Investigations on the reactions of thioamides and related 1,3-diazabuta-1,3-dienes with dimethyl acetylenedicarboxylate: Synthesis of novel functionalized heterocycles

Article abstract of DOI:10.3987/COM-08-S(N)27

The manuscript describes an investigation on the reaction pathways followed in the reactions of variedly substituted thioamides and the corresponding 1,3-diazabuta-1,3-dienes with dimethyl acetylene dicarboxylate. The mechanistic rationales for the reacti

Full text of DOI:10.3987/COM-08-S(N)27

HETEROCYCLES, Vol. 76, No. 2, 2008
1087
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1087 - 1102. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd March, 2008, Accepted, 13th May, 2008, Published online, 15th May, 2008. COM-08-S(N)27
INVESTIGATIONS ON THE REACTIONS OF THIOAMIDES AND
RELATED
ACETYLENEDICARBOXYLATE:
1,3-DIAZABUTA-1,3-DIENES WITH
SYNTHESIS
DIMETHYL
OF NOVEL
FUNCTIONALIZED HETEROCYCLES
Alka Marwaha, Vishal Sudan, and Mohinder P. Mahajan*
Department of Applied Chemistry, Guru Nanak Dev University, Amritsar – 143005,
Punjab, India
Phone +91 (0183)2258802-09* 3320, Fax +91(183)2258819-20
E-mail: mahajanmohinderp@yahoo.co.in
Abstract – The manuscript describes an investigation on the reaction pathways
followed in the reactions of variedly substituted thioamides and the corresponding
1,3-diazabuta-1,3-dienes with dimethyl acetylene dicarboxylate. The mechanistic
rationales for the reactions pathways followed have been plausibly explicated. The
study assumes considerable significance because of the formation of novel
functionalized heterocycles.
INTRODUCTION
In the last few decades there has been a rapid surge in the synthesis of the compounds containing thioamide
moiety because of the remarkable pharmacological potential and diverse range of biological properties such
as bactericides, radical scavangers, in congenital hypothyroidism and anticarcinogenic agents etc. possessed
by such scaffolds. Simple modifications of the fragments linked up with the thiocarbonyl group or with the
thioamide nitrogen atom may give rise to the formation of new reactive centers and thus opens up
functionalization possibilities.1 Much work has been done on the functionalization of thioamides and their
use in organic synthesis, including regio- and stereo-selective heterocyclization reactions.2 Reactions of
acetylenic esters with thioamides are known to generate various heterocyclic compounds such as
thiazolidinones,3a thiazolinones,3b thiazonones,3c thiazolotriazinediones.3c However, the reactions of
thioamides with dimethyl acetylenedicarboxylate are studied to a lesser extent. Recently, Bakulev et al.

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HETEROCYCLES, Vol. 76, No. 2, 2008
reported the reactions of 5-mercaptazoles and pyridine-2-thiones with DMAD.3d Recently, Nakano et al.
reported the reactions of thioamides with two and five equivalents of DMAD leading to the formation of
pyrrole and thiophene derivatives, respectively.4 As part of our continuing interest in the synthesis of
biologically important heterocycles,5 in a recent communication,6 we have reported a single pot synthesis of
functionalized imidazole derivatives by the reaction of thioamides 1 with DMAD. The present manuscript
describes a detailed investigation of the reactions of variedly substituted thioamides with DMAD in order to
examine the reaction pathways followed and the nature of the products formed.
RESULTS AND DISCUSSION
A solution of secondary amino-N-carbothioic acid (phenyl-p-toylimino-methyl) amides popularly known as
thioamides 1 (1 mmol) and DMAD (1.2 mmol) was stirred in dry dichloromethane for 2-3hrs at room
temperature. Interestingly, these reactions did not yield either the thiazines or any of the heterocyclic
compounds like thiazolidinones,3a thiazolinones,3b thiazinones,3c thiazolotriazinediones3c etc. as expected
based on the literature reports. Instead, the purification of reaction mixture by silica gel chromatography gave
the isolated products as imidazoles 2, characterized on the basis of spectral evidences (Scheme 1).
R
R
CO2Me
Ph
HN
N
+
Ph
N
CO2Me
R1
S
CO2Me
N
R1
2
1
N
a. R = Me, R1 =
b. R = Me, R1 =
c. R = Me, R1 =
d. R = Me, R1 =
NMe2
g. R = H, R1 =
h. R = H, R1 =
i. R = H, R1 =
N
N
O
N
N
O
N
N
j. R = H, R1 =
N
H
N
e. R = Me, R1 =
f. R = H, R1 =
k. R = Cl, R1 =
l. R = Cl, R1 =
NMe2
N
N
H
NMe2
Scheme 1

HETEROCYCLES, Vol. 76, No. 2, 2008
1089
The
1H
NMR
spectrum
of
compound
2a,
for
example,
characterized
as
5-dimethylamino-2-phenyl-3-p-tolyl-3H-imidazole-4-carboxylic acid methyl ester, exhibited singlets at δ
3.08 (6H) and 3.63 (3H) corresponding to the -NMe2 and the -OMe protons, respectively, and a multiplet
13
for the aromatic protons at δ 7.06-7.35 (9H). The C NMR spectrum exhibited signals at δ 21.2 (CH3),
42.7 (NMe2), 50.7 (OMe), 158.6 (-C=N) and 160.3 (-C=O) ppm. Its IR spectrum showed a carbonyl
absorption at 1689 cm-1 whilst the mass spectrum exhibited a molecular ion peak [M+] at m/z = 335 for
C20H21O2N3. The structure was unambiguously established with the help of x-ray crystallographic studies.
The ORTEP diagram of 2a is shown in the Figure 1 and the crystal data for the structure refinement of 2a
has been provided in the experimental. The crystal structure studies exhibit that in the five-membered
imidazole ring system the C5-N1, C2-C3 distances are 1.327(3) Å and 1.397(3) Å, respectively indicating
the double bond character in these bonds. The angles inside the five member ring are in the range
104.9(2)° for C2-C3-N4 and 111.4(2)° for N4-C5-N1. The average value of these five angles is 107.98°.
The bond distance of 1.192(3) Å between C22-O23 corresponds to a normal C=O bond.
A plausible mechanism underlying the formation of the imidazole derivatives is shown in Scheme 2.6
Me
Me
N
Me
N
CO2Me
CO2Me
H
CO2Me
CO2Me
CO2Me
CO2Me
Ph
N
S
Ph
Ph
HN
+
N
N
S
S
Me2N
NMe2
NMe2
4
3
1a
Me
Me
N
Me
CO2Me
CO2Me
CO2Me
Ph
N
N
S
CO2Me
CO2Me
Ph
N
H
Ph
CO2Me
S
N
N
S
NMe2
Me2N
NMe2
7
5
6
S
-
H
CO2Me
Me
N
Ph
CO2Me
NMe2
Scheme 2
N
2a

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HETEROCYCLES, Vol. 76, No. 2, 2008
The sulfur atom of thioamide being nucleophilic attacks one of the acetylenic carbons of DMAD to form
and intermediate 3, which undergoes intramolecular cyclization to give thiocarbonyl ylide 5 via another
intermediate 4. Thiocarbonyl ylide 5 is then converted to thermodynamically more stable azomethine ylide
6, which after intramolecular cyclization leads to the formation of bicyclic intermediate 7. This bicyclic
intermediate being unstable dissociates to give imidazole 2 after the facile elimination of a thioaldehyde
molecule.
Figure 1. ORTEP Diagram of 2a
Thus, the reactions of thioamides 1 with DMAD have provided a single-pot and exclusive synthetic route
leading to novel imidazole derivatives via a cyclic azomethine ylide intermediate. Imidazoles are a
common integral of a large number of natural products and pharmacologically active molecules.7 The
prevalence and prominence of this component makes methods, which expedite their preparation, highly
valuable. The method reported herein assumes significance because of the regio-specific introduction of
latent amine and carbomethoxy (-CO2Me) groups, which are amenable to further elaboration through N-C
and N-heteroatom bond formation thereby leading to the concise syntheses of purine analogues. Such
poorly represented functionalized imidazoles having latent/masked amine functionality are nevertheless
the potential pre-constructed heterocyclic precursors in the succinct synthesis of purine analogues,8a
interesting insecticides,8b alkaloids8c and other natural products.8d
In view of the interesting synthetic and mechanistic chemistry followed in the above reactions, it was
thought worthwhile to extend these studies to the reactions of thioamides 8 obtained by replacing the
secondary amine moiety at the thiocarbonyl carbon of 1 with primary arylamine function. Accordingly, the
treatment of a solution of thioamide 8 (1 mmol) with DMAD (1.2 mmol) in dry dichloromethane at room

HETEROCYCLES, Vol. 76, No. 2, 2008
1091
temperature for 15-18 h resulted in the formation of products which were characterized as
(4-Oxo-2-benzoylimino-3-aryl-thiazolidin-5-ylidene)-acetic acid methyl ester derivatives 9 on the basis of
analytical data and spectral evidences (Scheme 3). The 1H NMR spectra of the products showed the absence
of one of the methoxy group and presence of a characteristic olefinic/vinylic proton. Their elemental
analyses showed the presence of sulfur.
R1
O
CO2Me
dry DCM
N
H
S
N
+
N
HN
S
CO2Me
CO2Me
O
HN
R
9
8
R
a. R = Me, R1 = H
b. R = Me, R1 = Me
c. R = H, R1 = Me
d. R = H, R1 = H
e. R = Me, R1 = Cl
Scheme 3
The 1H NMR spectrum of compound 9a, for example, characterized as (2-benzoylimino-
4-oxo-3-p-tolyl-thiazolidin-5-ylidene)-acetic acid methyl ester, exhibited a singlet at δ 3.91 (3H)
corresponding to the -OMe protons and a singlet characteristic of a vinylic proton at δ 7.06 (1H). The signals
for the carbonyl carbons appeared at δ 164.9, 165.4 and 176.9 ppm, in its 13C NMR spectrum. The IR spectrum
of 9b showed three carbonyl absorption at 1615, 1719 and 1731 cm-1 respectively, whilst the mass spectrum
exhibited a molecular ion peak [M+] at m/z = 380 for C20H16O4N2S. The assigned structure was unambiguously
established with the help of X-ray crystallographic studies (ORTEP diagram, Figure 2)9 and the crystal data for
the structure refinement of 9a has been provided in the experimental.
A plausible mechanism underlying the formation of thiazolidinone derivatives 9 is shown in the Scheme 4. It
is assumed that sulfur being a strong nucleophile attacks one of the acetylenic carbons of DMAD to give a 1:1
adduct, which undergoes N-H proton migration to generate 10. Intramolecular cyclization of 10 after the facile
elimination of a molecule of CH3OH yields 11. The iminic nitrogen of the product thus formed 11, by some
obscure mechanism, undergoes hydrolysis eventually to form the final product 9, after the elimination of
primary amine (Path I, Scheme 4).

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HETEROCYCLES, Vol. 76, No. 2, 2008
R1
N
R1
N
H
S
CO2Me
OMe
O
CO2Me
N
HN
S
CO2Me
NH
NH
10
R
R
8
R1
O
N
hydrolysis
R1
N
N
H
CO2Me
N
S
-
NH2
H
N
S
CO2Me
O
O
R
9
R
11
Scheme 4
Thus the reactions of thioamides 1 and 8 with DMAD resulted in the unprecedented formation of
imidazoles and thiazolidin-5-ylidene-acetic acid methyl esters, respectively, of significant synthetic and
pharmaceutical value.10
Figure 2. ORTEP Diagram of 9a
As a part of our continued interest in the chemistry of 1,3-diazabuta-1,3-dienes,11 we have also explored the
reactions of diazabutadienes 12 with DMAD. The present work also describes an unprecedented reaction
pathway and a thorough rationalization of the reaction mechanism followed in these reactions.

HETEROCYCLES, Vol. 76, No. 2, 2008
1093
Thus, a solution of diazabutadiene 12 (4 mmol) and DMAD (4.2 mmol) in dry dichloromethane was
allowed to stir at r.t. for 15-18 h. The completion of the reaction was ensured with the help of TLC. The
crude reaction mixture on separation by silica gel column chromatography gave products 13 and 14 as
shown in Scheme 5. The products 13 and 14 were characterized as dihydropyrimidine-4,5-dicarboxylic
esters and imidazoles, respectively on the basis of spectral evidences and analytical data. The compound
13a, for example, characterized
as
2-Phenyl-6-phenylimino-3-p-tolyl-3,6-dihydro-pyrimidine-4,5-
dicarboxylic acid dimethyl ester. It exhibited a singlet at δ 2.43 corresponding to methyl protons, two
singlets at δ 3.59 and 3.62 corresponding to methoxy protons (2 × OMe), two doublets at δ7.05 and 7.24 (J
= 7.4 Hz) for two sets of two protons each of p-tolyl group and a multiplet at δ 7.32-7.53 corresponding to
the aromatic protons (10H) in its 1H NMR spectrum. Its mass spectrum exhibited molecular ion peak [M+]
at m/z = 453. The signals in its 13C NMR spectrum also attest to the assigned structure. On the other hand,
the compound 14a, analyzed for C19H18O2N2S, exhibited three singlets at 2.41, 2.72 and 3.75 corresponding
to methyl (3H), thiomethyl (3H) and methoxy protons (3H). Its mass spectrum exhibited a molecular ion
peak [M+] at m/z = 338.
R1
R1
R1
CO2Me
CO2Me
Ph
N
Ph
N
N
CO2Me
CO2Me
dry DCM
N
CO2Me
+
N
+
N
N
SMe
SMe
HN
R2
14
13
R2
12
a. R1 = Me, R2 = H
b. R1 = H, R2 = Me
c. R1 = Me, R2 = Me
d. R1 = Me, R2 = Cl
e. R1 = H, R2 = H
f. R1 = H, R2 = Cl
Scheme 5
The most plausible mechanism underlying the formation of the products 13 and 14 is depicted in the
Scheme 6. The formation of the product 13 can be explained via path I which involves the nucleophilic
attack of N-1 of the diazadiene resulting in the formation of a cyclic adduct 15 which then underwent the
elimination of methyl thio group to form the adduct 13. The formation of 14 can be explained by the initial
nucleophilic attack of N-1 of the diazadiene at the acetylenic carbon of DMAD to form 1:1 adduct, which
undergoes NH proton migration to form 16 (path-II). Intramolecular cyclization of 16 generates azomethine
ylide 17. This azomethine ylide undergoes further intramolecular cyclization to form an unstable bicyclic

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HETEROCYCLES, Vol. 76, No. 2, 2008
intermediate 18, which after the loss of an imine forms the desired imidazole 14 as shown in the Scheme 6.
R1
R1
R1
CO2Me
CO2Me
N
N
CO2Me
CO2Me
path-I
N
CO2Me
CO2Me
N
N
SMe
MeS
NH
HN
R2
R2
13
15
R2
R1
R1
12
R1
N
CO2Me
CO2Me
N
CO2Me
CO2Me
CO2Me
N
N
N
path-II
N
N
MeS
17
N
SMe
MeS
CO2Me
R2
HN
R2
R2
12
16
R1
N
CO2Me
CO2Me
R2
N
N
N
MeS
CO2Me
N
-
SMe
N
R2
18
MeO2C
14
Scheme 6
EXPERIMENTAL
GENERAL REMARKS
Melting points were determined by open capillary method using Veego Precision Digital Melting Point
apparatus (MP-D) and are uncorrected. IR spectra were recorded on a Shimadzu D-8001
1
spectrophotometer. H NMR spectra were recorded in deuterochloroform with Brucker AC-E 200
(200MHz) and AC-E 300 (300MHz) spectrometers using TMS as internal standard. Chemical shift values
are expressed as δ (ppm) downfield from TMS and J values are in Hz. Splitting patterns are indicated as
13
s: singlet, d: doublet, t: triplet, m: multiplet, q: quartet and br: broad peak. C-NMR spectra were also
recorded on a Brucker AC- 200E (50.4 MHz) or Brucker AC-300E (75.0 MHz) spectrometers in a
deuterochloroform using TMS as internal standard. Mass spectra were recorded on Shimadzu

HETEROCYCLES, Vol. 76, No. 2, 2008
1095
GCMS-QP-2000 mass spectrometer. Elemental analyses were performed on Heraus CHN-O-Rapid
Elemental Analyzer. Column chromatography was performed on a silica gel (60-120) mesh or Harrison
Research Chromatotron using 2 mm plates (Silica gel 60 PF254).
STARTING MATERIALS
All the thioamides 1 and 8 were prepared by reported procedures.12a All the dienes 1 were prepared by
reported procedures.12b Dimethyl acetylenedicarboxylate (DMAD) was commercially available.
Dichloromethane (CH2Cl2) dried over di-phosphorous pentoxide and stored over molecular sieve (4Ǻ).
General procedure for the reaction of thioamides 1 and DMAD
A solution of thioamides 1 (4 mmol) and DMAD (4.2 mmol) in dry CH2Cl2 was stirred at rt for about 4-5
h. The progress of the reaction was checked with the help of TLC monitoring. After the completion of the
reaction, the mixture was concentrated under vacuo and the crude reaction mixture thus obtained was
chromatographed on 60-120-mesh silica gel to yield imidazoles 2 [eluent:: 1 : 5 = EtOAc : hexane]. The
products were recrystallized from 1 : 2 = CH2Cl2 : hexane.
5-Dimethylamino-2-phenyl-3-p-tolyl-3H-imidazole-4-carboxylic acid methyl ester (2a):
o
1
White crystalline solid; mp 139-140 C, Yield: 71%; IR (KBr) νmax : 1689 cm-1; H NMR (200 MHz;
CDCl3; Me4Si) : δ 2.38 (s, 3H,-CH3), 3.08 (s, 6H, -N(CH3)2 , 3.63 ( s, 3H, -OCH3), 7.06-7.35 (m, 9H, arom);
13C NMR (200 MHz, CDCl3, Me4Si) δ 21.2 (-CH3), 42.7 (-N(CH3)2), 50.7 (-OCH3), 108.7, 127.8, 127.9,
128.7, 128.9, 129.2, 129.9, 135.6, 138.2, 148.1, 158.6 (-C=N) and 160.3 (-C=O); MS: m/z 335; Anal. Calcd
for C20H21O2N3 : C, 71.64; H, 6.27; N, 12.54. Found: C, 71.59; H, 6.30; N, 12.61%.
Crystal data and structure refinement for 2a (JS04):
CCDC 235730; Empirical formula:C20H21N3O2; Formula Weight: 335.40; Temperature: 293(2) K;
Wavelength: 0.71073 Å; Crystal system: Monoclinic; Space group: P21; Unit cell dimensions: a=
5.9295(6) Å, a=90o, b=10.0750(10) Å, b=92.603(2)o, c=14.9191(15) Å, g=90o; Volume:890.34(15) Å3;
Z:2; Density(calculated): 1.251 Mg/m3; Absorption coefficient: 0.082 mm-1; F(000):356; Theta range for
data collection: 2.44 to 28.03o; Index ranges: -7<=h<7,-13<=k<=13,-19<=l<=17 Reflection collected:
5480 Independent reflections: 3626[R(int)=0.0164] Completeness to theta: 28.03o 95.6%; Refinement
2
2:
method: Full-matrix least-squares on F ; Data/restraints/parameters:3626/1/230; Goodness-of-fit on F
1.031; Final indices [I>2sigma(I)]; R1=0.0482, wR2=0.1183; indices (all
R
R
data):R1=0.0565,wR2=0.1245; Absolute structure parameter:2.0 (17); Largest diff. peak and hole: 0.170
and -0.205 e.Å-3

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HETEROCYCLES, Vol. 76, No. 2, 2008
2-Phenyl-5-pyrrolidin-1-yl-3-p-tolyl-3H-imidazole-4-carboxylic acid methyl ester (2b):
o
1
White crystalline solid; mp 160-161 C, Yield: 72 %; IR (KBr) νmax : 1719 cm-1 ; H NMR (200 MHz;
CDCl3; Me4Si) : δ 1.88-1.92 (m, 4H, -CH2-CH2-), 2.35 (s, 3H, -CH3); 2.99-3.02 (m, 2H, -N-CH2-),
3.34-3.37 (m, 2H, -N-CH2-), 3.60 (s, 3H, OCH3), 7.07 (d, J = 8.0 Hz, 2H, ArH), 7.18 (d, J = 8.0 Hz, 2H,
ArH), 7.23-7.33 (m, 5H, ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 21.1 (-CH3), 25.1 (CH2-CH2), 47.5
(-N(CH2)2), 50.7 (-OCH3), 110.7, 127.8, 128.0, 128.7, 128.8, 129.4, 129.7, 134.2, 138.5, 147.9, 157.9
(-C=N) and 160.1 (-C=O); MS: m/z 361; Anal. Calcd for C22H23O2N3 : C, 73.11; H, 6.41; N, 11.63. Found:
C, 73.18; H, 6.38; N, 11.67%.
5-Morpholin-4-yl-2-phenyl-3-p-tolyl-3H-imidazole-4-carboxylic acid methyl ester (2c):
o
1
White crystalline solid; mp 142-143 C, Yield: 70%; IR (KBr) νmax : 1721 cm-1 ; H NMR (200 MHz;
CDCl3; Me4Si) : δ 2.35 (s, 3H, -CH3); 3.46-3.51 (m, 4H, -CH2-N-CH2-); 3.60 ( s, 3H, -OCH3); 3.87-3.91 (m,
13
4H, -CH2-O-CH2-); 7.06-7.33 (m, 9H, arom); C NMR (200 MHz, CDCl3, Me4Si) δ 21.3 (-CH3), 30.9
(-CH2-N-CH2-), 50.8 (-OCH3), 67.0 ( -CH2-O-CH2), 110.1, 127.7, 128.0, 128.9, 129.0, 129.4, 129.7, 135.5,
138.4, 147.9, 157.7 (-C=N) and 160.0 (-C=O); MS: m/z 377; Anal. Calcd for C22H23O3N3 : C, 70.01; H,
6.14; N, 11.13. Found: C, 69.95; H, 6.27; N, 11.20%.
2-Phenyl-5-piperidin-1-yl-3-p-tolyl-3H-imidazole-4-carboxylic acid methyl ester (2d):
Light yellow crystalline solid; mp 167-168 oC, Yield: 75 %; IR (KBr) νmax : 1725 cm-1; 1H NMR (200 MHz;
CDCl3; Me4Si) : δ 1.65 (brs, 6H, -CH2-CH2-CH2-), 2.34 (s, 3H, -CH3); 2.98-3.02 (m, 2H, -N-CH2-),
3.15-3.19 (m, 2H, -N-CH2-), 3.67 (s, 3H, OCH3), 7.08 (d, J = 8.0 Hz, 2H, ArH), 7.16 (d, J = 8.0 Hz, 2H,
ArH), 7.21-7.35 (m, 5H, ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 20.9 (-CH3), 25.9 (CH2), 27.8
(-CH-CH2-), 47.5 (-N(CH2)2), 50.9 (-OCH3), 108.9, 127.7, 128.1, 128.7, 128.8, 128.9, 129.5, 135.2, 138.5,
148.1, 157.9 (-C=N) and 163.2 (-C=O); MS: m/z 375; Anal. Calcd for C23H25O2N3 : C, 73.57; H, 6.71; N,
11.19. Found: C, 73.62; H, 6.66; N, 11.25%.
2-Phenyl-5-piperazin-1-yl-3-p-tolyl-3H-imidazole-4-carboxylic acid methyl ester (2e):
Light yellow crystalline solid; mp 175-176 oC, Yield: 78 %; IR (KBr) νmax : 1689 cm-1 ; 1H NMR (200 MHz;
CDCl3; Me4Si) : δ 1.55-1.58 (m, 6H, -CH2-CH2-CH2-), 2.34 (s, 3H, -CH3); 2.82-3.09 (m, 2H, -CH2-N-CH2-),
3.24-3.52 (m, 2H, -CH2-N-CH2-), 3.69 (s, 3H, OCH3), 7.04 (d, J = 8.7 Hz, 2H, ArH), 7.15 (d, J = 8.7 Hz, 2H,
13
ArH), 7.22-7.35 (m, 5H, ArH); C NMR (200 MHz, CDCl3, Me4Si) δ 20.9 (-CH3), 25.1 (CH2-CH2), 26.2
(CH2), 51.1 (OCH3), 53.9 (CH2-N-CH2-), 110.5, 122.3, 123.4, 126.8, 128.4, 133.8, 134.2, 137.9, 146.9, 147.8,
158.0 (C=N), 160.2 (C=O); MS: m/z: 376. Anal. Calcd for C22H24O2N4 : C, 70.19; H, 6.43; N, 14.88. Found:
C, 70.21; H, 6.45; N, 14.86%.

HETEROCYCLES, Vol. 76, No. 2, 2008
1097
5-Dimethylamino-2,3-diphenyl-3H-imidazole-4-carboxylic acid methyl ester (2f):
White crystalline solid; mp 177-178 oC, Yield: 73 %; IR (KBr) νmax : 1699 cm-1; 1H NMR (200 MHz; CDCl3;
Me4Si) : δ 3.06 (s, 6H, -N(CH3)2 , 3.61 ( s, 3H, -OCH3), 7.05-7.33 (m, 10H, arom); 13C NMR (200 MHz, CDCl3,
Me4Si) δ 42.9 (-N(CH3)2), 50.7 (-OCH3), 108.6, 127.2, 127.7, 128.5, 128.8, 129.2, 129.7, 134.9, 138.5, 148.2,
158.7 (-C=N) and 162.7 (-C=O); MS: m/z 321; Anal. Calcd for C19H19O2N3: C, 71.01; H, 5.96; N, 13.08.
Found: C, 71.10; H, 6.02; N, 13.00%.
2,3-Diphenyl-5-pyrrolidin-1-yl-3H-imidazole-4-carboxylic acid methyl ester (2g):
o
1
White crystalline solid; mp 156-157 C, Yield: 75 %; IR (KBr) νmax : 1705 cm-1; H NMR (200 MHz;
CDCl3; Me4Si) : δ 1.86-1.91 (m, 4H, -CH2-CH2-), 2.97-3.02 (m, 2H, -N-CH2-), 3.30-3.34 (m, 2H, -N-CH2-),
3.59 (s, 3H, OCH3), 7.02-7.35 (m, 10H, ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 25.6 (CH2-CH2), 47.5
(CH2-N-CH2), 50.7 (-OCH3), 109.9, 127.5, 127.9, 128.5, 128.9, 129.2, 129.5, 135.2, 138.2, 147.7, 157.7
(-C=N) and 160.2 (-C=O); MS: m/z 347; Anal. Calcd for C21H21O2N3 : C, 72.60; H, 6.09; N, 12.10. Found:
C, 72.67; H, 6.02; N, 12.15%.
5-Morpholin-4-yl-2,3-diphenyl-3H-imidazole-4-carboxylic acid methyl ester (2h):
o
1
White crystalline solid; mp 165-166 C, Yield: 72 %; IR (KBr) νmax : 1719 cm-1; H NMR (200 MHz;
CDCl3; Me4Si) : δ 3.44-3.46 (m, 4H, -CH2-N-CH2-); 3.62 ( s, 3H, -OCH3); 3.81-3.87 (m, 4H,
13
-CH2-O-CH2-); 7.07-7.38 (m, 10H, arom); C NMR (200 MHz, CDCl3, Me4Si) δ 35.2 (-CH2-N-CH2-),
50.7 (-OCH3), 66.9 (-CH2-O-CH2), 110.0, 127.9, 128.2, 128.7, 128.9, 129.3, 129.7, 135.4, 138.6, 148.1,
157.9 (-C=N) and 160.3 (-C=O); MS: m/z 363; Anal. Calcd for C21H21O3N3 : C, 69.41; H, 5.82; N, 11.56.
Found: C, 69.48; H, 5.76; N, 11.62%.
2,3-Diphenyl-5-piperidin-1-yl-3H-imidazole-4-carboxylic acid methyl ester (2i):
Light yellow crystalline solid; mp 184-185 oC, Yield: 73 %; IR (KBr) νmax : 1715 cm-1; 1H NMR (200 MHz;
CDCl3; Me4Si) : δ 1.59 (brs, 6H, -CH2-CH2-CH2-), 3.00-3.05 (m, 2H, -CH2-N-), 3.19-3.31 (m, 2H,
-CH2-N-), 3.61 (s, 3H, OCH3), 7.02-7.39 (m, 10H, ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 25.5 (CH2),
27.9 (-CH2-CH2-), 51.2 (OCH3), 53.9 ((CH2-N-CH2-), 110.1, 128.2, 128.5, 128.7, 128.8, 128.9, 129.3,
135.7, 138.9, 148.8, 158.1 (-C=N) and 160.4 (-C=O); MS: m/z 361; Anal. Calcd for C22H23O2N3 : C, 73.11;
H, 6.41; N, 11.63. Found: C, 73.14; H, 6.44; N, 11.60%.
2,3-Diphenyl-5-piperazin-1-yl-3H-imidazole-4-carboxylic acid methyl ester (2j):
1
Yield: 78 %; IR (KBr) νmax : 1689 cm-1; H NMR (200 MHz; CDCl3; Me4Si) : δ 1.53-1.58 (m, 6H,
-CH2-CH2-CH2-), 2.81-3.11 (m, 2H, -CH2-N-), 3.23-3.50 (m, 2H, -CH2-N-), 3.68 (s, 3H, OCH3), 7.11-7.23
(m, 6H, ArH), 7.25-7.34 (m, 4H, ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 24.9 (CH2-CH2), 26.1 (CH2),
51.4 (OCH3), 53.8 (CH2-N-CH2-), 110.6, 121.9, 123.5, 124.8, 125.7, 125.9, 127.4, 129.7, 135.3, 146.7, 159.2

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HETEROCYCLES, Vol. 76, No. 2, 2008
(C=N), 160.3 (C=O); MS: m/z: 362. Anal. Calcd for C22H24O2N4 : C, 69.59; H, 6.12; N, 15.46. Found: C,
69.61; H, 6.11; N, 15.45%.
3-(4-Chlorophenyl)-5-dimethylamino-2-phenyl-3H-imidazole-4-carboxylic acid methyl ester (2k):
o
1
White crystalline solid; mp 179-180 C, Yield: 79 %; IR (KBr) νmax : 1720 cm-1; H NMR (200 MHz;
13
CDCl3; Me4Si) : δ 3.05 (s, 6H, -N(CH3)2), 3.63 (s, 3H, -OCH3), 6.98-7.35 (m,9H, ArH); C NMR (200
MHz, CDCl3, Me4Si) δ 42.6 (-N(CH3)2), 50.8 (OCH3), 109.9, 125.8, 127.1, 127.9, 128.8, 129.1, 130.2,
134.5, 139.1, 148.3, 158.6 (-C=N) and 160.3 (-C=O); MS: m/z 355; Anal. Calcd for C19H18ClN3O2: C,
64.10; H, 5.01; Cl, 9.87; N, 11.89. Found: C, 64.15; H, 5.08; Cl, 9.94; N, 11.83%.
3-(4-Chlorophenyl)-2-phenyl-5-pyrrolidin-1-yl-3H-imidazole-4-carboxylic acid methyl ester (2l):
o
1
White crystalline solid; mp 171-172 C, Yield: 80 %; IR (KBr) νmax : 1721 cm-1; H NMR (200 MHz;
CDCl3; Me4Si) : δ 1.84-1.90 (m, 4H, (-CH2)2), 2.95-3.00 (m, 2H, -NCH2), 3.31-3.35 (m, 2H, -NCH2),
3.63 (s, 3H, OCH3), 6.99-7.36 (m, 9H, ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 25.7 (-CH2)2), 47.8
(-N(CH2), 50.9 (OCH3), 110.9, 126.8, 127.1, 127.8, 129.1, 130.6, 133.8, 134.7, 138.9, 148.4, 158.5
(-C=N), 160.4 (-C=O); MS: m/z 381; Anal. Calcd for C21H20ClN3O2: C, 66.05; H, 5.28; Cl, 9.28; N, 11.00.
Found: C, 66.11; H, 5.32; Cl, 9.22; N, 11.08%.
General procedure for the reaction of thioamides 8 and DMAD
A solution of thioamides 8 (4 mmol) and DMAD (4.2 mmol) in dry CH2Cl2 was stirred at rt for about
15-18 h. The progress of the reaction was checked with the help of TLC monitoring. After the completion
of the reaction, the mixture was concentrated under vacuo and the crude reaction mixture thus obtained
was subjected to column chromatography on 60-120-mesh silica gel. The thiazolidinone derivatives 9
were obtained from 1 : 4 = EtOAc : hexane and were recrystallized from 3 : 10 = CH2Cl2 : hexane.
(2-Benzoylimino-4-oxo-3-phenylthiazolidin-5-ylidene)acetic acid methyl ester (9a):
Creamish white crystalline Solid; mp 162-163 oC, Yield: 78 %; IR (KBr) νmax : 1610, 1703, 1730 cm-1; 1H
NMR (200 MHz; CDCl3; Me4Si) : δ 3.94 (s, 3H, OCH3), 7.13 (s, 1H, vinylic), 7.31-7.47 (m, 4H, ArH),
13
7.54-7.68 (m, 4H, ArH), 8.04-8.08 (m, 2H, ArH); C NMR (200 MHz, CDCl3, Me4Si) δ 52.7 (OCH3),
120.6, 127.8, 128.5, 129.3, 130.4, 133.6, 134.2, 134.7, 136.9, 141.1, 158.2 (C=N), 164.2 (C=O), 165.5
(C=O) and 185.2 (C=O); MS: m/z 366; Anal. Calcd for C19H14N2O4S : C, 62.28; H, 3.85; N, 7.65; S, 8.75.
Found: C, 62.35; H, 3.88; N, 7.71; S, 8.69 %.
Crystal data and structure refinement for 9a:
Empirical formula: C20H16N2O4S; Formula weight: 380.41; Temperature: 293(2) K; Wavelength: 0.71069
Å; Crystal system: Monoclinic; Space group: P21/n; Unit cell dimensions: a = 12.919(5) Å; a=

HETEROCYCLES, Vol. 76, No. 2, 2008
1099
3;
90°.000(5)°; b = 7.461(5); b=97.520(5)°; c = 19.034(5) Å; g = 90.000(5)°; Volume: 1818.9(15) Å Z: 4;
3
-1
Density (calculated) 1.389 mg/m ; Absorption coefficient: 0.207 mm ; F (000) : 792; Crystal size:
0.4 × 0.3 × 0.3 mm; Theta range for data collection: 1.80 to 25.00°; Limiting indices: 0<=h<=15,
0<=k<=8, -22<=1<=22; Reflections collected: 3338 / 3188 [R(int) = 0.0417; Completeness to theta: 25.00°
2
99.6 %; Absorption corrections: None; Refinement method: Full-matrix least squares on F ; Data /
2
restraints / parameters: 3188 / 0 / 245; Goodness-of-fit on F : 1.155; Final R indices [I>2sigma(I)]: R1 =
0.0454, wR2 = 0.1322; R indices (all data): R1 = 0.0660, wR2 = 0.1557; Extinction coefficient: 0.049 (4);
-3
Largest diff. peak and hole: 0.357 and -0.255 e.Å
(2-Benzoylimino-4-oxo-3-p-tolylthiazolidin-5-ylidene)acetic acid methyl ester (9b):
o
1
Light yellow crystalline solid; mp 238-239 C, Yield: 75 %; IR (KBr) νmax : 1615, 1717, 1731 cm-1; H
NMR (200 MHz; CDCl3; Me4Si) : δ 2.26 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 7.06 (s, 1H, vinylic), 7.27 (d, J
= 8.0 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.40-7.52 (m, 3H, ArH), 8.03 (m, 2H, ArH); 13C NMR
(200 MHz, CDCl3, Me4Si) δ 21.2 (CH3), 52.9 (OCH3), 123.2, 124.7, 129.0, 129.7, 131.5, 133.5, 134.5,
134.7, 136.2, 139.4, 148.9, 164.2, 165.4 and 179.9; MS: m/z 380; Anal. Calcd for C20H16N2O4S: C, 63.14;
H, 4.24; N, 7.36; S, 8.43. Found: C, 63.21; H, 4.19; N, 7.44; S, 8.35 %.
[2-Benzoylimino-3-(4-chlorophenyl)-4-oxo-thiazolidin-5-ylidene]acetic acid methyl ester (9e):
o
1
White solid; mp 226-227 C, Yield: 75 %; IR (KBr) νmax : 1625, 1712, 1735 cm-1; H NMR (200 MHz;
CDCl3; Me4Si) : δ 3.88 (s, 3H, OCH3), 7.13 (s, 1H, vinylic), 7.17-7.35 (m, 5H, ArH), 7.39-7.53 (m, 4H,
ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 52.3 (OCH3), 120.6, 126.8, 129.1, 130.8, 132.4, 134.9,
135.2, 137.2, 142.1, 151.2, 165.4, 166.2 and 178.8; MS: m/z 400; Anal. Calcd for C19H13ClN2O4S: C,
56.93; H, 3.27; Cl, 8.84; N, 6.99; S, 8.00. Found: C, 56.99; H, 3.19; Cl, 8.92 N, 7.04; S, 8.07%
General procedure for the reaction of 2-methyl-1,3-diaryl-isothioureas 13 and DMAD
A solution of 2-methyl-1,3-diaryl-isothioureas 13 (4 mmol) and DMAD 2 (4.2 mmol) in dry CH2Cl2 was
stirred at rt for about 15-18 h. The progress of the reaction was checked with the help of TLC monitoring.
After the completion of the reaction, the mixture was concentrated under vacuo and the crude reaction
mixture thus obtained was subjected to column chromatography on 60-120-mesh silica gel. The
imidazoles 14 and 15 were obtained from 1 : 50 and 1 : 10 EtOAc : hexane. The products 14 and 15 were
recrystallized from dichloromethane-hexane (2:1) and EtOAc-hexane (1:5).
2-Phenyl-6-phenylimino-3-p-tolyl-3,6-dihydropyrimidine-4,5-dicarboxylic acid dimethyl ester
(13a):
o
1
Red crystalline solid; mp 175-176 C, Yield: 30 %; IR (KBr) νmax : 1623 and 1716 cm-1; H NMR (200

1100
HETEROCYCLES, Vol. 76, No. 2, 2008
MHz; CDCl3; Me4Si) : δ 2.43 (s, 3H, CH3), 3.59 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 7.05 (d, J = 7.2 Hz, 2H,
ArH), 7.24 (d, J = 7.4 Hz, 2H, ArH), 7.32-7.51 (m, 8H, ArH), 7.53-7.62 (m, 2H, ArH); 13C NMR (200 MHz,
CDCl3, Me4Si) δ 21.3 (CH3), 51.9 (OCH3), 53.2 (OCH3), 102.6, 123.0, 127.9, 128.2, 128.8, 129.9, 130.0,
130.5, 132.2, 135.1, 138.2, 139.4, 144.7, 147.9, 154.3, 163.3, 165.1 and 168.4; MS: m/z 453; Anal. Calcd
for C27H23O4N3: C, 71.51; H, 5.11; N, 9.27. Found: C, 71.59; H, 5.06; N, 9.32 %.
5-Methylsulfanyl-2-phenyl-3-p-tolyl-3H-imidazole-4-carboxylic acid methyl ester (14a):
o
1
White crystalline solid; mp 160-161 C, Yield: 32 %; IR (KBr) νmax : 1717 cm-1; H NMR (200 MHz;
CDCl3; Me4Si) : δ 2.41 (s, 3H, CH3), 2.72 (s, 3H, SCH3), 3.75 (s, 3H, OCH3), 7.10 (d, J = 8.0 Hz, 2H, ArH),
7.20 (d, J = 8.0 Hz, 2H, ArH), 7.23-7.27 (m, 3H, ArH), 7.37 (d, 2H, ArH); 13C NMR (200 MHz, CDCl3,
Me4Si) δ 17.9 (SCH3), 20.9 (CH3), 51.3, 127.4, 127.7, 127.8, 128.2, 128.4, 128.9, 129.1, 129.2, 129.6,
133.2, 141.5 and 165.5; MS: m/z 338; Anal. Calcd for C19H18O2N2S: C, 67.43; H, 5.36; N, 8.28; S, 9.48.
Found: C, 67.48; H, 5.30; N, 8.32; S, 9.40 %.
2,3-Diphenyl-6-p-tolylimino-3,6-dihydropyrimidine-4,5-dicarboxylic acid dimethyl ester (13b):
1
Red crystalline solid; Yield: 35 %; IR (KBr) νmax : 1627 and 1721 cm-1; H NMR (200 MHz; CDCl3;
Me4Si) : δ 2.39 (s, 3H, CH3), 3.57 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 7.02 (d, J = 8.0 Hz, 2H, ArH), 7.21 (d,
J = 8.0 Hz, 2H, ArH), 7.35-7.52 (m, 10H, ArH), 13C NMR (200 MHz, CDCl3, Me4Si) δ 21.5 (CH3), 52.1
(OCH3), 53.1 (OCH3), 104.5, 123.2, 127.7, 128.1, 128.7, 129.8, 129.9, 130.2, 132.5, 135.2, 138.5, 139.7,
144.9, 148.0, 154.2, 161.1, 165.3 and 168.5; MS: m/z 453; Anal. Calcd for C27H23O4N3: C, 71.51; H, 5.11;
N, 9.27. Found: C, 71.58; H, 5.05; N, 9.33 %.
5-Methylsulfanyl-2,3-diphenyl-3H-imidazole-4-carboxylic acid methyl ester (14b):
o
1
White crystalline solid; mp 144-145 C, Yield: 30 %; IR (KBr) νmax : 1719 cm-1; H NMR (200 MHz;
CDCl3; Me4Si) : δ 2.77 (s, 3H, SCH3), 3.80 (s, 3H, OCH3), 7.09-7.24 (m, 4H, ArH); 7.30-7.52 (m, 6H,
ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 18.5 (SCH3), 51.1, 127.2, 127.5, 127.7, 128.1, 128.2, 128.7,
129.1, 129.5, 134.7, 139.0, 142.5 and 165.5; MS: m/z 324; Anal. Calcd for C18H16O2N2S: C, 66.64; H, 4.97;
N, 8.64; S, 9.88. Found: C, 66.70; H, 4.91; N, 8.70; S, 9.93 %.
2-Phenyl-3-p-tolyl-6-p-tolylimino-3,6-dihydropyrimidine-4,5-dicarboxylic acid dimethyl ester
(14c):
Brown crystalline solid; mp 152-153 oC, Yield: 38 %; IR (KBr) νmax : 1625 and 1717 cm-1; 1H NMR (200
MHz; CDCl3; Me4Si) : δ 2.26 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.55 (s, 3H, OCH3), 3.59 (s, 3H, OCH3), 6.92
13
(d, J = 8.0 Hz, 2H, ArH), 6.94 (d, J = 8.0 Hz, 2H, ArH), 7.23-7.50 (m, 9H, ArH); C NMR (200 MHz,
CDCl3, Me4Si) δ 20.9 (CH3), 21.3 (CH3), 52.1 (OCH3), 53.5 (OCH3), 104.7, 123.1, 127.8, 128.1, 128.7,
129.7, 130.1, 130.2, 132.1, 135.7, 138.2, 139.5, 141.8, 147.9, 152.2, 161.1, 165.2 and 168.4; MS: m/z 467;

HETEROCYCLES, Vol. 76, No. 2, 2008
1101
Anal. Calcd for C28H25O4N3: C, 71.93; H, 5.39; N, 8.99. Found: C, 72.01; H, 5.31; N, 8.90 %.
6-(4-Chlorophenylimino)-2-phenyl-3-p-tolyl-3,6-dihydropyrimidine-4,5-dicarboxylic acid dimethyl
ester (13d):
o
1
Red crystalline solid; mp 135-136 C, Yield: 35 %; IR (KBr) νmax 1623 and 1730: cm-1; H NMR (200
MHz; CDCl3; Me4Si) : δ 2.41 (s, 3H, CH3), 3.57 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 6.96 (d, J = 6.6 Hz, 2H,
ArH), 7.18 (d, J = 6.6 Hz, 2H, ArH), 7.26-7.38 (m, 4H, ArH), 7.39-7.48 (m, 5H, ArH); 13C NMR (200 MHz,
CDCl3, Me4Si) δ 20.9 (CH3), 52.5 (OCH3), 53.2 (OCH3), 102.5, 123.2, 127.7, 128.2, 128.5, 129.8, 130.3,
130.5, 132.1, 135.5, 138.4, 139.2, 142.9, 147.7, 153.7, 158.5, 164.9 and 167.5; MS: m/z 487; Anal. Calcd
for C27H22O4N3Cl: C, 66.46; H, 4.54; N, 8.61; Cl, 7.27. Found: C, 66.52; H, 4.60; N, 8.67; Cl, 7.32 %.
2,3-Diphenyl-6-phenylimino-3,6-dihydropyrimidine-4,5-dicarboxylic acid dimethyl ester (13e):
Dark red crystalline solid; mp 154-155 oC, Yield: 35 %; IR (KBr) νmax : 1627 and 1731 cm-1; 1H NMR (200
MHz; CDCl3; Me4Si): δ 3.59 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 6.91-7.32 (m, 10H, ArH), 7.35-7.44 (m,
5H, ArH); 13C NMR (200 MHz, CDCl3, Me4Si) δ 52.2 (OCH3), 53.1 (OCH3), 102.2, 123.0, 127.5, 128.1,
128.8, 129.2, 129.7, 130.2, 132.0, 135.1, 137.7, 138.2, 142.9, 146.9, 153.1, 158.4, 165.1 and 167.9; MS:
m/z 439; Anal. Calcd for C26H21N3O4: C, 71.06; H, 4.82; N, 9.56. Found: C, 71.11; H, 4.78; N, 9.62; %.
6-(4-Chlorophenylimino)-2,3-diphenyl-3,6-dihydropyrimidine-4,5-dicarboxylic
ester (13f):
acid
dimethyl
Brown crystalline solid; mp 183-185 oC, Yield: 37 %; IR (KBr) νmax : 1621 and 1719 cm-1; 1H NMR (200
MHz; CDCl3; Me4Si) : δ 3.56 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 7.01-7.15 (m, 5H, ArH), 7.26-7.38 (m,
13
4H, ArH), 7.39-7.48 (m, 5H, ArH); C NMR (200 MHz, CDCl3, Me4Si) δ 52.4 (OCH3), 53.1 (OCH3),
104.4, 123.5, 127.9, 128.4, 128.7, 129.9, 130.1, 130.3, 132.0, 135.4, 138.2, 139.1, 144.1, 147.2, 153.7,
159.5, 165.4 and 168.0; MS: m/z 473; Anal. Calcd for C26H20ClN3O4: C, 65.89; H, 4.25; Cl, 7.48; N, 8.87.
Found: C, 65.94; H, 4.29; N, 8.92; Cl, 7.41 %.
ACKNOWLEDGEMENTS
the authors are thankful to Professor D. Velumurugun and Professor M. S. Hundal for the X-ray
crystallographic studies of compounds 2a and 9a respectively.
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