An efficient FeCl3-catalyzed condensation of thiols with 1,3-dicarbonyl compounds under solvent-free conditions

Article abstract of DOI:10.1055/s-0033-1340054

A practical and environmentally friendly method has been developed for the synthesis of thiol-substituted cyclohex-2-enones using a FeCl ₃-catalyzed condensation of cyclic 1,3-dicarbonyl compounds and aromatic/aliphatic thiols under solvent-fre

Full text of DOI:10.1055/s-0033-1340054

LETTER
▌213
lAettner Efficient FeCl3-Catalyzed Condensation of Thiols with 1,3-Dicarbonyl
Compounds under Solvent-Free Conditions
FeCl3-Catalyzed Condensation of Thiols with 1,3-Dicarbonyl Compounds
Kumkum Kumari, Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Faculty of Science, Banaras Hindu University, Varanasi-221005, India
Fax +91(542)2368127; E-mail: knsinghbhu@yahoo.co.in; E-mail: knsingh@bhu.ac.in
Received: 07.09.2013; Accepted after revision: 30.09.2013
work in an open vessel, circumventing the risk of pressure
build up in a closed system.
Abstract: A practical and environmentally friendly method has
been developed for the synthesis of thiol-substituted cyclohex-2-
enones using a FeCl3-catalyzed condensation of cyclic 1,3-dicar-
bonyl compounds and aromatic/aliphatic thiols under solvent-free
conditions at ambient temperature.
In view of the above and as a part of our ongoing research
program,13 we report herein a rapid and solvent-free anhy-
drous FeCl3-catalyzed condensation of thiols and 1,3-di-
ones to afford thiol-substituted cyclohex-2-enones in
excellent yields (Scheme 1). In this regard, it is important
to note that 3-substituted 5,5-dimethylcyclohex-2-ene-1-
ones constitute an important class of agrochemicals.14
Further, there exists only one report for their synthesis in-
volving the solitary reaction of 4-methoxybenzyl mer-
captan with cyclohexan-1,3-dione in acetonitrile using
gold(III) catalysis.15
Key words: condensation, thiols, green chemistry, Lewis acids,
iron
Organosulfur compounds represent an important class of
bioactive organic molecules and have been widely used as
pharmaceuticals, functional materials, and synthetic inter-
mediates.1 Indeed, a number of drugs in therapeutic areas
such as inflammatory, diabetes,2 cancer,3 HIV,4 and neu-
rodegenerative (Alzheimer’s and Parkinson’s) diseases5
contain a sulfide functional moiety. Due to their broad
spectrum of pharmaceutical activity, organosulfur com-
pounds have triggered ever-increasing attention in the
synthetic and medicinal chemistry areas. Thiols, being the
simplest organic sulfur compounds, are not only manifest-
ed in natural products, but are also utilized in the synthesis
of valuable organosulfur compounds.6,7
Table 1 Optimization of Reaction Conditions for 3aa
SH
O
S
EtO
+
O
O
O
1a
2a
3a
4a
Entry
Catalyst (mol%)
Solvent
Yield (%)
The exploration of transition-metal catalysts for the con-
struction of carbon–sulfur bonds is of widespread interest
due to the growing need for versatile, mild, and selective
methods.8 However, in comparison to C–N and C–O bond
formation, the transition-metal-catalyzed construction of
C–S bond has been less studied due to the deactivation of
metal catalysts by the strongly coordinating sulfur com-
pounds.9 In recent years, iron-based catalysts have risen
notably in popularity for promotion of a wide range of or-
ganic transformations.10 The continued need for environ-
mentally benign organic transformations has also focused
on the replacement of volatile organic reaction media,
leading to the development of solvent-free reactions.11
Solvent-free conditions have many advantages12 and are
especially appealing as they provide the opportunity to
1
2
–
–
–
Zn(L-proline)2 (20)
CAN (20)
PTSA (20)
AlCl3 (20)
FeCl3 (20)
FeCl2·4H2O (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (15)
FeCl3 (10)
–
19
28
51
75
80
–
3
–
4
–
5
–
6
–
7
–
8
benzene
MeCN
DMF
1,4-dioxane
CH2Cl2
H2O
68
60
50
65
69
50
n.r.b
81
71
9
10
11
12
13
14
15
16
O
O
O
FeCl3
R2 SH
+
R1
R1
R1
R1
R2
R1
R1
r.t. to 50 °C
solvent-free
O
OH
S
EtOH
–
Scheme 1 Synthesis of thiol-substituted cyclohex-2-enones
–
SYNLETT 2014, 25, 0213–0216
Advanced online publication: 08.11.2013
DOI: 10.1055/s-0033-1340054; Art ID: ST-2013-D0865-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
a Conditions: 1a (1.2 mmol), 2a (1 mmol), r.t., 5 h.
b Compound 4a formed; n.r. = no reaction.

214
K. Kumari, K. N. Singh
LETTER
In a preliminary trial, a model reaction using thiophenol solvent-free conditions. When ethanol was used as a sol-
1a and dimedone 2a was carried out without a catalyst un- vent, it reacted preferentially to form product 4a. In terms
der solvent-free conditions at room temperature, which of catalyst concentration, 15 mol% of FeCl3 were found
led to no coupled product (Table 1, entry 1). The reaction sufficient to bring about the highest conversion (Table 1,
was then examined using various catalysts under the same entry 15), as the reaction remained incomplete when 10
conditions (Table 1, entries 2–7). Poor conversions were mol% of the catalyst was used (Table 1, entry 16).
observed using Zn(L-proline)2 and ceric ammonium
nitrate (CAN) (Table 1, entries 2 and 3). The use of
Brønsted acid (PTSA) produced the coupled product in
Having the optimized conditions in hand, the scope of the
reaction was extended using a variety of thiols 1 and 1,3-di-
ones 2, and the outcome is summarized in Table 2. It is evi-
somewhat moderate yield (Table 1, entry 4). The best re-
dent that both the aromatic as well as aliphatic thiols
sults were, however, obtained when Lewis acids were
participate well in the reaction. However, when 2-mercapto-
used as catalyst; AlCl3 and FeCl3 produced the condensa-
benzothiazole (1g) was employed, it did not work at all (Ta-
ble 2, entry 7) probably due to the lower nucleophilicity of
the thiol. With reference to the reactivity of cyclic-1,3-di-
ones, cyclohexan-1,3-dione (2b) afforded higher yields in
tion product 3a in 75% and 80% yields, respectively (Ta-
ble 1, entries 5 and 6), although no product was observed
when FeCl2·4H2O was used as catalyst (Table 1, entry 7).
Consequently, FeCl3 was chosen as the best catalyst to
general compared to 2a. Other active methylene compounds
carry out further studies. To explore the effect of solvent,
viz. acetylacetone and Meldrum’s acid were also tried but
the model reaction was studied in different solvents using
they did not react (Table 2, entries 14 and 15).
20 mol% of FeCl3 at room temperature (Table 1, entries
8–14), but none of them could match the efficacy of the
Table 2 Reaction of Various Thiols with 1,3-Diones16
Entry
Thiol
1,3-Dione
Product
Time (h)
Yield (%)a
S
O
SH
1
5
81
O
O
1a
3a
3b
2a
S
O
SH
2
3
4
5
5
5
85
O
O
1b
2a
S
O
MeO
SH
MeO
87
O
O
1c
3c
2a
S
O
Cl
SH
80b
Cl
O
O
1d
3d
2a
S
O
SH
5
6
4
4
97
81
O
O
1e
2a
3e
O
S
O
SH
O
O
O
1f
2a
3f
Synlett 2014, 25, 213–216
© Georg Thieme Verlag Stuttgart · New York

LETTER
FeCl3-Catalyzed Condensation of Thiols with 1,3-Dicarbonyl Compounds
215
Table 2 Reaction of Various Thiols with 1,3-Diones16 (continued)
Entry
7
Thiol
1,3-Dione
Product
Time (h)
Yield (%)a
O
S
N
S
SH
8
nrc
N
S
O
O
1g
1a
3g
2a
O
S
SH
8
9
4
4
4
4
80
88
89
90b
O
O
2b
3h
3i
O
S
SH
O
O
1b
2b
O
S
MeO
SH
MeO
10
11
O
O
1c
2b
3j
S
O
Cl
SH
Cl
O
O
1d
2b
3k
O
S
SH
12
3.5
3.5
96
92
O
O
1e
2b
3l
O
S
O
SH
O
13
14
O
O
1f
2b
3m
3n
S
O
O
SH
n.r.c
n.r.c
O
O
8
8
1a
1a
2c
O
O
O
SH
15
O
O
S
O
2d
3o
a Isolated yield.
b Reaction at 50 °C.
c n.r. = no reaction.
In conclusion, we have developed an efficient and mild substituted cyclohex-2-enones in excellent yields. The
protocol for the condensation of 1,3-dicarbonyl com- procedure uses FeCl3 as catalyst under solvent-free condi-
pounds with thiols (aliphatic and aromatic) to afford thiol- tions and may serve as a practical alternative to the exist-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 213–216

216
K. Kumari, K. N. Singh
LETTER
(10) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2008,
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Acknowledgment
We are thankful to the Department of Biotechnology, New Delhi for
financial assistance.
(13) (a) Singh, R.; Raghuvanshi, D. S.; Singh, K. N. Org. Lett.
2013, 15, 4202. (b) Raghuvanshi, D. S.; Gupta, A. K.; Singh,
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References and Notes
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(16) General Experimental Procedure
The requisite thiol 1 (1.2 mmol), cyclic 1,3-dione 2 (1mmol),
and anhydrous FeCl3 (15 mol%) were placed in a round-
bottomed flask and then stirred at r.t. to 50 °C for the
specified time (Table 2). After completion of the reaction (as
monitored by TLC), H2O was added to the reaction mixture,
and then it was extracted with EtOAc (3 × 10 mL). The
combined organic phases were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated on a rotary
evaporator. The crude product was purified by column
chromatography using EtOAc–hexane as eluent to afford
pure product 3.
Representative Data
5,5-Dimethyl-3-(phenylthio)cyclohex-2-enone (3a)
Solid; mp 50–52 °C (lit.17 mp 50–51 °C). FTIR (KBr): 2955,
2868, 1662, 1574, 1454, 1305, 1279, 1239, 1021, 716 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.07 (s, 6 H), 2.22 (s, 2 H),
2.39 (s, 2 H), 5.47 (s, 1 H), 7.40–7.48 (m, 5 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 27.8, 34.1, 43.7, 50.9, 119.6,
127.9, 129.7, 130.0, 135.3, 164.8, 196.1 ppm.
3-(Phenylthio)cyclohex-2-enone (3h)
Solid; mp 44–45 °C (lit.18 mp 43–44 °C). FTIR (KBr): 2950,
2868, 1655, 1580, 1454, 1310, 1280, 1240, 1020, 710 cm–1.
1H-NMR (300 MHz, CDCl3): δ = 1.99–2.03 (m, 2 H), 2.32–
2.36 (m, 2 H), 2.48–2.51 (m, 2 H), 5.47 (s, 1 H), 7.38–7.47
(m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.8, 29.8,
36.8, 120.5, 127.6, 129.5, 129.8, 135.1, 166.5, 195.6 ppm.
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Comprehensive Coordination Chemistry; Vol. 5; Wilkinson,
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Synlett 2014, 25, 213–216
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