Azodicarboxylates: Valuable reagents for the multicomponent synthesis of novel 1,3,4-thiadiazoles and imidazo[2,1-b][1,3,4]thiadiazoles

Article abstract of DOI:10.1016/j.tet.2013.03.096

Upon reaction of 4,5-disubstituted-N-arylaminoimidazole-2-thiones with isocyanides in the presence of azodicarboxylates (1.2 equiv) at rt, the imidazo[2,1-b][1,3,4]thiadiazoles were formed as the only reaction products in very good yields, whereas by usin

Full text of DOI:10.1016/j.tet.2013.03.096

Tetrahedron 69 (2013) 5008e5015
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Azodicarboxylates: valuable reagents for the multicomponent
synthesis of novel 1,3,4-thiadiazoles and imidazo[2,1-b][1,3,4]
thiadiazoles
Tryfon Zarganes-Tzitzikas a, Constantinos G. Neochoritis a,
,
a,
*
Julia Stephanidou-Stephanatou a , Constantinos A. Tsoleridis
,
*
Gernot Buth b, George E. Kostakis c
a Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
b Institute for Synchrotron Radiation, Karlsruhe Institute of Technology, Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
c Institute of Nanotechnology, Karlsruhe Institute of Technology, Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Upon reaction of 4,5-disubstituted-N-arylaminoimidazole-2-thiones with isocyanides in the presence of
azodicarboxylates (1.2 equiv) at rt, the imidazo[2,1-b][1,3,4]thiadiazoles were formed as the only reaction
products in very good yields, whereas by using higher reaction temperatures, along with the imidazo
[2,1-b][1,3,4]thiadiazoles, the three component reaction products, namely thiadiazoles, were also iso-
lated, their formation being dependent on the 5-thione substituent. The thiadiazoles became the only
reaction products, formed in very good yield by using 2 equiv of azodicarboxylates. The sodium cya-
noborohydride and sodium borohydride reductions to thiadiazoles 11, and 12 were also studied. Plausible
mechanistic schemes for the formation of the thiadiazoles are proposed.
Received 22 January 2013
Received in revised form 6 March 2013
Accepted 26 March 2013
Available online 2 April 2013
Keywords:
Azodicarboxylates
Isocyanides
Ó 2013 Elsevier Ltd. All rights reserved.
Thiones
Imidazo[2,1-b][1,3,4]thiadiazoles
Multicomponent reactions
Thiadiazoles
1. Introduction
As a continuation of our work on imidazole derivatives15 and
also on isocyanide multicomponent chemistry16 we wish in the
The practically planar and rigid heteroaromatic imidazo[2,1-b]
[1,3,4]thiadiazole ring system is expected to have interesting
physicochemical and biological properties, because of the presence
of four heteroatoms and two condensed heterocycles with different
present work to describe our study concerning a one-pot method
for the construction of the imidazo[2,1-b][1,3,4]thiadiazole scaffold
by using imidazole-2-thiones, isocyanides, and azodicarboxylates
as a basic catalyst. The subsequent transformation of the isolated
imidazo[2,1-b][1,3,4]thiadiazole derivatives to new interesting
multi-substituted [1,3,4]thiadiazoles by using excess of azodi-
carboxylates, acting as an electrophile in the presence of the five-
membered heterocycle, is also described. Finally, the synthesis of
the same multi-substituted [1,3,4]thiadiazoles through a one-pot
multicomponent reaction between imidazole-2-thiones, iso-
cyanides and excess of DEAD is reported.
p-conjugation. Indeed, imidazo[2,1-b][1,3,4]thiadiazole, but also
thiadiazole derivatives, are known to possess interesting pharma-
cological properties, such as anticancer,1,2 antitubercular,3,4 anti-
bacterial,5,6 antifungal,7 anti-inflammatory,8 antimicrobial,9,10
anticonvulsant and analgesic,11 and antisecretory12 activities.
The classical method for the synthesis of imidazo[2,1-b][1,3,4]
thiadiazole derivatives involves reaction of 2-amino[1,3,4]thiadia-
zoles with appropriate
a
-haloketones,13 whereas very recently
a synthesis involving SuzukieMiyaura cross-coupling reactions has
2. Results and discussion
been reported.14
Initially, the reactivity of the imidazole-2-thione 1a toward
isocyanides was examined by reacting imidazolethione 1a with
cyclohexylisocyanide in the presence of a Lewis acid (BF3$Et2O)
whereupon after stirring at ambient temperature for 4 h the imi-
dazoformamidine 3a was isolated in good yield (70%, Scheme 1).
* Corresponding authors. Fax: þ30 2310 997679; e-mail addresses: ioulia@
chem.auth.gr (J. Stephanidou-Stephanatou), tsolerid@chem.auth.gr (C.A. Tsoleridis).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.096

T. Zarganes-Tzitzikas et al. / Tetrahedron 69 (2013) 5008e5015
5009
Table 1. However, when the 4-phenyl-5-methyl thione 1d was used
(entries 16 and 17, Table 1), even with 2 equiv of DEAD, regardless of
the reflux time, the imidazothiadiazoles 4 were isolated as the only
reaction products in high yields, and no trace of compounds 5 was
detected. Analogous results were obtained by using DIAD instead of
DEAD (entries 19e21, Table 1).
Finally, the imidazothiadiazole 4a could be transformed into
thiadiazole 5a by refluxing with 1.2 equiv of DEAD in toluene for
2 h, and to imidazolethiones 6 after 5 h reflux in CH2Cl2 in the
presence of acetic acid (Scheme 3).
Concerning the reaction mechanism, for the formation of the
imidazothiadiazoles 4 it can be proposed that the zwitterion 7,
initially formed from the reaction between isocyanide and DEAD,
abstracts the thione 2-NH proton forming finally intermediate 8,
which cyclizes to the end product 4 by loss of a diethyl (or dii-
sopropyl) hydrazinedicarboxylate molecule (Scheme 4). However,
by using excess of DEAD (2 equiv) and higher reaction temper-
atures (110 ꢀC) a multicomponent reaction takes place, imida-
Scheme 1. Reaction of thione 1a with cyclohexylisocyanide at ambient temperature in
the presence or absence of azodicarboxylates.
An analogous reaction of benzothiazoles with isocyanides
leading to different formamidine derivatives has very recently been
reported in the literature.17 In contrast, by using DEAD (1.2 equiv),
4,5-dimethyl-thione 1a, and cyclohexylisocyanide, after stirring at
room temperature for 6 h the imidazo[2,1-b][1,3,4]thiadiazole 4a
was isolated as the only reaction product in 86% yield (Scheme 1).
However, when the same reaction was repeated in boiling toluene
for 2 h, two products were formed, 4a isolated in 55% yield and
a three component product the tri-substituted thiadiazole 5a iso-
lated in 25% yield (Scheme 2). By using longer reaction times the
zothiadiazole
4
constituting in this case the reaction
intermediate, formed during the first step of the reaction se-
quence. In the next step, an electrophilic attack of an azodi-
carboxylate molecule to the C5]C6 double bond of 4 leads
initially to the formation of the dipolar intermediate 9 (Scheme
4), from which by formation of the diaziridine intermediate 10,
subsequent fission of the N4eC5 bond, and ‘migration’ of an
ethoxycarbonyl group the end product 5 can be obtained. In favor
of the proposed mechanism is the fact that the reaction proceeds
only with the 5-methyl substituted thiones 1aec, whereas no
Scheme 2. Reaction of thiones with isocyanides and azodicarboxylates.
yield of the three component product 5a was slightly increased at
the expense of 4a, whereas by using 2 equiv of DEAD 5a was iso-
lated as the only reaction product in 87% yield. The reaction pro-
ceeded analogously by using other 4,5-dimethyl substituted
thiones 1aec or other isocyanides, such as tert-butyl-, benzyl-, or
phenylisocyanide and the results are shown in Scheme 2 and
reaction is observed using the 5-phenyl substituted thione 1d.
Most probably, steric hindrance but also extensive delocalization
offered by the phenyl substituent renders the electrophilic attack
of an azodicarboxylate molecule to C5]C6 double bond of 4feg
unfavorable. An analogous electrophilic attack of a heterocyclic
double bond to azodicarboxylate has also recently been

5010
T. Zarganes-Tzitzikas et al. / Tetrahedron 69 (2013) 5008e5015
Table 1
HMBC), MS and elemental analysis data. The HMBC correlations of
protons with carbons via 2J, 3J, and 4J coupling are depicted in
Fig. 2 for compounds 4a and 5a, and in Fig. 3 for compounds 11b
and 12e.
Summary of the reactions between imidazole-2-thiones 1aed, isocyanides, and
azodicarboxylates
Entry Thione Isocyanide Azodicarboxylate Reaction
Product Product
Concerning the identification of compound 4a, the 1H NMR
spectrum showed the presence of the thione and isocyanide moi-
eties. The most characteristic HMBC correlation was the one be-
tween the 100-H cyclohexyl proton with the C-5 thiadiazole carbon.
Concerning compounds 5, the presence in 5a of a N]C(Me)ꢁ
C(Me)]N moiety could be hinted by the absorption of the two
carbons at 170.6 and 174.9 ppm correlating with both methyl group
protons. In both 5a and the cyanoborohydride reduction product
11b, the C-5 thiadiazole side chain could be characterized from
successive HMBC correlations as shown in Figs. 2 and 3. In com-
pound 11b the N]C(Me)ꢁC(Me)]N moiety remained unchanged,
one of the two carbons correlating with the newly formed NH
proton, which was also correlating with the remaining carbonyl
carbon of the ethoxycarbonyl group. The sodium borohydride
product 12e differs from compounds 11 only in the structure of the
side chain. The position of the reduced double bond was confirmed
by the HMBC correlations of the new-formed CeH group. The 7-H is
correlated with the C-5 thiadiazole ring atom, indicating their
neighborhood (Fig. 3).
(equiv)
conditions 4 (%)
5 (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1d
1d
1a
1a
1a
1b
Cyclohexyl DEAD (1.2)
Cyclohexyl DEAD (1.2)
Cyclohexyl DEAD (1.2)
Cyclohexyl DEAD (2.0)
rt, 6 h
rt, 5 d
4a (86)
4a (53) 5a (28)
Reflux, 2 h 4a (55) 5a (25)
Reflux, 2 h
rt, 6 h
Reflux, 2 h 4b (51) 5b (29)
Reflux, 2 h
rt, 6 h
Reflux, 2 h 4c (56) 5c (26)
Reflux, 2 h
rt, 6 h
5a (87)
tert-Butyl
tert-Butyl
tert-Butyl
Benzyl
Benzyl
Benzyl
DEAD (1.2)
DEAD (1.2)
DEAD (2.0)
DEAD (1.2)
DEAD (1.2)
DEAD (2.0)
4b (81)
5b (85)
4c (77)
9
10
11
12
13
14
15
16
17
18
19
20
21
5c (78)
Cyclohexyl DEAD (1.2)
Cyclohexyl DEAD (2.0)
4d (84)
4e (77)
Reflux, 2 h
rt, 6 h
Reflux, 2 h
Reflux, 2 h
5d (73)
tert-Butyl
tert-Butyl
tert-Butyl
DEAD (1.2)
DEAD (2.0)
DEAD (2.0)
5e (71)
5f (72)
Cyclohexyl DEAD (1.2)
Reflux, 2 h 4f (87)a
Reflux, 2 h 4g (86)a
Reflux, 2 h
tert-Butyl
Phenyl
DEAD (1.2)
DEAD (2.0)
5g (78)
5h (74)
5i (69)
5j (72)
Cyclohexyl DIAD (2.0)
tert-Butyl DIAD (2.0)
Cyclohexyl DIAD (2.0)
Reflux, 2 h
Reflux, 2 h
Reflux, 2 h
a
Using 2 equiv of 2 afforded the same results.
3. Conclusions
In conclusion, in the present work a new one-step method for
the construction of the imidazo[2,1-b][1,3,4]thiadiazole scaffold, in
very good yields, by using an unusual azodicarboxylate promoted
reaction between imidazole-2-thiones and isocyanides is de-
scribed. Moreover, the isolated imidazo[2,1-b][1,3,4]thiadiazoles
could be transformed into new multi-substituted [1,3,4]thiadia-
zoles by refluxing with DEAD. The same multi-substituted [1,3,4]
thiadiazoles were also formed through a one-pot multicomponent
reaction between imidazole-2-thiones, isocyanides, and excess of
DEAD. In addition, the ability of the azodicarboxylate moiety to act
as an electrophile in the presence of five-membered heterocycles
was established.
Scheme 3. Transformation reaction of imidazothiadiazoles 4 to thiadiazoles 5 and 6.
4. Experimental section
4.1. General
observed,18 and migration of a DEAD ethoxycarbonyl group has
also been previously reported.19
Thiones 1 were synthesized, as previously described, from
substituted hydrazines, bromoketones, and potassium thio-
cyanate.15a Column chromatography was carried out using silica gel
(70e230 mesh) and TLC was performed using precoated silica gel
glass plates 0.25 mm containing fluorescent indicator UV254 using
a 3:1 mixture of petroleum ethereethyl acetate. Petroleum ether
refers to the fraction boiling between 60 and 80 ꢀC. NMR spectra
were recorded at room temperature (25 ꢀC) at 300 MHz for 1H and
75 MHz for 13C, respectively, using CDCl3 as solvent. Chemical shifts
Since compounds 5 are oils, thus unsuitable for crystallographic
analysis, and their structure consists of many heteroatoms and only
a few protons, rendering their identification by 2D NMR ambigu-
ous, reduction was attempted in order to introduce some more
protons into the molecule but also hoping to obtain solid reduction
products.
Initially, sodium cyanoborohydride reduction was attempted on
compounds 5b and 5d leading to the isolation of the thiadiazolyl-
hydrazine carboxylates 11b and 11d, respectively, in high yields
(80 and 77%), where only an ethoxycarbonyl group was expelled
(Scheme 5). Fortunately, 11b was a solid product, whose structure
was confirmed by the use of crystal X-ray diffraction analysis20
(Fig. 1). Reduction was also studied with sodium borohydride on
compound 5e, whereupon 12e was isolated in 41% yield, as an oil
with additional reduction of N6]C7 double bond (Scheme 5).
are expressed in
d values (parts per million) relative to TMS as in-
ternal standard for 1H and relative to TMS (0.00 ppm) or to CDCl3
(77.05 ppm) for 13C NMR spectra. Coupling constants nJ are reported
in Hertz. Moreover, the complete assignment of 1H and 13C NMR
signals was possible using 1D and 2D experiments using the
standard commercial pulse programs. IR spectra were recorded on
a FTIR spectrometer and are reported in wave numbers (cmꢁ1).
Low-resolution mass spectra were obtained with the LC-ESI
method at 1.65 eV ionization potential and are reported as m/z
(relative intensity to the base peak), and elemental analyses per-
formed with a CHN analyzer. For the XRD study we were able to
identify the structure of this compound by measuring at synchro-
tron at 150 K.
2.1. Structure assignments of the new compounds
The assigned molecular structures of the new compounds 4, 5,
11, and 12 were based on rigorous spectroscopic analysis in-
cluding IR, NMR (1H, 13C, HeH COSY, HeH NOESY, HMQC and

T. Zarganes-Tzitzikas et al. / Tetrahedron 69 (2013) 5008e5015
5011
Scheme 4. Rational mechanism for the formation of compounds 4 and 5.
Scheme 5. Sodium borohydride and sodium cyanoborohydride reduction of thiadiazoles 5.
4.2. Reaction of thione 1a with cyclohexylisocyanide in the
presence of BF3$Et2O
dried, the solvent was evaporated, and the residue was subjected to
column chromatography on silica gel using petroleum ethereAcOEt
(1:1) as eluent to give 1-[[(cyclohexylimino)methyl]phenylamino]-
2,3-dihydro-4,5-dimethyl-2-thioxo-1H-imidazole (3a). White solid;
0.230 g (70%); mp 177e179 ꢀC (CH2Cl2ꢁpet. ether); 1H NMR
To a mixture of thione 1a (0.219 g, 1.0 mmol) and BF3$Et2O
(1.2 mmol) in toluene (25 mL), cyclohexylisocyanide (0.109 g,
1.0 mmol) was added. The reaction mixture was stirred at room
temperature until thione was consumed completely (followed by
TLC, approximately 4 h). The solvent was distilled off in vacuo and
the resulting residue was dissolved in CH2Cl2, washed with water,
(300 MHz, CDCl3)
d
1.10e1.50 (m, 5H, Hax), 1.55e1.66 (m, 1H, 400-
Heq), 1.67e1.84 (m, 4H, 200,300,500,600-Heq), 1.89 (s, 3H, 5-CH3), 2.06 (s,
3H, 4-CH3), 3.12e3.25 (m, 1H, 100-H), 7.04e7.14 (d, J¼7.8 Hz, 2H,
20,60-H), 7.28e7.49 (m, 3H, 30,40,50-H), 8.14 (s, 1H, NeCH]N), 10.2

5012
T. Zarganes-Tzitzikas et al. / Tetrahedron 69 (2013) 5008e5015
Fig. 1. ORTEP diagram of the molecular structure of compound 11b as determined by crystal XRD (atoms ellipsoid probability 30%).
(very broad, 1H, 3-NH); 13C NMR (75 MHz, CDCl3)
d 8.4 (5-CH3), 9.5
(4-CH3), 24.9 (C-300,C-500), 25.6 (C-400), 35.09 and 35.13 (C-200,C-600),
64.6 (C-100), 116.8 (C-20,C-60), 118.9 (C-5), 122.7 (C-4), 123.8 (C-40),
129.5 (C-30,C-50), 141.8 (C-10), 144.7 (NeCH]N), 160.3 (C-2); IR
(KBr) 3436, 3090, 2924, 1649 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 329
[100, (MþH)þ]. Anal. Calcd for C18H24N4S (328.48): C, 65.82; H,
7.36; N, 17.06. Found: C, 65.99; H, 7.31; N 16.95.
4.3. General procedure for the reaction of thiones (1aed)
with isocyanides in the presence of azodicarboxylates
A reaction mixture of thione 1 (1.0 mmol), isocyanide (1.0 mmol)
and DEAD or DIAD (1.2 mmol) in toluene (25 mL), was stirred at
room temperature until thione 1 was consumed completely (fol-
lowed by TLC, approximately 6 h). The solvent was distilled off in
vacuo and the resulting residue was subjected to column chroma-
tography on silica gel using petroleum ethereAcOEt (3:1) as eluent
to give the isolated product 4 (Scheme 1). When the same reaction
was repeated in refluxing toluene for 2 h a mixture of 5 and 4 was
obtained in the above elution order. In addition, when the same
2
Fig. 2. Diagnostic HMBC correlations between protons and carbons (via JCeH
and JCeH) observed in compounds 4a and 5a.
,
3JCeH
,
4
2
4
Fig. 3. Diagnostic HMBC correlations between protons and carbons (via JCeH,
3JCeH, and JCeH) observed in compounds 11b and 12e.

T. Zarganes-Tzitzikas et al. / Tetrahedron 69 (2013) 5008e5015
5013
reaction was repeated by using 2.0 equiv of azodicarboxylate in
refluxing toluene for 2 h only compound 5 was isolated (Table 1,
Scheme 2).
[25, (MþNa)þ], 335/337 [100, (MþH)þ]; Anal. Calcd for C16H19ClN4S
(334.87): C, 57.39; H, 5.72; N,16.73. Found: C, 57.27; H, 5.65; N,16.59.
4.3.6. 2-Cyclohexylimino-2,3-dihydro-3,5-diphenyl-6-methyl-imi-
4.3.1. 2-Cyclohexylimino-2,3-dihydro-5,6-dimethyl-3-phenyl-imi-
dazo[2,1-b][1,3,4]thiadiazole (4a). Yellow solid; 0.281 g (86%); mp
70e72 ꢀC (CH2Cl2ꢁpet. ether); 1H NMR (300 MHz, CDCl3)
dazo[2,1-b][1,3,4]thiadiazole (4f). Yellowish solid (0.338 g, 87%
yield), mp 105e106 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.15e1.46 (m,
5H, Hax), 1.52e1.62 (m, 1H, 400-Heq), 1.63e1.75 (m, 4H, 200,300,500,600-
Heq), 2.35 (s, 3H, 6-CH3), 2.88e3.00 (m, 1H, 100-H), 6.98e7.18 (m, 8H,
30,40,50-H and 5-Ph), 7.24e7.29 (m, 2H, 20,60-H); 13C NMR (75 MHz,
d
1.20e1.45 (m, 5H, 200,300,400,500,600-Hax), 1.50e1.63 (m, 1H, 400-Heq),
1.63e1.77 (m, 4H, 200,300,500,600-Heq), 1.79 (s, 3H, 5-CH3), 2.17 (s, 3H, 6-
CH3), 2.88e2.92 (m, 1H, 100-H), 7.26e7.42 (m, 5H, 20,30,40,50,60-H);
CDCl3) d
14.4 (6-CH3), 24.1 (C-300,C-500), 25.4 (C-400), 32.7 (C-200,C-600),
13C NMR (75 MHz, CDCl3)
d
9.2 (5-CH3), 13.2 (6-CH3), 24.2 (C-300,C-
64.8 (C-100), 122.8 (C-20,C-60), 124.4 (C-5), 126.9 (C-4000), 127.3 (C-40),
127.86 and 127.91 (C-2000,C-6000 and C-3000,C-5000), 128.1 (C-1000), 128.4
(C-30,C-50), 135.8 (C-7a), 137.0 (C-6), 144.4 (C-10), 154.8 (C-2); IR
(KBr) 1662, 1644 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 443 [25,
(MþMeOHþNa)þ], 389 [100, (MþH)þ]. Anal. Calcd for C23H24N4S
(388.53): C, 71.10; H, 6.23; N, 14.42. Found: C, 71.07; H, 6.35; N,
14.28.
500), 25.5 (400-CH3), 32.7 (C-200,C-600), 64.7 (C-100), 120.2 (C-5), 123.5
(C-20,C-60), 127.5 (C-40), 129.1 (C-30,C-50), 133.9 (C-7a), 135.4 (C-6),
144.6 (C-10), 155.0 (C-2); IR (KBr) 1671, 1593 cmꢁ1; LCeMS (ESI,
1.65 eV) m/z 381 [100, (MþMeOHþNa)þ], 349 [30, (MþNa)þ], 327
[100, (MþH)þ]. Anal. Calcd for C18H22N4S (326.46): C, 66.22; H,
6.79; N, 17.16. Found: C, 66.07; H, 6.85; N, 17.18.
4.3.2. 2,3-Dihydro-2-(tert-butylimino)-5,6-dimethyl-3-phenyl-imi-
4.3.7. 2,3-Dihydro-2-(tert-butylimino)-3,5-diphenyl-6-methyl-imi-
dazo[2,1-b][1,3,4]thiadiazole (4b). Yellow solid; 0.243 g (81%); mp
dazo[2,1-b][1,3,4]thiadiazole (4g). Yellow solid; 0.312 g (86%); mp
55e57 ꢀC (CH2Cl2ꢁpet. ether); 1H NMR (300 MHz, CDCl3)
d
1.24 (s,
110e111 ꢀC (CH2Cl2ꢁpet. ether); 1H NMR (300 MHz, CDCl3)
d 1.26
9H, C(CH3)3), 1.78 (s, 3H, 5-CH3), 2.17 (s, 3H, 6-CH3), 7.25e7.33 (m,
(s, 9H, C(CH3)3), 2.34 (s, 3H, 6-CH3), 6.95e7.17 (m, 8H, 30,40,50-H and
3H, 20,40,60-H), 7.34e7.42 (m, 2H, 30,50-H); 13C (75 MHz, CDCl3)
d
9.0
5-Ph), 7.23e7.29 (m, 2H, 20, 60-H); 13C NMR (75 MHz, CDCl3)
d 14.4
(5-CH3), 13.0 (6-CH3), 28.2 (C(CH3)3), 55.0 (C(CH3)3), 120.0 (C-5),
123.2 (C-20,C-60), 127.1 (C-40), 128.7 (C-30,C-50), 134.4 (C-7a), 135.1
(C-6), 144.8 (C-10), 149.3 (C-2); IR (KBr) 1656 cmꢁ1; LCeMS (ESI,
1.65 eV) m/z 301 [100, (MþH)þ]. Anal. Calcd for C16H20N4S (300.42):
C, 63.97; H, 6.71; N, 18.65. Found: C, 64.08; H, 6.65; N, 18.78.
(6-CH3), 28.3 (C(CH3)3), 55.2 (C(CH3)3),122.8 (C-20,C-60),124.3 (C-5),
126.7 (C-4000), 127.2 (C-40), 127.80 and 127.82 (C-2000,C-3000,C-5000,C-
6
000), 128.1 (C-1000), 128.2 (C-30,C-50), 136.4 (C-7a), 136.8 (C-6), 144.8
(C-10),149.2 (2-C); IR (KBr) 1669 cmꢁ1; LCeMS (ESI,1.65 eV) m/z 417
[45, (MþNa)þ], 385 [30, (MþNa)þ], 363 [100, (MþH)þ]. Anal. Calcd
for C21H22N4S (362.49): C, 69.58; H, 6.12; N, 15.46. Found: C, 69.47;
H, 6.05; N, 15.30.
4.3.3. 2-(Benzyl)imino-2,3-dihydro-5,6-dimethyl-3-phenyl-imidazo
[2,1-b][1,3,4]thiadiazole (4c). Yellow solid; 0.257
g (77%); mp
145e147 ꢀC (CH2Cl2ꢁpet. ether); 1H NMR (300 MHz, CDCl3)
d
1.77
4.3.8. (2Z)-5-[[(1E,2E)-2-[2,2-Bis(ethoxycarbonyl)hydrazono]-1-
methylpropylidene]amino]-2-(cyclohexylimino)-3-phenyl-2,3-
dihydro-1,3,4-thiadiazole (5a). Yellowish oil; 0.436 g (87%); 1H NMR
(s, 3H, 5-CH3), 2.17 (s, 3H, 6-CH3), 4.42 (s, 2H, CH2), 7.14e7.30 (m,
5H, AreH), 7.32e7.48 (m, 5H, AreH); 13C NMR (75 MHz, CDCl3)
d 9.3
(5-CH3), 13.2 (6-CH3), 58.2 (CH2), 120.2 (C-5), 124.6 (C-20,C-60), 127.0
(C-40), 127.2 (C-200,C-600), 128.1 (C-400), 128.4 (C-30,C-50), 129.3 (C-
300,C-500), 133.3 (C-7a), 136.2 (C-6), 138.4 (C-100), 143.7 (C-10), 158.4
(C-2); IR (KBr) 1676 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 389 [30,
(MþMeOHþNa)þ], 358 [45, (MþNaþH)þ], 335 [100, (MþH)þ];
Anal. Calcd for C19H18N4S (334.44): C, 68.23; H, 5.42; N, 16.75.
Found: C, 68.47; H, 5.35; N, 16.88.
(300 MHz, CDCl3)
d
1.34 (t, J¼7.1 Hz, 6H, 2ꢂCOOCH2CH3), 1.25e1.45
(m, 5H, Hax), 1.60e1.68 (1H, m, 400-Heq), 1.72e1.91 (m, 4H,
200,300,500,600-Heq), 2.12 (s, 3H, 8-CH3), 2.60 (s, 3H, 7-CH3), 2.68e2.79
(m, 1H, 100-H), 4.34 (q, J¼7.1 Hz, 4H, 2ꢂCOOCH2CH3), 7.13e7.20 (m,
1H, 40-H), 7.33e7.42 (m, 2H, 30,50-H), 8.00e8.05 (m, 2H, 20,60-H); 13C
NMR (75 MHz, CDCl3)
d
14.2 (2ꢂCOOCH2CH3), 14.3 (8-CH3), 17.8 (7-
CH3), 24.6 (C-300,C-500), 25.8 (C-400), 33.1 (C-200,C-600), 63.7
(2ꢂCOOCH2CH3), 68.2 (C-100), 121.3 (C-20,C-60), 124.9 (C-40), 128.5
(C-30,C-50), 140.2 (C-10), 148.6 (C-5), 150.7 (2ꢂCO), 151.0 (C-2), 170.6
(C-7), 174.9 (C-8); IR (neat) 1794, 1758, 1630 cmꢁ1; LCeMS (ESI,
1.65 eV) m/z 523 [100, (MþNa)þ], 501 [44, (MþH)þ]. Anal. Calcd for
C24H32N6O4S (500.62): C, 57.58; H, 6.44; N, 16.79. Found: C, 57.67;
H, 6.35; N, 16.61.
4.3.4. 3-(4-Chlorophenyl)-2-cyclohexylimino-2,3-dihydro-5,6-
dimethyl-imidazo[2,1-b][1,3,4]thiadiazole (4d). Yellow solid; 0.303 g
(84%); mp 98e100 ꢀC (CH2Cl2ꢁpet. ether); 1H NMR (300 MHz,
CDCl3) d
1.20e1.45 (m, 5H, Hax),1.52e1.62 (m,1H, 400-Heq),1.62e1.75
(m, 4H, 200,300,500,600-Heq), 1.82 (s, 3H, 5-CH3), 2.17 (s, 3H, 6-CH3),
2.85e2.97 (m, 1H, 100-H), 7.30 (d, J¼9.0 Hz, 2H, 20,60-H), 7.37 (d,
J¼9.0 Hz, 2H, 30,50-H); 13C NMR (75 MHz, CDCl3)
d
9.1 (5-CH3), 13.0
4.3.9. (2Z)-5-[[(1E,2E)-2-[2,2-Bis(ethoxycarbonyl)hydrazono]-1-
methylpropylidene]amino]-2-(tert-butylimino)-3-phenyl-2,3-
dihydro-1,3,4-thiadiazole (5b). Yellowish oil; 0.403 g (85%); 1H NMR
(6-CH3), 24.0 (C-300,C-500), 25.3 (400-CH3), 32.6 (C-200,C-600), 64.5 (C-
100),120.0 (C-5),124.5 (C-20,C-60),129.0 (C-30,C-50),132.9 (C-40),133.7
(C-7a), 135.6 (C-6), 142.8 (C-10), 154.4 (C-2); IR (KBr) 1671 cmꢁ1
;
(300 MHz, CDCl3)
d
1.335 (t, J¼7.1 Hz, 6H, 2ꢂCOOCH2CH3),1.36 (s, 9H,
LCeMS (ESI, 1.65 eV) m/z 415/417 [40, (MþMeOHþNa)þ], 383/385
[20, (MþNa)þ], 361/363 [100, (MþH)þ]. Anal. Calcd for C18H21ClN4S
(360.90): C, 59.90; H, 5.86; N, 15.52. Found: C, 59.97; H, 5.75; N,
15.39.
(C(CH3)3)), 2.12 (s, 3H, 8-CH3), 2.62 (3H, s, 7-CH3), 4.32 (q, J¼7.1 Hz,
4H, 2ꢂCOOCH2CH3), 7.12e7.19 (1H, m, 40-H), 7.32e7.40 (2H, m, 30,50-
H), 7.96e8.01 (m, 2H, 20,60-H); 13C NMR (75 MHz, CDCl3)
d 14.0
(2ꢂCOOCH2CH3), 14.1 (8-CH3), 17.7 (7-CH3), 27.7 (C(CH3)3), 54.0
(C(CH3)3), 63.4 (2ꢂCOOCH2CH3),122.0 (C-20,C-60),124.8 (C-40),128.0
(C-30,C-50), 140.3 (C-10), 145.4 (C-2), 148.2 (C-5), 150.5 (2ꢂCO), 170.1
(C-7),174.6 (C-8); IR (neat) 1765,1759,1754,1632 cmꢁ1; LCeMS (ESI,
1.65 eV) m/z 529 [20, (MþMeOHþNa)þ], 497 [80, (MþNa)þ], 475
[100, (MþH)þ]. Anal. Calcd for C22H30N6O4S (474.58): C, 55.68; H,
6.37; N, 17.71. Found: C, 55.56; H, 6.30; N, 17.62.
4.3.5. 3-(4-Chlorophenyl)-2,3-dihydro-2-(tert-butylimino)-5,6-
dimethyl-imidazo[2,1-b][1,3,4]thiadiazole (4e). Yellow solid (0.258 g,
77% yield), mp 67e68 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.25 (s, 9H,
C(CH3)3),1.81 (s, 3H, 5-CH3), 2.17 (s, 3H, 6-CH3), 7.26 (d, J¼9.0 Hz, 2H,
20,60-H), 7.36 (d, J¼9.0 Hz, 2H, 30,50-H); 13C NMR (75 MHz, CDCl3)
d
9.2 (5-CH3), 13.2 (6-CH3), 28.4 (C(CH3)3), 55.3 (C(CH3)3), 120.2 (C-
5),124.5 (C-30,C-50),129.0 (C-20,C-60),132.7 (C-40),134.7 (C-7a),135.6
(C-6), 143.4 (C-10), 149.1 (C-2); IR (KBr) 1664 cmꢁ1; LCeMS
(ESI, 1.65 eV) m/z 389/387 [45, (MþMeOHþNa)þ], 357/359
4.3.10. (2Z)-2-(Benzylimino)-5-[[(1E,2E)-2-[2,2-bis(ethoxycarbonyl)
hydrazono]-1-methylpropylidene]amino]-3-phenyl-2,3-dihydro-
1,3,4-thiadiazole (5c). Yellowish oil; 0.397
g
(78%); 1H NMR

5014
T. Zarganes-Tzitzikas et al. / Tetrahedron 69 (2013) 5008e5015
(300 MHz, CDCl3)
d
1.34 (t, J¼7.1 Hz, 6H, 2ꢂCOOCH2CH3), 2.12 (s, 3H,
2ꢂCOOCH2CH3), 7.07 (d, J¼8.1 Hz, 2H, 200,600-H), 7.12 (t, J¼7.5 Hz, 1H,
40-H), 7.27 (t, J¼7.1 Hz, 1H, 400-H), 7.37 (dd, J¼8.4, 7.5 Hz, 2H, 30,50-H),
7.45 (dd, J¼8.2, 7.1 Hz, 2H, 300,500-H), 8.01 (d, J¼8.4 Hz, 2H, 20,60-H);
8-CH3), 2.61 (s, 3H, 7-CH3), 4.33 (q, J¼7.1 Hz, 4H, 2ꢂCOOCH2CH3),
4.44 (s, 2H, CH2), 7.17e7.22 (m, 1H, 40-H), 7.22e7.28 (m, 1H, 400-H),
7.31e7.36 (m, 2H, 30,50-H), 7.35e7.45 (m, 4H, 200,300,500,600-H),
13C NMR (75 MHz, CDCl3)
d
14.3 (2ꢂCOOCH2CH3), 14.4 (8-CH3), 17.9
7.99e8.05 (m, 2H, 20,60-H); 13C NMR (75 MHz, CDCl3)
d
14.25
(7-CH3), 63.9 (2ꢂCOOCH2CH3), 120.8 (C-200,C-600), 122.3 (C-20,C-60),
124.2 (C-40), 126.1 (C-400), 128.8 (C-30,C-50), 129.7 (C-300,C-500), 139.5
(C-10), 149.2 (C-5), 150.7 (2ꢂCO), 151.8 (C-2), 155.2 (C-100), 171.9 (C-
7),174.6 (C-8); IR (neat) 1760,1752,1619 cmꢁ1; LCeMS (ESI,1.65 eV)
m/z 549 [5, (MþMeOHþNa)þ], 517 [100, (MþNa)þ], 495 [75,
(MþH)þ]. Anal. Calcd for C24H26N6O4S (494.57): C, 58.28; H, 5.30; N,
16.99. Found: C, 58.37; H, 5.42; N, 17.18.
(2ꢂCOOCH2CH3), 14.36 (8-CH3), 17.9 (7-CH3), 61.5 (CH2), 63.8
(2ꢂCOOCH2CH3), 122.0 (C-20,C-60), 125.6 (C-40), 126.9 (C-400), 127.5
(C-200,C-600), 128.4 (C-30,C-50), 128.7 (C-300,C-500), 139.5 (C-100), 140.0
(C-10), 148.8 (C-5),150.8 (2ꢂCO), 155.1 (C-2),171.3 (C-7), 174.7 (C-8);
IR (neat) 1762, 1750, 1629 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 563 [25,
(MþMeOHþNa)þ], 531 [92, (MþNa)þ], 509 [100, (MþH)þ]. Anal.
Calcd for C25H28N6O4S (508.59): C, 59.04; H, 5.55; N, 16.52. Found:
C, 58.87; H, 5.41; N, 16.67.
4.3.15. (2Z)-5-[[(1E,2E)-2-[2,2-Bis[(1-methylethoxy)carbonyl]hydra-
zono]-1-methylpropylidene]amino]-2-(cyclohexylimino)-3-phenyl-
4.3.11. (2Z)-5-[[(1E,2E)-2-[2,2-Bis(ethoxycarbonyl)hydrazono]-1-
methylpropylidene]amino]-3-(4-chlorophenyl)-2-(cyclohexylimino)-
1,3,4-thiadiazole (5h). Yellowish oil; 0.391
(300 MHz, CDCl3)
g
(74%); 1H NMR
1.33 (d, J¼7.5 Hz, 12H, 2ꢂCOOCH(CH3)2),
d
1,3,4-thiadiazole (5d). Yellowish oil; 0.391
(300 MHz, CDCl3)
g
(73%); 1H NMR
1.25e1.55 (m, 5H, Hax), 1.56e1.66 (m, 1H, 400-Heq), 1.75e1.92 (m, 4H,
200,300,500,600-Heq), 2.10 (s, 3H, 8-CH3), 2.59 (s, 3H, 7-CH3), 2.70e2.80
(m, 1H, 100-H), 5.05e5.15 (m, 2H, 2ꢂCOOCH(CH3)2), 7.15 (t, J¼7.3 Hz,
1H, 40-H), 7.37 (dd, J¼8.4, 7.3 Hz, 2H, 30,50-H), 8.04 (d, J¼8.4 Hz, 2H,
d
1.36 (t, J¼7.1 Hz, 6H, 2ꢂCOOCH2CH3), 1.30e1.67
(m, 5H, 200,300,400,500,600-Hax), 1.73e1.90 (m, 5H, 200,300,400,500,600-Heq),
2.12 (s, 3H, 8-CH3), 2.53 (s, 3H, 7-CH3), 2.66e2.78 (m,1H,100-H), 4.34
(q, J¼7.1 Hz, 4H, 2ꢂCOOCH2CH3), 7.33 (d, J¼7.3 Hz, 2H, 30,50-H), 8.02
20,60-H); 13C NMR (75 MHz, CDCl3)
d 14.4 (8-CH3), 17.7 (7-CH3), 21.8
(d, J¼7.3 Hz, 2H, 20,60-H); 13C NMR (75 MHz, CDCl3)
d
14.2
(2ꢂCOOCH(CH3)2), 24.6 (C-300,C-500), 25.9 (400-CH3), 33.2 (C-200,C-600),
68.2 (C-100), 71.9 (2ꢂCOOCH(CH3)2), 121.3 (C-20,C-60), 124.9 (C-40),
128.5 (C-30,C-50), 140.4 (C-10), 148.7 (C-5), 150.6 (2ꢂCO), 151.0 (C-2),
171.0 (C-7), 173.8 (C-8); IR (neat) 1762, 1754, 1631 cmꢁ1; LCeMS
(ESI,1.65 eV) m/z 583 [5, (MþMeOHþNa)þ], 551 [45, (MþNa)þ], 529
[100, (MþH)þ]. Anal. Calcd for C26H36N6O4S (528.67): C, 59.07; H,
6.86; N, 15.90. Found: C, 58.92; H, 6.95; N, 17.08.
(2ꢂCOOCH2CH3), 14.4 (8-CH3), 17.8 (7-CH3), 24.6 (C-300,C-500), 25.7
(C-400), 33.1 (C-200,C-600), 63.8 (2ꢂCOOCH2CH3), 68.2 (C-100), 122.2 (C-
20,C-60), 128.5 (C-30,C-50), 129.8 (C-40), 138.8 (C-10), 148.9 (C-5),
150.68 (2ꢂCO), 150.73 (C-2), 171.2 (C-7), 174.7 (C-8); IR (neat) 1761,
1633 cmꢁ1
;
LCeMS (ESI, 1.65 eV) m/z 589/591 [5,
(MþMeOHþNa)þ], 557/559 [20, (MþNa)þ], 535/537 [100, (MþH)þ].
Anal. Calcd for C24H31ClN6O4S (535.06): C, 53.87; H, 5.84; N, 15.71.
Found: C, 53.69; H, 5.74; N, 15.60.
4.3.16. (2Z)-5-[[(E)-2-[(E)-2,2-Bis[(1-methylethoxy)carbonyl]hydra-
zono]-1-methylpropylidene]amino]-2-(tert-butylimino)-3-phenyl-
4.3.12. (2Z)-5-[[(1E,2E)-2-[2,2-Bis(ethoxycarbonyl)hydrazono]-2,3-
dihydro-1-methylpropylidene]amino]-3-(4-chlorophenyl)-2-(tert-bu-
tylimino)-1,3,4-thiadiazole (5e). Yellowish oil; 0.361 g (71%); 1H
1,3,4-thiadiazole (5i). Yellowish oil; 0.347
(300 MHz, CDCl3)
(9H, s, C(CH3)3), 2.11 (s, 3H, 8-CH3), 2.61 (s, 3H, 7-CH3), 5.08 (sept,
J¼6.3 Hz, 2H, 2ꢂCOOCH(CH3)2), 7.14 (t, J¼7.5 Hz, 1H, 40-H), 7.35 (dd,
J¼7.9, 7.5 Hz, 2H, 30,50-H), 8.00 (d, J¼7.9 Hz, 2H, 20,60-H); 13C NMR
g
(69%); 1H NMR
1.330 (d, J¼6.3 Hz, 12H, 2ꢂCOOCH(CH3)2), 1.335
d
NMR (300 MHz, CDCl3)
d
1.33 (9H, s, (C(CH3)3)), 1.35 (6H, t, J¼7.1 Hz,
2ꢂCOOCH2CH3), 2.12 (3H, s, 8-CH3), 2.60 (3H, s, 7-CH3), 4.33 (4H, q,
J¼7.1 Hz, 2ꢂCOOCH2CH3), 7.32 (d, J¼8.9 Hz, 2H, 30,50-H), 7.98 (d,
(75 MHz, CDCl3)
d
14.3 (CH3),17.8 (CH3), 21.7 (2ꢂCOOCH(CH3)2), 27.9
J¼8.9 Hz, 2H, 20,60-H); 13C NMR (75 MHz, CDCl3)
d
14.2
(C(CH3)3), 54.2 (C(CH3)3), 71.8 (2ꢂCOOCH(CH3)2), 122.1 (C-20,C-60),
(2ꢂCOOCH2CH3), 14.4 (8-CH3), 17.9 (7-CH3), 27.8 (C(CH3)3), 54.3
(C(CH3)3), 63.8 (2ꢂCOOCH2CH3), 123.1 (C-20,C-60), 128.3 (C-30,C-50),
129.9 (C-40),138.9 (C-10),145.4 (C-2),148.8 (C-5),150.7 (2ꢂCO),170.8
(C-7), 174.9 (C-8); IR (neat) 1758, 1632 cmꢁ1; LCeMS (ESI, 1.65 eV)
m/z 563/565 [5, (MþMeOHþNa)þ], 531/533 [40, (MþNa)þ], 509/511
[100, (MþH)þ]. Anal. Calcd for C22H29ClN6O4S (509.02): C, 51.91; H,
5.74; N, 16.51. Found: C, 51.77; H, 5.89; N, 16.68.
124.9 (C-40), 128.2 (C-30,C-50), 140.5 (C-10), 145.5 (C-5), 148.4 (C-2),
150.5 (2ꢂCO), 170.5 (C-7), 173.8 (C-8); IR (neat) 1753, 1635 cmꢁ1
;
LCeMS (ESI, 1.65 eV) m/z 557 [10, (MþMeOHþNa)þ], 525 [45,
(MþNa)þ], 503 [100, (MþH)þ]. Anal. Calcd for C24H34N6O4S
(502.63): C, 57.35; H, 6.82; N,16.72. Found: C, 57.49; H, 6.90; N,16.92.
4.3.17. (2Z)-5-[[(E)-2-[(E)-2,2-Bis[(1-methylethoxy)carbonyl]hydra-
zono]-1-methylpropylidene]amino]-2-(cyclohexylimino)-3-(4-
chlorophenyl)-1,3,4-thiadiazole (5j). Yellowish oil; 0.405 g (72%); 1H
4.3.13. (2Z)-5-[[(1E,2E)-2-[2,2-Bis(ethoxycarbonyl)hydrazono]-2,3-
dihydro-1-methylpropylidene]amino]-2-(tert-butylimino)-3-(4-
methylphenyl)-1,3,4-thiadiazole (5f). Yellowish oil; 0.352 g (72%);
NMR (300 MHz, CDCl3)
d
1.34 (d, J¼6.3 Hz, 12H, 2ꢂCOOCH(CH3)2),
1.20e1.55 (m, 5H, Hax), 1.55e1.67 (m, 1H, 400-Heq), 1.75e1.90 (m, 4H,
200,300,500,600-Heq), 2.10 (s, 3H, CH3), 2.59 (s, 3H, CH3), 2.67e2.78 (m,
1H, 100-H), 5.10 (sept, J¼6.3 Hz, 2H, 2ꢂCOOCH(CH3)2), 7.33 (d,
J¼8.8 Hz, 2H, 30,50-H), 8.02 (d, J¼8.8 Hz, 2H, 20,60-H); 13C NMR
1H NMR (300 MHz, CDCl3)
d
1.34 (s, 9H, (C(CH3)3)), 1.35 (t, J¼7.1 Hz,
6H, 2ꢂCOOCH2CH3), 2.12 (s, 3H, 8-CH3), 2.37 (s, 3H, 40-CH3), 2.61 (s,
3H, 8-CH3), 4.33 (q, J¼7.1 Hz, 4H, 2ꢂCOOCH2CH3), 7.17 (d, J¼8.6 Hz,
2H, 30,50-H), 7.82 (d, J¼8.6 Hz, 2H, 20,60-H); 13C NMR (75 MHz,
(75 MHz, CDCl3)
d
14.5 (8-CH3), 17.8 (7-CH3), 21.8
CDCl3)
d
14.3 (2ꢂCOOCH2CH3), 14.4 (8-CH3), 17.9 (7-CH3), 21.0 (40-
(2ꢂCOOCH(CH3)2), 24.6 (C-300,C-500), 25.7 (400-CH3), 33.2 (C-200,C-600),
68.3 (C-100), 72.1 (2ꢂCOOCH(CH3)2), 122.3 (C-20,C-60),128.5 (C-30,50),
129.8 (C-40), 138.8 (C-10), 149.1 (C-2), 150.6 (2ꢂCO), 150.9 (C-2),
171.4 (C-7), 173.5 (C-8); IR (neat) 1757, 1635 cmꢁ1; LCeMS (ESI,
1.65 eV) m/z 595/597 [30, (MþMeOHþH)þ], 563/565 [20, (MþH)þ],
437/439 (100). Anal. Calcd for C26H35ClN6O4S (563.11): C, 55.46; H,
6.26; N, 14.92. Found: C, 55.62; H, 6.15; N, 15.09.
CH3), 27.9 (C(CH3)3), 54.2 (C(CH3)3), 63.8 (2ꢂCOOCH2CH3), 122.3 (C-
20,C-60), 128.9 (C-30,C-50), 134.8 (C-40), 137.8 (C-10), 145.7 (C-2), 148.0
(C-5), 150.7 (2ꢂCO), 169.7 (C-7), 175.3 (C-8); IR (neat) 1770, 1762,
1633, 1626 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 511 [40, (MþNa)þ], 489
[100, (MþH)þ]. Anal. Calcd for C23H32N6O4S (488.60): C, 56.54; H,
6.60; N, 17.20. Found: C, 56.77; H, 6.73; N, 17.41.
4.3.14. (2Z)-5-[[(1E,2E)-2-[2,2-Bis(ethoxycarbonyl)hydrazono]-2,3-
dihydro-1-methylpropylidene]amino]-3-phenyl-2-(phenylimino)-
4.3.18. Reduction of compounds 5 with NaBH4 and NaBH3CN. A
mixture of compound 5 (1.0 mmol) and NaBH3CN (or NaBH4,
1.1 mmol) was dissolved in MeOH (5 mL) and was stirred at am-
bient temperature for 2 h and then concentrated in vacuum. The
residue was in partition with ethyl acetate (10 mL) and water
1,3,4-thiadiazole (5g). Yellowish oil; 0.386
(300 MHz, CDCl3)
1.34 (t, J¼7.1 Hz, 6H, 2ꢂCOOCH2CH3), 2.09
(s, 3H, 8-CH3), 2.58 (s, 3H, 7-CH3), 4.33 (q, J¼7.1 Hz, 4H,
g
(78%); 1H NMR
d

T. Zarganes-Tzitzikas et al. / Tetrahedron 69 (2013) 5008e5015
5015
(10 mL). The organic layer was separated, and the aqueous layer
was extracted again with ethyl acetate (10 mL). The organic layers
were combined, washed with brine, dried with anhydrous Na2SO4,
concentrated in vacuum, and purified with silica gel column
chromatography using petroleum ethereAcOEt (1:1) as eluent to
give the isolated product 11 or 12 depending on the use of NaBH3CN
or NaBH4, respectively.
(89%), mp 86e88 ꢀC (CH2Cl2ꢁpet. ether); 1H NMR (300 MHz, CDCl3)
d
1.37 (s, 9H, C(CH3)3), 2.16 (s, 3H, 4-CH3), 4.80 (s, 1H, CONH),
7.09e7.22 (m, 5H), 7.26e7.31 (m, 2H), 7.32e7.40 (m, 3H), 12.12 (br s,
1H, 3-H); 13C NMR (75 MHz, CDCl3)
9.9 (4-CH3), 29.2 (C(CH3)3), 51.7
d
(C(CH3)3),121.0 (C-4),125.1 (C-20,C-60),126.6 (C-40), 126.9 (C-5), 127.3
(C-100), 128.4 (C-200,C-600), 128.90 (C-300,C-500), 128.92 (C-400), 129.6 (C-
30,C-50), 140.5 (C-10), 153.2 (NeCO), 162.5 (C-2); IR (KBr) 3431, 3061,
1705 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 403 [45, (MþNa)þ], 381 [100,
(MþH)þ]. Anal. Calcd for C21H24N4OS (380.51): C, 66.29; H, 6.36; N,
14.72. Found: C, 66.58; H, 6.45; N 14.99.
4.3.19. (2Z)-2-(tert-Butylimino)-5-[[(1E,2E)-2-[2-(ethoxycarbonyl)
hydrazono]-1-methylpropylidene]amino]-3-phenyl-1,3,4-thiadiazole
(11b). Yellow solid; 0.322 g (80%); mp 160e162 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
1.33 (s, 9H, (CH3)3)), 1.36 (t, J¼7.1 Hz, 3H,
Supplementary data
COOCH2CH3), 2.11 (s, 3H, CH3), 2.55 (s, 3H, CH3), 4.33 (q, J¼7.1 Hz,
2H, COOCH2CH3), 7.13 (t, J¼7.5 Hz, 1H, 40-H), 7.34 (dd, J¼8.1, 7.5 Hz,
2H, 30,50-H), 7.99 (d, J¼8.1 Hz, 2H, 20,60-H), 8.03 (br s, 1H, NeH); 13C
1H and 13C NMR spectra of all compounds. Crystallographic
data, bond lengths, bond angles and structure refinement for
compound 11b are included. This material is available free of
charge via the Internet at http://pubs.acs.org. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2013.03.096. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
NMR (75 MHz, CDCl3)
d 9.6 (8-CH3), 14.5 (COOCH2CH3), 17.0 (7-
CH3), 28.0 (CH3)3), 54.2 (C(CH3)3), 62.5 (COOCH2CH3), 122.0 (C-
20,C-60),124.7 (C-40),128.2 (C-30,C-50),140.8 (C-10), 145.9 (C-2), 149.2
(C-8),* 149.3 (C-5),* 153.1 (CO), 171.0 (C-7); IR (KBr) 3442, 3237,
1702, 1633 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 425 [30, (MþNa)þ], 403
[100, (MþH)þ]. Anal. Calcd for C19H26N6O2S (402.52): C, 56.69; H,
6.51; N, 20.88. Found: C, 56.22; H, 6.65; N, 20.61. (*The assignment
may be interchanged).
References and notes
4.3.20. (2Z)-3-(4-Chlorophenyl)-2-(cyclohexylimino)-5-[[(1E,2E)-2-
[2-(ethoxycarbonyl)hydrazono]-1-methylpropylidene]amino]-1,3,4-
thiadiazole (11d). Yellowish oil; 0.356 g (77%); 1H NMR (300 MHz,
€
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Panjamurthy, K.; Kumar, S.; Nambiar, M.; Ramareddy, S. A.; Chiruvella, K. K.;
Raghavan, S. C. Eur. J. Med. Chem. 2011, 46, 2109e2116.
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d
1.35 (t, J¼7.1 Hz, 3H, COOCH2CH3), 1.30e1.64 (m, 6H,
200,300,400,500,600-Hax,400-Heq), 1.73e1.90 (m, 4H, 200,300,500,600-Heq), 2.10
(s, 3H, 8-CH3), 2.52 (s, 3H, 7-CH3), 2.70e2.80 (m, 1H, 100-H), 4.33 (q,
J¼7.1 Hz, 2H, COOCH2CH3), 7.30 (d, J¼9.1 Hz, 2H, 30,50-H), 7.95 (br s,
1H, NeH), 8.02 (d, J¼9.1 Hz, 2H, 20,60-H); 13C NMR (75 MHz, CDCl3)
d
9.6 (8-CH3),14.5 (COOCH2CH3),16.9 (7-CH3), 24.6 (C-300,C-500), 25.8
5. Gadad, A. K.; Mahajanshetti, C. S.; Nimbalkar, S.; Raichurkar, A. Eur. J. Med.
(C-400), 33.3 (C-200,C-600), 62.6 (COOCH2CH3), 68.2 (C-100), 122.2 (C-
20,C-60), 128.5 (C-30,C-50), 129.6 (C-40), 139.1 (C-10), 149.1 (C-5),*
149.8 (C-8),*,x 151.0 (C-2),x 153.0 (CO), 171.9 (C-7); IR (neat) 3442,
3237, 1705, 1630 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z 567/569 [15,
(MþNa)þ], 535/537 [100, (MþH)þ]. Anal. Calcd for C21H27ClN6O2S
(463.00): C, 54.48; H, 5.88; N, 18.15. Found: C, 54.56; H, 5.97; N,
18.48. (*,xThe assignment may be interchanged).
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20. Complete crystallographic data for compound 11b have been deposited with
the Cambridge Crystallographic Data Center as supplementary publication No.
CCDC 887831. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223 336 033,
e-mail: deposit@ccdc.cam.ac.uk.
4.3.21. (2Z)-3-(4-Chlorophenyl)-2-(tert-butylimino)-5-[[2-[2-(ethox-
ycarbonyl)hydrazino]-1-methylpropylidene]amino]-1,3,4-thiadiazole
(12e). Yellowish oil; 0.180 g (41%); 1H NMR (300 MHz, CDCl3)
d 1.29
(s, 9H, C(CH3)3), 1.32 (t, J¼7.1 Hz, 3H, COOCH2CH3), 1.45 (d, J¼6.7 Hz,
3H, 7-CH3), 1.88 (s, 3H, 8-CH3), 4.28 (q, J¼7.1 Hz, 2H, COOCH2CH3),
4.44 (qui, J¼6.7 Hz, 1H, 7-H), 5.37 (br d, J¼6.7 Hz, 1H, N6eH), 7.24
(d, J¼9.3 Hz, 2H, 30,50-H), 7.95 (br s, 1H, N10eH), 8.02 (d, J¼9.1 Hz,
2H, 20,60-H); 13C NMR (75 MHz, CDCl3)
d 13.0 (8-CH3), 14.5
(COOCH2CH3), 19.0 (7-CH3), 28.3 (C(CH3)3), 54.2 (C(CH3)3), 54.6 (C-
7), 62.0 (COOCH2CH3), 121.4 (C-20,C-60), 127.5 (C-40), 128.0 (C-30,C-
50), 140.3 (C-10), 144.1 (C-2), 147.6 (C-5), 151.9 (C-8), 154.0 (CO); IR
(neat) 3291, 1719, 1638, 1601 cmꢁ1; LCeMS (ESI, 1.65 eV) m/z
461/463 [100, (MþNa)þ], 439/441 [90, (MþH)þ]. Anal. Calcd for
C19H27ClN6O2S (438.97): C, 51.99; H, 6.20; N, 19.14. Found: C, 52.15;
H, 5.99; N, 19.03.
4.3.22. Reaction of compound 4g with AcOH. The compound 4g
(1.0 mmol) dissolved in dichloromethane (5 mL) and AcOH
(1.1 mmol) were refluxed for 5 h. The reaction mixture was washed
with water, dried with Na2SO4, concentrated in vacuum and puri-
fied with silica gel column chromatography using petroleum
ethereAcOEt (3:1) as eluent to give the isolated product 6.
4.3.23. 1-[[(1-(tert-Butylimino)carbonyl)](phenyl)amino]-4-methyl-5-
phenyl-2-thioxo-2,3-dihydro-1H-imidazole (6). White solid; 0.339 g