Beutner et al.
Hz), 142.0 (d, J ) 3.6 Hz), 137.17, 128.6, 128.1, 122.3 (d, J ) 6.8
Hz), 122.2, 118.0 (d, J ) 31.8 Hz), 75.5 (d, J ) 11.2 Hz), 73.7;
HRMS calcd for C14H12FNO2 (M+H): 246.0930, found: 246.0957.
Preparation of 3-(Benzyloxymethyl)-1H-pyrazolo[3,4-b]pyri-
dine (10a). To a solution of 5.90 g of 1-(2-fluoro-pyridin-3-yl)-2-
benzyloxy-ethanone 7a (22.37 mmol) in 10 mL of isopropanol was
added 10.1 mL of a 35 wt % aqueous solution of hydrazine (112
mmol, 5.0 equiv). The resulting yellow solution was then heated
at 80 °C for 15 h or until complete conversion was observed by
HPLC. The solution was then cooled to room temperature, diluted
with 10 mL EtOAc, washed with 20 mL water, dried over MgSO4,
filtered and concentrated. Purification by silica gel chromatography
(7:3 hexane:ethyl acetate, Rf ) 0.14) afforded 4.29 g (80% yield)
conditions then provided the desired pyrazolo[4,3-c]pyridine 28.
Due to the instability of 27, its isolation was avoided, and crude
27 was used in the cyclization step without purification (29%
yield over 2 steps).
3. Conclusion
In summary, we have developed an efficient method for the
preparation of a structurally diverse group of 3-alkoxymethyl-
and 3-aminomethyl-pyrazolo[3,4-b]pyridines. The use of R-sub-
stituted Weinreb amides as a starting point for the synthesis of
3-substituted pyrazolo[3,4-b]pyridines provides a facile way to
introduce functionality in a rapid manner. In cases where the
desired substituent might be incompatible with these conditions,
the mesylation/displacement of alcohols 13 and 16 allows for
the rapid diversification of pyrazolo[3,4-b]pyridines. The in-
vestigation of 2-chloro-6-fluoro pyridine revealed that subtle
changes in the electronic nature of the pyridine ring can lead to
significant reactivity differences in the pyrazole formation.
Taken together, these results demonstrate that this is a versatile
strategy for pyrazolo[3,4-b]pyridine synthesis, allowing for
straightforward preparation of a wide range of compounds.
These results should enable further exploration of the medicinal
properties of this interesting class of heterocycles.
1
of 10a as a colorless solid. mp 96-97 °C; H (400 MHz, CDCl3)
δ 8.62 (dd, 1H, J ) 4.6, 1.5 Hz), 8.26 (dd, 1H, J ) 8.0, 1.5 Hz),
7.36 (m, 5H), 7.20 (dd, 1H, J ) 8.0, 4.6 Hz), 4.97 (s, 2H), 4.62 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 152.8, 148.9, 143.3, 137.9,
130.8, 128.5, 128.0, 127.9, 117.0, 114.5, 72.5, 65.9; HMRS calcd
for C14H13N3O (M+H): 240.1137, found: 240.1184.
Preparation of 3-(4-tert-Butoxycarbonyl-piperazin-1-ylmethyl)-
pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (21). To
a solution of 1.10 g of 3-hydroxymethyl-pyrazolo[3,4-b]pyridine-
1-carboxylic acid tert-butyl ester 13 (4.41 mmol, 1.0 equiv) in 15
mL of 2-Me-THF at 0 °C was added 0.7 mL of triethylamine (4.85
mmol, 1.1 equiv). To the mixture was added dropwise 0.36 mL of
methanesulfonyl chloride (4.63 mmol, 1.05 equiv) at such a rate
that the internal temperature was maintained <8 °C and the resulting
slurry was stirred at this temperature for 45 min. The mixture was
filtered and the filtrate was concentrated under reduced pressure.
The crude mesylate was dissolved in 7 mL of DMAc and added
dropwise to a slurry of 822 mg of 1-N-Boc-piperazine (4.41 mmol,
1.0 equiv), 1.25 g of KI (7.50 mmol, 1.7 equiv), and 3.35 g of CsF
(22.06 mmol, 5.0 equiv) in 12 mL of DMAc. The reaction mixture
was stirred at rt for 18 h and diluted with 25 mL of MTBE and 25
mL of water. The layers were separated and the aqueous layer back
extracted with 15 mL of MTBE. The combined organic extracts
were washed with water (3 × 20 mL) and dried over MgSO4. The
solvent was removed under reduced pressure and the residue was
purified by silica gel chromatography (6:4 hexane:ethyl acetate, Rf
) 0.10) to afford 1.84 g (97% yield) of 21 as a clear oil. 1H (CDCl3,
400 MHz) δ 8.66 (dd, 1H, J ) 4.7, 1.7 Hz), 8.32 (dd, 1H, J ) 7.9,
1.7 Hz), 7.27 (m, 1H), 3.88 (s, 2H), 3.39 (m, 4H), 2.43 (m, 4H),
1.67 (s, 9H), 1.40 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 154.7,
152.8, 150.7, 148.0, 147.0, 131.1, 119.0, 117.5, 85.1, 79.7, 56.2,
55.1, 43.3, 28.2, 28.1; HRMS calcd for C21H31N5O4 (M+H):
418.2454, found: 418.2478.
4. Experimental Section
Preparation of 1-(2-Fluoro-pyridin-3-yl)-2-benzyloxy-ethanone
(7a). To a solution of 4.4 mL diisopropylamine (31.1 mmol, 1.3
equiv) in 25 mL THF at -40 °C was added 12.4 mL 2.5 M n-BuLi
in hexanes (31.1 mmol, 1.3 equiv), dropwise. The resulting yellow
solution was stirred at -40 °C for 30 min then cooled to -70 °C
for dropwise addition of 2.6 mL 2-fluoropyridine (31.1 mmol, 1.3
equiv). The resulting yellow suspension was stirred for 30 min at
-70 °C prior to slow addition of a solution of 5 g of N-methoxy-
2-benzyloxy-N-methyl-acetamide 6a36 (23.9 mmol) in 5 mL THF
from a dropping funnel. The internal temperature was kept below
-60 °C. After completion of the addition, the solution was stirred
for 30 min at -70 °C prior to pouring into 100 mL saturated
aqueous ammonium chloride, extraction with 25 mL MTBE and
drying the combined organic layers over MgSO4, filtration and
concentration. The resulting orange oil could be purified by silica
gel chromatography (7:3 hexane:ethyl acetate, Rf ) 0.37), to afford
1
3.6 g (61% yield) of 7a as a colorless solid. mp 45-47 °C; H
(400 MHz, CDCl3) δ 8.42 (m, 2H), 7.41-7.31 (m, 6H), 4.73 (d,
2H, J ) 3.1 Hz), 4.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
193.7 (d, J ) 8.8 Hz), 161.4 (d, J ) 243.3 Hz), 152.1 (d, J ) 16.1
Acknowledgment. We thank Dr. Robert Reamer for his
valuable assistance with NMR spectroscopy.
(35) (a) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151–169.
(b) Marsais, F.; Tre´court, F.; Bre´ant, P.; Que´guiner, G. J. Heterocyclic Chem.
1988, 25, 81–87. (c) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980,
21, 4137–4140.
(36) Williams, R. M.; Ehrlich, P. P.; Zhai, W.; Hendrix, J. J. Org. Chem.
1987, 52, 2615–2617.
Supporting Information Available: Experimental proce-
dures and data for all compounds. This material is available
JO802363Q
794 J. Org. Chem. Vol. 74, No. 2, 2009