Reaction of aryl isothiocyanate with pyridines and dialkyl acetylenedicarboxylates to afford novel heterocycles

Article abstract of DOI:10.3184/174751913X13726957255037

The reactive intermediate produced in the reaction between pyridines and dialkyl acetylenedicarboxylates was trapped by aryl isothiocyanates to afford 2-thioxo-1,9a-dihydro-2H-pyrido [1,2,a]pyrimidine derivatives in good yields.

Full text of DOI:10.3184/174751913X13726957255037

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 455
AUGUST, 455–457
Reaction of aryl isothiocyanate with pyridines and dialkyl
acetylenedicarboxylates to afford novel heterocycles
Alireza Hassanabadia* and Rahele Zhianib
aDepartment of Chemistry, Zahedan Branch, Islamic Azad University, PO Box 98135-978, Zahedan, Iran
bDepartment of Chemistry, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
The reactive intermediate produced in the reaction between pyridines and dialkyl acetylenedicarboxylates was
trapped by aryl isothiocyanates to afford 2-thioxo-1,9a-dihydro-2H-pyrido [1,2,a]pyrimidine derivatives in good
yields.
Keywords: three-component reaction, dialkyl acetylenedicarboxylates, pyridines, aryl isothiocyanates
Multi-component reactions (MCRs) are powerful tools in
modern drug discovery processes and allow fast, automated
and high throughput generation of organic compounds.1,2
Bridgehead nitrogen heterocycles are of interest because they
constitute an important class of natural and unnatural products,
many of which exhibit useful biological activity.3,4 The interest
in bicyclic 6–6 systems with one ring junction and one extra
nitrogen atom, stems from the appearance of saturated and
partially saturated pyrido[1,2-a]pyrimidine ring systems in
many biologically active compounds and natural products,4–10
some of which are key intermediates for the synthesis of rutae-
carpine alkaloids. Some have characteristic pharmacological
properties such as analgesic anti-allergic, anti-asthmatic and
anti-psychotic agents, and some are neutral hydrogen chloride
acceptors in organic synthesis.4
Results and discussion
The reaction of aryl isothiocyanates 1 with dialkyl acetylene-
dicarboxylates 2 in the presence of pyridines 3 produces 2-
thioxo-1,9a-dihydro-2H-pyrido [1,2,a]pyrimidine derivatives
4a–g in excellent yields (Scheme 1).
The structures of compounds 4a–g were deduced from their
elemental analyses and their IR, H NMR, 13C NMR spectra.
1
The mass spectra of these compounds displayed molecular ion
peaks at appropriate m/z values.
The 1H NMR spectrum of compound 4a exhibited two single
sharp lines readily recognised as arising from methoxy protons
(3.78 and 3.96) along with four multiplets for the protons of an
electron rich diene and an allylic proton as well as characteris-
tic multiplets for the aromatic protons. The 13C NMR spectrum
of compound 4a showed 16 distinct signals in agreement with
the proposed structure. The 13C NMR spectrum of 4a showed
the thiocarbonyl resonance at δ = 194.08 ppm. The mass spec-
trum of 4a displayed the molecular ion peak at m/z = 356. The
IR spectrum of compound 4a also supported the suggested
structure.
As part of an ongoing development of efficient protocols
for the preparation of biologically active heterocycles,11,12 we
report here the results of our study on the reaction between
aryl isothiocyanates and dialkyl acetylenedicarboxylates in the
presence of pyridines.
Scheme 1 Reaction of aryl isothiocyanate and dialkyl acetylenedicarboxylates in the presence of pyridines.
* Correspondent. Email: ar_hasanabadi@yahoo.com

456 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 2 Suggested mechanism for formation of compound 4.
N–CH=CH), 7.18 (2H, d, J = 7.5 Hz, ortho CH), 7.31 (1H, dt, J =
2.4 Hz and J = 7.1 Hz, para CH), 7.38 (2H, t, J = 7.0 Hz, meta CH)
ppm. 13C NMR (125.8 MHz, CDCl3): δ 13.81, 14.27 (2CH3), 62.56,
62.77 (2OCH2), 69.37 (N-CH-N), 104.28, 105.19, 115.71, 123.52,
123.85, 127.74, 128.68, 129.52, 134.63 and 149.37 (aromatic and
olefinic), 163.04 and 164.76 (2C=O), 194.02 (C=S) ppm.
Dimethyl-8-methyl-1-phenyl-2-thioxo-1,9a-dihydro-2H-pyrido[1,2,a]-
pyrimidine-3,4-dicarboxylate (4c): Yellow powder; yield 88%; m.p.
124–126 °C, IR (KBr) (νmax/cm−1): 1735, 1643, 1350 and 1268. Anal.
Calcd for C19H18N2O4S, C, 61.61; H, 4.90; N, 7.56. Found: C, 61.65;
H, 4.86; N, 7.50%. MS (m/z, %): 370 (7).1H NMR (500 MHz, CDCl3):
δ 2.23 (3H, s, CH3), 3.73 and 3.92 (6H, 2s, 2OCH3), 5.21 (1H, d,
J = 3.1 Hz, CH), 5.35 (1H, d, J = 7.6 Hz, CH), 6.22 (1H, d, J = 3.1 Hz,
N–CH–N), 6.45 (1H, d, J = 7.6 Hz, N–CH=CH), 7.11 (2H, d, J =
7.5 Hz, ortho CH), 7.19 (1H, dt, J = 2.4 Hz and J = 7.1 Hz, para CH),
7.42 (2H, t, J = 7.0 Hz, meta CH) ppm. 13C NMR (125.8 MHz, CDCl3):
δ 18.54 (CH3), 52.31 and 53.60 (2OCH3), 69.55 (N-CH-N), 104.46,
105.27, 115.62, 123.30, 123.89, 127.75, 128.72, 129.50, 134.59 and
149.43 (aromatic and olefinic), 162.88 and 164.73 (2C=O), 193.85
(C=S) ppm.
Diethyl-8-methyl-1-phenyl-2-thioxo-1,9a-dihydro-2H-pyrido[1,2,a]-
pyrimidine-3,4-dicarboxylate (4d): Yellow powder; yield 82%; m.p.
107–109 °C, IR (KBr) (νmax/cm−1): 1740, 1652, 1353 and 1266. Anal.
Calcd for C21H22N2O4S, C, 63.30; H, 5.56; N, 7.03. Found: C, 63.27;
H, 5.44; N, 7.10%. MS (m/z, %): 398 (4). 1H NMR (500 MHz, CDCl3):
δ 1.22 and 1.36 (6H, 2t, J = 7.1 Hz, 2CH3), 2.20 (3H, s, CH3), 4.17–
4.38 (4H, m, 2OCH2), 5.10 (1H, d, J = 3.1 Hz, CH), 5.41 (1H, d,
J = 7.6 Hz, CH), 6.33 (1H, d, J = 3.1 Hz, N–CH–N), 6.44 (1H, d,
J = 7.6 Hz, N–CH=CH), 7.23 (2H, d, J = 7.5 Hz, ortho CH), 7.25 (1H,
dt, J = 2.4 Hz and J = 7.1 Hz, para CH), 7.39 (2H, t, J = 7.0 Hz, meta
CH) ppm. 13C NMR (125.8 MHz, CDCl3): δ 13.74, 14.25 (2CH3),
18.51 (CH3), 62.53, 62.74 (2OCH2), 69.42 (N-CH-N), 104.15, 105.22,
115.61, 123.50, 123.84, 127.63, 128.70, 129.55, 134.60 and 149.34
(aromatic and olefinic), 163.00 and 164.71 (2C=O), 193.90 (C=S)
ppm.
The formation of compounds 4 can be rationalised as shown
in Scheme 2. The first step may involve addition of the
pyridine to the dialkyl acetylenedicarboxylateand formation of
the 1:1 adduct 5. Subsequent nucleophilic attack of the adduct
to the aryl isothiocyanate would yield anion 6. The observed
product is formed from the intramolecular addition of the
nitrogen to the pyridinium moiety.
In summary, we have observed a three-component conden-
sation reaction that offers an easy and effective one-pot syn-
thesis of 2-thioxo-1,9a-dihydro-2H-pyrido [1,2,a]pyrimidine
derivatives. The present method has the advantage that the
reaction is performed under neutral conditions and the sub-
stances can be mixed without any activation or modification.
Experimental
Melting points were determined with an Electrothermal 9100 appara-
tus and are uncorrected. Elemental analyses were performed using a
Heraeus CHN-O-Rapid analyser. Mass spectra were recorded on a
FINNIGAN-MAT 8430 mass spectrometer operating at an ionisation
potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470
spectrometer. 1H and 13C NMR spectra were recorded on Bruker
DRX-500 Avance spectrometer at solution in CDCl3 using TMS as
internal standard. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without further
purification.
General procedure
A mixture of dialkyl acetylenedicarboxylate (1 mmol) in acetonitrile
(3 mL) via a syringe was added dropwise to a magnetically stirred
solution of aryl isothiocyanate (1 mmol) and pyridine in acetonitrile
(15 mL) at –5 °C over 10 min. The reaction mixture was then stirred
for 24 h at room temperature. The solvent was removed under reduced
pressure and the residue was purified by silica gel column chromato-
graphy using hexane–ethyl acetate as eluent. The solvent was removed
under reduced pressure and the resulting precipitate washed with cold
diethyl ether (10 mL) to afford the product.
Dimethyl-2-thioxo-1-ρ-tolyl-1,9a-dihydro-2H-pyrido[1,2,a]pyrimidine-
3,4-dicarboxylate (4e): Yellow powder; yield 91%; m.p. 134–136 °C,
IR (KBr) (νmax/cm−1): 1732, 1645, 1352 and 1261. Anal.Calcd for
C19H18N2O4S, C, 61.61; H, 4.90; N, 7.56. Found: C, 60.75; H, 4.83; N,
Dimethyl-1-phenyl-2-thioxo-1,9a-dihydro-2H-pyrido[1,2,a]pyrimidine-
3,4-dicarboxylate (4a): Yellow powder; yield 90%; m.p. 111–113 °C,
IR (KBr) (νmax/cm−1): 1734, 1648, 1358 and 1264. Anal.Calcd for
C18H16N2O4S, C, 60.66; H, 4.53; N, 7.86. Found: C, 60.50; H, 4.60; N,
1
7.60%. MS (m/z, %): 370 (4). H NMR (500 MHz, CDCl3): δ 2.41
(3H, s, CH3), 3.72 and 3.98 (6H, 2s, 2OCH3), 5.25 (1H, dd, J =
10.1 Hz and J = 3.1 Hz, CH), 5.32 (1H, dd, J = 6.9 Hz and J = 7.6 Hz,
CH), 6.08 (1H, dd, J = 8.3 Hz and J = 7.9 Hz, CH), 6.14 (1H, dd, J =
3.1 Hz and J = 1.9 Hz, N–CH–N), 6.49 (1H, d, J = 7.6 Hz, N–CH=CH),
7.21 (2H, d, J = 7.8 Hz, aromatic), 7.50 (2H, d, J = 7.8 Hz, aromatic)
ppm. 13C NMR (125.8 MHz, CDCl3): δ 21.44 (CH3), 52.45 and 53.58
(2OCH3), 68.95 (N–CH–N), 103.88, 105.26, 114.92, 123.59, 123.67,
128.35, 128.84, 129.97, 134.82 and 149.40 (aromatic and olefinic),
162.85 and 164.67 (2C=O), 193.53 (C=S) ppm.
1
7.94%. MS (m/z, %): 356 (10). H NMR (500 MHz, CDCl3): δ 3.78
and 3.96 (6H, 2s, 2OCH3), 5.17 (1H, dd, J = 10.1 Hz and J = 3.1 Hz,
CH), 5.36 (1H, dd, J = 6.9 Hz and J = 7.6 Hz, CH), 6.03 (1H, dd, J =
8.3 Hz and J = 7.9 Hz, CH), 6.18 (1H, dd, J = 3.1 Hz and J = 1.9 Hz,
N–CH–N), 6.47 (1H, d, J = 7.6 Hz, N–CH=CH), 7.16 (2H, d, J =
7.5 Hz, ortho CH), 7.26 (1H, dt, J = 2.4 Hz and J = 7.1 Hz, para CH),
7.36 (2H, t, J = 7.0 Hz, meta CH) ppm. 13C NMR (125.8 MHz, CDCl3):
δ 52.37 and 53.64 (2OCH3), 69.42 (N-CH-N), 104.34, 105.12, 115.79,
123.44, 123.78, 127.82, 128.60, 129.61, 134.72 and 149.24 (aromatic
and olefinic), 162.96 and 164.80 (2C=O), 194.08 (C=S) ppm.
Diethyl-1-phenyl-2-thioxo-1,9a-dihydro-2H-pyrido[1,2,a]pyrimidine-
3,4-dicarboxylate (4b): Yellow powder; yield 87%; m.p. 101–103 °C,
IR (KBr) (νmax/cm−1): 1736, 1645, 1351 and 1262. Anal.Calcd for
C20H20N2O4S, C, 62.48; H, 5.24; N, 7.29. Found: C, 62.55; H, 5.30; N,
7.41%. MS (m/z, %): 384 (5). 1H NMR (500 MHz, CDCl3): δ 1.16 and
1.35 (6H, 2t, J = 7.1 Hz, 2CH3), 4.12–4.34 (4H, m, 2OCH2), 5.15 (1H,
dd, J = 10.1 Hz and J = 3.1 Hz, CH), 5.33 (1H, dd, J = 6.9 Hz and
J = 7.6 Hz, CH), 6.07 (1H, dd, J = 8.3 Hz and J = 7.9 Hz, CH), 6.24
(1H, dd, J = 3.1 Hz and J = 1.9 Hz, N–CH–N), 6.45 (1H, d, J = 7.6 Hz,
Diethyl-2-thioxo-1-ρ-tolyl-1,9a-dihydro-2H-pyrido[1,2,a]pyrimidine-
3,4-dicarboxylate (4f): Yellow powder; yield 88%; m.p. 116–118 °C,
IR (KBr) (νmax/cm−1): 1737, 1643, 1354 and 1265. Anal.Calcd for
C21H22N2O4S, C, 63.30; H, 5.56; N, 7.03. Found: C, 63.26; H, 5.65; N,
1
7.10%. MS (m/z, %): 398 (7). H NMR (500 MHz, CDCl3): δ 1.22
and 1.34 (6H, 2t, J = 7.1 Hz, 2CH3), 2.35 (3H, s, CH3), 4.10–4.47 (4H,
m, 2OCH2), 5.11 (1H, dd, J = 10.1 Hz and J = 3.1 Hz, CH), 5.38 (1H,
dd, J = 6.9 Hz and J = 7.6 Hz, CH), 6.15 (1H, dd, J = 8.3 Hz and
J = 7.9 Hz, CH), 6.30 (1H, dd, J = 3.1 Hz and J = 1.9 Hz, N–CH–N),
6.46 (1H, d, J = 7.6 Hz, N–CH=CH), 7.26 (2H, d, J = 7.8 Hz, aroma-
tic), 7.52 (2H, d, J = 7.8 Hz, aromatic) ppm. 13C NMR (125.8 MHz,
CDCl3): δ 13.94, 14.25 (2CH3), 21.52 (CH3), 62.51, 62.80 (2OCH2),

JOURNAL OF CHEMICAL RESEARCH 2013 457
69.42 (N-CH-N), 104.25, 105.13, 114.70, 123.75, 123.94, 128.36,
128.72, 130.06, 134.51 and 149.32 (aromatic and olefinic), 163.12
and 164.80 (2C=O), 194.15 (C=S) ppm.
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Received 21 April 2013; accepted 20 May 2014
Paper 1301904 doi: 10.3184/174751913X13726957255037
Published online: 9 August 2013

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