Catalyst-free conjugate addition of thioacids to activated olefins accelerated in water

Article abstract of DOI:10.1080/00397911003587515

Michael addition of thioacetic and thiobenzoic acids to activated olefins was investigated in the presence of water under catalyst-free conditions. This process, in addition to being green, has an excellent yield. With simple filtration, high-quality products were obtained on a large scale. Competitive dithiane formation and ester cleavage were not observed. Also, excellent yield was obtained using this simple process for the final step of spironolactone synthesis.

Full text of DOI:10.1080/00397911003587515

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Catalyst-Free Conjugate Addition
of Thioacids to Activated Olefins
Accelerated in Water
Katayoun Marjani a , Maryam Khalesi a , Akram Ashouri a , Aazam
Jalali a & Azim Ziyaei-Halimehjani a
a Faculty of Chemistry, Tarbiat Moallem University, Tehran, Iran
Version of record first published: 13 Jan 2011.
To cite this article: Katayoun Marjani, Maryam Khalesi, Akram Ashouri, Aazam Jalali & Azim Ziyaei-
Halimehjani (2011): Catalyst-Free Conjugate Addition of Thioacids to Activated Olefins Accelerated
in Water, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 41:3, 451-458
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Synthetic Communications1, 41: 451–458, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003587515
CATALYST-FREE CONJUGATE ADDITION OF
THIOACIDS TO ACTIVATED OLEFINS ACCELERATED
IN WATER
Katayoun Marjani, Maryam Khalesi, Akram Ashouri,
Aazam Jalali, and Azim Ziyaei-Halimehjani
Faculty of Chemistry, Tarbiat Moallem University, Tehran, Iran
Michael addition of thioacetic and thiobenzoic acids to activated olefins was investigated in
the presence of water under catalyst-free conditions. This process, in addition to being green,
has an excellent yield. With simple filtration, high-quality products were obtained on a large
scale. Competitive dithiane formation and ester cleavage were not observed. Also, excellent
yield was obtained using this simple process for the final step of spironolactone synthesis.
Keywords: Activated olefins; Michael addition; thioacid; water
INTRODUCTION
Aqueous media is attractive for many organic reactions. Reactions in aqueous
media are generally environmentally safe, devoid of any carcinogenic effects, simple
to handle, cheaper to operate, and especially important in industry.[1] Also
catalyst-free synthesis is desirable as the tight legislations on maintaining green
chemistry in synthetic pathways and processes demand us to prevent waste, avoid
the use of hazardous auxiliary substances, and minimize energy requirements.[2]
Michael addition is one of the most important reactions in organic synthesis.
Thiols are known as good nucleophiles for the reactions.[3,4] Generally, harsh
reaction conditions are required for the conversion of the newly formed thioether
group to more synthetically versatile SH group.[5] To avoid this problem, the use
of a thioacid (RCOSH) as a nucleophile for the Michael addition is more attractive
because the resulting thioester can be readily transformed into an SH group under
mild reaction conditions.[5]
Conjugate addition of thioacids to enones has attracted considerable interest as
it leads to the synthesis of biologically active compounds such as diltiazem,[6]
thiobutacin,[7] captopril,[8] and spironolactone.[9] Usually, conjugate addition
of thioacids to activated olefins has been done in the presence of a base or using
thioacid salts in organic solvents.[10] However, there are various limitations with
the reported works such as long reaction times, use of dry organic solvents, difficulty
Received September 21, 2009.
Address correspondence to Azim Ziyaei-Halimehjani, Faculty of Chemistry, Tarbiat Moallem
University, 49 Mofatteh Street, Tehran, Iran. E-mail: ziyaei@tmu.ac.ir
451

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K. MARJANI ET AL.
in recovery of solvents especially on an industrial scale, high temperatures, use
of costly catalysts, moderate yields, and use of excess amount of thioacids. So, devel-
opment of a simple, green, and cost-effective procedure would extend the scope of
this reaction.
RESULTS AND DISCUSSION
There are a few reports in the literature on reactions catalyzed by water without
using any catalyst, such as the Michael addition of thiols to unsaturated compounds,[11]
ring opening of epoxides by amines,[12] synthesis of dithiocarbamate,[13] and N-tert-
butyloxy-carbonylation of amines.[14] Recently, we have disclosed a different
approach, with excellent yields, for the Michael addition of naphthols, amines, and
thiols to nitrostyrenes and dimethyl acetylenedicarboxylate (DMAD) in water without
use of catalysts.[15] According to our knowledge, there are no reports on the Michael
addition of thioacids to enones in water and in catalyst-free conditions. Herein, we
report the conjugate addition of thioacids to a,b-unsaturated carbonyl compounds
in water at room temperature without the use of any metal catalyst and Lewis bases,
leading to an easy, cost-effective, and highly efficient synthesis of thioester derivatives
in concurrence with the three-part philosophy of green chemistry (Scheme 1).
To show the importance of water in promoting this process, we screened the
reaction of thioacetic acid and thiobenzoic acid with chalcone in different solvents
such as methanol, ethanol, CHCl3, tetrahydrofuran (THF), dimethylformanide
(DMF), acetone and diethyl ether. As shown in Table 1, the great yield was obtained
in water, while moderate to good yields were obtained in organic solvents. Also mod-
erate yield was obtained in solvent-free conditions (Table 1, entry 6). This shows that
water can facilitate the process because of dual activation of enones and thioacids by
hydrogen bonding or more dissociation of thioacids. The same reaction was also
carried out with different equivalents of thioacids with chalcone. Only about 1.1
equivalents of thioacid are sufficient for complete conversion of chalcone to thioester.
After optimization of the reaction conditions, the efficiency of the process was
investigated with the reaction of thioacetic and thiobenzoic acids with different
a,b-unsaturated carbonyl compounds. The results are summarized in Table 2. As
shown in Table 2, the chalcone derivatives with electron-donating and electron-
withdrawing substitutions give a good yield. Excellent yields were also obtained
with cyclic a,b-unsaturated carbonyl compounds (Table 2, entry 24). Reaction of
thioacids with acrylamide derivatives affords the products with complete conversion
(Table 2, entry 26). However, cinnamaldehyde gives good yield of Michael adducts
without affecting the aldehyde group. The reaction is also applicable for heterocyclic
Scheme 1. Conjugate addition of thioacids to activated olefins.

MICHAEL ADDITION OF THIOACIDS TO OLEFINS
453
Table 1. Solvent effect on conjugate addition of thioacetic acid and thiobenzoic acid to chalcone
a,b
a,b
=
Yield (%, R CH3)
=
Yield (%, R Ph)
Entry
Solvent
1
2
3
4
5
6
7
8
9
H2O
DMF
CH3OH
100
62
88
70
55
52
70
57
78
78
73
60
66
C2H5OH
CHCl3
79
––
Solvent-free
Diethyl ether
Tetrahydrofuran
Acetone
100
83
100
aIsolated yield.
bReaction conditions: chalcone (5 mmol), thioacid (5.5 mmol), and water (10 mL).
systems (entries 20–23, Table 2). The enones containing aliphatic groups were also
converted to their thioesters with excellent yields.
In all cases, except in the case of entry 23 (Table 2), no hydrolysis of thioester
group to SH is observed in water. In this case, because of the presence of the pyridine
group in the structure of chalcone and the basicity of the aqueous solution, a
hydrolysis product was observed.
The final step in the synthesis of spironolactone 2 is the conjugate addition of
thioacetic acid to canrenone 1. To show the ability of this process for industrial
application, the reaction was carried out in water medium at room temperature
and resulted in excellent yields (Scheme 2).
We also attempted the reaction of thioacids and chalcones in a large-scale
system. The reaction proceeded well without using any organic solvents for extrac-
tion of products; filtration or decanting gives the crude products with high purity
(more than 98%).
We have described herein an efficient methodology for water-mediated conju-
gate addition of thioacids to a,b-unsaturated carbonyl compounds, providing an
easy synthesis of thioester compounds. The metal-free, catalyst-free, and nonhazar-
dous experimental conditions, room-temperature operation, ease of reaction, short
reaction times, and excellent yields of products are the advantages of this report,
especially for industrial use.
EXPERIMENTAL
Material
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 300-MHz spectrometers.

454

455

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K. MARJANI ET AL.
Scheme 2. Spironolactone synthesis in water.
General Procedure for Conjugate Addition of Thioacids to
a,b-Unsaturated Carbonyl Compounds
In a round-bottomed flask equipped with a magnetic stirrer, thioacid
(5.5 mmol), a,b-unsaturated carbonyl compound (5 mmol), and water (10 mL) were
charged. The reaction mixture was stirred vigorously at room temperature (2 h for
thioacetic acid and 15 h for thiobenzoic acid). In most of the cases, filtration of solids
in the reaction mixtures gave the crude products with excellent purity. Further puri-
fication was achieved by crystallization from ethanol or by column chromatography
(silica gel; ethyl acetate=petroleum ether; 1:5). In the case of oily products, extraction
by ethyl acetate, a wash of the organic layer with 10% aqueous NaHCO3 solution,
and evaporation of the solvent gave pure products. It is notable that on large scale
no solvent was required for extraction; only filtration of the solids or decanting of
oily products is sufficient.
Selected Spectroscopic Data
Table 2, Entry 5 (Thioacetic Acid). 1H NMR (300 MHz, CDCl3) d 7.95
3
3
(2H, d, J ¼ 7.1 Hz), 7.35–7.56 (5H, m), 7.17–7.22 (2H, m), 5.66 (1H, t, J ¼ 7.1 Hz),
3.8 (2H, d, 3J ¼ 7.2), 2.32 (3H, s) ppm. 13C NMR (300MHz, CDCl3) d 196.1,
194.1, 137.3, 136.2, 133.2, 129.9, 129.5, 128.6, 127.9, 126.8, 43.3, 40.9, 36.1 ppm.
Table 2, Entry 8 (Thiobenzoic Acid). 1H NMR (300 MHz, CDCl3) d 7.98–
8.04 (4H, m), 7.42–7.58 (8H, m), 7.16 (2H, d, 3J ¼ 8.0 Hz), 5.53 (1H, dd, 3J ¼ 8.5 and
5.9 Hz), 3.77–3.93 (2H, m), 2.35 (3H, s) ppm. 13C NMR (300 MHz, CDCl3) d 196.3,
190.6, 137.1, 136.5, 136.3, 133.3, 133.1, 128.8, 128.5, 128.3, 127.9, 127.6, 127.2, 127.1,
45.6, 43.2, 20.5 ppm.
Table 2, Entry 15 (Thioacetic Acid). 1H NMR (300 MHz, CDCl3) d 8.26
(1H, s), 8.06 (1H, d, 3J ¼ 8.2 Hz), 7.91 (2H, d, 3J ¼ 8.8 Hz), 7.77 (1H, d, 3J ¼ 7.7 Hz),
3
3
3
7.45 (1H, t, J ¼ 8.1 Hz), 6.90 (2H, d, J ¼ 8.8 Hz), 5.32 (1H, t, J ¼ 6.8 Hz), 3.84
(3H, s), 3.66 (2H, d, J ¼ 7.1 Hz), 2.31 (3H, s) ppm. 13C NMR (300 MHz, CDCl3)
3
d 194.1, 193.7, 163.7, 148.1, 143.3, 134.4, 130.4, 130.2, 129.2, 122.5, 122.2, 113.7,
55.4, 43.3, 42.5, 30.2 ppm.
Table 2, Entry 24 (Thioacetic Acid). 1H NMR (300 MHz, CDCl3) d 3.75
(1H, m), 2.60 (1H, dd, 3J ¼ 4.9 and 1.2 Hz), 2.26 (3H, s), 2.27–2.37 (3H, m),

MICHAEL ADDITION OF THIOACIDS TO OLEFINS
457
1.96–2.23 (2H, m), 1.73 (2H, m) ppm. 13C NMR (300 MHz, CDCl3) d 208.1, 194.2,
47.5, 42.7, 34.8, 29.8, 28.5, 20.8 ppm.
ACKNOWLEDGMENTS
Many thanks to the Faculty of Chemistry of Tarbiat Moallem University for
supporting this work.
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