Facile synthesis of 2-aryl-3-phenyl-5-phenylamino-2,5-dihydro-1,2,4- thiadiazole-5-carbonitriles

Article abstract of DOI:10.1080/10426500701744876

Syntheses of various 2-aryl-3-phenyl-5-phenylamino-2,5-dihydro-1,2,4- thiadia- zole-5-carbonitriles are reported. The key to their successful synthesis is represented by the reaction of N-imidoylthioureas with 2-(1,3-dioxoindan-2-ylidene)malononitrile. Co

Full text of DOI:10.1080/10426500701744876

Phosphorus, Sulfur, and Silicon, 183:1783–1789, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701744876
Facile Synthesis of 2-Aryl-3-phenyl-5-phenylamino-2,5-
dihydro-1,2,4-thiadiazole-5-carbonitriles
Ashraf A. Aly, Ahmed M. Nour-El-Din,
Mohsen A.-M. Gomaa, and Magda S. Fahmi
Chemistry Department, Faculty of Science, El-Minia University,
El-Minia, A. R. Egypt
Syntheses of various 2-aryl-3-phenyl-5-phenylamino-2,5-dihydro-1,2,4-thiadia-
zole-5-carbonitriles are reported. The key to their successful synthesis is
represented by the reaction of N-imidoylthioureas with 2-(1,3-dioxoindan-2-
ylidene)malononitrile.
Keywords 1,2,4-thiadiazole-5-carbonitriles; 2-(1,3-dioxoindan-2-ylidene)malononitrile;
cyano-group transfer; N-Imidoylthioureas
INTRODUCTION
The derivatives of 2-amino-3-benzoylthiophene proved capable of en-
hancing the binding and activity of reference A1 receptor agonists,
such as N6-cyclopentyladenosine (CPA). However, the compounds were
found to also act as competitive antagonists at these receptors of
PDS81723 (Figure 1) and therefore they became the reference al-
losteric modulator with the best ratio of enhancement to antagonistic
action.1,2
Other derivatives of 2-amino-3-benzoylthiophene based on the struc-
ture of PDS81723 have been synthesized.3−6 In previous work,7
a
number of 2,3,5-substituted-1,2,4-thiadiazoles (II) were tested as po-
tential allosteric modulators of adenosine receptors.8 1,2,4-Thiadiazol-
5(2H)-imines III (Figure 1) became accessible when Barnikow9 and
later Goerdeler10 proposed a simple method for the preparation of
these compounds from imidoyl chlorides. Recently, it has been proven
that type III substances show high reactivity as sulfhydryl modify-
ing agents rather than acting as allosteric inhibitors.11 In particular,
there are numerous studies on the reaction of imidoyl chlorides with
Received 24 May 2007; accepted 14 October 2007.
Address correspondence to Ashraf A. Aly, Chemistry Department, Faculty of Science,
El-Minia University, 61519-El-Minia, A. R. Egypt. E-mail: ashraf160@yahoo.com
1783

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A. A. Aly et al.
FIGURE 1 Structural variety with allosteric modulator activity
isocyanates, isothiocyanates, and carbodiimides.12−15 Some time ago,
we investigated the reactions of amidine analogues with π-acceptors
and the synthesis of various heterocycles such as dihydropyridines,16
acridinones,17,18 pyrazolidines, and pyridazines.18 Recently, we have re-
ported a very convenient procedure to synthesize 1,2,4-triazoles in one
step involving a rapid reaction of amidrazones with 2-(1,3-dioxoindan-2-
ylidene)malononitrile (1).19 Compound 1 can react by net cyanation and
most likely by initial hydride abstraction and subsequent transfer of a
cyanide ion.20 Additionally, compound 1 shows electron-transfer medi-
ated rearrangement process during its reaction with isoindolines, which
leads to the formation of 2-cyano-1,4-naphthoquinon-1-yl.20 Moreover 1
is well-known for its oxidizing activity along with its basic character.21
In addition, compound 1 has an exocyclic π-deficient double bond, which
indicates its ability to undergo [2 + 3] cycloaddition reactions.22 The
most interesting aspect of imidoyl chlorides is their ability to act as
precursors of nitrilum ylides and therefore to take part as 1,3-dipoles
in [3+2] cycloadditions.12−15 Kihara et al.23 described the reaction of
diethyl diazenedicarboxylate with amidinothioureas, imidoylthioureas
and thioacylamidines, which yielded the corresponding thiadiazoles by
oxidative cyclic S-N bond formation. From the above findings, it is valu-
able to investigate the behavior of the target acceptor announcing by
compound 1 during its reaction with N-imidoylthioureas.
RESULTS AND DISCUSSION
Scheme 1 shows the reaction of 2a–d11 with 1 in anhydrous ethyl
acetate. The reaction proceeded in a few hours to yield after chro-
matographic purification the 1,2,4-thidiazoles 3a–d (62–78%). We have
chosen the N-imidoylthioureas 2a–d having aryl groups with electron
donating and withdrawing substituents at the benzene ring, in order to
examine their reactivity, which might affect the course of the reaction.
The structure of 3a–d was established on the basis of mass, IR, 1H NMR,
and 13C NMR spectra as well as elemental analyses. The products 3a–d

Synthesis of 2,5-dihydro-1,2,4-thiadiazoles
1785
SCHEME 1 Reactions of 1 with N-imidoylthioureas 2a–d.
showed spectral data similes to those reported for 2-aryl-3-phenyl-5-
phenylamino-2,5-dihydro-1,2,4-thiadiazoles.11,15 The main differences
found were the following: 1) the IR spectra indicated the presence of
nitrile groups at ν = 2220–2212 cm−1; 2) the 13C NMR spectra showed
the appearance of a signal in a range typical for a quaternary carbon
atom (C-5) at δ = 95.5–96.2; and 3) the 1H NMR spectra of 3a–d showed
the protons of the phenyl ring at the nitrogen atom in position-2 to be
the most deshielded. For example, in the case of 3c, the aforesaid dis-
tinguished phenyl protons resonated as two doublets of doublets at δ =
8.00 and 7.70 (J = 8.2, 1.2 Hz). Moreover, the NH protons appeared
superimposed on the aromatic protons (see the Experimental Section).
The 13C NMR spectra of compounds 3a–d further support their iden-
tity. Thus the 13C NMR spectrum of compound 3c shows a signal for
the cyano group at δ = 113.4, whereas C-3 ot the azomrthine moiety
resonates at δ = 155.0.
Calculations of the bond lengths of imidoylthioureas indicated that
there is a shortening of the distance between the nitrogen and the sulfur
atom, which might be caused by the difference in electronegativity.15
Since compound 1 can act as an oxidizing, as well as a cyano-
transferring reagent,20,21,24 the proposed mechanism for the forma-
tion of thiadiazoles 3a–d might involve the initial oxidation of the
N-imidoylthioureas 2a–d by the acceptor 1. Oxidation process is ac-
companied by a formal hydride transfer process generating species A
and B (Scheme 1). The intermediate B picks up a cyanide anion from
A to form product 3. Although the cyanation process according to that

1786
A. A. Aly et al.
pathway appears reasonable, we could not isolate the expected com-
pound C (Scheme 1). The yields of the 1,2,4-thiadiazoles 3a–d depend
on the type of substituents at the aromatic ring attached to the amino
group in 1a–d. The presence of electron donating substituents such as
methyl and methoxy groups increases the yield of the product, while
in the case of electron withdrawing groups like chlorine the yield de-
creases. In conclusion, scope and limitations of this process have not
been explored yet.
EXPERIMENTAL
1
All melting points were recorded on a Gallenkamp apparatus. H and
1
13C NMR spectra (Bruker AM 400, H: 400.13 MHz, 13C: 100.6 MHz)
were obtained from CDCl3 solutions; the chemical shifts are given rel-
ative to TMS. Coupling constants are given in Hz. For preparative
thin layer chromatography (PLC), glass plates (20 × 48 cm) were cov-
ered 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 UV light. Elemental
analyses were carried out with an Elemental analyzer Model 2400
Perkin-Elmer at Cairo Microanalysis lab in Cairo University. Mass
spectrometry was performed with a Finnigan MAT 8430 spectrometer
at 70 eV in the Institute of Organic Chemistry, TU-Braunschweig, Ger-
many. IR spectra were run on a Shimadzu 470 spectrometer using KBr
pellets.
Starting Materials
N-Imidoylthioureas 2a–d were prepared according to Go¨blyo¨s et al.11
The acceptor 1 was prepared following the procedure mentioned in
Chaterjee.25
Reaction of 2a–d with 2-(1,3-dioxoindan-2-ylidene)
malononitrile (1)
In a 250 mL two-necked round bottom flask a mixture of 2a–d (2
mmol) and 1 (0.42 g, 2 mmol) dissolved in absolute ethyl acetate (100
mL) was gently refluxed for 10–18 h. The reaction was followed by TLC
analysis. The solvent was removed in vacuo and the residue was sep-
arated by preparative plate chromatography (silica gel, toluene : ethyl
acetate 5:1). Compounds 3a–d were recrystallized from the solvents
given below.

Synthesis of 2,5-dihydro-1,2,4-thiadiazoles
1787
2,3-Diphenyl-5-phenylamino-2,5-dihydro-1,2,4-thiadiazole-5-
carbonitrile (3a)
Yellow needles (0.50 g, 70 %); Rf = 0.3 (CH2Cl2), m.p. 240◦C (EtOH).
1H NMR (CDCl3): δ = 7.70 (dd, J = 8.0, 1.2 Hz, 2H, ortho-H), 7.60–7.30
(m, 9H, arom-H, NH), 7.24–7.10 (m, 5H, arom-H). 13C NMR (CDCl3):
δ = 95.5 (C−5), 112.6 (CN), 124.6, 125.8, 126.4, 127.6, 128.0, 128.4,
128.9, 130.0, 132.0, 134.0, 138.9, 142.4, 153.6 (C−3). IR, νmax (cm−1):
3270 (NH), 3040–2990 (arom-CH), 2212 (CN), 1596 (C N). UV, λmax
(CH3CN, nm, lg ε): 414 (4.0). MS (EI, 70 eV): m/z (%) = 357 ([M+1], 18),
356 ([M+], 70), 298 (54), 264 (20), 252 (12), 180 (76), 104 (16), 77 (100),
51 (34). C21H16N4S (356.49): found C, 70.80; H, 4.46; N, 15.85; S, 9.04
%. Calcd. C, 70.76; H, 4.52; N, 15.72; S, 9.00%.
2-(4ꢀ-Methylphenyl)-3-phenyl-5-phenylamino-2,5-dihydro-
1,2,4-thiadiazole-5-carbonitrile (3b)
Yellow crystals (0.52 g, 72%); Rf = 0.5 (CH2Cl2), m.p. 260◦C (EtOH).
1H NMR(CDCl3): δ = 7.80 (dd, J = 8.2, 1.2 Hz, 2H, ortho-H), 7.60–
7.30 (m, 13H, arom-H, NH), 2.34 (s, 3H, CH3).13C NMR(CDCl3): δ =
32.8 (CH3), 95.8 (C-5), 113.9 (CN), 125.2, 126.2, 127.2, 128.4, 128.8,
130.0, 132.8, 134.0, 134.6, 136.6, 138.9, 142.8, 154.8 (C−3). IR, νmax
(cm−1): 3260 (NH), 3090-3010 (arom-CH), 2970–2862 (aliph-CH), 2216
(CN),1600 (C N). UV, λmax (CH3CN, nm, lg ε): 430 (4.18). MS (EI, 70 eV):
m/z (%) = 371 ([M + 1], 26) 370 ([M+], 64), 354 (10), 312 (58), 310 (30),
278 (20), 266 (10), 219 (12), 208 (20), 194 (54), 183 (18), 180 (8), 146 (76),
104 (100), 91 (46), 76 (82), 65 (28), 50 (42). C22H18N4S (370.48): found
C, 71.50; H, 4.85; N, 15.10; S, 8.60 %. Calcd. C, 71.33; H, 4.90, N, 15.12;
S, 8.65 %.
2-(4ꢀ-Methoxyphenyl)-3-phenyl-5-phenylamino-2,5-dihydro-
1,2,4-thiadiazole-5-carbonitrile (3c)
Yellow crystals (0.60 g, 78%); Rf = 0.6 (CH2Cl2), m.p. 290◦C (EtOAc).
1H NMR(CDCl3): δ = 8.00 (dd, J = 8.0, 1.2 Hz, 2H, arom-H), 7.73 (dd,
J = 8.2, 1.2 Hz, 2H, arom-H), 7.60–7.20 (m, 11H, arom-H, NH), 3.95 (s,
3H, OCH3). 13C NMR(CDCl3): δ = 50.9 (OCH3), 96.2 (C−5), 113.4 (CN),
125.6, 126.8, 127.6, 128.2, 128.6, 130.2, 132.6, 133.2, 134.8, 140.0, 142.4,
146.0, 155.0 (C−3). IR, νmax (cm−1): 3250 (NH), 3090-3020 (arom-CH),
2980–2850 (aliph-CH), 2220 (CN), 1610 (C N). UV, λmax (CH3CN, nm,
lg ε): 440 (4.24). MS (EI, 70 eV): m/z (%) = 387 ([M + 1], 22), 386 ([M+],
60), 355 (28), 316 (50), 268 (24), 208 (30), 194 (56), 160 (28), 146 (70),
106 (100), 91 (62), 76 (80), 50 (32). C22H18N4OS (386.48): found C, 68.46;
H, 4.60; N, 14.48; S, 8.26%. Calcd. C, 68.37; H, 4.69; N, 14.50; S, 8.30%.

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A. A. Aly et al.
2-(4ꢀ-Chlorophenyl)-3-phenyl-5-phenylamino-2,5-dihydro-
1,2,4-thiadiazole-5-carbonitrile (3d)
Yellow crystals (0.48 g, 62%); Rf = 0.3 (CH2Cl2), m.p. 267◦C (MaOH).
1H NMR (CDCl3): δ = 7.64–7.40 (m, 13H, arom-H, NH), 7.30 (dd, J =
8.2, 1.4 Hz, 2H, arom-H). 13C NMR (CDCl3): δ = 96.0 (C−5), 112.6 (CN),
125.9, 125.0, 126.4, 126.9, 127.8, 128.0, 128.4, 128.8, 129.0, 134.0, 138.0,
139.0, 152.8 (C−3). IR, νmax (cm−1): 3256 (NH), 3020-2970 (arom-CH),
2218 (CN), 1596 (C N). UV, λmax (CH3CN, nm, lg ε): 420 (3.90). MS (EI,
70 eV): m/z (%) = 392 ([M + 2], 20), 390 ([M+], 100), 389 ([M − 1], 32),
370 (16), 370 (18), 363 (20), 336 (12), 308 (14), 239 (16), 228 (14), 192
(16), 177 (18), 125 (20), 110 (14), 77 (20), 44 (60). C21H15ClN4S(390.89):
found C, 64.40; H, 3.82; Cl, 9.00; N, 14.30; S, 8.16%. Calcd. C, 64.53; H,
3.87; Cl, 9.07; N, 14.33; S, 8.20%.
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