Conventional and microwave irradiation assisted synthesis of new 1,2,4-triazepine-3-thiones

Article abstract of DOI:10.1002/jhet.5570450234

(Chemical Equation Presented) New 1,2,4-triazepine-3-thiones have been obtained during the respective reactions of N-substituted-hydrazino carbothioamides with dimethyl acetylenedicarboxylate and dibenzoyl acetylene under prolonged reflux in acetic acid a

Full text of DOI:10.1002/jhet.5570450234

Mar-Apr 2008
521
Conventional and Microwave Irradiation Assisted Synthesis of New
1,2,4-Triazepine-3-thiones
Ashraf A. Aly,*a Alaa A Hassan,a Essmat M. El-Sheref,a
Mamdouh A. Mohameda and Alan B. Brownb
a Chemistry Department, Faculty of Science, Minia University, 61519 Minia, A. R. Egypt
b Chemistry Department, Florida Institute of Technology, 150 W University Blvd, Melbourne, Florida 32901,
U.S.A.
Received July 30, 2007
2
R
S
N
N
1
R
N
COPh
Ph
2
R
N
PhOC
COPh
S
MeO2C
2
CO2Me
NH
1
R
N
CO2Me
R
O
H
N
1
R
N
NH2
S
New 1,2,4-triazepine-3-thiones have been obtained during the respective reactions of N-substituted-
hydrazino carbothioamides with dimethyl acetylenedicarboxylate and dibenzoyl acetylene under prolonged
reflux in acetic acid and/or DMF. However, the reaction of the starting materials in DMF under microwave
irradiation afforded the same products in higher yields within a few minutes.
J. Heterocyclic Chem., 45, 521 (2008).
INTRODUCTION
intramolecular heterocyclization of thiosemicarbazides
has been previously investigated [9,10]. Synthetic organic
reactions performed under non-traditional conditions are
gaining popularity, primarily to circumvent growing
environmental concerns [11-13]. Microwave technology
has become a powerful tool in organic synthesis, since by
employing this technique it is generally possible to
prepare organic compounds very fast, with high purity
and better yields compared to conventional methods
[14,15]. Some time ago, we synthesized many
heterocyclic ring systems such as thiazoles, thiazines,
thiadiazoles, thiadiazines, pyrazines and indazoles from
the reactions of thiosemicarbazides with π-deficient
compounds [16,17]. Besides, Aly et al reported on the
synthesis of various thiazin-4-ones from the reactions of
aroylthioureas (ArCONHCSNHR) with dimethyl acetyl-
enedicarboxylates [18]. In addition, thiosemicarbazides
show unusual reactivity towards 2,3-diphenylcyclo-
propenone, giving a variety of pyridazinethiones and
1,2,4-triazolo[4,3-b]pyridazinethiones [19]. Recently, we
have utilized microwave irradiation to assist the synthesis
of triazoloquinazolinones and benzimidazoquinazolinones
Thiosemicarbazides are easily cyclized by the action of
acids, bases or oxidants; therefore they are useful versatile
building blocks for the preparation of heterocyclic ring
systems. The heterocyclization of 1,4-disubstituted
thiosemicarbazides - in basic or acidic media and under
various reaction conditions - were investigated [1-3].
Four-, five-, six- and seven-membered heterocyclic
compounds were prepared by the reaction of thiosemi-
carbazide derivatives with α- and β-haloketones [4-6].
The N2 of the thiosemicarbazide group is a softer
nucleophilic center than the harder and more powerful
terminal nitrogen N1. Thus, reagents susceptible to
nucleophilic attack by N1 may in a second step undergo
cyclization to afford the aforesaid heterocycles in
excellent yields, even under mild reaction conditions
[4,5]. Microwave (MW) irradiation of thiosemicarbazides
has been employed for rapid synthesis of a wide variety of
heterocyclic compounds such as thiadiazoles, triazole-3-
thiols, thioxoimidazoles and thiadiazepines [6-8]. The
course of microwave assisted or conventional thermal

522
A. A. Aly, A. A Hassan, E. M. El-Sheref, M. A. Mohamed and A. B. Brown
Vol 45
1
[20]. It was also reported [21] on the synthesis of 7-alkyl-
5-aryl-1,2,4-triazepine-3-thiones using hydrazinediium
dithiocyanate and α,β-unsaturated ketones as starting
materials. Viallefont and his co-workers reported on the
methods used to prepare various derivatives of 1,2,4-
triazepines disubstituted by oxo, thioxo, methoxy or
methylthio groups [22]. Interestingly, triazepines and their
fused derivatives exhibit interesting biological properties
[23]. Moreover, it was also demonstrated that those
compounds might serve as black toning agents for
laminated photographs or as starting materials for the
synthesis of thiazolo[3,2-b][1,2,4]triazepines, which are
supposed to have immunomodulating activities [24].
Yamamoto et al [25] patented triazepine derivatives as
inhibitors of cytokine production. In this publication our
goal is to synthesize new triazepine-3-thiones from the
1). A singlet at δ 6.20 assigned to H-6 appeared in the H
nmr spectrum of 3a, and CH-6 resonated in the 13C nmr
spectrum at δ 110.2. By contrast, in the H nmr spectrum
1
of compound 4a (as an example), the presence of two
hydrazine protons was indicated by two broad singlets at
δ 7.30 and 7.60. Moreover the absence of the CO-acetyl
carbon signal and the appearance of another hydrazine-
NH proton (N1) indicated that acetylation had not
occurred at this nitrogen atom. Indeed, acetylation process
had occurred with acetic acid under long refluxing time.
In COSY C H studies of 3c or 4c, the allylic aliphatic CH2
showed a correlation with the amide carbonyl, but not
with the ester carbonyl. These data unambiguously
exclude the formation of isomers 6a-c (Scheme 1).
Because the magnitude of the Nuclear Overhauser Effect
(NOE) depends upon the internuclear distance as 1/r6, in
practice, NOE’s are rarely seen between pairs of protons
that are separated by more than about 4.5 Å. [28] NOE’s
have been correlated with distance as follows: strong
(1.8–2.9 Å), medium (1.8–3.7 Å) and weak (3.0–4.5 Å)
[29]. Irradiation of the ester protons of the products gave a
strong NOE in the hydrazine proton (NH1), and a medium
enhancement in the other one (NH2), which agrees with
structures 4a-c, but is inconsistent with structures 6a-c.
The products were therefore assigned as 1-acetyl-1,2,4-
triazepine-3-thiones 3a-c and 1,2,4-triazepine-3-thiones
4a-c, respectively (Scheme 1).
reaction
of
thiosemicarbazides
with
dimethyl
acetylenedicarboxylate and dibenzoyl acetylene under
conventional methods and/or microwave irradiation.
RESULTS AND DISCUSSION
The synthesis of 4-substituted 1-acetyl-7-oxy-3-thioxo-
2,3,4,7-tetrahydro-1H-1,2,4-triazepine-5-carboxylic acid
methyl esters 3a-c was accomplished by refluxing
equimolar amounts of N-aryl-hydrazino carbothioamides
1a-c with dimethyl acetylenedicarboxylate (2) in acetic
acid (Method A, Scheme 1). Unfortunately, on applying
the same procedure using microwave irradiation in a
small amount of DMF, the triazepines 3a-c were not
obtained. Instead, the reaction afforded, within a few
minutes, the triazepine derivatives 4a-c in 70-87% yields
(Method B, Scheme 1). The structure of compounds 3a-c
To establish the scope of the phenomena, we treated
thiosemicarbazides 1d-g with 2 in refluxing DMF or
methanol (Method A, Scheme 2). The reaction produced
the corresponding 2-aryl-triazepine-4-substituted-2-thiones
7a-d in good yields (Scheme 2). However, the reaction of
1d-g with 2 under microwave irradiation in a small
amount of DMF produced 7a-d (Method B, Scheme 2) in
better yields and in a shorter time than the conventional
method (Method A). In order to explore another mode of
synthesis of triazepines, compounds 1a-c reacted with
dibenzoyl acetylene (8) in acetic acid, but the reaction
failed. The reaction of 1a-c with 8 in DMF afforded, after
24-48 hours of reflux, the triazepines 9a-c (Method A,
Scheme 3). Compounds 9a-c, could also be obtained from
the reaction of 1a-c with 8 under microwave irradiation in
a small amount of DMF (Method B, Scheme 3) for 10-20
minutes. The vibration coupling of C=S and C-N groups
could be assigned in the ir spectra of the products 9a-c,
whilst the 13C nmr spectra showed the thione carbon
1
and 4a-c is in accord with their ir, H nmr, 13C nmr and
mass spectral data in addition to elemental analyses. The
ir and nmr spectra of compounds 3a-c and 4a-c showed
that the structural difference between compounds 3a-c
and 4a-c is related to the numbers of acetyl groups. The ir,
nmr and mass spectra as well as the elemental analyses of
3a-c and 4a-c proved the presence of the substructures R1-
N-CS-HN-N(COCH3) in 3a-c and R1-N-CS-HN-NH- in
4a-c (Scheme 1). For example, the mass spectrum and
elemental analysis proved the structural formula of 3a as
C14H13N3O4S. The 1H nmr spectrum of 3a (as an example)
contained a broad singlet at δ 8.60, assignable to the
hydrazine-proton. The 13C nmr spectrum of 3a contained
three carbonyl carbon signals at δ 169.0, 170.3 and 175.0
assigned to C-5, CO-ester and CO-acetyl, respectively.
Another deshielded carbon signal assigned to the thione
group resonated at δ 181.6, and the ir spectrum of 3a
showed bands characteristic of vibration coupling of C=S
and C-N groups at νmax 1370-1350 and 988-1015 cm-1
[26,27]. Due to the appearance of the thione group, we
have excluded the formation of compounds 5a-c (Scheme
1
signals at their expected chemical shifts. The H NMR
spectrum of 9a showed a singlet for H-6 at δ 6.10, and the
corresponding CH-6 resonated in the 13C nmr spectrum at
δ
109.0. Additionally, the hydrazine-proton of N2
1
1
appeared in the H nmr spectrum at δ 7.50. In 9b, the H
nmr spectrum revealed three singlets at δ 5.30, 6.20 and
7.40 assigned to CH2-Ph, H-6 and hydrazine-NH,
respectively. COSY C H of 9a indicated a correlation

Mar-Apr 2008 Conventional and Microwave Irradiation Assisted Synthesis of New 1,2,4-Triazepine-3-thiones
523
EXPERIMENTAL
between H-6 and both C-7 (δ 160.0) and C-5 (δ 156.0).
In 9b, COSY C H experiment showed correlation between
C-5 (δ 156.4) and the CH2-Ph protons. The 1H nmr
spectra of compounds 9a-c revealed the ortho-benzoyl
protons as the most deshielded aromatic protons.
Irradiation of the ortho-benzoyl protons in 9c (δ ∼ 7.80)
had no effect on the allylic protons. These results
indicated the presence of compounds 9a-c and excluded
their isomeric products 10a-c (Scheme 3). The products
obtained under irradiation (Method B) have the same
spectral data as those obtained from the conventional
refluxing method (Method A).
General. Melting points are uncorrected. 1H- and 13C-nmr
spectra were recorded in chloroform-d and measured on a Bruker
AM 400 (400.134 MHz and 100.60 MHz) instrument. The
chemical shifts (δ's) were measured versus the internal standard
TMS. Elemental analyses were performed by the Microanalysis
Center of the Institut für Anorganische Chemie, Technische
Universität Braunschweig, Germany. Mass spectra were obtained
on a Finnigan MAT 8430 spectrometer at 70 eV. The ir spectra
were obtained on a Nicolet 320 FT-ir using KBr pellets.
Starting Materials. 4-Phenyl- and allylthiosemicarbazide
(1a,c) [30,31], and 4-benzylthiosemicarbazide (1b) [32] were
H
S
H
S
N
COCH3
N
NH
H
H
N
Method B
Method A
N
N
1
R
1
R
+
NH2
MeO2C
CO2Me
N
1
R
N
CO2Me
CO2Me
S
2
1a-c
O
O
3a-c
4a-c
H
N
S
1
H
CO2Me
NH
N
HN
R1
N
O
R
N
S
MeO2C
O
6a-c
5a-c
Method A
AcOH, reflux
10-18 h
Method B
DMF, MW
5-10 min
1, 3-6
R1
Time (h) Yield of 3 (%) Time (min) Yield of 4 (%)
a
b
c
C6H5-
C6H5-CH2-
CH2=CH-CH2- 18
14
10
56
60
54
5
7
10
75
87
70
Scheme 1. Synthesis of 4-substituted-1,2,4-triazepine-3-thiones 3a-c and 4a-c
2
R
2
R
S
N
H
NH
Method A
1
R
N
N
2
+
NH2
1
R
N
CO2Me
R1
C6H5-
C6H5-CH2-
C6H5-CH2-
C6H5-
or Method B
R2
1
S
1d-g
C6H5-
C6H5-
4-CH3-C6H4-
4-Cl-C6H4-
d
e
f
O
7a-d
g
Method A
Method B
MeOH or DMF
reflux 15-36 h
DMF, MW
10-20 min
7
R1
R2
Time (h)
Yield of 7 (%) Time (min )
Yield of 7 (%)
a
b
c
C6H5-
C6H5-
C6H5-
4-CH3-C6H4- 24
4-Cl-C6H4- 36
20
15
64
68
77
60
15
10
12
20
84
92
96
76
C6H5-CH2-
C6H5-CH2-
C6H5-
d
Scheme 2. Synthesis of 2,4-disubstituted-1,2,4-triazepine-3-thiones 7a-d

524
A. A. Aly, A. A Hassan, E. M. El-Sheref, M. A. Mohamed and A. B. Brown
Vol 45
H
S
N
H
S
N
N
N
Method A
1
R
N
Ph
PhOC
+
COPh
1a-c
1
R
N
COPh
or Method B
8
PhOC
9a-c
10a-c
Ph
Method A
DMF, reflux
24-48 h
Method B
DMF, MW
10-20 min
1, 9 and 10
R1
Time (h) Yield of 9 (%) Time (min) Yield of 9 (%)
a
b
c
C6H5-
C6H5-CH2-
CH2=CH-CH2 48
36
24
82
72
76
10
12
20
98
82
92
-
Scheme 3. Synthesis of 7-benzoyl-5-phenyl-2H-3-substituted-1,2,4-triazepine-3-thiones 9a-c
prepared according to literature procedures. 1,2-Dimethyl
acetylenedicarboxylate (2) was bought from Fluka, whereas
dibenzoyl acetylene (8) was prepared according to literature
[33].
(30), 91 (46), 77 (70), 59 (18), 51 (32), 44 (40). Anal. Calcd. for
C15H15N3O4S: C, 54.04; H, 4.54; N, 12.60 Found: C, 54.20; H,
4.48; N, 12.50.
1-Acetyl-4-allyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1H-1,2,4-
triazepine-7-carboxylic acid methyl ester (3c). Pale yellow
crystals of 3c (0.15 g, 54%), m.p. 155° C (ethyl acetate); 1H nmr
(chloroform-d): δ 2.30 (s, 3 H, CH3CO), 3.92 (s, 3 H, CH3-
ester), 4.50-4.56 (m, 2 H, allyl-CH2), 5.18-5.26 (m, 2 H, allyl-
CH2=), 5.76-5.80 (m, 1 H, allyl-CH=), 6.14 (s, 1 H, H-6), 8.70
(br, s, 1 H, NH2) ppm; 13C nmr (chloroform-d): δ 22.4 (CH3CO),
45.0 (allyl-CH2-N), 52.0 (CH3-ester), 112.0 (CH-6), 116.0 (allyl-
CH2=), 131.0 (ally-CH=), 151.0 (C-7), 170.0 (C-5), 172.0 (CO-
ester), 176.8 (CO-acetyl), 182.4 (C-3); ir (potassium bromide):
3420 (NH), 2992-2894 (Aliph-CH), 1732-1694 (CO), 1596
(C=C), 1365, 1015 (C=S, C-N), 1260 (st C=S) cm-1; ms
(electron impact, 70 eV): m/z (%) 283 [M+] (48), 243 (100), 200
(58), 130 (34), 91 (46), 59 (18), 51 (32), 32 (36). Anal. Calcd.
for C11H13N3O4S: C, 46.64; H, 4.63; N, 14.83. Found: C, 46.50;
H, 4.60; N, 14.80.
Method A
Synthesis of 3a-c. A mixture of 1a-c (1 mmol) and 2 (1
mmol, 142 mg) in glacial acetic acid (50 ml) was heated under
reflux for 10-18 h (the reaction was followed by TLC analysis).
The solvent was evaporated under vacuum to half of its volume
and the product obtained was recrystallized from the stated
solvents.
1-Acetyl-5-oxo-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1H-
1,2,4-triazepine-7-carboxylic acid methyl ester (3a). Yellow
1
crystals of 3a (0.18 g, 56%), m.p. 175° C (ethanol); H nmr
(chloroform-d): δ 2.30 (s, 3 H, CH3CO), 3.82 (s, 3 H, CH3-
ester), 6.20 (s, 1 H, H-6), 6.60-6.78 (m, 3 H, Ph-H), 7.20-7.74
(m, 2 H, Ph-H), 8.60 (br, s, 1 H, NH2) ppm; 13C nmr
(chloroform-d): δ 22.0 (CH3CO), 51.0 (CH3-ester), 110.2 (CH-
6), 127.6 (p-Ph-CH), 128.2 (2 m-Ph-CH), 128.8 (2 o-Ph-CH),
133.5 (Ph-C), 150.0 (C-7), 169.0 (C-5), 170.3 (CO-ester), 175.0
(CO-acetyl), 181.6 (C-3) ppm; ir (potassium bromide): 3410
(NH), 3030-3000 (Ar-CH), 1735-1695 (C=O), 1592 (C=C),
1370, 988 (C=S, C-N), 1265-1256 (st. C=S) cm-1; ms (electron
impact, 70 eV): m/z (%) 319 [M+] (62), 277 (100), 262 (14), 245
(12), 220 (16), 160 (14), 142 (32), 77 (72), 59 (20), 51 (36), 44
(44); Anal. Calcd. for C14H13N3O4S: C, 52.66; H, 4.10; N, 13.16.
Found: C, 52.80; H, 4.15; N, 13.05.
Method B
Synthesis of 4a-c by MW. Equimolar amounts of 1a-c (1
mmol) and 2 (1 mmol, 142 mg) were well-mixed in DMF (5-8
ml). The mixture was irradiated in a microwave oven for 5-10
min (100 °C). On cooling to room temperature, the precipitated
products 4a-c were collected by filtration and recrystallized
from the stated solvents.
5-Oxo-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1H-1,2,4-tri-
azepine-7-carboxylic acid methyl ester (4a). Pale yellow
1
crystals of 4a (0.23 g, 75%), m.p. 240° C (acetonitrile); H nmr
1-Acetyl-4-benzyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1H-
1,2,4-triazepine-7-carboxylic acid methyl ester (3b). Yellow
1
crystals of 3b (0.20 g, 60%), m.p. 142° C (ethanol); H nmr
(chloroform-d): δ 3.90 (s, 3 H, CH3-ester), 6.34 (s, 1 H, H-6),
6.56-6.70 (m, 3 H, Ph-H), 7.20-7.24 (m, 2 H, Ph-H), 7.30 (br, s,
1 H, NH1), 7.60 (br, s, 1 H, NH2) ppm; 13C nmr (chloroform-d): δ
51.8 (CH3-ester), 100.2 (CH-6), 127.4 (p-Ph-CH), 128.2 (2 m-
Ph-CH), 128.6 (2 o-Ph-CH), 134.0 (Ph-C), 152.0 (C-7), 166.0
(C-5), 168.0 (CO-ester), 183.0 (C-3) ppm; ir (potassium
bromide): 3420-3180 (NH), 3045-3010 (Ar-CH), 1720-1700
(CO), 1596 (C=C), 1350, 988 (C=S, C-N), 1220 (C=S) cm-1; ms
(electron impact, 70 eV): 277 [M+] (100), 262 (20), 246 (24),
218 (40), 194 (64), 165 (32), 88 (22), 77 (40), 74 (26), 51 (36),
44 (40). Anal. Calcd. for C12H11N3O3S: C, 51.98; H, 4.00; N,
15.15. Found: C, 52.20; H, 4.00; N, 15.05.
(chloroform-d): δ 2.26 (s, 3 H, CH3CO), 3.90 (s, 3 H, CH3-
ester), 5.20 (s, 2 H, CH2-Ph), 6.28 (s, 1 H, H-6), 6.56-6.62 (m, 2
H, Ph-H), 7.16-7.30 (m, 3 H, Ph-H), 8.62 (br, s, 1 H, NH2) ppm;
13C nmr (chloroform-d): δ 22.4 (CH3CO), 51.4 (CH3-ester), 58.0
(CH2-Ph), 111.0 (CH-6), 126.2 (p-Ph-CH), 127.0 (2 m-Ph-CH),
128.2 (2 o-Ph-CH), 134.6 (Ph-C), 150.8 (C-7), 169.6 (C-5),
170.8 (CO-ester), 175.4 (CO-acetyl), 182.0 (C-3) ppm; ir
(potassium bromide): 3415 (NH), 3040-3008 (Ar-CH), 2990-
2890 (Aliph-CH), 1732-1690 (C=O), 1594 (C=C), 1360, 1000
(C=S, C-N), 1265-1256 (st. C=S) cm-1; ms (electron impact, 70
eV): m/z (%) 333 [M+] (68), 290 (100), 200 (64), 160 (24), 142

Mar-Apr 2008 Conventional and Microwave Irradiation Assisted Synthesis of New 1,2,4-Triazepine-3-thiones
525
128.8 (2 m-Ph-CH), 129.2, 129.6 (2 o-Ph-CH), 130.5, 130.8 (Ph-
C), 153.0 (C-5), 165.4 (C-7), 170.0 (CO-ester), 182.0 (C-3) ppm;
ir (potassium bromide): 3400 (NH), 3060-3008 (Ar-CH), 2990-
2960 (Aliph-CH), 1722-1700 (CO), 1592 (C=C), 1350, 988 (C=S,
C-N), 1262-1257 (st. C=S) cm-1; ms (electron impact, 70 eV): m/z
(%) 367 [M+] (100), 352 (18), 336 (16), 290 (22), 276 (24), 207
(46), 232 (20), 167 (30), 116 (34), 88 (26), 105 (80), 91 (60), 77
(48). Anal. Calcd. for C19H17N3O3S: C, 62.11; H, 4.66; N, 11.44.
Found: C, 62.30; H, 4.60; N, 11.40.
4-Benzyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1H-1,2,4-triaz-
epine-7-carboxylic acid methyl ester (4b). Pale yellow crystals
of 4b (0.25 g, 87%), m.p. 190° C (methanol); 1H nmr
(chloroform-d): δ 3.94 (s, 3 H, CH3-ester), 5.40 (s, 2 H, CH2-
Ph), 6.30 (s, 1 H, H-6), 6.70-6.76 (m, 2 H, Ph-H), 7.18-7.30 (m,
3 H, Ph-H), 7.34 (br, s, 1 H, NH1), 7.66 (br, s, 1 H, NH2) ppm;
13C nmr (chloroform-d): δ 48.60 (CH2-Ph), 50.9 (CH3-ester),
100.4 (CH-6), 127.0 (p-Ph-CH), 127.6 (2 m-Ph-CH), 128.4 (2 o-
Ph-CH), 133.8 (Ph-C), 153.2 (C-7), 165.0 (C-5), 168.8 (CO-
ester), 182.2 (C-3) ppm; ir (potassium bromide): 3400-3190
(NH), 3030-3000 (Ar-CH), 2980-2967 (Aliph-CH), 1718-1700
(CO), 1592 (C=C), 1360, 990 (C=S, C-N), 1230 (C=S) cm-1; ms
(electron impact, 70 eV): m/z (%) 291 [M+] (100), 276 (18), 260
(26), 232 (20), 200 (50), 116 (34), 88 (26), 91 (38), 77 (30), 60
(30), 44 (30). Anal. Calcd. for C13H13N3O3S: C, 53.60; H, 4.50;
N, 14.42. Found: C, 53.40; H, 4.40; N, 14.50.
4-Allyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1H-1,2,4-triaze-
pine-7-carboxylic acid methyl ester (4c). Pale yellow crystals
of 4c (0.17 g, 70%), m.p. 212° C (ethanol); 1H nmr (chloroform-
d): δ 3.96 (s, 3 H, CH3-ester), 4.28-4.34 (m, 2 H, allyl-CH2),
5.20-5.30 (m, 2 H, allyl-CH2=), 5.70-5.76 (m, 1 H, allyl-CH=),
6.28 (s, 1 H, H-6), 7.30 (br, s, 1 H, NH1), 7.60 (br, s, 1 H, NH2);
13C nmr (chloroform-d3): δ 45.8 (allyl-CH2-N), 50.8 (CH3-ester),
112.6 (CH-6), 116.0 (allyl-CH2=), 131.4 (allyl-CH=), 153.0 (C-
7), 165.6 (C-5), 169.2 (CO-ester), 182.0 (C-3) ppm; ir
(potassium bromide): 3400-3180 (NH), 2986-2960 (Aliph-CH),
1722-1700 (CO), 1596 (C=C), 1370, 988 (C=S, C-N), 1220
(C=S) cm-1; ms (electron impact, 70 eV): m/z (%) 241 [M+]
(100), 200 (50), 185 (22), 169 (24), 141 (18), 116 (34), 88 (36),
74 (30), 44 (38). Anal. Calcd. For C9H11N3O3S: C, 44.80; H,
4.60; N, 17.42. Found: C, 44.90; H, 4.50; N, 17.52.
4-Benzyl-5-oxo-2-(4'-methylphenyl)-3-thioxo-2,3,4,5-tetra-
hydro-1H-1,2,4-triazepine-7-carboxylic acid methyl ester
(7c). Pale yellow crystals of 7c (0.29 g, 77%), m.p. 225° C
1
(methanol); H nmr (chloroform-d): δ 2.38 (s, 3 H, CH3-tolyl),
3.98 (s, 3 H, CH3-ester), 5.20 (s, 2 H, CH2-Ph), 6.60 (s, 1 H, H-
6), 6.70-6.90 (m, 5 H, Ph-H), 7.30-7.56 (m, 4 H, Ph-H), 7.76 (br,
s, 1 H, NH1) ppm; 13C nmr (chloroform-d): δ 32.8 (CH3Ph), 50.2
(CH2-Ph), 52.4 (CH3-ester), 107.0 (CH-6), 127.8 (p-Ph-CH),
128.4, 128.8 (2 m-Ph-CH), 129.2, 132.6 (2 o-Ph-CH), 130.8,
133.2 (Ph-C), 134.8 (CH3-Ph-C), 153.8 (C-7), 166.8 (C-5),
172.0 (CO-ester), 181.0 (C-3) ppm; ir (potassium bromide):
3420 (NH), 3060-3008 (Ar-CH), 2980-2960 (Aliph-CH), 1725-
1700 (CO), 1598 (C=C), 1340, 1000 (C=S, C-N), 1260 (st. C=S)
cm-1; ms (electron impact, 70 eV): m/z (%) 381 [M+] (100), 366
(18), 288 (64), 198 (30), 169 (30), 92 (84), 77 (60). Anal. Calcd.
for C20H19N3O3S: C, 62.98; H, 5.20; N, 11.02. Found: C, 63.10;
H, 5.10; N, 11.12.
2-(4'-Chlorophenyl)-5-oxo-4-phenyl-3-thioxo-2,3,4,5-tetra-
hydro-1H-1,2,4-triazepine-7-carboxylic acid methyl ester
(7d). Pale red crystals of 7d (0.23 g, 60%), m.p. 170° C
1
(ethanol); H nmr (chloroform-d): δ 3.92 (s, 3 H, CH3-ester),
6.30 (s, 1 H, H-6), 6.50-6.66 (m, 4 H, Ph-H), 7.20-7.36 (m, 5 H,
Ph-H), 7.70 (br, s, 1 H, NH1) ppm; 13C nmr (chloroform-d): 52.4
(CH3-ester), 107.0 (CH-6), 127.8 (p-Ph-CH), 128.4, 128.8 (2 m-
Ph-CH), 129.2, 132.6 (2 o-Ph-CH), 130.8, 133.2 (Ph-C), 134.8
(CH3-Ph-C), 153.8 (C-5), 166.8 (C-7), 172.0 (CO-ester), 181.0
(C-3) ppm; ir (potassium bromide): 3430 (NH), 3050-3012 (Ar-
CH), 1725-1700 (CO), 1596 (C=C), 1350, 1000 (C=S, C-N),
1250 (st. C=S) cm-1; ms (electron impact, 70 eV): m/z (%) 389
[M+2] (34), 387 [M+] (100), 386 (32), 372 (18), 356 (42), 352
(46), 366 (18), 277 (34), 275 (36), 190 (30), 112 (24), 98 (20),
77 (50). Anal. Calcd. for C18H14ClN3O3S: C, 55.74; H, 3.64; Cl,
9.14; N, 10.83. Found: C, 55.60; H, 3.60; Cl, 9.00; N, 10.70.
Method A
Synthesis of 7a-d. A mixture of 1d-g (1 mmol) and 2 (1
mmol, 142 mg) in absolute methanol (100 ml) or DMF (30 ml)
was heated under reflux for 15-36 h (the reaction was followed
by TLC analysis). The solvent was evaporated under vacuum to
half its volume to give compounds 7a-d. These compounds were
recrystallized from the stated solvents.
2,4-Diphenyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1H-1,2,4-
triazepine-7-carboxylic acid methyl ester (7a). Pale red
crystals 7a (0.23 g, 64%), m.p. 282° C (ethanol); 1H nmr
(chloroform-d): δ 3.95 (s, 3 H, CH3-ester), 6.50 (s, 1 H, H-6),
6.60-6.90 (m, 5 H, Ph-H), 7.20-7.30 (m, 3 H, Ph-H), 7.50 (br, s,
1 H, NH1), 7.70-7.78 (m, 2 H, Ph-H) ppm; 13C nmr: (chloroform-
d): δ 52.2 (CH3-ester), 105.0 (CH-6), 127.0, 127.6 (p-Ph-CH),
128.0, 128.6 (2 m-Ph-CH), 129.4, 130.0 (2 o-Ph-CH), 132.8,
134.2 (Ph-C), 154.0 (C-5), 168.0 (C-7), 168.8 (CO-ester), 182.4
(C-3) ppm; ir (potassium bromide): 3422 (NH), 3060-3020 (Ar-
CH), 1725-1708 (CO), 1592 (C=C), 1360, 988 (C=S, C-N),
1260-1255 (st. C=S) cm-1; ms (electron impact, 70 eV): m/z (%)
353 [M+] (40), 276 (30), 208 (40), 200 (50), 194 (64), 135 (42),
91 (100), 77 (40), 51 (34). Anal. Calcd. for C18H15N3O3S: C,
61.18; H, 4.28; N, 11.89. Found: C, 61.30; H, 4.20; N, 12.05.
4-Benzyl-5-oxo-2-phenyl-3-thioxo-2,3,4,5-tetrahydro-1H-1,
2,4-triazepine-7-carboxylic acid methyl ester (7b). Red crystals
of 7b (0.25 g, 68%), m.p. 258° C (methanol); 1H nmr (chloroform-
d): δ 3.96 (s, 3 H, CH3-ester), 5.30 (s, 2 H, CH2-Ph), 6.50 (s, 1 H,
H-6), 6.60-6.80 (m, 5 H, Ph-H), 7.20-7.50 (m, 5 H, Ph-H), 7.70
(br, s, 1 H, NH1) ppm; 13C nmr (chloroform-d): δ 48.8 (CH2-Ph),
52.0 (CH3-ester), 106.4 (CH-6), 126.8, 127.4 (p-Ph-CH), 128.2,
Method B
Synthesis of 7a-d by MW. As stated above, the mixture of
1a-g and 2 was well-mixed in DMF (10 ml). The mixture was
irradiated in a microwave oven for 10-20 min (100 °C). On
cooling to room temperature, the precipitated products 7a-d
were collected by filtration and recrystallized from the stated
solvents.
Method A
Synthesis of triazepines 9a-c. A mixture of 1a-c (1 mmol) and
8 (1 mmol, 234 mg) in DMF (20 ml) was gently heated at 80 °C for
24-48 h (the reaction was followed by TLC analysis). The solvent
was evaporated under vacuum to half of its volume and the
obtained products 9a-c were recrystallized from the stated solvents.
4,7-Diphenyl-3-thioxo-3,4-dihydro-2H-(1,2,4-triazepin-5-
yl)-phenyl methanone (9a). Yellow crystals of 9a (0.31 g,
82%), m.p. 210-2° C (ethanol); 1H nmr (chloroform-d): δ 6.10 (s,
1 H, H-6), 6.62-6.80 (m, 5 H, Ph-H), 7.10-7.30 (m, 8 H, Ph-H),

526
A. A. Aly, A. A Hassan, E. M. El-Sheref, M. A. Mohamed and A. B. Brown
Vol 45
7.50 (br, s, 1 H, NH2), 7.60-7.64 (m, 2 H, Ph-H) ppm; 13C nmr
(chloroform-d3): δ 109.0 (CH-6), 126.0, 127.7, 128.2 (p-Ph-CH),
128.6, 129.0, 129.4, 130.2, 130.6, 131.0 (2 Ph-CH), 132.0,
132.6, 134.0 (Ph-C), 156.0 (C-5), 160.0 (C-7), 175.0 (COPh),
182.2 (C-3) ppm; ir (potassium bromide): 3400 (NH), 3070-
3020 (Ar-CH), 1695 (CO), 1590 (C=C), 1350, 988 (C=S, C-N),
1270-1254 (st. C=S) cm-1; ms (electron impact, 70 eV): m/z (%)
383 [M+] (54), 322 (10), 280 (24), 223 (10), 191 (24), 147 (10),
105 (100), 77 (76). Anal. Calcd. for C23H17N3OS: C, 72.04; H,
4.47; N, 10.96. Found: C, 72.20; H, 4.55; N, 11.06.
[2] Koren, B.; Stanovnik, B.; Tišler, M. Monatsh Chem. 1988,
119, 333.
[3] Koren, B.; Stanovnik, B.; Tišler, M. Heterocycles 1985, 23,
913.
[4] Dobosz, M.; Pitucha, M.; Wujec, M. Acta Pol. Pharm 1996,
53, 31.
[5] Paul, S.; Gupta, V.; Gupta, R. Synth. Commun. 2003, 33,
1917.
[6] Tomita, Y.; Kabashima, S.; Okawara, Y.; Yamasaki, T.;
Furukawa, M. J. Heterocycl. Chem. 1990, 27, 707.
[7] Suni, M. M.; Nair, V. A.; Joshua, C. P. Tetrahedron Lett.
2001, 42, 97.
4-Benzyl-7-phenyl-3-thioxo-3,4-dihydro-2H-(1,2,4-triaze-
pin-5-yl)-phenyl methanone (9b). Yellow crystals of 9b (0.29 g,
72%), m.p. 200-2° C (methanol); H nmr (chloroform-d): δ 5.30
[8] Okawara, T.; Kato, R.; Yasuda, N.; Yamasaki, T. J. Chem.
Res. (S) 1987, 254.
1
(s, 2 H, CH2-Ph), 6.20 (s, 1 H, H-6), 6.70-6.84 (m, 5 H, Ph-H),
7.00-7.30 (m, 8 H, Ph-H), 7.40 (br, s, 1 H, NH2), 7.70-7.74 (m, 2
H, Ph-H) ppm; 13C nmr (chloroform-d): δ 48.6 (CH2Ph), 110.8
(CH-6), 126.4, 127.2, 128.0 (p-Ph-CH), 128.8, 130.0 130.4, 130.6,
130.8, 131.4 (2 Ph-CH), 132.4, 133.0, 133.8 (Ph-C), 156.4 (C-5),
158.8 (C-7), 176.0 (COPh), 182.0 (C-3) ppm; ir (potassium
bromide): 3380 (NH), 3080-3026 (Ar-CH), 2980-2890 (Aliph-
CH), 1700 (CO), 1594 (C=C), 1350, 988 (C=S), 1256 (st. C=S)
cm-1; ms (electron impact, 70 eV): m/z (%) 397 [M+] (60), 320
(20), 306 (30), 292 (48), 280 (20), 223 (10), 191 (24), 147 (10), 84
(34), 91 (100), 77 (36). Anal. Calcd. for C24H19N3OS: C, 72.52; H,
4.82; N, 10.57. Found: C, 72.70; H, 4.78; N, 10.68.
[9] Hassan, A. A.; Mourad, A. E.; El-Shaieb, K. M.; Abou-Zeid,
A. H; Döpp, D. Heteroatom Chem. 2003, 14, 535.
[10] Hassan, A. A.; Döpp, D. J. Heterocycl. Chem. 2006, 43, 592.
[11] a) Pillai, U. R.; Sahle-Demessie, E.; Varma, R. S. Mater.
Chem. 2002, 12, 3199; b) Oussaid, A.; Thach, L. N.; Loupy, A.
Tetrahedron Lett. 1997, 38, 451.
[12] Tierney, J. P.; Lidstrِöm, P., Eds. Microwave Assisted
Organic Synthesis, Blackwell, Oxford, 2005.
[13] Loupy, A., Ed. Microwaves in Organic Synthesis; Wiley-
VCH, Weinheim, 2002.
[14] Hayes, B. L. Microwave Synthesis: Chemistry at the Speed
of Light, CEM Publishing, Matthews, NC, 2002.
[15] Kappe, C. O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry, Wiley-VCH, Weinheim, 2005.
[16] Hassan, A. A.; Mourad, A. E.; El-Shaieb, K. M.; Abou-Zeid,
A. H. J. Heterocycl. Chem. 2006, 43, 471.
[17] Hassan, A. A.; Mohamed, N. K.; Shawky, A. M.; Döpp, D.
Arkivoc 2003, 118.
[18] Aly, A. A.; Ahmed, E.-K., El-Mokdem K. M. J. Heterocycl.
Chem. 2007, 44, 1431.
[19] Aly, A. A.; Hassan, A. A.; Gomaa M. A.-M.; El-Sheref, E.
Arkivoc 2007, xiv, 1.
[20] Mourad, A. E.; Aly, A. A.; Farag, H. F.; Beshr E. A. Beilstein
J. Org. Chem. 2007, 3, 1.
[21] Seebacher, W.; Michl, G.; Weis, R. Tetrahedron Lett. 2002,
43, 7481.
[22] Hasnaoui, A.; Lavergne, J.-P.; Viallefont, P. J. Heterocycl.
Chem. 1978, 15, 71.
[23] Esseffar, M.; Jalal, R.; El Messaoudi, M.; El Mouhtadi, M. J
Mol. Struct. (THEOCHEM). 1998, 433, 301.
[24] a) Groszkowski, S.; Wrona, J. Pol. J. Pharmacol. Pharm.
1978, 30, 713; b) Lenman, M.; Lewis, A.; Gani, D. J. Chem. Soc.,
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Chem. Soc., Chem. Commun. 1996, 85.
[25] Yamamoto, Y.; Shindo, M.; Nakamura, T. PCT Int. Appl.
WO 9747622, 1998; Chem. Abstr. 1998, 128, 75427e.
[26] Nakanishi, K.; Solomon, P. H. Infrared Absorption
Spectroscopy, 2nd ed., Holden-Day, San Francisco, 1977; pp 50.
[27] Socrates, G. Infrared Characteristic Group Frequencies.
Wiley & Sons: Chichester, 1980, pp. 116.
4-Allyl-7-phenyl-3-thioxo-3,4-dihydro-2H-(1,2,4-triazepin-
5-yl)-phenyl methanone (9c). Yellow crystals of 9c (0.26 g,
1
76%), m.p. 125 °C (ethanol); H nmr (chloroform-d): δ 4.40 (m,
2 H, allyl-CH2), 5.20-5.34 (m, 2 H, allyl-CH2=), 5.80-5.85 (m, 1
H, allyl-CH=), 6.04 (s, 1 H, H-6), 7.06-7.26 (m, 8 H, Ph-H),
7.38 (br, s, 1 H, NH2), 7.80-7.84 (m, 2 H, Ph-H) ppm; 13C nmr
(chloroform-d): δ 46.0 (allyl-CH2-N), 116.2 (allyl-CH2=), 112.0
(CH-6), 127.0, 127.8 (p-Ph-CH), 138.4, 128.6, 130.0, 130.4 (2
Ph-CH), 131.8 (ally-CH=), 132.4, 133.0 (Ph-C), 156.2 (C-5),
158.4 (C-7), 176.2 (COPh), 182.4 (C-3) ppm; ir (potassium
bromide): 3360 (NH), 3090-3010 (Ar-CH), 2986-2880 (Aliph-
CH), 1706 (C=O), 1590 (C=C), 1360, 988 (C=S), 1254 (st. C=S)
cm-1; ms (electron impact, 70 eV): m/z (%) 347 [M+] (40), 306
(30), 242 (34), 223 (10), 202 (26), 191 (24), 126 (40), 105 (100),
77 (34). Anal. Calcd. for C20H17N3OS: Found: C, 69.14; H, 4.93;
N, 12.09. Found: C, 69.30; H, 4.90; N, 11.98.
Method B
As described above, 1a-c (1 mmol) and 8 (1 mmol, 234 mg)
were well mixed in DMF (5 ml). The mixture was irradiated in a
microwave oven for 10-20 min (100 °C). On cooling to room
temperature, the precipitated products 9a-c were collected by
filtration and recrystallized from the stated solvents. The spectral
data were in good agreements with those given before.
Acknowledgement: Prof Dr. Ashraf A. Aly thanks DAAD
committee for its financial support for the scholarship at
Braunschweig University, Institute of Organic Chemistry, and
Germany.
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East German Patent 1971, 83, 559; Chem. Abstr. 1973, 78, 96674g.
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