Reaction of N-imidoylthioureas with dimethyl acetylenedicarboxylate: Synthesis of new 1,3,5-thiadiazepines

Article abstract of DOI:10.3184/030823407X255579

The reaction of N-imidoylthioureas 2a-e with dimethyl acetylenedicarboxylate (DMAD, 1) led unexpectedly to the 1,3,5-thiadiazepines 6a-e. The mechanism of the reaction is discussed.

Full text of DOI:10.3184/030823407X255579

JOURNAL OF CHEMICAL RESEARCH 2007
OCTObER, 563–565
RESEARCH PAPER 563
Reaction of N-imidoylthioureas with dimethyl acetylenedicarboxylate:
synthesis of new 1,3,5-thiadiazepines
Ashraf A. Aly* and Kamal M. El-Shaieb
Chemistry Department, Faculty of Science, El-Minia University, 61519-El-Minia, A. R. Egypt
The reaction of N-imidoylthioureas 2a–e with dimethyl acetylenedicarboxylate (DMAD, 1) led unexpectedly to the
1,3,5-thiadiazepines 6a–e. The mechanism of the reaction is discussed.
Keywords: imidoylthioureas, DMAD, stepwise mechanism, cyclisation, 1,3,5-thiadiazepines
The cyclisation of compounds having an extended urea-
like chain has been shown to be an excellent method for
the synthesis of several heterocycles like 1,3,4-thiadiazoles,
1,2,4-triazoles and 1,3,5-triazines. 1-Substituted benzoyl
thiosemicarbazide on irradiation with microwaves in aqueous
alkali is reported to form 3-aryl-1,2,4-triazoline-5-thiones.1
N-Imidoylthioureas have been shown attention in the field
of thiadiazole synthesis.2,3 Oxidation of N-imidoylthioureas
with bromine yielded 2,3,5-substituted-1,2,4-thiadiazoles
as their hydrobromide salts.3 We have recently investigated
the chemistry of N-imidoylthioureas towards p-deficient
compounds. In this point of view, we isolated pyrimidin-
4(3H)-ones from the reaction of 2,3-diphenylcyclopropenone
with N-imidoylthioureas.4 Aly et al. also demonstrated that
N-imidoylthioureas reacted with 1,1,2,2-tetracyanoethylene
to form the corresponding thiadiazines.5 Also, syntheses
of various diastereomeric 1,2,4-thiadiazole-5-carbonitriles
were reported. Their successful synthesis depends on the
reaction of N-imidoylthioureas with 2-(1,3-dioxoindan-2-
ylidene)-malononitrile.6 Synthetic potential and biological
activity of benzodiazepines has been explored to the
maximum extent.7-9 Owing to their well-established role
as psychotherapeutics,10 benzodiazepines have been the
object of intense investigation in medicinal chemistry. The
area of biological interest of this family of compounds has
been extended recently to various diseases such as cancer,11
viral infections (HIV)12 and cardiovascular disorders.13,14
To the best of our knowledge only a few reports are available
for the synthesis, and pharmacological activity of 1,3,5-
thiadiazepines, 1,2,7-thiadiazepines, 1,3,4-thiadiazepines, and
1,4,5-thiadiazepines.15,16 Renewed interest in the chemistry
of organosulfur systems,17-21 prompted us to explore the
chemistry of N-imidoyl-thioureas 2a–e towards dimethyl
acetylenedicarboxylate (DMAD, 1) aiming to shed more light
on the selectivity of the reaction pathway.
Results and discussion
In the light of the aforementioned promising results,
our attention turned to the reactions of DMAD (1) with
N-imidoylthioureas 2a–e (Scheme 1).
We chose N-imidoylthioureas 2a–e having aryl groups
with electron donating and withdrawing substituents on the
benzene ring, in order to examine their reactivity and effect
on the course of reaction. The reactions of 2a–e with 1 were
carried out in acetic acid at reflux temperature, and afforded
the thiadiazepines 6a–e in 65–84% yields (Scheme 1). The
structures 6a–e were characterised on the basis of mass,
1H NMR, 13C NMR and IR spectra as well as elemental
analyses. For example, reaction of compound 1 with 2a, for
10 h, furnished yellow crystals of 6a in 84% yield (Scheme 1).
Mass spectrometry and elemental analysis proved the
molecular formula of 6a as C27H23N3O5S. The IR spectrum
did not reveal any absorption assigned to the presence of NH,
CS, or OH groups. Moreover, the structure feature of 1,3,5-
thiadiazepines 6a–e could be ruled out, owing to the absence
of C=S signals in the 13C NMR spectra. However, a broad
band appeared at n = 1725–1716 cm-1 due to the presence
of a carbonyl ester group. The aromatic protons resonated in
the 1H NMR spectrum of 6a as two double-doublets and two
multiplets, respectively corresponding to the p-methoxyphenyl
group and the other two phenyl groups. The 13C DEPT 135/90
spectrum of 6a supported the 1H NMR spectroscopic data by
the appearance with positive amplitude of only eight aromatic-
NHPh
CO2Me
Ar
NHPh
..
N
NHPh
S
HN
S
N
AcOH
Ph
Ar
S
Ph
N
H
6a-e
Ph
N
Ar
CO2Me
1
N
CO2Me
CO2Me
reflux, 10-16 h
2
CO2Me
CO2Me
4
3
Ph
H
N
H
NPh
N
N
Ph
Ar
Ph
- H2
S
S
N
N
H
Ar
CO2Me
CO2Me
MeO2C
MeO2C
6
5
Scheme 1 Synthesis of 1,3,5-thiadiazepines 6.
a: Ar = 4-CH3OC6H4 (84%); b: Ar = 4-CH3C6H4 (80%); c: Ar = 4-ClC6H4 (75%); d: 4-O2NC6H4 (65%); e: Ar = Ph (82%).
* Correspondent. E-mail: ashraf160@yahoo.com
PAPER: 07/4847

564 JOURNAL OF CHEMICAL RESEARCH 2007
CH signals In the case of 6d, the 1H NMR spectrum revealed
the most deshielded aromatic protons as double-doublets at
d = 7.95 and 6.80 ppm (J = 8.0, 1.2 Hz) corresponding to
the p-nitrophenyl group. NOE experiments for compounds
6a–e proved their proposed structure (Fig. 1). For example,
irradiation of the methyl–ester protons (d = 3.95 ppm), in 6a
moderately enhances the ortho-protons of the neighbouring
phenyl group (d = 6.60 ppm), and strongly enhances the other
methyl-ester (d = 3.92 ppm). besides, irradiation of the ortho-
protons (d = 6.60 ppm) of substituted phenyl group causes
moderately enhancement of the neighbour phenyl group
(d = 7.30 ppm) and strong enhancement to the methyl-ester
(Fig. 1). The same tendency of NOE experiments was noted
in the case of 6d (Fig. 1). The fragment ions in the mass
spectrum of 6a appeared at m/z = 396, 140, 134 and 77. The
same aforesaid fragmentation patterns are also appeared in
compounds 6b–e (see Experimental). As shown from Fig. 2,
consequently, the structure 6a fits best to all the spectroscopic
data (see Experimental). The reaction mechanism can be
simply described as due to sulfur atoms attacking the triple
bond of DMAD in conjugate fashion, followed by proton
transfer and nucleophilic attack of the amidine group on the
double bond in 3 to form the intermediates 4 (Scheme 1).
Nucleophilic attack of the amidine-like on the ethylenic-
ester would form the salt 5 (Scheme 1). Aromatisation of 5
is accompanied by the extrusion of a hydrogen molecule to
produce the stable compounds 6a-e (Scheme 1). Similar
observation was reported by Alajarín and his group.22 It
was also reported that compound 4,5-dihydrodibenzo-
1,4,5-thiadiazepine S,S-dioxides can be oxidised to give
the corresponding dibenzo-1,4,5-thiadiazepines,23 which is
isoelectronic with compound 6, so it is also logically to accept
oxidation as the last step. It is notable that aromatic rings on
the imidoyl moiety, which bear electron-donating substituents
at the 4-position, accelerate the reactions (entries 2a and 2b
versus 2c and 2d).
d = 3.95
d = 3.93
d = 3.90
(d = 50.8)
(d = 50.4)
(d = 50.2)
d = 3.92
CO2Me
NOE
(d = 50.5)
CO2Me
NOE
S
N
S
N
Ph
CO2Me
NOE
Ph
N
CO2Me
d = 7.36
N
N
(d = 128.0)
NOE
N
d = 7.30
(d = 126.8)
NOE
NOE
NO2
O
d = 6.80
(d =124.0)
d = 6.60
(d = 125.8)
6d
6a
Fig. 1 NOE experiments for compounds 6a and 6d.
m/z = 134
CO2Me
S
N
m/z = 140
Ph
CO2Me
N
N
m/z = 396
m/z = 105
OMe
m/z = 77
Fig. 2 Possible fragmentation ions in compound 6a.
J = 8.0, 1.2 Hz, ArH), 7.50–7.33 (m, 6 H, PhH), 7.30 (dd, 2 H,
J = 8.0, 1.2 Hz, PhH), 6.76–6.66 (m, 2 H, PhH), 6.60 (dd, 2 H,
J = 8.0, 1.2 Hz, ArH), 3.98 (s, 3 H, OCH3), 3.95 (s, 3 H, CH3–ester),
3.92 (s, 3 H, CH3–ester). 13C NMR: (DMSO-d6): d = 166.8 (CO–
ester), 165.8 (CO–ester), 160.0 (C-2), 158.0 (C-4), 150.5 (OCH3-
Ph C), 143.2 (NAr C), 142.0 (N-Ph C), 132.0 (C-6), 131.8 (Ph C),
128.0 (CH3O–Ph 2CH), 127.6, 127.3, 127.0 (Ph 2CH), 126.8 (C-4,
Ph 2CH), 125.8 (CH3O–Ph 2CH), 125.6, 125.2 (para-Ph CH), 125.0
(C-7), 54.5 (OCH3), 50.8 (CH3-ester), 50.5 (CH3-ester). IR (Kbr):
3070–3018 (w, ArCH), 2960–2860 (m, aliph-CH), 1725–1716
(s, CO), 1612 (s, C=N), 1580 (m, C=C), 1450 (s), 918 (m) cm-1. lmax
(CH3CN, lg e, nm): 380 (3.6). MS (m/z,%): 501 [M+] (100), 406 (18),
396 (24), 378 (24), 360 (34), 354 (10), 316 (24), 275 (26), 248 (14),
222 (36), 197 (12), 140 (26), 134 (26), 105 (60), 77 (28), 51 (22).
C27H23N3O5S (501.57): Calcd: C, 64.66; H, 4.62; N, 8.38; S, 6.39.
Found: C, 64.50; H, 4.60; N, 8.30; S, 6.34.
Dimethyl ester 5-(4-methylphenyl)-4-phenyl-2-phenylimino-2,5-
dihydro-1,3,5-thia-diazepine-6,7-dicarboxylate (6b): Compound 6b
was obtained as yellow crystals (0.78 g, 80%), m.p. 260oC (methanol).
1H NMR (DMSO-d6): d = 7.56–7.34 (m, 10 H, PhH), 6.80–6.62 (m,
4 H, PhH), 3.94 (s, 3 H, CH3–ester), 3.92 (s, 3 H, CH3–ester), 2.34
(s, 3 H, CH3). 13C NMR: (DMSO-d6): d = 166.2 (CO–ester), 165.8
(CO–ester), 158.8 (C-2), 157.6 (C-4), 143.2 (NAr C), 142.0 (NPh C),
134.0 (CH3Ph C), 132.4 (C-6), 131.6 (Ph C), 130.0, 128.0, 127.6,
127.4, 127.0 (Ph 2CH), 126.4, 126.0 (para-Ph-CH), 124.8 (C-7),
120.2 (NPh 2CH), 50.2 (CH3–ester), 50.0 (CH3–ester), 34.6 (CH3–
Ph) . IR (Kbr): 3070–3010 (w, ArCH), 2950-2870 (m, aliph.–CH),
1725–1715 (s, CO), 1610 (s, C=N), 1588 (m, C=C), 1450 (s), 920
(m) cm-1. lmax (CH3CN, lg e, nm): 366 (3.5). MS (m/z,%): 485 [M+]
(100), 470 (18), 420 (22), 406 (30), 396 (22), 378 (24), 348 (34), 354
(10), 275 (30), 265 (26), 248 (14), 206 (32), 197 (12), 140 (24), 134
(24), 105 (60), 77 (28), 51 (20). C27H23N3O4S (485.57): Calcd: C,
66.79; H, 4.77; N, 8.65; S, 6.60. Found: C, 66.60; H, 4.70; N, 8.60;
S, 6.54.
Experimental
General
All melting points were recorded on a Gallenkamp apparatus. The
IR spectra were obtained on a Shimadzu 470 spectrophotometer
1
using potassium bromide pellets. The H NMR (400.134 MHz) and
13C NMR (100.6 MHz) spectra were measured in DMSO-d6 using a
bruker AM 400 Spectrometer. Coupling constants are expressed in
Hz. Mass spectra were recorded on a Finnigan MAT 8430 instrument
at 70 eV. Elemental analyses were carried out in the Microanalysis
Centre of Cairo University. For preparative TLC (plc), glass plates
(20 ¥ 48 cm) were covered with a slurry of silica gel Merck PF254
and air-dried using the solvents listed for development. Zones were
detected by quenching of indicator fluorescence upon exposure to
254 nm light; elution of the different bands with toluene afforded the
pure products.
Starting materials
N-Imidoylthioureas 2a–e were prepared according to ref.2.
General procedure
Into a 250 cm3 two-necked round bottom flask containing a
solution of 2a–e (2 mmol) in glacial acetic (100 ml), a solution of
1 (0.284 g, 2 mmol) in glacial acetic acid (30 ml) was added
dropwise with stirring. The mixture was stirred at room temperature
for 1 h, and at reflux for 10–16 h (the reaction was monitored by TLC
analyses). The solvent was evaporated under vacuum and the formed
solid products were purified by dissolving them in dry acetone
(30 ml) and then subjected to preparative plate chromatography
(silica gel), toluene: ethyl acetate (10:1). The obtained products 6a-e
were recrystallised from the stated solvents.
Dimethyl ester 5-(4-chlorophenyl)-4-phenyl-2-phenylimino-2,5-
dihydro-1,3,5-thia-diazepine-6,7-dicarboxylate (6c): Compound 6c
was obtained as pale yellow crystals (0.76 g, 75%), m.p. 186oC (ethyl
acetate). 1H NMR (DMSO-d6): d = 7.40–7.24 (m, 5 H, PhH), 7.16–
7.00 (m, 5 H, PhH), 6.80–6.62 (m, 4 H, PhH), 3.94 (s, 3 H, CH3–
ester), 3.90 (s, 3 H, CH3–ester). 13C NMR: (DMSO-d6): d = 166.6
(CO-ester), 165.6 (CO–ester), 159.6 (C-2), 157.8 (C-4), 142.6 (NAr
C), 141.7 (NPh C), 132.2 (C-6), 131.6 (Ph C), 127.8, 127.6, 127.2
(Ph 2CH), 127.0 (ClPh C), 126.6 (C-4, Ph 2CH), 126.0, 125.8 (ClPh
2CH), 125.4, 125.0 (para-Ph CH), 124.8 (C-7), 51.0 (CH3–ester),
Dimethyl ester 5-(4-methoxyphenyl)-4-phenyl-2-phenylimino-
2,5-dihydro-1,3,5-thiadiazepine-6,7-dicarboxylate
(6a):
Compound 6a was obtained as yellow crystals (0.84 g, 84%),
m.p. 220oC (ethanol). 1H NMR (DMSO-d6): d = 7.80 (dd, 2 H,
PAPER: 07/4847

JOURNAL OF CHEMICAL RESEARCH 2007 565
References
50.6 (CH3–ester). IR (Kbr): 3068–3008 (w, ArCH), 1722–1710
(s, CO), 1600 (s, C=N), 1590 (m, C=C), 1450 (s), 922 (m) cm-1. lmax
(CH3CN, lg e, nm): 354 (3.4). MS (m/z,%): 507 [M + 2] (28), 505
[M+] (100), 490 (12), 472 (22), 470 (34), 396 (24), 392 (22), 426
(24), 282 (60), 252 (34), 236 (24), 234 (26), 194 (24), 192 (28), 140
(26), 134 (24), 115 (30), 113 (34), 77 (38). C26H20ClN3O4S (505.98):
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7.60–7.40 (m, 5 H, PhH), 7.10–6.90 (m, 5 H, PhH). 6.80 (dd, 2 H,
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ester). d = 13C NMR (DMSO-d6): d = 166.8 (CO–ester), 166.0 (CO–
ester), 158.8 (C-2), 157.6 (C-4), 143.8 (O2NPh C), 136.0 (NPh C),
132.8 (C-6), 131.6 (Ph C), 128.8 (O2NPh 2CH), 127.6, 127.4, 127.0
(Ph 2CH), 126.8 (C-4, Ph 2CH), 126.0 (C-7), 125.8, 125.5 (para-
Ph CH), 126.0 (C-7), 124.0 (O2NPh 2CH), 50.4 (CH3–ester), 50.2
(CH3–ester). IR (Kbr): 3090–2998 (w, ArCH), 1720–1710 (CO),
1610 (s, C=N), 1500 (s, C=C), 920 (s) cm-1. lmax (CH3CN, lg e, nm):
340 (3.3). MS (m/z,%): 516 [M+] (100), 501 (18), 485 (20), 440 (22),
396 (28), 362 (34), 322 (30), 276 (24), 246 (30), 238 (36), 192 (30),
140 (30), 134 (28), 122 (34), 88 (32), 77 (40). C26H20N4O6S (516.54):
Calcd; C, 60.46; H, 3.90; N, 10.85; S, 6.21. Found; C, 60.30; H, 3.80;
N, 10.90; S, 6.18.
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thiadiazepine-6,7-dicarboxylate (6e): Compound 6e was obtained
as pale yellow plates (0.77 g, 82%), m.p. 160oC (acetonitrile).
1H NMR: d = 7.50–7.20 (m, 10 H, PhH), 7.10–6.90 (m, 3 H, PhH),
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Received 21 September 2007; accepted 26 October 2007
Paper 07/4847 doi: 10.3184/030823407X255579
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PAPER: 07/4847