New access to pyrazole, oxa(thia)diazole and oxadiazine derivatives

Article abstract of DOI:10.1002/hc.20071

1,4-Disubstituted thiosemicarbazides 1b-f reacted with ethenetetracarbonitrile (5) in dimethylformamide with formation of 2-substituted 5-phenyl-1,3,4-thiadiazoles 2a-f and 2-substituted 5-phenyl-1,3,4-oxadiazoles 4a-f. Upon addition of 5 to 1c-e in chlorobenzene, 3-amino-2-benzoyl-4,5,5- tricyano-2,5-dihydro-1H-pyrazole- 1-[N-(4-tricyanovinyl)phenyl]carbothioamide (12), 5-benzylamino-, and 5-allylamino-4-benzoyl-2,3-dihydro-[1,3,4]thiadiazol- 2,2-dicarbonitrile (13a,b) and 5-amino-1-benzoylpyrazole-3,4-dicarbonitrile (14) as well as 2-phenyl-4H-[1,3,4]-oxadiazine-5,6-dicarbonitrile (15) were formed. Rationales for the role of the solvent and the conversions observed are presented.

Full text of DOI:10.1002/hc.20071

Heteroatom Chemistry
Volume 16, Number 1, 2005
New Access to Pyrazole, Oxa(Thia)diazole
and Oxadiazine Derivatives
Alaa A. Hassan,1 Kamal M. El-Shaieb,1 Raafat M. Shaker,1
and Dietrich Do¨pp2
1Chemistry Department, Faculty of Science, El-Minia University, El-Minia, A. R. Egypt
2Institut fu¨ r Chemie, Universita¨t Duisburg-Essen, D-47048 Duisburg, Germany
Received 25 November 2003; revised 17 February 2004
either acid or alkali, and disubstituted thiosemi-
ABSTRACT: 1,4-Disubstituted thiosemicarbazides
1b–f reacted with ethenetetracarbonitrile (5) in di-
methylformamide with formation of 2-substituted
5-phenyl-1,3,4-thiadiazoles 2a–f and 2-substituted 5-
phenyl-1,3,4-oxadiazoles 4a–f. Upon addition of 5 to
1c–e in chlorobenzene, 3-amino-2-benzoyl-4,5,5-tri-
cyano-2,5-dihydro-1H-pyrazole-1-[N-(4-tricyanovi-
nyl)phenyl]carbothioamide (12), 5-benzylamino-, and
5-allylamino-4-benzoyl-2,3-dihydro-[1,3,4]thiadiazol-
2,2-dicarbonitrile (13a,b) and 5-amino-1-benzoyl-
pyrazole-3,4-dicarbonitrile (14) as well as 2-phenyl-
4H-[1,3,4]-oxadiazine-5,6-dicarbonitrile (15) were
formed. Rationales for the role of the solvent and
carbazides on reaction with acetone in an acidic
medium afforded 1,2,4-triazolidine-3-thione deriva-
tives [3]. 3-Alkylthio-4-phenyl-ꢀ2-1,2,4-triazolin-5-
ones have been obtained by S-alkylation of 1-amino-
carbonyl-4-phenylthiosemicarbazides followed by
acid catalyzed cyclization with liberation of ammo-
nia [4]. Recently, the synthesis of some 1,3,4-oxa-
(thia)diazole derivatives from the readily available
1-(4,6-diphenyl-2-pyrimidinylcabonyl)-4-phenylthio-
semicarbazide (1a) has been reported [5] (Scheme 1).
Brief heating of 1a in concentrated sulfuric acid
gave the corresponding 2-anilino-1,3,4-thiadiazole
2a, whereas treatment of 1a with KOH brought
about the alternative C N cyclization with for-
mation of the triazolethione derivative 3. Heating
of 1a in ethoxyethanol effected the formation of
1,3,4-oxadiazole 4a with evolution of H2S [5]. Some
recent publications have reported mild cyclization
methods [6–10] for this heterocyclic system.
ꢀ
C
the conversions observed are presented.
2005 Wiley
Periodicals, Inc. Heteroatom Chem 16:12–19, 2005; Pub-
lished online in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/hc.20071
In medicinal chemistry, there is interest in the
aforementioned heterocycles. For example, 1,3,4-
oxadiazol-2-ylmethyl and various 1,2,4-triazol-3-
ylmethyl groups have been tested as replacements for
aminocarbonylmethyl groups in a piperidino ether
based human NK1-antagonist [11].
As a part of our program aimed at the devel-
opment of new simple and efficient procedures for
the synthesis of some important heterocyclic sys-
tems from thiosemicarbazide derivatives, we have
recently reported different successful approaches for
synthesis of thiazole, thiazine, thiadiazole, thiadi-
azine, thiadiazepine, oxathiadiazole and indazole, as
INTRODUCTION
Cyclization of 1,4-disubstituted thiosemicarbazides
may be achieved under various conditions [1–5].
For example, 4-substituted 1-phenylacetylthiosemi-
carbazides undergo cyclization to yield 3-benzyl-
ꢀ2-1,2,4-triazoline-5-thiones and 2-amino-5-benzyl-
1,3,4-thiadiazoles, respectively, in the presence of
Correspondence to: A. A. Hassan; e-mail: alaahassan2001@
yahoo.com.
Contract grant sponsor: Alexander von Humboldt Foundation.
2005 Wiley Periodicals, Inc.
c
ꢀ
12

New Access to Pyrazole, Oxa(Thia)diazole and Oxadiazine Derivatives 13
thiosemicarbazide (1b) rather than in the formation
of compounds 7 or 8 (Scheme 2). Interaction of dou-
ble molar amounts of hydrazine with 6 did not ter-
minate at the monoaddition stage, but gave again the
product 1b. In this respect, the rapid addition of 6
to hydrazine may afford the formation of hydrazide
9 via substitution of thiocyanate anion followed by
the addition of another molecule of 6 to 9. On the
other hand, heating equimolar amounts of hydrazide
9 and 6 in ethanol gave again 1b [24]. The other 1-
benzolylthiosemicarbazides 1c–f were prepared ac-
cording to literature procedures (see Experimental
section for references).
SCHEME 1
Reactions of Thiosemicarbazides 1b–f with
Ethenetetracarbonitrile (5) in DMF
well as pyridazine derivatives [12–17]. As will be out-
lined in detail below, in this paper we report several
heterocyclizations of 4-substituted 1-benzoylthio-
semicarbazides (1b–f) using ethenetetracarbonitrile
(“tetracycanoethylene”, 5) either as a reaction medi-
ator or as a building block.
Treatment of 1b–f with two molar equivalents of 5
in DMF as solvent at room temperature resulted in
a pink coloration of the solution that quickly turned
into brown. Concentration of the preparative runs re-
sulted in formation of colorless precipitates of oxadi-
azole derivatives 4b–f (28–39%, Scheme 3). Of these,
4b–d,f are known from the literature, while the
structure of 4e was derived by analogy taking into
account the NH absorption at 3193 cm−1 and the
characteristic absorption of the C O C fragment at
1086 cm−1 [25]. The 300 MHz 1H NMR (in DMSO-d6)
displayed broadened signals at δ 4.10 (allyl CH N)
and 8.27 ppm (NH) as well as multiplets at 5,02–
2
Ethenetetracarbonitrile (5) is the simplest of
percyanoalkenes (cyanocarbons) [18]. The general
chemistry of 5 had been reviewed with emphasis
on molecular complexes, reactions with ketones and
amines, tricyanovinylation reactions [18], additions
[18] and cycloaddition reactions [19] as well as syn-
thesis of heterocycles [18–23].
5.16 (allyl H C ) and 5.78–5.85 ppm (allyl CH ).
2
The elemental analysis supported the gross compo-
sition C11H11N3O, and the mass spectrum revealed
the expected molecular ion.
The filtrates were concentrated to dryness and
the residue subjected to vacuum sublimation to re-
move any unreacted 5. Chromatographic separation
of the residue in each case gave only one signifi-
cant zone containing the known thiadiazole deriva-
tives 2b–f in 38–47% yield (Scheme 3), which were
also identified by means of their spectroscopic data
and by comparison with the literature data and/or
authentic samples.
RESULTS AND DISCUSSION
Preparation of Thiosemicarbazides 1b–f
Mixing equimolar amounts of each hydrazine and
benzoylisothiocyanate (6) in DMF at room temper-
ature resulted in an excellent yield of 1,4-dibenzoyl-
SCHEME 2

14 Hassan et al.
SCHEME 3
Since the aforementioned reactions do not take
1b–f. “Catalytic” amounts of 5 have not been applied
place when no 5 is added to the solution of 1b–f
in DMF, the presence of 5 is definitely required
for the transformations observed. Charge-transfer
complexes may (but not necessarily have to) play an
intermediate role. Since the cyclizations involve in-
tramolecular nucleophilic attacks on either a thio-
carbonyl or a carbonyl group, it is conceivable that
5 accelerates the process in the sense of a proton or
a Lewis acid, possibly through intermediates 10 and
11 (Scheme 3), activating the respective C O/C S
bonds toward nucleophilic addition. This behavior
may well be supported by the polar nature of the sol-
vent stabilizing zwitterionic adducts.
After cyclization, 5 is released and the libera-
tion of H2O or H2S ensues as usual. While 5 is not
consumed in these cyclizations as such and is in-
deed recovered to a large extent (200–220 mg, 1.56–
1.72 mmol, 78–86%), the only reason for losses of 5
may be seen in the reactions with water or hydrogen
sulfide being released during the cyclization. Reduc-
ing the amount of 5 applied to 1.5 mmol resulted in
incomplete transformation of the starting materials
for this reason.
Reactions of Thiosemicarbazides 1c–e with
Ethenetetracarbonitrile (5) in Chlorobenzene
as Solvent
While the reactions of 1b–f in DMF and me-
diated by 5 were found to run relatively smoothly,
the conversions of starting materials 1c–e (1b was
too sparingly soluble) in chlorobenzene as solvent
went comparatively slowly. No products 2 and 4 were
formed, instead compounds 12 (79% from 1c) and
13a (27%), 13b (31%), 14 (34% from 1d, 36% from
1e), and 15 (23% from 1d, 19% from 1e) were ob-
tained as products (Scheme 4). In these cases, 5 is
“built in” completely or partially into the new struc-
tures. It may thus be concluded that the less polar
solvent fails to stabilize bipolar intermediates as 10
and 11 sufficiently but allows for addition of the nu-
cleophilic sites (N H bonds or formally S H) of the
starting materials 1c–e across the C C double bond
of 5. These additions may generate the four primary

New Access to Pyrazole, Oxa(Thia)diazole and Oxadiazine Derivatives 15
SCHEME 4
adducts A–D (Chart 1) or tautomers thereof, capa-
ble of releasing either HCN (which effects a net tri-
cyanovinylation [18]) or malononitrile. On the other
hand, any [ꢀ4 + ꢀ2]-cycloadditions of 5 to dehydro-
genated 1 are not suggested to occur from the nature
of the products formed, except perhaps in the forma-
tion of 15. Thus, the structures of products 12–15
need to be derived from one or two suitable precur-
sor(s) out of the options A–D.
3-Amino-2-benzoyl-4,5,5-tricyano-2,5-dihydro-
1H-pyrazole-1-[N-(4-tricyanovinyl)-phenyl]carbo-
thioamide (12) was obtained as a characteristically
blue powder, the color being due to the p-tricyano-
vinyl-phenylamino moiety. Its molecular structure
is supported by the following findings:
– The gross formula C25H12N10OS represents a prod-
uct from one molecule of 1c and two molecules
of 5 with loss of one molecule of HCN (liber-
ated in the p-tricyanovinylation of the thiocar-
bonylaminophenyl group, a reaction which can
occur only with 1c and is taking place indepen-
dently of the cyclization forming the pyrazoline
ring).
– The presence of both an amide (δC = 167.3 ppm)
=
O
and a thioamide function (δC = 186.6 ppm) rules
=
S
out any oxa- or thiacyclic structures.
– Both a NH2 (δH = 7.14 ppm) and a low-field NH
group (δH = 9.61 ppm) are present.
– The mass spectrum shows fragments at m/z
263 (representing the polysubstituted pyrazolinyl
residue) and 237 (representing the p-tricyano-
vinylphenylaminothiocarbonyl residue) resulting
from the cleavage of the N1 CS bond.
– The amide carbonyl stretch wavenumber (1706
cm−1) points to some degree of electron with-
drawal from N2, therefore structure 12 resulting
from precursor B is given preference over 12ꢁ de-
rived from precursor A (Scheme 5).
For compounds 13a,b:
– The gross formulas (confirmed by MS)
C18H13N5OS (13a) and C14H11N5OS (13b) clearly
demonstrate the loss of a C(CN)2 unit (probably
in the form of CH2(CN)2).
– The absence of a 13C C S signal but the presence of
an amide C O signal (165.2 ppm) and only one CN
CHART 1

16 Hassan et al.
SCHEME 5
resonance (117.8 ppm) in the case of 13a points
to the 1,3,4-thiadiazole structure 13 as assigned.
Thus 13a,b could have emanated from either A or
C (Scheme 5) but not from B or D.
14ꢁ would be accessible from A via 17 (Scheme 5).
The mass spectral fragmentation of the product (see
Fig. 1), however, is well in agreement with structure
14 but not with structure 14ꢁ.
Compound 15 (C11H6N4O) is derived from start-
ing materials 1d,e and 5 by loss of RN C S and
two molecules of HCN. This way of formation is not
possible from precursors A, C, and D. From its IR
and 13C NMR this product does not contain a free
benzoyl group any more, thus the oxadiazine struc-
ture 15 is suggested and rationalized by the sequence
B → 18 → 19 → 15 (Scheme 5).
Compound 14 does not contain sulfur but con-
tains five N atoms, thus the molecular mass repre-
sents a gross composition C12H7N5O reached from
1d,e and 5 after loss of HCN and R N C S. A five-
membered ring structure was thus accessible from
both precursors A and B but not from C and D. While
B would lead to 14 via 16, the isomeric structure

New Access to Pyrazole, Oxa(Thia)diazole and Oxadiazine Derivatives 17
were detected by indicator fluorescence quenching
upon 254 nm excitation, removed from plates and
extracted with cold acetone.
Starting materials
Synthesis of 1,4-Dibenzoylthiosemicarbazide (1b).
To a stirred solution of hydrazine hydrate (5 g, 10
mmol) in 30 mL dimethylformamide, benzoylisoth-
iocyanate (6, 16.3 g, 10 mmol) was added dropwise
at room temperature. Stirring at room temperature
was continued for 3 h, the mixture set aside over-
night, then added to ice/water. A white precipitate
was formed, recrystallized from ethanol to give
colorless crystals (20.3 g, 68%), mp 172–174◦C (lit.
173–176◦C) [24]. IR (KBr) ν = 3213 (NH), 1674 (CO),
1643, 1600 (Ar C C) and 1354 cm−1 (C S) [27]. 1H
NMR (DMSO-d6) δ 7.52–7.99 (m, 10H, Ar-H), 11.13
(s, br, 1H, N2-H), 11.77 (s, br, 1H, N1-H), 12.39 (s, br,
1H, N4-H), 13C NMR δ 126.90, 127.60, 127.91, 129.00,
129.60. 129.80, 130.05, 130.14, 132.02, 132.11,
132.22, 132.31 (Ar-C), 164.78 (CON1H), 168.06
(CON4H), and 180.83 (C S); MS (70 eV) m/z (%)
299 (M+, 3), 266 (6), 223 (8), 195 (8), 105 (100), 77
(72), 51 (18). C15H13N3O2S (299.35); calcd C, 60.19;
H, 4.38; N, 14.04; S, 10.71; found: C, 60.33; H, 4.26;
N, 14.17; S, 10.58.
FIGURE 1 The mass spectrum fragments of compound 14.
CONCLUSION
In this study two kinds of ring-forming reactions of
1-benzoylthiosemicarbazides 1 with ethenetetracar-
bonitrile (5) have been observed: (i) Cyclizations of 1
by intramolecular nucleophilic attack on either the
carbonyl or thiocarbonyl C atom may be activated
by ethenetetracarbonitrile (5) in the sense that 5 acts
like a Lewis acid on the heteroatom of the C X bond
being involved. It is suggested that the highly polar
aprotic solvent DMF stabilizes the resulting transient
intermediates and thereby enhances the probabil-
ity for intramolecular cyclizations. (ii) On the other
hand, the tendency of 5 to effect tetracyanoethyla-
tion (with the option for subsequent tricyanovinyla-
tion) of secondary amino functions (where bipolar
intermediates may be less important) is exercised in
the less polar chlorobenzene as solvent. The four a
priori possible types of tetracyanoethylation adducts
(A–D) of 5 to 1 may in principle release either HCN
or malononitrile but do so with different probabili-
ties as can be concluded from the products observed.
Thus, ethenetetracarbonitrile (5) may act either as a
mediator or as a building block in heterocyclizations
of thiosemicarbazides.
1-Benzoyl-4-phenylthiosemicarbazide (1c): mp
170–172◦C (lit. [28] 170–173◦C).
1-Benzoyl-4-benzylthiosemicarbazide (1d): mp
160–162◦C (lit. [28] 159–160◦C).
4-Allyl-1-benzoylthiosemicarbazide (1e): mp 171–
173◦C (lit. [29] 171–173◦C).
N-(2-Benzoylhydrazinothiocarbonyl)carbamic
acid ethyl ester (1f). A solution of 10 mmol (1.36 g)
of benzoyl hydrazine (9) and 10 mmol (1.31 g) of
ethoxycarbonylisothiocyanate in ethanol was re-
fluxed for 2 h, the white precipitate was recrystal-
lized from ethanol (1.71 g, 64%), mp 178–180◦C,
IR ν = 3320–3230 (NH), 1722, 1670 (CO), 1620
EXPERIMENTAL
Mps have been determined using open glass capil-
laries on a Gallenkamp melting point apparatus and
are uncorrected. The IR spectra were recorded with
a Shimadzu 408 or a Bruker Vector 22 FT-IR instru-
ment using potassium bromide pellets. A Bruker WM
300 instrument has been used to determine 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra, assign-
ments of carbon resonances have been supported
by DEPT experiments. Mass spectra have been ob-
tained with an AMD 604 doubly focusing instrument
using electron impact ionization (70 eV). Elemental
analyses have been determined by the Microanalyti-
cal Centre, Cairo University. Preparative layer chro-
matography (plc) was made using 48 cm × 20 cm
glass plates covered with slurry applied and air dried
1 mm thick layers of Merck silica gel PF254. Zones
1
(Ar C C). H NMR (DMSO-d6) δ 1.22–1.27 (t, 3H,
CH3), 4.18–4.21 (q, 2H, CH2), 7.47–7.58 (m, 3H,
Ar-H), 7.87–7.90 (m, 2H, Ar-H), 10.93 (s, br, 1H,
N2-H), 11.31 (s, br, 1H, N1-H), 11.38 (N4-H). MS
(70 eV), m/z (%) 267 (M+, 24), 134 (37), 105 (100),
77 (32), 60 (3), 51 (6). C11H13N3O3S (267.31); calcd
C, 49.43; H, 4.90; N, 15.72; S, 12.00; found: C, 49.31;
H, 4.77; N, 15.88; S, 11.83.
Preparation of 1,3,4-thiadiazoles 2b–f and 1,3,4-
oxadiazoles 4b–f. To 2 mmoles of 5 in dry dimethyl-
formamide (10 mL), 1 mmol of 1b–f in 15 mL of dry
dimethylformamide was added with stirring within
2 h. The pink coloration of the solution quickly

18 Hassan et al.
became brown, and the mixture was left standing
for 48 h at room temperature, during which time a
crystalline colorless product separated. The result-
ing solid material was filtered and the precipitate
was washed with ethanol, dried, and recrystallized
from suitable solvent to give 1,3,4-oxadiazoles 4b–
f. The filtrate was concentrated to dryness and the
residue was sublimed at 80◦C under vacuum to re-
move unreacted 5, then subjected to PLC using cy-
clohexane/ethyl acetate (2:1) as eluent to give only
one zone which was removed and extracted to give
1,3,4-thiadiazole derivatives 2b–f.
2-Benzoylamino-5-phenyl-1,3,4-oxadiazole (4b):
Colorless crystals from methanol (103 mg, 39%), mp
200–202◦C, (lit. [30] 198–200◦C).
2-Anilino-5-phenyl-1,3,4-oxadiazole (4c): Color-
less crystals from ethanol (96 mg, 40%), mp 218–
220◦C (lit. [31,32] 219–221◦C).
a solution of 1.0 mmol of 1c–e was added dropwise,
which caused a spontaneous change of color from
yellow to blue (in the reaction of 1c with 2) or dark
green (in the reaction of 1d,e with 5), respectively.
The mixture was stirred for 3 h and left standing
for 48 h at room temperature. After concentration
to dryness, the residues were sublimed at 80◦C and
then subjected to PLC using cyclohexane/ethyl ac-
etate (3:1) as eluent. From the reaction of 1c with 5,
only one zone (deep blue, Rf = 0.35) containing the
pyrazole 12 was extracted. On the other hand, for the
reaction of 1d,e with 5, chromatographic separation
of the residue (after sublimation) gave numerous col-
ored zones, three of which (with high intensity) were
removed and extracted. The fastest moving zone
(Rf = 0.43) contained the pyrazole derivative 14, the
second zone (Rf = 0.39, orange) contained the oxadi-
azine 15, while the slowest moving zone (Rf = 0.15)
contained the thiadiazole derivatives 13a,b. Extrac-
tion of the zones with acetone and concentration
gave residues, which were rechromatographed to im-
prove the purification.
2-Benzylamino-5-phenyl-1,3,4-oxadiazole (4d):
Colorless crystals from ethanol (91 mg, 36%), mp
203–205◦C (lit. [33,34] 203◦C).
2-Allylamino-5-phenyl-1,3,4-oxadiazole (4e): Col-
orless crystals from ethanol (63 mg, 31%), mp 126–
128◦C; IR(KBr), ν = 3193 (NH), 1086 (C O C), 1620
(C N), 1590 (C C); 1H NMR (DMSO-d6) δ = 4.10 (br,
s, 2H, allyl-CH2N), 5.02–5.16 (m, 2H, allyl-CH2 ),
5.78–5.85 (m, 1H, allyl-CH ), 7.46–7.93 (m, 5H, Ar-
H), 8.27(NH). MS (70 eV), m/z (%) 201 (M+, 13),
160 (6), 119 (13), 105 (100), 91 (8), 77 (69), 41 (30).
C11H11N3O (201.23); calcd C, 65.66; H, 5.51; N, 20.88;
found C, 65.47; H, 5.66; N, 20.71.
Ethyl (5-phenyl-[1,3,4]oxadiazol-2-yl)carbamate
(4f): Colorless crystals from ethanol (66 mg, 28%),
mp 205–207◦C (lit. [35] 205–207◦C).
2-Benzoylamino-5-phenyl-1,3,4-thiadiazole (2b):
Colorless crystals from ethanol, (132 mg, 47%), mp
232–234◦C, (lit. [36] 235◦C).
2-Anilino-5-phenyl-1,3,4-thiadiazole (2c): Color-
less crystals from ethanol (109 mg, 43%), mp 200–
202◦C (lit. [32,37] 198–200◦C).
2-Benzylamino-5-phenyl-1,3,4-thiadiazole (2d):
Colorless crystals from acetonitrile (117 mg, 44%),
mp 183–185◦C (lit. [38] 183–185◦C).
2-Allylamino-5-phenyl-1,3,4-thiadiazole (2e): Col-
orless crystals from ethanol (82 mg, 38%), mp 114–
115◦C (lit. [39] 114–115◦C).
Ethyl (5-phenyl-[1,3,4]thiadiazol-2yl)carbamate
(2f): Colorless crystals from ethanol (95 mg, 41%),
mp 197–199◦C (lit. [40] 198–200◦C).
3-Amino-2-benzoyl-4,5,5-tricyano-2,5-dihydro-
1H-pyrazole-1-carbothio-N-[4-(tricyanovinyl)phenyl]-
amide (12): Blue crystals (acetonitrile), mp 301–
303◦C (395 mg, 79%), IR (KBr) νmax 3311 (NH),
1
2224 (CN), 1706 (CO), 1608 (C C) cm−1. H NMR
(DMS-d6) δ 7.14 (s, br, 2H, NH2), 7.37–7.45, 7.64–
7.67, 7.89 (m, 9H, Ar-H), 9.61 (s, br, 1H, NH). 13C
NMR (DMSO-d6) 48.41 (C-5), 63.27 (C-4), 92.36
(tricyanovinyl ꢁ-C); 117.19, 117.21, 117.29, 119.30,
(CN); 126.71, 127.98, 128.77, 129.41, 130.33, 131.53,
132.94, 133.50, 148.21 (Ar-C); 147.63 (tricyanovinyl
ꢂ-C), 158.42 (C-3), 167.30 (CO), and 186.60 (C S).
MS (70 eV), m/z (%) 500 (M+, 16), 263 (12), 237 (63),
194 (9), 145 (18), 119 (100), 105 (65), 93 (92), 77
(13), 65 (23), 51 (36), 44 (50). C25H12N10OS (500.50);
calcd C, 60.0; H, 2.42; N, 27.99; S, 6.41; found: C,
59.83; H, 2.56; N, 28.17; S, 6.58.
3-Benzoyl-5-benzylamino-2,3-dihydro-[1,3,4]-
thiadiazol-2,2-dicarbonitrile (13a): Orange crystals
(ethanol), mp 263–265◦C, (80 mg, 27%). IR (KBr)
νmax 3355 (NH), 2213 (CN), 1670 (CO) cm−1. 1H
NMR (acetone-d6) δ 4.60 (s, 2H, CH2), 7.18–7.64 (m,
8H, Ar-H), 7.90–8.10 (m, 2H, Ar-H), 9.12 (s, br, 1H,
NH). 13C NMR (acetone-d6) 43.20 (C-5), 46.80 (CH2),
117.80 (CN); 127.82, 128.93, 129.22, 130.44, 131.21,
131.48, 133.72, 141.14 (Ar-C); 152.40 (C-2), 165.20
(CO). MS (70 eV), m/z (%) 347 (M+, 11), 285 (4), 240
(18), 150 (6), 132 (12), 119 (75), 106 (71), 105 (100),
91 (41), 77 (91), 65 (11), 51 (29), 44 (15). C18H13N5OS
(347.40); calcd C, 62.23; H, 3.77; N, 20.16; S, 9.23;
found: C, 62.06; H,3.59; N, 20.33; S, 9.12.
Preparation of Thiadiazole, Pyrazole, and
Oxadiazine Derivatives 12–15
General Procedure. To a stirred solution of
256 mg (2.0 mmol) of 5 in 15 mL of chlorobenzene
5-Allylamino-3-benzoyl-2,3-dihydro-[1,3,4]thia-
diazol-2,2-dicarbonitrile (13b): Orange crystals

New Access to Pyrazole, Oxa(Thia)diazole and Oxadiazine Derivatives 19
(ethanol), mp 144–146◦C (108 mg, 31%), IR (KBr):
[8] Brown, B. J.; Clemens, I. R.; Neeson, J. K. Synlett
2000,1, 131.
[9] Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J. Tetra-
hedron Lett 1999, 40, 3275.
[10] Wipf, P.; Venkatraman, S. Tetrahedron Lett 1996, 37,
4659.
[11] Ladduwahetty, T.; Baker, R.; Cascieri, M. A.;
Chamber, J. M.; Haworth, K.; Keown, L. E.;
MacIntyre, D. E.; Metzger, J. M.; Owen, S.; Ryeroft,
W.; Sadowski, S.; Seward, E. M.; Shepheard, S. L.;
Swain, C. J.; Tattersall, F. D.; Watt, A. P.; Williamson,
D. W.; Hargreaves, R. J. J Med Chem 1996, 39, 2907.
[12] Hassan, A. A. Bull Soc Chim Fr 1994, 131, 424.
[13] Hassan, A. A.; Ibrahim, Y. R.; Semida, A. A.; Mourad,
A. E. Liebigs Ann Chem 1994, 989.
[14] Hassan, A. A. Phosphorus, Sulfur Silicon, 1995, 101,
189.
[15] Hassan, A. A.; Mourad, A. E.; El-Shaieb, K. M.; Abou-
Zied, A. H.; Do¨pp, D. Heteroatom Chem 2003, 14, 535.
[16] Hassan, A. A.; Mohamed, N. K.; Ali, A. A.; Mourad,
A. E. Monatsh Chem 1997, 128, 61.
[17] Hassan, A. A.; Mohamed, N. K.; Shawky, A. M.;
Do¨pp, D. Arkivoc, 2003, (i), 118. Available at http://
www.arkat-usa.org/ark/journal/2003/General/3-708H/
708H.pdf
[18] Fataidi, A. J. Synthesis 1986, 249.
[19] Fataidi, A. J. Synthesis 1987, 749.
[20] Bruni, P.; Tosi, G. Gazz Chim Ital 1997, 127, 435.
[21] Huisgen, R.; Li, X.; Giera, H.; Langhals, E. Helv Chim
Acta 2001, 84, 981.
[22] Huisgen, R.; Mloston, G.; Langhals, E. Helv Chim
Acta 2002, 84, 1805.
[23] Do¨pp, D.; Hassan, A. A.; Mourad, A. E.; Nour El-Din,
A. M.; Angermund, K.; Kru¨ger, C.; Lehmann, C. W.;
Rust, J. Tetrahedron 2003, 59, 5073.
[24] Curd, F. H. S.; Hoggarth, E.; Landquist, J. K.; Rose,
F. L. J Chem Soc 1948, 1766.
νmax 3345 (NH), 2225 (CN), 1668 (CO), 1600 (C C)
1
cm−1. H NMR (DMSO-d6) 4.67–4.11 (m, 2H, allyl-
CH N), 5.05–5.15 (m, 2H, allyl-CH ), 5.77–5.86 (m,
2
2
1H, allyl-CH ), 7.45–7.56 (m, 3H, Ar-H), 7.89–7.92
(m, 2H, Ar-H), 8.28 (s, br, 1H, NH). MS (70 eV), m/z
(%) 297 (M+, 7), 198 (12), 178 (13), 121 (48), 105
(100), 77 (75), 56 (8). C14H11N5OS (297.34); calcd C,
56.55; H, 3.73; N, 23.55; S, 10.78, found: C, 56.38;
H, 3.64; N, 23.64; S, 10.92.
1-Benzoyl-5-aminopyrazole-3,4-dicarbonitrile
(14): Colorless crystals (81 mg (34%) from the
reaction of 1d, 85 mg (36%) from the reaction of
1e), mp 202–204◦C (lit. [26] 200◦C). IR (KBr) νmax
3320–3170 (NH), 2220 (CN), 1710 (CO), 1640 (C N),
1
1600 (C C) cm−1. H NMR (DMSO-d6) δ 7.55–7.71
(m, 3H, Ar-H), 7.86–7.89 (m, 2H, Ar-H), 8.49 (s, br,
2H, NH2). MS (70 eV), m/z (%) 237 (M+, 6), 171
(3), 105 (100), 77 (48), 66 (26), 52 (13). C12H7N5O
(237.22); calcd C, 60.76; H, 2.97; N, 29.52; found: C,
60.89; H, 3.12; N, 29.68.
2-Phenyl-4H-[1,3,4]oxadiazine-5,6-dicarbonitrile
(15): Yellow crystals (acetonitrile), mp 187–189◦C
[48 mg (23%) from 1d, 40 mg (19%) from 1e]. IR
(KBr) νmax 3230 (NH), 2225 (CN), 1620 (C N), 1600
1
(C C) cm−1. H NMR (DMSO-d6) δ 7.46–7.81 (m,
5H, Ar-H), 8.21 (s, br, 1H, NH). 13C NMR (DMSO-d6)
106.23 (C-5), 123.31 (C-6); 117. 82, 117.91 (CN);
126.94, 127.18, 128.36, 136.22 (Ar-C); 159.86 (C-2).
MS (70 eV), m/z (%) 210 (M+, 12), 184 (14), 119
(26), 105 (54), 92 (43), 77 (52), 66 (100), 44 (61).
C11H6N4O (210.20); calcd C, 62.86; H, 2.88; N, 26.65;
found: C, 63.02; H, 2.75; N, 26.84.
[25] Charistos, D. A.; Vagenas, G. V.; Tzavellas, L. C.;
Tsoleridis, C. A.; Rodios, N. A. J Heterocycl Chem
1994, 31, 1593.
[26] Dickinson, C. L.; Williams, J. K.; McKusick, B. C. J
Org Chem 1964, 29, 1915.
[27] Smicius, R.; Jakubkiene, V.; Burbuliene, M. M.;
Mikalainyte, A.; Vainilavicius, P. J Chem Res (S) 2002,
170.
[28] Saegusa, Y.; Harada, S.; Shigeo, N. J Heterocycl Chem
1988, 25, 1337.
[29] Oliveri-Mandala, E. Gazz Chim Ital 1914, 44, 670.
[30] Kubota, S.; Toyooka, K.; Yamamoto, N.; Kasai, T.;
Shibuya, M. Heterocycles 1986, 24, 21.
ACKNOWLEDGMENTS
A. A. Hassan is indebted to the Alexander von
Humboldt Foundation for the donation of the
Shimadzu 408 IR spectrophotometer. Support of this
work by Fonds der Chemischen Industrie is grate-
fully acknowledged.
[31] Fro¨yen, P. Phosphorus Sulfur Silicon 1991, 57, 11.
[32] Wamhoff, H.; Zahran, M. Synthesis 1987, 876.
[33] Madhavan, M. R.; Srinivasan, V. R. Indian J Chem
1969, 7, 760.
[34] Brain, C. T.; Brunton, S. A. Synlett 2001, 3, 382.
[35] Singh, H.; Misra, A. R.; D’S Yadav, L. Indian J Chem
1987, 26B, 1000.
[36] Malbec, F.; Milcent, R.; Barbier, G. J Heterocyclic
Chem 1984, 21, 1689.
[37] Dobosz, M.; Pitucha, M.; Wujec, M. Acta Pol Pharm
1996, 53, 31.
REFERENCES
[1] Dobosz, M.; Pachuta-Stec, A. Acta Pol Pharm 1996,
53, 123.
[2] Dobosz, M.; Pachuta-Stec, A. Acta Pol Pharm 1994,
51, 457.
[3] Korzycka, L.; Glowka, M.; Janicka, J. Pol J Chem
1998, 72, 73.
[4] Suni, M. M.; Nair, V. A.; Joshua, C. P. Tetrahedron
2001, 57, 2003.
[5] Mekuskiene, G.; Tumkevicius, S.; Vainilavicius, P. J
Chem Res (S), 2002, 213.
[6] Isobe, T.; Ishikawa, T. J Org Chem 1999, 64, 6989.
[7] Lutun, S.; Hasaik, B.; Couturier, D. Synth Commun
1999, 29, 111.
[38] L’abbe, G.; Verhelst, G.; Huybrechts, L.; Toppet, S. J
Heterocyclic Chem 1977, 14, 515.
[39] Strzemecka, L. Pol J Chem 1983, 57, 561.
[40] Doyle, K. M.; Kurzer, F. Tetrahedron, 1976, 32, 2347.