Boric acid/glycerol as an efficient catalyst for synthesis of thiomorpholine 1,1-dioxide by double michael addition reaction in water

Article abstract of DOI:10.1080/00397911.2011.594930

Thiomorpholine 1,1-dioxides were prepared with double Michael addition reaction of aromatic amines to divinyl sulfone catalyzed by boric acid/glycerol in water. This catalyst system was also used for the Michael addition reaction of aromatic amines to electron-deficient alkenes. The reaction is simple and green and gives good to excellent yields.

Full text of DOI:10.1080/00397911.2011.594930

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Boric Acid / Glycerol as an Efficient
Catalyst for Synthesis of Thiomorpholine
1,1-Dioxide by Double Michael Addition
Reaction in Water
Azim Ziyaei Halimehjnai a , Seyedmorteza Hosseyni b , Hadi Gholami
b & Mohammed M. Hashemi b
a Faculty of Chemistry, Tarbiat Moallem University, Tehran, Iran
b Department of Chemistry, Sharif University of Technology, Tehran,
Iran
Accepted author version posted online: 01 Feb 2012.Version of
record first published: 18 Oct 2012.
To cite this article: Azim Ziyaei Halimehjnai , Seyedmorteza Hosseyni , Hadi Gholami & Mohammed
M. Hashemi (2013): Boric Acid / Glycerol as an Efficient Catalyst for Synthesis of Thiomorpholine 1,1-
Dioxide by Double Michael Addition Reaction in Water, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:2, 191-197
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Synthetic Communications1, 43: 191–197, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.594930
BORIC ACID / GLYCEROL AS AN EFFICIENT CATALYST
FOR SYNTHESIS OF THIOMORPHOLINE 1,1-DIOXIDE
BY DOUBLE MICHAEL ADDITION REACTION IN WATER
Azim Ziyaei Halimehjnai,1 Seyedmorteza Hosseyni,2
Hadi Gholami,2 and Mohammed M. Hashemi2
1Faculty of Chemistry, Tarbiat Moallem University, Tehran, Iran
2Department of Chemistry, Sharif University of Technology, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract Thiomorpholine 1,1-dioxides were prepared with double Michael addition reaction
of aromatic amines to divinyl sulfone catalyzed by boric acid / glycerol in water. This cata-
lyst system was also used for the Michael addition reaction of aromatic amines to
electron-deficient alkenes. The reaction is simple and green and gives good to excellent
yields.
Keywords Aromatic amines; boric acid; Michael addition; thiomorpholine 1,1-dioxide;
water
INTRODUCTION
Synthesis of N-substituted thiomorpholine 1,1-dioxide is the key step for the
synthesis of PNU-288034 (linezolid family), which was recently targeted for clinical
development.[1] One of the most important ways to access these biologically active
compounds is the double Michael addition reaction of aniline derivatives to divinyl
sulfone. Michael addition reaction of amines to divinyl sulfone has not been fre-
quently reported. Steves et al. have reported the reaction of aniline with methyl vinyl
sulfone to give only a trace amount of the Michael addition product after 48 h.[2] The
reaction between aniline and divinyl sulfone was reported by Ford-Moore in neat
conditions to give 56% of the desired double Michael addition product, 4-
phenylthiomolpholine 1,1-dioxide.[3] Chen et al. reported good to excellent yields
Received April 17, 2011.
Address correspondence to Azim Ziyaei Halimehjnai, Faculty of Chemistry, Tarbiat Moallem
University, P. O. Box 11465-9516, Tehran 11365, Iran. E-mail: ziyaei@tmu.ac.ir
191

192
A. Z. HALIMEHJNAI ET AL.
of double Michael addition products were obtained when AlCl3 or phosphoric acid
were used as catalyst.[4]
In recent years, boric acid has gained special attention as a catalyst in organic
synthesis, because of many advantages such as excellent solubility in water, easy
handling, low cost, commercial availability, and environmentally friendliness. There-
fore, boric acid has successfully utilized in numerous reactions.[5] In addition boric
acid was used for the Michael addition of aliphatic amines in water by Chaudhuri
et al.[6] It is well known that boric acid and glycerol form a boron chelate complex
in water. Because of boron chelate complex formation and release of Hþ, this
complex is more acidic than boric acid.[7]
RESULTS AND DISCUSSION
In continuation of our research in green organic chemistry using water as the
reaction medium or performing organic transformations under solvent-free and
catalyst-free conditions,[8] herein we report an efficient, novel, and environmentally
benign procedure for the synthesis of thiomorpholine 1,1-dioxide and b-amino car-
bonyl compounds by the Michael addition reaction of aromatic amines to
electron-deficient alkenes in aqueous medium using boric acid = glycerol as catalyst.
The reaction conditions were optimized with the reaction of aniline and divinyl
sulfone as a simple model substrate by varying the solvent, the temperature, and the
equivalents of amine and divinyl sulfone and catalyst (Scheme 1). The best yield was
obtained when 3 equivalents of aniline reacted with 3 equivalents of divinyl sulfone
in the presence of 30 mol% of boric acid and two to three drops of glycerol in water
at reflux conditions. The reaction is effective only in water, and organic solvents are
not suitable for this reaction.
After optimization of the reaction conditions, the generality of these conditions
were examined using different aromatic amines. We have found that the reaction
gave good to excellent yields of the N-substituted thiomorpholine 1,1-dioxide as
the only product (Table 1). Electron-donating and electron-withdrawing groups
on the aromatic ring do not affect the reaction yields. Reaction of 1,4-phenylenedia-
mine and 1,3-phenylenediamine with divinyl sulfone gave 1,4- and 1,3-(dithiomor-
pholine 1,1-dioxide) benzene in 90% and 95% isolated yields (Table 1, entry 6 and 8).
Also the same conditions were used in the Michael addition reaction of a wide
range of aromatic amines such as aniline, p- and m-chloroaniline, p-bromoaniline,
p-and m-toluidine, and m-anisidine to different Michael acceptors such as methyl
acrylate, acrylonitrile, methylvinyl ketone, and butyl acrylate (Scheme 2). The results
are summarized in Table 2. As shown in Table 2, good to excellent yield were
obtained in all reactions. 4-Nitroaniline gave only a trace amount of products when
it was reacted with methyl acrylate. Butyl acrylate as Michael acceptor did not give
any desired products.
In conclusion, we have shown a facile, efficient, and environmentally benign
procedure for the synthesis of N-substituted thiomorpholine 1,1-dioxide in water
by using boric acid = glycerol as catalyst. Also Michael addition reaction of aromatic
amines to electron-deficient alkenes was investigated using this catalyst system in
water. This procedure avoids using toxic catalysts and solvents and can be applicable
for industrial use.

BORIC ACID / GLYCEROL AS CATALYST
193
Scheme 1. Double Michael addition of aromatic amines to divinyl sulfone.
Table 1. Double Michael addition of aromatic amines to divinyl sulfone
Entry
1
Amine
Product
Yield (%)a,b
PhNH2
95[4]
2
3
p-CH3-C6H4
m-CH3-C6H4
86
97
4
5
6
p-Cl-C6H4
p-Br-C6H4
92
90
90
p-NH2-C6H4
7
8
m-OCH3-C6H4
m-NH2-C6H4
81
95
aIsolated yield.
bReaction condition: aromatic (3 mmol), divinyl sulfome (3 mmol), boric acid (30 mol%), glycerol (2–3
drops), and water (5 mL).

194
A. Z. HALIMEHJNAI ET AL.
Scheme 2. Michael addition of aromatic amines to electron-deficient alkenes.
Table 2. Michael addition of different aromatic amines to electron-deficient alkenes
Entry
Amine
Acceptor
Yield (%)a,b,c
1
2
3
PhNH2
71[9]
88 (12)[10]
84[10]
p-Cl-C6H4NH2
p-CH3-C6H4NH2
4
PhNH2
78[9]
90[11]
63[11]
90[9]
5
p-CH3-C6H4NH2
m-OCH3-C6H4NH2
m-CH3-C6H4NH2
PhNH2
6
7
8
72[9]
9
p-CH3-C6H4NH2
p-Cl-C6H4NH2
m-CH3-C6H4NH2
m-OCH3-C6H4NH2
83[9]
10
11
12
71[12]
95[12]
64[12]
aIsolated yield.
bReaction condition: aromatic (3 mmol), electron-deficient alkenes (5 mmol), boric acid (30 mol%), (2–3
drops), and water (5 mL).
cThe yields in parentheses are for the the bis-adduct. References are given for the known compounds.
EXPERIMENTAL
All reactions were carried out in an atmosphere of air. Chemicals and solvents
were purchased from Merck and Fluka and used as received. The 1H and 13C NMR
spectra were recorded on a Brucker 500-MHz spectrometer. Chemical shifts are
reported in parts per million (ppm) relative to tetramethylsilane (TMS) or CDCl3
as internal reference.

BORIC ACID / GLYCEROL AS CATALYST
195
General Procedure for the Synthesis of N-Substituted
Thiomorpholine 1,1-Dioxide
Water (5 mL), boric acid (30 mol %), and glycerol (2–3 drops) were addedd to a
stirred solution of an aromatic amine (3 mmol) and divinyl sulfone (3 mmol). The
resulting mixture was stirred under reflux for 18 h. The reaction mixture was
extracted with ethyl acetate (3 ꢀ 10 mL), and the organic layer was washed three
times with water. After the solvent was evaporated, the crude product was pure
enough to give the satisfactory spectroscopic data. Furthur purification was achieved
with washing the precipitate with hot petroleum ether. In the case of 1,4-diamino-
benzene and 1,3-diaminobenzene, 6 mmol of divinyl sulfone was used, and the pro-
ducts were precipitated in the reaction medium and obtained by simple filtration and
1
washing. All compounds were characterized using H NMR, 13C NMR, and mass
spectroscopy.
N-(4-Methylphenyl)thiomorpholine 1,1-dioxide. Mp 116–120 ꢁC; 1H
NMR (CDCl3, 500 MHz) d (ppm) 2.30 (3H, s), 3.13 (4H, t, J ¼ 4.6 Hz), 3.85 (4H,
t, J ¼ 5.2 Hz), 6.86 (2H, d, J ¼ 8.5 Hz), 7.13 (2H, d, J ¼ 8.4 Hz); 13C NMR (CDCl3,
125 MHz) d (ppm) 20.8, 48.6, 51.0, 117.3, 130.7, 131.1, 146.1; MS (EI): m=z ¼ 225,
159, 119, 118, 91, 65, 28 (100), 27. Anal. calcd. for C11H15NO2S: C, 58.67; H,
6.67; N, 6.22. Found: C, 58.62; H, 6.84; N, 6.26.
1
N-(3-Methylphenyl)thiomorpholine 1,1-dioxide. Mp 88–91 ꢁC; H NMR
(CDCl3, 500 MHz) d (ppm) 2.36 (3H, s), 3.12 (4H, t, J ¼ 4.7 Hz), 3.86 (4H, t,
J ¼ 4.9 Hz), 6.75–6.79 (3H, m), 7.22 (1H, t, J ¼ 7.7 Hz); 13C NMR (CDCl3,
125 MHz) d (ppm) 22.3, 48.1, 51.0, 113.5, 117.6, 122.2, 129.4, 139.8, 148.1. MS
(EI): m=z ¼ 225, 159, 118 (100), 91, 65, 27. Anal. calcd. for C11H15NO2S: C, 58.67;
H, 6.67; N, 6.22. Found: C, 58.94; H, 6.75; N, 6.03.
N-(4-Chlorophenyl)thiomorpholine 1,1-dioxide. Mp 147–150 ꢁC; 1H
NMR (CDCl3, 500 MHz) d (ppm) 3.13 (4H, t, J ¼ 4.8 Hz), 3.83 (4H, t, J ¼ 5.3 Hz),
6.83 (2H, dd, J ¼ 6.8 and 2.2 Hz), 7.25 (2H, dd, J ¼ 6.7 and 2.3 Hz); 13C NMR
(CDCl3, 125 MHz) d (ppm) 48.3, 50.9, 118.2, 126.6, 130.0, 145.3; MS (EI):
m=z ¼ 247, 246, 245, 178, 137, 111, 28 (100), 27, 26.
N-(4-Bromophenyl)hiomorpholine 1,1-dioxide. Mp 190–193 ꢁC; 1H
NMR (CDCl3, 500 MHz) d (ppm) 3.13 (4H, t, J ¼ 4.7 Hz), 3.85 (4H, t, J ¼ 5.4 Hz),
6.82 (2H, dd, J ¼ 6.8 and 2.2 Hz), 7.43 (2H, dd, J ¼ 6.8 and 2.2 Hz); 13C NMR
(CDCl3, 125 MHz) d (ppm) 48.1, 50.6, 113.6, 118.5, 133.0, 147.2; MS (EI):
m=z ¼ 291, 289, 225, 223, 184, 117 (100), 89, 75, 28, 27. Anal. calcd. for
C10H12BrNO2S: C, 41.39; H, 4.17; N, 4.83. Found: C, 41.96; H, 4.33; N, 4.58.
1,4-(Dithiomorpholine 1,1-dioxide)benzene. Decomposed at more than
250 ꢁC;=1H NMR (DMSO-d6, 500 MHz) d (ppm) 3.14 (8H, t, J ¼ 4.5 Hz), 3.76
(8H, t, J ¼ 4.7 Hz), 6.90 (4H, s); 13C NMR (DMSO-d6, 125 MHz) d (ppm) 49.8,
50.9, 114.3, 142.8; MS (EI): m=z ¼ 344, 224, 143, 132, 129 (100), 116, 102, 90, 28.
Anal. calcd. for C14H20N2O4S2: C, 48.82; H, 5.85; N, 8.13. Found: C, 48.56; H,
6.04; N, 7.84.

196
A. Z. HALIMEHJNAI ET AL.
N-(3-Methoxyphenyl)thiomorpholine 1,1-dioxide. 1H NMR (CDCl3,
500 MHz) d (ppm) 3.07 (4H, t, J ¼ 4.7 Hz), 3.76–3.84 (7H, m), 6.43–6.53 (3H, m),
7.23 (1H, m); 13C NMR (CDCl3, 125 MHz) d (ppm) 47.8, 50.8, 55.7, 103.4, 105.5,
109.2, 130.9, 143.2, 161.4; MS (EI): m=z ¼ 241, 134, 92, 77, 65, 28 (100), 26, 15. Anal.
calcd. for C11H15NO3S: C, 54.75; H, 6.27; N, 5.80. Found: C, 54.53; H, 6.44; N, 5.71.
1,3-(Dithiomorpholine 1,1-dioxide)benzene. Decomposed at more than
219 ꢁC; 1H NMR (DMSO-d6, 500 MHz) d (ppm) 3.05 (8H, t, J ¼ 4.7 Hz), 3.70
(8H, t, J ¼ 4.9 Hz), 6.26–6.44 (3H, m), 7.10 (1H, t, J ¼ 8.1 Hz); 13C NMR (DMSO-d6,
125 MHz) d (ppm) 47.7, 50.8, 104.5, 108.2, 130.9, 149.8; MS (EI): m=z ¼ 344, 143,
130, 129 (100), 116, 102, 90, 28. Anal. calcd. for C14H20N2O4S2: C, 48.82; H, 5.85;
N, 8.13. Found: C, 48.45; H, 5.95; N, 7.85.
General Procedure for the Aza-Michael Addition Reaction
Water (5 mL), boric acid (30 mol%), and glycerol (2–3 drops) were added to a
stirred solution of an amine (3 mmol) and an electron-deficient alkene (5 mmol). The
resulting mixture was stirred under reflux for 18 h. The reaction mixture was
extracted with ethyl acetate (3 ꢀ 10 mL). After the solvent was evaporated, the crude
product was purified by flash column chromatography to provide the pure products.
All compounds are known and were characterized on the basis of their spectroscopic
data (1H NMR and 13C NMR) and by comparison with those reported in the
literature.
ACKNOWLEDGMENTS
We are grateful to the Research Council of Sharif University of Technology
for financial support. We also thank the Faculty of Chemistry of Tarbiat Moallem
University for supporting this work.
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