A straightforward, one-pot protocol for the synthesis of fused 3-aminotriazoles

Article abstract of DOI:10.1021/jo9009084

(Chemical Equation Presented) A simple protocol for the synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines is reported. The newly developed one-pot methodology involves the reaction of hydrazinopyridine with isothiocyanates to give the corresponding thiosemicarbazides, which are further desulfurized in situ using polymer-supported Mukaiyama's reagent to promote the final cyclization and formation of the central core. Aryl isothiocyanates bearing both electron-donating and electron-withdrawing groups are well tolerated, and the expected compounds were obtained in excellent purities and yields after removal of salts with a SPE-NH₂ column. This methodology proved to be robust in the extension to 3-amino-[1,2,4]triazolo[4,3-a]-pyrazines and 3-amino-[1,2,4]triazolo[4,3-c]-pyrimidines, and no significant differences were noticed in terms of purities and yields. The straightforward protocol developed, mix, filter, and evaporate, is appropriate for performing multiple reactions in parallel fashion without need of purification.

Full text of DOI:10.1021/jo9009084

pubs.acs.org/joc
A Straightforward, One-Pot Protocol for the Synthesis of Fused
3-Aminotriazoles
†
Horacio Comas, Gerald Bernardinelli, and Dominique Swinnen*
‡
,†
ꢀ
†Chemistry Department, Merck Serono Geneva Research Center, 9 Chemin des Mines, 1202 Geneva,
Switzerland, and ‡Laboratoire de Crystallographie, Universiteꢀ de Geneꢁve, 24 quai Ernest Ansermet,
1211 Geneva, Switzerland
dominique.swinnen@merckserono.net
Received May 1, 2009
A simple protocol for the synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines is reported. The newly
developed one-pot methodology involves the reaction of hydrazinopyridine with isothiocyanates to give
the corresponding thiosemicarbazides, which are further desulfurized in situ using polymer-supported
Mukaiyama’s reagent to promote the final cyclization and formation of the central core. Aryl isothio-
cyanates bearing both electron-donating and electron-withdrawing groups are well tolerated, and the
expected compounds were obtained in excellent purities and yields after removal of salts with a SPE-NH2
column. This methodology proved to be robust in the extension to 3-amino-[1,2,4]triazolo[4,3-a]-pyrazines
and 3-amino-[1,2,4]triazolo[4,3-c]-pyrimidines, and no significant differences were noticed in terms of
purities and yields. The straightforward protocol developed, mix, filter, and evaporate, is appropriate for
performing multiple reactions in parallel fashion without need of purification.
Introduction
3-amino-[1,2,4]triazolo[1,5-a]pyridines as central scaffolds
in drug discovery is very limited due to the lack of generally
applicable methodology for their synthesis starting from
commercially readily available precursors. To the best of
our knowledge, only three approaches have described the
synthesis of N-unsubstituted 3-amino-[1,2,4]triazolo[1,5-a]-
pyridines (R2=H) (Scheme 1).2
Triazolopyridine derivatives are an important class
of molecules in medicinal chemistry and can be found in
many biologically active compounds.1 However, the use of
(1) For recent examples of biologically active [1,2,4]triazolo[1,5-a]pyri-
dines, see: (a) Samori, C.; Guerrini, A.; Varchi, G.; Fontana, G.; Bombardelli,
E.; Tinelli, S.; Beretta, G. L.; Basili, S.; Moro, S.; Zunino, F.; Battaglia, A. J.
Med. Chem. 2009, 52, 1029–1039. (b) Guan, L.-P.; Jin, Q.-H.; Wang, S.-F.; Li,
F.-N; Quan, Z.-S. Arch. Pharm. Chem. Life Sci. 2008, 341, 774–779. (c) Roma,
G.; Grossi, G.; Di Braccio, M.; Piras, D.; Ballabeni, V.; Tognolini, M.;
Bertoni, S.; Barocelli, E. Eur. J. Med. Chem. 2008, 43, 1665–1680. (d) Cappelli,
A.; Giuliani, G.; Anzini, M.; Riitano, D.; Giorgi, G.; Vomero, S. Bioorg. Med.
Chem. 2008, 16, 6850–6859. (e) Pierce, A. C.; Jacobs, M.; Stuver-Moody, C. J.
Med. Chem. 2008, 51, 1972–1975. (f) Nayana, M. R. S.; Sekhar, Y. N.;
Kumari, N. S.; Mahmood, S. K.; Ravikumar, M. Eur. J. Med. Chem. 2008,
43, 1261–1269. (g) Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He,
J.; Harper, B.; Park, Y.-J.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He, H.;
Leiting, B.; Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.;
Petrov, A.; Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu, J. K.; Xu, S.; Zhu,
B.; Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2006, 49, 3614–3627. (h)
Kenyon, V.; Chorny, I.; Carvajal, W. J.; Holman, T. R.; Jacobson, M. P. J.
Med. Chem. 2006, 49, 1356–1363. (i) McClure, K. F.; Letavic, M. A.;
Kalgutkar, A. S.; Gabel, C. A.; Audoly, L.; Barberia, J. T.; Braganza, J. F.;
Carter, D.; Carty, T. J.; Cortina, S. R.; Dombroski, M. A.; Donahue, K. M.;
Elliott, N. C.; Gibbons, C. P.; Jordan, C. K.; Kuperman, A. V.; Labasi, J. M.;
LaLiberte, R. E.; McCoy, J. M.; Naiman, B. M.; Nelson, K. L.; Nguyen, H. T.;
Peese, K. M.; Sweeney, F. J.; Taylor, T. J.; Trebino, C. E.; Abramov, Y. A.;
Laird, E. R.; Volberg, W. A.; Zhou, J.; Bach, J.; Lombardo, F. Bioorg. Med.
Chem. Lett. 2006, 16, 4339–4344.
The first synthesis involves the reaction of 2-bromopyr-
idine with thiosemicarbazide via an oxidative cyclization of
the corresponding adduct under heating conditions, afford-
ing the product after purification in moderate yield.2a In the
second approach, the expected product was obtained in good
yield from 6-chloro-2-hydrazinopyridine and cyanogen bro-
mide.2b Later, this highly toxic reagent was replaced by di-
(imidazol-1-yl)methanimine but with a moderate yield in this
case.2c Concerning the N-substituted 3-amino-[1,2,4]tria-
zolo[4,3-a]pyridines (R2 ¼ H), their syntheses have not
been extensively explored (Scheme 1).3 The synthesis of the
(2) (a) Heinisch, L. Z. Chem. (Leipzig, Ger.) 1970, 10, 188. (b) Schneller,
S. W.; Bartholomew, D. G. J. Heterocycl. Chem. 1978, 15, 439–444. (c) Wu,
Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S. J. Heterocycl.
Chem. 2003, 40, 191–193.
(3) (a) Reimlinger, H.; Lingier, W. R. F.; Vandewalle, J. J. M.; Goes, E.
Synthesis 1970, 2, 433. (b) Koren, B.; Stanovnik, B.; Tisler, M. Monatsh.
Chem. 1988, 119, 83–90.
DOI: 10.1021/jo9009084
r
Published on Web 07/02/2009
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2009 American Chemical Society

Comas et al.
JOCArticle
SCHEME 1. Synthesis of 3-Amino-[1,2,4]triazolo[1,5-a]pyridines
SCHEME 2. Proposed Synthetic Pathway for Synthesis of
3-Amino-[1,2,4]triazolo[4,3-a]pyridines
In our case, the precursor thiosemicarbazide 3 could be
easily obtained from 2-hydrazinopyridine and the isothio-
cyanate, which in the presence of a desulfurizing agent could
undergo intramolecular cyclization to form the triazole ring 5.
Following this pathway, we also envisaged to synthesize the
N-unsubstituted derivative (R1=H) through the correspond-
ing acid-labile N-tert-octyl derivative (R1=tert-octyl).
Several methods have been described for the desulfuriza-
tion of thioureas that could be applied to thiosemicarba-
zides, which include the use of heavy metal salts and oxides
(e.g., Pb2O4, HgCl2, Hg(OAc)2, HgO), methyl iodide, or
highly reactive acid halides (e.g., phosgene, thionylchlo-
ride).9 Mukaiyama’s reagent in the presence of a weak base
such as triethylamine10 has been shown to be effective for this
transformation under milder conditions, but the removal of
the spent reagent (1-methyl-pyridine-2-thione) usually re-
quires column chromatography. Since the use of resin-bound
reagents can often accelerate purification,11 the polymer-
supported version of Mukaiyama’s reagent was first consid-
ered to promote the desulfurization step.12 In this case, the
spent reagent can be easily removed by simple filtration since
it is bound to the insoluble solid support.
N-phenyl derivative was reported starting from 2-hydrazi-
nopyridine and diphenylcarbodiimide.3a Hence, this ap-
proach is not general and is limited to specific symmetric
carbodiimides. The N-ethoxycarbonyl derivative was ob-
tained from the corresponding thiosemicarbazide.3b The
limitation is the use of bromine to promote the cyclization,
which might not be compatible with all heterocycles.
In the present work, the synthesis of 3-amino-[1,2,4]-
triazolo[4,3-a]pyridines via the cyclodesulfurization of the corre-
sponding thiosemicarbazide was chosen for further investigations
(Scheme 2). This strategy, which has precedence in the synthesis
of other heterocyclic amidines (e.g., 2-aminobenzimidazoles,4
2-aminobenzothiazoles,5,6 2-aminobenzoxazoles,6 2-amino-
1,3,4-oxadiazoles7 and imidazopyridines)8 is based on the
formation of a carbodiimide as reactive intermediate.
To determine the scope of the reaction, five different aryl-
isothiocyanates were chosen, bearing electron-donating and
electron-withdrawing groups. One alkyl derivative was also
included, the tert-octylisothiocyanate, as it provides the
possibility of further derivation after acidic cleavage.13
(4) (a) Kiffer, D.; Levy, R. C. R. Seances Acad. Sci., Ser. C 1968, 267,
1730–2. (b) Omar, A. M. M. E.; El-Dine, S. A. S.; Hazzaa, A. A. B. Pharmazie
1975, 30, 85–86. (c) Hamley, P.; Tinker, A. C. Bioorg. Med. Chem. Lett. 1995,
5, 1573–1576. (d) Janssens, F.; Torremans, J.; Janssen, M.; Stokbroekx, R.
A.; Luyckx, M.; Janssen, P. A. J. J. Med. Chem. 1985, 28, 1925–1933. (e)
Sasikumar, T. K.; Li, Q.; Burnett, D. A.; Greenlee, W. J.; Hawes, B. E.;
Kowalski, T. J.; O’Neill, K.; Spar, B. D.; Weig, B. Bioorg. Med. Chem. Lett.
2006, 16, 5427–5431. (f) Carpenter, R. D.; DeBerdt, P. B.; Lam, K. S.; Kurth,
M. J. J. Comb. Chem. 2006, 8, 907–914. (g) AboulWafa, O. M.; Omar, A. M.
M. E. Sulfur Lett. 1992, 14, 181–188. (h) Cee, V. J.; Downing, N. S.
Tetrahedron Lett. 2006, 47, 3747–3750.
Results and Discussion
To validate the proposed synthetic pathway, the stepwise
approach was first investigated, and the thiosemicarbazides
3 were synthesized, isolated, and purified by recrystallization
prior to the second step. The reactions proceeded smoothly
at room temperature using equimolar amounts of 2-hydra-
zinopyridine and the corresponding isothiocyanates in THF
as solvent, and no significant differences were observed
among the six derivatives (Table 1).
(5) Garin, J.; Melendez, E.; Merchan, F. L.; Merino, P.; Orduna, J.;
Tejero, T. J. Heterocycl. Chem. 1991, 28, 359–363.
(6) (a) Dai, Y.; Guo, Y.; Frey, R. R.; Ji, Z.; Curtin, M. L.; Ahmed, A. A.;
Albert, D. H.; Arnold, L.; Arries, S. S.; Barlozzari, T.; Bauch, J. L.; Bouska,
J. J.; Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Guo, J.; Li, J.; Marcotte,
P. A.; Marsh, K. C.; Moskey, M. D.; Pease, L. J.; Stewart, K. D.; Stoll, V. S.;
Tapang, P.; Wishart, N.; Davidsen, S. K.; Michaelides, M. R. J. Med. Chem.
2005, 48, 6066–6083. (b) Heinelt, U.; Schultheis, D.; Jaeger, S.; Lindenmaier,
M.; Pollex, A.; Beckmann, H. S. G. Tetrahedron 2004, 60, 9883–9888. (c)
Hwang, J. Y.; Gong, Y.-D. J. Comb. Chem. 2006, 8, 297–303. (d) Qian, X.;
Xu, X.; Li, Z.; Li, Z.; Song, G. J. Fluorine Chem. 2004, 125, 1609–1620.
(7) (a) Coppo, F. T.; Evans, K. A.; Graybill, T. L.; Burton, G. Tetra-
hedron Lett. 2004, 45, 3257–3260. (b) Dolman, S. J.; Gosselin, F.; O’Shea, P.
D.; Davies, I. W. J. Org. Chem. 2006, 71, 9548–9551.
With the thiosemicarbazides 3 in hands, we investigated
the ability of polymer-supported Mukaiyama’s reagent to
(9) (a) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589–636. (b)
Kurzer, F.; Douraghi-Zadeh, K. Chem. Rev. 1967, 67, 107–152.
(10) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett. 1977, 575–
576.
(11) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A.
G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J.
Chem. Soc., Perkin Trans. 1 2000, 3815–4195.
(12) Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–
4582.
(13) Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495–1500.
(8) (a) Flemer, S.; Wurthmann, A.; Mamai, A.; Madalengoitia, J. S. J.
Org. Chem. 2008, 73, 7593–7602. (b) Bourdais, J.; Omar, A.; Mohsen, M. E.
J. Heterocycl. Chem. 1980, 17, 555–558. (c) Fitzmaurice, R. J.; Gaggini, F.;
Srinivasan, N.; Kilburn, J. D. Org. Biomol. Chem. 2007, 5, 1706–1714.
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TABLE 1. Synthesis of Thiosemicarbazides 3
TABLE 2. Synthesis of 5 using PS-Muk1
entry
R1
phenyl
3-F-phenyl
4-MeO-phenyl
2-Me-phenyl
4-CF3-phenyl
tert-octyl
compound
yield (%)a
composition (%)a
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
71
69
85
88
58
77
1 h at 1 h at 4 h at 21 h at
5 °Cc
entry
1
R
compound
rtb
5 °Cc 5 °Cc
phenyl
3a
5a
8a
3b
5b
8b
3c
5c
8c
3d
5d
8d
3e
5e
8e
3f
8
55
37
11
50
34
12
67
21
23
57
20
21
76
4
87
8
82
13
aAfter recrystallization from ACN (not optimized).
2
3
4
5
6
3-F-phenyl
37
60
3
92
1
93
2
4-MeO-phenyl
2-Me-phenyl
4-CF3-phenyl
tert-octyl
17
82
0
2
94
2
SCHEME 3. Synthesis of PS-Muk1 from Wang Resin12
96
3
32
67
2
87
8
85
12
77
23
15
64
18
97
94
2
92
2
19
41
37
57
29
27
45
23
promote their desulfurization and subsequent spontaneous
cyclization of the carbodiimides leading to the target hetero-
cycles. We used polymer-supported Mukaiyama0s reagent
previously developed in our laboratory (PS-Muk1) because
it is easy to synthesize from relative cheap starting materials
and stable under standard storage conditions (Scheme 3).12
The cyclization was carried out at room temperature using
PS-Muk1 (2.0 equiv) in the presence of TEA (5.0 equiv) in a
mixture of DCM/DMF 9:1 to ensure the dissolution of the
thiosemicarbazides 3. After 1 h at room temperature, the
desired heterocycles 5 were present in 50-77% (determined
by HPLC), proving that PS-Muk1 was effective to promote
this transformation (Table 2, entries 1-5).14 However, a
major side product (8) was observed in each reaction, and
decreasing the amount of PS-Muk1 (from 2.0 to 1.25 equiv)
and TEA (from 5.0 to 2.5 equiv) did not suppress the
side reaction completely. There was a big improvement
when performing the reaction at lower temperature (5 °C)
for 21 h, and the 3-aryl-amino-[1,2,4]triazolo[4,3-a]pyridines
5a-e were obtained as the main product (>82%, Table 2,
entries 1-5).
We then decided to focus our attention on the formation of
the side product. Mass spectra analysis suggested that a
pyridyl moiety was incorporated to the molecule.15 To
determine whether the polymer-supported reagent or the
2-hydrazinopyridine was responsible for the side reaction,
the same transformation was carried out in solution with
Mukaiyama’s reagent (1.2 equiv) in the presence of TEA
(2.4 equiv). In this case, a total conversion into the expected
compounds was achieved after 2-3 h and no side products
were observed (Table 3).
5f
8f
aDetermined by HPLC (254 nm). PS-Muk1 (2.0 equiv), TEA (5.0
b
equiv), rt. cPS-Muk1 (1.25 equiv), TEA (2.5 equiv), 5 °C
TABLE 3. Synthesis of 5 using Mukaiyama’s Reagent
entry
R1
phenyl
3-F-phenyl
4-MeO-phenyl
2-Me-phenyl
4-CF3-phenyl
tert-octyl
compound
yield (%)b
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
78
63
69
75
72
68
aMukaiyama’s reagent (1.2 equiv), TEA (2.4 equiv). bAfter an acidic
aqueous extraction followed by precipitation at pH 6.
equiv). Despite extensive analyses (1H NMR, 13C NMR,
19F NMR, 2D NMR, MS, IR, elemental analysis),16 the
structural formula of 8f could only be unambiguously de-
termined by X-ray crystal structure analysis (Figure 1).17
(16) 1H NMR (DMSO-d6) clearly showed the signals corresponding to
the tert-octyl, 2-pyridyl, and triazolopyridinyl moieties and one exchange-
able proton (confirmed by adding MeOD-d4) at 7.63 ppm. Moreover,
19F NMR (DMSO-d6, singlet at -78.2 ppm) and 13C NMR (DMSO-d6,
1
quadruplet with JC-F=322.4 Hz at 120 ppm) suggested the presence of
To further characterize the side product 8, we chose to
synthesize 8f from the thiosemicarbazide 3f (R1=tert-octyl)
using a large excess of PS-Muk1 (3.0 equiv) and TEA (5.0
trifluoromethanesulfonate group.
(17) In 8f the pyridine-2-yl substituent is bound directly to the triazole
ring giving a cationic compound with the trifluoromethanesuphonate pre-
sent as a counterion. Hence, in the mass spectrometry (positive mode) the
observed m/z corresponds to the MW and not to MW þ 1 (observed m/z=
324). The ortep view of the crystal structure of 8f is provided in Supporting
Information and has been deposited in the Cambridge Data Centre (CCDC
730713).
(14) Compound 5c was isolated and fully characterized.
(15) The measured mass/charge (m/z) ratio of the side product corre-
sponded of the desired heterocycles 5 plus a mass of 77.
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Comas et al.
JOCArticle
FIGURE 2. New polymer-supported Mukaiyama’s reagent analo-
gues.
FIGURE 1. Structure of 8f.
TABLE 4. Comparison of PS-Muk1, PS-Muk2, and PS-Muk3
SCHEME 4. Plausible Mechanism for Formation of 8f
A plausible mechanism for the formation of 8f is depicted
in Scheme 4. Compound 5f could further react with the
excess of PS-Muk1 (with loss of chloride) and a benzylic
cleavage released the compound 8f from the polymer sup-
port. This cleavage could be promoted by a nucleophilic
addition (chloride or TEA) at the benzylic position (SN2)
or by a SN1 mechanism involving the stabilized benzylic
carbocation.18
The first step involved in the side-product formation
appears to be a limitation of the methodology. However,
the kinetic of the benzylic cleavage could be slowed down by
choosing the appropriate solid support and hence increasing
the purity of the desired heterocycle. For this purpose,
hydroxymethyl polystyrene and 4-hydroxymethylbenzoic
acid aminomethyl polystyrene were used for the synthesis
of PS-Muk2 and PS-Muk3, respectively (Figure 2), which
would be more stable toward the benzylic cleavage than PS-
Muk1. Their preparation was carried out following the same
protocol as for PS-Muk1, achieving a quantitative attach-
ment for both versions.
composition (%)a
entry
1
resin
compound
1 h
21 h
PS-Muk1
3a
5a
8a
3a
5a
8a
3a
5a
8a
8
55
37
7
56
37
2
3
PS-Muk2
PS-Muk3
99
99
98
2
95
3
aDetermined by HPLC (254 nm).
Using this methodology, 5a was isolated in good yield with-
out any chromatographic separation.
PS-Muk2 was chosen as the best reagent candidate for
further studies because its preparation is cheaper and easier
to handle as compared to PS-Muk3.
The reactions of 3 with PS-Muk2 (1.2 equiv) in DCM/
DMF 9:1 at ambient temperature in the presence of TEA (2.4
equiv) gave complete conversion for the six derivatives after
1 h. Even the most problematic tert-octyl thiosemicarbazide
3f gave the product in excellent purity.19 The final hetero-
cycles were easily isolated in good yields (71-85%) and
excellent purities (>99%) without any chromatographic
separation or any further purification, as shown by eleme-
ntal analysis of the final heterocycles 5 (see Experimental
Section).
Our next goal was to develop a one-pot protocol from the
previous results, which consisted of reacting 2-hydrazino-
pyridine with the isothiocyanate during 2 h before adding the
TEA and PS-Muk2 (Table 5). While attempting to simplify
the one-pot protocol mixing all the reagents at once, we
observed that 2-hydrazinopyridine was scavenged by PS-
Muk2.20 Consequently, the stepwise one-pot protocol was
required to obtain the final compounds in good purities and
The results of the reactions of the new supported reagents
PS-Muk2 and PS-Muk3 following the same conditions
described before for PS-Muk1 for the preparation of 5a
are summarized below (Table 4).
Gratifyingly, the two new linkers showed a better stability
toward the benzylic cleavage and provided 99% of the
desired heterocycles in the crude mixture after 1 h (deter-
mined by HPLC analysis of the supernatants). Only after
21 h were traces of the side product 8a detected. Under these
new conditions, it was the first time the starting thiosemi-
carbazide 3a was totally consumed before the side product
was released. The resin-bound pyridine-2-thione was re-
moved by simple filtration, and the triethylammonium salts
were removed using a SPE-NH2 column followed by eva-
poration of the resulting TEA at the solvent removal stage.
(18) Benzylic cleavages of N-benzyl pyridinium salts: (a) Katritzky, A. R.
Tetrahedron 1980, 36, 679–699. (b) Katritzky, A. R.; Musumarra, G.;
Sakizadeh, K. Tetrahedron Lett. 1980, 21, 2701–2703. (c) Katritzky, A. R.;
Musumarra, G.; Sakizadeh, K.; Misic-Vukovic, M. J. Org. Chem. 1981, 46,
3820–3823. (d) Katritzky, A. R.; El-Mowafy, A. M.; Musumarra, G.;
Sakizadeh, K.; Sana-Ullah, C.; El-Shafie, S. M. M.; Thind, S. S. J. Org.
Chem. 1981, 46, 3823–3830. (e) Katritzky, A. R.; Musumarra, G.; Sakizadeh,
K. J. Org. Chem. 1981, 46, 3831-3835. Benzylic cleavages of quaternary
ammonium salts: (f) Miller, M. W.; Vice, S. F.; McCombie, S. W. Tetrahedron
Lett. 1998, 39, 3429–3432.
(19) The tert-octyl group of 5f could be removed under acidic conditions,
simply by reaction in a 1:1 mixture of aqueous 5 N HCl/methanol at rt for
16 h. After evaporation of the solvents, the residue was dissolved in MeOH
and passed through a plug of basic alumina to give the NH2-substituted
derivative in 77% yield.
(20) It was confirmed later mixing both reagents under the same condi-
tions of solvent, concentration, and temperature, where only 25% of the
hydrazinopyridine was recovered after washing the resin and solvent re-
moval.
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TABLE 5. Synthesis of 3-Aminotriazoles Using a One-Pot Protocol
analytically pure compounds 9-11 (Table 5). The moderate
yields are explained by the partial scavenging of the for-
med heterocycles by the resin (step 1, Scheme 4).21
Conclusions
We have developed a convenient one-pot protocol for the
synthesis of 3-amino-[1,2,4]triazolo[4,3-a]pyridines. The use of
a new linker for the polymer-supported Mukaiyama0s reagent
(PS-Muk2) is essential to achieve high purities of the products,
since it was shown to be more stable than the previously
reported analogue PS-Muk1. This protocol was shown to be
robust in the extension to other related heterocycles, which
broadens the scope of the presented methodology. The sim-
plicity of the reaction and the purification step make this one-
pot protocol an excellent choice for parallel synthesis.
Experimental Section
Polymer-supported Mukaiyama0s reagent 1 (PS-Muk1). In a
250 mL, 3-necked, round-bottom flask and under argon, Wang
resin (15 g, 1.7 mmol/g, 25.5 mmol, 1.0 equiv) was swollen in dry
DCM (150 mL), and 2-chloropyridine (12.0 mL, 127.5 mmol,
5.0 equiv) was added with stirring . The mixture was cooled in an
ice-water bath before neat trifluoromethanesulfonic anhydride
(6.0 mL, 35.7 mmol, 1.4 equiv) was added at such rate that the
temperature did not rise above 20 °C (internal temp). The
mixture was stirred gently overnight. The resin was filtered,
washed with DCM, DMF, DCM (several times), and Et2O, and
dried under high vacuum at rt. Elemental analysis of the resin
gave 3.38% Cl, 6.35% F, which corresponds to a loading of
1.1 mmol/g.
Polymer-supported Mukaiyama0s reagent (PS-Muk2). The
same procedure as for PS-Muk1 but using hydroxymethyl
polystyrene (40 g, 0.98 mmol/g, 39.2 mmol, 1.0 equiv), DCM
(400 mL), 2-chloropyridine (18.5 mL, 196 mmol, 5.0 equiv), and
trifluoromethanesulfonic anhydride (9.27 mL, 54.9 mmol, 1.4
equiv). Elemental analysis of the resin gave 2.97% Cl, 4.92% F,
which corresponds to a loading of 0.85 mmol/g.
Polymer-supported Mukaiyama0s reagent (PS-Muk3). The
same procedure as for PS-Muk1 but using 4-hydroxymethylben-
zoicacid aminomethylpolystyrene(2.0g, 0.85 mmol/g, 1.7 mmol,
1.0 equiv), DCM (20 mL), 2-chloropyridine (0.8 mL, 8.3 mmol,
5.0 equiv), and trifluoromethanesulfonic anhydride (0.4 mL,
2.3 mmol, 1.4 equiv). Elemental analysis of the resin gave
2.52% Cl, 4.46% F, which corresponds to a loading of
0.75 mmol/g.
General Procedure for the Preparation of 1-(Pyridine-2-yl)
thiosemicarbazides (3). 2-Hydrazinopyridine (2.73 g, 25 mmol,
1.00 equiv) was dissolved in THF (100 mL), and a solution of the
corresponding isothiocyanate (25 mmol, 1.00 equiv) in THF
(25 mL) was added over a period of 5 min using a dropping
funnel. The reaction was stirred until completion (monitored by
HPLC), and the solvent was evaporated under reduced pressure.
The resulting solid was recrystallized from ACN and dried
under vacuum at 40 °C.
b
aR1-NCS (1.0 equiv), hydrazino derivative (1.4 equiv) for 2 h. PS-
Muk2 (1.5 equiv), TEA (2.5 equiv) for 1 h.
yields but with the ability of using one reagent in excess that
is often desirable in parallel synthesis.
Encouraged by these results, we were prompted to extend
this methodology to the synthesis of related fused 3-amino-
triazoles. A priori, any other hydrazine derivative bearing a
nitrogen atom in the R position of an aromatic ring can
replace the 2-hydrazinopyridine, leading to novel and inter-
esting heterocycles. As examples we chose 6-chloro-2-hydra-
zinopyridine, 2-hydrazinopyrazine, and 2-methylsulfanyl-4-
hydrazinopyrimidine, and we kept the 5 aryl isothiocyanates
used before (Table 5). The reactions were carried out in a
parallel fashion, using the optimized conditions (i.e., letting
react at rt the isothiocyanate (1.0 equiv) with hydrazine
derivative (1.4 equiv) in a mixture DMF/DCM for 2 h,
before adding PS-Muk2 (1.5 equiv) and TEA (2.5 equiv)).
The isolation was carried out as mentioned before, affording
N-Phenyl-2-pyridin-2-ylhydrazinecarbothioamide (3a). Yie-
ld 71%; mp 180.1-180.6 °C; 1H NMR (300 MHz, DMSO-d6) δ
9.83 (s, 1H), 9.73 (s, 1H), 8.55 (s, 1H), 8.14 (dd, J = 4.9, 0.9 Hz,
1H), 7.68-7.58 (m, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 8.0
Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 6.87-6.77 (m, 1H), 6.66 (d,
J = 8.3 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 181.2, 159.2,
(21) The fused 3-aminotriazole 5f was reacted with PS-Muk2 (1 equiv)
and TEA (2 equiv) for 1 h. HPLC analysis of the supernatant using internal
reference showed 66% of the initial amount of 5f, suggesting it was partially
scavenged by the resin (step 1, Scheme 4).
J. Org. Chem. Vol. 74, No. 15, 2009 5557

Comas et al.
JOCArticle
147.6, 139.2, 137.8, 127.9, 125.2, 124.7, 115.7, 107.2; IR 3149.3,
1545.7, 1434.8 cm-1; MS (ESI) m/z 245 (M þ H)þ; HPLC tR=
1.62 min. Anal. Calcd for C12H12N4S: C, 58.99; H, 4.95; N, 22.93.
Found: C, 59.03; H, 4.95; N, 23.00.
The compound characterization data for 3b-f are provided in
Supporting Information.
General Protocol for 3-Amino-[1,2,4]triazolo[4,3-a]pyridines
instead of 2-hydrazinopyridine. (9a, 78%; 9b, 63%; 9c, 69%; 9d,
75%; 9e, 72%)
N-Phenyl-3-amino-5-chloro[1,2,4]triazolo[4,3-a]pyridine (9a).
Mp 200 °C (dec); 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H),
7.71 (d, J = 9.0 Hz, 1H), 7.29 (dd, J = 9.4, 7.2 Hz, 1H), 7.20 (t, J
= 7.9 Hz, 2H), 7.06 (d, J = 6.8 Hz, 1H), 6.86-6.77 (m, 3H); 13
C
NMR (75 MHz, DMSO-d6) δ 150.1, 144.9, 143.6, 129.1, 128.1,
124.2, 119.6, 115.1, 115.0, 114.9; IR 1624.8, 1534.8, 1480.7,
788.0 cm-1; MS (ESI) m/z=247 (M þ H)þ; HPLC tR=2.57 min.
Anal. Calcd for C12H9ClN4: C, 58.91; H, 3.71; N, 22.90. Found:
C, 58.53; H, 3.65; N, 22.77.
(5). Condition 1. From thiosemicarbazides
3 and using
Mukaiyama’s reagent. In a round-bottom flask, thiosemicarba-
zides 3 (2.0 mmol, 1.0 equiv) was dissolved in THF (10 mL), and
a solution of triethylamine (0.66 mL, 4.8 mmol, 2.4 equiv) in
THF (2 mL) was added followed by 2-chloro-1-methylpyridi-
nium iodide (0.62 g, 2.4 mmol 1.2 equiv). The mixture was
stirred at rt until completion (1-2 h, monitored by HPLC), and
the solvent was evaporated under vacuum. The residue was
taken up in EtOAc (50 mL) and washed with HCl 0.1 N (2 ꢀ
10 mL). The aqueous layers were combined, and NaOH (1 N)
was added until pH 6. The resulting solid was filtered, washed
with water, and dried under vacuum at 40 °C. (5a, 78%; 5b,
63%; 5c, 69%; 5d, 75%; 5e, 72%; 5f, 68%)
The compound characterization data for 9b-e are provided
in Supporting Information.
General Protocol for 3-Amino-[1,2,4]triazolo[4,3-a]pyrazines
(10). The same protocol as for 5 (condition 3) but using
2-hydrazinopyrazine (23 mg, 0.21 mmol, 1.4 equiv) instead of
2-hydrazinopyridine. (10a, 78%; 10b, 79%; 10c, 69%; 10d, 77%;
10e, 70%)
N-Phenyl-3-amino-[1,2,4]triazolo[4,3-a]pyrazine (10a). Mp
1
262 °C (dec); H NMR (300 MHz, DMSO-d6) δ 9.54 (s, 1H),
Condition 2. From thiosemicarbazides 3 and using PS-Muk2.
Thiosemicarbazide 3 (0.05 mmol, 1.0 equiv) was dissolved in
DMF (0.1 mL), and a solution of TEA (2.4 equiv) in DCM
(0.9 mL) was added followed by PS-Muk2 (1.2 equiv). The capped
vial was shaken at rt for 1 h, and MeOH (1 mL) was added.
The crude was passed through a SPE-NH2 column (500 mg,
0.56 mmol/g) and eluted with DCM (4.0 mL). Evaporation of the
solvent under reduced pressure afforded the title compound.
(5a, 79%; 5b, 77%; 5c, 85%; 5d, 74%; 5e, 71%; 5f, 81%)
Condition 3. One-pot protocol from 2-hydrazinopyridine and
using PS-MUk2. 2-Hydrazinopyridine (23 mg, 0.21 mmol, 1.4
equiv) was dissolved in DMF (0.3 mL), a solution of the
corresponding isothiocyanate (0.15 mmol, 1.0 equiv) in DCM
(1.0 mL) was added, and the mixture was shaken at rt for 2 h.
Then, TEA (52 uL, 0.38 mmol, 2.5 equiv) was added followed by
PS-Muk2 (1.5 equiv), and the mixture was shaken at rt for 2 h.
MeOH (1 mL) was added, and the crude was passed through a
SPE-NH2 column (500 mg, 0.56 mmol/g) and eluted with DCM
(4.0 mL). Evaporation of the solvent under reduced pressure
afforded the title compound. (5a, 67%; 5b, 48%; 5c, 56%; 5d,
69%; 5e, 43%; 5f, 54%; 5g, 72%)
N-Phenyl-3-amino-[1,2,4]triazolo[4,3-a]pyridine (5a). Mp
232.5-233.3 °C; 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s,
1H), 8.34 (dt, J = 6.9, 1.0 Hz, 1H), 7.61 (dt, J = 9.4, 1.0 Hz,
1H), 7.56 (dd, J = 8.6, 1.0 Hz, 2H), 7.35-7.27 (m, 2H), 7.24 (ddd,
J = 9.3, 6.4, 1.0 Hz, 1H), 6.95-6.86 (m, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 146.3, 144.3, 141.4, 129.0, 126.5, 122.6, 120.4, 116.2,
115.5, 112.3; IR 1606.2, 1556.7, 1498.4 cm-1; MS (ESI) m/z=211
(M þ H)þ; HPLC tR=1.77 min. Anal. Calcd for C12H10N4: C,
68.56; H, 4.79; N, 26.65. Found: C, 68.21; H, 4.81; N, 26.45.
The compound characterization data for 5b-f are provided in
Supporting Information.
9.21 (d, J =1.6 Hz, 1H), 8.39 (dd, J= 5.1, 1.6 Hz, 1H), 7.81 (d,
J = 4.9 Hz, 1H), 7.68 (dd, J = 8.7, 0.8 Hz, 2H), 7.35 (dd, J =
8.6, 7.3 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 145.2, 144.1, 142.0, 140.5, 129.0, 127.6, 121.1,
116.7, 115.5; IR 1614.0, 1564.7, 1377.8 cm-1; MS (ESI) m/z=
212 (M þ H)þ; HPLC tR 1.83 min. Anal. Calcd for C11H9N5 þ
(0.06% DMF) C3H7NO: C, 62.28; H, 4.40; N, 32.87. Found: C,
62.01; H, 5.00; N, 33.15.
The compound characterization data for 10b-e are provided
in Supporting Information.
General Protocol for 3-Amino-5-methylsulfanyl[1,2,4]triazolo
[4,3-a]pyrimidines (11). The same protocol as for 3 (condition 3)
but using 4-hydrazino-2-(methylthio)pyrimidine (33 mg, 0.21
mmol, 1.40 equiv) instead of 2-hydrazinopyridine. (11a, 60%;
11b, 51%; 11c, 56%; 11d, 66%; 11e, 45%)
N-Phenyl-3-amino-5-methylsulfanyl[1,2,4]triazolo[4,3-a]pyr-
imidine (11a). Mp 197.6-198.2 °C; 1H NMR (300 MHz,
DMSO-d6) δ 8.65 (s, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.43 (d,
J = 6.6 Hz, 1H), 7.20 (t, J = 7.7 Hz, 2H), 6.83 (t, J = 7.3 Hz,
1H), 6.76 (d, J = 7.5 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 151.1, 148.3, 145.1, 143.0, 140.4, 129.1, 119.8,
115.1, 105.9, 13.5; IR 1536.9, 1645.5, 1307.6 cm-1; MS (ESI) -
m/z =258 (M þ H)þ; HPLC tR =2.62 min. Anal. Calcd for
C12H11N5S: C, 56.1; H, 4.31; N, 27.22; S, 12.46. Found: C, 56.12;
H, 4.46; N, 27.26; S, 12.32.
The compound characterization data for 11b-e are provided
in Supporting Information.
Acknowledgment. We thank Prof. A. Alexakis and Prof.
J. Lacour for helpful discussion and Merck Serono for
publishing these results.
Supporting Information Available: 1H and 13C NMR spec-
tra of the synthesized compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
General Protocol for 3-Amino-5-chloro[1,2,4]triazolo[4,3-a]-
pyridines (9). The same protocol as for 5 (condition 3) but using
6-chloro-2-hydrazinopyridine (30 mg, 0.21 mmol, 1.4 equiv)
5558 J. Org. Chem. Vol. 74, No. 15, 2009