An efficient protocol for the formation of aminothiatriazoles from thiocarbamoylimidazolium salts

Article abstract of DOI:10.1016/S0040-4039(02)01714-8

A new protocol for the formation of substituted aminothiatriazoles from thiocarbamoylimidazolium salts is outlined. Thiocarbamoylimidazolium salts are synthesized from the corresponding amines by treatment with thiocarbonyldiimidazole (TCDI) followed by methylation with iodomethane. Thiocarbamoylimidazolium salts are shown to act as thiocarbamoyl cation equivalents. Substitution of the salts by azide anion followed by electrocyclization affords substituted aminothiatriazoles in good to excellent yields.

Full text of DOI:10.1016/S0040-4039(02)01714-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7601–7604
An efficient protocol for the formation of aminothiatriazoles
from thiocarbamoylimidazolium salts
Marisa G. Ponzo, Ghotas Evindar and Robert A. Batey*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6
Received 1 August 2002; accepted 16 August 2002
Abstract—A new protocol for the formation of substituted aminothiatriazoles from thiocarbamoylimidazolium salts is outlined.
Thiocarbamoylimidazolium salts are synthesized from the corresponding amines by treatment with thiocarbonyldiimidazole
(TCDI) followed by methylation with iodomethane. Thiocarbamoylimidazolium salts are shown to act as thiocarbamoyl cation
equivalents. Substitution of the salts by azide anion followed by electrocyclization affords substituted aminothiatriazoles in good
to excellent yields. © 2002 Published by Elsevier Science Ltd.
Heterocyclic compounds occupy a prominent position
amongst modern pharmaceuticals and crop protection
agents.1 Whether they are generated by traditional,
structure-based or combinatorial approaches, new
methods for their synthesis are required.2 This is partic-
ularly true in the case of lead generation, where efficient
and operationally straightforward synthetic methods
are required to meet the growing demands of creating
diverse compound libraries. One important family of
heterocycles are the azoles,3 which are important both
as biologically active compounds as well as synthetic
intermediates. As part of our research into these com-
pounds,4–6 we have become interested in the synthesis
of substituted thiatriazoles,7 and aminothiatriazoles in
particular. Monosubstituted aminothiatriazoles 1 (Fig.
1) have been reported to possess a range of interesting
biological properties, including antihypertensive,8
antibacterial,9 antitubercular,10 antiviral,11 fungicidal,12
anticancer,13 central nervous system stimulant and mus-
cle relaxant activities.14 Of the currently available pro-
cedures for the synthesis of monosubstituted
aminothiatriazoles 1, the most widely used is based
upon the method originally outlined by Freund and
co-workers,15 which involves treatment of thiosemicar-
bazides with nitrous acid.10,13,14,16 A related aza transfer
procedure with diazonium salts has also been
reported.17 Monosubstituted aminothiatriazoles 1 have
also been synthesized through the reaction of hydrazoic
acid,16b,c,18 trimethylsilyl azide18b,19 or sodium azide20
with isothiocyanates. These latter reactions are pre-
sumed to occur by both 1,3-dipolar cycloaddition and
electrocyclization mechanisms. Limitations of these
methods include low product yields and the use of
hazardous reagents and intermediates.
The synthesis of disubstituted aminothiatriazoles is
much less common, despite the fact that such com-
pounds are more stable and less prone to decomposi-
tion than their monosubstituted analogs. Lieber and
co-workers have reported a two-step protocol for the
synthesis of disubstituted aminothiatriazoles from
amines, thiophosgene and sodium azide in poor to
moderate yields.21 Thiocarbonyldiimidazole (TCDI)
also reacts with hydrazoic acid and trimethylsilyl azide
to form 5-(1-imidazolyl)-1,2,3,4-thiatriazole in moder-
ate yields.22 A lack of a safe and practical synthesis for
disubstituted aminothiatriazoles 2 has greatly hindered
biological evaluation of these compounds. Conse-
quently, there is a need for an efficient and general
method for the synthesis of mono- and disubstituted
aminothiatriazoles.
Figure 1.
We have recently shown that carbamoylimidazolium
salts 3 act as stable and efficient carbamoylation
reagents, effectively replacing the use of their unstable
and unpleasant carbamoyl chloride equivalents. Nucle-
* Corresponding author. Tel./fax: (+1)-416-978-5059; e-mail: rbatey@
chem.utoronto.ca
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01714-8

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M. G. Ponzo et al. / Tetrahedron Letters 43 (2002) 7601–7604
Table 1. Formation of monosubstituted aminothiatriazoles
1 via thiocarbamoylimidazolium salts
ophilic displacement of the salts 3 results in their ready
conversion to ureas,4a,c carbamates and thiocarba-
mates.4b By analogy, thiocarbamoylimidazolium salts 4
should act as thiocarbamoylating reagents, and poten-
tially provide a means to synthesize aminothiatriazoles.
The requisite thiocarbamoylimidazolium salts 4 are
readily prepared by a two step route involving treat-
ment of primary or secondary amines 5 with TCDI to
generate thiocarbamoylimidazole intermediates
6
(Scheme 1). Although these intermediates can act as
thiocarbamoylating reagents, application of the imida-
zolium effect, via alkylation of the imidazole ring of 6,
provides the more activated salts 4. Nucleophilic attack
of azide anion would then result in displacement of the
N-methylimidazole, forming intermediate thiocar-
bamoyl azides 7, which can then undergo rapid
electrocyclization23 at room temperature to give the
corresponding aminothiatriazoles 1 or 2.
Our initial studies focussed upon the synthesis of
monosubstituted aminothiatriazoles 1. Reaction of pri-
mary amines (1.0 equiv.) with TCDI (1.0 equiv.) in
MeCN furnished the thiocarbamoyl imidazoles 6 after
30 minutes of stirring at room temperature. Reaction of
6 with MeI (10 equiv.) over 18–24 hours at room
temperature produced the imidazolium salts 4. The
imidazolium salts 4 were then azeotroped with MeCN
(2×) to remove excess MeI before reaction with sodium
azide (3.0 equiv.) in MeCN for 3–18 hours to afford the
monosubstituted aminothiatriazoles 1 (Table 1). In the
majority of cases, the only detectable by-product pro-
duced was N-methyl imidazole, which was easily
removed by washing the organic layer (EtOAc) with
dilute ammonium chloride. All reactions gave mono-
substituted aminothiatriazoles within 2 days at room
temperature in good to excellent yields (reaction yields
are unoptimized). The protocol for this synthesis does
not involve chromatographic purification of the inter-
mediates. Compared to existing protocols for the for-
mation of monosubstituted aminothiatriazoles 1, this
procedure avoids the use of harsh reaction conditions,
unpleasant reagents or extremes of pH.
Interestingly, treatment of the thiocarbamoyl imida-
zoles 6 with sodium azide at room temperature gave
products in half the reaction time but in lower yields
than when the activated salts 4 were employed. Heating
the thiocarbamoyl imidazoles 6 with sodium azide at
60°C was also attempted, but not pursued, since this
method was found to result in by-product formation.
The existing method for the synthesis of disubstituted
aminothiatriazoles utilizes highly toxic thiophosgene.
The application of this protocol for the preparation of
disubstituted aminothiatriazoles 2 is hence of greater
significance (Scheme 1 and Table 2). For example,
reaction of morpholine with TCDI (1.0 equiv.) at room
temperature generated the corresponding thiocar-
bamoyl imidazole intermediate 6 in 1 hour, which was
then activated to the salt 4 by treatment with MeI (10
equiv.) for 1 day. Optimal reaction times for the methyl-
ation were 1 or 2 days, depending upon the substrate
used. Thus, the starting materials 1,2,3,4-tetra-
hydroquinoline and N-isopropylbenzylamine required 2
days for methylation, while all others required 1 day. A
10-fold excess of iodomethane was used in these
exploratory studies, but less alkylating agent can also
be used. Azeotropic removal of the excess MeI with
Scheme 1.

M. G. Ponzo et al. / Tetrahedron Letters 43 (2002) 7601–7604
7603
Table 2. Formation of disubstituted aminothiatriazoles 2
Table 3. Formation of mono- and disubstituted amino
acid derived aminothiatriazoles
via thiocarbamoylimidazolium salts24
on 6 occurring in good yields. Thus, the primary
amines, Phe-OtBu·HCl and Leu-OtBu·HCl, react with
TCDI (1.0 equiv.) and triethylamine (1.1 equiv.) at
room temperature for 15 minutes to afford intermedi-
ates 6 which required no additional purification. Direct
treatment with sodium azide (3.0 equiv.) and stirring at
room temperature for 1 hour gave monosubstituted
amino acid derived thiatriazoles in good yield (method
A) (Table 3, entries 1 and 2). For the synthesis of
disubstituted amino acid thiatriazoles, activation as the
salts 4 was required (method B) (Table 3, entries 3 and
4).24,25
MeCN, followed by reaction with azide ion (3.0 equiv.)
for 18–24 hours afforded the disubstituted aminothia-
triazoles in good to excellent yields (Table 2). The
products require column chromatography to remove
minor impurities after the final step. Although the
protocol for this synthesis does not involve purification
of the intermediates, the disubstituted intermediates 6
and 4 can be purified and stored if necessary. For
comparison, the monosubstituted intermediates 6 and 4
(R1"H, R2=H) are less stable, and were always used
directly for the next reaction.
In conclusion, mild methods for the preparation of
mono- and disubstituted aminothiatriazoles from com-
mercially available starting materials have been devel-
oped. The products are easily isolated by simple
extraction or column chromatography techniques and
are obtained in high yields. The method is particularly
useful for the preparation of disubstituted aminothiatri-
azoles, which despite their greater stability have not
been thoroughly biologically evaluated, due to
difficulties in their synthesis using highly toxic thio-
phosgene. We are now integrating this method into our
combinatorial chemistry program, and will report fur-
ther applications of thiocarbamoylimidazolium salts to
solution phase and polymer-supported chemistry in due
course.
We are also interested in the use of heterocycle-peptide
conjugates as peptidomimetics. As a preliminary test of
this chemistry N-terminal aminothiatriazole modified
amino acids have been synthesized using two methods
(Table 3). In the case of monosubstituted aminothiatri-
azoles, the amino acid derivatives are converted into
the thiocarbamoyl imidazoles 6, but here activation to
the salts 4 is not required, with attack by azide anion

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Lieber, E.; Ramachandran, J. Can. J. Chem. 1959, 37,
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(ESTAC), and the Ontario Government supported this
work. M.P. thanks NSERC for an Undergraduate
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