An efficient conjugate hydrothiocyanation of chalcones with a task-specific ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2007.09.024

A new and efficient method of conjugate hydrothiocyanation of chalcones along with the preparation of a probe for demonstrating the utility of the resulting β-thiocyanato ketones in heterocyclic synthesis is reported. Chalcones undergo an efficient conjugate hydrothiocyanation with the task-specific ionic liquid (TSIL), 1-n-butyl-3-methylimidazolium thiocyanate ([bmim]SCN) followed by reaction with AcONH₄ or an amine to afford chemically and pharmaceutically interesting 2-amino-1,3-thiazines at room temperature in a one-pot procedure. After isolation of the product, the ionic liquid [bmim]OH could be used for the synthesis of [bmim]SCN, thus allowing recycling of the TSIL for further use.

Full text of DOI:10.1016/j.tetlet.2007.09.024

Tetrahedron Letters 48 (2007) 7793–7795
An efficient conjugate hydrothiocyanation of chalcones
with a task-specific ionic liquid
Lal Dhar S. Yadav,* Rajesh Patel, Vijai K. Rai and Vishnu P. Srivastava
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Received 19 July 2007; revised 28 August 2007; accepted 4 September 2007
Available online 8 September 2007
Abstract—A new and efficient method of conjugate hydrothiocyanation of chalcones along with the preparation of a probe for dem-
onstrating the utility of the resulting b-thiocyanato ketones in heterocyclic synthesis is reported. Chalcones undergo an efficient con-
jugate hydrothiocyanation with the task-specific ionic liquid (TSIL), 1-n-butyl-3-methylimidazolium thiocyanate ([bmim]SCN)
followed by reaction with AcONH4 or an amine to afford chemically and pharmaceutically interesting 2-amino-1,3-thiazines at
room temperature in a one-pot procedure. After isolation of the product, the ionic liquid [bmim]OH could be used for the synthesis
of [bmim]SCN, thus allowing recycling of the TSIL for further use.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Organic thiocyanates are of considerable importance
from both the chemical and biological viewpoints. They
are versatile intermediates for the synthesis of various
heterocycles;1,2 some of which exhibit herbicidal and
other important biological activities.3,4 The thiocyanate
functionality is useful as a masked mercapto group. Fur-
thermore, the thiocyanato group occurs as an important
functionality in several anticancer natural products
formed by deglycosylation of glucosilonates derived
from cruciferous vegetables.5
cularly for b-thiocyanation of carbonyl compounds as
the ease of nucleophilic substitution at the b-carbon is
far less than that at the a-carbon. Thus, an efficient
method for the introduction of a thiocyanate functional-
ity at the b-position of carbonyl compounds under mild
conditions appeared interesting.
Ionic liquids (ILs) have attracted increasing interest in
the context of green chemistry owing to their great
potential as environmentally benign reaction media.12–15
ILs also play significant roles as catalysts15–17 and re-
agents18,19 and are easy to recycle.18,19 A recent review20
presents studies on applications of ILs to asymmetric
syntheses showing their ever-increasing importance.
Thiocyanation is generally carried out via nucleophilic
substitution using thiocyanate anions. The low nucleo-
philicity of the SCN anion requires rather harsh reaction
conditions. Metal thiocyanates and organic halides or
sulfonates are generally used to introduce the thiocya-
nate functionality into an organic molecule.6 However,
thiocyanates are not very stable when heated or under
acidic conditions. Chromatography on silica gel or pro-
longed heating over 50 ꢁC can cause intramolecular
rearrangement of the thermodynamically favoured iso-
thiocyanate isomers.7 Thiocyanates have been obtained
from alcohols,8 silyl ethers9 or amines10 using
Ph3P(SCN)2. However, many drawbacks have been
observed in these thiocyanation methodologies,11 parti-
The literature records only one report describing a single
example of conjugate hydrothiocyanation of a chalcone
using ammonium thiocyanate and sulfuric acid to afford
the b-thiocyanato ketone in 63% yield.21 The present
Letter reports a new and efficient method of conjugate
hydrothiocyanation of chalcones using a task-specific
ionic liquid to afford b-thiocyanato ketones in 85–93%
yields without requiring any other catalyst or solvent.
The present work is part of our continuing drive to
devise new one-pot cyclization processes under environ-
mentally benign conditions.22–26 The strategy reported
herein was successfully realized by stirring a mixture of
a task-specific ionic liquid (TSIL)18 [bmim]SCN 1 and a
chalcone 2 at room temperature for 2–3 h to afford
b-thiocyanato ketones 3 in 85–93% yields (Scheme 1).27
Keywords: Hydrothiocyanation; Conjugate addition; Chalcones; Ionic
liquids; Thiocyanates; 1,3-Thiazines.
*
Corresponding author. Tel.: +91 5322500652; fax: +91 5322461157;
e-mail: ldsyadav@hotmail.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.024

7794
L. D. S. Yadav et al. / Tetrahedron Letters 48 (2007) 7793–7795
that the nucleophilicity of the SCN anion is much higher
N
O
O
in [bmim]SCN compared to that from KSCN in
[bmim]BF4. After isolation of products 3 or 6, the ionic
liquid [bmim]OH 7 could be recycled to [bmim]SCN 1
for use in subsequent runs. This was accomplished by
treating 7 with conc. HCl in acetone followed by stirring
with KSCN at room temperature for 48 h.
S
H2O
r. t.
Ph
Ar
[bmim]SCN
Ph
Ar
2
3
1
AcONH4
or
RNH2
4
r. t.
(i) HCl
(ii)KSCN
Ph
Ph
S
2-Amino-1,3-thiazines have also been prepared from
chalcones and thiourea in a one-pot procedure.21,33–35
The reaction of thiourea, as an ambident nucleophile,
with enones in the presence of a strong base in refluxing
ethanol is a point of argument among synthetic organic
chemists. For example, Madkour et al.,21 Takamizawa
et al.33 and Ingarsal et al.34 have found that the reaction
provides a synthetic route to thiazines, whereas El-Has-
hash et al.35 isolated pyrimidine-2-thione derivatives.
However, the method reported herein (Scheme 1) has
several advantages, such as exclusive formation of 2-
amino-1,3-thiazines 6, high yields (81–92%), a one-pot
reaction at room temperature, use of an easily recyclable
hydrothiocyanating agent 1 and does not require any
other catalyst or solvent.
O
NH
N
[bmim]OH
-H2O
NHR
Ar
Ar
S
7
NHR
6
5
N
[bmim]SCN =
N
SCN
1
Yield (%)*
Product
Ar
R
3a
3b
3c
6a
6b
6c
Ph
-
91
85
4-MeOC6H4
4-ClC6H4
Ph
-
-
88
87
H
Ph
Ph
86
89
Ph
In summary, we have developed an efficient protocol for
the synthesis of b-thiocyanato ketones via the conjugate
hydrothiocyanation of chalcones with the task-specific
ionic liquid [bmim]SCN. The application of this proto-
col in heterocyclic chemistry is demonstrated by a
one-pot synthesis of chemically and pharmaceutically
interesting 2-amino-1,3-thiazines.
4-MeOC6H4
6d
6e
6f
Ph
4-FC6H4
82
86
85
87
81
91
92
92
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
H
Ph
6g
6h
6i
4-MeOC6H4
4-FC6H4
H
6j
Ph
4-MeOC6H4
6k
6l
4-FC6H4
83
Acknowledgements
* Yields of isolated and purified products.
We sincerely thank SAIF, CDRI, Lucknow, for provid-
ing microanalyses and spectra. One of us (R.P.) is grate-
ful to the CSIR, New Delhi, for the award of a Junior
Research Fellowship.
Scheme 1. Postulated intermediates leading to the formation of
thiazines 6.
The pure products 3 were extracted with ether from the
ionic liquid. No column chromatography or recrystalli-
zation was required thus avoiding the possibility of rear-
rangement of thiocyanates 3 to the thermodynamically
favoured isothiocyanates.
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As a probe for demonstrating the application of b-thio-
cyanato ketones 3 in heterocyclic synthesis, we have syn-
thesized 2-amino-1,3-thiazines 6 which are chemically
and pharmaceutically interesting entities.28–31 These
were synthesized from chalcones 2, task-specific ionic
liquid 1 and AcONH4 or an amine 4 in a one-pot proce-
dure at room temperature in 81–92% yields.32 Postu-
lated intermediates leading to the formation of
thiazines 6 are depicted in Scheme 1. The pathway is
supported by the observation that an isolated and puri-
fied b-thiocyanato ketone 3 reacts with AcONH4 or an
amine 4 to afford a thiazine 6. A comparison with 1
was carried out by reacting chalcone 2, (Ar = Ph) in
[bmim]BF4 with 1.5 equiv of KSCN at rt. In this case,
the hydrothiocyanation resulting in the corresponding
b-thiocyanato ketones 3 took place with only 35% con-
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1585, 1452 cmÀ1. 1H NMR (400 MHz; DMSO-d6/TMS) d:
3.03 (dd, 1H, J = 13.7 Hz, J = 8.4 Hz, 2-Ha), 3.35 (dd,
1H, J = 13.7 Hz, J = 3.1 Hz, 2-Hb), 4.92 (dd, 1H,
J = 8.4 Hz, J = 3.1 Hz, 3-H), 7.09–7.85 (m, 9Harom). 13C
NMR (100 MHz; DMSO-d6/TMS) d: 41.1 (CHPh), 50.5
(CH2CO), 112.7 (CN), 127.4, 128.3, 129.1, 131.3, 132.7,
133.6, 134.2, 135.7 (Ph, 4-ClC6H4), 192.5 (CO). EIMS
(m/z): 301 (M+). Anal. Calcd for C16H12ClNOS: C, 63.68;
H, 4.01; N, 4.64. Found: C, 63.97; H, 4.33; N, 4.28.
28. Kai, H.; Morioko, Y.; Tomida, M.; Takahashi, T.;
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32. General procedure for the synthesis of 2-amino-1,3-thiazines
6: A mixture of [bmim]SCN 1 (6.0 mmol), chalcone 2
(5.0 mmol) and a few drops of distilled water was taken in
a 50 mL round-bottomed flask and stirred at rt for 2–3 h.
Then, AcONH4 or an amine 4 (5.0 mmol) was added and
the reaction mixture was stirred at rt for a further 3–4 h.
After completion of the reaction as indicated by TLC, the
product was extracted with ether (3 · 25 mL). The com-
bined ether extracts were evaporated under reduced
pressure to leave the crude product, which was recrystal-
lized from EtOH to afford an analytically pure sample of 6
as yellowish crystals. The remaining ionic liquid [bmi-
m]OH 7 was converted into [bmim]SCN 1 for use in
subsequent runs as described above.27 Physical data of
representative compounds: 6a: yellowish crystals, yield
87%, mp 110–112 ꢁC. IR (KBr) mmax 3341, 3027, 1643,
27. General procedure for the hydrothiocyanation of chalcones
2: A mixture of [bmim]SCN 1 (6.0 mmol), chalcone 2
(5.0 mmol) and a few drops of distilled water was taken in
a 50 mL round-bottomed flask and stirred at rt for 2–3 h.
After completion of the reaction as indicated by TLC, the
product was extracted with ether (3 · 20 mL). The com-
bined ether extracts were dried over anhydrous sodium
sulfate and evaporated under reduced pressure to give a
pure b-thiocyanato ketone 3 as yellowish solid. The
remaining ionic liquid, [bmim]OH 7 was dissolved in
acetone (10 mL) and treated with conc. HCl (1.2 equiv)
followed by reaction with KSCN (2 equiv) at rt for 48 h to
afford TSIL [bmim]SCN 1 which was used in subsequent
runs. Physical data of representative compounds: 3a:
yellowish solid, yield 91%, mp 61–62 ꢁC. IR (KBr) mmax
1599, 1582, 1451 cmÀ1 1H NMR (400 MHz; DMSO-d6/
.
TMS) d: 3.81 (s, 2H, NH2 exchangeable with D2O), 3.96 (d,
1H, J = 7.6 Hz, 6-H), 6.12 (d, 1H, J = 7.6 Hz, 5-H), 7.06–
7.30 (m, 10Harom). 13C NMR (100 MHz; DMSO-d6/TMS)
d: 35.3 (4-C), 110.9 (5-C), 126.5, 127.9, 128.7, 131.2, 131.9,
132.7, 133.4, 134.6 (2 · Ph), 142.7 (6-C), 161.2 (SC@N).
EIMS (m/z): 266 (M+). Anal. Calcd for C16H14N2S: C,
72.15; H, 5.30; N, 10.52. Found: C, 71.91; H, 5.21; N,
10.72. 6j: yellowish crystals, yield 92%, mp 183–185 ꢁC. IR
1
(KBr) mmax 3343, 3025, 1645, 1602, 1585, 1449 cmÀ1. H
NMR (400 MHz; DMSO-d6/TMS) d: 5.23 (s, 1H, NHPh
exchangeable with D2O), 3.98 (d, 1H, J = 7.6 Hz, 6-H),
6.15 (d, 1H, J = 7.6 Hz, 5-H), 7.11–7.78 (m, 14Harom). 13
C
NMR (100 MHz; DMSO-d6/TMS) d: 35.5 (4-C), 111.7 (5-
C), 126.2, 127.1, 127.8, 128.4, 129.6, 130.5, 131.2, 131.9,
132.7, 133.5, 134.2, 134.9 (4-ClC6H4, 2 · Ph), 143.1 (6-C),
161.5 (SC@N). EIMS (m/z): 376 (M+). Anal. Calcd for
C22H17ClN2S: C, 70.11; H, 4.55; N, 7.43. Found: C, 70.37;
H, 4.39; N, 7.51.
3021, 2069, 1691, 1603, 1579, 1456 cmÀ1 1H NMR
.
(400 MHz; DMSO-d6/TMS) d: 3.01 (dd, 1H, J = 13.7 Hz,
J = 8.4 Hz, 2-Ha), 3.32 (dd, 1H, J = 13.7 Hz, J = 3.1 Hz,
2-Hb), 4.88 (dd, 1H, J = 8.4 Hz, J = 3.1 Hz, 3-H), 7.05–
7.81 (m, 10Harom). 13C NMR (100 MHz; DMSO-d6/TMS)
d: 41.3 (CHPh), 50.3 (CH2CO), 112.4 (CN), 126.9, 128.2,
129.4, 131.5, 132.7, 133.5, 134.3, 135.9 (2 · Ph), 192.8
(CO). EIMS (m/z): 267 (M+). Anal. Calcd for
C16H13NOS: C, 71.88; H, 4.90; N, 5.24. Found: C,
71.52; H, 4.99; N, 5.46%. 3c: yellowish solid, yield 88%,
mp 120–121 ꢁC. IR (KBr) mmax 3023, 2070, 1692, 1601,
33. Takamizawa, A.; Hirai, K. J. Org. Chem. 1965, 30, 2290–
2296.
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2006, 27, 455–459.
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rus, Sulfur, Silicon, Relat. Elem. 1991, 55, 279–283.