Direct access to 1-aryl-5-amino-1,2,4-triazoles and [1,2,4]triazolo[1,5-a] pyridines by two new single-step reactions from 1,3,4-thiadiazol-2-amines

Article abstract of DOI:10.1016/j.tet.2012.11.101

Two new single-step reactions allowing the construction of two heterocyclic motifs are reported. Both processes involve 5-substituted 1,3,4-thiadiazol-2- amines as starting materials. Reaction with 1-fluoro-2-nitrobenzenes in presence of Hünig's base permitted the convenient synthesis of various 3-substituted 1-aryl-5-amino-1,2,4-triazoles. Reaction with 2-chloro-3- nitropyridines and 2-chloro-5-nitropyridines in similar conditions readily gave access to a number of [1,2,4]triazolo[1,5-a]pyridines. In absence of base, adducts composed by one aromatic unit and two thiadiazole units were formed. This observation and previous work by Anders and co-workers led to the suggestion of plausible mechanisms for these reactions.

Full text of DOI:10.1016/j.tet.2012.11.101

Tetrahedron 69 (2013) 1669e1680
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct access to 1-aryl-5-amino-1,2,4-triazoles and
[1,2,4]triazolo[1,5-a]pyridines by two new single-step reactions
from 1,3,4-thiadiazol-2-amines
,
a
a
a
b
Oscar Mammoliti a , Evelyne M. Quinton , Kristof T.J. Loones , Anh Tho Nguyen , Johan Wouters ,
*
Guy Van Lommen a
a Department of Medicinal Chemistry, Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Belgium
b Department of Chemistry, University of Namur (FUNDP), 61 rue de Bruxelles, B-5000 Namur, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 August 2012
Received in revised form 10 November 2012
Accepted 14 November 2012
Available online 8 December 2012
Two new single-step reactions allowing the construction of two heterocyclic motifs are reported. Both
processes involve 5-substituted 1,3,4-thiadiazol-2-amines as starting materials. Reaction with 1-fluoro-2-
€
nitrobenzenes in presence of Hunig’s base permitted the convenient synthesis of various 3-substituted 1-
aryl-5-amino-1,2,4-triazoles. Reaction with 2-chloro-3-nitropyridines and 2-chloro-5-nitropyridines in
similar conditions readily gave access to a number of [1,2,4]triazolo[1,5-a]pyridines. In absence of base,
adducts composed by one aromatic unit and two thiadiazole units were formed. This observation and
previous work by Anders and co-workers led to the suggestion of plausible mechanisms for these reactions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aminotriazole
Triazolopyridine
Ring formation
Condensation
Dimroth rearrangement
Single-step synthesis
1. Introduction
Ueda23 reported a convenient Cu(I) catalyzed condensation be-
tween 2-aminopyridines VI and aromatic nitriles (Scheme 1B, route
Aromatic heterocycles are fundamental building blocks of bi-
ologically active molecules. Among these, 5-amino-1,2,4-triazoles
constitute an interesting motif found regularly in medicinal chem-
istry.1e4 Various methods have been developed for their preparation.
In particular, some reports focused on the construction of 1,3-bis-
substituted 5-amino-1,2,4-triazoles III (Scheme 1A).5e11 Condensa-
tion between N-cyanoimidates I and mono-substituted hydrazines
(Scheme 1A, route (i)) is the most commonly used method.5e8 Al-
ternatively, triazoles III can be obtained from the reaction between
hydrazonoylderivativesIIandcyanamide(Scheme1A, route(ii)).9e11
[1,2,4]Triazolo[1,5-a]pyridines VIII (Scheme 1B) are fused bi-
cyclic heterocycles widely used in medicinal chemistry.12e15 Various
procedures to access derivatives VIII having aryl oralkyl groups as R2
(Scheme 1B) have been reported. Condensation of 1,2-
diaminopyridiniums IV with carboxylic acid derivatives,16e18 or al-
dehydes under oxidative conditions,19,20 has been extensively used
(Scheme 1B, route (i)). Triazolopyridines VIII canalso be obtainedvia
1,3-dipolar cycloaddition between 1-aminopyridiniums V and ni-
trile derivatives (Scheme 1B, route (ii)).21,22 Recently, Nagasawa and
(iii)). This reaction can be viewed as the latest improvement of
a general approach involving the oxidative ring closure of amidines
VII (Scheme 1B, route (iv)).16,24,25
Apart from the Cu(I) catalyzed condensation (Scheme 1B, route
(iii)), all the presented procedures require, in general, preparation
of the starting materials. Besides, 1-aminopyridiniums IV and V are
prepared from pyridines after reaction with hydroxylamine-are-
nesulfonates.26 These reagents are quite sensitive27 and can lead to
explosions.28 For all these reasons, the development of direct
methods for the synthesis of heterocycles III and VIII is particularly
desirable. We report below two serendipitously discovered single-
step reactions, allowing direct access to a set of triazoles III and to
a set of triazolopyridines VIII, respectively, from commercially
available starting materials. To the best of our knowledge, these
reactions are reported for the first time.
2. Results and discussion
2.1. Initial discovery and optimization
Our initial aim was the synthesis of intermediate products by
SNAr reactions between electron-deficient aromatic halides and
* Corresponding author. Tel.: þ32 15 342 917; fax: þ32 15 342 901; e-mail
address: oscar.mammoliti@glpg.com (O. Mammoliti).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.101

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O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
Scheme 1. Synthesis of 1,3-bis-substituted 5-amino-1,2,4-triazoles and [1,2,4]triazolo[1,5-a]pyridines.
various amines. In one case, we explored the reaction between 1-
fluoro-2-nitrobenzene 1a and thiadiazole 2a (Scheme 2). To our
surprise, only trace quantities of the desired adduct 3 were ob-
served, however two major by-products with different polarity
were observed. Reaction between 1 equiv of 2a and 2 equiv of 1a in
2.2. Application of reaction conditions to different 1,3,4-
thiadiazol-2-amines and different 1-fluoro-2-nitrobenzenes
The synthesis of different analogues of triazole 4a was un-
dertaken. NMP was preferred over DMSO, due to the cleaner re-
Scheme 2. Observation and isolation of unexpected reaction products (isolated yields).
presence of 2 equiv of i-Pr2NEt in NMP at 140 ꢀC allowed us to
isolate the two unexpected products. LCeMS and 1He15N HMBC
NMR indicated triazole 4a to be the more polar product. The
structure was confirmed by single crystal X-ray diffraction (see
Supplementary data). The less polar product was found to be sul-
fane 5a.
action profile. Pleasingly, we were able to observe and isolate
a variety of triazoles 4 with different substituents at the 3-position
(Table 2, entries 1e7). Differently substituted 1-fluoro-2-
nitrobenzenes 1 also gave the expected products (entries 8e13),
indicating the tolerance to functional groups of the reaction.
Table 1
Intrigued by this discovery we sought to optimize conversion
of thiadiazole 2a to triazole 4a. Varying conditions were applied,
including use of different solvents, temperatures and reaction
times. It was rapidly found that best conditions were to heat in
sealed tubes at 140 ꢀC (thermal heating) for 16 h at 1 M thia-
diazole concentration, as lower temperatures and shorter re-
action times were less efficient, and higher concentrations did
not bring any improvement. These results are summarized in
Table 1, which shows the formation of 4a was clearly favored by
high-boiling aprotic polar solvents (DMSO and NMP, entries 6
and 7). With less polar solvents or EtOH (entries 1, 2, and 4),
yields were poor. Addition of water (entry 8) did not compromise
the yield. The reaction was also performed under microwave
conditions. Again, NMP was superior to EtOH or MeCN, but the
yields were lower in comparison with thermal conditions (en-
tries 9e11).
Screening of different solvents for the synthesis of triazole 4a
Entry
Solvent
Conditions
Reaction time (h)
% Yielda
1
2
3
4
5
6
7
8
1,4-Dioxane
EtOH
BuOH
Toluene
MeCN
DMSO
NMP
NMP/10% H2O
NMP
MeCN
EtOH
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Thermal
Microwave
Microwave
Microwave
Thermal
16
16
16
16
16
16
16
16
2
13
16
23
9
24
47
44
43
28
16
9
Different bases were also tested, and Et3N gave similar results
when compared to i-Pr2NEt (Table 1, entry 12). When the stronger
organic base DBU was used, no product was detected. When the
inorganic base Cs2CO3 was used in 1,4-dioxane, the initially ex-
pected product 3 (Scheme 2) was observed instead of 4a (see Ex-
perimental section, x 4.3).
9
10
11
12b
2
2
16
NMP
38
a
Yields were determined by LCeMS after calibration with standard.
Et3N was used as base instead of i-Pr2NEt.
b

O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
1671
Table 2
Synthesis of various 1,2,4-triazol-5-amines
Entry
1
1
2
4
Yield determined by LCeMS (%)a
Isolated yield (%)
30
dc
36
47
67
13b
10b
22b
29b
62d
2
3
4
5
1a
1a
1a
1a
6
7
1a
1a
64
74
48d
78d
8
9
53e
47d,f
2a
10
6b
(continued on next page)

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O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
Table 2 (continued )
Entry
1
2
4
Yield determined by LCeMS (%)a
Isolated yield (%)
10
11
2a
2a
91g
78d,g
29
15b
12
1b
1d
2h
2h
80f
64d,f
13
83f
59d,f
a
Yields determined by LCeMS after calibration with standard.
Isolated yields after HPLC purification. HPLC isolated yields and LCeMS yields refer to the same experiment.
Yield could not be determined due to overlap with other peaks.
Isolated yields after silica chromatography. These yields refer to a repeated experiment. HPLC isolated yields for these reactions are reported in Experimental section.
Reaction carried out using 3.6 equiv of compound 1.
b
c
d
e
f
Reaction carried out using 1.5 equiv of compound 1.
Reaction carried out using 2.9 equiv of compound 1.
g
Yields were determined by LCeMS, and were found to range
2.3. Discovery of a direct method to prepare [1,2,4]triazolo
from modest to good (29e91% Table 2), apart from the labile
benzyl alcohol 1c (entry 9). When reacting different thiadiazoles
2, the best yields were observed with 5-cyclopropyl substituted 2f
(67%, entry 5) and 5-methyl substituted 2h (74%, entry 7). With
different 1-fluoro-2-nitrobenzenes 1, good yields were observed
with the more activated 1,4-difluoro-2-nitrobenzene 1d (91%,
entry 10). In this case, 0.9 extra equivalents of 1d were added.
Extra equivalents of nitrobenzene starting material were also
used for the synthesis of triazole 4i (entry 8), with less success.
When two or more equivalents of nitrobenzene 1b or 1d were
reacted with 5-methyl substituted thiadiazole 2h (entries 12 and
13), by-products resulting from the coupling of an extra nitro-
benzene to the desired triazoles 4m and 4n were observed by
LCeMS. For this reason, only 1.5 equiv of 1 were used. The
products were formed with good LCeMS yields (80% and 83%,
respectively).
[1,5-a]pyridines
The reaction between thiadiazole 2a and 2-chloro-3-
nitropyridine 6a was investigated to explore the reactivity of dif-
ferent electrophilic aromatic substrates (Scheme 3).
Scheme 3. Unexpected formation of [1,2,4]triazolo[1,5-a]pyridine 7a (isolated yield).
Products were isolated by automated reverse phase HPLC. In
To our surprise, instead of the expected triazole, another prod-
uct was observed by LCeMS. Initially, we speculated that the
structure could be [1,2,4]triazolo[4,3-a]pyridine 8 (Scheme 4),
however, on isolation, the product was found to be [1,2,4]triazolo
most cases, poor recovery was observed (see Table
2 and
Experimental section).29 The reactions, which showed good LCeMS
yields were therefore repeated and the products purified by silica
gel chromatography (entries 5, 6, 7, 8, 10, 12, and 13), giving isolated
yields in line with those determined by LCeMS. In particular, tri-
azoles 4h (entry 7) and 4k (entry 10) were obtained in good iso-
lated yields (78% in both cases).
For all reactions involving 1a (entries 1e7), LCeMS analysis
showed formation of sulfane 5a in quantities proportional to the
formation of 4. For the other reactions (entries 8e13), peaks with
similar retention times were observed, although the corresponding
products were not isolated.
Scheme 4. Probable formation of [1,2,4]triazolo[1,5-a]pyridine 7a after Dimroth re-
arrangement of [1,2,4]triazolo[4,3-a]pyridine 8.

O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
1673
[1,5-a]pyridine 7a (Scheme 3). The structure of 7a was assigned on
2.5. Synthesis of compounds 9a and 9b in absence of base and
the basis of 1He15N HMBC NMR experiments and was confirmed by
single crystal X-ray diffraction (see Supplementary data). Early
optimization based on LCeMS analysis suggested a temperature of
120 ꢀC to be the best compromise between conversion to products
and degradation. Sulfane 5b was also isolated, indicating that
a similar mechanism could lead to the formation of triazolopyridine
7a and triazole 4a. Compound 7a may have been formed after
a Dimroth rearrangement30e32 of the condensation product [1,2,4]
triazolo[4,3-a]pyridine 8 (see Section 2.5 for a more detailed
mechanistic discussion).
Various conditions were screened to increase the yield. As in
the case of triazoles 4, bases such as DBU or Cs2CO3 did not give
the desired product. Several solvents were then tested (Table 3),
and the presence of H2O was also tolerated in this case (entry 7).
Contrary to the observation for triazoles 4, less polar solvents
were not inferior to more polar solvents (e.g., entries 1 and 3 vs
entries 5, 6, and 9) and toluene was found to give the best LCeMS
yield (entry 3). Microwave conditions did not bring any im-
provement (data not shown). Triazolopyridine 7a was isolated in
37% yield after reaction in toluene (entry 3). The change of solvent
improved also the recovery (compare Table 3, entry 3, with
Scheme 3).
suggestion of a plausible mechanism
An interesting result came from the reaction between 1a and 2a
without base (Scheme 5), where 9a was isolated with low yield. The
same result, with better yield, was obtained with 2-chloro-3-
nitropyridine 6a, which gave 9b. The structure of 9b was de-
termined by single crystal X-ray diffraction (Fig. 1). The structure of
9a was unambiguously assigned after NMR experiments (see
Supplementary data). The two compounds resulted from the
combination of one unit of aromatic halide (1a or 6a) and two units
of 2a, with loss of ammonia.
Mechanistically, sequential attack of two molecules of 2a can
lead to the formation of intermediates such as 10 (Scheme 6). The
sequence then continues with a proton shift and elimination of
ammonium halide from 11 to give isolated products 9.
The formation of 9 proved that thiadiazoles 2 attack aromatic
halides 1 and 6 with the endocyclic N-3 (Scheme 5).33,34 For-
mation of 9 also shows that the amino group of 2 can attack
another thiadiazole moiety at C-2. This event requires activation
from the presence of the aromatic halide. In fact, by submitting
2a alone to various reaction conditions (NMP, 140 ꢀC in presence
and absence of base), adduct 12 (Scheme 6, frame) was never
observed.
This peculiar reactivity of thiadiazoles 2 (the combination of two
thiadiazole units with loss of ammonium halide, after N-3 attack to
an electron-deficient center) was already described by Anders’
group. Their research focused on triazinium salts formed after the
reaction between thiadiazoles 2 and alkyl or aryl pyridinium ha-
lides (Scheme 7).35e38
Table 3
Screening of different solvents for the synthesis of [1,2,4]triazolo[1,5-a]pyridine 7a
The presence of a suitable base can help the formation of in-
termediates such as 13 (Scheme 8).
Equilibrium with the ring-opened species 14 can reveal the
nucleophilic sulfur, which can then react with the excess 1a or 6a to
form intermediates 15. At this stage, the hypothetical routes lead-
ing to 4a and 7a diverge.
Intermediate 15a (or a tautomeric form) can undergo a ring
closure to form species like 16 (Scheme 9A) with elimination of
thiolate 17a, which can in turn attack a molecule of 1 to form the
observed 5a.
Triazole 4a can then derive from 16 after hydrolysis or another
process. The observed ratios between 4 and 5a were always con-
sistent with the suggested mechanism. On the other hand, in-
termediate 15b (or a tautomeric form) can undergo ring closure
after the intramolecular attack of the pyridine nitrogen to form
intermediate 18 and thiolate 17b (Scheme 9B). At this point, frag-
mentation can lead to 8. Finally, reaction conditions and the pres-
ence of the nitro group are favorable for a Dimroth rearrangement
to form 7a.32 A plausible mechanism for the Dimroth rearrange-
ment of 8 into 7a involves attack of a nucleophile at the C-5, ring
opening, rotation of the triazole moiety and subsequent ring clo-
sure (Scheme 10).
Entry
Solvent
% Yielda
1
2
3
4
5
6
7
8
9
1,4-Dioxane
EtOH
Toluene
MeCN
DMSO
30
13
42 (37)b
20
30
35
28
32
NMP
NMP/25% H2O
50:50 1,4-Dioxane/NMP
DMA
30
a
Yields were determined by LCeMS after calibration with standard.
Isolated yield from the same experiment after silica chromatography.
b
2.4. Application of reaction conditions to different 1,3,4-
thiadiazol-2-amines and different 2-chloropyridines bearing
a nitro group
To probe the reaction scope, differentially substituted tri-
azolopyridines 7 (Table 4) were synthesized. Although the yields
were generally modest, all the compounds were easily isolated.
Formation of [1,2,4]triazolo[4,3-a]pyridines such as 8 (Scheme 4)
instead of [1,2,4]triazolo[1,5-a]pyridines 7 could not be ruled out
a priori and so all structures were unambiguously assigned by
1He15N HMBC and, when necessary, NOESY NMR experiments (see
Supplementary data).
In support to the suggested mechanism, species such as 14
(Scheme 8) were isolated36 by Anders’ group in a zwitterionic form
and were subsequently alkylated,37 an event that can corroborate
the formation of species like 15.
3. Conclusions
6-Nitro-triazolopyridines (entries 9 and 11) could also be iso-
lated. The best results were obtained with thiadiazoles 2i and 2f
(entries 4 and 6) with reasonable LCeMS yields (51% and 57%,
respectively).
All reactions involving 6a (entries 1e8) showed formation of
sulfane 5b by LCeMS. Similar products (expected masses and re-
tention time) were observed with pyridines 6b-d. Such products
were not isolated.
In this work we presented the discovery and the application of
two new convenient single-step reactions for the synthesis of tri-
azoles 4 and triazolopyridines 7, two interesting heterocyclic motifs
that have found wide application in medicinal chemistry. Both re-
actions were serendipitously discovered and share thiadiazoles 2 as
common starting materials. The single-step nature of these trans-
formations is advantageous when compared with previously

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O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
Table 4
Synthesis of various [1,2,4]triazolo[1,5-a]pyridines
Entry
1
6
2
7
Yield determined by LCeMS (%)a
Isolated yield (%)
2b
45
10
21b
2
6a
6a
6a
2c
8b
13b
47d
3c
2d
19
51
4
5
6a
2e
23
20b
6
7
6a
6a
2f
57
43
56d
2g
33b
8
6a
2h
31
15b
9
2a
2a
49
26
37d
10
19b

O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
1675
Table 4 (continued )
Entry
6
2
7
Yield determined by LCeMS (%)a
Isolated yield (%)
11
2a
32
22b
a
Yields determined by LCeMS after calibration with standard.
Isolated yields after HPLC purification. HPLC isolated yields and LCeMS yields refer to the same experiment.
Reaction performed in NMP.
b
c
d
Isolated yields after silica chromatography. These yields refer to a repeated experiment. HPLC isolated yields for these reactions are reported in Experimental section.
sequence, namely the formation of 4a and 7a from the putative 16
and 18, respectively (Scheme 9), remain unclear. Further in-
vestigation should elucidate these aspects.
4. Experimental section
4.1. General
Commercially available starting materials and solvents were
used without prior purification. All reactions, which were per-
formed in sealed tubes with thermal heating were placed on
a preheated heating block for the time of the reaction. All re-
actions were analyzed by LCeMS. Melting points were reported
without correction. All NMR spectra were recorded at 300 K on
a spectrometer operating at the frequencies of 400.13 MHz (1H),
100.62 MHz (13C), and 40.56 MHz (15N). The 1H and the 13C NMR
spectra were calibrated using the residual solvent peak as stan-
Scheme 5. Synthesis of compounds 9a and 9b (aNMP for 1a, toluene for 6a. bIsolated
yields.).
reported multistep methods and allowed the rapid synthesis of
a set of differently substituted products belonging to the two het-
erocyclic classes. Reaction in absence of base led to the formation of
adducts 9 (Scheme 5). This finding permitted to suggest related
mechanisms for the formation of products 4, 5, and 7, where the
formation of key intermediates 15 is postulated (Scheme 8). Prod-
ucts related to 14 (Scheme 8) and their subsequent alkylation were
already described by Anders and co-workers, giving support to the
presented mechanism. However, some aspects of the mechanistic
dard. Chemical shifts (d) are given in parts per million, coupling
constants (J) in hertz. 15N chemical shifts obtained with 2D
1He15N HMBC experiments, when recorded, are reported in
Supplementary data using nitromethane as reference. HPLC
analyses were run on an apparatus equipped with a C18 column
(1.7
m
m, 2.1ꢁ50 mm). The analyses were executed with a gradient
elution at 0.8 ml/min starting at 95:5 (v/v) 0.1% formic acid in
Fig. 1. X-ray crystal structure of 9b (50% probability ellipsoids).

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O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
Scheme 6. Plausible mechanism for the formation of compounds 9a and 9b.
purifications were performed with a gradient of H2O/MeCN.
Positive ion mode accurate mass spectra (HRMS) were acquired
with a mass spectrometer equipped with a TOF analyzer using
positive electrospray ionization. The MS was calibrated prior to
use with a sodium formate solution. Ions resulting from phtha-
lates present in the mobile phase were used as a lock mass. Re-
actions carried out under microwave irradiation were performed
in sealed tubes in a Biotage InitiatorÔ 2.0 with a maximum ap-
plied power of 400 W.
Scheme 7. Formation of Anders’ triazinium salts.
Scheme 8. Plausible mechanisms for the formation of compounds 4a and 7a (first part).
H2O/MeCN. The composition of the mobile phase was altered to
5:95 (v/v) 0.1% formic acid in H2O/MeCN in 1.2 min. The total cycle
time was 2 min. The preparative HPLC purifications were per-
formed with a mass-directed auto-purification system coupled
Crystallographic data presented in the text (9b) and in
Supplementary data (4a and 7a) are deposited under CCDC num-
bers 894882e894884 and can be obtained free of charge from the
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
with
a ZQ single quadrupole mass spectrometer. All HPLC
Scheme 9. Plausible mechanism for the formation of compounds 4a and 7a (second part).

O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
1677
concentrated and purified by flash column chromatography (SiO2,
50:50/100:0 EtOAc/petroleum ether) to afford 130 mg of com-
pound 4a (48% yield).
4.3.2.1. Compound 4a. Yellow solid; mp 167e169 ꢀC (EtOAc); 1H
NMR (400 MHz, DMSO-d6)
d
8.07 (dd, J¼8.4, 1.6 Hz, 1H), 7.83 (td,
J¼7.6, 1.4 Hz, 1H), 7.69e7.65 (m, 2H), 6.39 (s, 2H), 2.41 (q, J¼7.6 Hz,
2H), 1.13 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d 163.7,
156.3, 145.5, 134.6, 130.3, 129.9, 129.0, 125.6, 21.7, 12.6; HPLC
tR¼0.82 min; HRMS (ESI) m/z calcd for C10H12N5O2 [MþH]þ
234.0986, found 234.0992.
4.3.2.2. Compound 5a. Yellow solid; 123e125 ꢀC (lit.39 mp
Scheme 10. Plausible mechanism for the Dimroth rearrangement of 8 into 7a.
122 ꢀC); 1H NMR (400 MHz, DMSO-d6)
d
8.21 (dd, J¼8.1, 1.5 Hz, 2H),
7.72 (ddd, J¼7.8, 7.6, 1.5 Hz, 2H), 7.64 (ddd, J¼8.1, 7.6, 1.4 Hz, 2H),
7.40 (dd, J¼7.8, 1.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
d 149.5,
4.2. General procedure for the calculation of the LCeMS
yields
134.8, 134.1, 130.4, 129.9, 126.0; HPLC tR¼1.41 min; HRMS (ESI) m/z
calcd for C12H9N2O4S [MþH]þ 277.0278, found 277.0271.
The reported calculated yields were determined by LCeMS.
Calibration curves were made for each compound by measuring
the UV response of three solutions of the purified desired product
at different concentrations (1 mM, 0.1 mM, and 0.01 mM in
MeCN). The yields were then calculated on the basis of the relative
% UV response of the desired product present in a sample pre-
pared by diluting a measured aliquot, taken from the crude re-
action mixture. The analyses were executed on an apparatus
4.4. General procedure for synthesis of triazoles 4
A mixture of 1 (1.55 mmol, unless otherwise stated), 2
(0.77 mmol), and i-Pr2NEt (1.55 mmol) in NMP (0.77 mL) was
stirred at 140 ꢀC in a sealed tube for 16 h. The mixture was
allowed to cool to room temperature, diluted (DCM), washed
(satd Na2CO3), dried (filtered through a BiotageÒ phase separator),
and concentrated. Purification method A: the residue was purified
by reverse phase automated preparative HPLC. Purification method
B: the residue was purified by flash column chromatography
(SiO2).
equipped with a C18 column (1.7
m
m, 2.1ꢁ50 mm) with a gradient
elution at 0.8 ml/min starting at 95:5 (v/v) 14 mM NH3 in H2O/
MeCN. The composition of the mobile phase was altered to 5:95
(v/v) 14 mM in H2O/MeCN in 1.2 min. The total cycle time was
2 min.
4.4.1. 3-tert-Butyl-1-(2-nitrophenyl)-1H-1,2,4-triazol-5-amine (4b,
Table 2, entry 1). Purification method A afforded 13 mg (13% yield)
of desired product. Yellow solid; mp 185e188 ꢀC; 1H NMR
4.3. Preparation of compounds 3, 4a, and 5a
(400 MHz, DMSO-d6)
1.4 Hz, 1H), 7.71e7.64 (m, 2H), 6.40 (s, 2H), 1.20 (s, 9H); 13C NMR
(100 MHz, DMSO-d6) 169.8, 156.2, 145.5, 134.4, 130.4, 129.7, 128.7,
d
8.05 (dd, J¼8.1, 1.4 Hz, 1H), 7.82 (td, J¼7.8,
4.3.1. 5-Ethyl-N-(2-nitrophenyl)-1,3,4-thiadiazol-2-amine
(3). A
mixture of 1-fluoro-2-nitrobenzene 1a (1.00 g, 7.09 mmol), 5-ethyl-
1,3,4-thiadiazol-2-amine 2a (1.10 g, 8.52 mmol), and Cs2CO3 (2.30 g,
7.04 mmol) in 1,4-dioxane (15 ml) was stirred at 100 ꢀC in a round
bottomed flask for 1 h. The mixture was diluted (EtOAc), washed
(0.5 N HCl, satd NaHCO3 and H2O), dried (Na2SO4), and concen-
trated. The residue was purified by flash column chromatography
(SiO2, 95:5/70:30 petroleum ether/EtOAc) to afford 520 mg (29%
yield) of desired product. Orange solid; mp 84e86 ꢀC; 1H NMR
d
125.5, 32.8, 29.5; HPLC tR¼1.02 min; HRMS (ESI) m/z calcd for
C12H16N5O2 [MþH]þ 262.1299, found 262.1294.
4.4.2. 1-(2-Nitrophenyl)-3-phenyl-1H-1,2,4-triazol-5-amine
(4c,
Table 2, entry 2). Purification method A afforded 11 mg (10% yield)
of desired product. Yellow solid; mp 226e227 ꢀC; 1H NMR
(400 MHz, DMSO-d6)
d
8.15 (dd, J¼8.1, 1.4 Hz, 1H), 7.92e7.86 (m,
(400 MHz, CDCl3)
d
10.62 (s, 1H), 8.74 (dd, J¼8.6, 1.0 Hz, 1H), 8.27
3H), 7.79 (dd, J¼8.0, 1.4 Hz, 1H), 7.74 (ddd, J¼8.1, 7.6, 1.4 Hz, 1H),
(dd, J¼8.4, 1.5 Hz, 1H), 7.69e7.65 (m, 1H), 7.11e7.07 (m, 1H), 3.06 (q,
7.45e7.39 (m, 3H), 6.66 (s, 2H); 13C NMR (100 MHz, DMSO-d6)
J¼7.6 Hz, 2H), 1.42 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
159.6, 156.9, 145.5, 134.8, 131.5, 130.5, 130.1, 129.4, 129.4, 128.9,
d
165.3, 162.6, 137.3, 136.6, 134.5, 126.2, 121.4, 119.9, 24.0, 13.9; HPLC
126.0, 125.8; HPLC tR¼1.16 min; HRMS (ESI) m/z calcd for
tR¼1.24 min; HRMS (ESI) m/z calcd for C10H11N4O2S [MþH]þ
C14H12N5O2 [MþH]þ 282.0986, found 282.0992.
251.0597, found 251.0615.
4.4.3. 3-Benzyl-1-(2-nitrophenyl)-1H-1,2,4-triazol-5-amine
Table 2, entry 3). Purification method A afforded 25 mg (22% yield).
Yellow solid; mp 170e172 ꢀC; 1H NMR (400 MHz, DMSO-d6)
8.09
(4d,
4.3.2. 3-Ethyl-1-(2-nitrophenyl)-1H-1,2,4-triazol-5-amine (4a) and
bis(2-nitrophenyl)sulfane
nitrobenzene 1a (489
(5a). A
mixture
of
1-fluoro-2-
d
m
l, 4.64 mmol), 5-ethyl-1,3,4-thiadiazol-2-
(dd, J¼8.2, 1.4 Hz, 1H), 7.83 (td, J¼7.6, 1.4 Hz, 1H), 7.71e7.67 (m, 2H),
amine 2a (300 mg, 2.32 mmol), and i-Pr2NEt (0.81 ml,
4.64 mmol) in NMP (2.3 ml) was stirred at 140 ꢀC in a sealed tube
for 16 h. The mixture was allowed to cool to room temperature,
diluted (DCM), washed (satd NaHCO3), dried (filtered through
a BiotageÒ phase separator), and concentrated. The residue was
loaded on an ion exchange resin (BiotageÒ SCX-3). The adsorbed
material was first eluted with MeOH and then with 2 N NH3/MeOH.
The first fraction was concentrated, diluted (EtOAc), washed
(H2Oꢁ5), dried (Na2SO4), and concentrated. The residue was puri-
fied by flash column chromatography (SiO2, 2:98/20:80 EtOAc/
petroleum ether) to afford 136 mg of compound 5a (21% yield). Also
6 mg (1% yield) of 3 were obtained. The second fraction was
7.31e7.23 (m, 4H), 7.22e7.19 (m, 1H), 6.44 (s, 2H), 3.74 (s, 2H); 13C
NMR (100 MHz, DMSO-d6)
d 161.5, 156.5, 145.5, 138.7, 134.6, 130.1,
130.0, 129.1, 129.1, 128.6, 126.5, 125.7, 34.6; HPLC tR¼1.11 min;
HRMS (ESI) m/z calcd for C15H14N5O2 [MþH]þ 296.1142, found
296.1141.
4.4.4. 3-(Methoxymethyl)-1-(2-nitrophenyl)-1H-1,2,4-triazol-5-
amine (4e, Table 2, entry 4). Purification method A afforded 28 mg
(29% yield) of desired product. Beige solid; mp 122e124 ꢀC; 1H
NMR (400 MHz, CDCl3)
J¼7.7, 1.5 Hz, 1H), 7.68e7.61 (m, 2H), 4.77 (s, 2H), 4.40 (s, 2H), 3.43
(s, 3H); 13C NMR (100 MHz, CDCl3)
159.8, 155.6, 145.8, 134.0,
d
8.07 (dd, J¼8.2, 1.4 Hz, 1H), 7.77 (td,
d

1678
O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
130.5, 129.6, 129.1, 125.7, 67.5, 58.5; HPLC tR¼0.84 min; HRMS
(ESI) m/z calcd for C10H12N5O3 [MþH]þ 250.0935, found
250.0934.
HRMS (ESI) m/z calcd for C11H14N5O3 [MþH]þ 264.1091, found
264.1094.
4.4.10. 3-Ethyl-1-(4-fluoro-2-nitrophenyl)-1H-1,2,4-triazol-5-amine
(4k, Table 2, entry 10). In a first experiment, 2.23 mmol of 1,4-
difluoro-2-nitrobenzene 1d were used. Purification method A
afforded 45 mg (47% yield) of desired product. In a second exper-
iment, 2.23 mmol of 1,4-difluoro-2-nitrobenzene 1d were used.
Purification method B (eluent: 20:80/100:0 EtOAc/DCM) afforded
75 mg (78% yield) of desired product. Yellow solid; mp 188e190 ꢀC;
4.4.5. 3-Cyclopropyl-1-(2-nitrophenyl)-1H-1,2,4-triazol-5-amine (4f,
Table 2, entry 5). In a first experiment, purification method A
afforded 37 mg (39% yield) of desired product. From a second
experiment, carried out in the same conditions as the first one,
purification method B (eluent: 20:80/100:0 EtOAc/DCM and then
100:0/98.5:1.5 DCM/2 N NH3 in MeOH) afforded 59 mg (62%
yield) of desired product. Yellow solid; mp 160e162 ꢀC; 1H NMR
1H NMR (400 MHz, DMSO-d6)
d 8.12e8.10 (m, 1H), 7.76e7.74 (m,
(400 MHz, CDCl3)
1.5 Hz, 1H), 7.64e7.58 (m, 2H), 4.61 (s, 2H), 1.92e1.85 (m, 1H),
0.92e0.90 (m, 4H); 13C NMR (100 MHz, CDCl3)
164.9, 154.9,
d
8.02 (dd, J¼8.2, 1.4 Hz, 1H), 7.74 (td, J¼7.9,
2H), 6.39 (s, 2H), 2.41 (q, J¼7.6 Hz, 2H), 1.13 (t, J¼7.6 Hz, 3H); 13C
NMR (100 MHz, DMSO-d6)
d 163.7, 162.3, 159.8, 156.6, 146.2, 146.1,
d
131.6, 131.6, 126.9, 126.9, 121.7, 121.5, 113.6, 113.4, 21.7, 12.6; HPLC
tR¼0.89 min; HRMS (ESI) m/z calcd for C10H11N5O2F [MþH]þ
252.0891, found 252.0900.
145.8, 133.9, 130.1, 129.8, 129.0, 125.6, 8.9, 7.4; HPLC tR¼0.91 min;
HRMS (ESI) m/z calcd for C11H12N5O2 [MþH]þ 246.0986, found
246.0997.
4.4.11. 3-Ethyl-1-(2-methyl-6-nitrophenyl)-1H-1,2,4-triazol-5-amine
(4l, Table 2, entry 11). Purification method A afforded 14 mg (15%
yield) of desired product. Yellow solid; mp 160e163 ꢀC; 1H NMR
4.4.6. 1-(2-Nitrophenyl)-3-propyl-1H-1,2,4-triazol-5-amine
(4g,
Table 2, entry 6). In a first experiment, purification method A
afforded 33 mg (35% yield) of desired product. From a second
experiment, carried out in the same conditions as the first one,
purification method B (eluent: 25:75/100:0 EtOAc/DCM) affor-
ded 46 mg (48% yield) of desired product. Beige solid; mp
(400 MHz, DMSO-d6)
d
7.92 (d, J¼8.0 Hz, 1H), 7.76 (d, J¼7.9 Hz, 1H),
7.63 (t, J¼7.9 Hz, 1H), 6.26 (s, 2H), 2.41 (q, J¼7.6 Hz, 2H), 2.15 (s, 3H),
1.13 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d 163.9, 156.9,
147.6, 139.9, 136.1, 130.4, 128.9, 123.0, 21.8, 17.5, 12.7; HPLC
tR¼0.88 min; HRMS (ESI) m/z calcd for C11H14N5O2 [MþH]þ
248.1142, found 248.1153.
146.5e147.4 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.03 (dd, J¼7.9, 1.5 Hz,
1H), 7.75 (td, J¼7.7, 1.5 Hz, 1H), 7.64e7.60 (m, 2H), 4.79 (s, 2H), 2.54
(t, J¼7.4 Hz, 2H), 1.73 (sext, J¼7.4 Hz, 2H), 0.97 (t, J¼7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d
163.5, 155.0, 145.9, 133.8, 130.1, 129.9,
4.4.12. 1-(4-Bromo-2-nitrophenyl)-3-methyl-1H-1,2,4-triazol-5-
amine (4m, Table 2, entry 12). In a first experiment, 1.16 mmol of 4-
bromo-1-fluoro-2-nitrobenzene 1b were used. Purification method
A afforded 52 mg (45% yield) of desired product. In a second ex-
periment, 1.16 mmol of 4-bromo-1-fluoro-2-nitrobenzene 1b were
used. Purification method B (eluent: 30:70/100:0 EtOAc/DCM)
afforded 74 mg (64% yield) of desired product. Brown solid; mp
128.9, 125.6, 30.3, 21.1, 13.7; HPLC tR¼0.94 min; HRMS (ESI) m/z
calcd for C11H14N5O2 [MþH]þ 248.1142, found 248.1158.
4.4.7. 3-Methyl-1-(2-nitrophenyl)-1H-1,2,4-triazol-5-amine
(4h,
Table 2, entry 7). In a first experiment, purification method A
afforded 28 mg (33% yield) of desired product. From a second
experiment, carried out in the same conditions as the first one,
225e226 ꢀC; 1H NMR (400 MHz, DMSO-d6)
8.04 (dd, J¼8.5, 2.2 Hz, 1H), 7.62 (d, J¼8.5 Hz, 1H), 6.46 (s, 2H), 2.04
(s, 3H); 13C NMR (100 MHz, DMSO-d6)
159.3, 156.4, 145.9, 137.2,
d
8.34 (d, J¼2.2 Hz, 1H),
purification method
afforded 66 mg (78% yield) of desired product. Yellow solid; mp
183e184 ꢀC; 1H NMR (400 MHz, CDCl3)
8.03 (dd, J¼8.1, 1.2 Hz,
1H), 7.75 (td, J¼7.7, 1.5 Hz, 1H), 7.65e7.58 (m, 2H), 4.62 (s, 2H),
2.26 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.9, 155.1, 145.8,
B (eluent: 40:60/100:0 EtOAc/DCM)
d
d
130.7, 129.4, 128.2, 121.5, 14.2; HPLC tR¼0.95 min; HRMS (ESI) m/z
calcd for C9H9N5O2Br [MþH]þ 297.9934, found 297.9938.
d
133.9, 130.2, 129.8, 129.0, 125.6, 14.0; HPLC tR¼0.69 min; HRMS
(ESI) m/z calcd for C9H10N5O2 [MþH]þ 220.0829, found
220.0842.
4.4.13. 1-(4-Fluoro-2-nitrophenyl)-3-methyl-1H-1,2,4-triazol-5-
amine (4n, Table 2, entry 13). In a first experiment,1.16 mmol of 1,4-
difluoro-2-nitrobenzene 1d were used. Purification method A
afforded 25 mg (27% yield) of desired product. In a second exper-
iment, 1.16 mmol of 1,4-difluoro-2-nitrobenzene 1d were used.
Purification method B (eluent: 40:60/100:0 EtOAc/DCM) afforded
54 mg (59% yield) of desired product. Yellow solid; mp 201e204 ꢀC;
4.4.8. 1-(4-Bromo-2-nitrophenyl)-3-ethyl-1H-1,2,4-triazol-5-amine
(4i, Table 2, entry 8). In a first experiment, 2.75 mmol of 4-bromo-
1-fluoro-2-nitrobenzene 1b were used. Purification method A
afforded 38 mg (32% yield) of desired product. In a second exper-
iment, 1.16 mmol of 4-bromo-1-fluoro-2-nitrobenzene 1b were
used. Purification method B (eluent: 30:70/100:0 EtOAc/DCM)
afforded 56 mg (47% yield) of desired product. Brown solid; mp
1H NMR (400 MHz, DMSO-d6)
2H), 6.39 (s, 2H), 2.04 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d
8.13e8.10 (m, 1H), 7.76e7.73 (m,
162.3,
d
159.8, 159.0, 156.6, 146.2, 146.1, 131.7, 131.6, 126.8, 126.8, 121.7, 121.5,
113.6, 113.4, 14.3; HPLC tR¼0.78 min; HRMS (ESI) m/z calcd for
C9H9N5O2F [MþH]þ 238.0735, found 238.0742.
186e188 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
8.33 (d, J¼2.2 Hz, 1H),
8.03 (dd, J¼8.5, 2.2 Hz, 1H), 7.64 (d, J¼8.5 Hz, 1H), 6.46 (s, 2H), 2.40
(q, J¼7.5 Hz, 2H), 1.13 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, DMSO-
4.5. Preparation of compounds 7a and 5b
d6)
d 164.0, 156.4, 145.9, 137.2, 130.7, 129.5, 128.2, 121.5, 21.7, 12.5;
HPLC tR¼1.04 min; HRMS (ESI) m/z calcd for C10H11N5O2Br [MþH]þ
4.5.1. 2-Ethyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7a). A mixture
of 2-chloro-3-nitropyridine 6a (246 mg, 1.55 mmol), 5-ethyl-1,3,4-
thiadiazol-2-amine 2a (100 mg, 0.77 mmol), and i-Pr2NEt (0.27 ml,
1.55 mmol) in toluene (0.77 ml) was stirred at 120 ꢀC in a sealed
tube for 16 h. The mixture was allowed to cool to room tempera-
ture, diluted (DCM), washed (satd NaHCO3), dried (filtered through
a BiotageÒ phase separator), and concentrated. The residue was
purified by flash column chromatography (SiO2, 100:0/90:10
DCM/EtOAc) to afford 55 mg of compound 7a (37% yield). Beige
312.0091, found 312.0096.
4.4.9. (4-(5-Amino-3-ethyl-1H-1,2,4-triazol-1-yl)-3-nitrophenyl)
methanol (4j, Table 2, entry 9). Purification method A afforded
6 mg (6% yield) of desired product. Yellow solid; mp 243e246 ꢀC;
1H NMR (400 MHz, DMSO-d6)
d
7.99 (d, J¼1.8 Hz, 1H), 7.75 (dd,
J¼8.1, 1.8 Hz, 1H), 7.62 (d, J¼8.1 Hz, 1H), 6.34 (s, 2H), 5.58 (t,
J¼5.8 Hz, 1H), 4.64 (d, J¼5.8 Hz, 2H), 2.41 (q, J¼7.6 Hz, 2H), 1.13 (t,
J¼7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d
163.5, 156.4, 145.3,
solid; mp 161e162 ꢀC; 1H NMR (400 MHz, DMSO-d6)
J¼6.7, 1.1 Hz, 1H), 8.62 (dd, J¼7.9, 1.1 Hz, 1H), 7.33 (dd, J¼7.9, 6.7 Hz,
d 9.31 (dd,
145.2, 131.8, 129.0, 128.7, 122.8, 61.9, 21.7, 12.6; HPLC tR¼0.75 min;

O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
1679
1H), 2.94 (q, J¼7.6 Hz, 2H),1.36 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
desired product. From a second experiment, carried out in the same
conditions as the first one, purification method (eluent:
DMSO-d6)
d
170.2, 145.2, 135.9, 135.6, 129.3, 112.3, 22.1, 12.6; HPLC
B
tR¼0.88 min; HRMS (ESI) m/z calcd for C8H9N4O2 [MþH]þ 193.0720,
100:0/90:10 DCM/EtOAc) afforded 75 mg (47% yield) of desired
found 193.0730.
product. Brown solid; mp 100e101 ꢀC; 1H NMR (400 MHz, DMSO-
d6)
d
9.32 (dd, J¼6.7, 1.0 Hz, 1H), 8.62 (dd, J¼7.9, 1.0 Hz, 1H), 7.33 (dd,
4.5.2. Bis(3-nitropyridin-2-yl)sulfane (5b). A mixture of 2-chloro-3-
nitropyridine 6a (1.47 g, 9.29 mmol), 5-ethyl-1,3,4-thiadiazol-2-
amine 2a (600 mg, 4.65 mmol), and i-Pr2NEt (1.60 ml,
4.64 mmol) in NMP (4.6 ml) was stirred at 120 ꢀC in a sealed tube
for 16 h. The mixture was allowed to cool to room temperature,
diluted (DCM), washed (satd NaHCO3), dried (filtered through
a BiotageÒ phase separator), and concentrated. The residue was
purified by flash column chromatography (SiO2, 50:50/70:30
EtOAc/petroleum ether and then 100:0/95:5 DCM/MeOH) to af-
ford 55 mg of compound 5b (4% yield). Also 150 mg of 7a were
obtained (17% yield). Compound 5b: yellow solid; mp 165e168 ꢀC;
J¼7.9, 6.7 Hz, 1H), 3.28e3.23 (m, 1H), 1.39 (d, J¼6.9 Hz, 6H); 13C
NMR (100 MHz, DMSO-d6)
d 173.7, 145.2, 136.0, 135.7, 129.3, 112.3,
28.6, 21.9; HPLC tR¼1.01 min; HRMS (ESI) m/z calcd for C9H11N4O2
[MþH]þ 207.0877, found 207.0885.
4.6.5. 2-(Methoxymethyl)-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7f,
Table 4, entry 5). Purification method A afforded 32 mg (20% yield)
of desired product. Brown solid; mp 137e140 ꢀC; 1H NMR
(400 MHz, DMSO-d6)
d
9.37 (dd, J¼6.7, 1.0 Hz, 1H), 8.68 (dd, J¼7.9,
1.0 Hz, 1H), 7.41 (dd, J¼7.9, 6.7 Hz, 1H), 4.71 (s, 2H), 3.40 (s, 3H); 13C
NMR (100 MHz, DMSO-d6)
d 165.4, 145.3, 136.4, 136.0, 129.8, 113.0,
1H NMR (400 MHz, DMSO-d6)
d
8.73 (dd, J¼4.7,1.6 Hz, 2H), 8.63 (dd,
67.4, 58.7; HPLC tR¼0.77 min; HRMS (ESI) m/z calcd for C8H9N4O3
J¼8.2, 1.6 Hz, 2H), 7.66 (dd, J¼8.2, 4.7 Hz, 2H); 13C NMR (100 MHz,
[MþH]þ 209.0669, found 209.0678.
DMSO-d6)
d
154.1, 150.3, 146.1, 134.6, 124.1; HPLC tR¼1.20 min;
HRMS (ESI) m/z calcd for C10H7N4O4S [MþH]þ 279.0183, found
4.6.6. 2-Cyclopropyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7g, Table
4, entry 6). Purification method A afforded 39 mg (25% yield) of
desired product. From a second experiment, carried out in the same
279.0187.
4.6. General procedure for synthesis of triazopyridines 7
conditions as the first one, purification method B (eluent:
100:0/90:10 DCM/EtOAc) afforded 88 mg (56% yield) of desired
A mixture of 6 (1.55 mmol), 2 (0.77 mmol), and i-Pr2NEt
(1.55 mmol) in toluene (unless otherwise stated) (0.77 ml) was
stirred at 120 ꢀC in a sealed tube for 16 h. The mixture was allowed
to cool to room temperature. Purification method A: the mixture was
concentrated and the residue was purified by reverse phase auto-
mated preparative HPLC. Purification method B: the mixture was
concentrated and the residue was purified by flash column chro-
matography (SiO2). Purification method C: the mixture was diluted
(DCM), washed (satd Na2CO3), dried (filtered through a BiotageÒ
phase separator), and concentrated. The residue was purified by
reverse phase automated preparative HPLC.
product. Brown solid; mp 124e125 ꢀC; 1H NMR (400 MHz, DMSO-
d6)
J¼7.9, 6.7 Hz, 1H), 2.29e2.23 (m, 1H), 1.15e1.09 (m, 2H), 1.08e1.03
(m, 2H); 13C NMR (100 MHz, DMSO-d6)
170.8, 145.3, 135.6, 135.3,
d
9.25 (dd, J¼6.7, 1.0 Hz,1H), 8.59 (dd, J¼7.9, 1.0 Hz, 1H), 7.30 (dd,
d
129.2, 112.1, 9.6, 9.6; HPLC tR¼0.96 min; HRMS (ESI) m/z calcd for
C9H9N4O2 [MþH]þ 205.0720, found 205.0734.
4.6.7. 8-Nitro-2-propyl-[1,2,4]triazolo[1,5-a]pyridine (7h, Table 4,
entry 7). Purification method A afforded 52 mg (33% yield) of de-
sired product. Brown solid; mp 79e81 ꢀC; 1H NMR (400 MHz,
DMSO-d6)
d
9.31 (dd, J¼6.7, 1.0 Hz, 1H), 8.62 (dd, J¼7.9, 1.0 Hz, 1H),
7.33 (dd, J¼7.9, 6.7 Hz, 1H), 2.89 (t, J¼7.4 Hz, 2H), 1.83 (sext,
4.6.1. 2-tert-Butyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7b, Table 4,
entry 1). Purification method A afforded 35 mg (21% yield) of de-
sired product. Yellow solid; mp 133e135 ꢀC; 1H NMR (400 MHz,
J¼7.4 Hz, 2H), 0.98 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d
169.1, 145.2, 135.9, 135.6, 129.3, 112.3, 30.5, 21.4, 14.2; HPLC
tR¼1.01 min; HRMS (ESI) m/z calcd for C9H11N4O2 [MþH]þ
DMSO-d6)
d
9.33 (dd, J¼6.6, 1.0 Hz, 1H), 8.61 (dd, J¼7.9, 1.0 Hz, 1H),
207.0877, found 207.0883.
7.33 (dd, J¼7.9, 6.6 Hz, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, DMSO-
d6)
d
176.2, 145.2, 136.1, 135.8, 129.3, 112.3, 33.6, 29.8; HPLC
4.6.8. 2-Methyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7i, Table 4,
entry 8). Purification method A afforded 21 mg (15% yield) of de-
sired product. Yellow solid; mp 193e194 ꢀC (lit.32 mp 195e196 ꢀC);
tR¼1.16 min; HRMS (ESI) m/z calcd for C10H13N4O2 [MþH]þ
221.1033, found 221.1047.
1H NMR (400 MHz, DMSO-d6)
d
9.29 (dd, J¼6.7, 0.9 Hz, 1H), 8.62
4.6.2. 8-Nitro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (7c, Table 4,
entry 2). Purification method A afforded 15 mg (8% yield) of desired
product. Yellow solid; mp 227e229 ꢀC (lit.31 mp 226 ꢀC); 1H NMR
(dd, J¼7.9, 0.9 Hz, 1H), 7.33 (dd, J¼7.9, 6.7 Hz, 1H), 2.57 (s, 3H); 13C
NMR (100 MHz, DMSO-d6)
d 165.7, 145.5, 135.8, 135.5, 129.3, 112.3,
14.6; HPLC tR¼0.75 min; HRMS (ESI) m/z calcd for C7H7N4O2
(400 MHz, DMSO-d6)
8.28e8.26 (m, 2H), 7.61e7.58 (m, 3H), 7.41 (dd, J¼7.9, 6.8 Hz, 1H);
13C NMR (100 MHz, DMSO-d6)
165.1, 146.0, 136.3, 135.9, 131.4,
d
9.42 (d, J¼6.8 Hz, 1H), 8.68 (d, J¼7.9 Hz, 1H),
[MþH]þ 179.0564, found 179.0573.
d
4.6.9. 2-Ethyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (7j, Table 4, entry
9). Purification method A afforded 38 mg (26% yield) of desired
product. From a second experiment, carried out in the same con-
ditions as the first one, purification method B (eluent: 95:5/70:30
petroleum ether/EtOAc and then 100:0/80:20 DCM/EtOAc)
afforded 55 mg (37% yield) of desired product. Yellow solid; mp
130.0, 129.7, 129.5, 127.7, 113.1; HPLC tR¼1.21 min; HRMS (ESI) m/z
calcd for C12H9N4O2 [MþH]þ 241.0720, found 241.0723.
4.6.3. 2-Benzyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7d, Table 4,
entry 3). NMP was used instead of toluene as solvent. Purification
method C afforded 25 mg (13% yield) of desired product. Yellow
solid; mp 137e138 ꢀC (lit.32 mp 137e143 ꢀC); 1H NMR (400 MHz,
133e135 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
10.03 (dd, J¼2.2,
0.7 Hz, 1H), 8.32 (dd, J¼9.7, 2.2 Hz, 1H), 7.89 (dd, J¼9.7, 0.7 Hz, 1H),
DMSO-d6)
d
9.33 (dd, J¼6.7, 1.0 Hz, 1H), 8.63 (dd, J¼7.9, 1.0 Hz),
2.92 (q, J¼7.6 Hz, 2H), 1.33 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
7.38e7.30 (m, 5H), 7.24 (t, J¼7.1 Hz, 1H), 4.29 (s, 2H); 13C NMR
DMSO-d6) d 171.9, 152.6, 137.8, 129.4, 124.9, 115.3, 22.2, 12.5; HPLC
(100 MHz, DMSO-d6)
d
167.9, 145.4, 137.8, 136.1, 135.7, 129.5, 129.4,
tR¼1.01 min; HRMS (ESI) m/z calcd for C8H9N4O2 [MþH]þ 193.0720,
128.9,127.0,112.6, 34.8; HPLC tR¼1.15 min; HRMS (ESI) m/z calcd for
found 193.0726.
C13H11N4O2 [MþH]þ 255.0877, found 255.0892.
4.6.10. 6-Chloro-2-ethyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7k,
Table 4, entry 10). Purification method A afforded 33 mg (19% yield)
of desired product. Light brown solid; mp 135e137 ꢀC; 1H NMR
4.6.4. 2-Isopropyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (7e, Table 4,
entry 4). Purification method A afforded 26 mg (16% yield) of

1680
O. Mammoliti et al. / Tetrahedron 69 (2013) 1669e1680
(400 MHz, DMSO-d6)
d
9.74 (d, J¼1.9 Hz, 1H), 8.74 (d, J¼1.9 Hz, 1H),
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.11.101.
2.94 (q, J¼7.6 Hz, 2H), 1.35 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6)
d 170.7, 144.4, 135.3, 134.2, 129.6, 118.5, 22.1, 12.6; HPLC
tR¼1.06 min; HRMS (ESI) m/z calcd for C8H8N4O2Cl [MþH]þ
References and notes
227.0330, found 227.0341.
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4.6.11. 2-Ethyl-7-methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine
(7l,
Table 4, entry 11). Purification method A afforded 35 mg (22% yield)
of desired product. Beige solid; mp 134e135 ꢀC; 1H NMR (400 MHz,
DMSO-d6)
d
9.85 (s, 1H), 7.80 (s, 1H), 2.88 (q, J¼7.6 Hz, 2H), 2.64 (s,
3H), 1.33 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d 171.7,
151.8, 139.5, 135.8, 129.2, 116.2, 22.1, 20.5, 12.5; HPLC tR¼1.09 min;
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207.0888.
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4.7.1. 5-Ethyl-N-(5-ethyl-3-(2-nitrophenyl)-1,3,4-thiadiazol-2(3H)-
ylidene)-1,3,4-thiadiazol-2-amine (9a). A mixture of 1-fluoro-2-
nitrobenzene 1a (100 mg, 0.71 mmol) and 5-ethyl-1,3,4-
thiadiazol-2-amine 2a (92 mg, 0.71 mmol) in NMP (0.5 ml) was
stirred at 140 ꢀC in a sealed tube for 16 h. The reaction was stopped
and the mixture was purified by automated preparative HPLC. The
purification afforded 11 mg (9% yield) of desired product. Yellow
solid; 164e166 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
8.18 (dd, J¼8.1,
1.3 Hz, 1H), 7.98e7.94 (m, 1H), 7.90 (dd, J¼8.1, 1.5 Hz, 1H), 7.79 (ddd,
J¼8.1, 7.3, 1.5 Hz, 1H), 2.98e2.92 (m, 4H), 1.30 (t, J¼7.5 Hz, 3H), 1.26
(t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d 170.4, 167.2, 159.4,
159.4, 144.9, 135.1, 130.9, 130.8, 129.8, 125.8, 24.3, 24.0, 14.2, 12.6;
HPLC tR¼1.44 min; HRMS (ESI) m/z calcd for C14H15N6O2S2 [MþH]þ
363.0692, found 363.0712.
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2(3H)-ylidene)-1,3,4-thiadiazol-2-amine (9b). A mixture of 2-
chloro-3-nitropyridine 6a (244 mg, 1.54 mmol) and 5-ethyl-1,3,4-
thiadiazol-2-amine 2a (200 mg, 1.54 mmol) in toluene (1.5 ml)
was stirred at 140 ꢀC in a sealed tube for 16 h. The mixture was
allowed to cool to room temperature, diluted (DCM), washed (satd
NaHCO3), dried (filtered through a BiotageÒ phase separator), and
concentrated. The residue was purified by flash column chroma-
tography (SiO2, 90:10/50:50 petroleum ether/EtOAc). The purifi-
cation afforded 146 mg (52% yield) of desired product. Yellow solid;
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mp 152e154 ꢀC (MeOH); 1H NMR (400 MHz, DMSO-d6)
d 8.98 (dd,
J¼4.8, 1.6 Hz, 1H), 8.71 (dd, J¼8.2, 1.6 Hz 1H), 7.93 (dd, J¼8.2, 4.8 Hz,
1H), 3.01e2.93 (m, 4H), 1.31 (t, J¼7.4 Hz, 3H), 1.26 (t, J¼7.4 Hz, 3H);
13C NMR (100 MHz, DMSO-d6)
d 170.0, 167.8, 159.9, 159.5, 154.0,
141.8, 141.6, 136.0, 126.9, 24.5, 24.1, 14.3, 12.6; HPLC tR¼1.32 min;
HRMS (ESI) m/z calcd for C13H14N7O2S2 [MþH]þ 364.0645, found
364.0647.
Acknowledgements
We greatly acknowledge Dr. Martin Andrews for assisting the
revision of the manuscript.
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Supplementary data
€
€
36. Wermann, K.; Walther, M.; Gunther, W.; Gorls, H.; Anders, E. Eur. J. Org. Chem.
1H, 13C NMR spectra and LCeMS reports of compounds 3, 4aen,
5a,b, 7ael, and 9a,b, 1He15N HMBC 2D spectra and relative
chemical shifts of compounds 3, 4aen, 7ael and 9a,b, 1He15N
HMQC 2D spectrum of compound 3, NOESY spectra of compounds
8jel, ORTEP representations of compounds 4a, 7a, and 9b.
2003, 1389e1403.
€
€
37. Wermann, K.; Walther, M.; Gunther, W.; Gorls, H.; Anders, E. Tetrahedron 2005,
61, 673e685.
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€
€
39. Farrington, K. J. Aust. J. Chem. 1959, 12, 196e198.