Three-component reaction of β-ketosulfone, formaldehyde, and thiol or thiophenol in water

Article abstract of DOI:10.1080/10426507.2012.657505

A three-component reaction of β-ketosulfone, formaldehyde, and thiol or thiophenol was developed. The reaction was performed in pure water under a catalyst-free condition, and the corresponding Mannich-type thioethers were obtained in good to excellent yields. Finally, a one-pot stepwise four-component reaction of sodium benzenesulfinate, α-bromoketone, β-ketosulfone, and thiophenol was also developed. Copyright

Full text of DOI:10.1080/10426507.2012.657505

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Phosphorus, Sulfur, and Silicon and the
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Three-Component Reaction of β-
Ketosulfone, Formaldehyde, and Thiol or
Thiophenol in Water
Yuying Du a , Fuli Tian b , Limin Han a & Ning Zhu a
a Chemical Engineering College, Inner Mongolia University of
Technology, Hohhot, PR China
b Department of Chemestry, College of Chemistry and Chemical
Engineering, Inner Mongolia University, Hohhot, PR China
Accepted author version posted online: 31 Jan 2012.Version of
record first published: 19 Jun 2012.
To cite this article: Yuying Du , Fuli Tian , Limin Han & Ning Zhu (2012): Three-Component Reaction
of β-Ketosulfone, Formaldehyde, and Thiol or Thiophenol in Water, Phosphorus, Sulfur, and Silicon and
the Related Elements, 187:9, 1011-1016
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Phosphorus, Sulfur, and Silicon, 187:1011–1016, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.657505
THREE-COMPONENT REACTION OF β-KETOSULFONE,
FORMALDEHYDE, AND THIOL OR THIOPHENOL
IN WATER
Yuying Du,1 Fuli Tian,2 Limin Han,1 and Ning Zhu1
1Chemical Engineering College, Inner Mongolia University of Technology,
Hohhot, PR China
2Department of Chemestry, College of Chemistry and Chemical Engineering,
Inner Mongolia University, Hohhot, PR China
GRAPHICAL ABSTRACT
Abstract A three-component reaction of β-ketosulfone, formaldehyde, and thiol or thiophenol
was developed. The reaction was performed in pure water under a catalyst-free condition, and
the corresponding Mannich-type thioethers were obtained in good to excellent yields. Finally,
a one-pot stepwise four-component reaction of sodium benzenesulfinate, α-bromoketone, β-
ketosulfone, and thiophenol was also developed.
Keywords β-Ketosulfone; mannich reaction; organic reaction in water; three-component
reaction
INTRODUCTION
In 1980, Breslow discovered that the Diels–Alder reaction performed in water can
be subject to huge rate accelerations.1 Since then, organic reactions in water have attracted
Received 5 December 2011; accepted 7 January 2012.
The authors are thankful to the Fund of Inner Mongolia Natural Science Foundation for the financial
support (No. 2010MS0211). The Science Research Foundation of Inner Mongolia University of Technology
(No. X200812) is highly acknowledged.
Address correspondence to Fuli Tian, Department of Chemestry, College of Chemistry and Chemical
Engineering, Inner Mongolia University, Hohhot 010021, PR China. E-mail: bmc2007xlht@yahoo.com.cn
1011

1012
Y. DU ET AL.
considerable interest in recent times because of their environmental acceptability and unique
reactivity that cannot be attained in conventional organic solvents.2 On the other hand,
the ever increasing demand for novel medicinally active compounds and the laborious
process of lead discovery and optimization have resulted in the continuous search for
simple and efficient methods for generation of libraries for biological screening. In this
context, multicomponent reactions are a promising tool for synthetic chemists, since they
allow complicated molecules to be created using one reaction in a fast, efficient, and
timesaving manner.3 Particularly, multicomponent reactions in water have gained much
attention because of their green characteristics in meeting the sustainability requirements
of current organic synthesis.4 Although some promising results were obtained in this field,
in order to further improve the synthetic efficiency and extend the applicability of water
solvent, new examples of water-mediated multicomponent reactions that enable selective
formation of complex molecules from simple substrates are still appealingly needed.
β-Ketosulfones are active C H acids, and have been widely used in many organic
transformations.5 However, multicomponent reactions by using a β-ketosulfone as a nucle-
ophile have been rarely investigated.6 Because C H acids are generally very active in the
electrophilic alkylation of an aldehyde, it is conceivable that a β-ketosulfone should also be
a viable nucleophile in this type of reaction. Recently, electrophilic reactions of an aldehyde
with two kinds of nucleophiles have frequently been considered as an effective method for
developing three-component reactions.7 In view of the high reactivity of β-ketosulfones,
we envisaged that, under suitable conditions, β-ketosulfones might be good nucleophiles
to react with aldehyde and another nucleophile, accomplishing a new three-component re-
action. Herein, we wish to report our preliminary results on this topic. A three-component
reaction of formaldehyde, β-ketosulfone, and thiol or thiophenol will be presented in this
communication, which provides a specific class of thioethers in good to excellent yields.
Particularly, the reaction was performed in pure water without the use of any catalyst.
RESULTS AND DISCUSSION
Initially, a three-component reaction of β-ketosulfone 1a, formaldehyde, and thio-
phenol 2a was investigated. As shown in Table 1, when formalin was used as source of
formaldehyde, the reaction proceeded very well in water, and a thioether 3a was obtained
in 90% of yield after 10 h of reaction at 90 ◦C (entry 1). Paraformaldehyde that is a solid
at room temperature can also be used in this system, but the yield is inferior as compared
with formalin (entry 2). Another form of formaldehyde, 1,3,5-trioxane, was also examined,
however, only a trace amount of 3a was obtained (entry 3). Further investigation revealed
that the reaction was also affected by reaction time and temperature, and the optimal condi-
tion was found to be 10 h and 90 ◦C (entries 4 and 5). The solvent also played an important
role in this reaction. Addition of some extra amount of water into the system was proved to
be helpful for improving the reaction yield (entry 6). Replacement of water with ethanol,
acetonitrile, and 1,4-dioxane results in an appreciable decrease of the reaction yield (entries
7 to 9). In order to check the applicability of our reaction in practical synthesis, the reaction
was then performed in a large scale, i.e., 10 mmol. As we expected, the yield of 3a remains
unchanged (entry 10), and therefore, the presented reaction herein is, indeed, valuable for
organic synthesis.
The substrate scope with respect to both thiophenol and β-ketosulfone was then ex-
amined. As shown in Table 2, when 1a was used as substrate, various thiophenols and thiols

THREE-COMPONENT MANNICH REACTION IN WATER
1013
Table 1 Three-component reaction of 1a with 2a and formaldehyde in different solventsa
Entry
Formaldehyde form
Solvent
water
water
water
water
water
water
ethanol
CH3CN
1,4-dioxane
water
Time (h)
Temperature (◦C)
Yield (%)
1
2
3
4
5
6b
7
8
HCHO aqu. (37%)
(HCHO)n
(HCHO)3
HCHO aqu. (37%)
HCHO aqu. (37%)
HCHO aqu. (37%)
HCHO aqu. (37%)
HCHO aqu. (37%)
HCHO aqu. (37%)
HCHO aqu. (37%)
10
10
10
6
10
10
10
10
10
10
90
90
90
90
70
90
90
90
90
90
90
78
trace
70
61
77
82
68
59
90
9
10c
aSolvent: 1.0 mL, 1a: 1.0 mmol, 2a: 1.0 mmol, formaldehyde: 1.0 mmol; bNo extra water solvent was added;
cThe reaction scale: 10 mmol.
could be used in the three-component reaction, and the corresponding thioethers were ob-
tained in generally high yields. The scope of the reaction with respect to β-ketosulfone was
next investigated and also found to be excellent. As Table 3 illustrates, many β-ketosulfones
could be employed without significantly affecting the yield of the three-component reaction
with 2a and formalin. Particularly, β-ketosulfones containing sulfur- or oxygen-heterocycle
functionalities were also applied in the reaction uneventfully (entries 7 and 8). It should
be noted that synthesis of 3a-type thioethers has been rarely investigated before. The
only available method was reported by Yamauchi,8 who utilized N-(methylthiomethyl)
piperidine-HCl salt as a methylthiomethylation reagent of β-ketosulfone. Obviously, our
method showed a clear advantage in terms of using cheap and easily available material as
substrate and avoiding the generation of waste.
The model three-component reactions might proceed through a cascade reaction
pathway involving (i) a Knovenagel reaction between 1a and formaldehyde that was known
to be preferably performed in water,9 which provides an α-methylene-β-ketosulfone (I, see
Table 2 Three-component reactions of 1a with formalin and thiophenol or thiol in watera
Entry
Thiophenol or thiol
4-methoxythiophenol
4-chlorothiophenol
2-methylthiophenol
2-methoxythiophenol
3,5-dimethylthiophenol
benzylthiol
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
2b
2c
2d
2e
2f
3b
3c
3d
3e
3f
10
10
10
10
10
12
18
91
86
92
91
93
95
87
2g
2h
3g
3h
cyclohexylthiol
aWater: 1.0 mL, 2a: 1.0 mmol, HCHO: 1.0 mmol, thiol or thiophenol: 1.0 mmol.

1014
Y. DU ET AL.
Table 3 Substrate scope for β-ketosulfonesa
Entry
β-ketosulfone
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
1i
1j
1k
1l
1m
1n
1o
1p
3i
3j
3k
3l
3m
3n
3o
3p
10
12
10
18
10
10
24
24
93
95
92
90
86
91
88
94
aAcetonitrile: 1.0 mL, indole: 1.0 mmol, α,β-unsaturated compound: 1.0 mmol.
Table 1); and (ii) Michael addition of thiophenol to the intermediate (I) to form 3a. It is
well known that β-ketosulfone could be obtained by a reaction of sodium benzenesulfinate
and α-bromoketone.10 In view of the fact that this is a typical SN2-type reaction, we
envisaged that the condition of the synthesis of β-ketosulfones might be compatible with
the present three-component reaction. We, thus, investigated the feasibility of preparing 3a
from sodium benzenesulfinate and α-bromoketone. As shown in Scheme 1, 1a was initially
prepared in an ionic liquid, [BMIm]BF4, from 4a and 5a. By monitoring the reaction with
TLC, we are able to know the end of the first reaction. When the other materials including
forma◦lin, 2a and water were added into the reaction system, after 10 hours of reaction
at 90 C, 3a was obtained in 84% of yield. After removal of all the organic components
by extraction with ethyl acetate, the recovered aqueous solution was then subjected to a
vacuum condition (10 mmHg). After 30 min of treatment at 80 ◦C, [BMIm]BF4 could be
recovered quantitatively. In a reaction with the recovered ionic liquid, 85% of yield was
obtained, indicating the good performance of [BMIm]BF4.
O
S
O
HCHO (aqu. 1.0 equiv)
2a (1.0 equiv)
water, 90 oC, 10 h
Br
ONa +
1a
3a
[BMIm]BF4, 80 oC,
6 h
4a
5a
no isolation
yield = 84%
[BMIm]BF4 was used in the second run: yield = 85%
Scheme 1 One-pot stepwise synthesis of 3a from 4a and 5a.
In conclusion, a three-component reaction of β-ketosulfone, formaldehyde, and thio-
phenol or thiol in water was developed. Many substrates could be used in these reactions,
and the corresponding products were obtained in good to excellent yields. This reaction was
found to be compatible with the synthesis of β-ketosulfones from sodium benzenesulfinate

THREE-COMPONENT MANNICH REACTION IN WATER
1015
and α-bromoketones. Thus, a one-pot stepwise reaction of 4a, 5a, formaldehyde, and 2a
was then developed successfully.
EXPERIMENTAL
All reagents were obtained from commercial suppliers and used without further
purification. All melting points were determined uncorrected. NMR spectra were mea-
sured using a Bruker AV400 Avance spectrometer at 400.13 MHz (1H) and 100.62 MHz
(13C), respectively. Chemical shifts were reported in ppm relative to TMS in CDCl3.
IR spectra were recorded on a Nicolet6700 FT spectrometer in KBr with absorptions
in cm−1
.
General Procedure
All reactions were conducted in a 10 mL U-type tube equipped with magnetic stirring.
In a typical reaction, 1a (260.0 mg, 1.0 mmol) and 2a (110.0 mg, 1.0 mmol) were mixed
with formalin (37 wt%, 81.0 mg, 1.0 mmol) and water (1.0 mL) under air. The mixture
◦
was then heated at 90 C for 10 h. After the reaction, the mixture was cooled to room
temperature, and then extracted with ethyl acetate (4.0 mL × 3). The obtained organic
phase was then combined and dried with anhydrous Na2SO4. After concentration, the
solution was subjected to isolation with preparative TLC. The desired product 3a was
obtained in 90% of yield (344.0 mg).
Selected Spectroscopic Data of New Compounds
1-Phenyl-2-(phenylsulfonyl)-3-(phenylthio)propan-1-one (3a): Yellow solid, mp:
80–81 ◦C; 1H NMR: 3.47 (dd, Ja = 11.2 Hz, Jb = 13.6 Hz, 1H), 3.69 (dd, Ja = 2.8 Hz, Jb =
13.2 Hz, 1H), 5.22 (dd, Ja = 2.8 Hz, Jb = 11.2 Hz, 1H), 7.18–7.29 (m, 5H), 7.42 (t, J =
7.6 Hz, 2H), 7.50 (t, J = 8.0 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H),
7.70–7.79 (m, 4H); 13C NMR: 31.4, 68.5, 127.7, 128.7, 129.1, 129.3, 129.4, 129.7, 130.9,
133.4, 134.3, 134.7, 136.3, 137.2, 191.4; IR: 3077, 2928, 1686, 1584, 1482, 1442, 1413,
1331, 1308, 1211, 1132, 1054, 1020, 998, 915, 834, 764, 734; HRMS m/z (ESI) calcd. for
C21H18NaO3S2 [M + Na]+ 405. 0595 found 405.0588.
2-(Phenylsulfonyl)-3-(phenylthio)-1-(thiophen-2-yl)propan-1-one (3o): Yellow
liquid; 1H NMR: 3.41 (dd, Ja = 11.6 Hz, Jb = 13.6 Hz, 1H), 3.66 (dd, Ja = 2.8 Hz, Jb =
13.2 Hz, 1H), 4.92 (dd, Ja = 2.8 Hz, Jb = 11.6 Hz, 1H), 7.04 (dd, Ja = 3.2 Hz, Jb = 4.8
Hz, 1H), 7.20–7.28 (m, 5H), 7.44–7.54 (m, 3H), 7.64 (tt, Ja = 1.2 Hz, Jb = 7.6 Hz, 1H),
7.71 (dd, Ja = 1.2 Hz, Jb = 4.8 Hz, 1H), 7.76 (dd, Ja = 1.2 Hz, Jb = 8.0 Hz, 2H); 13C
NMR: 31.1, 70.9, 127.4, 128.7, 129.2, 129.4, 129.8, 130.8, 133.1, 134.5, 134.6, 136.2,
136.3, 144.5, 182.8; IR: 3099, 2930, 1721, 1657, 1581, 1514, 1474, 1448, 1412, 1353,
1271, 1244, 1155, 1087, 846, 821, 738; HRMS m/z (ESI) calcd. for C19H16NaO3S3 [M +
Na]+ 411.0159 found 411.0150.
Supplementary Data
Selected data for products 3b–3p are available. Supplementary data associated with
this article can be found in the online version.

1016
Y. DU ET AL.
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