Facile synthesis of new (Z)-6-arylmethylidene-1,3,4-thiadiazin-5(6H)-one derivatives

Article abstract of DOI:10.1007/s10593-013-1195-3

3-Aryl-2-sulfanylpropenoic acids reacted with acetohydrazonyl chlorides in refluxing absolute ethanol in the presence of equimolar amounts of triethylamine, forming (Z)-6-arylmethylidene-1,3,4-thiadiazin-5-one derivatives. X-ray study on the crystal of on

Full text of DOI:10.1007/s10593-013-1195-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
FACILE SYNTHESIS OF NEW (Z)-6-ARYLMETHYLIDENE-
1,3,4-THIADIAZIN-5(6H)-ONE DERIVATIVES
N. H. Metwally1*, F. M. Abdelrazek1, and A. Jaeger2
3-Aryl-2-sulfanylpropenoic acids reacted with acetohydrazonyl chlorides in refluxing absolute ethanol
in the presence of equimolar amounts of triethylamine, forming (Z)-6-arylmethylidene-1,3,4-thiadiazin-
5-one derivatives. X-ray study on the crystal of one of the obtained products was carried out.
Keywords: N'-arylacetonitrilimines, (Z)-6-arylmethylidene-1,3,4-thiadiazin-5(6H)-one derivatives,
3-aryl-2-sulfanylpropenoic acids.
The synthetic utility of 3-aryl-2-sulfanylpropenoic acids has been well known for more than a century.
They have been widely used as versatile intermediates for the synthesis of nitriles, amino acids, α-thio acids [1],
and thiazoles [2-4]. In addition, 3-aryl-2-sulfanylpropenoic acids are known as antidotes for heavy metal
poisoning [5-7].
It is well known that 1,3,4-thiadiazinone derivatives have attracted a great deal of interest due to a
variety of interesting biological activities. They are known as spasmolytic [8] and antibacterial agents [9], and
important matrix metalloproteinase inhibitors [10, 11], and they also display cardiotonic, hypertensive [12, 13],
and other biological activities [14-16].
In continuation of our interest in synthesis of some new heterocyclic compounds with biological activity
[17-24], we report here a simple preparation of (Z)-6-arylmethylidene-1,3,4-thiadiazin-5-one derivatives via a
one-step reaction of 3-aryl-2-sulfanylpropenoic acids with hydrazonyl chlorides.
The reaction of equimolar amounts of 3-aryl-2-sulfanylpropenoic acids 1a-c, N-aryl-substituted
acetohydrazonyl chlorides 2a-c, and triethylamine in refluxing absolute ethanol afforded stable adducts. The IR
spectra of the isolated products showed two absorption bands in each case in the region of 1667-1697 cm-1 due
to two carbonyl groups. Thus the IR spectra of the isolated products supported the formation of cyclic structures
1
5 or 6 and ruled out structure 4 by the absence of NH and OH absorption bands. The H NMR spectra in each
case revealed a singlet signal at 2.60-2.66 ppm due to acetyl protons in addition to a singlet signal at ~8.0 ppm
attributable to olefinic protons. The mass spectrum of compound 6b taken as a typical example of the prepared
series showed a molecular ion peak at m/z 328 [M]+. From the above data, as well as elemental analyses,
_______
*To whom correspondence should be addressed, e-mail: nhmmohamed@yahoo.com.
1Cairo University, Cairo University St., Giza 12613, Egypt.
2Institute of Organic Chemistry, Technical University of Dresden, Dresden 01069, Germany; е-mail:
anne.jaeger@chemie.tu-dresden.de.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1813-1816, November, 2012.
Original article submitted June 20, 2011.
1696
0009-3122/13/4811-1696©2013 Springer Science+Business Media New York

R
R
O
O
Et3N
N
N
Me
N
Me
N
H
–
+
Cl
2a–c
3a–c
COOH
Ar
EtOH
SH
1a–c

R
H
O
R
O
O
Me
Ar
N
N
N
Me
N
H
S
N
COOH
N
S
SH
COOH
Ar
R
H
O
Me
6a–h
Ar
5
4
1 a Ar = piperonyl, b Ar = 2-thienyl, c Ar = 2-furyl; 2, 3 a R = H, b R = Me, c R = Cl;
6a R = H, Ar = piperonyl; b R = H, Ar = 2-thienyl; c R = H, Ar = 2-furyl; d R = Me, Ar = piperonyl;
e R = Me, Ar = 2-thienyl; f R = Cl, Ar = piperonyl; g R = Cl, Ar = 2-thienyl; h R = Cl, Ar = 2-furyl
Fig. 1. Molecular structure of compound 6b.
structures 6a-h were assigned to these products, and the structure 5 was ruled out. Additional evidence was
obtained from the X-ray crystallography of compound 6b (Fig. 1), which showed that the structure has
Z-configuration. It should be mentioned that the reaction of hydrazonyl halides with thioglycolic acid or its
derivatives afforded the same thiadiazinones, but with E-configuration [25, 26].
Thus, an efficient and simple one-step route for the synthesis of (Z)-6-aryl-methylidene-1,3,4-thia-
diazin-5(6H)-one derivatives from the reaction of 3-aryl-2-sulfanylpropenoic acids and N'-arylacetonitrilimines
is described.
1697

EXPERIMENTAL
1
The IR spectra were recorded in KBr pellets on a Perkin-Elmer 1430 spectrophotometer. H NMR
13
spectra were recorded on a Varian Gemini 200 spectrometer (200 MHz), and C NMR spectra – on a Varian
Gemini 300 spectrometer (300 MHz). All NMR spectra are registered in DMSO-d6 using TMS as internal
standard. Electron ionization mass spectra were recorded on a Shimadzu GCMS-QP 1000 Ex mass spectrometer
at 70 eV. Elemental analyses were carried out at the Microanalysis Center of Cairo University, Giza, Egypt.
Melting points were determined on an electrothermal (9100) apparatus and are uncorrected. The X-ray
crystallography was carried out in the Institute of Organic Chemistry, Technical University of Dresden,
Germany.
The starting compounds 1a-c [27] and hydrazonyl chlorides 2a-c [28] were prepared according to
published procedures.
Reaction of 3-Aryl-2-sulfanylpropenoic Acids with Hydrazonyl Chlorides (General Method). A
mixture of 3-aryl-2-sulfanylpropenoic acids 1a-c (0.01 mol) and the corresponding hydrazonyl chlorides 2a-c
(0.01 mol) was stirred under reflux in abs. EtOH (30 ml) with Et3N (0.01 mol) for 10 h. The solvent was
evaporated under reduced pressure. The precipitate that formed was filtered off and recrystallized from AcOH.
(Z)-2-Acetyl-6-(benzo[1,3]dioxol-5-ylmethylidene)-4-phenyl-4H-1,3,4-thiadiazin-5(6H)-one
(6a).
1
Yield 2.6 g (71%). Pale-yellow crystals; mp 210-211°C. IR spectrum, ν, cm-1: 1670, 1680 (CO). H NMR
spectrum, δ, ppm: 2.65 (3H, s, CH3); 6.17 (2H, s, CH2); 6.80-7.18 (8H, m, H Ar); 8.05 (1H, s, ArCH). Mass
spectrum, m/z (Irel, %): 366 [M]+ (39). Found, %: C 62.49; H 3.63; N 7.83; S 8.55. C19H14N2O4S. Calculated, %:
C 62.29; H 3.85; N 7.65; S 8.75.
(Z)-2-Acetyl-4-phenyl-6-(thiophen-2-ylmethylidene)-4H-1,3,4-thiadiazin-5(6H)-one (6b). Yield
1
2.2 g (67%). Yellow crystals; mp 178-179°C. IR spectrum, ν, cm1: 1667, 1681 (CO). H NMR spectrum, δ,
ppm: 2.66 (3H, s, CH3); 7.20-7.90 (8H, m, H Ar); 8.01 (1H, s, ArCH). 13C NMR spectrum, δ, ppm: 192.9
(C=O); 160.5 (C=O); 146.0 (C=N); 142.3; 141.0; 135.1; 132.6; 129.0; 128.7; 128.1; 125.4; 115.6 (C Ar); 110.0
(ArCH); 26.6 (CH3). Mass spectrum, m/z (Irel, %): 328 [M]+ (46). Found, %: C 58.70; H 3.51; N 8.70; S 19.37.
C16H12N2O2S2. Calculated, %: C 58.52; H 3.68; N 8.53; S 19.53.
(Z)-2-Acetyl-6-(furan-2-ylmethylidene)-4-phenyl-4H-1,3,4-thiadiazin-5(6H)-one (6c). Yield 2.0 g (64%).
1
Yellow crystals; mp 167-168°C (mp 148°C [26]). IR spectrum, ν, cm-1: 1680, 1697 (CO). H NMR spectrum, δ,
ppm: 2.61 (3H, s, CH3); 6.90-7.92 (8H, m, H Ar); 8.04 (1H, s, ArCH). Mass spectrum, m/z (Irel, %): 312 [M]+
(34). Found, %: C 61.74; H 3.69; N 8.80; S 10.48. C16H12N2O3S. Calculated, %: C 61.53; H 3.87; N 8.97;
S 10.27.
(Z)-2-Acetyl-6-(benzo[1,3]dioxol-5-ylmethylidene)-4-(4-methylphenyl)-4H-1,3,4-thiadiazin-5(6H)-one
(6d). Yield 2.7 g (71%). Pale-yellow crystals; mp 205-206°C. IR spectrum, ν, cm-1: 1678, 1688 (CO). 1H NMR
spectrum, δ, ppm: 2.32 (3H, s, ArCH3); 2.62 (3H, s, COCH3); 6.08 (2H, s, CH2); 6.83-7.44 (7H, m, H Ar); 7.87
(1H, s, ArCH). Found, %: C 63.36; H 4.05; N 7.59; S 8.61. C20H16N2O4S. Calculated, %: C 63.15; H 4.24;
N 7.36; S 8.43.
(Z)-2-Acetyl-6-(thiophen-2-ylmethylidene)-4-(4-methylphenyl)-4H-1,3,4-thiadiazin-5(6H)-one (6e).
Yield 2.3 g (67%). Yellow crystals; mp 179-180°C. IR spectrum, ν, cm-1: 1673, 1687 (CO). 1H NMR spectrum,
δ, ppm: 2.35 (3H, s, ArCH3); 2.65 (3H, s, COCH3); 7.23-8.06 (7H, m, H Ar); 8.10 (1H, s, ArCH). Mass
spectrum, m/z (Irel, %): 342 [M]+ (40). Found, %: C 59.85; H 4.30; N 8.40; S 18.55. C17H14N2O2S2. Calculated,
%: C 59.63; H 4.12; N 8.18; S 18.73.
(Z)-2-Acetyl-6-(benzo[1,3]dioxol-5-ylmethylidene)-4-(4-chlorophenyl)-4H-1,3,4-thiadiazin-5(6H)-one
(6f). Yield 2.9 g (72%). Yellow crystals; mp 214-215°C. IR spectrum, ν, cm-1: 1672, 1681 (CO). 1H NMR spectrum,
δ, ppm: 2.65 (3H, s, CH3); 6.19 (2H, s, CH2); 6.82-7.68 (7H, m, H Ar); 7.86 (1H, s, ArCH). Found, %: C 57.12;
H 3.10; N 6.77; S 8.18. C19H13ClN2O4S. Calculated, %: C 56.93; H 3.27; N 6.99; S 8.00.
1698

(Z)-2-Acetyl-4-(4-chlorophenyl)-6-(thiophen-2-ylmethylidene)-4H-1,3,4-thiadiazin-5(6H)-one (6g).
Yield 2.4 g (66%). Yellow crystals; mp 187-188°C. IR spectrum, ν, cm-1: 1678, 1684 (CO). 1H NMR spectrum,
13
δ, ppm: 2.66 (3H, s, CH3); 7.54-8.00 (7H, m, H Ar); 8.11 (1H, s, ArCH). C NMR spectrum, δ, ppm: 193.1
(C=O); 160.3 (C=O); 147.0 (C=N); 142.6; 139.5; 135.6; 133.8; 129.4; 128.6; 128.0; 126.7; 116.3 (C Ar); 110.6
(ArCH); 26.8 (CH3). Found, %: C 53.17; H 3.24; N 7.96; S 17.85. C16H11ClN2O2S2. Calculated, %: C 52.96;
H 3.06; N 7.72; S 17.67.
(Z)-2-Acetyl-4-(4-chlorophenyl)-6-(furan-2-ylmethylidene)-4H-1,3,4-thiadiazin-5(6H)-one
(6h).
Yield 2.1 g (61%). Yellow crystals; mp 196-197°C. IR spectrum, ν, cm-1: 1672, 1680 (CO). 1H NMR spectrum,
δ, ppm: 2.60 (3H, s, CH3); 7.68-8.00 (7H, m, H Ar); 8.07 (1H, s, ArCH). Found, %: C 55.20; H 3.39; N 8.32; S
9.07. C16H11ClN2O3S. Calculated, %: C 55.42; H 3.20; N 8.08; S 9.25.
X-Ray Structure Investigation of Compound 6b. The X-ray diffraction measurements were carried out
at wavelength 0.71073 Å. Crystal parameters for compound 6b: C16H12N2O2S2; M 328.40; crystal system
orthorhombic, space group Pbca. Unit cell dimensions: a 12.158(2), b 7.391(2), c 33.885(7) Å; α 90, β 90,
γ 90°; V 3044.9(12) Å3; T -75(2)°C; Z 8; dcalc 1.433 g/cm3; μ 0.357 cm-1. Total 45297 reflections are measured,
[sin(θ)/λ]max 0.64°·Å-1 / 99.8%; wR2 factor 0.100; ρ 0.53 (-0.37) e·Å-3. Crystallographic data of compound 6b
have been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 746860).
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
D. Villemin and A. B. Alloum, Phosphorus, Sulfur Silicon Relat. Elem., 79, 33 (1993).
K. H. Patel and A. G. Mehta, E-J. Chem., 3, 103 (2006).
S. Kambe, K. Saito, A. Sakurai, and H. Midorikawa, Synthesis, 531 (1981).
S. O. Abd Allah, H. A. Hammouda, and F. A. Ali, J. Heterocycl. Chem., 22, 497 (1985).
D. N. Kachru, S. Singh, and S. K. Tandon, Toxicol. Lett., 57, 251 (1991).
S. K. Tandon, S. Prasad, and S. Singh, Biomed. Environ. Sci., 3, 205(2000).
M. Chatterjee, V. K. Dwivedi, K. Khandekar, and S. K. Tandon, Biomed. Environ. Sci., 17, 27 (2004).
A. K. Shakya, P. Mishra, G. K. Patnaik, R. Shukla, and R. C. Srimal, Arch. Pharm. Res., 21, 753
(1998).
9.
10.
M. J. Pawar, A. B. Burungale, and B. K. Karale, ARKIVOC, xiii, 97 (2009).
J. Schroder, A. Henke, H. Wenzel, H. Brandstetter, H. G. Stammler, A. Stammler, W. D. Pfeiffer, and
H. Tschesche, J. Med. Chem., 44, 3231 (2001).
11.
12.
13.
14.
H. Tschesche and J. Schroder, EP Pat. Appl. 1191024.
H. Sugawara and M. Endoh, Jpn. J. Pharmacol., 80, 55 (1999).
H. M. Himmel, G. J. Amos, E. Wettwer, and U. Ravens, J. Cardiovasc. Pharmacol., 33, 301 (1999).
H. N. Dogan, A. Duran, S. Rollas, G. Sener, M. K Uysal, and D. Gulen, Bioorg. Med. Chem., 10, 2893
(2002).
15.
16.
S. A. Carvalho, E. F. Da-Silva, R. M. Santa-Rita, S. L. De-Castro, and C. A. M. Fraga, Bioorg. Med.
Chem. Lett., 14, 5967 (2004).
S. N. Swamy, Basappa, B. S. Priya, B. Prabhuswamy, B. H. Doreswamy, J. S. Prasad, and
K. S. Rangappa, Eur. J. Med. Chem., 41, 531 (2006).
17.
18.
19.
20.
21.
22.
23.
S. O. Abd Allah, H. A. Ead, N. A. Kassab, and N. H. Metwali, Heterocycles, 20, 637 (1983).
S. O. Abdallah, H. A. Hammoude, and N. H. Metwally, Egypt. J. Chem., 28, 497 (1985).
H. A. Ead and N. H. Metwally, Arch. Pharm., 323, 57 (1990).
H. A. Ead, M. A. Abdelaziz, and N. H. Metwally, Pol. J. Chem., 65, 1291 (1991).
H. A. Ead, S. O. Abdallah, N. A. Kassab, and N. H. Metwally, Sulfur Lett., 9, 23 (1989).
H. A. Ead, N. H. Metwalli, and N. M. Morsi, Arch. Pharm. Res., 13, 5 (1990).
N. H. Metwally, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 39B: 757 (2000).
1699

24.
25.
26.
N. H. Metwally, Phosphorus, Sulfur Silicon Relat. Elem., 183, 34 (2008).
B. A. Thaher and H. H. Otto, Monatsh. Chem., 133, 1011 (2002).
H. M. Dalloul and A. Z. El-Shorafa, Khim. Geterotsikl. Soedin., 918 (2009). [Chem. Heterocycl.
Compd., 45, 735 (2009).]
27.
28.
E. Campaigne and R. E. Cline, J. Org. Chem., 21, 32 (1956).
N. F. Eweiss and A. Osman, J. Heterocycl. Chem., 17, 1713 (1980).
1700