Synthesis of 1,3-thiazin-2-ylidene-substituted hydrazides via reaction of N-substituted-hydrazino-carbothioamides with 1,4-diphenylbut-2-yne-1,4-dione

Article abstract of DOI:10.3184/030823408X384575

1,4-Diphenylbut-2-yne-1,4-dione reacts with N-substituted-hydrazino- carbothioamides to form the corresponding N'-6-benzoyl-4-phenyl-2H-1,3-thiazin- 2-y[idene]-substituted-hydrazides.

Full text of DOI:10.3184/030823408X384575

JOURNAL OF CHEMICAL RESEARCH 2008
DECEMBER, 699-701
RESEARCH PAPER 699
Synthesis of 1,3-thiazin-2-ylidene-substituted hydrazides via reaction of
N-substituted-hydrazino-carbothioamides
with 1,4-diphenylbut-2-yne-
1,4-dione
Ashraf A. Aly*, Alaa A. Hassan and Vusria R. Ibrahim
Department of Chemistry, Faculty of Science, EI-Minia University, 61519-EI-Minia, Egypt
1,4-Diphenylbut-2-yne-1,4-dione
reacts with N-substituted-hydrazino-carbothioamides
to form the corresponding
N' -6-benzoyl-4-phenyl-2H-1 ,3-th iazin-2-yl idene ]-su bstituted-hyd razi des.
Keywords: N-substituted-hydrazino-carbothioamides, 1,4-diphenylbut-2-yne-l,4-dione, amidine-like addition, cyclisation, 1,3-thiazines
The chemistry of 1,4-diphenylbut-2-yne-l,4-dione
(DBD)
7.36-7.20 (m, 4 H) and 6.90-6.82 (2 H, ArH). The hydrazine
proton resonated in the IH NMR spectrum of3a at ~ = 6.60.
The H-5 proton in the IH NMR spectrum of 3a resonated at
OR = 7.10. The 13CNMR spectrum supported the IH NMR
spectroscopic data by the distinctive appearance of the carbon
signals representing the thiazine skeleton at Oc = 162.8 (C-4),
158.2 (C-2), 132.0 (C-6) and 124.2 (C-5). The carbonyl
carbon signals resonated at Oc = 186.2 and 168.0 assigned to
COPh and CONH, respectively (see Experimental).
In 3b, mass spectrometry and elemental analysis proved the
molecular formula as C24H17N303S,The IR spectrum did not
reveal any absorption due to C=S group, whereas the spectrum
revealed absorption bands at v = 3490, 3330, 1700 and
1680 cm-Iassigned to the OH, NH, COPhand CONH stretching,
respectively. In the IH NMR spectrum of 3b, the OH and the
NH protons resonated at OR = 9.10 and 6.80 respectively.
Distinctive 13CNMR signals of 3b appeared at Oc = 186.6
(COPh), 168.4 (CONH), 163.0 (C-4), 158.4 (C-2), 148.8 (OH-
Ar-C), 132.4 (C-6), 134.0 (OH-Ph-C), 134.4, 133.0 (ph-C),
128.6, 127.2, 127.0 (ortho-2Ar CH), 126.2, 125.4 (meta-Ar
2CH), 125.0, 124.6 (para-Ar 2CH), 124.0 (CH-5), 120.6
(ortho-Ar 2CH). The NMR of compound 3d, showed the
benzyl protons as a singlet at OR = 5.10, whereas its carbon
signal absorbed at Oc = 42.0. Whilst the IH NMR spectrum of
3e showed the methyl moiety as a singlet at OR = 2.10, and its
carbon signal appeared at Oc = 20.0.
The reaction of Ie with 2 took the most time of refluxing
(48 h) compared with the other substituents. Note that the
yield percentages of the obtained products increase in case of
presence of electron donating groups of the aromatic moiety
such as hydroxyl and methoxy in lb and Ie. However, here
and in (4-bromophenylaceto)thiosemicarbazide ld, the yield
percentage decreases. On the other hand, the methyl derivative,
as in case of Ie, shows less yield percentage and the reaction
requires more time compared with the other derivatives of
la-d. The reaction mechanism depends on the presence of a
tautomerism between the NH and the C=S into the N=C-SH
groups in la-e (Scheme 1). It is logical to assume that any
nucleophilic centre of la-e has to attack firstly the triple
bond in 2. Additionally it is believed that attachment by the
SH group proceeds faster compared to the aromatic amine
(Scheme 1).19,20Therefore we excluded the possibility of the
formation of any other regio-isomers as in compounds 4a-e
(Scheme 1). Accordingly, the reaction of la-e with 2 can be
described as being due to nucleophilic attack of the thiol group
to the triple bond carbon to form the intermediate 5. Thereafter
another nucleophilic attack from the terminal NH via amidine-
like addition to the carbonyl carbon in 5 has occurred to form
the salt 6. Neutralisation of 6 gives 7, which is accompanied
by water elimination to afford compounds 3a-e (Scheme 1).
In conclusion N-substituted-hydrazino-carbothioamides react
with 1,4-diphenylbut-2-yne-l,4-dione by way of an initial
thiol addition followed by another cyclisation process.
has been extensively investigated. For example, DBD reacts
with benzimidazole-2-thione to produce 2-(acylvinylthio)-
benzimidazoles, I whilst diarylazines react with DBD to
produce pyridazines via a Diels-Alder reaction.2 An effective
route to the pyrrol-2-ones involves the reaction of enamines
with DBD.3 Additionally, DBD reacts with enaminocarbonyl
compounds to afford pyrrol-2-ol derivatives.4 Thioamides
and their derivatives occupy a special place among the N,S-
containing compounds used in the synthesis of heterocyclic
systems due to their accessibility and ability to act as
difunctional nucleophiles. Four-, five-, six- and seven-
membered heterocyclic compounds have been prepared
by reaction of thiosemicarbazide derivatives with u- and
~-haloketones.5-10 Reaction of acetylenecarboxylic acid
derivatives with N,S-dinucleophiles provides the general
approach for construction of 1,3-thiazolidine and 1,3-
thiazine systems which are of great interest.1I,121,3-Thiazine
compounds have shown wide biological activities such
as their potential CNS,13 analgesic,14 antiinflammatory I5
and antifungal activities.15 1,3-Thiazines are also used as
chemotherapeutic agents (i.e.leishmanicides ).16Recent reports
have been indicated that 1,3-thiazines provide as useful control
of M griseal7 and they are also been found as cannabinoid
receptor agonists.18 AIy et al. have recently reported the
synthesis of thiazinones, during the reaction of N-aroyl
thioureas with ethyl propiolate, dimethyl but-2-ynedioate and
(£)-1 ,4-diphenylbut-2-ene-l ,4-dione.19 Moreover, we have
investigated the reaction between 2,3-dipheny1cyclopropenone
and ylidene-N-phenyl-hydrazine-carbothioamides.2o Various
(2Z)-2-( {(£)[arylamino ]phenylmethylene} hydrazono )-1,4-
diphenylbutan-l,4-diones are obtained during the reaction
of amidrazones with DBD.21 We now report on the reaction
of N-substituted-hydrazino-carbothioamides la-e22 with 1,4-
diphenylbut-2-yne-l,4-dione (2, DBD). That reactions give
mainly the corresponding N-[6-benzoyl-4-phenyl-2H-l,3-
thiazin-2-ylidene ]-substituted-hydrazides 3a-e (Scheme 1).
We chose compounds la-e having aryl groups with electron
donating and withdrawing substituents on the benzene ring,
in order to examine their reactivity. Moreover we chose the
benzyl and methyl derivative ld and Ie in order to generalise
the idea beyond benzenoid aromatics, to alkyl-substituted
starting materials. The structural proof of 3a-e was based
upon the mass, IH NMR, 13CNMR and IR spectra as well
as elemental analyses. The IR and 13CNMR spectra of 3a-e
supported the disappearance of any thione. Mass spectrometry
and elemental analysis confirmed the molecular formula
of 3a as C24H17N302S,The IH NMR spectrum of 3a, as an
example, showed one double-doublets of the aromatic phenyl
protons at ~ = 8.10-8.0 (2 H, J = 8.0, 1.0 Hz). Besides the
former three multiplets appeared at ~ = 7.90-7.40 (m, 7 H),
* Correspondent. E-mail: ashrafaly63@yahoo.com

700 JOURNAL OF CHEMICAL RESEARCH 2008
time
(h)
1,3 and 5-7
R
Yield of3 (%)
I
C6HS-
28
30
24
34
48
80
83
86
72
62
a
b
c
d
e
4-HO-C6H4-
4-CH3O-C6H4-
4-Br-C6H4-CHr
CH3
Ph
CH3CN, reflux
•
1- 2 d
Ph
Scheme
1
Reaction of N-substituted-hydrazino-carbothioimides
1a-e with 1.4-diphenylbut-2-yne-1.4-dione
(2).
126.2, 126.0 (meta-Ar 2CH), 125.2 (CH-5), 125.0, 124.8 (para-
Ar CH), 120.6 (meta-Ar 2CH). IR (KBr): vmax = 3490 (s, OH),
3330 (m, NH), 3096-3012 (m, Ar-CH), 1700 (s, COPh), 1680 (s,
CONH-), 1610 (s, C=N), 1596 (m, C=C), 1450 (s), 1118(m, C-S), em-I.
A.max (CH3CN, 19 e, urn): 375 (3.6). MS (EI): m/z (%) = 428
[M + 1] (38), 427 [W] (100), 411 (18), 335 (22), 322 (28), 246
(18), 220 (34), 216 (26), 208 (30), 120 (34), 104 (44), 76 (32).
C24H17N303S(427.49): Ca1cd C, 67.43; H, 4.01; N, 9.83; S, 7.50%.
Found C, 67.28; H, 3.94; N, 9.80; S, 7.46%.
Experimental
All melting points were recorded on a Gallenkamp apparatus.
IH NMR and BC NMR spectra (Broker AM 400, IH: 400.13 MHz,
BC: 100.6 MHz); s = singlet, d = doublet, dd = double-doublet
and m = multiplet. The NMR samples were dissolved in DMSO-d6
and/or CDC13 solutions. Coupling constants were expressed in Hz.
Elemental analyses were carried at the Cairo Microanalysis Centre of
Cairo University. Mass spectroscopy was performed with a Finnigan
MAT 8430 spectrometer at 70 eV, Institute of Organic Chemistry,
Technical University-Braunschweig, Germany. IR spectra were run
on a Shimadzu 470 spectrometer using KBr pellets.
N' -(6-Benzayl-4-phenyl- 2H-I, 3-thiazin- 2-ylidene )-( 4'-methaxy-
phenyl)hydrazide (3c): Yellow crystals (0.76 g, 86%), m.p. 210°C
(acetonitrile). IH NMR (400 MHz, CDCI3):
~ = 8.17-8.10 (dd,
Starting
materials:
N-Substituted-hydrazino-carbothioamides
2 H, J = 7.8, 1.0 Hz, ArH), 7.68-7.48 (m, 5 H, ArH), 7.36--7.22 (m,
5 H, ArH), 7.10 (s, 1 H, H-5), 6.80-6.75 (dd, 2 H, J= 8.0,1.0 Hz,
ArH), 6.70 (s, 1 H, NH-N), 3.95 (s, 3 H, OCH3). BC NMR (100.6
MHz, CDCI3): Be= 186.4 (COPh), 168.0 (CONH), 163.2 (C-4), 158.6
(C-2), 153.8 (H3CO-Ar-C), 134.0 (Ph-C), 132.4 (C-6), 132.4, 132.0
(Ph-C), 128.6, 127.2, 127.0 (artha-2Ar CH), 126.2, 125.4 (meta-Ar
2CH), 125.3 (C-5), 124.6, 124.2 (para-Ar CH), 122.6 (meta-Ar 2CH),
52.0 (OCH3). IR (KBr): vmax = 3330 (m, NH), 3070-3010 (w,Ar-CH),
2996--2880 (m, aliph.-CH), 1700 (s, COPh), 1700 (s, CONH), 1612
(s, C=N), 1590 (s, C=C), 1452 (s), 1122 (m, C-S) em-I. A.",ax (CH3CN,
19 e, urn): 382 (4.1). MS (EI): m/z (%) = 441 [M+] (100),426 (24),
410 (24), 365 (28), 336 (42),286 (32), 254 (24), 222 (34), 190 (26),
135 (42),104 (56), 77 (26). C25HI~303S (441.51): Calcd C, 68.01; H,
4.34; N, 9.52; S, 7.26%. Found C, 68.11; H, 4.28; N, 9.62; S, 7.12%.
N'-(6-Benzayl-4-phenyl-2H-I ,3-thiazin-2-ylidene)-( 4'-bromabenzyl)
hydrazide (3d): Orange crystals (0.71 g, 72%), m.p. 320°C (ethyl
acetate). IHNMR (400 MHz, DMSO-d6): BH= 7.72 (dd, dd,2H,J= 8.0,
1.0 Hz, ArH), 7.68-7.46 (m, 6 H, ArH), 7.36--7.28 (m, 4 H, ArH),
7.00 (s, 1 H, H-5), 6.80-6.65 (dd, 2 H, J = 8.0, 1.2 Hz, ArH), 6.62 (s,
1 H, NH-N), 5.10 (s, 2 H, CH2). BC NMR (100.6 MHz, DMSO-d6):
Be = 186.3 (COPh), 168.0 (CONH), 162.8 (C-4), 158.6 (C-2), 134.2
(C-6), 133.4 (artha-2Ar CH), 134.0 (ph-C), 132.0 (Br-Ar-C4'), 131.6
(Ph-C), 128.0 (Br-Ar-C), 127.6, 127.4 (artha-2Ar CH), 126.0, 125.6
(meta-Ar 2CH), 125.2 (C-5), 125.0, 124.8 (para-Ar CH), 118.8
(meta-Ar 2CH), 42.0 (CH2). IR (KBr): vmax = 3334 (m, NH), 3050-
3012 (w,Ar-CH), 2980-2860 (aliph.-CH), 1702 (s, COPh), 1684 (s,
CONH2), 1610 (s, C=N), 1592 (s, C=C), 1450 (s), 1120 (m, C-S) em-I.
A.max (CH3CN, 19e, urn): 382 (4.1). MS (EI): m/z (%) = 506 [M + 2]
(96), 504 [M+] (100), 412 (22), 429 (40), 427 (42), 426 (34), 402
(60),400 (42), 337 (26), 335 (36), 309 (18), 307 (26), 302 (22), 300
(24),272 (22), 270 (26), 226 (34), 224 (36), 186 (28), 186 (34), 184
(38), 106 (40), 104 (44), 78 (34), 76 (36). C25HISBrN302S(504.41):
Ca1cd C, 59.53; H, 3.60; Br, 15.84; N, 8.33; S, 6.36. Found C, 59.68;
H, 3.50; Br, 15.90; N, 8.40; S, 6.40%.
la-e and 1,4-diphenylbut-2-yne-l,4-dione (DBA, 2) were prepared
according to references 22 and 23, respectively.
General procedure: To a 250 cm3 two-necked round bottom flask
containing a solution ofla--e (1 mmol) in acetonitrile (100 ml) and a
solution of 2 (0.468 g, 1 mmol) in acetonitrile (30 ml) was refluxed
for 1-2 days (the reaction was monitored by TLC). The solvent was
evaporated under vacuum and the solid residue was dissolved in
dry acetone (20 ml) and the solution was chromatographed on thin
layer plates (silica gel) using toluene. The mobile phases containing
products 3a--e were extracted by acetone. The obtained products were
recrystallised from the stated solvents.
N'-(6-Benzayl-4-phenyl-2H-I, 3-thiazin-2-ylidene)-benzahydrazide
(3a): Yellow crystals (0.66 g, 80%), m.p. 310°C (ethanol). IH NMR
(400 MHz, CDCI3): BH = 8.10-8.0 (dd, 2 H, J = 8.0, 1.0 Hz, ArH),
7.90-7.40 (m, 7 H,ArH), 7.36--7.20 (m, 4 H,ArH), 7.10 (s, 1 H, H-5),
6.90-6.82 (m, 2 H, ArH), 6.60 (s, 1H, NH-N). BC NMR (100.6 MHz,
CDCI3): Be = 186.2 (COPh), 168.0 (CONH), 162.8 (C-4), 158.2
(C-2), 132.0 (C-6), 135.2, 133.8, 130.0 (ph-C), 127.2, 127.0, 126.8
(artha-2Ar CH), 126.4, 126.2, 126.0 (meta-Ar 2CH), 125.6, 125.0,
124.8 (para-Ar CH), 124.2 (CH-5). IR (KBr): vmax = 3320 (m, NH),
3090-3010 (w,Ar-CH), 1700 (s, COPh), 1680 (s, CONH), 1612-1600
(hr, s, C=N), 1590 (m, C=C), 1120 (m, C-S) em-I. A.",ax (CH3CN, 19
e, urn): 360 (3.4). MS (EI): m/z (%) = 411 [M+] (100),335 (22), 306
(24),292 (18), 286 (14), 278 (14), 202 (34), 128 (24), 126 (26), 105
(62), 77 (24). C2JI17N302S (411.49): Calcd C, 70.06; H, 4.16; N,
10.21; S, 7.79%. Found C, 70.20; H, 4.08; N, 10.16; S, 7.71%.
N' -(6-B enzayl-4-phenyl- 2H-I, 3-thiazin- 2-ylidene)-( 4'-hydraxy-
phenyl)hydrazide (3b): Yellow plates (0.71 g, 83%), m.p. 234°C
(ethanol). IH NMR (400 MHz, CDCI3): BH = 9.10 (s, 1 H, OH),
7.90-7.75 (dd, 2 H, J = 8.0, 1.2 Hz, ArH), 7.60-7.42 (m, 6 H,
ArH), 7.30-7.12 (m, 6 H, ArH), 6.98 (s, 1 H, H-5), 6.80 (s, 1 H,
NH-N). BC NMR (100.6 MHz, CDCI3): Be= 186.6 (COPh), 168.4
(CONH), 163.0 (C-4), 158.4 (C-2), 148.8 (OH-Ar-C), 132.4 (C-6),
133.8, 133.6, 133.0 (Ph-C), 128.6, 127.2, 127.0 (artha-2Ar CH),

JOURNAL OF CHEMICAL RESEARCH 2008 701
5
6
7
8
9
E. Raphael, C.P. Joshua and L. Koshy, Indian J. Chern., 1989, 28B, 635
B. Koren, B. Stanovnik and M. TiSler, Monatsh. Chern., 1988,119,333.
B. Koren, B. Stanovnik and M. TiSler, Heterocycles, 1985,23,913.
M. Dobosz, M. Pitucha and M. Wujec, Acta Pol. Pharm., 1996, 53, 31.
S. Paul, V. Gupta and R. Gupta, Synth. Cornrnun., 2003, 33,1917.
N'-(6-B enzayl-4-phenyl-2H-I,
hydrazide (3e): Pale yellow crystals (0.43 g, 62%), m.p. 198°C
(methanol). IH NMR (400 MHz, CDC13): = 7.80-7.70 (dd, 2 H,
J = 8.0, 1.2 Hz, ArH), 7.60-7.48 (m, 3 H, ArH), 7.30-7.16 (m, 3 H,
ArH), 7.00 (s, 1 H, H-5), 6.88--6.66 (m, 3 H, ArH, NH-N), 2.10 (s, 3
H, CH3). BC NMR (100.6 MHz, CDC13): Be = 186.0 (COPh), 167.6
(CONH), 162.3 (C-4), 158.5 (C-2), 134.0 (C-6), 133.4, 132.6 (Ph-C),
127.2, 126.8 (artha-2Ar CH), 126.6, 126.2 (meta-Ar 2CH), 125.2,
3-thiazin-2 -ylidene)-methyl-
~
10 Y. Tomita, S. Kabashima, T. Okawara, T. Yamasaki and M. Furukawa,
J. Heterocycl. Chern., 1990,27,707.
11 Yu.I. Ryabukhin, O.B. Korzhavina and S.E. Suzda1ev, Adv. Heterocycl.
Chern., 1996, 66, 131.
12 S. Coen, B. Ragonnet, C. Vieillescazes and J.-P. Roggero, Heterocycles
1985,23,1225.
13 G. Grandolini, M.C. Tiralti, C. Rossi, V. Ambrogi, G. Orza1esi and
M. De Regis, Farmaco, 1987,2,43.
14 B. Tozkoparan, G. Aktay and E. Yesilada, Farmaco, 2002, 57,145.
15 L.-D.S.Yadav, A.R. Misra and H. Singh, J. Agric. Food Chern., 1988,
36,633.
16 V.J. Ram, U K Singha and P.Y. Guru, Eur. J. Med. Chern., 1990,25,533.
17 D. Mares, C. Romagnoli, E. Andreotti, G. Forlani, S. Guccione and
C.B. Vicentini, Microbiol. Res., 2006, 110, 686.
18 H. Kai, Y. Morioka, T. Murashi, K. Morita, S. Shinonome, H. Nakazato,
K. Kawamoto, K. Hanasaki, F. Takahashi, S. Mihara, T. Arai, K. Abe,
H. Okabe, T. Baba, T. Yoshikawa and H. Takenaka, Bioorg. Med. Chern.
Lett., 2007, 17,4030.
19 A.A. A1y, E.K. Ahmed and K.M. El-Mokadam, J. Heterocycl. Chern.,
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125.0 (para-Ar CH), 124.6 (CH-5), 20.0 (CH3). IR (KEr): vrnax
=
33325 (m, NH), 3080-3006 (w, Ar-CH), 2987-2880 (m, aliph.-CH),
1700 (COPh), 1700 (s, CONH), 1610 (s, C=N), 1590 (s, C=C), 1120
(m, C-S) em-I. "-max (CH3CN, 19 e, nm): 360 (3.4). MS (E1): m/z = 349
[W] (100), 334 (24), 273 (26),244 (40), 216 (32),194 (24), 166 (24),
151 (18), 130 (24), 105 (62), 77 (26), 72 (24). CI9HISN302S (349.41):
Calcd C, 65.31; H, 4.33; N, 12.03; S, 9.18%. Found C, 65.24; H,4.30;
N, 12.10; S, 9.10%.
Received 13 August 2008; accepted 19 September 2008
Paper 08/0058 doi:10.3184/030823408X384575
Published online: 17 December 2008
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