Unexpected product distributions in the synthesis of 2,6-bis-(indazolyl)pyridine and 2-(pyrazol-1-yl)-6-(indazolyl)pyridine

Article abstract of DOI:10.1016/j.tetlet.2009.03.035

Reaction of 2-bromopyridine with 2 equiv of sodium indazolide in diglyme at 140 °C affords 2,6-bis-(indazol-1-yl)pyridine and 2-(indazol-1-yl)-6-(indazol-2-yl)pyridine in purified yields of 24% and 68% respectively. A similar reaction, using 1 equiv of so

Full text of DOI:10.1016/j.tetlet.2009.03.035

Tetrahedron Letters 50 (2009) 2484–2486
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Tetrahedron Letters
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Unexpected product distributions in the synthesis of 2,6-bis-(indazolyl)pyridine
and 2-(pyrazol-1-yl)-6-(indazolyl)pyridine
*
Ruth Pritchard, Colin A. Kilner, Malcolm A. Halcrow
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 2-bromopyridine with 2 equiv of sodium indazolide in diglyme at 140 °C affords 2,6-bis-
(indazol-1-yl)pyridine and 2-(indazol-1-yl)-6-(indazol-2-yl)pyridine in purified yields of 24% and 68%
respectively. A similar reaction, using 1 equiv of sodium indazolide at 70 °C, gives a low-yield mixture
of 2-(indazol-1-yl)-6-bromopyridine and 2-(indazol-2-yl)-6-bromopyridine. Both these intermediates
are transformed into 2-(pyrazol-1-yl)-6-(indazol-1-yl)pyridine and 2,6-di(pyrazol-1-yl)pyridine upon
treatment with 1 equiv of sodium pyrazolide in diglyme at 140 °C. These observations imply that the
indazolyl group is a leaving group comparable to a bromo substituent under nucleophilic attack by
pyrazolide or indazolide ions under these conditions. No reaction was observed between 2-(pyrazol-1-
yl)-6-bromopyridine and 1 equiv of sodium indazolide under the same conditions. A single crystal struc-
ture of its iron(II) complex confirmed the regiochemistry of 2,6-bis-(indazol-1-yl)pyridine, and revealed
significant conformational flexibility in the distal ligand indazolyl groups.
Received 9 December 2008
Revised 24 February 2009
Accepted 6 March 2009
Available online 13 March 2009
Keywords:
Indazolylpyridines
Nucleophilic substitution
Regiochemistry
Crystal structure
Ó 2009 Elsevier Ltd. All rights reserved.
2,6-Di(pyrazol-1-yl)pyridine (1-bpp) derivatives are finding
increasing use as ligands for d- and f-block metal ions.1 Their
homoleptic iron(II) complexes have been of particular interest,
since these often undergo thermal spin-crossover2,3 at accessible
temperatures. We1,4–6 and others7–9 have exploited the relative
ease of incorporating substituents onto the 1-bpp backbone, to
yield materials showing a wide variety of different spin-transition
regimes, based around the same metal:ligand core. In our work, we
have noted that several [FeL2]X2 salts (L = 1-bpp, 2,6-di(pyrazol-1-
yl)pyrazine or a derivative thereof; XÀ = a monovalent anion) exhi-
bit extremely consistent abrupt thermal spin-transitions, despite
adopting different crystallographic space groups.5 This cooperativ-
Reaction of 2,6-dibromopyridine with 2 equiv of Na[Ind]
(IndH = indazole) in hot diglyme, under the normal conditions for
the synthesis of 1-bpp and its derivatives,6,12,13 affords a mixture
of products. Flash silica chromatography of the crude mixture in
CHCl3 allowed the isolation of pure 2,6-bis-(indazol-1-yl)pyridine
(1) and 2-(indazol-1-yl)-6-(indazol-2-yl)pyridine (2) in 24% and
68% yields, respectively (Scheme 1). A small amount of the third
potential regioisomer, 2,6-bis-(indazol-2-yl)pyridine, also ap-
peared to be present in the crude reaction mixture by 1H NMR
but was not isolated in pure form. The regiochemistry of 1 was
confirmed by the crystal structure determination of its iron(II)
complex described below, and by 13C NMR spectroscopy (the
chemical shifts of the C3, C7 and C7a resonances all differ by ca.
10 ppm in 1-substituted and 2-substituted indazole regioisom-
ers14). Two 1H NMR resonances from the 2-(indazolyl)pyridine res-
ity appears to be mediated by p–p stacking between the pyrazolyl
groups of neighbouring molecules. To extend these ideas, we were
keen to gain access to related tridentate ligands incorporating
indazolyl functionality. We reasoned that replacement of pyrazolyl
by indazolyl groups in a terpyridine embrace structure should lead
to stronger intermolecular p–p stacking within the fourfold layers,
which could afford increased spin-crossover cooperativity.10 No
bis-(azolyl)pyridines incorporating indazolyl groups have been re-
ported to date, although a small number of comparable mono-
(indazol-1-yl)pyridines have been made before.11 We report here
that the usual method used to make 1-bpp derivatives yields unex-
pected product distributions when applied to indazolylpyridines.
* Corresponding author. Tel.: +44 113 343 6506; fax: +44 113 343 6565.
E-mail address: M.A.Halcrow@leeds.ac.uk (M.A. Halcrow).
Scheme 1. Synthesis of 2,6-bis-(indazolyl)pyridine derivatives. Reagents and
conditions: (i) 2 equiv Na[Ind], diglyme, 140 °C, 4 d.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.035

R. Pritchard et al. / Tetrahedron Letters 50 (2009) 2484–2486
2485
idue are also diagnostic in these compounds, and those described
below. First is the singlet for the indazole H3 atoms. This appears
near 8.3 ppm for (indazol-1-yl)pyridine groups and at 9.1 ppm
for the (indazol-2-yl)pyridines, the latter being >0.5 ppm down-
field of the usual range for 2-substituted indazoles.15 Second is
the doublet for the pyridine H3 or H5 atom, adjacent to the inda-
zole substituent. This appears at 8.8 ppm in the (indazol-1-yl)pyr-
idine compounds (around 1 ppm higher compared to most 1-bpp
derivatives6,12), and near 8.3 ppm in the (indazol-2-yl)pyridines.
We also investigated the synthesis of unsymmetric 2-(indazol-
yl)-6-(pyrazol-1-yl)pyridine derivatives (Scheme 2). Reaction of
2,6-dibromopyridine with 1 equiv of Na[Ind] in diglyme at
70 °C,12 gives the expected mixture of 2-(indazol-1-yl)-6-bromo-
pyridine (3) and 2-(indazol-2-yl)-6-bromopyridine (4), in purified
yields of 33% and 18%, respectively.
Unexpectedly, however, treatment of both these intermediates
with a twofold excess of Na[Pz] (PzH = pyrazole) in diglyme at
130 °C yielded the same two isolable products: 2-(pyrazol-1-yl)-
6-(indazol-1-yl)pyridine (5), and 1-bpp (Scheme 2). The yield of
each product was broadly similar, whether 3 or 4 was used as
starting material. The alternative approach, of reacting pre-formed
2-(pyrazol-1-yl)-6-bromopyridine (6)12 with 2 equiv of Na[Ind]
under the same conditions as before, produced no reaction
(Scheme 2). The bromo substituent in 2-(azolyl)-6-bromopyridines
is deactivated towards substitution compared to 2,6-dibromopyri-
dine itself,12 and IndÀ (a weaker nucleophile than PzÀ) is appar-
ently insufficiently reactive to undergo this reaction.
Given that indazolide anions undergo electrophilic attack pref-
erentially at the 1- rather than at the 2-position,15,16 all the above-
mentioned results can be explained if the indazolyl ring is a leaving
group comparable to a bromo substituent under these conditions.
This would allow an incoming PzÀ or IndÀ nucleophile to displace
an indazolyl group rather than a bromo group from the pyridine
ring. The liberated IndÀ anion is then free to re-attack a second
equivalent of bromopyridyl reagent or intermediate, resulting in
enrichment of the preferred indazol-1-yl regioisomer in the prod-
uct mixture. This suggestion accounts for the higher-than-ex-
pected yield of 2 (68%, when the maximum possible theoretical
yield without nucleophilic exchange of IndÀ groups would be
50% on statistical grounds); and, for the isomerisation of 4 during
its reaction with Na[Pz].
Figure 1. One of the three unique molecules (molecule A) in the crystal solvate of
[Fe(1)2][BF4]2.17 All H atoms have been omitted for clarity, and thermal ellipsoids
are at the 50% probability level. Molecules B and C use the same atom numbering
scheme as shown here (see Supplementary data).
imply that they are low-spin at the temperature of measurement
150 K (Fig. 1 and Supplementary data). However, the molecules
differ significantly in the conformations of the ligands 1, some of
which are significantly distorted from planarity. This is exemplified
by the dihedral angles between the least squares planes of the pyr-
idyl groups, and the annelated benzo groups, which span a range of
2.8(2)–17.5(3)°. These distortions give rise to either a bowl-shaped
or S-shaped ligand conformation; three of the six unique ligands in
the model adopt each type of conformation, to differing degrees
(Fig. 2). We attribute these distortions from planarity to intramo-
lecular steric repulsion between the pyridyl H3 and H5 atoms,
and the H7 atoms on the neighbouring indazolyl rings, all of which
lie 2.0–2.1 Å apart. These distances should be treated with caution
as the H atoms in the structure were placed in calculated positions
Since 1 did not form single crystals, to confirm its regiochemist-
ry a structure determination was achieved from a solvated crystal
of its iron(II) complex [Fe(1)2][BF4]2.17 The crystal contained three
formula units per asymmetric unit, with several disordered anions
and solvent molecules. The three unique complex cations have
similar bond lengths and angles at their iron centres, all of which
Scheme 2. Synthesis of 2-(indazol-1-yl)-6-(pyrazol-1-yl)pyridine. Reagents and conditions: (i) 1 equiv Na[Ind], diglyme, 70 °C, 2 d; (ii) 2 equiv Na[Pz], diglyme, 140 °C, 4 d;
(iii) 1 equiv Na[Pz], diglyme, 70 °C, 2 d; (iv) 2 equiv Na[Ind], diglyme, 140 °C, 4 d.

2486
R. Pritchard et al. / Tetrahedron Letters 50 (2009) 2484–2486
Na[Pz]. The synthetic yield of 2 is higher than expected on statisti-
cal grounds, while the isolation of 1-bpp as a byproduct in the syn-
thesis of 5 shows that indazolyl groups can be displaced from the
pyridine ring by pyrazolyl groups during the reaction. These obser-
vations imply that indazolyl substituents can serve as leaving
groups from the pyridine ring during the reaction, resulting in
enrichment of the preferred indazol-1-yl products.
Acknowledgements
This work was funded by the EPSRC and the University of Leeds.
Supplementary data
Supplementary data (Experimental procedures and character-
isation data for the compounds in this study, and further details
on the crystal structure, its data collection and refinement) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.03.035.
References and notes
1. Halcrow, M. A. Coord. Chem. Rev. 2005, 249, 2880. and references therein.
2. Gütlich, P.; Goodwin, H. A.; Eds., Spin Crossover in Transition Metal Compounds I–
III, Top. Curr. Chem.; 2004, pp 233–235.
3. (a) Gütlich, P.; van Koningsbruggen, P. J.; Renz, F. Struct. Bond. (Berlin) 2004,
107, 27; (b) Real, J. A.; Gaspar, A. B.; Muñoz, M. C. Dalton Trans. 2005, 2062; (c)
Sato, O.; Tao, J.; Zhang, Y.-Z. Angew. Chem., Int. Ed. 2007, 46, 2152; (d) Halcrow,
M. A. Chem. Soc. Rev. 2008, 37, 278.
4. (a) Carbonera, C.; Costa, J. S.; Money, V. A.; Elhaïk, J.; Howard, J. A. K.; Halcrow,
M. A.; Létard, J.-F. Dalton Trans. 2006, 3058; (b) Money, V. A.; Carbonera, C.;
Elhaïk, J.; Halcrow, M. A.; Howard, J. A. K.; Létard, J.-F. Chem. Eur. J. 2007, 13,
5503.
5. (a) Pritchard, R.; Kilner, C. A.; Halcrow, M. A. Chem. Commun. 2007, 577; (b)
Carbonera, C.; Kilner, C. A.; Létard, J.-F.; Halcrow, M. A. Dalton Trans. 2007,
1284.
6. Elhaïk, J.; Pask, C. M.; Kilner, C. A.; Halcrow, M. A. Tetrahedron 2007, 63, 291.
7. (a) Han, L.; Nihei, M.; Oshio, H. Polyhedron 2005, 24, 2409; (b) Nihei, M.; Han, L.;
Oshio, H. J. Am. Chem. Soc. 2007, 129, 5312; (c) Nihei, M.; Maeshima, T.; Kose, Y.;
Oshio, H. Polyhedron 2007, 26, 1993.
8. (a) Rajadurai, C.; Schramm, F.; Brink, S.; Fuhr, O.; Ghafari, M.; Kruk, R.; Ruben,
M. Inorg. Chem. 2006, 45, 10019; (b) Rajadurai, C.; Fuhr, O.; Kruk, R.; Ghafari,
M.; Hahn, H.; Ruben, M. Chem. Commun. 2007, 2636; (c) Rajadurai, C.; Qu, Z.;
Fuhr, O.; Gopalan, B.; Kruk, R.; Ghafari, M.; Ruben, M. Dalton Trans. 2007, 3531;
(d) Chandrasekar, R.; Schramm, F.; Fuhr, O.; Ruben, M. Eur. J. Inorg. Chem. 2008,
2649.
9. (a) Matsuda, M.; Tajima, H. Chem. Lett. 2007, 700; (b) Matsuda, M.; Isozaki, H.;
Tajima, H. Chem. Lett. 2008, 374.
ˇ
ˇ
ˇ
10. See, for example: Boca, R.; Boca, M.; Dlhán, L.; Falk, K.; Fuess, H.; Haase, W.;
ˇ
Jarošciak, R.; Papánková, B.; Renz, F.; Vrbová, M.; Werner, R. Inorg. Chem. 2001,
40, 3025. and references therein.
11. (a) Zaidi, S. A. A.; Shahjahan, M.; Siddiqui, K. S. Transition Met. Chem. 1993, 18,
51; (b) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S.
Tetrahedron Lett. 2003, 44, 3863.
12. Jameson, D. L.; Goldsby, K. A. J. Org. Chem. 1990, 55, 4992.
13. Palladium catalysis of this reaction leads to reduced reaction times, but with no
significant increase in yield or product purity. See: Sun, X.; Yu, Z.; Wu, S.; Xiao,
W.-J. Organometallics 2005, 24, 2959.
14. Begtrup, M.; Claramunt, R. M.; Elguero, J. J. Chem. Soc., Perkin Trans. 2 1978, 99.
15. (a) Palmer, M. H.; Findlay, R. H.; Kennedy, S. M. F.; McIntyre, P. S. J. Chem. Soc.,
Perkin Trans. 2 1975, 1695; (b) Claramunt, R. M.; Elguero, J.; Garceran, R.
Heterocycles 1985, 23, 2895; (c) Isin, E. M.; de Jonge, M.; Castagnoli, N. J. Org.
Chem. 2001, 66, 4220.
Figure 2. Alternative views of molecules A (top), B (centre) and C (bottom) in the
crystal solvate of [Fe(1)2][BF4]2,17 showing the flexibility of the ligands 1. All atoms
have arbitrary radii.
16. Luo, G.; Chen, L.; Dubowchik, G. J. Org. Chem. 2006, 71, 5392.
17. Crystal
C38.60H28.51B2F8FeN10.33O1.15
b = 20.037(2), c = 23.558(3) Å,
V = 5939.4(11) Å3, Z = 6, T = 150 K,
data
for
[Fe(1)2][BF4]2Á0.33CH3NO2Á0.067C4H10OÁ0.42H2O:
ꢀ
,
Mr = 884.96, triclinic, P1, a = 12.8173(11),
a
= 96.548(3), b = 98.378(3),
c
= 91.830(4)°,
rather than being directly refined. However, they are clearly short-
er than the sum of the van der Waals radii of two H atoms, 2.4 Å.18
In conclusion, the 2,6-di(indazolyl)pyridines 1 and 2 can be ac-
cessed from 2,6-dibromopyridine by nucleophilic substitution with
2 equiv of Na[Ind]. Similar reactions using 1 equiv of Na[Ind] affor-
ded the 2-(indazolyl)-6-bromopyridines 3 and 4, both of which
gave 2-(pyrazol-1-yl)-6-(indazolyl)pyridine 5 upon reaction with
l
(Mo
Ka
) = 0.466 mmÀ1
,
R1(I > 2r
(I)) = 0.078, wR2(all data) = 0.251. The asymmetriÀc unit contains three
complex dications, labelled ‘A’, ‘B’ and ‘C’; six BF4 anions (four of them
disordered); and several partially occupied nitromethane, diethyl ether and
water sites. See Supplementary data for more detailed information. CCDC
713035.
18. Pauling, L. The Nature of the Chemical Bond, 3rd ed.; Cornell University: Ithaca
NY, USA, 1960.