 129.7, 129.1, 72.3, 63.8, 53.5, 27.3. HRMS (ESI) exact mass calcd for
C11H13BrNaO5S [M+Na] m/z 358.9565, found 358.9558.
methyl 2-hydroxy-2-methyl-3-(phenylsulfonyl)propanoate (3gm) The desired pure product was
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obtained in 67% yield (86.5 mg) as a white solid, mp 72ꢀ76 °C. H NMR (400 MHz, CDCl3) δ
7.92 – 7.85 (m, 2H), 7.67 – 7.61 (m, 1H), 7.58 – 7.52 (m, 2H), 3.80 – 3.73 (m, 5H), 3.55 (d, J =
14.7 Hz, 1H), 1.45 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.3, 140.5, 133.8, 129.1, 128.0,
72.3, 63.8, 53.4, 27.2. HRMS (ESI) exact mass calcd for C11H14NaO5S [M+Na] m/z 281.0460,
found 281.0464.
methyl 2-hydroxy-2-methyl-3-(m-tolylsulfonyl)propanoate (3hm) The desired pure product was
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obtained in 85% yield (115.7 mg) as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.72 – 7.68
(m, 2H), 7.46 – 7.41 (m, 2H), 3.79 (s, 3H), 3.78 (s, 1H), 3.75 (d, J = 14.6Hz, 1H), 3.54 (d, J =
14.6 Hz, 1H), 2.45 (s, 3H), 1.46 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.3, 140.4, 139.4,
134.6, 129.0, 128.3, 125.1, 72.3, 63.8, 53.3, 27.2, 21.3. HRMS (ESI) exact mass calcd for
C12H16NaO5S [M+Na] m/z 295.0616, found 295.0607.
methyl 2-hydroxy-2-methyl-3-(naphthalen-2-ylsulfonyl)propanoate (3im) The desired pure
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product was obtained in 47% yield (72.5 mg) as a white solid, mp 102ꢀ104 °C. H NMR (600
MHz, CDCl3) δ 8.46 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 8.6,
1.8 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.64 ꢀ 7.61 (m,1H), 3.83 (d, J = 14.7 Hz, 1H), 3.79 (s, 1H),
3.76 (s, 3H), 3.63 (d, J = 14.7 Hz, 1H), 1.46 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 174.4, 137.3,
135.3, 132.0, 129.9, 129.5, 129.4, 129.4, 128.0, 127.7, 122.6, 72.4, 63.8, 53.4, 27.2. HRMS (ESI)
exact mass calcd for C15H16NaO5S [M+Na] m/z 331.0616, found 331.0624.
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allyl 2-hydroxy-2-methyl-3-tosylpropanoate (3an) The desired pure product was obtained in
86% yield (128.3 mg) as a colorless oil. 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H),
7.33 (d, J = 8.0 Hz, 2H), 5.97 – 5.90 (m, 1H), 5.35 (dd, J = 17.2, 1.3 Hz, 1H), 5.28 (dd, J = 10.4,
1.0 Hz, 1H), 4.71 (dd, J = 12.9, 6.0 Hz, 1H), 4.60 (dd, J = 12.9, 5.8 Hz, 1H), 3.78 (s, 1H), 3.75 (d,
J = 14.6 Hz, 1H), 3.53 (d, J = 14.6 Hz, 1H), 2.43 (s, 3H), 1.45 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 173.7, 144.8, 137.7, 131.3, 129.7, 128.1, 119.3, 72.4, 67.2, 63.9, 27.2, 21.6. HRMS
(ESI) exact mass calcd for C14H18NaO5S [M+Na] m/z 321.0773, found 321.0778.
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2-hydroxyethyl 2-hydroxy-2-methyl-3-tosylpropanoate (3ao) The desired pure product was
obtained in 64% yield (96.7 mg) as a colorless oil. 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.3
Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.59 – 4.53 (m, 1H), 4.24 (ddd, J = 11.5, 6.8, 2.5 Hz, 1H), 3.95
(ddd, J = 13.0, 6.8, 2.3 Hz, 1H), 3.85 (ddd, J = 13.1, 5.8, 2.5 Hz, 1H), 3.80 (d, J = 14.6 Hz, 1H),
3.55 (d, J = 14.6 Hz, 1H), 3.06 (s, 1H), 2.42 (s, 3H), 1.45 (s, 3H). 13C NMR (151 MHz, CDCl3)
δ 174.2, 145.1, 137.4, 129.8, 128.0, 72.5, 68.6, 64.1, 60.5, 27.5, 21.6. HRMS (ESI) exact mass
calcd for C13H18NaO6S [M+Na] m/z 325.0722, found 325.0720.
2-hydroxy-2-methyl-N-phenyl-3-tosylpropanamide (3ap) The desired pure product was obtained
in 78% yield (130.0 mg) as a white solid, mp 155ꢀ157 °C. 1H NMR (600 MHz, CDCl3) δ 8.68 (s,
1H), 7.72 (d, J = 8.3 Hz, 2H), 7.39 – 7.35 (m, 2H), 7.29 (t, J = 7.9 Hz, 2H), 7.19 (d, J = 8.1 Hz,
2H), 7.13 – 7.09 (t, J = 7.4 Hz, 1H), 5.17 (s, 1H), 3.99 (d, J = 14.6 Hz, 1H), 3.46 (d, J = 14.6 Hz,
1H), 2.33 (s, 3H), 1.58 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 170.2, 145.5, 137.0, 135.8, 129.9,
128.9, 128.0, 124.5, 119.5, 74.0, 61.4, 27.8, 21.6. HRMS (ESI) exact mass calcd for
C17H19NNaO4S [M+Na] m/z 356.0933, found 356.0936.
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-tosylpropanamide (3aq) The
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desired pure product was obtained in 70% yield (149.2 mg) as a white solid, mp 179ꢀ181 °C. H
NMR (600 MHz, DMSOꢀd6) δ 10.33 (s, 1H), 8.41 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.06 (d, J =
8.6 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.38 (s, 1H), 3.89 (d, J = 14.7 Hz,
1H), 3.63 (d, J = 14.8 Hz, 1H), 2.25 (s, 3H), 1.39 (s, 3H). 13C NMR (151 MHz, DMSOꢀd6) δ
173.7, 143.9, 143.2, 137.8, 136.1, 135.8, 131.5, 131.2, 131.0, 129.3, 128.1, 125.2, 123.4, 122.8,
121.6, 119.8, 117.5, 117.4, 115.8, 101.8, 73.1, 63.5, 27.2, 20.9. HRMS (ESI) exact mass calcd
for C19H17F3N2NaO4S [M+Na] m/z 449.0759, found 449.0765.
N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorophenyl)sulfonyl)-2-hydroxy-2-
methylpropanamide (3dq) The desired pure product was obtained in 74% yield (159.2 mg) as a
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white solid, mp 191ꢀ192 °C. H NMR (600 MHz, DMSOꢀd6) δ 10.36 (s, 1H), 8.42 (s, 1H), 8.21
(d, J = 8.6 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.94 – 7.90 (m, 2H), 7.37 – 7.32 (m, 2H), 6.39 (s,
1H), 3.94 (d, J = 14.9 Hz, 1H), 3.70 (d, J = 14.9 Hz, 1H), 1.40 (s, 3H). 13C NMR (151 MHz,
DMSOꢀd6) δ 173.7, 165.7, 164.0, 143.1, 137.1, 137.1, 136.2, 131.8, 131.5, 131.3, 131.1, 125.2,
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123.4, 122.9, 122.8, 121.6, 119.8, 117.6, 116.1, 115.9, 115.8, 102.0, 73.1, 63.5, 27.2. HRMS
(ESI) exact mass calcd for C18H14F4N2NaO4S [M+Na] m/z 453.0508, found 453.0501.
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1-((2-hydroperoxy-2-phenylethyl)sulfonyl)-4-methylbenzene (Intermediate B) H NMR (600
MHz, CDCl3) δ 8.79 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.35 – 7.25 (m, 7H), 5.43 (dd, J = 8.7, 3.9
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Hz, 1H), 3.86 (dd, J = 14.8, 8.9 Hz, 1H), 3.45 (dd, J = 14.7 4.0 Hz, 1H), 2.43 (s, 3H). C NMR
(151 MHz, CDCl 3) δ 145.0, 137.1, 136.3, 129.9, 129.0, 128.8, 128.2, 127.0, 81.5, 59.5, 21.6.
HRMS (ESI) exact mass calcd for C15H16NaO4S [M+Na] m/z 315.0667, found 315.0664.
Supporting Information. NMR spectra of the products and ORTEP drawing of the compound 3aa
and intermediate B
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: huocongde1978@hotmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDEGEMENT
We thank the National Natural Science Foundation of China (21562037) and the Fok Ying
Tong Education Foundation (141116) for financially supporting this work.
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