Synthesis of novel triazolopyridylboronic acids and esters. Study of potential application to Suzuki-type reactions

Article abstract of DOI:10.1016/j.tet.2004.03.083

This paper describes a general method for the synthesis of novel [1,2,3]triazolo[1,5-a]pyridylboronic acids and esters, and the first results on Suzuki cross-coupling reactions with these new compounds and [1,2,3]triazolo[5,1-a]isoquinolylboronic acid, re

Full text of DOI:10.1016/j.tet.2004.03.083

Tetrahedron 60 (2004) 4887–4893
Synthesis of novel triazolopyridylboronic acids and esters.
Study of potential application to Suzuki-type reactions
a
Belen Abarca, Rafael Ballesteros, Fernando Blanco, Alexandre Bouillon, Valerie Collot,
a
a
b
b
,
*
´
´
†
Jose-Reynaldo Domınguez, Jean-Charles Lancelotb and Sylvain Raultb
a
,
´
´
a
´ ´ ´ ´
Departamento de Quımica Organica, Facultad de Farmacia, Universidad de Valencia, Avda. Vicente Andres Estelles s/n,
46100 Burjassot (Valencia), Spain
´ ´
Centre d’Etudes et de Recherche sur le Medicament de Normandie, 5 rue Vaubenard, 14032 Caen Cedex, France
b
Received 26 December 2003; revised 24 March 2004; accepted 29 March 2004
Abstract—This paper describes a general method for the synthesis of novel [1,2,3]triazolo[1,5-a]pyridylboronic acids and esters, and the
first results on Suzuki cross-coupling reactions with these new compounds and [1,2,3]triazolo[5,1-a]isoquinolylboronic acid, reacting with a
variety of aryl halides as a route to 7-aryltriazolopyridines and 5-aryltriazoloisoquinolines.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
During our research on the chemistry of [1,2,3]triazolo[1,5-
a]pyridines 1 and [1,2,3]triazolo[5,1-a]isoquinoline 2, we
discovered a facile route to new bistriazolopyridines and
related compounds, which are potential helicating ligands,
using compounds 1 and 2 as building blocks.1–3 The interest
of this type of compounds,4 led us to attempt to widen the
scope of their synthesis by alternative routes. The Suzuki
reaction would be applicable to the preparation of hetero-
aryltriazolopyridines and heteroaryltriazoloisoquinolines,
which are also potentially interesting in the field of new
selective inhibitors of cyclooxygenase 2. In contrast of the
many examples of Suzuki coupling reactions between
heterocyclic halides and phenyl boronic acids that have
appeared in the literature over the past two decades,5,6 the
corresponding reactions involving heterocyclic boronic
acids or esters are noticeably fewer,7 nevertheless interest
in heterocyclic boronic derivatives continues to grow and
we wish to report here the synthesis of novel [1,2,3]tria-
zolo[1,5-a]pyridylboronic acids 3a–c, esters 4a–c and 5,
and the first results on Suzuki cross-coupling reactions with
these new compounds and [1,2,3]triazolo[5,1-a]isoquinolyl
boronic acid 6 reacting with a variety of aryl halides.
The starting materials 1a–c, and 2, were prepared by
procedures described in the literature.8,2,9 We used the
classical preparation of boronic acids which requires the
reaction of an organolithium intermediate, generated by
deprotonation, with a trialkylborate.10–12 The correspond-
ing lithium derivatives 7 and 8 were formed in toluene at
240 8C with n-BuLi,13 followed by reaction with triiso-
propyl borate. The reaction mixture was quenched with
slow addition of 5% aqueous NaOH solution and the
resulting aqueous layer neutralized by careful addition of
concentrated HCl. The new triazolopyridyl boronic acids
3a–c were stable yellow solids, the triazoloisoquinolyl
boronic acid 6 was a stable white solid.3 All acids were
insoluble in usual organic solvents, were relatively easy to
handle and purify, could be analyzed by ESI-MS, and were
obtained with yields from 40 to 78%. The pinacol esters 4a–c
were obtained using similar conditions to those described
previously to obtain pinacol esters from the halopyridyl
boronic acids, in an one pot procedure.14 Compounds 4a–c
are stable and were obtained in high yield. The borolane 5b
waspreparedbytheproceduredescribedbysomeofus,15 from
the corresponding boronic acid by reaction with N-methyl-
diethanolamine in excellent yield (Scheme 1).
The boronic acids were directly subjected to modified
Suzuki cross-coupling conditions, (DME/aqueous K2CO3/
Pd(PPh3)4/80 8C),11,16 with 4-iodoanisole. The triazolo-
pyridyl derivatives 3a,b gave protodeboronation as the main
result and triazolopyridines 1a,b were recovered from the
reaction mixture in almost quantitative yield (Scheme 2).
Keywords: Triazolopyridines; Triazoloisoquinolines; Boronic acids and
esters; Suzuki cross-coupling reaction.
*
Corresponding author. Tel.: þ34963544933; fax: þ34963544939;
e-mail address: belen.abarca@uv.es
Actual address, Departamento de Quımica, Universidad de Oriente,
Santiago de Cuba, Cuba.
†
´
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.083

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B. Abarca et al. / Tetrahedron 60 (2004) 4887–4893
Scheme 1. i, n-BuLi/toluene; ii, B(OiPr)3; iii, pinacol; iv, MgSO4/N-methyldiethanolamine (from 3b).
The triazoloisoquinoline boronic acid 6 gave a mixture of
three compounds that were characterized as triazoloiso-
quinoline 2 (31%), bistriazoloisoquinoline 9 (30%),3 and the
heterobiaryl derivative 10a (25%) (Scheme 3).
The pinacol esters 4a and 4c gave only protodeboronation
(Scheme 4), nevertheless the pinacol ester 4b under
standard Suzuki-type conditions, (DMF/K3PO4/
Pd(PPh3)4/65 8C),14 gave better results furnishing further-
more protodeboronation, the heterobiaryl derivative 11a but
Scheme 2.
Scheme 3. i, DME/NaHCO3/H2O, 45 8C, 15 m; ii, 4-iodoanisol/Pd(PPh3)4/DME/reflux, 6 h; iii, 2-bromothiophene/Pd(PPh3)4/DME/reflux, 6 h; iv, 3-bromo-
pyridine/Pd(PPh3)4/DME/reflux, 6 h.
only in low yield (20%) (Scheme 5). Such different
reactivity is probably due to the better solubility and
stability of the compound 4b.
We followed the research with the boronic ester 4b and the
boronic acid 6, that underwent Suzuki couplings. We did
several attempts to improve the results modifying the
reaction conditions, a number of bases (K2CO3, Na3PO4,
K3PO4, NaHCO3, KOH, Ba(OH)2·8H2O), solvents
Scheme 4.

B. Abarca et al. / Tetrahedron 60 (2004) 4887–4893
4889
Scheme 5. i, 4-iodoanisol/Pd(PPh3)4/DMF; ii, K3PO4/H2O, 70 8C, 16 h; iii, 4-iodopyridine/Pd(PPh3)4/dioxane; iv, Ba(OH)2.8H2O/H2O/90–100 8C, 20 h;
v, 2-chloro-5-iodopyridine/Pd(PPh3)4/dioxane; vi, Ba(OH)2.8H2O/H2O/80–100 8C, 24 h; vii, 5-bromo-2-fluorpyridine/Pd(PPh3)4/dioxane; viii, Ba(OH)2.
8H2O/H2O/50–608C, 72 h.
(DME/H2O, DMF/H2O, toluene, acetone, dioxane), cata-
lysts (Pd(PPh3)4 purchased from commercial sources:
Aldrich; Lancaster, Pd/C 10%), and co-reagents (2-bromo-
pyridine, 2-bromothiophene, 3-bromopyridine, 4-iodo-
pyridine, 2-chloro-5-iodopyridine, 2-fluor-5-bromo-
pyridine) were investigated. The boronic derivatives 4b
and 6 coupled to some of these heteroarylhalides in modest
to low yield and compounds 11b–d, and 10b,c were
synthesized (Schemes 5 and 3). The reaction of triazolo-
isoquinoline boronic acid 6 with iodoanisol and with
2-bromothiophen resulted in a competitive formation of
homo-coupling derivative 9. In all reactions studied the
protodeboronation is always the main result. The analytical
and spectroscopic data for all new compounds are in
Tables 1–3.
Protodeboronation is a known issue for heteroarylboronic
acids, specifically when the boron is on a carbon adjacent to
a heteroatom.17 Triazolopyridines are easily quaternizated
in N2,18,19 and as Stevens et al. suggest for pyridineboronic
1
Table 1. H NMR shifts (ppm) and J values (Hz) for triazolopyridine derivatives
H3
H4
H5
H6
Others
3aa
7.90, s
—
7.53, d,
J¼8, 7 Hz
7.17, dd, J1¼8.7 Hz,
J2¼6.7 Hz
6.98, d,
J¼6.7 Hz
3ba
7.59, d,
J¼8.7 Hz
8.75, d,
7.28, dd, J1¼8.7 Hz,
J2¼6.6 Hz
7.15, d,
J¼6.6 Hz
7.66, d,
2.54, s, (CH3)
3cb
—
7.52, dd, J1¼8.9 Hz,
J2¼6.8 Hz
8.59, d, J¼4.8 Hz, H60; 8.22, d, J¼8.1 Hz, H30; 7.82, dd, J1¼7.7 Hz,
J2¼8.1 Hz, H40; 7.23, dd, J1¼4.8 Hz, J2¼7.7 Hz, H50
1.38, s, 4(CH3)
J¼8.9 Hz
J¼6.8 Hz
4ac
8.04, s
—
7.73, d,
J¼8.9 Hz
7.60, d,
7.13, dd, J1¼8.9 Hz,
J2¼6.6 Hz
7.43, d,
J¼6.6 Hz
7.40, d,
4bc
7.05, dd, J1¼8.9 Hz,
J2¼6.6 Hz
1.37, s, 4(CH3)
J¼8.9 Hz
J¼6.6 Hz
4cc
—
8.76, d,
J¼8.9 Hz
7.51, d,
7.26, dd, J1¼8.9 Hz,
J2¼6.6 Hz
7.46, d,
J¼6.6 Hz
7.36, d,
8.59, d, J¼4.9 Hz, H60; 8.32, d, J¼7.9 Hz, H30; 7.72, t, J¼7.7 Hz, H40; 7.14,
dd, J1¼4.9 Hz, J2¼7.5 Hz, H50
5c,d
—
7.12, dd, J1¼8.7 Hz,
J2¼6.3 Hz
4.27, m, 4H; 3.61, m, 2H; 3.32, m, 2H; 2.70, s, 3H; 2.59, s, 3H
J¼8.7 Hz
J¼6.3 Hz
11ac
11bc,d
11cc,d
11dc,d
—
7.50, d,
J¼8.8 Hz
7.71, d,
7.17, dd, J1¼8.8 Hz,
J2¼6.9 Hz
6.89, d,
J¼6.9 Hz
7.14, d,
7.92, d, J¼9.0 Hz, H20þH60; 7.00, d, J¼9.0 Hz, H30þH50; 3.83, s, (OCH3);
2.59, s, (CH3)
8.82, d, J¼5.6 Hz, H20þH60; 7.99, d, J¼5.6 Hz, H30þH50; 2.68, s, (CH3)
—
7.31, dd, J1¼8.8 Hz,
J2¼6.8 Hz
J¼8.8 Hz
J¼6.8 Hz
—
7.69, d,
J¼8.8 Hz
7.68, d,
7.30, dd, J1¼8.8 Hz,
J2¼6.8 Hz
7.07, d,
J¼6.8 Hz
7.05, d,
8.88, d, J¼2.3 Hz, H60; 8.55, dd, J1¼8.4 Hz, J2¼2.3 Hz, H40; 7.53, d,
J¼8.4 Hz, H30; 2.68, s, (CH3)
—
7.30, dd, J1¼8.9 Hz,
J2¼6.8 Hz
8.72, d, J¼2.5 Hz, H60; 8.67, ddd, JHF¼9.0 Hz, J1¼8.6 Hz, J2¼2.5 Hz;
7.14, dd, JHF¼2.8 Hz, J¼8.6 Hz; 2.68, s, (CH3)
J¼8.9 Hz
J¼6.8 Hz
a
Solvent: D2O/NaOH.
Solvent: CD3COCD3.
Solvent: Cl3CD.
b
c
d
NMR spectrum 400 MHz.

4890
Table 2. 1H NMR shifts (ppm) and J values (Hz) for triazoloisoquinoline derivatives
H1 H6 H7 H8 H9 H10
B. Abarca et al. / Tetrahedron 60 (2004) 4887–4893
Others
6a
8.36, s 7.20, s 7.66, d,
J¼7.3 Hz
k7.48–7.36, ml
k7.62–7.49, ml
7.96, d,
J¼7.6 Hz
8.12, dd,
J1¼7.4 Hz,
J2¼2.9 Hz
10ab 8.45, s 7.15, s 7.76, dd,
J1¼7.4 Hz,
10bb 8.47, s 7.47, s 7.78–7.75 m
7.87, d, J¼8.7 Hz, 2H; 7.20, d, J¼8.7 Hz, 2H; 3.8, s, 3H
J2¼2.9 Hz
k7.58–7.55, ml
k7.68–7.59, ml
8.11–8.08, m 8.23, dd, J1¼3.7 Hz, J2¼1.5 Hz; 7.48, dd, J1¼5.1 Hz, J2¼1.5 Hz; 7.18, dd,
J1¼5.1 Hz, J2¼3.7 Hz
10cb
8.47, s 7.28, s 7.81, dd,
J1¼7.5 Hz,
8.14, dd,
J1¼7.5 Hz,
9.08, sbr; 8.71, dd, J1¼4.5 Hz, J2¼1.5 Hz; 8.48, ddd, J1¼7.5 Hz,
J2¼1.5 Hz, J3¼1.5 Hz; 7.47, dd, J1¼7.5 Hz, J2¼4.5 Hz
J2¼2.2 Hz
J2¼2.2 Hz
a
Solvent: D2O/NaOH.
Solvent: Cl3CD.
b
Table 3. Mass spectroscopic data, melting points, and preparative yields for new compounds
Formula
MS
Mp (8C)
Yield %
3a
3b
3c
4a
4b
4c
5
11a
11b
11c
11d
10a
10b
10c
C6H6BN3O2
C7H8BN3O2
C11H9BN4O2
C12H16BN3O2
C13H18BN3O2
C17H19BN4O2
C12H17BN4O2
C14H13N3O
C12H10N4
C12H9ClN4
C12H9FN4
C17H13N3O
C14H9N3S
C15H10N4
ESI 163, MW 163
ESI 177, MW 177
ESI 240, MW 240
.300
.300
.300
72–74
77–79
185–187
130–132
134–136
132–134
178–180
206–208
117–120
131–132
208–209
66
40
78
65
55
31
90
20
18
10
15
25
26
5
HRMS found 245.1340, calcd 245.1335
HRMS found 259.1243, calcd 259.1492
HRMS found 322.1602, calcd 322.1601
HRMS found 260.0804, calcd 260.1441
HRMS found 239.1134, calcd 239.1059
HRMS found 210.0941, calcd 210.0905
HRMS found 244.0337, calcd 244.0516
HRMS found 228.0596, calcd 228.0811
HRMS found 275.1059, calcd 275.1056
HRMS found 251.0517, calcd 251.0518
HRMS found 246.0905, calcd 246.0912
Scheme 6.
ester,20 it is possible that the boronic derivatives 3 and 4
coordinate to Lewis acids and bases present in solution
forming the zwitterions 12 that through ylides 13 gave
triazolopyridines (Scheme 6).
We tried the reaction of 5 with 4-iodopyridine using the best
conditions found in the reaction of 4b with the same co-
reagent, nevertheless compound 11b was obtained in
smaller yield (8%) and triazolopyridine 1b was also formed
(65% yield) (Scheme 7).
In another hand, the ester 5 possess a tetra-coordinated
boron which can no interact with other atom, for this we
thought it could be better substrate for coupling reactions.21
3. Conclusion
In summary, we have successfully formed and characterized
some 7-triazolopyridylboronic acids and esters, that are
stable solids when have been stored, as well as 5-triazolo-
isoquinolylboronic acid. Nevertheless, in solution under
the various Suzuki reaction conditions experimented
they are not very stable and underwent protodeboronation.
7-Triazolopyridylboronic acids are the most unstable
compounds. Still we were able to synthesize some new
7-aryltriazolopyrines and 5-aryltriazolisoquinolines in
modest to low yields, as result of Suzuki type cross-
coupling reactions. Investigations are continuing on boronic
Scheme 7. i, 4-iodopyridine/Pd(PPh3)4/dioxane; ii, Ba(OH)2.8H2O/H2O/
H2O/90–100 8C, 20 h.

B. Abarca et al. / Tetrahedron 60 (2004) 4887–4893
4891
esters to improve these yields by study of the recently
developed methodologies, a solventless Suzuki coupling
reaction,21 and an in situ formation and reaction of
heteroarylboronic esters.20,22
triazoloazine (1 equiv.) in dry toluene and the solution kept
at this temperature 4 h. A solution of triisopropyl borate
(1.2 equiv.) in toluene was then added and the mixture was
allowed to react at this temperature for over 2 h, and then
allowed to warm to 0–5 8C. A solution of anhydrous pinacol
(1.3 equiv.) in toluene was added and, after 5 min, a solution
of glacial acetic acid (1.05 equiv.). The mixture was filtered
through Celite, and extracted with 5% aqueous NaOH
solution. The resulting aqueous layer was collected and
acidified to pH¼5 by dropwise addition of concentrated
HCl, keeping the internal temperature below 5 8C. Extrac-
tion with dichloromethane, evaporation of the organic layer
and washing with ether/hexane gave the corresponding
dioxaborolanes.
4. Experimental
Melting points were determined on a Kofler heated stage
and are uncorrected. NMR spectra were recorded on a
Bruker AC300 MHz or on a JEOL Lambda 400 MHz
spectrometers. HRMS (EI) determinations were made using
a VG Autospec Trio 1000 (Fisons). ESI-MS was performed
using an ion trap mass spectrometer (Esquire 3000 Plus,
Bruker) coupled to a liquid chromatograph (Agilet LC 1100
Chemstation), the ionization method was electrospray with
positive ion polarity (ESIþ). Samples were dissolved in
acetonitrile/water (2/3) containing 0.5% formic acid.
Infrared spectra were recorded in KBr discs on a Bio-Rad
FTS-7. Chromatography was performed on a Chromatotron,
using 2 cm plates of silica Merck Pf254. Pd(PPh3)4 supplier
Lancaster.
4.2.1. 2-(7-[1,2,3]Triazolo[1,5-a]pyridyl)-4,4,5,5-tetra-
methyl[1,3,2]dioxaborolane 4a. Yellow solid. IR nmax
(KBr) (cm21) 3477, 1366, 1150, 979, 758. 13C NMR d
(CDCl3) 134.00 (C), 126.17 (CH), 125.84 (CH), 124.37
(CH), 120.92 (CH), 110.00 (C), 85.70 (C)£2, 24.20
(CH3)£4. MS m/z 245, 217, 216, 118.
4.2.2. 2-(3-Methyl-7-[1,2,3]triazolo[1,5-a]pyridyl)-
4,4,5,5-tetramethyl[1,3,2]dioxaborolane 4b. Yellow
solid. IR nmax (KBr) (cm21) 3410, 1329, 1134, 978, 738.
13C NMR d (CDCl3) 133.57 (C), 131.02 (C), 125.08 (CH),
124.84 (CH), 123.04 (CH), 120.52 (CH), 84.51 (C£2),
24.64 (CH3£4), 9.96 (CH3). MS m/z 259, 231, 216, 188,
172, 149, 132.
4.1. General procedure for preparation of boronic acids
To a 2.5 M solution of n-BuLi (1.2 equiv.) in hexane, cooled
to 240 8C, was added a solution of the corresponding
triazoloazine (1 equiv.) in dry toluene and the solution kept
at this temperature 4 h. A solution of triisopropyl borate
(1.2 equiv.) in toluene was then added and the mixture was
allowed to react at this temperature for over 2 h, and then
allowed to warm to room temperature. The mixture was
quenched by slow addition of 5% aqueous NaOH solution.
The resulting aqueous layer was collected and acidified to
pH¼5 by dropwise addition of concentrated HCl, keeping
the internal temperature below 5 8C. Extraction with ethyl
acetate, evaporation of the organic layer and washing with
ether gave the corresponding boronic acids.
4.2.3. 2-[3-(2-Pyridyl)-7-[1,2,3]Triazolo[1,5-a]pyridyl]-
4,4,5,5-tetramethyl[1,3,2]dioxaborolane 4c. Yellow
solid. IR nmax (KBr) (cm21) 3468, 1378, 1179, 846, 739.
13C NMR d (CDCl3) 153.00 (C), 149.44 (C), 137.09 (CH),
132.23 (C), 127.00 (C), 126.18 (CH), 125.65 (CH), 124.13
(CH), 122.27 (CH), 121.12 (CH), 96.94 (C), 85.69 (C£2),
23.45 (CH3£4). MS m/z 322, 295, 195, 168.
4.3. 2-(3-Methyl-7-[1,2,3]triazolo[1,5-a]pyridyl)-1,3,6-
dioxazaborolane 5
4.1.1. 7-[1,2,3]Triazolo[1,5-a]pyridylboronic acid 3a.
Yellow solid. IR nmax (KBr) (cm21) 3201, 1352, 822, 756.
13C NMR d (D2O/NaOH) 130.00 (C), 126.79 (CH), 124.96
(CH), 119.00 (C), 118.23 (CH), 115.32 (CH). MS m/z 163,
145, 135.
To a mixture of 3-methyl-7-triazolopyridylboronic acid 3a
(516 mg, 2.91 mmol) and MgSO4 (ca. 1 g per mmol) in dry
dichloromethane (50 mL) was added dropwise a solution of
N-methyldiethanolamine (365 mg, 3.08 mmol) in dichloro-
methane. The mixture was allowed to react under stirring at
room temperature for 48 h. Then the mixture was filtered
under reduced pressure. The filtrate was dried over MgSO4
and concentrated to dryness. A yellow oil was obtained that
was precipitate by ethyl acetate/ether, after filtration
compound 5 was obtained almost pure as a yellow solid
(655 mg, 87%). 13C NMR d (CDCl3) 133.11 (C), 131.90
(C), 123.58 (CH), 121.28 (CH), 116.46 (CH), 62.58
(CH2£2), 61.16 (CH2£2), 44.46 (CH3), 10.36 (CH3). MS
m/z 260, 259, 232, 231, 217, 216, 132, 128, 127, 104.
4.1.2. 7-(3-Methyl-[1,2,3]triazolo[1,5-a]pyridyl)boronic
acid 3b. Yellow solid. IR nmax (KBr) (cm21) 3423, 1316,
868, 772. 13C NMR d (D2O/NaOH) 133.80 (CH), 132.08
(C), 125.52 (CH), 118.09 (CH), 117.00 (C), 114.81 (CH),
9.49 (CH3). MS m/z 177, 159, 149, 131.
4.1.3. 7-[3-(2-Pyridyl)-[1,2,3]triazolo[1,5-a]pyridyl]-
boronic acid 3c. Yellow solid. IR nmax (KBr) (cm21
3368, 1316, 830, 753. MS m/z 240, 212, 194.
)
4.1.4. [1,2,3]Triazolo[5,1-a]isoquinolylboronic acid 6.
Prepared as described.3
4.4. General procedure for preparation of 5-aryl-
[1,2,3]triazolo[5,1-a]isoquinolines
4.2. General procedure for preparation of boronic
pinacol esters
A mixture of 5-[1,2,3]triazolo[5,1-a]isoquinolylboronic
acid 6 (85 mg, 0.4 mmol), DME (10 mL), sodium hydrogen
carbonate (100 mg, 1.2 mmol) and water (5 mL), was
heated at 45 8C under nitrogen atmosphere with vigorous
To a 2.5 M solution of n-BuLi (1.2 equiv.) in hexane, cooled
to 240 8C, was added a solution of the corresponding

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B. Abarca et al. / Tetrahedron 60 (2004) 4887–4893
stirring (15 min). A solution of the corresponding
co-reactive (0.3 mmol), and Pd[PPh3]4 (23 mg,
0.039 mmol) in DME (5 mL) was added. The reaction
mixture was heated to reflux with vigorous stirring under
nitrogen atmosphere, the rate of reaction was followed by
TLC. (6 h). Water was added (50 mL) and the mixture was
extracted with dichloromethane (3£50 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated under
reduced pressure. The reaction crude was purified by
chromatotron using ethyl acetate/hexane in increasing
amounts as eluent.
4-iodoanisol as co-reactive (0.32 mmol), catalyst (33 mg,
5%), DMF as solvent (7 mL), K3PO4 as base (103 mg,
0.48 mmol), water (7 mL), temperature (70 8C), time (16 h),
water (5 mL), extraction solvent ethyl acetate. Purified by
chromatotron, the isolated products were: triphenyl-
phosphine oxide (17 mg), 3-methyl-[1,2,3]triazolo[1,5-
a]pyridine 1b (37 mg, 70%), 7-(4-methoxyphenyl)-3-
methyl-[1,2,3]triazolo[1,5-a]pyridine 11a (19 mg, 20%).
IR nmax (KBr) (cm21) 1636, 1606, 1505, 1283. 13C NMR
d (CDCl3) 161.25 (C), 138.46 (C), 134.85 (C), 133.07 (C),
130.97 (CH£2), 129.00 (C), 124.95 (CH), 124.48 (CH),
115.84 (CH), 114.51 (CH£2), 55.52 (CH3), 10.92 (CH3).
MS m/z 239, 227, 211, 196, 185, 168.
4.4.1. 5-(4-Methoxyphenyl)-[1,2,3]triazolo[5,1-a]iso-
quinoline 10a. The co-reactive was 4-iodoanisol (58 mg).
The isolated products were: [1,2,3]triazolo[5,1-a]isoquino-
line 2 (21 mg, 31%), 5-(4-methoxyphenyl)-[1,2,3]tria-
zolo[5,1-a]isoquinoline 10a (27 mg, 25%). 13C NMR d
(CDCl3) 160.62 (C), 135.75 (C), 133.20 (C), 130.64 (CH),
129.65 (CH), 128.92 (CH), 128.02 (CH), 127.16 (CH), 125.89
(C), 124.31 (CH), 123.66 (CH), 121.93 (C), 114.59 (CH),
113.83 (CH), 55.24 (OCH3). MS m/z 275, 247, 232, 203, and
5,50-bi[1,2,3]triazolo[5,1-a] isoquinoline 9 (20 mg, 30%).
4.5.2. 7-(4-Pyridyl)-3-methyl-[1,2,3]triazolo[1,5-a]pyri-
dine 11b. Starting material 4b (205 mg, 0.8 mmol),
4-iodopyridine as co-reactive (0.7 mmol), catalyst (40 mg,
5%), dioxane as solvent (25 mL), Ba(OH)2.8H2O as base
(224 mg, 0.71 mmol), water (4 mL), temperature (90–
100 8C), time (20 h), water (5 mL), extraction solvent
dichloromethane. Purified by column chromatography, the
isolated products were: 3-methyl-[1,2,3]triazolo[1,5-a]-
pyridine 1b (58 mg, 55%), 7-(4-pyridyl)-3-methyl-
[1,2,3]triazolo[1,5-a]pyridine 11b (30 mg, 18%). IR
nmax (KBr) (cm21) 1606,1572, 1553, 1424, 1401, 783.
13C NMR d (CDCl3) 150.38 (CH£2), 139.49 (C), 135.40
(C), 135.19 (C), 132.61 (C), 123.81 (CH), 123.00 (CH£2),
117.97 (CH), 115.87 (CH), 10.48 (CH3). MS m/z 210, 182,
181, 155, 78.
4.4.2. 5-(2-Thienyl)-[1,2,3]triazolo[5,1-a]isoquinoline
10b. The co-reactive was 2-bromothiophene (57 mg). The
isolated products were: [1,2,3]triazolo[5,1-a]isoquinoline 2
(18 mg, 26%), 5-(2-thienyl)-[1,2,3]triazolo[5,1-a]isoquino-
line 10b (26 mg, 26%). 13C NMR d (CDCl3) 132.15 (C),
132.14 (C), 128.89 (CH), 128.57 (CH), 128.33 (CH), 127.54
(CH), 127.29 (CH), 126.82 (CH), 126.53 (CH), 125.21
(CH), 122.91 (C), 121.96 (C), 112.58 (CH). MS m/z 251,
223, 222, 190, and 5,50-bi[1,2,3]triazolo[5,1-a]isoquinoline
9 (25 mg, 36%).
4.5.3. 7-(2-Chloro-5-pyridyl)-3-methyl-[1,2,3]tria-
zolo[1,5-a]pyridine 11c. Starting material 4b (315 mg,
1.21 mmol), 2-chloro-5-iodopyridine as co-reactive
(310 mg, 1.3 mmol), catalyst (60 mg, 4%), dioxane as
solvent (40 mL), Ba(OH)2·8H2O as base (400 mg), water
(8 mL), temperature (80–100 8C), time (24 h), water
(5 mL), extraction solvent dichloromethane. Purified by
column chromatography, the isolated products were:
3-methyl-[1,2,3]triazolo[1,5-a]pyridine 1b (100 mg, 62%),
7-(2-chloro-5-pyridyl)-3-methyl-[1,2,3]triazolo[1,5-a]pyri-
dine 11c (30 mg, 10%). IR nmax (KBr) (cm21) 1633,1588,
1556, 1112, 783. 13C NMR d (CDCl3) 152.62 (C), 149.29
(CH), 139.27 (CH), 135.26 (C), 133.76 (C), 132.53 (C),
127.24 (C), 124.03 (CH), 123.89 (CH), 117.55 (CH), 115.33
(CH), 10.46 (CH3). MS m/z 246, 244, 218, 217, 216, 215,
191, 189, 181, 78.
4.4.3. 5-(3-Pyridyl)-[1,2,3]triazolo[5,1-a]isoquinoline
10c. The co-reactive was 3-bromopyridine (78 mg). The
isolated products were: triphenylphosphine oxide (18 mg),
[1,2,3]triazolo[5,1-a]isoquinoline 2 (23 mg, 35%), 5-(3-
pyridyl)-[1,2,3]triazolo[5,1-a] isoquinoline 10c (5 mg, 5%).
13C NMR d (Cl3CD) (DEPT) 148.44 (CH), 148.21 (CH),
138.14 (CH), 130.20 (CH), 129.71 (CH), 129.62 (CH),
128.79 (CH), 128.28 (CH), 124.43 (CH), 116.84 (CH). MS
m/z 246, 218.
4.5. General procedure for preparation of 7-aryl-3-
methyl-[1,2,3]triazolo[1,5-a] pyridines
A mixture of 2-(3-methyl-7-[1,2,3]triazolo[1,5-a]pyridyl)-
4,4,5,5-tetramethyl[1,3,2]dioxaborolane 4b (mg, mmol), the
corresponding co-reactive (mmol), and Pd[PPh3]4 as
catalyst (mg, %) was dissolved in the appropriate solvent
(mL), then a base (g, mmol) dissolved in water (mL) was
added and the mixture was heated (8C) with vigorous
stirring (h), the rate of reaction was followed by TLC, and
then was cooled to room temperature. Water was added
(mL) and the mixture was extracted with a organic solvent.
The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. The reaction crude
was purified by chromatotron or column chromatography
using ethyl acetate/hexane in increasing amounts as eluent.
4.5.4. 7-(2-Fluor-5-pyridyl)-3-methyl-[1,2,3]triazolo[1,5-
a]pyridine 11d. Starting material 4b (400 mg, 1.54 mmol),
5-bromo-2-fluorpyridine
as
co-reactive
(246 mg,
1.4 mmol), catalyst (80 mg, 5%), dioxane as solvent
(20 mL), Ba(OH)2·8H2O as base (2.8 mmol), water
(4 mL), temperature (50–60 8C), time (72 h), water
(5 mL), extraction solvent dichloromethane. Purified by
column chromatography using cyclohexane/ethyl acetate/
methanol in increasing amounts as eluent, the isolated
products were: 3-methyl-[1,2,3]triazolo[1,5-a]pyridine 1b
(143 mg, 70%), 7-(2-fluor-5-pyridyl)-3-methyl-[1,2,3]tria-
zolo[1,5-a]pyridine 11d (53 mg, 15%). IR nmax (KBr)
(cm21) 1635,1598, 1486, 1257, 793. 13C NMR d (CDCl3)
1
164.00 (C) (d, JCF¼241.90 Hz), 147.89 (CH) (d,
3
4.5.1. 7-(4-Methoxyphenyl)-3-methyl-[1,2,3]triazolo[1,5-
a]pyridine 11a. Starting material 4b (100 mg, 0.4 mmol),
3JCF¼14.96 Hz), 142.13 (CH) (d, JCF¼8.33 Hz), 135.25
(C), 133.88 (C), 132.56 (C), 126.48 (C) (d, 4JCF¼4.92 Hz),

B. Abarca et al. / Tetrahedron 60 (2004) 4887–4893
4893
10. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
123.96 (CH), 117.36 (CH), 115.19 (CH), 109.50 (CH) (d,
2JCF¼37.95 Hz), 10.49 (CH3). MS m/z 228, 200, 199, 173.
11. (a) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui,
M. A.; Snieckus, V. J. J. Org. Chem. 1991, 56, 3763–3768.
(b) Gronowitz, S.; Bobosik, V.; Lawitz, K. Chem. Scripta.
1984, 23, 120–122.
Acknowledgements
12. Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron
1993, 49, 49–64.
Our thanks are due to the Ministerio de Ciencia y
´
financial support, to the Vicerrectorado de Relaciones
Exteriores de la Universidad de Valencia for a grant to
J.R.D., to the Generalitat Valenciana for a grant to F.B. and
to the SCSIE for the realization of the HRMS spectra.
Tecnologıa (Project ref. BQU2003-09215-C03-03) for its
13. Abarca, B.; Ballesteros, R.; Mojarrad, F.; Jones, G.; Mouat,
J. M. J. Chem. Soc. Perkin Trans. 1 1987, 1865–1868.
14. Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2002, 58, 2885–2890. Bouillon, A.; Lancelot,
J. C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58,
3323–3328.
15. Bouillon, A.; Lancelot, J. C.; Sopkova, J.; Collot, V.; Bovy,
P. R.; Rault, S. Tetrahedron 2003, 59, 10043–10049.
16. Lisowski, V.; Robba, M.; Rault, S. J. Org. Chem. 2000, 65,
4193–4194.
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