Synthesis of heterocyclic compounds by reaction of dialkyl acetylenedicarboxylates with thiourea derivatives

Article abstract of DOI:10.1515/hc-2013-0041

Phosphorus ylides have been prepared in excellent yields by the three-component reaction of activated electron-deficient acetylenic esters (dimethyl and diethyl acetylenedicarboxylate) and thiourea derivatives in the presence of triphenylphosphine. In som

Full text of DOI:10.1515/hc-2013-0041

ꢁꢁꢁꢂ
ꢀHeterocycl. Commun. 2013; 19(4): 271–274
DOI 10.1515/hc-2013-0041ꢀ
Hossein Eshghi*, Mehdi Bakavoli, Javad Abedini-Torghabeh, Mohammad Rahimizadeh and
Amir Keykha
Synthesis of heterocyclic compounds by reaction
of dialkyl acetylenedicarboxylates with thiourea
derivatives
Abstract: Phosphorus ylides have been prepared in and anti-herpes simplex virus HSV-1 agents [8]. An earlier
excellent yields by the three-component reaction of acti- report has indicated that the reaction of dimethyl acety-
vated electron-deficient acetylenic esters (dimethyl and lenedicarboxylate (DMAD) with thienopyrimidine deriva-
diethyl acetylenedicarboxylate) and thiourea derivatives tives produces thienopyrimidothiazine derivatives. Some
in the presence of triphenylphosphine. In some cases, thienopyrimidothiazines are promising antitumor agents
these ylides were cyclized to dihydropyrimidothiazine, against Hep-G2 cells with IC50 ꢀ< ꢀ20 μm [9]. This study
thioxoimidazolidine, and thioxotetrahydropyrimidine aimed to test the reactivity of dialkyl acetylenedicarboxy-
derivatives.
lates towards thiourea derivatives in the presence of triph-
enylphosphine [10–13] (Schemes 1 and 2).
Keywords: DEAD; DMAD; thiourea derivatives;
triphenylphosphine.
Results and discussion
*Corresponding author: Hossein Eshghi, Department of Chemistry,
School of Sciences, Ferdowsi University of Mashhad, P.O. Box
91775-1436, Mashhad, Iran, e-mail: heshghi@um.ac.ir
Mehdi Bakavoli, Javad Abedini-Torghabeh, Mohammad
Rahimizadeh and Amir Keykha: Department of Chemistry, School of
Sciences, Ferdowsi University of Mashhad, Mashhad, Iran
The structures of products 3a–c and 4a–c were deduced
1
1
from their IR, H NMR, and 13C NMR spectral data. The H
O
O
MeO
N
S
N
4a
Introduction
[3d]
Electron-deficient acetylenic esters are versatile reagents
for the preparation of stable phosphorus ylides [1, 2]. The
reactions of dialkyl acetylenedicarboxylates with 2-mer-
captopyrimidine and 2-mercapto-4,6-dimethylpyrimidine
in the presence of triphenylphosphine leads to stable
phosphorus ylides [3]. Recently, a simple synthesis of
stable phosphorus ylides derived from imidazolidine-
2-thione [4], one-pot synthesis of α-amino esters with
β-phosphorus substituents [5], chemoselective synthe-
sis of sulfur containing organic compounds, and three-
component reaction among triphenylphosphine, dialkyl
acetylenedicarboxylate, and 4-amino-5-alkyl-2,4-dihydro-
1,2,4-triazole-3-thiones have been reported [6]. Several
heterocyclic compounds possessing a bridgehead thia-
zole or thiazine moiety play a vital role in many biologi-
cal activities [7]. Such heterocyclic systems have found
n = 2, R = Me
S
COOR
S
Ph3P
H
PPh3
HN
NH
HN
N
Toluene
∆, 2h
ROOC
COOR
n
COOR
n
1a-b
2a-b
O
PPh3
1a: R = Me
OR
1b: R = Et
RO
2a: n = 2
O
N
2b: n = 1
S
3a: n = 2, R = Et
3b: n = 1, R = Me
3c: n = 1, R = Et
HN
3a-c
n
[3d]: n = 2, R = Me
broad application in drug development as the anti-HIV-1 Scheme 1ꢀ
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272ꢀ ꢀH. Eshghi et al.: Reaction of dialkyl acetylenedicarboxylates with thiourea derivatives
EtOOC
Ph
O
O
PPh3
O
PPh3
O
PPh3
N
NH
OMe
O
O
MeO
MeO
MeO
S
O
S
N
S
N
N
S
N
4c
N
N
- MeOH
[3d]
H
S
Ph3P
H
S
PPh3
1a-b
O
PPh3
O
O
H2N
NHPh
H3N
NPh
Toluene ROOC
∆, 2h
COOR
O
S
MeO
MeO
N
S
N
N
-PPh3
N
4a
O
MeOOC
Scheme 4ꢀ
NH
N
Ph
S
4b-(Z): 55%,4b-(E): 45%
In other cases, nucleophilic attack of primary amine com-
petes with thione attacks. In the case of methyl esters,
the formation of a five-membered ring is favored but with
ethyl esters a six-membered ring is formed by attack on
Scheme 2ꢀ
NMR and 13C NMR spectra of phosphorus ylides 3a–c are the reactive carboxyl group.
consistent with a mixture of two rotational isomers. The
1
The H NMR spectrum of 3a is consistent with the
ylide moiety of these compounds is strongly conjugated given structure. The 13C NMR spectrum of 3a displays 34
with the adjacent carbonyl group, and rotation about the distinct resonances in agreement with the presence of a
partial double bond in 3-(E) and 3-(Z) geometrical isomers mixture of two rotamer structures. Although the presence
1
is low on the NMR timescale at ambient temperature of the 31P nucleus complicates both the H NMR and 13C
(Scheme 3).
NMR spectra of 3a, it helps in the assignment of signals
1
Stable rotamers of phosphoranes have been pre- by long-range spin-spin couplings with H and 13C nuclei.
viously reported in the literature [14–16]. However, in The 1H NMR and 13C NMR spectra of 3b and 3c are similar
cyclized products 4a–c, only in 4b two isomers which to those of 3a, except for the signals from the ester groups.
correlate with E and Z isomers of exo double bonds are The structural assignments made for phosphoranes 3a–c
1
observed. We suggest that in the intermediate product on the basis of the H NMR and 13C NMR spectra are also
3d a nucleophilic attack of secondary amine is restricted supported by their IR spectra.
and only thione attack is possible to give 4a (Scheme 4).
Conclusion
The procedure described herein provides an acceptable
O
O
H
PPh3
PPh3
OR1
method for preparation of highly stable phosphorus
ylides. In some cases, these ylides can be cyclized to dihy-
dropyrimidothiazine, thioxoimidazolidine, and thioxotet-
rahydropyrimidine derivatives.
O
R1O
S
R1O
S
OR1
O
N
N
R2
R2
R3
R3
N
N
H
3-(E)
3-(Z)
Experimental
MeO
O
O
O
MeO
NH
NH
O
General
N
N
Ph
4b-(Z)
Scheme 3ꢀ
Ph
4b-(E)
S
S
Melting points were measured on an Electrothermal 9100 melting
point apparatus and are uncorrected. IR spectra were measured on
an AVATAR 370 FT-IR Thermo Nicolet Infrared spectrophotometer. 1H
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H. Eshghi et al.: Reaction of dialkyl acetylenedicarboxylates with thiourea derivativesꢀ
ꢀ273
and 13C NMR spectra were recorded on a BRUKER DRX-400 AVANCE
spectrometer at 400 MHz and 100 MHz, respectively.
Hz, Cipso); IR: ν 3464, 1742, 1631 cm-1. Anal. Calcd for C27H27N2O4PS: C,
64.02; H, 5.37; N, 5.53; S, 6.33. Found: C, 63.95; H, 5.34; N, 5.51; S, 6.35.
(Data for two rotamers.)
Diethyl
2-(2-thioxoimidazolidin-1-yl)-3-(triphenylphosphor-
General procedure for the preparation of
phosphorus ylides 3a–f and compounds
4a–c
At ambient temperature, dimethyl acetylenedicarboxylate (0.24 mL,
2 mmol) was added dropwise to a stirred solution of triphenylphos-
phine (0.53 g, 2 mmol) and a thiourea derivative (2 mmol) in toluene
(7 mL). Afer the addition was complete (approximately 10 min), the
mixture was heated under reflux for an additional 2 h. The solvent
was removed under reduced pressure and the residue was crystal-
lized from ethyl acetate and then from ethanol.
anylidene) succinate (3c)ꢀWhite powder; yield 89% for the mix-
1
ture, 65% for major isomer (Z)-3c; mp 184–186°C; H NMR (DMSO-
3
3
d6) for (Z)-3c: δ 0.35 (t, JHH ꢀ= ꢀ 7.2 Hz, CH3), 1.25 (t, JHH ꢀ= ꢀ 7.2 Hz, CH3),
3
2.40–2.60 (m, 8H, 4CH2), 3.41–4.35 (m, 8H, 4CH2), 4.85 (d, JPH ꢀ= ꢀ 18.5
Hz, Pꢀ= ꢀC-CH), 7.34–7.71 (m, 30H, arom) 7.9 (s, 1H, NH); yield 35% for
minor isomer (E)-3c; 1H NMR (DMSO-d6): δ 1.25 (t, 3JHH ꢀ= ꢀ 7.2 Hz, CH3),
3
3
1.34 (t, JHH ꢀ= ꢀ 7.1 Hz, CH3), 5.21(d, JPH ꢀ= ꢀ20.4 Hz, Pꢀ= ꢀC-CH), 7.82 (s, 1H,
NH); IR ν 3431, 1743, 1633. Anal. Calcd for C29H31N2O4PS: C, 65.15; H,
5.84; N, 5.24; S, 6.00. Found: C, 65.12; H, 5.81; N, 5.22; S, 5.97. (Data for
two rotamers.)
Methyl 2-oxo-2,6,7,8-tetrahydropyrimido[2,1-b][1,3]thiazine-4-
1
Diethyl 2-(2-thioxotetrahydropyrimidin-1(2H)-yl)-3-(triphenyl-
phosphoranylidene) succinate (3a)ꢀYellowish powder; yield
96% for the mixture, 71% for major isomer (Z)-3a; mp 191–193°C; 1H
NMR (DMSO-d6) for (Z)-3a: δ 0.33 (t, 3JHH ꢀ= ꢀ 7.2 Hz, CH3), 1.33 (t, 3JHH ꢀ= ꢀ
7.2 Hz, CH3), 1.81–1.90 (m, 2CH2), 3.01–3.10 (m, 4CH2), 3.45–4.13 (m,
carboxylate (4a)ꢀYellowish powder; yield 86%; mp 173–175°C; H
NMR (CDCl3): δ 2.05 (m, 2H, CH2), 3.61–3.92 (m, 4H, CH2), 3.90 (s, 3H,
CH3), 6.90 (s, 1H, CH); 13C NMR (CDCl3): δ 19.5, 40.5, 46.8, 52.5, 115.2,
142.2, 150.3, 163.6, 166.5; IR: ν 1720, 1689. Anal. Calcd for C9H10N2O3S:
C, 47.78; H, 4.45; N, 12.38; S, 14.17. Found: C, 47.80; H, 4.43; N, 12.37;
S, 14.15.
3
4CH2), 5.79 (d, JPH ꢀ= ꢀ 18.8 Hz, Pꢀ= ꢀC-CH), 7.53–7.66 (m, 30H, arom); 13C
NMR (DMSO-d6) for (Z)-3a: δ 14.2 and 14.7 (2CH3), 21.4 (2CH2), 57.3,
1
2
and 60.4 (2OCH2), 41.9 (d, JPC ꢀ= ꢀ 126.4 Hz, Pꢀ= ꢀC), 63.5 (d, JPC ꢀ= ꢀ 18.0
Methyl 2-(5-oxo-3-phenyl-2-thioxoimidazolidin-4-ylidene) ace-
1
3
Hz, Pꢀ= ꢀC-CH), 126.7 (d, JPC ꢀ= ꢀ 90.0 Hz, Cipso), 129.4 (d, JPC ꢀ= ꢀ 12.0 Hz,
Cmeta), 132.6 (d, 4JPC ꢀ= ꢀ 2.0 Hz, Cpara), 133.6 (d, 2JPC ꢀ= ꢀ 9.0 Hz, Cortho), 169.0
(d, 2JPC ꢀ= ꢀ 13.0 Hz, 2Cꢀ= ꢀO), 171.8 (d, 3JPC ꢀ= ꢀ 15.0 Hz, 2Cꢀ= ꢀO), 177.4 (1Cꢀ= ꢀS);
tate (4b)ꢀYellow powder; yield 84% for the mixture, 55% for major
1
isomer (Z)-4b; mp 246–249°C H NMR (DMSO-d6) for (Z)-4b: δ 3.95
(s, 3H, CH3), 6.75 (s, 1H, Cꢀ= ꢀCH), 12.2 (2H, broad, NH); yield 29% for
1
yield 25% for minor isomer (E)-3a; H NMR (DMSO-d6) for (E)-3a: δ
1
minor isomer (E)-4b; H NMR (CDCl3) for (E)-4b: δ 3.81 (s, 3H, CH3),
3
3
3
0.98 (t, JHH ꢀ= ꢀ 7.2 Hz, CH3), 1.28 (t, JHH ꢀ= ꢀ 7.1 Hz, CH3), 5.83 (d, JPH ꢀ= ꢀ
6.65 (s, 1H, Cꢀ= ꢀCH); 13C NMR (CDCl3) for (E)-4b: δ 52.0, 107.0, 128.4,
129.0, 133.0, 152.7, 164.7, 165.6, 166.4; IR: ν 3280, 1711, 1681. Anal. Calcd
for C12H10N2O3S: C, 54.95; H, 3.84; N, 10.68; S, 12.23. Found: C, 54.94; H,
3.81; N, 10.64; S, 12.19. (Data for two isomers.)
20.4 Hz, Pꢀ= ꢀC-CH) ppm; 13C NMR (DMSO-d6) for (E)-3a: δ 14.6 and 15.1
1
(2CH3), 58.0 and 60.4 (2OCH2), 41.5 (d, JPC ꢀ= ꢀ 128.4 Hz, Pꢀ= ꢀC), 62.8 (d,
2JPC ꢀ= ꢀ 17.9 Hz, Pꢀ= ꢀC-CH), 126.0 (d, 1JPC ꢀ= ꢀ 91.0 Hz, Cipso), 177.8 (1Cꢀ= ꢀS); IR:
ν 3444, 1743, 1732 cm-1. Anal. Calcd for C30H33N2O4PS: C, 65.68; H, 6.06;
N, 5.11; S, 5.84. Found: C, 65.65; H, 6.04; N, 5.08; S, 5.81. (Data for two
rotamers.)
Ethyl 6-oxo-3-phenyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-
carboxylate (4c)ꢀYellow powder; yield 85%; mp 182–185°C;
3
3
1H NMR (CDCl3): δ 1.31 (t, JHH ꢀ= ꢀ 7.2 Hz, CH3), 4.25 (q, JHH ꢀ= ꢀ 7.5 Hz,
CH2), 6.9 (s, 1H, Cꢀ= ꢀCH), 7.17–7.45 (m, 5H, arom), 8.57 (s, 1H, NH); 13C
NMR (CDCl3): δ 14.1, 61.9, 117.6, 122.6, 125.1, 126.7, 127.8, 129.6, 130.2,
142.4, 166.1, 169.6, 181.2; IR: ν 3422–3272, 1685, 1708. Anal. Calcd for
C13H12N2O3S: C, 56.51; H, 4.38; N, 10.14; S, 11.60. Found: C, 56.47; H,
4.34; N, 10.12; S, 11.57.
Dimethyl 2-(2-thioxoimidazolidin-1-yl)-3-(triphenylphosphor-
anylidene) succinate (3b)ꢀWhite powder; yield 95% for the mix-
ture, 58% for major isomer (Z)-3b; mp 267–271°C (dec.); 1H NMR
(CDCl3) for (Z)-3b: δ 3.75 (s, 3H, CH3), 3.78 (s, 3H, CH3), 3.81–4.10 (m,
3
8H, 2CH2), 5.01 (d, JPH ꢀ= ꢀ 18.8 Hz, Pꢀ= ꢀC-CH), 7.25–7.76 (m, 30H, arom),
7.65 (s, 1H, NH); 13C NMR (CDCl3) for: δ 39.51 and 39.86 (2CH3), 43.75
and 44.03 (2CH2), 49.0 (d, 1JPC ꢀ= ꢀ 125.4 Hz, Pꢀ= ꢀC), 51.8 (d, 2JPC ꢀ= ꢀ 17.5 Hz,
1
3
Pꢀ= ꢀC-CH), 126.5 (d, JPC ꢀ= ꢀ 90.0 Hz, Cipso), 129.0 (d, JPC ꢀ= ꢀ 11.5 Hz, Cmeta),
Acknowledgment: We are grateful to the Department
of Chemistry, Ferdowsi University of Mashhad, Iran for
financial support (grant no. 49-P-24–01–89).
133.4 (d, 4JPC ꢀ= ꢀ 2.0 Hz, Cpara), 132.5 (d, 2JPC ꢀ= ꢀ 8.5 Hz, Cortho), 181.3 (d, 2JPC ꢀ= ꢀ
3
12.5 Hz, 2Cꢀ= ꢀO), 181.3 (d, JPC ꢀ= ꢀ 14.5 Hz, 2Cꢀ= ꢀO); yield 37% for minor
1
isomer (E)-3b; H NMR (CDCl3) for (E)-3b: δ 3.55 (s, 3H, CH3), 3.76 (s,
3H, CH3), 5.15 (d, JPH ꢀ= ꢀ 20.4 Hz, Pꢀ= ꢀC-CH), 7.78 (s, 1H, NH); 13C NMR
3
(CDCl3) for (E)-3b: δ 41.1 and 41.2 (2CH3), 43.8 and 44.1 (2CH2), 49.9 (d, Received March 13, 2013; accepted April 16, 2013; previously
1JPC ꢀ= ꢀ 127.3 Hz, Pꢀ= ꢀC), 51.9 (d, 2JPC ꢀ= ꢀ 17.5 Hz, Pꢀ= ꢀC-CH), 125.3 (d, 1JPC ꢀ= ꢀ 92.5 published online July 6, 2013
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