Construction of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines by ring closure of 3-acylpyridine N-oxide tosylhydrazones

Article abstract of DOI:10.1016/j.tetlet.2011.12.055

3-Acylpyridine N-oxide tosylhydrazones give good overall yields of a mixture of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines when treated with an electrophilic additive and an amine base. (Z)-Hydrazones cyclize readily, while (E)-hydrazones fail

Full text of DOI:10.1016/j.tetlet.2011.12.055

Tetrahedron Letters 53 (2012) 906–909
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Tetrahedron Letters
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Construction of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines by
ring closure of 3-acylpyridine N-oxide tosylhydrazones
William J. Lominac a, Megan L. D’Angelo a, Mark D. Smith b, Darius A. Ollison a, James M. Hanna Jr. a,
⇑
a Department of Chemistry, Physics, and Geology, Winthrop University, Sims Science Building, Rock Hill, SC 29733, USA
b Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Acylpyridine N-oxide tosylhydrazones give good overall yields of a mixture of pyrazolo[3,4-b]pyridines
and pyrazolo[4,3-c]pyridines when treated with an electrophilic additive and an amine base. (Z)-Hydra-
zones cyclize readily, while (E)-hydrazones fail to react under the reported conditions. The reaction takes
place at room temperature, and moderate regiocontrol over the cyclization can be achieved by varying
the electrophile/solvent combination.
Received 29 November 2011
Revised 12 December 2011
Accepted 13 December 2011
Available online 19 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolo[3,4-b]pyridines
Pyrazolo[4,3-c]pyridines
Pyridine N-oxide hydrazones
Cyclization
Introduction
that attack would be possible at C4, so intramolecular attack of the
hydrazone NH onto the pyridine ring could lead to dihydropyri-
Nitrogen-containing heterocycles are common structural units
found in many natural products and pharmaceuticals.1 In particu-
lar, compounds containing the pyrazolo[3,4-b]pyridine ring system
(1) exhibit a wide variety of biological activities.1–11 A common
strategy for the synthesis of 1 involves the annulation of a pyrazole
ring onto an existing pyridine as shown in Scheme 1.11–23
dines 5 and/or 50. These intermediates could then undergo elimina-
tion in the presence of a base to regenerate the pyridine ring and
afford the pyrazolopyridines 1 and/or 10. We were attracted to the
R1
R3
R3
This approach requires the presence of a leaving group (often a
halogen) at the 2-position of the pyridine ring prior to cyclization,
and introduction of this functionality often necessitates the use of
high temperatures and/or harsh reagents.13,24–27 One possible way
to eliminate this requirement is to take advantage of the electro-
philic 2-position of a suitably activated pyridine N-oxide using a
strategy (Scheme 2) similar to the Reissert–Henze reaction,28 an
approach which has been employed in the preparation of 2-amino-
pyridines29–32 via intermolecular amination of pyridine N-oxide,
and also has recently been used to functionalize the 2-position of
pyridine through the N-oxide with oxygen, sulfur, and carbon
nucleophiles.33 Since the introduction of a halogen to the 2-posi-
tion of pyridine typically requires prior formation of the N-oxide,13
this method would also eliminate a step in the formation of 1 and
thus be a more efficient route to these compounds.
(CN, CSR1) R2NHNH2
COR1
X
N
N
N
N
R2
1
Scheme 1. Synthesis of the pyrazolo[3,4-b]pyridine ring system (1).
R1
R1
R1
R2NHNH2
E-X
N
N
O
NHR2
NHR2
N
O
N
O
N
O E
2
3
4
R2
R1
R2
N
N
R1
When initially considering this approach, we reasoned that reac-
tion of hydrazone 3 with a suitable electrophile would give 4, which
would be activated for nucleophilic attack at C2. We also recognized
N
N
Base
- EOH
R1
N
+/or
N
+/or
R1
N
R2
N
N
O E
R2
N
O E
5'
N
N
5
1
1'
⇑
Corresponding author. Tel.: +1 803 323 4933; fax: +1 803 323 2246.
E-mail address: hannaj@winthrop.edu (J.M. Hanna).
Scheme 2. Proposed approach to pyrazolopyridines 1 and 10.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.055

W. J. Lominac et al. / Tetrahedron Letters 53 (2012) 906–909
907
possibility of regiocontrol in the proposed cyclization, which could
possibly provide an efficient approach to both pyrazolopyridine
ring systems from one common intermediate. Although we could
find no literature reports of this strategy being employed to con-
struct pyrazolopyridines through the pyridine N-oxide, we found
one closely-related account of the intramolecular amination of an
alkylpyridinium cation—the cyclization of a pyridinium tosylhyd-
razone methiodide to give a dihydropyridopyrazole.34
We can now report that tosylhydrazones derived from 3-benzo-
ylpyridine N-oxide and 3-pivaloylpyridine N-oxide can be cyclized
to a mixture of pyrazolopyridines in good overall yield by treat-
ment with an electrophilic additive and an amine base. The reac-
tion takes place under mild conditions (i.e., at room temperature)
and the regioselectivity of the cyclization can be controlled to a
moderate degree by varying the electrophile/solvent combination.
In this Letter we describe the results of our study.
to cyclization at the 4-position (entries 1–3), the use of trifluoro-
acetic anhydride (TFAA, entry 4) and the peptide coupling agent
bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP,
entry 5)32 completely abolished the formation of 1a0. The use of
acetic anhydride (entry 7) proved problematic. As with TFAA and
PyBroP, the formation of 1a0 was eliminated, but 1a could be iso-
lated in a ꢀ35% yield (estimated by 1H NMR) only as an inseparable
mixture with a byproduct which was not further characterized.
A very interesting result stemmed from the use of triflic anhy-
dride (entry 6). In this case, the regioselectivity of the cyclization
was reversed, leading to 1a0 as the major product. While a defini-
tive explanation for this reversal of regioselectivity cannot be ad-
vanced at this time, it is well-established that alkylpyridinium
ions are attacked at the 4-position by ‘soft’ nucleophiles via a single
electron-transfer (SET) process,35 and the proportion of 1a0 defi-
nitely increases as the electrophile employed in the cyclization be-
comes more electron-withdrawing. The regioselectivity trend may
therefore be the result of a shift in the cyclization mechanism from
primarily polar to mainly SET as the pyridine ring becomes more
electron deficient.36
Results and discussion
We began this project by examining the cyclization of 3-benzoyl-
pyridine N-oxide tosylhydrazone (3a). Compound 3a was produced
in moderate yield (65%) by the treatment of 3-benzoylpyridine
N-oxide (2a) with tosyl hydrazide in methanol. Proton NMR analysis
indicated that the isolated product consisted of a single stereoiso-
mer which was shown by X-ray analysis to have the (Z)-configura-
tion (see Supplementary data). Compound 3a was then treated
with tosyl chloride and triethylamine in dichloromethane solution
to effect the cyclization. After stirring the mixture overnight at room
temperature, we found that the starting tosylhydrazone had
disappeared (by TLC) and two products had been formed. Column
chromatography of the product mixture afforded the expected
products 1H-1-(4-methylphenylsulfonyl)-3-phenylpyrazolo[3,4-
b]pyridine (1a, 82%) and the regioisomeric 1H-1-(4-meth-
ylphenylsulfonyl)-3-phenylpyrazolo[4,3-c]pyridine (1a0, 12%).
Encouraged by this result, we explored the effect of other elec-
trophilic additives on the product yield and regioselectivity of the
reaction. These results are shown in Table 1.
All electrophilic additives gave moderate to very good overall
yields of cyclized products. Most electrophiles led to a preponder-
ance of 1a, derived from attack of the hydrazone NH at the 2-posi-
tion of the pyridine ring. This is not surprising in light of the
observation that ‘hard’ nucleophiles (e.g., nitrogen nucleophiles)
tend to attack alkylpyridinium salts primarily at the 2-position
via a charge-controlled (polar) mechanism.35 While most of the
sulfonic acid-derived activators led to a small amount of 1a0 due
It is apparent from the data in Table 1 that the use of tosyl anhy-
dride as the electrophilic additive gave the best overall yield with
good regioselectivity toward 1a (entry 2), while triflic anhydride
gave a good overall yield and produced primarily 1a0 (entry 6).
Therefore both of these electrophiles were employed in the
remainder of the experiments. We next examined the effect of
the base on the yield and regioselectivity of the cyclization. The re-
sults are shown in Table 2.
The results in Table 2 indicate that upon activation by tosyl
anhydride (entries 1–5), all of the bases we evaluated favored
the formation of 1a with comparable selectivity, and it appears tri-
ethylamine is optimum with respect to overall yield. The use of tri-
flic anhydride (entries 6–10) as the electrophile favored 1a0 in all
cases, and N-methylimidazole (MIm) seemed to give the best
selectivity.
We next investigated the effect of solvent on the reaction. The
results are shown in Table 3.
It appears that activation using tosyl anhydride (entries 1–4)
favored the formation of 1a in all solvents, although the less polar
solvents (entries 3 and 4) gave lower yields than the more polar sol-
vents (entries 1 and 2). The use of triflic anhydride gave predomi-
nantly 1a0 only in dichloromethane (entry 5). Much lower
regioselectivity toward 1a0 was seen in the other solvents evaluated,
and in acetonitrile and toluene (entries 6 and 8) the cyclization
Table 2
Table 1
Effect of additive/base combinations on the cyclization of 3aa
Effect of electrophilic additive on the cyclization of 3aa
Ph
N
NHTs
Ph
N
Ph
N
Ph
N
NHTs
Additive, Base
CH2Cl2, RT
Ph
N
Ph
N
N
+
Additive, Et3N
CH2Cl2, RT
N
N
N
N
O
N
+
Ts
Ts
N
N
N
O
N
Ts
Ts
3a
1a
1a'
3a
1a
1a'
Entry
Additive
Base
Yieldsb (%)
Entry
Additive
Yieldsb (%)
1a
1a0
1a
1a0
1
2
3
4
5
6
7
8
Ts2O
Ts2O
Ts2O
Ts2O
Tf2O
Tf2O
Tf2O
Tf2O
Et3N
DIPEA
85
70
68
63
25
28
26
14
11
9
15
9
56
52
51
60
1
2
3
4
5
6
7
TsCl
82
85
66
75
56
25
12
11
4
0
0
DABCO
MImc
Et3N
DIPEA
DABCO
MImc
Ts2O
Ms2O
TFAA
PyBroP
Tf2O
56
0
Ac2O
ꢀ35c
a
b
c
a
b
c
3a (0.5 mmol), additive (0.55 mmol), base (1.1 mmol), CH2Cl2 (5 mL).
Isolated yields; average of at least 2 experiments.
N-Methylimidazole.
3a (0.5 mmol), additive (0.55 mmol), Et3N (1.1 mmol), CH2Cl2 (5 mL).
Isolated yields; average of at least 2 experiments.
See text.

908
W. J. Lominac et al. / Tetrahedron Letters 53 (2012) 906–909
Table 3
Summary
Effect of additive/solvent combinations on the cyclization of 3aa
Ph
N
NHTs
Ph
N
Ph
N
We have developed a synthesis of regioisomeric pyrazolo[3,4-
b]pyridines and pyrazolo[4,3-c]pyridines via the cyclization of pyr-
idine N-oxide tosylhydrazones. Although the method is currently
limited to the use of (Z)-hydrazones, we believe it is a valuable
complement to existing methods of pyrazolopyridine synthesis
since it proceeds under mild conditions (i.e., room temperature)
and eliminates the need for the introduction of a leaving group
onto the pyridine ring. Furthermore, the regioselectivity of the
cyclization can be controlled to a moderate degree by varying
the electrophile/solvent combination. Additional studies of the
scope and limitations of this cyclization protocol and its applica-
tion to the synthesis of other nitrogen-containing heterocycles
are ongoing in our laboratory.
Additive, Et3N
Solvent, RT
N
+
N
N
N
O
N
Ts
Ts
3a
1a
1a'
Entry
Additive
Solvent
Yieldsb (%)
1a
1a0
1
2
3
4
5
6
7
8
Ts2O
Ts2O
Ts2O
Ts2O
Tf2O
Tf2O
Tf2O
Tf2O
CH2Cl2
CH3CN
PhCl
PhCH3
CH2Cl2
CH3CN
PhCl
85
79
57
57
25
63
39
59
11
9
10
9
56
8
39
31
PhCH3
a
Acknowledgments
3a (0.5 mmol), additive (0.55 mmol), Et3N (1.1 mmol), solvent (5 mL).
Isolated yields; average of at least 2 experiments.
b
The project described was supported by NIH Grant Number P20
RR-016461 from the National Center for Research Resources. Addi-
tional support was provided by the Winthrop University Depart-
ment of Chemistry, Physics, and Geology.
CH3
N
C(CH3)3
NHTs
N
NHTs
N
O
N
O
Supplementary data
3b (E)
3c (Z )
Supplementary data (experimental procedures, detailed prod-
uct characterization data, compound spectra, X-ray crystallo-
graphic data for 3a) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.055.
Figure 1. Compounds 3b and 3c (configurations determined by 13C NMR37).
Table 4
Cyclization of 3b and 3ca
R
References and notes
R
R
Additive, Et3N
CH2Cl2, RT
NNHTs
N
N
N
+
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