A facile method for the synthesis of substituted pyrazolo[3,4-c]pyridines

Article abstract of DOI:10.1016/j.tetlet.2008.11.013

Methods for a facile high-yielding synthesis of substituted pyrazolo[3,4-c]pyridines from 2-bromo-5-fluoropyridine are described, along with a brief mechanistic discussion for the key cyclization step. The methods utilize inexpensive commercially availabl

Full text of DOI:10.1016/j.tetlet.2008.11.013

Tetrahedron Letters 50 (2009) 383–385
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Tetrahedron Letters
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A facile method for the synthesis of substituted pyrazolo[3,4-c]pyridines
*
Sharad K. Verma , Louis V. LaFrance
Medicinal Chemistry, Oncology Research and Development, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Methods for a facile high-yielding synthesis of substituted pyrazolo[3,4-c]pyridines from 2-bromo-5-
fluoropyridine are described, along with a brief mechanistic discussion for the key cyclization step.
The methods utilize inexpensive commercially available starting materials and unlike previous methods,
are more suitable for SAR work and scale-up.
Received 4 September 2008
Revised 4 November 2008
Accepted 5 November 2008
Available online 8 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The reaction of 2-fluoro-acetophenones with hydrazine has
been reported for the preparation of indazoles.6. Based on this
The pyrazolo[3,4-c]pyridine group is present in compounds of
biological interest. For example, modified 4-deaza analogs of form-
ycins have been investigated as potential nucleoside antibiotics,1,2
and compound 1 was recently reported as a potent anti-cancer
agent (Figure 1).3 However, despite the value of the pyrazolo-
[3,4-c]pyridine group, an efficient, high-yielding synthesis is still
required. The standard method entails application of the Huisgen
indazole synthesis to functionalized pyridines, as first reported
by Chapman and Hurst.4 Unfortunately, this method is not optimal
for structure–activity relationship (SAR) work due to poor versatil-
ity, scalability, and low overall yields. A very creative approach was
recently reported by Heller, wherein the pyrazolo[3,4-c]pyridine
scaffold could be prepared in good to moderate yields via Ni/Zn
(or Pd) catalyzed annulation of alkynes with tert-butyl 4-iodopy-
razolocarboximines.5 However, this method is not totally regiose-
lective, involves expensive catalysts, and scalability has not been
established.
precedent, we reasoned that the pyrazolo[3,4-c]pyridine scaffold
should be accessible from an appropriately functionalized
fluoro-acetylpyridine, which in turn might be prepared from the
corresponding fluoropyridine. To this end, commercially available
2-bromo-5-fluoropyridine 2 was treated with LDA according to
the method of Queguiner, to effect a chemo- and regioselective
lithiation reaction (Scheme 1).7 Quenching the intermediate lithio
species with acetaldehyde furnished substituted pyridine alcohol 3
in 86% yield.8 Oxidation of alcohol 3 yielded the desired 2-bromo-
5-fluoro-acetylpyridine 4 in 88% yield.9,10 Reaction of 4 with a
slight excess of hydrazine in ethylene glycol furnished compound
5 in 99% yield. The product obtained following workup was of
sufficiently high purity such that no additional purification was
required. The bromo group of this product provides a handle for
diversification, thereby making the core amenable for SAR work.
This method was further extended to the synthesis of the 3-
substituted pyrazolo[3,4-c]pyridines 6–8. In each case, treatment
of the anion of 2 with the appropriate aldehyde followed by oxida-
tion led to ketone products suitable for reaction with hydrazine in
ethlyene glycol (i.e., Scheme 1, step iii).11 The reactions involving
As part of a medicinal chemistry research program, we required
a robust synthesis of the pyrazolo[3,4-c]pyridine group. Herein we
report a practical, high yielding, and scalable method for the prep-
aration of this group from inexpensive commercially available
starting materials.
F
F
N
N
i
Br
Br
OH
3
2
N
ii
N
O
H
NH2
N
F
iii
N
HN
N
1
N
N
Br
Br
4
5
O
Figure 1.
Scheme 1. Reaction conditions: (i) (1) LDA, THF, À78 °C to 0 °C, 4 h; (2) acetalde-
hyde, warm to rt, 86%; (ii) MnO2, CHCl3, 95 °C, 2.5 h (sealed flask), 88%; (iii) anhyd
hydrazine, ethylene glycol, 165 °C, 3.5 h (sealed flask), 99%.
* Corresponding author. Tel.: +1 610 917 7948.
E-mail address: sharad.k.verma@gsk.com (S. K. Verma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.013

384
S. K. Verma, L. V. LaFrance / Tetrahedron Letters 50 (2009) 383–385
Table 1
convenient incorporation of diversity at the 3-position, and is suit-
able for scale-up, as illustrated by the preparation of over 250 g of
compound 5. Although some limitations have already been identi-
fied, we believe the desirable features of this methodology more
than compensate, and will facilitate the further use of the pyra-
zole[3,4-c]pyridine group in drug discovery efforts.
H
N
N
N
Br
R
Compd
Structure (R=)
% Yielda
99
% Yield from 2
5
–CH3
75
2. Representative procedure (compound 5)
6b
60
48
2.1. 1-(2-Bromo-5-fluoro-4-pyridinyl)ethanol (3)
To a 1000 mL 3-neck flask was added THF (200 mL) with cooling
to À20 °C, followed by dropwise addition of n-BuLi (20.0 mL,
50 mmol, 2.5 M in hexanes). After stirring for 5 min, diisopropyl-
amine (7.0 mL, 50 mmol) was added dropwise via syringe, and
the mixture stirred with warming to 0 °C for 1 h. The contents were
cooled to À78 °C and a 20 mL THF solution of 2-bromo-5-fluoro-
pyridine (8.80 g, 50 mmol) was added via addition funnel. After
stirring at À78 °C for 4 h, acetaldehyde (3.1 mL, 55 mmol) was
added dropwise via syringe. The contents were removed from
the cold bath and stirred with warming to room temperature over-
night. The mixture was diluted with H2O (150 mL), and vigorously
stirred for 5 min. The contents were extracted with ethyl ether
(3 Â 150 mL), the combined organic layers dried over MgSO4,
filtered, and concentrated in vacuo to afford a yellow oil. The crude
product was passed through a short silica column (eluent: 3:1
hexanes/EtOAc) to afford the title compound as a white solid
(9.5 g, 86%). 1H NMR: (CD3OD-d4) d8.21 (d, J = 3 Hz, 1H), 7.72 (d,
J = 8 Hz, 1H), 5.06–5.11 (m, 1H), 1.45–1.47 (d, J = 8 Hz, 3H); LC/
MS (MH+) = 219.8, 221.9.
7b
8b
90
86
77
78
N
O
9
0
0c
a
Isolated yield using sealed flask conditions.
For workup and isolation of 6–8, see Ref. 12.
b
c
See Ref. 11.
hydrazine in ethylene glycol proceeded in typically good yields,
and products were obtained from 2 in good overall yields (Table
1).12 However, the hydrazine-mediated cyclization reaction was
not successful for the synthesis of 9 (R = furan) from its corre-
sponding ketone precursor. For this example, multiple products
were observed by both TLC and LC/MS.13 Only a trace amount of
a mass ion consistent with 9 was observed by LC/MS, and this
product was not isolated. The exact reasons for this observation
are unknown. This result would suggest that the scope of the
hydrazine-mediated cyclization reaction has some limitation.
Although the cyclization of 4 to 5 proceeds to completion in
3.5 h on heating in a sealed flask, it can also be conducted under
standard reflux conditions, albeit with a significantly longer reac-
tion time. For example, heating 4 with hydrazine-dihydrochloride
in ethylene glycol for 60 h under standard reflux conditions, gave
5 in 65% yield.14 These conditions were applied to a successful
scale-up campaign for the synthesis of over 250 g compound 5
from 2. We recommend using the standard reflux conditions for
larger scale reactions (>20 g).
We propose that the conversion of the functionalized pyridines
to pyrazolo[3,4-c]pyridines proceeds by way of an intermediary
hydrazone, which then undergoes in situ cyclization to furnish
the desired pyrazolo[3,4-c]pyridine scaffold (Fig. 2). This sequence
of events is based on observations made during careful reaction
monitoring by LC/MS. Early in the reaction, we observed a gradual
increase in an intermediate which had a mass ion consistent with
the proposed hydrazone, with concominant decrease in the start-
ing material. Subsequently, we observed a decrease in the putative
hydrazone intermediate, with a concominant increase in the mass
of the desired product.
2.2. 1-(2-Bromo-5-fluoro-4-pyridinyl)ethanone (4)
To a 350 mL sealed flask was dissolved 1-(2-bromo-5-fluoro-4-
pyridinyl)ethanol (9.4 g, 42.3 mmol) in 60 mL dry CHCl3. Added
next to the stirring solution was manganese(IV)oxide (14.7 g,
169 mmol). The vigorously stirring contents were sealed and
heated at 95 °C for 2.5 h. After cooling to room temperature, the
black heterogenous mixture was vacuum filtered through a pad
of Celite, and the filter pad washed with CH2Cl2 (10 mL). The
yellow colored filtrate was concentrated in vacuo to a yellow oil,
which was purified by silica gel column chromatography (eluent:
9:1 hexanes/EtOAc) to afford the final product as a pale yellow
oil (8.2 g, 88%) 1H NMR: (DMSO-d6) d 8.66, 7.92 (d, J = 8 Hz, 1H),
2.62 (s, 3H); LC/MS (MH+) = 217.9, 219.8. Note: Di-methyl ketal is
observed if CD3OD is used as NMR solvent.
2.3. 5-Bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine (5)
To a 150 mL sealed flask containing 50 mL dry ethylene glycol
was dissolved 1-(2-bromo-5-fluoro-4-pyridinyl)ethanone (8.2 g,
37.6 mmol). Added next was anhydrous hydrazine (1.24 mL,
39.5 mmol) dropwise via syringe. The stirring light yellow mixture
was sealed, and heated at 165 °C. After 3.5 h, the orange-tan reac-
tion mixture was removed from heating. After cooling to room
temperature, the contents were poured onto a stirring mixture of
300 g ice/water (1:1), wherein solid precipitation occurred. After
In summary, we have described a robust, high-yielding route to
substituted pyrazolo[3,4-c]pyridines. The method starts from
inexpensive, commercially available starting materials, allows for
H
F
N
F
N
N
N
NH2
N
O
N
H2N
Br
Br
NH2
Br
4
5
MH+ = 231 observed in LC/MS
Figure 2.

S. K. Verma, L. V. LaFrance / Tetrahedron Letters 50 (2009) 383–385
385
Luo, Y.; Liu, X.; Guan, R.; Klinghofer, V.; Johnson, E. F.; Stoll, V. S.; Mamo, M.; Li,
Q.; Rosenberg, S.; Giranda, V. L. Bioorg. Med. Chem. 2007, 15, 2441.
4. Chapman, D.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1980, 2398.
5. Heller, S. T.; Natarajan, S. R. Org. Lett. 2007, 9, 4947.
6. Woods, K. W.; Fischer, J. P.; Claiborne, A.; Li, T.; Thomas, S. A.; Zhu, G.-D.;
Diebold, R. B.; Liu, X.; Shi, Y.; Klinghofer, V.; Han, E. K.; Guan, R.; Magnone, S.;
Johnson, E. F.; Bouska, J. J.; Olson, A. M.; de Jong, R.; Oltersdof, T.; Luo, Y.;
Rosenberg, S. H.; Giranda, V. L.; Li, Q. Bioorg. Med. Chem. 2006, 14, 6832.
7. Marsais, F.; Queguiner, G. Tetrahedron 1983, 39, 2009.
stirring for 10 min, the off-white precipitate was collected. This so-
lid was dried in vacuo and collected as an off-white solid (7.9 g,
99%). 1H NMR: (CD3OD-d4) d 8.74 (s, 1H), 7.98 (s, 1H), 2.58 (s,
3H); LC/MS (MH+) = 211.7, 213.7.
Acknowledgment
8. The regiochemistry of 3 was verified by 2D NMR.
The authors wish to thank Mingui Wang for acquisition of 2D H
NMR spectra.
9. Attempts to treat the lithiated pyridine of 2 with acetyl chloride instead of
acetaldehyde to directly access 4 were unsuccessful, giving only complex
mixtures.
10. When conducting oxidations on larger scale (>20 g), IBX in refluxing EtOAc
(24 h) was found to be a superior choice of oxidizing condition.
11. The lithiation-trapping-oxidation sequence leading to the synthesis of the
ketone precursors of 6–9 proceeded in >90% yield for each step. The oxidation
reactions were conducted using Dess–Martin reagent.
12. For the synthesis of products 6–8 via hydrazine-mediated cyclization in
ethylene glycol, the following workup procedure was used for product
isolation: after equilibration to room temperature, reaction mixtures were
diluted with 200 mL saturated aqueous NH4Cl, and extracted with 1:9 THF/
EtOAc (2 Â 200 mL). The combined organic layers were dried (MgSO4), filtered,
and the filtrates concentrated in vacuo. The products were dried in a vacuum
oven at 45 °C for 24 h to afford the respective products as tan solids. The lower
yield of product 6 is attributed to its poor solubility in the extraction solvent.
13. For the attempted synthesis of 9, the reaction mixture turned nearly black
during heating. TLC analysis of the reaction mixture showed streaking, and LC/
MS analysis indicated several product peaks.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.013.
References and notes
1. Kourafalos, V. N.; Marakos, P.; Mikros, E.; Pouli, N.; Marek, J.; Marek, R.
Tetrahedron 2006, 62, 11987.
2. Marakos, P.; Pouli, N.; Wise, D.; Townsend, L. Synlett 1997, 561.
3. (a) Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Thomas, S.; Woods, K. W.; Song, X.; Li, T.;
Diebold, R. B.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.;
Olson, A.; Marsh, K. C.; Stoll, V. S.; Mamo, M.; Polakowski, J.; Campbell, T. J.;
Martin, R. L.; Gintant, G. A.; Penning, T. D.; Li, Q.; Rosenberg, S. H.; Giranda, V. L.
J. Med. Chem. 2007, 50, 2990; (b) Zhu, G.-D.; Gong, J.; Gandhi, V. B.; Woods, K.;
14. Hydrazine dihydrochloride was used as an alternative to anhydrous hydrazine
for the larger scale reactions.