Green and practical synthesis of functionalised 2H-thiopyrans via one-pot multicomponent reactions of aryl isothiocyanates in water

Article abstract of DOI:10.3184/174751913X13844245553486

An efficient synthesis of thiopyran derivatives via one-pot reactions between methyl propiolates, aryl isothiocyanates and acetylacetone in water is described.

Full text of DOI:10.3184/174751913X13844245553486

754 RESEARCH PAPER
DECEMBER, 754–756
JOURNAL OF CHEMICAL RESEARCH 2013
Green and practical synthesis of functionalised 2H-thiopyrans via one-pot
multicomponent reactions of aryl isothiocyanates in water
S. Zahra Sayyed-Alangi*
Department of Chemistry, Azadshahr Branch, Islamic Azad University, Azadshahr, Iran
An efficient synthesis of thiopyran derivatives via one-pot reactions between methyl propiolates, aryl isothiocyanates and
acetylacetone in water is described.
Keywords: acetylacetone, 2H-thiopyrans, aryl isothiocyanate, methyl propiolate, multicomponent reactions
Recently, the need has become apparent to extend
environmentally benign routes to synthesise numerous
materials.1 Green chemistry has considerable potential not only
for reduction of byproducts, a reduction in the waste produced,
and lowering of energy costs but also in the development of
new methodologies toward previously unobtainable materials,
using existing technologies.2 Medicinal and pharmaceutical
chemistry, with their traditionally large waste-to-product ratio,
are perhaps the most suitable for greening.3 Accordingly, there
has been a focus on the use of water as a green solvent in organic
synthesis. Other than the economic and environmental benefits
(abundant, cheap, nontoxic, nonflammable, nonexplosive),
water also has unique physical and chemical properties which
lead to unique reactivity and selectivity in comparison with
organic solvents. Thus, the development of organic reactions in
a water medium is of considerable interest.4–11
thiopyran derivatives.18 Other examples include, a one-pot
reaction of aromatic aldehydes, cyanothioacetamide and
malononitrile under microwave irradiation to synthesise
2,6-diamino-4-aryl-4H-thiopyran-3,5-dicarbonitriles.21
The imino-2H-thiopyrans are useful thiopyran derivatives.
Synthesis of 2-imino-2H-thiopyrans have been performed by
reaction of 1,6-diynes with isothiocyanates and carbon disulfide
via either Ru or Rh-catalysed [2+2+2] cycloadditions.22,23 The
use of Rh and/or Ru catalysts due to their high cost is one of the
disadvantages of those reactions. Derivatives of 2-imino-5,6-
dihydro-2H-thiopyran have been obtained in fair to good yields
by reaction of 1-heteroalkyl-1,3-butadienes and isothiocyanates
and with a calculated amount of dilute aqueous acid.24
As part of our continuing studies on the multicomponent
area and the synthesis of organosulfur compounds,25–28 we
report an efficient three-component reaction between aryl
isothiocyanates 1, activated esters 2 with acetylacetone 3, in
the presence of triethylamine in water (under green conditions),
which produce 2H-thiopyran derivatives 4 in good yields
(Scheme 1).
Combinatorial methods using multicomponent reactions
(MCRs) have been closely examined as fast and convenient
solutions for the synthesis of diverse classes of compounds.12,
13
MCRs, defined as one-pot reactions in which at least three
functional groups join through covalent bonds, have been
gaining importance in synthetic organic chemistry.12–15 Their
advantages include atom economy, convergent character, and
simplicity of one-pot procedures over other reactions.
Thiopyrans are heterocycles containing a sulfur atom and
are key units in organic synthesis and medicinal chemistry.16,17
Recently, some MCRs have been applied in the synthesis of
thiopyran derivatives, which are compatible with a green
chemistry approach.18–20 For example, the one-pot MCRs of
aldehydes, cyanothioacetamide and malononitrile promoted
by an ionic liquid proved to be an efficient way to synthesise
Results and discussion
As shown in Scheme 1, aryl isothiocyanates 1, methyl propiolate
2, and acetylacetone 3 undergo a 1:1:1 addition reaction in water
to produce 2H-thiopyrans 4 in 70–78% yields.
The data from elemental analysis, IR, H NMR, 13C NMR,
1
and mass spectra confirmed the identity of all of the products.
The mass spectrum of 4b exhibited a molecular ion peak at
m/z 346 and more importantly, an ion peak at m/z 303 showed
that the acetyl group has been lost and thus the presence of this
group on the structure was confirmed. The 1H NMR spectrum
O
H
CO2Me
O
O
H2O, Et3N
+
+
CO2Me
2
Ar
N
C
S
N
H
S
r.t.,24h
Ar
1
3
4
1, 2, 4
R
Ar
Yield % of 4
a
e
e
M
phenyl
75
75
70
b
M
4-nitrophenyl
4-bromophenyl
c
d
e
e
M
M
M
e
e
2-chlorophenyl
3-bromophenyl
78
70
Scheme 1 The reaction of aryl isothiocyanates, activated esters with acetylacetone in water.
* Correspondent. E-mail: zalangi@gmail.com
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JOURNAL OF CHEMICAL RESEARCH 2013 755
O
OH
O
N
OH
O
OH
CO2Me
H
2
H2O
4
1 + 3
CO2Me
N
Ar
N
Ar
S
S
S
H
Ar
7
5
6
Scheme 2 Proposed mechanism for the formation of compound 4.
2CH), 7.16 (1H, s, CH), 8.14 (2H, d, J=7.5 Hz, 2CH). 13C NMR (125.7 Hz,
CDCl3): δ 16.7 (CH3), 31.2 (CH3), 53.5 (MeO), 112.6 (CH), 120.4 (2CH),
126.7 (2CH), 135.3 (C), 137.3 (C), 140.8 (C), 145.2 (C), 155.0 (C–N), 155.4
(C=N), 161.2 (C=O), 202.3 (C=O). MS, m/z (%): 346 (M+, 20), 331 (43),
315 (54), 300 (24), 287 (34), 59 (33), 31 (88). Anal. Calcd for C16H14N2O5S
(346.35): C, 55.49; H, 4.07; N, 8.09. Found: C, 55.57; H, 4.27; N, 8.16%.
Methyl 3‑acetyl‑2‑(4‑bromophenylimino)‑4‑methyl‑2H‑thiopyran‑5‑
carboxylate (4c): Orange oil, yield 70%. IR (KBr) νmax/cm–1: 1736, 1685,
1524, 1425, 1268 and 1194. 1H NMR (500.1 Hz, CDCl3): δ 2.05 (3H, s,
CH3), 2.53 (3H, s, CH3), 3.83 (3H, s, MeO), 6.78 (2H, d, J=7.5 Hz, 2CH),
7.12 (1H, s, CH), 7.58 (2H, d, J=8.2 Hz, 2CH). 13C NMR (125.7 Hz,
CDCl3): δ 17.6 (CH3), 31.2 (CH3), 53.0 (MeO), 111.7 (CH), 122.4 (2CH),
132.3 (C), 133.4 (2CH), 134.8 (C), 135.8 (C), 140.6 (C), 148.4 (C–N),
154.2 (C=N), 170.3 (C=O), 210.7 (C=O). Anal. Calcd for C16H14BrNO3S
(380.25): C, 50.54; H, 3.71; N, 3.68. Found: C, 50.49; H, 3.67; N, 3.66%.
Methyl 3‑acetyl‑2‑(2‑chlorophenylimino)‑4‑methyl‑2H‑thiopyran‑5‑
carboxylate (4d): Colourless oil, yield 78%. IR (KBr) νmax/cm–1: 1730,
of 4b clearly showed four sharp singlet signals as arising from
methyl, acetyl, methoxy and methine protons (δH =2.12, 2.53,
and 3.85, 7.16) respectively. Two doublets at 7.02 and 8.14 ppm
are attributable to aromatic protons. The 13C NMR spectrum
of 4b showed 14 separate signals, which were in accord with
the proposed structure. The 13C chemical shifts for compounds
4a–e are given in the experimental section.
Although we have not verified the mechanism of our reaction
in an experimental manner, a possible explanation is proposed
in Scheme 2. It is conceivable that, the reaction involves the
initial formation of a 1,3-dipolar intermediate 5 between the
enol form of acetylacetone and the aryl isothiocyanate which
then reacts with the methyl propiolate to produce 6. Cyclisation
of zwitterionic intermediate 6 leads to the ketol 7. Subsequent
dehydration affords compound 4.
In summary, we have described an efficient method for the
synthesis of 2H-thiopyran derivatives in water. The benefits
include: (1) The reaction is carried out under green conditions,
and in water as the solvent. (2) No catalyst was required. (3)
The simplicity of the existing method makes it an appealing
alternative to complex multistep procedures.
1
1695, 1568, 1437 and 1325. H NMR (500.1 Hz, CDCl3): δ 2.07 (3H,
s, CH3), 2.55 (3H, s, CH3), 3.82 (3H, s, MeO), 7.14–7.32 (5H, m, 5 CH).
13C NMR (125.7 Hz, CDCl3): δ 17.5 (CH3), 31.2 (CH3), 53.5 (MeO), 112.6
(CH), 117.2 (CH), 125.6 (CH), 126.4 (CH), 129.2 (C), 130.7 (CH), 132.4
(C), 135.7 (C), 136.3 (C), 138.2 (C–N), 152.3 (C), 156.0 (C=N), 170.2
(C=O), 203.4 (C=O). Anal. Calcd for C16H14ClNO3S (335.80): C, 57.23; H,
4.20; N, 4.17. Found: C, 57.47; H, 4.17; N, 4.16%.
Experimental
Methyl 3‑acetyl‑2‑(3‑bromophenylimino)‑4‑methyl‑2H‑thiopyran‑5‑
All chemicals used in this work were purchased from Fluka (Buchs,
Switzerland) and were used without further purification. Elemental
analyses for C, H, and N were performed using a Heraeus CHN–O-
Rapid analyser. IR spectra were measured on a Shimadzu IR-460
spectrophotometer. Mass spectra were recorded on a Finnigan-MAT
carboxylate (4e): Colourless oil, yield 70%. IR (KBr) νmax/cm–1: 1742,
1
1697, 1587, 1464, 1389, 1254 and 1125. H NMR (500.1 Hz, CDCl3):
δ 2.05 (3H, s, CH3), 2.52 (3H, s, CH3), 3.85 (3H, s, MeO), 6.83 (1H, t,
J=7.5 Hz, CH), 7.12 (1H, d, J=7.6 Hz, CH), 7.14 (1H, s, CH), 7.27 (1H,
d, J=7.6 Hz, CH), 7.36 (1H, s, CH). 13C NMR (125.7 Hz, CDCl3): δ 17.5
(CH3), 31.0 (CH3), 53.4 (MeO), 110.6 (CH), 118.2 (CH), 122.7 (CH), 128.2
(CH), 129.0 (C), 130.4 (C), 132.2 (CH), 134.7 (C), 136.2 (C), 151.2 (C–N),
154.6 (C=N), 167.2 (C=O), 202.7 (C=O). Anal. Calcd for C16H14BrNO3S
(380.25): C, 50.54; H, 3.71; N, 3.68. Found: C, 50.57; H, 3.37; N, 3.56%.
1
8430 spectrometer operating at an ionisation potential of 70 eV. H
and 13C NMR spectra were measured with a Bruker DRX-500 Avance
spectrometer at 500.1 and 125.8 MHz, respectively. 1H, and 13C, spectra
were obtained for solutions in CDCl3 using TMS as internal standard.
Synthesis of 2‑imino‑2H‑thiopyran derivatives; general procedure
The mixture of acetylacetone 3 (2 mmol) and triethylamine (2 mmol)
was added slowly to a magnetically stirred solution of the appropriate
aryl isothiocyanate 1 (2 mmol) and alkyl propiolate 2 (2 mmol) in H2O
and the reaction mixture was stirred for 24H at room temperature.
After completion of the reaction, as indicated by TLC (ethyl acetate/
n-hexane, 5:1), the reaction mixture was extracted with EtOAc and
washed with cold diethyl ether to afford pure title compounds.
Methyl 3‑acetyl‑4‑methyl‑2‑(phenylimino)‑2H‑thiopyran‑5‑car‑
boxylate (4a): Yellow oil, yield 75%. IR (KBr) νmax/cm–1: 1735, 1692,
1576, 1384 and 1257. 1H NMR (500.1 Hz, CDCl3): δ 2.27 (3H, s, CH3),
2.38 (3H, s, CH3), 3.82 (3H, s, MeO), 7.06 (1H, s, CH), 7.54 (2H, t,
J=7.2 Hz, 2CH), 7.62 (1H, t, J=7.2 Hz, CH), 8.05 (2H, d, J=7.3 Hz,
2CH). 13C NMR (125.7 Hz, CDCl3): δ 16.9 (CH3), 28.5 (CH3), 52.6 (MeO),
112.3 (CH), 122.5 (2CH), 123.8 (CH), 129.2 (2CH), 133.6 (C), 134.5 (C),
138.8 (C), 148.9 (C–N), 157.6 (C=N), 161.5 (C=O), 207.1 (C=O). MS: m/z
(%)=301 [M+, 10], 286 (46), 270 (76), 258 (100), 242 (57), 224 (35), 31
(57), 15 (22). Anal. Calcd for C16H15NO3S (301.36): C, 63.77; H, 5.02; N,
4.65. Found: C, 63.84; H, 5.12; N, 4.73%.
We gratefully acknowledge the financial and spiritual support
from the Research Council of Azadshahr Branch, Islamic Azad
University.
Received 7 August 2013; accepted 13 October 2013
Paper 1302113 doi: 10.3184/174751913X13844245553486
Published online: 6 December 2013
References
1
P. Anastas and T. Williamson, Green chemistry, frontiers in benign
chemical synthesis and procedures. Oxford Science Publications, New
York, 1998.
2
3
4
5
G.W.V. Cave, C.L. Raston and J.L. Scott, Chem. Commun., 2001, 21, 2159.
R.A. Sheldon, Chem. Ind. (London), 1997, 12.
R. Breslow, Acc. Chem. Res., 1991, 24, 159.
C.J. Li and T.H. Chang, Organic reactions in aqueous media. Wiley, New
York, 1997, p. 795.
6
7
8
9
U.M. Lindström, Chem. Rev., 2002, 102, 2751.
K. Shu and M. Kei, Acc. Chem. Res., 2002, 35, 209.
C.J. Li, Chem. Rev., 2005, 105, 3095.
S. Narayan, J. Muldoon, M.G. Finn, V.V. Fokin, H.C. Kolb and K.B.
Sharpless, Angew. Chem., Int. Ed., 2005, 44, 3275.
Methyl
3‑acetyl‑4‑methyl‑2‑(4‑nitrophenylimino)‑2H‑thiopyran‑5‑
carboxylate (4b): Pale yellow oil, yield 75%. IR (KBr) νmax/cm–1: 1740,
1683, 1457, 1368, 1265, 1158 and 1109. 1H NMR (500.1 Hz, CDCl3): δ 2.12
(3H, s, CH3), 2.53 (3H, s, CH3), 3.85 (3H, s, MeO), 7.02 (2H, d, J=7.6 Hz,
JCR1302113_FINAL.indd 755
29/11/2013 12:06:22

756 JOURNAL OF CHEMICAL RESEARCH 2013
10 M.C. Pirrung, Chem. Eur. J., 2006, 12, 1312.
11 V. Polshettiwar and R.S. Varma, Acc. Chem. Res., 2008, 41, 629.
12 L.F. Tietze, Chem. Rev., 1996, 96, 115.
21 X. Fan, X. Wang, X. Zhang, X. Li and G. Qu, J. Chem. Res., 2007, 3, 693.
22 K. Tanaka, A. Wada and K. Noguchi, Org. Lett., 2006, 8, 907.
23 Y. Yamamoto, H. Takagishi and K. Itoh, J. Am. Chem. Soc., 2002, 124, 28.
24 N. Nedolya, L. Brandsma, H.D. Verkruijsse, A.H.T.M. van der Kerk, B.A.
Trofimov, Tetrahedron Lett., 1998, 39, 2631.
25 I. Yavari, R. Hajinasiri and S.Z. Sayyed-Alangi, Monatsh Chem., 2009,
140, 205.
26 I. Yavari, R. Hajinasiri, S.Z. Sayyed-Alangi H. Sajjadi-Ghotbabadi,
Monatsh Chem., 2009, 140, 209.
13 A.A. Domling, Chem. Rev., 2006, 106, 17.
14 A. Domling and I. Ugi, Angew. Chem., Int. Ed. Engl., 2000, 39, 3169.
15 I. Ugi, Angew. Chem., Int. Ed. Engl., 1982, 21, 810.
16 F. Tavakolinia, T. Baghipour, Z. Hossaini, D. Zareyee, M.A. Khalilzadeh
and M. Rajabi, Nucleic Acid Ther., 2012, 22(4), 265.
17 E. Vedeje and G.A. Krafft, Tetrahedron, 1982, 38, 2857.
18 X. Zhang, X. Li, X. Fan, X. Wang, D. Li, G. Qu and J. Wang, Mol. Divers.,
2009, 13, 57.
27 I. Yavari, S.Z. Sayyed-Alangi, M. Sabbaghan, R. Hajinasiril and N.
Iravani, Monatsh Chem., 2008, 139, 1025.
19 Z. Hossaini and F. Rostami-Charati, J. Appl. Chem. Res., 2012, 6, 48.
20 N.M. Hilmy Elnagdi and N.S. Al-Hokbany, Molecules, 2012, 17, 4300.
28 S.Z. Sayyed-Alangi, Z. Hossaini and F. Rostami-Charati, Chinese Chem.
Lett., 2012, 23, 1119.
JCR1302113_FINAL.indd 756
29/11/2013 12:06:22

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