Facile route to highly functionalized 2H-chromene-2-thiones via ring annulations of β-oxodithioesters with phenols catalyzed by AlCl3 under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.10.126

A facile synthesis of chromene-2-thiones by the Pechmann condensation of phenols and β-oxodithioesters catalyzed by AlCl₃ under solvent-free condition has been reported. The best results were obtained in the case of substituted phenols such as

Full text of DOI:10.1016/j.tetlet.2012.10.126

Tetrahedron Letters 54 (2013) 183–187
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Facile route to highly functionalized 2H-chromene-2-thiones via ring
annulations of b-oxodithioesters with phenols catalyzed by AlCl3 under
solvent-free conditions
⇑
Nepram Sushuma Devi, Sarangthem Joychandra Singh, Laishram Ronibala Devi, Okram Mukherjee Singh
Department of Chemistry, Manipur University, Canchipur 795003, Manipur, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Revised 27 October 2012
Accepted 30 October 2012
Available online 7 November 2012
A facile synthesis of chromene-2-thiones by the Pechmann condensation of phenols and b-oxodithioest-
ers catalyzed by AlCl3 under solvent-free condition has been reported. The best results were obtained in
the case of substituted phenols such as resorcinol, substituted resorcinol, and pyrogallol. The optimum
condition was observed with the use of 10 mol % of AlCl3 at 130 °C under solvent-free conditions. This
method offers a wide scope for the synthesis of coumarins in good yields during a short period of time.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Coumarin
b-oxodithioesters
AlCl3
Solvent-free
Phenols
Coumarins constitute an important class of oxygen heterocycles
and the coumarin structural motif is present in numerous natural
products including edible vegetables and fruits.1 Due to their broad
range of biological activities2 such as anticancer,3a,b anti-HIV,3c–e
antiinflammatory,3f,g antitumor,3h,i and antibiotic activity,3j–l lots
of interests have been devoted to their synthetic methods. Re-
cently, we have reported the radical scavenging potential of the
coumarin I (Fig. 1) toward the stable free radical 2,2-diphenyl-1-
picrylhydrazyl (DPPH) and found to scavenge DPPH free radical
efficiently.4a Furthermore, coumarin I was found to be a protective
agent of curcumin from the attack of sulfur free radical generated
by radiolysis of glutathione (GSH). Similarly, coumarins II and III
were reported as CA inhibitor4b and K.v 1.3 inhibitor,4c respectively
(Fig. 1).
Coumarins have been synthesized by several methods, includ-
ing Pechmann,5a Perkin,5b Knoevenagel,5c–e Reformatsky,5f and
Wittig5g,h reactions. Pechmann reaction is the most widely used
method for the condensation of phenols and b-ketonic esters. The
use of various catalysts such as P2O5,6a,b ZrCl4,6c BiCl3,6d ZrOCl2.8-
H2O,6e FeCl3,6f SmCl3,6g InCl3,6h trifluoroacetic acid,6i and hetero-
polyacids,6j and ionic liquids6k,l have been well documented in
the literature.
such as ethyl acetoacetate or methyl acetoacetate and thus struc-
tural variations are limited to those derived from these esters. Re-
cently, we reported the synthesis of a series of chromene-2-thiones
using b-oxodithioesters as substrates by the Knoevenagel type of
cyclocondensation.7 More recently, Singh et al reported extensive
work on the one-pot synthesis of 3-aroyl/heteroaroyl-2H-
chromene-2-thiones based on the Knoevenagel condensation of
b-oxodithioesters and salicylaldehydes in the presence of indium
trichloride5e and SiO2–H2SO4. However b-oxodithioesters have
8
not been exploited so far for the synthesis of such coumarin struc-
tural frameworks by the Pechmann type of cyclocondensations.
We report herein a facile route for the synthesis of highly function-
alized 2H-chromene-2-thiones via the Pechmann condensation of
phenols and b-oxodithioesters catalyzed by AlCl3 under solvent-
free conditions.
The desired b-oxodithioesters9 3a–d (Table 1) were synthesized
in good yields by reacting ketones 1 with (S,S)-dimethyl trithiocar-
bonate 2 in the presence of NaH in DMF–hexane (1:4) mixture at
room temperature (Scheme 1).
In a preliminary experiment, equimolar amounts of resorcinol
3a and acetophenone b-oxodithioester 4a were heated at 130 °C
with stirring in the presence of 10 mol % AlCl3 under solvent-free
condition. The reaction went smoothly and the coumarin product
5a was obtained which was characterized by spectroscopic and
analytical data. To establish the reaction conditions for the Pech-
mann condensation, the reaction of resorcinol with acetophenone
b-oxodithioester was taken as a model reaction (Scheme 2, Table 2).
Literature survey revealed that most of the reported methods
based on Knoevenagel and Pechmann used only the b-ketoesters
⇑
Corresponding author. Tel./fax: +91 0385 2435145.
E-mail address: ok_mukherjee@yahoo.co.in (O.M. Singh).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.126

184
N. S. Devi et al. / Tetrahedron Letters 54 (2013) 183–187
O
S
O
O
S
COOH
O
O
O
S
II
O
S
OCH3
I
III
CA inhibitor
Antioxidant activity
Kv1.3 inhibitor
Figure 1. Coumarin-based biologically active compounds.
Table 1
Synthesis of b-oxodithioesters
Table 2
Optimization of catalyst on model reactiona
Entry
1
Ar1
Dithioesters
yielda (%)
72
Entry
Catalyst
bMol %
Solvent
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
9
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
FeCl3
ZnCl2
CuCl2
SnCl2
None
5
Solvent-free
Solvent-free
Solvent-free
EtOH
30
15
12
30
30
15
20
25
15
30
80
80
80
Trace
Trace
56
61
59
O
S
10
15
20
20
15
25
20
15
—
SMe
S
3a
THF
O
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
CH3
OCH3
Cl
SMe
2
3
4
75
73
71
3b
63
nil
H3C
H3CO
Cl
10
O
S
a
Reaction conditions: Benzoyl dithioester (1 mmol), resorcinol (1 mmol) under
neat condition at 130 °C.
SMe
b
3c
Amount of catalyst used based on 3a.
Isolated yield based on 3a.
c
O
S
SMe
characteristic change in the reaction was observed up to 130 °C
(Table 2, entry 10).
Under these optimized reaction conditions, the scope and effi-
ciency of this reaction was explored for the synthesis of a wide
variety of 2H-chromene-2-thione 5 and results are summarized
in Table 3.
3d
a
Yield of isolated product.
O
S
O
S
+
NaH
DMF/Hexane
As can be seen from Table 3, a wide range of structurally varied
phenols reacted with b-oxodithioesters smoothly to give the corre-
sponding coumarins in good yields. The reaction proceeds faster in
case of polyhydroxy phenols such as resorcinol, methyl substituted
resorcinol, and pyrogallol with good yield of the products. This
shows that the reaction requires the presence of a strong activating
group in the phenol ring. Interestingly, polyhydroxyphenols having
electron donating groups in the meta position gave maximum
yields. The aroyl groups having both electron donating and neutral
substituents at the para-position of the b-oxodithioesters were
found reacting smoothly with the polyhydroxy phenols. However,
when we carried out the same reaction with phenol, 4-ethylphe-
nol, 4-tert-butyl-2-methylphenol, 2-bromophenol, 3-chlorophenol,
catechol, tert-butyl catechol, and 6-bromo-2-naphthol, the reaction
failed, yielding either the unreacted starting materials or an intrac-
table reaction mixture under more drastic condition. The structure
of all the products were characterized by IR, 1H NMR, 13C NMR,
CHN analysis, and mass spectrometry.10
Ar1
CH3
MeS
SMe
Ar1
SMe
3a-d
1a-d
2
Scheme 1. Synthesis of b-oxodithioesters.
O
S
130oC
Catalyst
+
SMe
HO
OH
O
S
HO
3a
4a
5a
Scheme 2. Reaction of b-oxodithioester 3a with resorcinol.
On the basis of the experimental results, a plausible mechanism
for the formation of substituted coumarin derivative is presented
in Scheme 3.
In this mechanism, the lone pair of electrons of the phenolic OH
group attacks at the thiocarbonyl carbon of dithioester 3 with the
elimination of methanethiol to give intermediate A. The intermedi-
ate A undergoes ring closure through electrophilic attack of the
Next, we focused on optimizing the reaction conditions by taking
various amounts of AlCl3 (5–15 mol %) and temperatures in the
range of 100–130 °C. It was observed that only 10 mol % of AlCl3
could effectively catalyze the reaction at 130 °C in 15 min. When
the reaction mixture was heated above 130 °C, the product decom-
poses giving many non-separable and unwanted products. Either
an increase in the catalyst loading or the presence of solvents like
EtOH and THF showed no substantial improvement in the yield.
We then examined the catalytic evaluation of metal salts like FeCl3,
ZnCl2, CuCl2, SnCl2, etc. The use of these Lewis acids afforded poor
yields of the product in comparison to AlCl3. The reaction was
also tested without any catalyst under neat conditions, but no
p-electrons at the activated carbonyl carbon to form intermediate
B. The intermediate B then undergoes elimination of one water
molecule to give product 5.
We have measured the antioxidant activity of the newly syn-
thesized compounds using the stable free radical 2,2-diphenyl-1-
picrylhydrazyl (DPPH) and glutathione (GSH).4a These compounds

N. S. Devi et al. / Tetrahedron Letters 54 (2013) 183–187
185
Table 3
Reaction of b-oxodithioesters 3 with phenol derivatives 4a
Ar1
AlCl3
(10 mol%)
O
S
R
130 o
C
R
+
Ar1
O
S
SMe
OH
solvent free
5a-l
4a-c
3a-d
Entry
1
Phenols
Dithioester
Product
mp (oC)
Yield (%)b
O
S
SMe
S
HO
OH
OH
228–229
80
74
5a
5b
HO
HO
O
S
O
CH3
SMe
SMe
HO
HO
2
3
232–233
215–216
H3C
O
OCH3
S
O
S
OH
OH
H3CO
68
5c
HO
HO
O
Cl
S
O
S
SMe
HO
4
5
260–261
209–210
83
81
Cl
5d
O
O
S
S
OH
OH
O
S
SMe
S
OH
5e
HO
HO
OH
OH
HO
HO
O
CH3
SMe
6
7
224–225
228–229
70
H3C
OH
OH
OH
5f
O
OCH3
S
OH
OH
O
S
SMe
H3CO
69
HO
HO
OH
OH
5g
HO
HO
O
Cl
S
S
O
S
SMe
8
Cl
234–235
85
5h
O
(continued on next page)

186
N. S. Devi et al. / Tetrahedron Letters 54 (2013) 183–187
Table 3 (continued)
Entry
Phenols
Dithioester
Product
mp (oC)
Yield (%)b
OH
OH
O
S
SMe
S
OH
OH
OH
OH
9
240–241
67
5i
H3C
OH
OH
H3C
O
CH3
S
S
S
S
O
SMe
H3C
H3CO
Cl
10
238–239
220–221
252–253
66
63
71
H3C
H3C
H3C
5j
H3C
H3C
H3C
O
OCH3
OH
OH
O
S
SMe
11
OH
OH
5k
5l
O
Cl
O
S
SMe
12
O
a
Reaction conditions: b-oxodithioesters(1 mmol), phenols (1 mmol) under neat condition at 130 °C.
Isolated yield after silica gel chromatography.
b
R2
AlCl3
AlCl3
R2
R2
O
+
O
O
H
R1
AlCl3
-CH3SH
+
R1
R1
H
OH
H3CS
S
O
O
S
S
4
3
A
B
R2
R1
O
S
5
Scheme 3. Plausible mechanism of the reaction.
exhibited promising antioxidant activities and the details will be
published elsewhere.
Shillong and SAIF, CDRI Lucknow for spectral recording. SJS is
thankful to UGC, New Delhi for D. S. Kothari Post Doctoral Fellow-
ship. NSD is also thankful to CSIR (New Delhi) for Senior Research
Fellowship.
In conclusion, we have successfully demonstrated the applica-
tion of b-oxodithioesters in the Pechmann reaction to synthesize
2H-chromene-2-thiones under solvent-free conditions. This meth-
od has the ability to tolerate a wide variety of substitutions in both
components. Thus, this method will offer easy access to substi-
tuted coumarins with varied substitution patterns in high yields
within a short period of time.
References and notes
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Sons: New York, 1982.
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10. General procedure for synthesis of 2H-chromene-2-thione (5a–m): a mixture of
resorcinol (1 mmol) and acetophenonedithioester (1 mmol) was heated at
130 °C with stirring in the presence of 10 mol % AlCl3 for 15 min under solvent-
free condition. Then water (30 mL) was added and the reaction mixture was
extracted with ethylacetate (20 mL). The organic layer was dried with
anhydrous Na2SO4 and evaporated. The crude products were subjected to
column chromatography using EtOAc/Hex(1:9) as eluent to give the pure
product.
7-hydroxy-4-phenyl-2H-chromene-2-thione (5a): 1H NMR (DMSO-d6, 400 MHz):
d 6.86–6.96 (m, 3H), 7.38 (d, J = 8.8 Hz, 1H), 7.53 (s, 5H), 11.01 (br s, 1H); 13C
NMR (DMSO-d6, 75 MHz): d 102.4, 112.3, 115.0, 124.3, 128.4, 128.6, 128.9,
129.9, 134.4, 147.8, 158.4, 162.1, 195.9; IR (KBr) (t
max, cmÀ1): 3422, 1623,
1389; MS (m/z): 254 (M+). Anal. Calcd for C15H10O2S: C, 70.84; H, 3.96; S,
12.61%. Found: C, 70.81; H, 3.97; S, 12.63%.