Novel synthesis of C-3-(hetero)aryl [1,2,3]triazolo[1,5-a]pyridines using the Stille reaction

Article abstract of DOI:10.1016/j.tetlet.2011.09.052

Herein, we report a novel and high yielding approach for the preparation of the first C-3-organometallic substituted [1,2,3]triazolo[1,5-a]pyridine and its application to the Stille reaction using MAOS.

Full text of DOI:10.1016/j.tetlet.2011.09.052

Tetrahedron Letters 52 (2011) 6376–6378
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Novel synthesis of C-3-(hetero)aryl [1,2,3]triazolo[1,5-a]pyridines
using the Stille reaction
⇑
Hervé Germain, Craig S. Harris , Honorine Lebraud
AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report a novel and high yielding approach for the preparation of the first C-3-organometallic
substituted [1,2,3]triazolo[1,5-a]pyridine and its application to the Stille reaction using MAOS.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 August 2011
Revised 8 September 2011
Accepted 12 September 2011
Available online 17 September 2011
Keywords:
[1,2,3]Triazolo[1,5-a]pyridine
Stille cross-coupling reaction
Microwave-assisted organic synthesis
(MAOS)
During a recent programme, we identified C-3-(hetero)aryl
substituted [1,2,3]triazolo[1,5-a]pyridines (1) as a potential scaf-
fold to explore. Inspection of the literature revealed the principal
strategy (Approach A) to access the core structure (1) relied upon
the preparation of the appropriate 2-pyridyl ketones (3), condensa-
tion with an excess of hydrazine affording the corresponding
hydrazones (4) followed by oxidative cyclisation using oxidising
agents such as nickel peroxide,1 cuprous nitrate,2 hypervalent io-
dine3 or manganese dioxide.4 The disadvantages of Approach A
were that it was linear and required 3 steps, use of strong bases
and oxidising agents, which were not compatible with our actual
target structures and thus, was not appropriate for multi-parallel
synthesis exploration. The first successful cross-coupling (Ap-
proach B) between 3-iodo-[1,2,3]triazolo[1,5-a]pyridine and (het-
ero)arylboronic acids was reported by Abarca et al.5 Through
simple curiosity, the nature of our elaborated chemical intermedi-
ates in hand and the larger potential substrate panel, that is, het-
ero(aryl) halides, we were keen to investigate the possibility of
reversing the electronics of the cross-coupling (Approach C)
(Scheme 1).
(Hetero)aryl
(Hetero)aryl
Approach A
M
N
O
NH2
N
N
N
(Hetero)aryl
N
4
3
2
I
Approach B
N
N
M = Metal
N
N
N
N
N
1
N
6
5
M
Approach C
?
N
N
N
N
N
N
7
5
Scheme 1. Strategies for the preparation of desired substructure 1.
⇑
Corresponding author. Tel.: +33(0)3 26 61 5912; fax: +33(0)3 26 61 6842.
E-mail address: craig.harris2@astrazeneca.com (C.S. Harris).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.052

H. Germain et al. / Tetrahedron Letters 52 (2011) 6376–6378
6377
Therefore, we decided to focus our attention on the synthesis of
an appropriate organometallic derived triazolo[1,5-a]pyridine
(Approach C, Scheme 1) for which there are no current references.
In order to realise this approach, it became clear from the pioneer-
ing work of Abarca,6 Quéguiner7 and Jones8 on this heterocycle
that we would need to protect the C-7 position before attempting
to manipulate the C-3 position. Therefore, deprotonation at C-7
and treatment of the anion with triisopropylsilyl chloride (TIPS-
Cl) gave a near quantitative yield of 8. We initially focused our
attention on the preparation of a suitable C-3 substituted boronic
ester but unfortunately application of traditional or more recent
direct borylation protocol, via C-H activation,9 failed raising ques-
tions about the stability of the boronate at C-3 itself.
dure ((Ph3P)2PdCl2, 3 equiv LiCl, 1,2-DME, 130 °C). The MAOS con-
ditions proved vastly superior affording a 70% yield of the coupled
product in just 30 min whereas classical thermal conditions, using
Table 1
Selected examples obtained from the Stille cross-coupling multi-parallel explora-
tion13
Sn(Bu)3
R
N
a
N
N
N
N
N
Si(i-Pr)3
Si(i-Pr)3
10
As a final resort, we decided to try and prepare the correspond-
ing tri-n-butyltin derivative, with the knowledge that organost-
annanes are well documented for their relative stability
compared to their boronic acid and ester counterparts.10 To our
satisfaction, classical conditions (LDA, THF, ꢀ78 °C followed by
tri-n-butyltin chloride, 0 °C) worked affording 10 in near quantita-
tive yield. In essence, the transformation of 5 to 8 to 10 was rea-
lised in over 90% isolated yield (Scheme 2).
With 10 in hand, we set about optimizing the Stille cross
-coupling. We were intrigued by a recent paper by Diaz-Ortiz
and co-workers reporting an efficient microwave assisted organic
synthesis (MAOS) using the Stille cross-coupling demonstrated
notably on 3,5-dibromo-1-methyl-(1H)-1,2,4-triazole with a di-
verse substrate panel.11 Therefore, we decided to run two reactions
in parallel comparing classical conditions used within the team
((Ph3P)4Pd, toluene, 100 °C, 16 h) with the adapted MAOS proce-
Entry
1
Compound
R
%Yield
70
*
*
11
12
2
3
4
76
56
66
*
13
14
*
N
*
*
5a
6
15
16
26
76
Bu3SnO
H2NO2S
NH2
O
O
B
7
8
17
18
*
66
67
N
N
4
N
3
O
N
5
a
b or c
d
Si(i-Pr)3
N
N
*
*
6
N
N
9
N
N
7
Sn(Bu)3
N
5
Si(i-Pr)3
8
9
10
11
19
20
21
54
56
—
N
N
*
N
Si(i-Pr)3
10
N
*
Scheme 2. Attempted preparation of the C-3-pinacolatoboronate derivative.
Reagents and conditions: (a) BuLi, THF, ꢀ78 °C, 30 min. followed by TIPS-Cl, 0 °C,
98%; (b) LDA, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, THF, ꢀ78 °C,
0%; (c) 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, bis-(1,5-cyclooctadiene)di-mu-
methoxydiiridium(I), 4,40-di-tert-butyl-2,20-bipyridine, heptane, traces; (d) freshly
prepared LDA, THF, ꢀ78 °C, 1 h followed by tri-n-butyltin chloride, ꢀ78 °C to 0 °C,
95%.
N
*
78
72*
O
12
22
O
NH2
N
*
Br
N
13
14
23
24
56
66
N
N
N
*
Sn(Bu)3
a
N
N
N
+
N
N
N
N
b
c
N
O
N
Si(i-Pr)3
*
Si(i-Pr)3
Si(i-Pr)3
15
25
41
O
10
11
8
a
Reaction product obtained using p-bromophenol afforded the tri-n-butyltin
ether.
Isolated yield obtained with a sample of 10 left at room temperature during a
two week period.
Scheme 3. Stille optimisation. Reagents and conditions: (a) Bromobenzene,
(Ph3P)4Pd, toluene, 100 °C, 16 h, 20% (11), 50% (8); (b) bromobenzene, (Ph3P)2PdCl2,
3 equiv LiCl, 1,2-DME, 130 °C, 30 min., 11 (70%), 8 (traces); (c) bromobenzene,
(Ph3P)2PdCl2, 3 equiv LiCl, dioxane, 100 °C, 4 h, 11 (54%), 8 (5%).
*

6378
H. Germain et al. / Tetrahedron Letters 52 (2011) 6376–6378
O
Supplementary data
O
NH2
a
Full experimental procedures and supporting LCMS and 1H and
NH2
13C NMR characterisation data are available at no extra charge via
the on-line version.
O
O
N
N
N
N
Acknowledgments
N
N
Si(i-Pr)3
22
The authors would like to acknowledge Mlle Ha Thi Hoang Ngu-
yen, Mr. Patrice Koza, Dr. Bénédicte Delouvrié, Dr. Gilles Ouvry, Dr.
Bernard Barlaam and Dr. Vanessa Gonnot for their interest, syn-
thetic and analytical support.
26
Scheme 4. Deprotection of TIPS group. Reagents and conditions: (a) 1.0 M TBAF in
THF, rt, 30 min, 78%.
References and notes
tetrakis afforded only a 20% conversion to the desired product with
50% of the destannylated by-product. However, we found that we
could adapt the MAOS procedure to the thermal conditions and
achieve satisfactory results (Scheme 3).
1. Mineo, S.; Kawamura, S.; Nakagawa, K. Synth. Commun. 1976, 6, 69–74.
2. Mori, H.; Sakamoto, K.; Mashito, S.; Matsuoka, Y.; Matsubayashi, M.; Sakai, K.
Chem. Pharm. Bull. 1993, 41, 1944–1947.
3. Prakash, O.; Gujral, H. K.; Rani, N.; Singh, S. P. Synth. Commun. 2000, 30, 417–
425.
Satisfied with the MAOS conditions, we decided to apply these
to investigate the structural group tolerance for this un-reported
cross-coupling. Indeed 10 proved to be a very reliable coupling
partner affording good to excellent yields of C-3-arylated products
in general (Table 1). For the preparation of C-3-phenyl derivatives
(entries 1–8), the coupling reaction proved very tolerant towards
steric hindrance (entries 2 and 3), electron deficient (entries 4
and 6) and electron-rich bromides (5, 7 and 8). Substituted azines
(entries 9 and 10) coupled well apart from 2-chloropyrimidine (en-
try 11) which, perhaps surprisingly looking at close analogies in
the literature,12 only gave the destannylated by-product 8. Substi-
tuted azoles (e.g., 1311) also coupled in acceptable yields as did
bicyclic aromatic systems (entries 14 and 15). We were also eager
to validate the stability of 10, therefore, we carried out the cou-
pling with a sample left out open to the air during 2 weeks at room
temperature and to our delight, we obtained a comparable result to
the first experiment which used freshly prepared organostannane
(entry 12*).
Deprotection of the triisopropylsilyl group of the coupled com-
pounds, for example, 22 to liberate the C-7 position was achieved
in high yield using TBAF (Scheme 4).14 Perhaps surprisingly, the C-
7-TIPS group did prove to be stable to neat TFA, even at elevated
temperatures, despite literature precedent.15
In conclusion, we have developed a novel and high yielding ap-
proach to prepare the first C-3 substituted organostannane of
[1,2,3]triazalo[1,5-a]pyridine, demonstrated its stability and appli-
cation to Stille aryl cross-coupling with a diverse substrate panel.
4. Abarca, B.; Ballesteros, R.; Chadlaoui, M. Tetrahedron 2004, 60, 5785–5792.
5. Abarca, B.; Aucejo, R.; Ballesteros, R.; Blanco, F.; Garcia-Espana, E. Tetrahedron
Lett. 2006, 47, 8101–8103.
6. (a) Jones, G.; Abarca, B. Adv. Heterocycl. Chem. 2010, 100, 195–252; (b) Abarca,
B.; Ballesteros, R.; Mojarred, F.; Jones, G.; Mouat, D. J. Chem. Soc., Perkin Trans. 1
1987, 1865–1868; (c) Abarca, B.; Ballesteros, R.; Ballesteros-Garrido, R.;
Colobert, F.; Leroux, F. R. Tetrahedron 2008, 64, 3794–3801.
7. Bentabed-Ababsa, G.; Blanco, F.; Derdour, A.; Mongin, F.; Trecourt, F.;
Queguiner, G.; Ballesteros, R.; Abarca, B. J. Org. Chem. 2009, 74, 163–169.
8. Jones, G.; Mouat, D. J.; Pitman, M. A.; Lunt, E.; Lythgoe, D. J. Tetrahedron 1995,
51, 10969–10978.
9. For an excellent review see Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931. and references cited
therein.
10. Tsuji, J. Palladium Reagents and Catalysis Perspectives for The 21st Century; Wiley
and Sons: New York, 2003.
11. Cebrian, C.; de Cozar, A.; Prieto, P.; Diaz-Ortiz, A.; de la Hoz, A.; Carrillo, J. R.;
Rodriguez, A. M.; Montilla, F. Synlett 2010, 55–60.
12. (a) Kondo, Y.; Watanabe, R.; Sakamoto, T.; Yamanaka, H. Chem. Pharm. Bull.
1989, 37, 2814–2816; (b) Solberg, J.; Undheim, K.; Roekens, B.; Van Tran, T.;
Ghosez, L. Acta Chem. Scand. 1989, 43, 62–68.
13. Typical procedure: In a microwave pressure tube was added 10 (1 equiv),
(hetero)aryl bromide or chloride (1 equiv), LiCl (3 equiv), Pd(PPh3)2Cl2, 1,2-
DME (2 mL/100 mg of 10). The reaction mixture was sparged with argon for 1
minute, capped and heated at 130 °C for 30 min. The reaction mixture was
cooled to room temperature and purified by mass-triggered preparative HPLC
using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm
diameter, 100 mm length, flow rate of 40 mL/min) and decreasingly polar
mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as
eluent. The fractions containing the desired compounds were evaporated to
dryness to afford the desired compounds (29–78%) usually as gums.
14. Davies, S. G.; Goodfellow, C. L. Synlett 1989, 59–62.
15. Differding, E.; Vandevelde, O.; Roekens, B.; Van Tran, T.; Ghosez, L. Tetrahedron
Lett. 1987, 28, 397–400.