Reaction of 5-halo-1,2,3-thiadiazoles with aliphatic diamines. Synthesis and intramolecular cyclization of bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides

Article abstract of DOI:10.1039/b307693h

Bis[1,2,3]triazolo[1,5-f:5′,1′-b][1,3,6]thiadiazepine and [1,5-g:5′,1′-b][1,3,7]thiadiazocine ring systems have been synthesized from 5-halo-1,2,3-thiadiazoles and aliphatic diamines. We have found that the last step of the process is the cyclization of initially formed bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides. The structures of the intermediates and products were supported by different NMR spectroscopic methods (¹H coupled ¹³C NMR, 2D HETCOR, HMBC and 1D INADEQUATE experiments) and mass spectrometry. Differences in the reaction pathway for aliphatic and less nucleophilic aromatic diamines were determined.

Full text of DOI:10.1039/b307693h

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Reaction of 5-halo-1,2,3-thiadiazoles with aliphatic diamines.
Synthesis and intramolecular cyclization of bis(1,2,3-triazolyl-
1,2,3-thiadiazolyl)sulfides
Natalya N. Volkova,a Evgeniy V. Tarasov,a Mikhail I. Kodess,b Luc Van Meervelt,c
Wim Dehaen*c and Vasiliy A. Bakulev*a
a TOSLab, The Urals State Technical University, Ekaterinburg, Russia
b Institution of Organic Synthesis, The Urals Branch of Russian Academy of Sciences,
Ekaterinburg, Russia
c Department of Chemistry, University of Leuven, Heverlee (Leuven), B-3001, Belgium.
E-mail: wim.dehaen@chem.kuleuven.ac.be
Received 8th July 2003, Accepted 2nd September 2003
First published as an Advance Article on the web 13th October 2003
Bis[1,2,3]triazolo[1,5-f:5Ј,1Ј-b][1,3,6]thiadiazepine and [1,5-g:5Ј,1Ј-b][1,3,7]thiadiazocine ring systems have been
synthesized from 5-halo-1,2,3-thiadiazoles and aliphatic diamines. We have found that the last step of the process is
the cyclization of initially formed bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides. The structures of the intermediates
and products were supported by different NMR spectroscopic methods (1H coupled 13C NMR, 2D HETCOR,
HMBC and 1D INADEQUATE experiments) and mass spectrometry. Differences in the reaction pathway for
aliphatic and less nucleophilic aromatic diamines were determined.
diamine 2a gives a 1,3,6-thiadiazepine derivative. Moreover,
Introduction
intermediates different to those found for ortho-phenylene-
diamines1 were isolated. In order to study the mechanism, and
to know the scope and limitations of this process, various
aliphatic di- and polyamines 2a–f were allowed to react with
1,2,3-thiadiazoles 1a,b. Monoamines react with bromide 1a in a
sequence of reactions, including (1) halogen substitution, (2)
Dimroth rearrangement and (3) heteroarylation of the resulting
thiolate 4 with a second equivalent of 1a. The same sequence is
followed for the aliphatic di- and polyamines 2a–f (Scheme 2,
Table 1). In general, polar solvents and base promote all three
processes.3 Although the second amino group of ortho-phenyl-
enediamine is not nucleophilic enough to substitute a halogen
under these conditions, all amino groups of aliphatic amines
2a–f are sufficiently reactive. As a result, the reaction readily
In a previous paper1 we reported the synthesis of 3,1,5-
benzothiadiazepines from 5-halo-1,2,3-thiadiazoles and vicinal
aromatic diamines which proceeded via sulfide as the inter-
mediate (Scheme 1). In continuation of this work we were
interested in studying the behavior of aliphatic diamines
towards the same 1,2,3-thiadiazoles. In this paper we would like
to report our results in this field.
Scheme 1
Results
A. Reaction of 5-halo-1,2,3-thiadiazoles with aliphatic
diamines
Our preliminary investigations2 have shown that the reaction of
ethyl 5-bromo-1,2,3-thiadiazole-4-carboxylate 1a with ethylene-
Scheme 2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1
Amine 2
3
5
R
R1
R1
R2
a
a
g
OEt
a
g
OEt
OEt
NHMe
NHMe
NHMe
h
i
b
OEt
NHMe
OEt
NHMe
OEt
OEt
b
b
OEt
c
d
e
c
d
e
OEt
OEt
OEt
c
d
e
OEt
OEt
OEt
OEt
OEt
OEt
f
f
OEt
f
OEt
OEt
affords multiply substituted products 3, and further transform-
ation yields symmetrical compounds 5 with a (1,2,3-triazolyl-
1,2,3-thiadiazolyl)sulfide moiety on each amino group.
Thus, upon treatment of 5-halo-1,2,3-thiadiazoles 1a,b with
ethylenediamines 2b–d in refluxing ethanol in the presence of
triethylamine, bis-sulfides 5b–d,g were obtained in good yields.
The multistep process itself, is working simultaneously and
independently on several reaction centers, providing a plethora
of intermediates. Indeed, however many of them can be
detected in the reaction of polyamine with 5-halo-1,2,3-thia-
diazole, they all finally yield poly(1,2,3-triazolyl-1,2,3-thiadia-
zolyl)sulfide 5 under the conditions mentioned above. On the
other hand, changing the reaction conditions and the ratio of
starting materials allows intermediate products to be obtained.
Oligo(1,2,3-thiadiazolyl)amines 3a–f can be obtained when a
non polar solvent such as chloroform, is used. However, the
rearrangement cannot be completely excluded because of the
strong basic character of the oligoamine. This observation, and
the necessity of obtaining a product that is substituted at all
amine functions with a thiadiazole, prevents the use of excess
amine. The latter is usual in the synthesis of 5-(N-alkyl)amino-
1,2,3-thiadiazoles, in order to trap the hydrogen bromide gener-
ated.3a The use of triethylamine as acid scavenger promotes the
Dimroth rearrangement. Therefore, the best yields were about
40–60%. As compounds of type 3 may undergo further trans-
formation even in chloroform, the reaction mixture contains
some thiolates of type 4 that are the products of the Dimroth
rearrangement of one or both 1,2,3-thiadiazole rings. The thi-
olates were visible on TLC but were not isolated, as well as any
other intermediates on the way to sulfide 5. The reaction of 1a
with 1,2-diaminopropane 2b in chloroform was the only case
where we have isolated an intermediate product. When the reac-
tion mixture was diluted with ethanol the [3ϩ1] adduct 6 (in
Scheme 3) was obtained in 12% yield. The formation of 6 does
show that the 1,2,3-thiadiazole ring at C-1 of the 1,2-propane
rearranges faster and this suggests that sterical hindrance
reduces the rate of Dimroth rearrangement of 5-alkylamino-
1,2,3-thiadiazoles.
temperature, presence of base) and the ratio of the starting
materials. The nature of the starting materials, which influences
the comparative rates of substitution of bromothiadiazole 1a,
Dimroth rearrangement and substitution of bromothiadiazole
1a with the resulting thiol also plays a significant role. Indeed,
treatment of 1a with ethylenediamine 2a in refluxing ethanol
without an additional base already afforded a significant
amount of bis(sulfide) 5a. On the other hand, 1,4-diamino-
butane derivative 3d requires stronger conditions for rearrange-
ment. Compound 3d does not rearrange in ethanol with 1
equivalent of triethylamine at room temperature. Only after
heating, does further reaction to 5d take place. In the case of
tris(aminoethyl)amine 2e and DAB-(NH2)4 2f, even after pro-
longed heating in ethanol–triethylamine, TLC control reveals
remaining tris-substituted compounds 3e,f. In order to convert
all intermediates into final polysulfides 5e,f, heating at 80–100
ЊC in DMF was necessary.
B. Unsymmetrically substituted sulfides
We were interested in preparing compounds 3a,g in order to
find a route to differently substituted (containing ester and
amide groups at the same time) bis(sulfides) 5h,i. Compound 3a
was easily obtained and upon heating at reflux in ethanol with
methylamide 1b afforded 5h. However, when the methylamide
1b was treated with ethylenediamine in chloroform we could
not obtain the disubstituted product 3g. Various reaction con-
ditions (change of solvent, temperature, the sequence of
reagents) resulted in almost the same mixture of products and
in all experiments most of amide 1b remained unconverted.
Therefore, 1b is reactive enough to be substituted by thiolates,
but fails to react with amines. Traces of compound 3g were
detected in the 1H NMR spectrum, displaying the characteristic
signal for the ethylene protons at 3.5 ppm whereas the other
material appeared to be bis(sulfide) 5g and the products of
single or double Dimroth rearrangement of 3g. These experi-
ments did not allow isolation of 3g but bis(sulfide) 5i could be
obtained. Indeed, when the reaction mixture was separated
from starting methylamide 1b and refluxed in ethanol with ester
1a, a mixture with an approximate 1 : 2 ratio of 5g and 5i was
obtained. The latter was isolated by column chromatography. It
Thus, the structure of the main product in the reaction of
5-halo-1,2,3-thiadiazole with oligoamines depends upon a
variety of factors including reaction conditions (solvent,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
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Scheme 3
Table 2 Compounds 3,5,8: yields (%)/melting points (ЊC)
is obvious that in this case the rates of the Dimroth rearrange-
ment and the second substitution of halogen by thiol are much
higher than that of the initial substitution of halogen.
Diamine
3
5
8
2a
2b
60/158
84/209
—
C. Cyclization reactions
With the compounds 3, 5 and 6 in hand, the possibility of their
cyclization into seven-membered and larger rings was investi-
gated. The results of this study are shown in Scheme 3 and
Table 2. Firstly, we observed that 3a was converted into
bis[1,2,3]triazolo[1,5-f:5Ј,1Ј-b][1,3,6]thiadiazepine 7a in a yield
of about 20% on heating at reflux in ethanol in the presence of
triethylamine. Later, it was found that sulfides 5a–c and 6
afforded 1,3,6-thiadiazepines (1,3,7-thiadiazocines) 7a–c under
the same conditions. Compound 6 gave only 30% of cyclic
product 7b whereas bis(sulfides) 5a–c surprisingly provided the
best yields of thiadiazepines 7a,b or 1,3,7-thiadiazocine 7c. All
attempts to obtain nine-membered rings by cyclization of bis-
(sulfide) 5d were unsuccessful. It is evident that cyclization of 3
goes through a double Dimroth rearrangement followed by an
intramolecular substitution of bis(thiolate) 4. However, this
process is not common in the literature. Examples of bis(thiol)
cyclization to cyclic sulfides via acid-catalyzed dehydration4 or
42/107
73/123
—
2c
2j
47/91
59/125
18/173
—
—
86/130
2k
2m
2n
—
35/210
76/190
—
89/158a
87/140b
93/145b
a
5
desulfurization of initially formed disulfides with P(NMe2)3
were reported. Intramolecular cyclization of bis(sulfides) seems
to be even more remarkable and also more promising for the
preparation of 1,3,6-thiadiazepines. Ring formation of this
type was described for compounds containing two methyl-
sulfanyl groups either under demethylation conditions (sodium
methanethiolate in DMF or lithium in liquid ammonia)6 or by
using pyridinium chloride.7 In the case of our bis(sulfides) 5,
bis(1,2,3-thiadiazole-5-yl)disulfide 9 (Scheme 4) was detected
after work-up indicating the easily oxidized 5-mercapto-1,2,3-
thiadiazole to be one of the by-products. The other 1,2,3-thia-
diazole ring probably decomposed after being removed from
5 with a nucleophile (hydroxide, triethylamine). It is also
necessary to outline the role of the ester groups on both the
—
a Was isolated when thiadiazepine 7m was formed from 1a and 2m.
b These compounds were characterized earlier.1
1,2,3-triazole and 1,2,3-thiadiazole rings in the formation of
thiadiazepine 7. Bis(sulfide) 5g, when heated in DMF–Et3N
for several days was unchanged and compounds 5h,i with com-
bined ester/amide functions produce only sulfide bond cleavage
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
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Scheme 4
products, with virtually no cyclization. Thus, ester functions are
necessary at the heterocyclic ring for the intra- and inter-
molecular nucleophilic aromatic substitutions to occur.
D. Structural investigations
The structures of dithiadiazolyldiamines 3, bis(sulfides) 5,
adduct 6 and 1,3,6-thiadiazepines 7 were completely supported
by NMR spectroscopy. 13C NMR chemical shifts are summar-
ized in Table 3. We can clearly distinguish the signals due to the
1,2,3-triazole or the 1,2,3-thiadiazole rings, that are either con-
nected through S or NH, and their substituents. The 1H NMR
spectra of these compounds are rather simple, especially for
symmetrical structures and contain characteristic signals for
the methylene protons at 3.64 ppm for compounds 3, and at
4.6–5.2 ppm for methylene groups attached to the triazole
nitrogen (5,6,7). Signals of ester groups on a thiadiazole ring
occupy a downfield position (4.58 and 1.52 ppm for CH2
and CH3, respectively) as compared with the corresponding
resonances for triazole ethoxycarbonyl groups at 4.37 and 1.33
ppm. The signals in the 1H and 13C NMR spectra were assigned
based on the analysis of HETCOR and HMBC data. 2D
experiments were made to reveal the 1JCH connectivities, but in
the case of bis(sulfides) 5, due to the lack of protons these data
were not sufficient to make a complete assignment. Therefore, a
1D INADEQUATE experiment was performed for compounds
5b and 5c because of their high solubility, and the carbon–
carbon coupling constants were determined. With the help of
this information we were able to assign these groups of signals
to either the 1,2,3-triazole or 1,2,3-thiadiazole ring. However it
was still impossible to establish the difference between similar
heterocyclic carbons in unsymmetrical bis(sulfide) 5b. Spin–
spin coupling constants between 13C nuclei for triazole and
thiadiazole rings which are of interest and are not readily
available in the literature8 are presented in Table 4.
Mass spectra of bis(sulfides) 5 were taken using the electro-
spray technique. It is worth knowing that the EI-MS technique,
though not allowing us to obtain molecular ions of bis(sulfides)
5a–c, showed the formation of corresponding heterocycles 7
during gas phase fragmentation. The most intensive peaks of
the electron impact MS of 5 corresponded to the molecular ion
following fragmentation of thiadiazepine(azocine). Interest-
ingly, the fragmentation pattern of 5d does not contain peaks
corresponding to the appropriate thiadiazonine.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
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Table 4 13C–13C coupling constants for compounds 4b,c measured in
1D INADEQUATE experiment
different intermediates 5 and 8. As proof of this supposition,
isolated 5m was transformed into 7m on refluxing in ethanol
with Et3N in 79% yield. Unexpectedly, 4-methylphenylene-
diamine 2m undergoes nucleophilic substitution of both amino
groups more readily then diamines 2k and 2j. So far, we are not
able to explain this fact. While diamines 2j,k produce only 18–
35% of bis(sulfides) 5j,k, and the other products were found to
be monosulfides 8 and even 5-arylamino-1,2,3-thiadiazoles 12,
the yield of 5m is remarkably high. The formation of bis-
(sulfide) 5m occurred even when starting materials 1a : 2m were
combined in a 2 : 1 ratio. In this case, when the reaction is over,
one can see by TLC control the unconverted diamine 2m along
with 5m. Moreover, when thiadiazepine 7m was formed from 1a
and 2m, bis(1,2,3-thiadiazolyl) substituted phenylenediamine
3m was unexpectedly obtained along with disulfide 9 as a by-
product. Compound 3m could be generated in this reaction
either by direct heteroarylation of phenylenediamine or by
transformation of sulfide 8m for which the transposition of
thiadiazole ring from sulfur to amino group (Smiles-type
rearrangement), followed by Dimroth rearrangement could be
supposed. We tried to obtain bis(substituted) 3m by heteroaryl-
ation of phenylenediamine 2m but the only product was the
monosubstituted compound 12m. On the contrary, treatment
of sulfide 8m with NaH in dimethyl formamide easily afforded
3m in more than 70% yield. The analogous product 3n was
obtained from sulfide 8n. Compounds 3m,n also afford
cyclization products 7m,n in a yield of 25–30%.
Triazole
Thiadiazole
Compound
1JC5–C4
1JC4–CO
1JC5–C4
1JC4–CO
4b
4c
73.6
73.9
73.4
95.2
94.7
95.0
90.2
90.7
91.0
66.3
66.9
66.8
The parent heterocyclic system 9,10-dihydrobis[1,2,3]tri-
azolo[1,5-f:5Ј,1Ј-b][1,3,6]thiadiazepine 11 was obtained from
ester 7a by saponification followed by decarboxylation of
diacid 10 (Scheme 5). Compound 11 was subjected to crystallo-
graphic analysis. The compound shows no molecular symmetry.
The thiadiazepine ring occurs in a boat conformation with
atoms S1 and C4 at the opposite side of the fused triazole rings
with respect to the best plane through the seven-membered
ring. This best plane makes an angle of 26.1(1)Њ and 13.0(1)Њ
with the best planes through the five-membered rings. Both tri-
azole rings make an angle of 49.0(1)Њ to each other. (Fig. 1).
Conclusion
In conclusion, various vicinal diamines react with 5-halo-1,2,3-
thiadiazoles to form the bis[1,2,3]triazolo[1,5-b:5Ј,1Ј-f][1,3,6]-
thiadiazepine system 7. The mechanism of the transformation
depends upon the reactivity of the diamine. This was proved
by isolation of the intermediates shown in Table 2. Thus, for
aromatic diamines sulfide 8 is initially formed, and electron-
rich phenylenediamines also produce bis(sulfides) 5. Highly
reactive aliphatic diamines in polar basic media gave com-
pounds 5 exclusively, while the use of nonpolar solvents
afforded bis(substituted) products 3. The intermediates 3,5,8
underwent transformation into seven (or eight)-membered
rings.
Scheme 5
Experimental
Materials and methods
Fig. 1 Molecular structure of parent heterocycle 11.
1H and 13C NMR spectra were recorded respectively on a
Bruker WM-250, Bruker WM-300 and Bruker DRX-400 in
either (CD3)2SO or CDCl3 solutions. 2D NMR experiments
were carried out using standard pulse sequences from the
Bruker NMR Suite 2.6 software. ESI-MS spectra were scanned
on a Micromass Quatro II (infusion of 50 ìl MeOH–CH2Cl2 –
NH4OAc(0.1 M in MeOH) with Harvard pump, model 11),
electron impact mass spectra were obtained on a Varian MAT
311 machine. Products were analyzed by TLC on DC-Plastik-
folien Kieselgel 60 F 254 plates. Melting points were taken in
open capillaries and are uncorrected. Commercial samples of
amines 2a–f,k–n were used. 4-Ethoxyphenylenediamine 2j was
obtained by reduction of 2-nitro-4-ethoxyaniline with hydra-
zine over palladium.
E. Reactions with aromatic diamines
For aromatic diamines, the main route to 3,1,5-benzo-
thiadiazepine 7 proceeds via sulfide 8, but for the reaction of
5-bromo-1,2,3-thiadiazole 1a with phenylenediamines contain-
ing electron rich functions 2j–m, the same pathway as for the
aliphatic oligoamines was observed. In this case, bis(sulfides) of
type 5 were detected among the intermediates. It was found that
in ethanol solution in the presence of triethylamine at room
temperature, with a 1 : 4 ratio of starting compounds 2j–m : 1a,
both amino groups were substituted and products of type 5j–m
were formed. The same conditions for 2n produce only sulfide
8n. Analogously to compounds 5a–c, the EI-MS spectra of
bis(sulfides) 5j–m revealed the transformation into thiadiaz-
epines 7j–m in the gas phase. At the same time, treatment of
initially isolated 5-amino-1,2,3-thiadiazole 12j–m with 1 eq.
bromoester 1a in basic media at room temperature afforded
sulfides 8j–m in good yields. When thiadiazepines 7 were
formed in refluxing ethanol–triethylamine, both compounds 5
and 8 were detected as intermediates in the reaction mixture by
means of TLC analysis, although both of them disappeared to
the extent that the thiadiazepine ring was formed. We may
argue that the reaction may simultaneously proceed via two
Diethyl 5,5Ј-[ethane-1,2-diyldi(imino)]bis(1,2,3-thiadiazole-4-
carboxylate) 3a. A solution of bromoester 1a (0.5 g, 2.1 mmol)
and 0.75 equivalents of ethylenediamine 2a (0.1 g) in chloro-
form (5 mL) was refluxed for 3 hours. After removal of the
solvent, the residue was dissolved in ethanol acidified with
hydrochloric acid, and the precipitated product was filtered off
and crystallized from ethanol yielding 0.47 g (60%) of white
crystals, mp 148 ЊC. 1H NMR δH (CDCl3, 400 MHz): 1.44 (6H,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
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t, J = 7.2 Hz, 2CH3), 3.64 (4H, m, CH2CH2), 4.45 (4H, q,
J = 7.2 Hz, 2OCH2), 8.06 (2H, t, 2NH). 13C NMR δC (CDCl3,
100 MHz): 14.39 (qt, J = 127.4, 2.7 Hz, 2CH3), 50.13 (tdt,
J = 139.9, 3.2, 3.2 Hz, CH2CH2), 61.62 (tq, J = 148.3, 4.4 Hz,
2OCH2), 132.39 (d, J = 1.5 Hz, C4-thiadiazole), 163.60
(t, J = 3.4 Hz, CO), 171.12 (td, J = 4.6, 2.6 Hz, C5-thiadiazole).
EIMS m/z (rel. int.): 372 (Mϩ,9), 190 (31). Anal. Calcd for
C12H16N6O4S2: C, 38.70; H, 4.33; N, 22.57; S, 17.22. Found C,
38.73; H, 4.30; N, 22.53; S, 17.29%.
Diethyl
5,5Ј-[(4-methyl-1,2-phenylene)di(imino)]bis(1,2,3-
thiadiazole-4-carboxylate) 3m. Sulfide 8m (0.15g, 0.34 mmol)
was dissolved in dry DMF under stirring and cooling on the ice
bath. Sodium hydride (0.1 g, 60% dispersion in mineral oil)
was added and reaction was stirred for 1 hour at room temper-
ature and quenched with water. Upon acidification, the product
precipitated and was filtered off and washed with ethanol. Yield
1
74%, mp 138 ЊC. H NMR δH (DMSO-D6ϩCCl4, 250 MHz):
1.40 (3H, t, J = 7.0 Hz, CH3), 1.41 (3H, t, J = 7.0 Hz, CH3),
2.41 (3H, s, CH3), 4.42 (2H, q, J = 7.0 Hz, CH2), 4.43 (2H, q,
J = 7.0 Hz, CH2), 7.21 (1H, d, J = 7.6 Hz, C3H), 7.34 (1H, s,
C1H), 7.43 (1H, d, J = 8.2 Hz, C4H), 9.93 (1H, s, NH), 10.04
(1H, s, NH). EIMS m/z (rel. int.): 434 (Mϩ,20). Anal. Calcd for
C17H18N6S2O4: C, 46.99; H, 4.18; N, 19.34. Found C, 46.91; H,
4.22; N, 19.30%.
Diethyl 5,5Ј-[propane-1,2-diyldi(imino)]bis(1,2,3-thiadiazole-
4-carboxylate) 3b. A solution of bromoester 1a (0.5 g,
2.1 mmol) and 0.75 equivalents of 1,2-propylenediamine 2b
(0.12 g) in chloroform (5 mL) was refluxed for 3 hours. The
solvent was evaporated and the crude product was purified by
column chromatography using chloroform as the eluent. Yield
1
Diethyl 5,5Ј-[(1,2-phenylene)di(imino)]bis(1,2,3-thiadiazole-4-
carboxylate) 3n. Prepared from 8n as described for 3m. Yield
79%, mp 132 ЊC. H NMR δH (DMSO-D6ϩCCl4, 250 MHz):
1.41 (6H, t, J = 7.0 Hz, 2CH3), 4.43 (4H, q, J = 7.0 Hz, 2CH2),
7.41–7.47 (2H, m, CH-arom.), 7.53–7.59 (2H, m, CH-arom),
10.07 (2H, s, 2NH). EIMS m/z (rel. int.): 420(Mϩ,31). Anal.
Calcd for C16H16N6S2O4: C, 45.71; H, 3.84; N, 19.99. Found C,
45.76; H, 3.81; N, 20.03%.
42%, mp 107 ЊC. H NMR δH (CDCl3, 400 MHz): 1.42–1.48
(9H, m, 3CH3), 3.50 (3H, m, CH ϩ CH2), 4.45 (4H, m, 2OCH2),
7.86 (1H, d, J = 7.2 Hz, NHCH), 8.07 (1H, t, J = 5.2 Hz,
NHCH2). EIMS m/z (rel. int.): 387 (MHϩ,100). Anal. Calcd for
C13H18N6O4S2: C, 40.40; H, 4.69; N, 21.75. Found C, 40.37; H,
4.70; N, 21.80%.
1
Diethyl 5,5Ј-[propane-1,3-diyldi(imino)]bis(1,2,3-thiadiazole-
4-carboxylate) 3c. Prepared from 1a and 2c as described for 3b.
5,5Ј-{Ethane-1,2-diylbis[(4-ethoxycarbonyl-1H-1,2,3-triazole-
1,5-diyl)sulfanyl]}bis(4- ethoxycarbonyl-1,2,3-thiadiazole) 5a. To
a solution of bromoester 1a (0.5 g, 2.1 mmol) and ethylene-
diamine 2a (0.03 g, 0.52 mmol) in ethanol (30 mL), triethyl-
amine (0.3 mL, 2.1 mmol) was added and the mixture was
refluxed for 5 hours. The product began to precipitate from the
boiling solution and after cooling was filtered off and crystal-
lized from ethanol yielding 0.30 g (84%) of white crystals, mp
209 ЊC. 1H NMR δH (CDCl3, 400 MHz): 1.33 (6H, t, J = 7.1 Hz,
2CH3-triaz.), 1.51 (6H, t, J = 7.1 Hz, 2CH3-thiadiaz.), 4.38 (4H,
q, J = 7.1 Hz, 2OCH2-triaz.), 4.57 (4H, q, J = 7.1 Hz, 2OCH2-
thiadiaz.), 5.18 (4H, s, CH2CH2). 13C NMR δC (CDCl3,
100 MHz): 14.04 (qt, J = 127.6, 2.7 Hz, 2CH3-triaz.), 14.31 (qt,
J = 127.6, 2.7 Hz, 2CH3-thiadiaz.), 47.69 (tt, J = 146.8, 3.6 Hz,
CH2CH2), 62.29 (tq, J = 148.8, 4.4 Hz, 2OCH2-triaz.), 62.93
(tq, J = 149.0, 4.4 Hz, 2OCH2-thiadiaz.), 131.95 (t, J = 1.1 Hz,
C5-triaz.), 141.91 (s, C4-triaz.), 147.26 (s, C4-thiadiaz.), 159.04
(t, J = 3.2 Hz, CO-triaz.), 159.68 (s, C5-thiadiaz.), 160.54 (t,
J 3.2 Hz, CO-thiadiaz.). ESI-MS 685 (MHϩ). EIMS m/z
(rel. int.): 529(1), 370(28), 339(38), 240(50), 199(32), 157(60),
114(55), 85(100). Anal. Calcd for C22H24N10O8S4: C, 38.59; H,
3.53; N, 20.46; S, 18.73. Found C, 38.62; H, 3.56; N, 20.74; S,
18.51%.
1
Yield 47%, mp 91 ЊC. H NMR δH (CDCl3, 250 MHz): 1.45
(6H, t, J = 7.1 Hz, 2CH3), 2.15 (2H, m, J = 6.7 Hz, CH2 centr.),
3.43 (4H, m, J = 6.1 Hz, 2CH2), 4.46 (4H, q, J = 7.1 Hz, 2CH2
ester), 7.93 (2H, m, 2NH). EIMS m/z (rel. int.): 386 (Mϩ, 4), 169
(100). Anal. Calcd for C13H18N6O4S2: C, 40.40; H, 4.69; N,
21.75. Found C, 40.33; H, 4.68; N, 21.72%.
Diethyl 5,5Ј-[butane-1,4-diyldi(imino)]bis(1,2,3-thiadiazole-4-
carboxylate) 3d. Prepared from 1a and 2d as described for 3a.
1
Yield 53%, mp 106 ЊC. H NMR δH (CDCl3, 250 MHz): 1.84
(4H, m, 2CH2), 3.34 (4H, m, 2NHCH2), 4.45 (4H, q, J = 7.0 Hz,
2OCH2), 7.88 (2H, m, 2NH).11.45 (6H, t, J = 7.0 Hz, 2CH3),
EIMS m/z (rel. int.): 400 (Mϩ, 0.8), 203 (9), 126 (20). Anal.
Calcd for C14H20N6O4S2: C, 41.99; H, 5.03; N, 20.98. Found C,
42.05; H, 5.09; N, 20.89%.
NЈ-4-Ethoxycarbonyl-1,2,3-thiadiazol-5-yl-N,N-bis[2-(4-
ethoxycarbonyl-1,2,3-thiadiazol-5-ylamino)ethyl]ethane-1,2-
diamine 3e. To a solution of 1a (1 g, 4.22 mmol) in ethanol
(50 mL), tris(2-aminoethyl)amine 2e (0.21 g, 1.40 mmol) was
added and the reaction mixture was refluxed overnight. After
cooling, the precipitate was filtered off and crystallized from
ethanol. Yield 44%, mp 144 ЊC. 1H NMR δH (CDCl3, 300
MHz): 1.35 (9H, t, J = 7.3, 3CH3), 2.93 (6H, m, 3NCH2), 3.32
(6H, m, 3NHCH2), 4.28 (6H, q, J = 7.3 Hz, 3OCH2), 8.16 (3H,
m, 3NH). ESI-MS 615 (MHϩ). Anal. Calcd for C21H30N10S3O6:
C, 41.03; H, 4.92; N, 22.79; S, 15.65. Found C, 40.97; H, 4.90;
N, 22.83; S, 15.56%.
5,5Ј-{Propane-1,2-diylbis[(4-ethoxycarbonyl-1H-1,2,3-tri-
azole-1,5-diyl)sulfanyl]}bis(4-ethoxycarbonyl-1,2,3-thiadiazole)
5b. Prepared from 1a and 2b as described for 5a. Yield 73%, mp
1
123 ЊC. H NMR δH (CDCl3, 400 MHz): 1.315 (3H, t, J = 7.1
Hz, CH3-triaz.), 1.317 (3H, t, J = 7.1 Hz, CH3-triaz.), 1.519
(3H, t, J = 7.1 Hz, CH3-thiadiaz.), 1.521 (3H, t, J = 7.1 Hz,
CH3-thiadiaz.), 1.77 (3H, d, J = 6.8 Hz, CH3), 4.366 (2H, q,
J = 7.1 Hz, OCH2-triaz.), 4.371 (2H, q, J = 7.1 Hz, OCH2-
triaz.), 4.581 (2H, q, J = 7.1 Hz, OCH2-thiadiaz.), 4.585 (2H, q,
J = 7.1 Hz, OCH2-thiadiaz.), 4.88, 5.43 (2H, AB-syst., J = 14.3,
Tetra-[4-ethoxycarbonyl-([1,2,3]-thiadiazol-5-yl)]-DAB-Am-4
3f. To a solution of 1a (1 g, 4.22 mmol) in 50 mL of ethanol
DAB-(NH2)4, 2f (0.44 g, 1.05 mmol, 75% reagent) was added
and the reaction mixture was refluxed for 2 days. The solvent
was removed, chloroform added and precipitate was filtered
off and dried in a vacuum over P2O5. Yield 25%, mp 188 ЊC.
1H NMR δH (DMSO-D6, 400 MHz): 1.33 (12H, t, J = 7.1
Hz, 4CH3), 1.65 (4H, m, NCH2CH2CH2CH2N), 2.00 (8H, m,
NHCH2CH2CH2N), 3.11 (12H, m, 6NCH2), 3.35 (8H, m,
4NHCH2), 4.35 (8H, q, J = 7.1 Hz, 4OCH2), 8.44 (4H, t, J = 5.4
Hz, 4NH). 13C NMR δC (DMSO-D6, 100 MHz): 14.28 (CH3),
21.90, 48.98, 49.51, 51.20, 60.44 (OCH2), 130.96 (C4-thia-
diazole), 162.21 (CO), 170.53 (C5-thiadiazole). Anal. Calcd for
C36H56N14S4O8: C, 45.94; H, 6.00; N, 20.83. Found C, 45.81; H,
6.07; N, 20.69%.
9.9, 4.0 Hz, CH2), 5.77 (1H, dqd, J = 9.9, 6.8, 4.0 Hz, CH). 13
C
NMR δC (CDCl3, 100 MHz): 13.95 (qt, J = 127.6, 3.6 Hz, CH3-
triaz.), 13.97 (qt, J = 127.5, 2.6 CH3-triaz.), 14.25 (qt J = 127.6,
2.7 Hz, 2CH3-thiadiaz.), 19.94 (qdt, J = 130.5, 3.9, 2.0 Hz,
CH3), 51.84 (tt, J = 145.7, 5.9Hz, CH2CH), 54.76 (dm,
J = 145.5 Hz, CH), 62.20 (tq, J = 148.6, 4.9 Hz, OCH2-triaz.),
62.25 (tq, J = 149.0, 4.6 Hz, OCH2-triaz.), 62.86 (tq J = 149.1,
4.5 Hz, 2OCH2-thiadiaz.), 131.40 (d, J = 1.8 Hz, C5-triaz.CH),
132.02 (t, J = 2.1 Hz, C5-triaz.CH2), 141.60 (s, C4-triaz.),
141.81 (s, C4-triaz.), 147.09 (s, C4-thiadiaz.), 147.18 (s,
C4-thiadiaz.), 158.88 (t, J = 3.2 Hz, CO-triaz.), 158.96 (t,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
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J = 3.2 Hz, CO-triaz.), 159.68 (s, C5-thiadiaz.), 159.99 (s,
C5-thiadiaz.), 160.48 (t, J = 3.4 Hz, CO-thiadiaz.), 160.53 (t,
J = 3.2 Hz, CO-thiadiaz.). ESI-MS 699 (MHϩ). EIMS m/z
(rel. int.): 514(1), 384(18), 352(12), 318(14), 235(43), 157(58),
129(37), 116(45), 85(100). Anal. Calcd for C23H26N10O8S4: C,
39.53; H, 3.75; N, 20.04. Found C, 39.59; H, 3.78; N, 20.01%.
Calcd for C56H72N22O16S8: C, 42.96; H, 4.63; N, 19.68. Found C,
42.76; H, 4.39; N, 19.73%.
5,5Ј-{Ethane-1,2-diylbis[(4-(N-methylcarbamoyl)-1H-1,2,3-
triazole-1,5-diyl)sulfanyl]}bis(4-(N-methylcarbamoyl)-1,2,3-thia-
diazole) 5g. Prepared from 1b and 2a as described for 5a. Yield
45%, mp 236 ЊC. 1H NMR δH (DMSO-D6 ϩ CCl4, 250 MHz):
2.76 (6H, d, J = 4.0 Hz, 2CH3), 2.91 (6H, d, J = 4.0 Hz, 2CH3),
5.04 (4H, s, 2CH2), 8.54 (2H, q, J = 4.3 Hz, 2NH), 8.94 (2H, q,
J = 4.0 Hz, 2NH). ESI-MS 625 (Mϩ). EIMS m/z (rel. int.):
300(1), 288(2), 231(2), 203(22), 174(6), 146(9), 114(6), 98(7),
86(24), 74(14), 58(100). Anal. Calcd for C18H20N14O4S4: C,
34.61; H, 3.23; N, 31.39. Found C, 36.65; H, 3.20; N, 31.42%.
5,5Ј-{Propane-1,3-diylbis[(4-ethoxycarbonyl-1H-1,2,3-tri-
azole-1,5-diyl)sulfanyl]}bis(4-ethoxycarbonyl-1,2,3-thiadiazole)
5c. Prepared from 1a and 2c as described for 5a. Yield 59%, mp
125 ЊC. 1H NMR δH (CDCl3, 400 MHz): 1.33 (6H, t, J = 7.1 Hz,
2CH3-triaz.), 1.52 (6H, t, J = 7.1 Hz, 2CH3-thiadiaz.), 2.66 (2H,
quintet, J = 6.7 Hz, CH2CH2CH2), 4.39 (4H, q, J = 7.1 Hz,
2OCH2-triaz.), 4.58 (4H, q, J = 7.1 Hz, 2OCH2-thiadiaz.), 4.64
(4H, t, J = 6.7 Hz, CH2CH2CH2). 13C NMR δC (CDCl3, 100
MHz): 14.01 (qt, J = 127.5, 2.6 Hz, 2CH3-triaz.), 14.26 (qt,
J = 127.6, 2.7 Hz, 2CH3-thiadiaz.), 29.35 (tq, J = 132.3, 3.0 Hz,
CH2CH2CH2), 46.05 (tt, J = 143.9, 4.5 Hz, CH2CH2CH2), 62.18
(tq, J = 148.7, 4.4 Hz, OCH2-triaz.), 62.88 (tq, J = 149.1, 4.4
Hz, OCH2-thiadiaz.), 131.06 (t, J = 2.4 Hz, C5-triaz.), 141.94
(s, C4-triaz.), 147.12 (s, C4-thiadiaz.), 159.13 (t, J = 3.4 Hz,
CO-triaz.), 160.29 (s, C5-thiadiaz.), 160.53 (t, J = 3.2 Hz,
CO-thiadiaz.). ESI-MS 699 (MHϩ). EIMS m/z (rel. int.):
384(18), 352(10), 318(18), 245(40), 218(33), 169(44), 130(30),
116(36), 85(100). Anal. Calcd for C23H26N10O8S4: C, 39.53; H,
3.75; N, 20.04. Found C, 39.54; H, 3.71; N, 20.29%.
5,5Ј-{Ethane-1,2-diylbis[(4-ethoxycarbonyl-1H-1,2,3-triazole-
1,5-diyl)sulfanyl]}bis(4-(N-methylcarbamoyl)-1,2,3-thiadiazole)
5h. To a solution of 3a (0.25 g, 0.67 mmol) and 5-chloro-1,2,3-
thiadiazole 1b (0.24 g, 1.30 mmol) in ethanol (30 mL), triethyl-
amine (0.1 mL, 0.70 mmol) was added and the mixture was
heated at reflux for 5 hours. After cooling, the product was
filtered off and crystallized from ethanol yielding 0.22 g (50%)
of 5h, mp 216 ЊC. 1H NMR δH (CDCl3, 400 MHz): 1.32
(6H, t, J = 7.2 Hz, 2CH3), 3.10 (6H, d, J = 5.1 Hz, 2NHCH3),
4.38 (4H, q, J = 7.2 Hz, 2OCH2), 5.10 (4H, s, 2CH2), 7.41 (2H,
q, J = 5.1 Hz, 2NH). ESI-MS 655 (Mϩ). EIMS m/z (rel. int.):
402 (1), 370 (22), 338 (27), 240 (22), 199 (20), 147 (42). Anal.
Calcd for C20H22N12O6S4: C, 36.69; H, 3.39; N, 25.67. Found C,
36.74; H, 3.35; N, 25.65%.
5,5Ј-{Butane-1,4-diylbis[(4-ethoxycarbonyl-1H-1,2,3-triazole-
1,5-diyl)sulfanyl]}bis(4-ethoxycarbonyl-1,2,3-thiadiazole)
5d.
Prepared from 1a and 2d as described for 5a. Yield 91%, mp 178
5,5Ј-{Ethane-1,2-diylbis[(4-(N-methylcarbamoyl)-1H-1,2,3-
triazole-1,5-diyl)sulfanyl]}bis(4-ethoxycarbonyl-1,2,3-thiadiaz-
ole) 5i. A solution of chloroamide 1b (1.0 g, 5.6 mmol) and
ethylenediamine 2a (0.25 g, 4.2 mmol) in chloroform (5 mL)
was heated at reflux for 3 hours. The reaction mixture was
diluted with ethanol, acidified with hydrochloric acid, and the
precipitate was filtered off, suspended in ethanol and refluxed
for 5 hours with bromoester 1a (1.33 g 5.6 mmol) and triethyl-
amine (0.8 mL, 5.6 mmol). After cooling, the precipitate was
filtered off and appeared to be a mixture of 5i and 5g (64 : 36)
1
ЊC. H NMR δH (CDCl3, 300 MHz): 1.34 (6H, t, J = 7.1 Hz,
2CH3), 1.51 (6H, t, J = 7.1 Hz, 2CH3), 1.97 (4H, m, 2CH2), 4.40
(4H, q, J = 7.1 Hz, 2COCH2), 4.54 (4H, m, 2NCH2), 4.58 (4H,
q, J = 7.1 Hz, 2COCH2). ESI-MS 713 (MHϩ). EIMS m/z
(rel. int.): 456(2), 428(3), 395(9), 256(100), 182(19), 70(17),
55(67). Anal. Calcd for C24H28N10O8S4: C, 40.44; H, 3.96; N,
19.65; S, 17.99. Found C, 40.38; H, 4.00; N, 17.93; S, 17.38%.
N,NЈ,NЉ-Tris{4-ethoxycarbonyl-5-[(4-ethoxycarbonyl-1,2,3-
thiadiazol-5-yl)sulfanyl]-1H-1,2,3-triazol-1-yl}aminoethylamine
5e. To a solution of bromoester 1a (1.0 g, 4.2 mmol) and tris-
(2-aminoethyl)amine 2e (0.11 g, 0.70 mmol) in DMF (15 mL),
triethylamine (0.6 mL, 4.2 mmol) was added and the mixture
was heated at 90 ЊC for 2 days. Then, the mixture was diluted
with water, the product filtered off and purified by column
chromatography with CH2Cl2–ethanol 10 : 1 yielding 0.58 g
(76%) of sulfide 5e, mp 114 ЊC. 1H NMR δH (CDCl3, 400 MHz):
1.30 (9H, m, 3CH3-triaz.), 1.48 (9H, m, 3CH3-thiadiaz.), 3.14
(6H, m, 3NCH2), 4.37 (6H, m, 3OCH2-triaz.), 4.52 (12H, m,
3OCH2-thiadiaz. ϩ 3N-triaz.-CH2). 13C NMR δC (CDCl3, 100
MHz): 13.98 (CH3-triaz.), 14.24 (CH3-thiadiaz.), 46.52
(NCH2CH2), 53.22 (NCH2CH2), 62.05 (OCH2-triaz.), 62.83
(OCH2-thiadiaz.), 131.31 (C5-triaz.), 141.44 (C4-triaz.), 147.05
(C4-thiadiaz.), 159.33 (CO-triaz.), 160.57 (CO-thiadiaz. ϩ C5-
thiadiaz.). ESI-MS 1083 (Mϩ). Anal. Calcd for C36H42N16O12S6:
C, 39.92; H, 3.91; N, 20.69. Found C, 39.89; H, 3.90; N,
20.71%.
1
according to H NMR data. The mixture was separated by
means of column chromatography using CH2Cl2–EtOH 10 : 1
as the eluent: d 0.4 gave 0.59 g (32%) of 5i, mp 220 ЊC. 1H NMR
δH (CDCl3, 400 MHz): 1.50 (6H, t, J = 7.2 Hz, 2CH3), 2.99 (6H,
d, J = 5.2 Hz, 2NHCH3), 4.57 (4H, q, J = 7.2 Hz, 2OCH2), 5.10
(4H, s, 2CH2), 7.12 (2H, q, J = 5.2 Hz, 2NH). Anal. Calcd for
C20H22N12O6S4: C, 36.69; H, 3.39; N, 25.67. Found C, 36.64; H,
3.43; N, 25.60%.
5,5Ј-{4-Ethoxy-1,2-phenylenebis[(4-methyl-1H-1,2,3-triazole-
1,5-diyl)sulfanyl]}bis(4-methyl-1,2,3-thiadiazole) 5j. Bromoester
1a (1.0 g, 4.2 mmol) and 4-ethoxy-1,2-phenylenediamine 2j
(0.16 g, 1.0 mmol) were suspended in ethanol (30 mL) triethyl-
amine (0.6 mL, 4.2 mmol) was added and the mixture was
stirred at room temperature for 2 days. The precipitate was fil-
tered off and crystallized from ethanol yielding 0.15 g (18%) of
5j, mp 173 ЊC. 1H NMR δH (DMSO-D6 ϩ CCl4, 400 MHz): 1.22
(6H, t, J = 7.1 Hz, 2CH3), 1.43 (9H, t, J = 7.0 Hz, 3CH3), 4.18
(2H, q, J = 7.0 Hz, CH2), 4.29 (2H, q, J = 7.1 Hz, OCH2), 4.30
(2H, q, J = 7.1 Hz, OCH2), 4.46 (2H, q, J = 7.1 Hz, OCH2), 4.47
(2H, q, J = 7.1 Hz, OCH2), 7.39 (1H, dd, J = 8.9, 2.8 Hz, C5H),
7.77 (1H, d, J = 2.8 Hz, C3H), 7.97 (1H, d, J = 8.9 Hz, C6H).
ESI-MS 777 (MHϩ). EIMS m/z (rel. int.): 530 (2), 502 (9), 430
(11), 330 (36), 302 (60), 258 (86), 229 (89), 202 (100). Anal.
Calcd for C28H28N10O9S4: C, 43.29; H, 3.63; N, 18.03. Found C,
43.34; H, 3.70; N, 18.10%.
DAB-dendr-([4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl]-NH)4
5f. Prepared from 1a and 2f as described for 5e. Yield 61%, mp
1
102 ЊC. H NMR δH (CDCl3, 400 MHz): 1.30 (12H, m, 4CH3-
triaz.), 1.39 (4H, m, NCH2CH2CH2CH2N), 1.49 (12H, t,
J = 7.1 Hz, 4CH3-thiadiaz.), 2.02 (8H, m, NHCH2CH2CH2N),
2.44 (12H, m, 6NCH2), 4.36 (8H, m, 4OCH2-triaz.), 4.53 (8H,
q, J = 7.1 Hz, 4OCH2-thiadiaz.), 4.62 (8H, m, 4N-triaz.-CH2).
13C NMR δC (CDCl3, 100 MHz): 14.07 (CH3-triaz.), 14.32
(CH3-thiadiaz.), 24.40, 27.88, 47.55, 50.48, 53.44, 62.07 (OCH2-
triaz.), 62.82 (OCH2-thiadiaz.), 130.83 (C5-triaz.), 141.59
(C4-triaz.), 146.88 (C4-thiadiaz.), 159.38 (CO-triaz.), 160.68
(CO-thiadiaz. ϩ C5-thiadiaz.). ESI-MS 1566 (MHϩ). Anal.
5,5Ј-{4,5-Dimethyl-1,2-phenylenebis[(4-methyl-1H-1,2,3-tri-
azole-1,5-diyl)sulfanyl]}bis(4-methyl-1,2,3-thiadiazole) 5k. Pre-
pared from 1a and 2k as described for 5j. Yield 35%, mp
210 ЊC. 1H NMR δH (DMSO-D6 ϩ CCl4, 250 MHz): 1.21 (6H,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
4036

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t, J = 7.0 Hz, 2CH3), 1.43 (6H, t, J = 7.0 Hz, 2CH3), 2.43 (6H, s,
2CH3), 4.29 (4H, q, J = 7.0 Hz, 2CH2), 4.47 (4H, q, J = 7.3 Hz,
2CH2), 7.84 (2H, s, 2CH). 13C NMR δC (CDCl3, 75 MHz): 14.0,
(2CH3-triaz.), 14.3, (2CH3-thiadiaz.), 20.1, (2 CH3), 62.4,
(2OCH2-triaz.), 62.7, (2OCH2-thiadiaz.), 128.2, (2CH-arom.),
129.1, (2NC-arom.), 134.4, (C5-triaz.), 141.3, (C4-triaz.), 142.3,
(2CH3C-arom.), 147.1, (C4-thiadiaz.), 158.9, (CO-triaz.), 160.2,
(C5-thiadiaz.), 160.7 (CO-thiadiaz.). ESI-MS 761 (MHϩ).
EIMS m/z (rel. int.): 514(1), 486(6), 414(15), 314(15), 286(54),
242(59), 214(100), 157(23). Anal. Calcd for C28H28N10O8S4: C,
44.20; H, 3.71; N, 18.41; S, 16.86. Found C, 44.16; H, 3.73; N,
18.35; S, 16.97%.
221(38), 139(55), 116(54), 85(86), 68(67). Anal. Calcd for
C18H22N8O6S3: C, 39.84; H, 4.09; N, 20.65. Found C, 39.92; H,
4.01; N, 20.49%.
Diethyl
9,10-dihydrobis[1,2,3]triazolo[1,5-f:5Ј,1Ј-b][1,3,6]-
thiadiazepine-3,5-dicarboxylate 7a. A suspension of 5a (1.0 g,
1.46 mmol) in ethanol (20 mL) with triethylamine (0.6 mL,
4.3 mmol) was refluxed and enough DMF was added to
dissolve all the starting material. After 2 days of refluxing the
reaction mixture was diluted with water (60 mL) and extracted
with dichloromethane (3 × 20 mL). Evaporation of the solvent
gave a crude product which was crystallized from ethanol
to give 0.45 g (91%) of thiadiazepine 7a, mp 192 ЊC. 1H
NMR δH (CDCl3, 400 MHz): 1.45 (6H, t, J = 7.1 Hz, 2CH3),
4.47 (4H, q, J = 7.1 Hz, 2OCH2), 5.12 (4H, s, CH2CH2). 13C
NMR δC (CDCl3, 100 MHz): 14.21 (qt, J = 127.5, 2.6 Hz,
2CH3), 49.33 (tt, J = 146.6, 3.7 Hz, CH2CH2), 61.99 (tq,
J = 148.7, 4.5 Hz, 2OCH2), 130.20 (tt, J = 1.5, 1.5 Hz,
C5-triaz.), 138.04 (s, C4-triaz.), 159.89 (t, J = 3.4 Hz, CO).
EIMS m/z (rel. int.): 338 (Mϩ, 100). Anal. Calcd for
C12H14N6O4S: C, 42.60; H, 4.17; N, 24.84; S, 9.48. Found
C, 42.53; H, 4.20; N, 24.91; S, 5.60%. When the ethanol
filtrate combined with the water layer from extraction was acid-
ified with HCl, the precipitated product (0.20 g) was character-
ized as bis(4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)disulfide 9.
The spectroscopic and analytical data of this product were
identical to those reported earlier.1
5,5Ј-{4-Methyl-1,2-phenylenebis[(4-methyl-1H-1,2,3-triazole-
1,5-diyl)sulfanyl]}bis(4-methyl-1,2,3-thiadiazole) 5m. Prepared
1
from 1a and 2m as described for 5j. Yield 76%, mp 190 ЊC. H
NMR δH (CDCl3, 400 MHz): 1.32 (6H, t, J = 7.2 Hz, 2CH3-
triaz.), 1.470 (3H, t, J = 7.1 Hz, CH3-thiadiaz.), 1.474 (3H, t,
J = 7.1 Hz, CH3-thiadiaz.), 2.55 (3H, dd, J = 0.9, 0.8 Hz, CH3),
4.386 (2H, q, J = 7.2 Hz, OCH2-triaz.), 4.388 (2H, q, J = 7.2 Hz,
OCH2-triaz.), 4.52 (2H, q, J = 7.2 Hz, OCH2-thiadiaz.), 4.53
(2H, q, J = 7.2 Hz, OCH2-thiadiaz.), 7.34 (1H, dq, J = 1.8,
0.9 Hz, C3H), 7.42 (1H, d, J = 8.2 Hz, C6H), 7.60 (1H, ddq,
J = 8.2, 1.8, 0.8 Hz, C5H). 13C NMR δC (CDCl3, 100 MHz):
13.95 (qt, J = 127.5, 2.6 Hz, 2CH3-triaz.), 14.20 (qt, J = 127.5,
2.6 Hz, 2CH3-thiadiaz.), 21.48 (qt, J = 128.4, 4.1 Hz, CH3),
62.32 (tq, J = 148.9, 4.4 Hz, 2OCH2-triaz.), 62.66 (tq, J = 148.7,
4.3 Hz, OCH2-thiadiaz.), 62.67 (tq, J = 148.9, 4.4 Hz, OCH2-
thiadiaz.), 128.19 (d, J = 167.6 Hz, C6-arom.), 128.24 (d,
J = 8.0 Hz, C2-arom.), 129.10 (dddd, J = 164.3, 6.7, 5.5, 1.1 Hz,
C3-arom.), 130.51 (dt, J = 8.7, 1.8 Hz, C1-arom.), 132.95
(dddq, J = 163.9, 9.0, 3.4, 1.8 Hz, C5-arom.), 134.26 (s,
C5-triaz.), 134.39 (s, C5-triaz.), 141.30 (s, C4-triaz.), 141.43
(s, C4-triaz.), 143.75 (dq, J = 8.2, 5.9 Hz, C4-arom.), 147.05 (s,
C4-thiadiaz.), 147.17 (s, C4-thiadiaz.), 158.81 (t, J = 3.2 Hz,
CO-triaz.), 159.86 (s, C5-thiadiaz.), 160.01 (s, C5-thiadiaz.),
160.62 (t, J = 3.4 Hz, CO-thiadiaz.), 160.64 (t, J = 3.4 Hz,
CO-thiadiaz.). ESI-MS 747 (MHϩ). EIMS m/z (rel. int.):
472(15), 400(9), 300(13), 272(46), 228(67), 200(100), 116(36),
89(57). Anal. Calcd for C27H26N10O8S4: C, 43.42; H, 3.51;
N, 18.75; S, 17.17. Found C, 43.38; H, 3.59; N, 18.55; S,
17.00%.
Diethyl 9-methyl-9,10-dihydrobis[1,2,3]triazolo[1,5-f:5Ј,1Ј-b]-
[1,3,6]thiadiazepine-3,5-dicarboxylate 7b. Prepared from 5b as
described for 7a. Yield 73%, mp 168 ЊC. 1H NMR δH (DMSO-
D6, 400 MHz): 1.33–1.37 (9H, m, 3CH3), 4.38 (2H, q, J = 7.1
Hz, CH2), 4.39 (2H, q, J = 7.1 Hz, CH2), 5.16, 5.27 (2H,
AB-syst., J = 15.1, 5.5, 1.1 Hz, CH2), 5.59 (1H, m, CH). 13C
NMR δC (CDCl3, 75 MHz): 14.3 (CH2CH3), 14.3 (CH2CH3),
17.8 (CH3), 53.0 (CH), 56.2 (CH2), 62.0 (OCH2), 62.1 (OCH2),
129.4, 130.6, 137.4, 138.5, 159.8 (CO), 160.2 (CO). EIMS m/z
(rel. int.): 352 (Mϩ, 100). Anal. Calcd for C13H16N6O4S: C,
44.31; H, 4.58; N, 23.85; S, 9.10. Found C, 44.38; H, 4.54; N,
23.97; S, 9.31%.
Diethyl
6,7-dihydro-5H-bis[1,2,3]triazolo[1,5-g:5Ј,1Ј-b]-
[1,3,7]thiadiazocine-1,11-dicarboxylate 7c. Prepared from 5c as
described for 7a. Yield 79%, mp 203 ЊC. 1H NMR δH (DMSO-
D6 ϩ CCl4, 250 MHz): 1.41 (6H, t, J = 7.0 Hz, 2CH3), 2.19 (2H,
m, CH2CH2CH2), 4.28–4.48 (8H, m, 2OCH2 ϩ CH2CH2CH2).
13C NMR δC (CDCl3, 75 MHz): 14.3 (2CH3), 27.7
(CH2CH2CH2), 44.9 (2NCH2), 62.1 (2OCH2), 131.3, 138.5,
160.2 (2CO). EIMS m/z (rel. int.): 352 (Mϩ, 100). Anal. Calcd
for C13H16N6O4S: C, 44.31; H, 4.58; N, 23.85. Found C, 44.29;
H, 4.61; N, 23.80%.
Ethyl 5-[(1-methyl-2-{4-ethoxycarbonyl-5-[(4-ethoxycarbonyl-
1,2,3-thiadiazol-5-yl)sulfanyl]-1H-1,2,3-triazol-1-yl}ethyl)-
amino]-1,2,3-thiadiazole-4-carboxylate 6. A solution of bromo-
ester 1a (0.5 g, 2.1 mmol) and 0.75 equivalents of 1,2-
propylenediamine 2b (0.12 g) in chloroform (5 mL) was refluxed
for 3 hours. After removal of the solvent, the residue was dis-
solved in ethanol and kept for two days, The product slowly
precipitated and was filtered off yielding 0.046 g (12%) of 6, mp
178 ЊC. 1H NMR δH (CDCl3, 400 MHz): 1.33 (3H, t, J = 7.2 Hz,
CH3-triaz.), 1.44 (3H, t, J = 7.2 Hz, CH3-thiadiaz.NH), 1.48
(3H, d, J = 6.5 Hz, CH3), 1.52 (3H, t, J = 7.2 Hz, CH3-
thiadiaz.), 3.87 (1H, dqt, J = 8.9, 6.5, 6.2 Hz, CH), 4.38 (2H, q,
J = 7.1 Hz, OCH2-triaz.), 4.42 (2H, qd, J = 7.1, 1.8 Hz, OCH2-
thiadiaz.NH), 4.58 (2H, q, J = 7.2 Hz, OCH2-thiadiaz.), 4.70
(1H, d, J = 6.2 Hz, CH2), 7.85 (1H, d, J = 8.9 Hz, NH). 13C
NMR δC (CDCl3, 100 MHz): 14.06 (qt, J = 127.5, 2.6 Hz, CH3-
triaz.), 14.33 (qt, J = 127.3, 2.6 Hz, CH3-thiadiaz.NH ϩ CH3-
thiadiaz.), 18.57 (qd, J = 128.8, 2.9 Hz, CH3), 52.60 (t, J = 143.2
Hz, CH2), 58.65 (d, J = 139.7 Hz, CH), 61.74 (tq, J = 148.2, 4.5
Hz, OCH2-thiadiaz.NH), 62.32 (tq, J = 148.7, 4.3 Hz, OCH2-
triaz.), 62.93 (tq, J = 149.1, 4.5 Hz, OCH2-thiadiaz.), 132.15 (t,
J = 2.5 Hz, C5-triaz.), 132.43 (d, J = 1.5 Hz, C4-thiadiaz.NH),
141.72 (s, C4-triaz.), 147.14 (s, C4-thiadiaz.), 159.15 (t, J = 3.2
Hz, CO-triaz.), 159.87 (s, C5-thiadiaz.), 160.61 (t, J = 3.4 Hz,
CO-thiadiaz.), 163.50 (t, J = 3.2 Hz, CO-thiadiaz.NH), 169.63
(dd, J = 3.8, 2.3 Hz, C5-thiadiaz.NH). ESI-MS 543 (MHϩ).
EIMS m/z (rel. int.): 514(3), 384(3), 352(68), 307(12), 235(100),
2-Ethoxy-8,10-bis(ethoxycarbonyl)di[1,2,3]triazolo[1,5-a;5Ј,
1Ј-d][3,1,5]benzothiadiazepine 7j. To a solution of 1a (1.0 g,
4.22 mmol) and 4-ethoxy-1,2-phenylenediamine 2j (0.33 g 2.1
mmol) in ethanol (80 mL), triethylamine (0.6 mL, 4.2 mmol)
was added and the reaction mixture was refluxed overnight.
Then a second portion of triethylamine (1.2 mL) was added
and soon the product precipitated from the boiling solution.
After refluxing for an additional hour, the reaction mixture
was cooled, and the product was filtered off and crystallized
from ethanol yielding 0.38 g (42%) of thiadiazepine 7j, mp
168 ЊC. 1H NMR δH (DMSO-D6 ϩ CCl4, 250 MHz): 1.42 (3H,
t, J = 7.0 Hz, CH2), 1.43 (3H, t, J = 7.0 Hz, CH3), 1.47 (3H, t,
J = 7.0 Hz, CH3ethoxy), 4.26 (2H, q, J = 7.0 Hz, OCH2ethoxy),
4.40 (2H, q, J = 7.0 Hz, OCH2), 4.41 (2H, q, J = 7.0 Hz, OCH2),
7.41 (1H, dd, J = 9.2, 2.7 Hz, C3H), 7.52 (1H, d, J = 2.7 Hz,
C1H), 7.99 (1H, d, J = 9.2 Hz, C4H). EIMS m/z (rel. int.): 430
(Mϩ, 18). Anal. Calcd for C18H18N6O5S: C, 50.23; H, 4.22; N,
19.52; S, 7.45. Found C, 50.31; H, 4.20; N, 19.70; S, 7.20%.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
4037

View Article Online
Ethyl 5-[1-(2-amino-4-ethoxyphenyl)-4-ethoxycarbonyl-1,2,3-
triazol-5-ylsulfanyl]-1,2,3-thiadiazole-4-carboxylate 8j. A solu-
tion of 12j (0.9 g, 2.9 mmol) and triethylamine (0.8 mL, 5.7
mmol) in ethanol (50 mL) was refluxed for 3 hours, then cooled
to room temperature and bromoester 1a (0.7 g, 2.9 mmol) was
added. The reaction mixture was stirred for 1 h and a half of
the solvent was removed. The product that precipitated from
the solution upon cooling was filtered off and crystallized from
and the residue was washed with ethanol to give 11 (1.13 g,
97%), mp 156 ЊC. 1H NMR δH (CDCl3, 400 MHz): 5.09 (4H, s,
CH2CH2), 7.76 (2H, s, 2CH-triaz.). 13C NMR δC (CDCl3, 100
MHz): 47.78 (tt, J 145.8, 3.7 Hz, CH2CH2), 124.60 (dt, J 14.7,
1.3 Hz, C5-triaz.), 134.72 (d, J 199.3 Hz, C4-triaz.). EIMS m/z
(rel. int.): 194 (Mϩ, 100). Anal. Calcd for C6H6N6S: C, 37.11; H,
3.11; N, 43.27; S, 16.51. Found C, 37.06; H, 3.13; N, 43.35; S,
16.75%.
1
ethanol (1.16 g) 86%, mp 130 ЊC. H NMR δH (DMSO-D6 ϩ
Single crystals of compound 11 suitable for X-ray diffraction
CCl4, 250 MHz): 1.23 (3H, t, J = 7.0 Hz, CH3ethoxy), 1.35 (3H,
t, J = 7.0 Hz, CH3), 1.41 (3H, t, J = 7.0 Hz, CH3), 3.97 (2H, q,
J = 7.0 Hz, OCH2ethoxy), 4.30 (2H, q, J = 7.0 Hz, OCH2), 4.43
(2H, q, J = 7.0 Hz, OCH2), 5.22 (2H, br s, NH2), 6.14 (1H, dd,
J = 8.5, 2.5 Hz, C5H), 6.35 (1H, d, J = 2.5 Hz, C3H), 6.94 (1H,
d, J = 8.5 Hz, C6H). EIMS m/z (rel. int.): 464 (Mϩ, 6), 205
(100). Anal. Calcd for C18H20N6O5S2: C, 46.54; H, 4.34; N,
18.09; S, 13.81. Found C, 46.60; H, 4.37; N, 17.98; S, 13.40%.
were obtained by crystallization from ethanol.
Crystal structure determination of compound 11:†
Crystal data: C6H6N6S, M = 194.24, monoclinic, a =
13.4019(2), b = 8.1355(1), c = 7.8447(1) Å, β = 101.744(1),
U = 837.41(2) Å3, T = 299(1) K, space group P21/c (no. 14),
Z = 4, µ(Cu–Kα) = 3.129 mmϪ1, 5685 measured reflections, 1513
unique (Rint = 0.046) which were used in all calculations. The
final R1 = 0.0437 (for 1421 data with I > 2σ(I )) and wR2 =
0.1405 (all data).
Ethyl 5-[N-(2-amino-4-ethoxyphenyl)amino]-1,2,3-thiadiaz-
ole-4-carboxylate 12j. A solution of ethyl 5-bromo-1,2,3-thia-
diazole-4-carboxylate 1a (1.71 g, 7.2 mmol) and diamine 2j
(2.2 g, 14.5 mmol) in DMF (20 mL) was stirred at room tem-
perature, and the reaction was monitored with TLC. After the
starting compound had disappeared, the reaction mixture was
diluted with water. The precipitate was filtered off and crystal-
lized from ethanol (0.94 g) 56%, mp 145 ЊC. 1H NMR
δH (DMSO-D6 ϩ CCl4, 250 MHz): 1.35 (3H, t, J = 7.0 Hz,
CH3), 1.42 (3H, t, J = 7.0 Hz, CH3), 3.96 (2H, q, J = 7.0 Hz,
OCH2), 4.41 (2H, q, J = 7.0 Hz, OCH2), 5.01 (2H, br s, NH2),
6.12 (1H, dd, J = 8.5, 2.4 Hz, C5H), 6.33 (1H, d, J = 2.4 Hz,
C3H), 6.96 (1H, d, J = 8.5 Hz, C6H), 8.98 (1H, s, NH). EIMS
m/z (rel. int.): 308 (Mϩ, 81). Anal. Calcd for C13H16N4O3S: C,
50.64; H, 5.23; N, 18.17; S, 10.40. Found C, 50.61; H, 5.28; N,
18.10; S, 10.37%.
Acknowledgements
We thank the Russian Foundation for Basic Research (grant
01-03-32609 and 00-03-40139) and CRDF RC-2393-EK-02 for
financial support. We also thank the F. W. O. - Vlaanderen, the
Ministerie voor Wetenschapsbeleid, INTAS and the University
of Leuven for financial support.
† CCDC reference number 214711. See http://www.rsc.org/suppdata/
ob/b3/b307693h/ for crystallographic data in .cif or other electronic
format.
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9,10-Dihydrobis[1,2,3]triazolo[1,5-f:5Ј,1Ј-b][1,3,6]thiadi-
azepine-3,5-dicarboxylic acid 10. To an aqueous solution of
NaOH (0.36 g, 9.0 mmol in 100 mL), thiadiazepine 7a (1.52 g,
4.5 mmol) was added and the suspension was refluxed until a
clear solution formed, then this was acidified with conc. HCl
and the precipitated acid filtered off as colourless crystals
(1.05 g, 83%), mp 213 ЊC. 1H NMR δH (DMSO-D6, 400 MHz):
5.08 (4H, s, 2CH2). EIMS m/z (rel. int.): 282 (Mϩ, 2), 238(46),
194(51). Anal. Calcd for C8H6N6O4S: C, 34.05; H, 2.14; N,
29.78; S, 11.36. Found C, 34.11; H, 2.17; N, 29.49; S, 11.53%.
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9,10-Dihydrobis[1,2,3]triazolo[1,5-f:5Ј,1Ј-b][1,3,6]thiadi-
azepine 11. Acid 10 (1.70 g, 6.0 mmol) was heated at 175 ЊC in
DMSO (20 mL) for 8 hours. The DMSO was removed in vacuo
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 3 0 – 4 0 3 8
4038