Reactivity of [1,2,3]Triazolo[1,5-a]pyridines as 1,3-dipoles

Article abstract of DOI:10.1016/j.tet.2016.11.006

We have studied the reactions between [1,2,3]Triazolo[1,5-a]pyridines 1a,b,c and electron-deficient ethylenes in different conditions. Compounds 1a and 1b react with ethyl propiolate, and dimethyl acetylene dicarboxylate giving a new class of biaryl compounds pyridyl pyrazoles, and with ethyl acrylate giving pyridyl cyclopropanes. Compound 1c did not give any product in the studied conditions. A proposal of mechanism of these reactions is done in which the triazolopyridines act as 1,3-dipoles giving 1,3-dipolar cycloadditions.

Full text of DOI:10.1016/j.tet.2016.11.006

Tetrahedron xxx (2016) 1e6
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Reactivity of [1,2,3]Triazolo[1,5-a]pyridines as 1,3-dipoles
*
**
ꢀ
Rosa Adam, Shamim Alom, Belen Abarca , Rafael Ballesteros
ꢀ
Departamento de Química Organica, Facultad de Farmacia, Universidad de Valencia, 46100, Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
We have studied the reactions between [1,2,3]Triazolo[1,5-a]pyridines 1a,b,c and electron-deficient
ethylenes in different conditions. Compounds 1a and 1b react with ethyl propiolate, and dimethyl
acetylene dicarboxylate giving a new class of biaryl compounds pyridyl pyrazoles, and with ethyl acrylate
giving pyridyl cyclopropanes. Compound 1c did not give any product in the studied conditions. A pro-
posal of mechanism of these reactions is done in which the triazolopyridines act as 1,3-dipoles giving 1,3-
dipolar cycloadditions.
Received 19 September 2016
Received in revised form
24 October 2016
Accepted 1 November 2016
Available online xxx
Dedicated to Prof. Gurnos Jones In
Memoriam.
© 2016 Elsevier Ltd. All rights reserved.
Keywords:
Triazolopyridines
1,3-Dipoles
Pyridyl pyrazoles
Pyridyl cyclopropanes
1. Introduction
triazolopyridines through the formation of a rhodium or copper
carbene.7 Only one mechanistic proposal of a 1,3-dipolar cycload-
1,3-Dipolar cycloaddition between diazo compounds and
electron-deficient (ED) ethylenes constitutes still nowadays an
attractive approach for acceding to the interesting pyrazole motif.1
Pyrazoles are considered privileged scaffolds due to their presence
in many drugs and phytosanitary. The description of novel ED
ethylenes which can become to more substituted pyrazoles by a
1,3-dipolar cycloaddition, or Lewis acid catalyzed cycloadditions,
have been key discoveries in the field. However, one of the major
drawbacks of this reaction is still the use of diazo compounds, due
to their toxicity and potentially explosive nature.
[1,2,3]Triazolo[1,5-a]pyridines 1 have shown to present an
equilibrium in solution with its corresponding 2-pyridyl diazo-
compound 2.2,3 Few examples of triazolopyridines reactivity as
diazo compounds, that involve the loss of nitrogen, can be found
(Scheme 1). Quinolizin-2,4-dione, ylides or cyclopropanes can be
obtained from triazolopyridines by flash vacuum thermolysis (a),4
photolysis (b),5 or thermic treatment (c),2a,6 respectively, through
the formation of a carbene. More recently Gevorgyan et al. (d) have
shown that cyclopropanes and indolizines can be obtained from
dition of the diazo compound derived from triazolopyridine can be
found in literature. In this case, a cyclopropane is obtained by
thermal treatment of a triazolopyridine in the presence of fumar-
onitrile (e), and the authors propose that this occurs through the
formation of a pyrazoline intermediate.2a However, there is no any
example in literature in which triazolopyridine in its open form of
diazo compound is able to react with an ED ethylene to form the
interesting pyridine pyrazole structure.
In this work we intend to explore the behavior of stable [1,2,3]
triazolo[1,5-a]pyridines 1a (R ¼ H), 1b (R ¼ CH3) and 1c (R ¼ Ph) as
1,3-dipoles using as (ED) ethylenes ethyl propiolate (EP), dimethyl
acetylene dicarboxylate (DMAD), and ethyl acrylate (EA). This re-
action would afford the interesting pyridine pyrazoles, a new class
of biaryl compounds. Moreover, the use of triazolopyridines as 1,3-
dipoles would imply an advance in its chemistry since they should
act as stable diazo compounds.
2. Results and discussion
Firstly, the reaction of [1,2,3]triazolo[1,5-a]pyridine 1a in pres-
ence of 3 equivalents of EP was performed at 150 ꢀC, using dime-
thylformamide (DMF) as solvent and reaction time of 24 h (Scheme
2). To our delight, in these conditions the pyridyl pyrazole 3 was
obtained as major product with 44% of yield, together with minor
regioisomer 4 (Table 1, entry 1). Compound 3 was obtained as a
* Corresponding author.
** Corresponding author.
E-mail addresses: Belen.abarca@uv.es (B. Abarca), Rafael.ballesteros@uv.es
(R. Ballesteros).
http://dx.doi.org/10.1016/j.tet.2016.11.006
0040-4020/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Adam R, et al., Reactivity of [1,2,3]Triazolo[1,5-a]pyridines as 1,3-dipoles, Tetrahedron (2016), http://
dx.doi.org/10.1016/j.tet.2016.11.006

2
R. Adam et al. / Tetrahedron xxx (2016) 1e6
Scheme 1. Ring chain isomerization and reactions known as diazo compounds of [1,2,3]Triazolo[1,5-a]pyridines.
Scheme 2. Reaction of triazolopyridines 1a-c with ethyl propiolate, toluene, 150 ꢀC, 24 h.
mixture of E and Z isomers. The most significate NMR characteristic
of these compounds are the coupling constant of the alkene hy-
drogens, 9.9 Hz for Z and 13.8 Hz for E isomers, and the pyrazole
proton in both compounds that appears at 7.6 ppm as a singlet. The
pyrazole 4 (10%) has a singlet at 7.19 ppm more shielded than
pyrazole proton in compound 3 due to the anisotropic effect of 2-
pyridyl substituent, and only the E isomer was detected.
The effect of different solvents in the reaction, dichloromethane
(DCM), acetonitrile (AcN) and toluene, was explored (Table 1, en-
tries 2e4), concluding that the best yield for pyridyl pyrazole 3
(65%) was obtained with toluene. Then, the reaction was performed
with different amounts of EP (Table 1, entries 5 and 6) demon-
strating that a minimum amount of 3 equivalents of ED ethylene
was required for obtaining good yields of 3. Different reaction
temperatures were also tested (Table 1, entries 7 and 8), concluding
that at 150 ꢀC the best results were obtained. In addition, at a
prolonged reaction time of 72 h better yields of 3 were obtained
(Table 1, entry 10).
The reaction between triazolopyridine 1a and EP was also per-
formed in presence of 7 mol % of several Lewis acids (CuI,
Please cite this article in press as: Adam R, et al., Reactivity of [1,2,3]Triazolo[1,5-a]pyridines as 1,3-dipoles, Tetrahedron (2016), http://
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R. Adam et al. / Tetrahedron xxx (2016) 1e6
3
Table 1
- Reaction of triazolopyridine 1a with ethyl propiolate in different conditions.a
Entry
Solvent
EP (eq)
t (h)
Temperature (ꢀC)
Yield (%)
3
3
4
Z: E
1
2
3
4
5
6
7
8
9
10
DMF
Toluene
DCM
3
3
3
3
5
2
3
3
3
3
24
24
24
24
24
24
24
24
15
72
150
150
150
150
150
150
130
180
150
150
44
65
60
64
61
46
34
57
41
70
10
10
19
20
24
15
13
26
20
23
0.36: 1
0.63: 1
0.72: 1
0.58: 1
0.66: 1
0.49: 1
0.56: 1
0.43: 1
0.51: 1
0.49: 1
AcN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
a
Standard reaction conditions: triazolopyridine (0.85 mmol, 100 mg), 24 h, solvent (6 ml) in autoclave.
Rh2(OAc)4, NiCl2,FeCl3 and AuCl3) with the aim to check whether
these species could act as catalysts. Unfortunately, none of them
afforded better yields of the desired pyridyl pyrazoles. However, it
is interesting to note that when CuI was used with 1.1 equivalents of
EP, the substituted indolizine 5 (Scheme 2) was obtained selectively
with 22% yield. A high selectivity to indolizines from triazolopyr-
idines in the presence of alkynes, catalyzed by copper species, has
been recently reported by Gevorgyan et al.7c
Next, the reactivity of 3-methyl and 3-phenyl triazolopyridines
1b and 1c in presence of EP was investigated (Scheme 2). In the case
of 3-methyl triazolopyridine 1b, pyridyl pyrazole 6 was obtained in
moderate yields. In the studied conditions, 3-phenyl triazolopyr-
idine 1c did not give any product.
regioselectively with ED ethylenes, EP, DMAD or EA to give the
intermediates A or B. These intermediates are unstable and there-
fore are able to react with another molecule of EP or DMAD in an
aza ene reaction8 to afford compounds 3, 4 and 8. From interme-
diate A when R ¼ Me and R’ ¼ H a 1,2-shift of methyl group could
give a new intermediate C that by reaction with another molecule
of EP, in an aza ene reaction, explain the formation of compound 6.
Compound 7 can be explained by a 1,2-shift of hydrogen atom from
the intermediate B. When R’ ¼ E and R ¼ CH3, intermediate B is
stable as 3H-pyrazol 9.
The formation of compound 5 can be explained by the formation
of a carbene intermediate D in a similar way as Gevorgian
described.7
With the aim of enlarging the structural diversity of pyridyl
pyrazole biaryls, reactions between DMAD and triazolopyridines 1a
and 1b were performed in DMF at 150 ꢀC during 24 h (Scheme 3). In
the case of triazolopyridine 1a, trisubstituted and tetrasubstituted
pyrazoles 7 and 8 were formed in 27% and 19% yield respectively.
Triazolopyridine 1b in the same reaction conditions gave place to
3H-pyrazole 9 in 63% of yield as unique product.
The intermediates derived from the reactions with EA cannot
give an aromatic system, therefore they undergo loss of nitrogen, as
has been described, to afford a diradical E.9 This diradical collapses
to give cyclopropanes 10a,b as Wentrup reported for the thermal
decomposition of triazolopyridine in presence of fumaronitrile.2a
3. Conclusion
At this point it was interesting to check the reactivity of [1,2,3]
triazolo[1,5-a]pyridines with EA (Scheme 4). Triazolopyridine 1a
gave rice to cyclopropane 10a in high yields (88%, obtained as a
mixture of Z/E isomers) at 150 ꢀC, using DMF as solvent and 3
equivalents of the ED ethylene (Table 2, entry 1). Both isomers
could be isolated by chromatotron.
The triazolopyridines 1a and 1b act as 1,3-dipoles through its
tautomeric form of diazocompounds. New biaryl compounds pyr-
idyl pyrazoles 3, 4, 6, 7, 8 and 9 are obtained by reaction with EP and
DMAD. Reaction with EA gives pyridyl cyclopropanes 10a, b in good
Further mitigation of reaction temperature or ED ethylene
amount (Table 2, entries 3 and 4) afforded the pyridyl cyclopro-
panes 10a in lower yields. In addition, triazolopyridine 1b also
underwent this reaction forming the corresponding pyridyl cyclo-
propanes 10b, in 61% of isolated yield, with a better selectivity to
the E isomer, using toluene as solvent (Table 2, entry 7). The
structures of the isomers have been elucidated by NOE-dif and
NOESY experiment (see Supporting Information).
To explain all these results a mechanism based in the tautomeric
equilibrium triazolopyridine 1-diazocompound
2 is proposed
(Scheme 5). The diazocompound forms, as 1,3-dipoles, react non-
Scheme 4. Reaction of triazolopyridines 1a and 1b with ethyl acrylate.
Scheme 3. Reactions of triazolopyridines 1a,b with dimethyl acetylenedicarboxylate.
Please cite this article in press as: Adam R, et al., Reactivity of [1,2,3]Triazolo[1,5-a]pyridines as 1,3-dipoles, Tetrahedron (2016), http://
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4
R. Adam et al. / Tetrahedron xxx (2016) 1e6
Table 2
- Reaction of triazolopyridines 1a and 1b with ethyl acrylate.a
Entry
Starting material
Solvent
Temp.
(ꢀC)
EA (eq)
Yield (%)
10
10 ratio
Z: E
1
2
3
4
1a
1a
1a
1a
1b
1b
1b
DMF
Toluene
DMF
DMF
DMF
150
150
100
150
150
150
150
3
3
3
1.1
3
88
67
45
70
41
55
61
0.66: 1
0.66: 1
0.64: 1
0.66: 1
0.47:1
0.45:1
0.22: 1
5b
6b,c
7b
DMF
Toluene
3
3
a
Standard reaction conditions: triazolopyridine (0.85 mmol, 100 mg), 24 h, solvent (6 ml) in autoclave.
(E)-ethyl 4-(pyridin-2-yl)-but-3-enoate was formed as by-product in 7% (entry 5), 10% (entry 6) and 1% (entry 7).
The reaction was run during 72 h.
b
c
Scheme 5. Mechanistic proposal.
yields. The mechanism of formation of these compounds can be
explained starting by a 1,3-dipolar cycloaddition.
4.2. General procedure
To a solution of the corresponding triazolopyridine (100 mg) in
DMF, reagent (3 eq), with catalyst (7 mol%) o without if is the case,
were added. The mixture was charged in an autoclave and was
maintained at 150 ꢀC for 24 h. After cooling to room temperature,
reaction mixture was filtered and washed with dichloromethane.
Then, water was added and was extracted with dichloromethane.
Organic solvent was evaporated and dried giving a residue which
was purified by chromatotron, eluting firstly with hexane and then
with mixtures ethyl acetate/hexane at increasing polarity.
4. Experimental
4.1. General methods
Melting points were determined on a Kofler heated stage and
are uncorrected. NMR spectra were recorded on
AC300 MHz in CDCl3 or DMSO-d6 as solvent. Chemical shifts are
reported in units, parts per million (ppm) and were measured
a Bruker
d
relative to the signals for residual chloroform (7.27 ppm). COSY
experiments were done for all compounds. In some cases Dif-NOE
or NOESY experiment was carried out. HRMS Electron Impact (EI).
Quadrupole time of flight (QqTOF) 5600 system (Applied
Biosystems-MDS Sciex). Positive mode. Conditions: Gas1 35 psi,
GS2: 35, CUR: 25, temperature: 450 ꢀC, ion spray voltage: 5500 V.
Collision energy (CE): 25e35 V. IR spectra were recorded using a
Thermo-scientific Nicolet FT IR iS10 ATR. Column chromatography
was carried out on a column packed with silica-gel 60 N spherical
4.2.1. Reaction with ethyl propiolate
4.2.1.1. Using as substrate [1,2,3]triazolo[1,5-a]pyridine 1a
4.2.1.1.1. (E)-Ethyl 1-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-(pyridin-
2-yl)-1H-pyrazole-4-carboxylate 3(E). White solid mp. 126-127 ꢀC:
IR (ATR) (cmꢁ1) 3317, 3106, 2978, 2917, 1718, 1693, 1637, 1543, 1515,
1443, 1393, 1288, 1216, 1182, 1152, 1080, 1021, 988, 955, 852, 783,
766, 730, 694. 1H NMR (300 MHz, Cl3CD)
d
¼ 8.99 (d, J ¼ 13.8 Hz,
1H), 8.65 (ddd, J ¼ 4.9, 1.8, 0.9 Hz, 1H), 8.10 (ddd, J ¼ 7.6, 1.1, 0.9 Hz,
1H), 7.78 (ddd, J ¼ 7.6, 7.6, 1.8 Hz, 1H), 7.67 (s, 1H), 7.28 (ddd, J ¼ 7.6,
4.9, 1.2 Hz, 1H), 6.76 (d, J ¼ 13.8 Hz, 1H), 4.40 (c, J ¼ 7.1 Hz, 2H), 4.28
neutral size 63e210 mm. Cromatotron were used in several cases.
All starting products used are from commercial sources (Aldrich).
[1,2,3]Triazolo[1,5-a]pyridine 1a,10 3-methyl-[1,2,3]Triazolo[1,5-a]
pyridine 1b,11 and 3-phenyl-[1,2,3] triazolo[1,5-a]pyridine 1c,11 are
synthesized as described elsewhere.
(c, J ¼ 7.1 Hz, 2H), 1.40 (t, J ¼ 7.1 Hz, 3H), 1.34 (t, J ¼ 7.1 Hz, 4H). 13
C
NMR (75 MHz, Cl3CD)
d 166.5 (CO), 159.1 (CO), 153.6 (C), 150.4 (C),
149.7 (CH), 138.1 (CH), 137.0 (CH), 134.9 (C), 123.9 (CH), 120.8 (CH),
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R. Adam et al. / Tetrahedron xxx (2016) 1e6
5
113.1 (CH),109.6 (CH), 61.9 (CH2), 60.7 (CH2),14.5 (CH3),14.3 (CH3).
4.2.3. Reaction with dimethyl acetylenedicarboxylate (DMAD)
MS (Q-TOF) m/z (%):316 (27), 288 (37), 260 (100), 242 (7), 216 (4),
198 (7), 190 (3), 172 (15), 146 (5), 116 (4). HRMS (ESI-TOF) m/z
C16H18N3O4 (Mþþ1): 316.1292, found 316.1293.
4.2.3.1. Using as substrate [1,2,3]triazolo[1,5-a]pyridine 1a
4.2.3.1.1. Dimethyl (E)-1-(1,4-dimetoxy-1,4-dioxobut-2-en-2-yl)-
3-(pyridin-2-yl)-1H-pyrazol-4,5-dicarboxylate 8. Wasꢁeluted first as
a yellow solid mp. 118-119 ꢀC (AcOEt), IR (ATR) (cm ) 3106, 3039,
3000, 2961, 1737, 1715, 1585, 1460, 1374, 1310, 1218, 1143, 1074, 949,
4.2.1.1.2. (Z)-Ethyl 1-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-(pyridin-
2-yl)-1H-pyrazole-4-carboxylate 3(Z). Yellow solid mp. 89-91 ꢀC
(AcOEt): IR (ATR) (cmꢁ1) 2986, 2920, 2845, 1715, 1643, 1587, 1543,
1438, 1288, 1288, 1229, 1188, 1168, 1071, 1018, 988, 957, 860, 788,
783, 735, 710. 1H NMR (300 MHz, Cl3CD)
d
8.56 (ddd, J ¼ 4.9, 1.8.
1.0 Hz, 1H), 7.88 (ddd, J ¼ 7.6, 1.1, 1.1 Hz, 1H), 7.70 (ddd, J ¼ 7.6, 7.6,
1.8 Hz, 1H), 7.19 (ddd, J ¼ 7.6, 4.9, 1.1 Hz, 1H), 4.56 (s, 1H), 4.20 (s,
3H), 3.91 (s, 3H), 3.89 (s, 3H), 2.85 (s, 3H). 13C NMR (75 MHz, Cl3CD)
168.2 (CO), 166.2 (CO), 165.6 (CO), 159.4 (CO), 155.3 (C), 150.3 (C),
149.6 (CH), 147.4 (C), 136.6 (CH), 131.8 (C), 123.1 (CH), 120.7 (CH),
117.7 (C), 84.5 (CH), 52.8 (CH3), 52.7 (CH3), 50.9 (CH3), 40.2 (CH3).
MS (Q-TOF) m/z (%):276 (5), 244 (100). HRMS (ESI-TOF) m/z
C13H14N3O4 (Mþþ1 - C5H4O4): 276.0979, found 276.0981.
4.2.3.1.2. Dimethyl-3-(pyridin-2-yl)-1H-pyrazol-4,5-
758, 744, 727. 1H NMR (300 MHz, Cl3CD)
d
¼ 8.63 (ddd, J ¼ 4.9, 1.8,
0.9 Hz,1H), 7.98 (ddd, J ¼ 7.9, 1.1 Hz, 1H), 7.90 (d, J ¼ 9.9 Hz,1H), 7.74
(ddd, J ¼ 7.6, 7.6, 1.8 Hz, 1H), 7.62 (s, 1H), 7.25 (m, 1H), 5.79 (d,
J ¼ 9.9 Hz, 1H), 4.37 (c, J ¼ 7.1 Hz, 2H), 4.24 (c, J ¼ 7.1 Hz, 2H), 1.39 (t,
J ¼ 7.1 Hz, 3H), 1.20 (t, J ¼ 7.1 Hz, 3H). 13C NMR (75 MHz, Cl3CD)
166.4 (CO), 159.5 (CO), 152.3 (C), 150.8 (C), 149.6 (CH), 136.9 (CH),
134.4 (C), 129.8 (CH), 123.5 (CH), 120.4 (CH), 112.0 (CH), 111.6 (CH),
61.7 (CH2), 61.2 (CH2), 14.3 (CH3), 14.2 (CH3). MS (Q-TOF) m/z
(%):316 (3), 288 (8), 270 (81), 260 (9), 242 (100), 226 (1), 218 (8),198
(38), 190 (11), 172 (28), 146 (19), 116 (4). HRMS (ESI-TOF) m/z
C16H18N3O4 (Mþþ1): 316.1292, found 316.1290.
dicarboxylate 7. Oil, 1H NMR (300 MHz, Cl3CD)
d
8.60 (ddd, J ¼ 4.9,
1.7, 0.9 Hz, 1H), 8.01 (ddd, J ¼ 8.0, 1.0, 1.0 Hz, 1H), 7.80 (ddd, J ¼ 8.0,
7.7, 1.8 Hz, 1H), 7.32 (ddd, J ¼ 7.6, 4.9, 1.1 Hz, 1H), 3.93 (s, 3H), 3.92 (s,
3H). 13C NMR (75 MHz, Cl3CD165.0 (CO), 161.7 (CO), 149.8 (C), 149.4
(CH), 146.5 (C), 137.7 (CH), 136.8 (C), 124.4 (CH), 122.4 (CH), 113.7
(C), 52.9 (CH3), 52.7 (CH3). MS (Q-TOF) m/z (%):262 (5), 230 (100),
198 (13). HRMS (ESI-TOF) m/z C12H12N3O4 (Mþþ1): 262.0822,
found 262.0823.
4.2.1.1.3. (E)-Ethyl 1-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-(pyridin-
2-yl)-1H-pyrazole-5-carboxylate 4. Yellow solid mp. 92-94 ꢀC
(AcOEt): IR (ATR) (cmꢁ1) 3134, 2984, 2928, 2856, 1743, 1699, 1643,
1582, 1471, 1432, 1424, 1354, 1218, 1085, 999, 857, 769, 688. 1H NMR
(300 MHz, Cl3CD)
d
¼ 9.09 (d, J ¼ 13.8 Hz, 1H), 8.76 (ddd, J ¼ 4.9, 1.8,
0.9 Hz, 1H), 7.83 (ddd, J ¼ 7.8, 7.8, 1.8 Hz, 1H), 7.64 (ddd, J ¼ 7.9, 1.1,
0.9 Hz, 1H), 7.35 (ddd, J ¼ 7.6, 4.9, 1.1 Hz, 1H), 7.19 (s, 1H), 6.84 (d,
J ¼ 13.8 Hz,1H), 4.45 (c, J ¼ 7.1 Hz, 2H), 4.25 (c, J ¼ 7.1 Hz, 2H),1.43 (t,
J ¼ 7.1 Hz, 3H), 1.31 (t, J ¼ 7.1 Hz, 3H). 13C NMR (75 MHz, Cl3CD)
166.8 (CO), 161.8 (CO), 149.9 (CH), 148.0 (C), 145.8 (C), 144.1 (C),
139.4 (CH), 137.5 (CH), 123.9 (CH), 123.8 (CH), 111.0 (CH), 110.5 (CH),
61.7 (CH2), 60.7 (CH2), 14.5 (CH3), 14.4 (CH3). MS (Q-TOF) m/z
(%):270 (100), 242 (50), 226 (23), 218 (10), 214 (4), 198 (26), 190 (9),
172 (15), 146 (8), 129 (1), 116 (3). HRMS (ESI-TOF) m/z C16H18N3O4
(Mþþ1): 316.1292, found 316.1282.
4.2.3.2. Using as substrate 3-methyl[1,2,3]triazolo[1,5-a]pyridine 1b
4.2.3.2.1. Dimethyl-3-methyl-3-(pyridin-2-yl)-3H-pyrazol-4ꢁ,51-
dicarboxylate 9. Yellow solid mp. 95-96 ꢀC (AcOEt), IR (ATR) (cm
)
2959, 2920, 1715, 1610, 1538, 1451, 1432, 1368, 1293, 1202 1154,
1080, 1032, 841, 783, 741, 691. 1H NMR (300 MHz, Cl3CD)
d
8.48
(ddd, J ¼ 4.9, 1.8, 1.0 Hz, 1H), 7.89e7.80 (m, 2H), 7.34e7.28 (m, 1H),
3.94 (s, 3H), 3.86 (s, 3H), 2.81 (s, 3H). 13C NMR (75 MHz, Cl3CD 163.5
(CO), 163.0 (CO), 152.3 (C), 148.0 (CH), 145.4 (C), 144.6 (C), 138.9
(CH), 123.3 (CH), 118.3 (CH), 114.2 (C), 52.7 (CH3), 52.0 (CH3), 13.1
(CH3). MS (Q-TOF) m/z (%):244 (100), 214 (34). HRMS (ESI-TOF) m/z
C13H14N3O4 (Mþþ1): 276.0979 found 276.0983.
4.2.1.2. Using as substrate 3-Methyl-[1,2,3]triazolo[1,5-a]pyridine 1b
4.2.1.2.1. (E)-Ethyl 1-(3-ethoxy-3-oxoprop-1-en-1-yl)-4-methyl-
4.2.4. Reaction with ethyl acrylate
4.2.4.1. Using as substrate [1,2,3]triazolo[1,5-a]pyridine 1a
3-(pyridin-2-yl)-1H-pyrazole-5-carboxylate 6. Oil: IR (ATR) (cmꢁ1
)
2981, 2934, 1718, 1654, 1596, 1449, 1388, 1365, 1282, 1260, 1163,
4.2.4.1.1. (E)-Ethyl
2-(pyridin-2-yl)cyclopropanecarboxylate
1093, 1030, 988, 946, 857, 783, 746, 724. 1H NMR (300 MHz, Cl3CD)
10a(E). Oil: IR (ATR) (cmꢁ1) 2978, 2928, 2903, 1718, 1596, 1568,
1476, 1429, 1327, 1260, 1174, 1043, 1021, 927, 846, 769, 744. 1H NMR
d
¼ 8.66 (ddd, J ¼ 4.9, 1.8, 0.9 Hz, 1H), 7.97 (d, J ¼ 13.7 Hz, 1H), 7.73
(ddd, J ¼ 7.8, 7.8, 1.8 Hz, 1H), 7.44 (ddd, J ¼ 7.8, 1.1, 1.1 Hz, 1H),
7.29e7.23 (m, 1H), 6.78 (d, J ¼ 13.7 Hz, 1H), 4.34e4.23 (m, 4H), 2.45
(s, 3H), 1.32 (t, J ¼ 7.1 Hz, 2H), 1.25 (t, J ¼ 7.1 Hz, 2H). 13C NMR
(75 MHz, Cl3CD) 166.6 (CO), 162.0 (CO), 151.0 (C), 149.4 (CH), 143.7
(C), 141.5 (C), 136.0 (CH), 135.6 (CH), 126.0 (CH), 124.3 (C), 122.4
(CH), 110.1 (CH), 61.5 (CH2), 61.0 (CH2), 14.4 (CH3), 14.2 (CH3), 10.2
(CH3). MS (Q-TOF) m/z (%):284 (35), 256 (100), 210 (3), 143 (1).
HRMS (ESI-TOF) m/z C17H20N3O4 (Mþþ1): 330.1448, found
330.1446.
(300 MHz, Cl3CD)
d
¼ 8.44 (ddd, J ¼ 4.9, 1.7, 0.9 Hz, 1H), 7.55 (ddd,
J ¼ 7.7, 7.7, 1.8 Hz, 1H), 7.22 (ddd, J ¼ 7.8, 1.0, 1.0 Hz, 1H), 7.08 (ddd,
J ¼ 7.5, 4.9, 1.2 Hz, 1H), 4.16 (c, J ¼ 7.2 Hz, 2H), 2.62e2.53 (m, 1H),
2.27e2.21 (m, 1H), 1.65e1.55 (m, 2H), 1.27 (t, J ¼ 7.1 Hz, 3H). 13C
NMR (75 MHz, Cl3CD) d 173.6 (CO), 159.1 (C), 149.6 (CH), 136.2 (CH),
122.7 (CH), 121.4 (CH), 60.9 (CH2), 27.4 (CH), 24.5 (CH), 17.4 (CH2),
14.4 (CH3). MS (Q-TOF) m/z (%): 146 (6), 118 (100), 91 (13). HRMS
(ESI-TOF) m/z C11H14NO2 (Mþþ1): 192.1019, found 192.1019.
4.2.4.1.2. (Z)-Ethyl
2-(pyridin-2-yl)cyclopropanecarboxylate
10a(Z). Oil: IR (ATR) (cmꢁ1) 3050, 2978, 2925, 2900, 1718, 1582,
1562, 1471, 1429, 1188, 1157, 1091, 1027, 999, 963, 849, 799, 746. 1H
4.2.2. Reaction with ethyl propiolate using as substrate [1,2,3]
triazolo[1,5-a]pyridine 1a and CuI as catalyst
NMR (300 MHz, Cl3CD)
d
¼ 8.47 (ddd, J ¼ 4.8, 1.7, 0.8 Hz, 1H), 7.56
(ddd, J ¼ 7.7, 7.7, 1.8 Hz,1H), 7.23 (d, J ¼ 7.9 Hz,1H), 7.08 (ddd, J ¼ 7.5,
4.9,1.1 Hz,1H), 3.88 (c, J ¼ 7.2 Hz, 2H), 2.70 (ddd, J ¼ 16.6, 8.8, 8.8 Hz,
1H), 2.18e2.10 (m, 1H), 1.86e1.75 (m, 1H), 1.45e1.33 (m, 1H), 0.99
(d, J ¼ 7.1 Hz, 3H). 13C NMR (75 MHz, Cl3CD) 171.1 (CO), 156.8 (C),
149.0 (CH), 135.9 (CH), 123.7 (CH), 121.7 (CH), 60.4 (CH2), 27.3 (CH),
21.7 (CH), 14.1 (CH), 11.7 (CH3). MS (Q-TOF) m/z (%):146 (19), 118
(100), 91 (13). HRMS (ESI-TOF) m/z C11H14NO2 (Mþþ1): 192.1019,
found 192.1017.
4.2.2.1. Ethyl indolizine-3-carboxylate 5. Oil: IR (ATR) (cmꢁ) 2981,
2923, 2853, 1687, 1471, 1402, 1332, 1227, 1179, 1132, 1049, 749. 1H
NMR (300 MHz, Cl3CD)
d
¼ 9.42 (dd, J ¼ 7.2, 0.8 Hz, 1H), 7.52 (d,
J ¼ 4.5 Hz, 1H), 7.49 (d, J ¼ 8.9 Hz, 1H), 7.00 (ddd, J ¼ 8.9, 6.9, 1.1 Hz,
1H), 6.79 (ddd, J ¼ 6.9, 6.9, 1.2 Hz, 1H), 6.47 (d, J ¼ 4.5 Hz, 1H), 4.37
(c, J ¼ 7.1 Hz, 2H), 1.40 (t, J ¼ 7.1 Hz, 3H). 13C NMR (75 MHz, Cl3CD)
161.6 (CO), 138.2 (C), 127.5 (CH), 121.8 (CH), 121.6 (CH), 119.0 (CH),
114.2 (C), 112.7 (CH), 101.2 (CH), 59.9 (CH2), 14.7 (CH3). MS (Q-TOF)
m/z (%):162 (14), 144 (35), 117 (100), 91 (9). HRMS (ESI-TOF) m/z
C11H12NO2 (Mþþ1): 190.0863, found 190.0863.
4.2.4.2. Using as substrate the 3-methyl-[1,2,3]triazolo[1,5-a]pyridine
1b
Please cite this article in press as: Adam R, et al., Reactivity of [1,2,3]Triazolo[1,5-a]pyridines as 1,3-dipoles, Tetrahedron (2016), http://
dx.doi.org/10.1016/j.tet.2016.11.006

6
R. Adam et al. / Tetrahedron xxx (2016) 1e6
4.2.4.2.1. (E)-Ethyl
2-methyl-2-(pyridin-2-yl)cyclo-
also to thank the SCSIE of the University of Valencia for recording
the ESI-MS spectra. R. A. wants to thank the Generalitat Valenciana
(Valencia, Spain) for a predoctoral grant. S.A wants to thank to the
University of Surrey (U. K.) for an Erasmus grant.
propanecarboxylate 10b(E). Oil: IR (ATR) (cmꢁ1)3050, 2981, 2942,
2884,1721,1579,1565,1468,1424,1371, 1293, 1266,1174,1132, 1071,
1046, 1018, 977, 846, 785, 746, 666. 1H NMR (300 MHz, Cl3CD)
d
¼ 8.48 (ddd, J ¼ 4.8, 1.9, 0.9 Hz, 1H), 7.61 (ddd, J ¼ 8.0, 7.5, 1.9 Hz,
1H), 7.37 (ddd, J ¼ 8.0, 1.0, 1.0 Hz, 1H), 7.08 (ddd, J ¼ 7.4, 4.8, 1,1 Hz,
1H), 4.17 (cd, J ¼ 7.2, 3.4 Hz, 2H), 2.38 (dd, J ¼ 8.4, 6.3 Hz, 1H), 1.79
(dd, J ¼ 8.4, 4.1 Hz, 1H),1.64 (s, 3H), 1.48 (dd, J ¼ 6.3, 4.0 Hz,1H), 1.26
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2016.11.006.
(t, J ¼ 7.1 Hz, 3H). 13C NMR (75 MHz, Cl3CD)
d 172.1 (CO), 162.6 (C),
149.2 (CH), 136.3 (CH), 121.1 (CH), 120.3 (CH), 60.7 (CH2), 30.0 (CH),
29.5 (C), 22.7 (CH2), 15.9 (CH3), 14.5 (CH3). MS (Q-TOF) m/z (%):160
(13), 145 (5), 132 (100), 117 (81), 90 (1). HRMS (ESI-TOF) m/z
C12H16NO2 (Mþþ1): 206.1176, found 206.1173.
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Acknowledgements
We are very grateful to the Ministerio de Economía y Com-
petitividad (Spain) (Project CONSOLIDER-INGENIO CSD 2010-
00065), and to Generalitat Valenciana (Valencia, Spain) (project
PROMETEO II 2015/002) for its financial support. We would like
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Please cite this article in press as: Adam R, et al., Reactivity of [1,2,3]Triazolo[1,5-a]pyridines as 1,3-dipoles, Tetrahedron (2016), http://
dx.doi.org/10.1016/j.tet.2016.11.006