Regiospecific synthesis of 2,6-bis-indazol-1-ylpyridines from 2,6-bis-hydrazinopyridine

Article abstract of DOI:10.1016/j.tetlet.2011.07.081

The synthesis of 2,6-bis-hydrazonopyridines from 2,6-bis-hydrazinopyridine and the conversion of these bis-hydrazones into 2,6-bis-indazol-1-ylpyridines were studied. The conversion of bis-haloarylhydrazones to bis-indazoles was systematically optimized u

Full text of DOI:10.1016/j.tetlet.2011.07.081

Tetrahedron Letters 52 (2011) 5214–5216
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Tetrahedron Letters
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Regiospecific synthesis of 2,6-bis-indazol-1-ylpyridines from
2,6-bis-hydrazinopyridine
⇑
Nathan C. Duncan, Charles M. Garner
Department of Chemistry and Biochemistry, Baylor University, One Bear Place, #97348, Waco, TX 76798, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 2,6-bis-hydrazonopyridines from 2,6-bis-hydrazinopyridine and the conversion of these
bis-hydrazones into 2,6-bis-indazol-1-ylpyridines were studied. The conversion of bis-haloarylhydraz-
ones to bis-indazoles was systematically optimized using iron and copper mediated reactions and various
bases and ligands. By varying solvent, base, transition metal, and ligand, a novel regiospecific route to the
2,6-bis-indazol-1-ylpyridine class of ligands was developed.
Received 22 December 2010
Revised 18 July 2011
Accepted 20 July 2011
Available online 30 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
2,6-Bis-iminopyridines have been demonstrated to be useful li-
gands in catalysis, particularly in olefin polymerization.1 A wide
variety of simple bis-iminopyridines are easily synthesized from
2,6-bis-carbonylpyridine derivatives and primary amines. We have
been developing new tridentate ligands based on the recently re-
ported 2,6-bis-hydrazinopyridine (BHP, 1).2 One such variation is
the 2,6-bis-indazolylpyridines (2, Scheme 1). Such tridentate li-
gands are almost unknown in the literature, with a total of two re-
ports3 (one of which is only a patent application). There is also one
report4 of a mono-indazolylpyridine. All existing3,4 indazolylpyri-
dines have been prepared by the reaction of the indazole anion
(typically a sodium salt) with a 2,6-dihalopyridine. Since these syn-
theses rely on nucleophilic aromatic substitution using an ambi-
dent indazole nucleophile, they suffer from poor yields and
formation of mixtures of regioisomers. In the case of the 2,6-bis-
indazolylpyridine, only 24% of the desired bis-indazol-1-yl pyri-
dine (2) was obtained, the major product (68%) being the mixed
2-indazol-yl-6-indazol-2-ylpyridine (3), with a trace of bis-inda-
zol-2-yl pyridine (4) also being detected (Scheme 1).3a For the
mono indazolylpyridine, only limited experimental details were gi-
ven, and only one isomer was reported (30% yield).4
We envisioned that BHP could be used to prepare 2,6-indazolyl-
pyridines without the regiochemistry problems of the indazole an-
ion approach of Scheme 1. Appropriate BHP-derived ortho-haloaryl
hydrazones might be induced to cyclize (Scheme 2), yielding the
2,6-bis-indazolylpyridines regiospecifically. Thus, we undertook
the development of an improved synthesis of 2,6-bis-indazolylin-
dazolylpyridine ligands from BHP.
We found that the requisite bis-hydrazones 5 and 6 could be
obtained easily by the reaction of BHP with 2 equiv of an aldehyde
and catalytic TFA or PTSA in THF, without the removal of water. Ke-
tones, however, required water removal by azeotropic distillation
with benzene using a Dean Stark trap to efficiently form hydrazone
7. We obtained the ortho-haloaryl hydrazones in 65–100% yield
(Scheme 2). None of these hydrazones have been previously re-
ported. The aldehyde hydrazones 5 and 6 appear to be single ster-
eoisomers (i.e., one set of 1H and 13C NMR peaks), but the ketone
hydrazone 7 exhibits some additional peaks in the 13C NMR sug-
gestive of E/Z isomerism. The hydrazones are shown here as (Z) iso-
mers for convenience, though the stereochemistry has not been
established. Presumably (E) isomers can equilibrate to (Z) under
conditions of the cyclization reaction (below).
The synthesis of indazole rings has been accomplished through
several routes, usually employing a reaction between a 2-halo-
benzaldehyde or an acetophenone and a hydrazine. Depending
on the reaction conditions, the hydrazone is formed and isolated
followed by a separate cyclization step, or in some cases the 1-H
indazole is formed in the presence of excess hydrazine.5,6 The cycli-
zation step is done under basic conditions, and has been done
either with a catalyst or by heating with excess hydrazine. Typical
catalytic systems for the synthesis of indazoles from haloarylhyd-
razones use either copper8,9 or palladium,7 an appropriate ligand,
and base such as K2CO3. For example, the use of copper(I) iodide,
DMEDA or N,N0-dimethyl-trans-1,2-diaminocyclohexane, and
potassium carbonate in NMP under microwave conditions yields
N-arylindazoles in yields ranging from 100% down to 40%.8 The
yields were typically in the range of 80–100%, under optimized
conditions. Catalysis using copper(II) oxide and potassium carbon-
ate in a one-pot reaction of 2-haloacetophenones with a substi-
tuted hydrazine to form indazoles has been reported in yields
ranging from 30% to 83%.9 Additionally, indazole synthesis was
demonstrated using catalytic copper(I) iodide and 1,10-phenathro-
line with KOH as the base in 1,4-dioxane.10 This study also showed
that the choice of ligand and base was vital to the success of the
reaction. In that study, 2-bromophenyl hydrazones were used as
the substrate of choice. The chlorohydrazones also produced prod-
ucts, but with a lower yield.
⇑
Corresponding author. Tel.: +1 254 710 6862; fax: +1 254 710 2403.
E-mail address: Charles_Garner@Baylor.edu (C.M. Garner).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.081

N. C. Duncan, C. M. Garner / Tetrahedron Letters 52 (2011) 5214–5216
5215
Scheme 1. Product distribution from nucleophilic reaction of indazolyl anion with dibromopyridine.3a
Scheme 2. Synthesis of bis-hydrazones from BHP.
Table 1
Table 2
Reaction conditions for FeCl3 mediated indazole formation from bis-bromoarylhyd-
razone 6 to form 2
Reaction conditions for copper-catalyzed indazole formation from bis-bromoarylhyd-
razone 6 to form 2 (or 8d)
Solvent
Ligand
Base
Yield (%)
Copper Source
Cu (%)
Solvent
Ligand
Base
Yield (%)
Toluene
Toluene
Toluene
NMP
DMF
DME
Acetonitrile
DCE
Toluene
Dioxane
Toluene
DMEDA
None
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
25a
CuI
CuI
CuO
CuI
CuI
None
CuCl
CuBr
CuOTf
CuI
10
10
10
10
10
Toluene
Dioxane
Toluene
Dioxane
Dioxane
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMEDA
Phena
DMEDA
DMEDA
TMEDA
None
Cs2CO3
KOH
Cs2CO3
KOH
KOH
K2CO3
KOH
KOH
KOH
Cs2CO3
KOH
0
Traceb
50b
0
TMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
Phenc
Traceb
Traceb
Tracec
Trace
0
Trace
20
0
0
0
0
10
10
10
10
10
Phen
Phen
34a
0
Phen
0
Phena
Phen
0
DMEDA
52d
CuI
98d
a
b
c
a
b
c
Isolated yield.
TLC analysis, 15% EtOAc/hexanes, 2% TEA.
1,10-Phenanthroline.
1,10-Phenanthroline.
Isolated yield.
TLC analysis, 15% EtOAc/hexanes, 2% TEA.
d
d
Pressure tube at 130 °C.
Using substrate 7.
Our first few attempts at the synthesis of this class of ligands fo-
Since the base-only method of cyclization was fruitless, atten-
cused on using BHP and 2 equiv of 2-fluorobenzaldehyde. At the
outset, it appeared that a single-flask preparation might be possi-
ble to form the dihydrazone under acidic conditions followed by
cyclization under basic conditions. These initial attempts allowed
for the formation of the hydrazone in THF at reflux for 12 h, fol-
lowed by the in situ addition of excess potassium carbonate and
refluxing for an additional 24 h. However, this failed to yield any
indazole product. Using Cs2CO3, NaH, KOtBu, or even LDA as the
base all failed to yield any indazole product. In order to more care-
fully study this route, dihydrazone 5 was isolated and purified. The
reaction of the dihydrazone with these various bases was followed
by GC, but while disappearance of dihydrazone was observed, no
indazole product was formed. Rather, a tarry residue was observed.
tion was turned toward some of the catalytic methods. The first
such method was using copper(II) oxide with a carbonate base,9
but this reaction also failed to form any indazole product. An
iron-catalyzed reaction using FeCl3, DMEDA, and a carbonate base
in toluene that had been shown to be successful for forming nitro-
gen-aryl bonds with aryl bromides11 was used with bis-hydrazone
6 formed from 2-bromobenzaldehyde and BHP. In this reaction,
20 mol % FeCl3 and 40 mol % DMEDA with potassium carbonate
or cesium carbonate base were used with a variety of refluxing sol-
vents for five days. The results are given in Table 1.
While the reaction lead to a large amount of decomposition
products, 2,6-bis-indazolylpyridine (2) was obtained in 25% yield
using toluene as the solvent. This is the first demonstration of an

5216
N. C. Duncan, C. M. Garner / Tetrahedron Letters 52 (2011) 5214–5216
Scheme 3. Synthesis of 2,6-bis-indazolylpyridines from bis-haloarylhydrazones.
iron-catalyzed indazole formation. The iron-catalyzed reaction was
then tested using a variety of ligands, bases, and solvents. When
TMEDA was used rather than DMEDA, no product was formed.
The addition of cesium carbonate rather than potassium carbonate
slightly increased the isolated yield to 34%. The use of NMP, DME,
1,2-dichloroethane, DMF, and acetonitrile all failed to produce
any of the desired products. A reaction was carried out in a pressure
tube at 130° C, and this allowed for an increase in yield to 52%. The
major drawback to this system was serious emulsions complicating
the workup. When the reaction medium was filtered through a pad
of Celite prior to a water workup, the emulsion problem was re-
duced but not eliminated. With iron catalysis, the five-day reaction
times were necessary to obtain even the modest yields.
served in the reaction of the benzaldehyde hydrazones. This result
is promising for the future synthesis of other more sterically-hin-
dered derivatives of this new class of ligands (Scheme 3).
Acknowledgments
This work was supported by The Robert A. Welch Foundation
(Grant # AA-1395). Baylor University’s 500 MHz NMR was funded
by the National Science Foundation’s Major Research Instrumenta-
tion program, Award # CHE-0420802.
Supplementary data
We then studied copper(I) iodide catalysis on the KOH/refluxing
dioxane/1,10-phenanthroline system (Table 2) using the bis-hydra-
zones from 2-bromobenzaldehyde (6) and 2-bromoacetophenone
(7).6 Under these conditions, 2,6-bis-(20-bromophenylhydrazon-
o)pyridine 6 yielded 50% of bis-indazolylpyridine 2 in 12 h. The
reaction still formed some byproducts, but these were more polar,
tarry materials and were easily separated by chromatography. We
also screened TMEDA and DMEDA as ligands, as well as using the
hydrazone itself. None of these reactions yielded a significant
amount of the product. When using other bases, such as carbonates,
no reaction was observed. Other copper salts were also screened,
such as copper(I) bromide, chloride, and triflate, and all showed a
decrease in activity. Fluoroaromatics appear to be unreactive; no
reaction was observed for bis-hydrazone 5 using either the copper
or iron catalysts.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.081.
References and notes
1. (a) Gibson, V. C.; Redshaw, C.; Solan, G. A. Chem. Rev. 2007, 107, 1745–1776; (b)
Tellman, K. P.; Gibson, V. C.; White, A. J. P.; Williams, D. J. Organometallics 2005,
24, 280–286.
2. Brien, K. A.; Garner, C. M.; Pinney, K. G. Tetrahedron 2006, 62, 3663–3666.
3. (a) Pritchard, R.; Kilner, C. A.; Halcrow, M. A. Tetrahedron. Lett. 2009, 50, 2484–
2486; (b) Charbonniere, L.; Kadjane, P.; Starck, M.; Ziessel, R.; Hildebrandt, N.
Fr. Demande (2010), FR 2935973 A1 20100319.
4. Zaidi, S. A. A.; Siddiqui, S.; Siddiqui, K. S. Transition Met. Chem. 1993, 18, 51–54.
5. Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org. Chem. 2006, 71, 8166–
8172.
6. Petrenko, N. I.; Gerasimova, T. N. J. Fluorine Chem. 1990, 49, 359–366.
7. Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroyaa, K.; Sakamoto, T.
Tetrahedron 2007, 63, 2695–2711.
8. Pabba, C.; Wang, H.-J.; Mulligan, S. R.; Chen, Z.-J.; Stark, T. M.; Gregg, B. T.
Tetrahedron Lett. 2005, 46, 7553–7557.
9. Vina, D.; Olmo, E. D.; Lopez-Perez, J. L.; Feliciano, A. S. Org. Lett. 2007, 9, 525–
528.
10. Liu, R.; Zhu, Y.; Qin, L.; Ji, S. Synth. Commun. 2008, 38, 249–254.
11. Correa, A.; Bolm, C. Adv. Synth. Catal. 2008, 350, 391–394.
The best Cu(I) conditions were then applied to bis-hydrazone 7
formed from 2-bromoacetophenone. Surprisingly, identical reac-
tion conditions produced a near quantitative yield of the previ-
ously unknown 2,6-bis-(30-methylindazol-1-yl)pyridine (8), with
almost no formation of the more polar byproducts that were ob-