An efficient access to 3,6-disubstituted 1H-pyrazolo[3,4-b]pyridines via a one-pot double SNAr reaction and pyrazole formation

Article abstract of DOI:10.1016/j.tetlet.2009.02.142

A general and efficient synthetic method for the synthesis of biologically important series of 3,6-disubstituted-1H-pyrazolo[3,4-b]pyridines was discovered. 2,6-Difluoropyridine was deprotonated using 1.1 equiv of n-BuLi in THF at <-60 °C, followed by que

Full text of DOI:10.1016/j.tetlet.2009.02.142

Tetrahedron Letters 50 (2009) 2293–2297
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Tetrahedron Letters
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An efficient access to 3,6-disubstituted 1H-pyrazolo[3,4-b]pyridines
via a one-pot double SNAr reaction and pyrazole formation
*
Yong-Li Zhong , Matthew G. Lindale , Nobuyoshi Yasuda
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient synthetic method for the synthesis of biologically important series of 3,6-disub-
stituted-1H-pyrazolo[3,4-b]pyridines was discovered. 2,6-Difluoropyridine was deprotonated using
1.1 equiv of n-BuLi in THF at <À60 °C, followed by quenching with a variety of Weinreb amides to gen-
erate 2,6-Difluoro-3-ketopyridines in high yields. A mild tandem reaction sequence of selective nucleo-
philic substitution of the 6-fluoride with a variety of nucleophiles, followed by hydrazine substitution
of the 2-fluoride and pyrazole formation in a one-pot fashion afforded a series of 3,6-disubstituted-1H-
pyrazolo[3,4-b]pyridines in moderate to good yields.
Received 24 January 2009
Revised 12 February 2009
Accepted 19 February 2009
Available online 25 February 2009
Keywords:
Lithiation
2,6-difluoro-3-ketopyridines
Double SNAr reaction
Pyrazole formation
One-pot synthesis
Ó 2009 Elsevier Ltd. All rights reserved.
Substituted pyrazolo[3,4-b]pyridines represent an important
class of heterocycles due to their well-documented biological
activity.1 We were particularly interested in the synthesis of 3,6-
disubstituted-1H-pyrazolo[3,4-b]pyridines due to their potent
antiviral activity on the inhibition of non-nucleoside reverse trans-
criptase.2 Despite continuing interest in these heterocycles, to date
a few published methods for the synthesis of this class of 3,6-
disubstituted-1H-pyrazolo[3,4-b]pyridines required harsh condi-
tions and a four-step sequence starting from commercially avail-
able 2,6-difluoropyridine in low overall yield.3 In our search for a
practical and mild synthesis of 3,6-disubstituted-1H-pyrazol-
o[3,4-b]pyridines, we reasoned that the desired compounds could
be assembled in a one-pot protocol from 2,6-difluoro-3-ketopyri-
dines via a selective double SNAr reaction followed by pyrazole for-
mation (Scheme 1). Herein, we report our efforts to accomplish the
described set of chemical transformations.
The first step was to generate lithiated 2,6-difluoropyridine and
to convert the 3-lithiated species into a variety of 2,6-difluoro-3-
ketopyridines. It is well known that ortho lithiation of 2-fluoropyr-
idine and 2,6-difluoropyridine can be performed using either LDA,4
or LiTMP.5 Stronger bases such as n-BuLi are known to add to the
pyridine ring, even at very low temperature.6 However, given the
cost benefit and convenience of using n-BuLi alone, it was worth
re-examining the deprotonation of 2,6-difluoropyridine with n-
BuLi. Thus, to a THF solution of 2,6-difluoropyridine was slowly
added 1.1 equiv of 1.6 M n-BuLi in hexane through a syringe pump
while maintaining an internal temperature below À60 °C. After the
addition was complete, the reaction mixture was stirred at À78 °C
for 0.5 h resulting in the formation of an orange slurry of the lith-
iate. Precooled (À55 °C) solution of the Weinreb amide 1a7 was
quickly added to the lithiated 2,6-difluoropyridine slurry through
a cannula. The reaction mixture was then stirred at À60 °C for
1 h. To our delight, the desired product 2,6-difluoro-3-benzothi-
ophenoyl-pyridine 2a was isolated in 93% yield (Table 1, entry
1).8 Inspired by this successful transformation, the 3-lithiated-
2,6-difluoropyridine intermediate was trapped with a variety of
aromatic Weinreb amides 1b–j, including those with a simple phe-
nyl ring (entry 2), halogen-substituted aromatic rings (entries 1, 3,
6, and 9), electron rich aromatics (entries 4, 7, and 8), an electron
deficient aromatic (entry 5), and a furanyl group (entry 10) to pro-
duce the corresponding 2,6-difluoro-3-ketopyridines 2a–j in good
to excellent yields. The 3-lithiated-2,6-difluoropyridine also re-
acted with an aliphatic Weinreb amide (entry 11) to generate the
corresponding 2,6-difluoro-3-acetoxypyridine in a moderate yield
without further optimization.
O
F
R
Nu,
NH2NH2
R
N
* Corresponding author. Tel.: +1 732 594 8372; fax: +1 732 594 5170.
E-mail address: yongli_zhong@merck.com (Y.-L. Zhong).
Present address: Department of Chemistry, Davidson College, Box 5288, David-
son, NC 28035, United State.
one-pot
N
Nu
N
F
N
H
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.142

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Y.-L. Zhong et al. / Tetrahedron Letters 50 (2009) 2293–2297
Table 1
Preparation of 2,6-difluoro-3-benzoylpyridines
O
O
O
F
R
N
Li
n-BuLi, THF
R
1a-k
-78 to -60 °C
F
N
F
F
N
F
N
F
2a-k
Entries
1
Substrates (1a–k)
Products (2a–k)
Isolated yields (%)
Cl
O
Cl
O
N
95
S
S
O
F
F
N
F
1a
2a
O
O
O
N
2
3
93
92
N
F
1b
2b
O
O
O
N
R
F
N
F
R
4
5
97
96
O
F
O
R
R
O
6
7
8
98
92
93
N
F
N
O
O
OMe
O
N
OMe
F
N
F
2h
1h
O
F
O
N
O
9
10
11
70
83
50
F
F
N
N
F
Cl
Cl
F
1i
2i
O
O
O
O
N
O
F
1j
2j
O
O
O
N
F
N
F
1k
2k
With the desired 2,6-difluoro-3-substituted-benzoyl-pyridines
in hand, a one-pot synthesis of 3,6-substituted-1H-pyrazolo[3,4-
b]pyridines was examined (Table 2). Selective replacement of the
6-fluorine with nucleophiles, followed by displacement of the 2-
fluoride by hydrazine and then closure of the pyrazole ring would
lead to the desired products. Our initial studies began with selec-
tive substitution of compound 2a with tert-butylamine.9 Accelera-
tion of SNAr reactions by using aprotic solvents is well known.
Thus, treatment of compound 2a with tert-butylamine in N,N-
dimethylacetoamide (DMAc) at 0–5 °C afforded a clean reaction
to a mixture of 6-tert-butylamino-2-fluoro-3-benzothiophenoyl-
pyridine 3a and 2-tert-butylamino-6-fluoro-3-benzothiophenoyl-
pyridine 4a in
a
4:1 ratio, as determined by 1H NMR
spectroscopy. A similar outcome was observed when the reaction
was run in DMF, NMP, and DMSO. In a reversal of selectivity, 4a
was the major product when the reaction was performed in EtOAc,
MTBE, and THF. A highly selective formation of 4a was found in tol-
uene (4a:3a = 16.7:1). A lower ratio of 3a:4a was obtained when

Y.-L. Zhong et al. / Tetrahedron Letters 50 (2009) 2293–2297
2295
Table 2
Synthesis of 6-tert-butylamino-1H-pyrazolo[3,4-b]pyridines via a one-pot double SNAr reaction/pyrazole formation
O
O
R
O
NH2
NH2NH2
R
R
R
N
+
F
N
HN
N
N
NH
N
N
F
F
N
F
H
H
3a-k
4a-k
2a-k
5a-k
Entries
Substrates
3a–k/4a–k Ratio
Products (5a–k)
Isolated yields (%)
S
N
1
2a
4.0:1
77
HN
N
5a
Cl
N
H
HN
2
3
2b
2c
2.0:1
2.3:1
67
70
N
N
N
H
5b
X
HN
N
N
N
H
4
5
2d
2e
1.1:1
4.1:1
51
80
X
HN
6
7
8
2f
2.9:1
2.0:1
3.2:1
73
61
75
N
N
N
H
2g
2h
HN
N
OMe
N
N
N
5h
H
Cl
9
10
11
2i
5.3:1
2.0:1
8.6:1
84
65
69
HN
HN
N
N
F
5i
5j
N
H
O
2j
N
N
H
HN
2k
N
5k
N
N
H
the reaction was run at higher temperature. A rationale for this sol-
vent dependence can be tentatively proposed based on hydrogen-
bonding effects. In non-polar solvents (e.g., toluene), hydrogen-
bonding between the carbonyl group and the incoming amine
nucleophile can direct the substitution reaction to the more steri-
cally hindered C-2 site. In polar solvents (e.g., DMAc) this interac-
tion is disfavored due to preferential hydrogen-bonding between
the amine and the solvent, which in turn generates an effectively

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Y.-L. Zhong et al. / Tetrahedron Letters 50 (2009) 2293–2297
Table 3
Synthesis of 3, 6-disubstituted-1H-pyrazolo[3,4-b]pyridines via a one-pot double SNAr reaction/pyrazole formation
O
O
O
Ar
Ar
Nu
Ar
Ar
Nu
NH2NH2
+
F
N
N
N
Nu
Nu
N
F
F
N
F
N
H
3l-q
4l-q
5l-q
Ar = 4-bromo-phenyl
2c
Entries
1
Nu
3c/4c ratio
Products
Isolated yields (%)
Br
19:1
91
S
SH
N
N
N
N
5l
H
Br
NH
2
3
4
5
6
3.2:1
1.5:1
20:1
1.2:1
1.7:1
75
59
84
43
55
Boc
N
N
Boc
N
N
N
5m
H
Br
NH2
HN
N
N
MeO
N
H
5n
MeO
Br
OH
O
N
N
Br
N
H
5o
Br
Br
Br
CO2H
N
N
H
N
N
N
CO2H
H
5p
HN
CO2H
H2N
N
N
N
H
CO2H
5q
larger solvated nucleophile, factors which together lead to selec-
tive substitution at the less hindered C-6 position.
After full conversion of the starting materials 2a–k to the inter-
mediates 3a–k and 4a–k, hydrazine monohydrate10 was slowly
added to the reaction mixture at 0–5 °C, and then warmed to room
temperature to afford 6-tert-butylamino-3-aryl-1H-pyrazolo[3,4-
b]pyridines 5a–k in 51–84% overall yield as a one-pot procedure
starting from 2a–k (Table 2).11 The second SNAr substitution of
the 2-fluorine by hydrazine and the pyrazole formation were
achieved in very mild conditions (0 °C to rt) in nearly quantitative
yields by HPLC analysis.
Employing the above protocol, a variety of 2,6-difluoro-3-keto-
pyridines 2b–k could be selectively converted to 6-tert-butylami-
no-2-fluoro-3-keto-pyridines 3a–k. Functional groups such as
bromo, chloro, fluoro, methoxy, nitro, furanyl, and benzothiophe-
nyl were well tolerated under the reaction conditions. Interest-
ingly, besides the solvent effects discussed above, both the
electronic and steric properties significantly affected the regiose-
lectivity of the initial displacement. An electron-donating group
at the para-position (entry 4, X = OMe) decreased the ratio of 3d
and 4d, wherein electron-withdrawing substituents (entries 1, 5,
and 9) favored formation of 6-substituted intermediates (3a, 3e,
3i) over the 2-substituted intermediates (4a, 4e, 4i). Substitution
at the ortho-position with electron-donating functional groups (en-
try 8) and electron-withdrawing groups (entries 1 and 9) signifi-
cantly increased the percentage of desired intermediates (3a, 3h,
and 3i), presumably due to steric effects.
To further demonstrate the utility of this one-pot protocol,
selective substitution of the 6-fluorine of 2,6-difluoro-3-substi-
tutedbenzoyl-pyridines was investigated using different nucleo-
philes followed by hydrazine substitution of the 2-fluorine and
pyrazole formation. As shown in the Table 3, reaction of compound
2c with tert-butyl thiol (entry 1) or phenol (entry 4) afforded excel-
lent regioselective substitution of the 6-fluorine, giving a high
overall yield for the one-pot transformation. Reaction with a sec-
ondary amine (entry 2) or an aniline (entry 3) also proceeded

Y.-L. Zhong et al. / Tetrahedron Letters 50 (2009) 2293–2297
2297
2004, 1018; (h) Skerlj, R. T.; Bogucki, D.; Bridger, G. J. Synlett 2000, 1488; (i)
Piccirilli, J.; Krauch, T.; MacPherson, L. J.; Benner, S. A. Helv. Chim. Acta 1991, 74,
397; (j) Terauchi, H.; Tanitame, A.; Tada, K.; Nakamura, K.; Seto, Y.; Nishikawa,
Y. Chem. Pharm. Bull. 1997, 45, 1027; (k) Rewcastle, G. W.; Palmer, B. D.;
Thompson, A. M.; Bridges, A. J.; Cody, D. R.; Zhou, H.; Fry, D. W.; McMicheal, A.;
Denny, W. A. J. Med. Chem. 1996, 39, 1823; (l) Beutner, G. L.; Kuethe, J. T.; Kim,
M. M.; Yasuda, N. J. Org. Chem. 2009, 74, 789; m Ref. 3.
smoothly. Addition of amino acids (entries 5 and 6) also proved
efficient, generating the corresponding pyrazoles in moderate
yields.12
In summary, the 2,6-difluoro-3-ketopyridines were generated
in high yields through a cost-effective and convenient protocol
involving deprotonation of 2,6-difluoropyridine using n-butyllith-
ium, followed by quenching with a variety of Weinreb amides. A
series of 3,6-disubstituted-1H-pyrazolo[3,4-b]pyridines could then
be efficiently prepared from the 2,6-difluoro-3-ketopyridines in
moderate to good yields by a tandem reaction sequence of selec-
tive nucleophilic substitution of the 6-fluoride, followed by hydra-
zine substitution of the 2-fluoride and pyrazole formation in a one-
pot fashion at very mild conditions (0 °C to room temperature).
This process could be performed with a variety of nitrogen-, oxy-
gen- and sulfur-containing nucleophiles. The high chemo- and reg-
ioselectivities observed in these reactions, the high yields after
multiple bond forming steps, and mild reaction conditions em-
ployed make this process broadly applicable to the synthesis of
the 3,6-disubstituted-1H-pyrazolo[3,4-b]pyridines both in acad-
emy and industry.
5. Moseley, J. D.; Moss, W. O.; Welham, M. J. Org. Proc. Res. Dev. 2001, 5, 491.
6. Marsais, F.; Granger, P.; Queguiner, G. J. Org. Chem. 1981, 46, 4494.
7. Williams, R. L.; Ehrlich, P. P.; Zhai, W.; Hendrix, J. J. Org. Chem. 1987, 52, 2615.
8. General procedure for the preparation of 2,6-difluoro-3-ketopyridines 2. To a
250 mL three-necked round-bottomed flask, equipped with an overhead
stirrer, thermocouple, and nitrogen inlet, was charged 2,6-difluoropyridine
(20.0 mmol), and dry THF (28 mL). The solution was cooled to about À70 °C. n-
butyllithium (2.5 M) in hexane solution (22.0 mmol) was slowly added through
a
syringe pump at <À60 °C over 0.5 h. After complete addition of the
butyllithium, the resulting mixture was stirred at À65 °C for 1 h. Weinreb’s
amide 1a–k (20.0 mmol) in THF (10 mL) solution, which was pre-cooled to
À55 °C, was quickly charged through a cannula without stopping. The resulting
reaction mixture was stirred at À60 °C for 1 h to go to completion. The reaction
mixture was reversely quenched to a solution of 5 N HCl/THF (2:1, 25 mL) at
À15 to À5 °C. The mixture was extracted by MTBE (30 mL). After phase
separation, the organic layer was washed with water (20 mL), and
concentrated. The resulting solid was recrystallized from MTBE/heptane to
afford desired 2,6-difluoro-3-ketopyridines 2. Selected example 2a was
isolated as a colorless crystalline solid, mp 99.2–100.1 °C. 1H NMR (400 MHz,
CDCl3) d: 8.17 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.32 (d, J = 8.0 Hz,
1H), 7.00 (dd, J = 8.0, 4.0 Hz, 1H), 2.52 (s, 3 H). 13C NMR (100 MHz, CDCl3) d:
183.0 (d, J = 4 Hz), 162.9 (dd, J = 252 Hz, 14 Hz), 158.6 (dd, J = 252, 15 Hz), 145.6
(dd, J = 9, 3 Hz), 145.5, 140.0, 135.0, 134.0, 127.9, 126.5, 124.0, 122.6, 119.4 (dd,
J = 27, 6 Hz), 106.9 (dd, J = 35, 6 Hz), 21.9. 19F NMR (376 MHz, CDCl3) d: À61.5
(d, J = 9 Hz), À64.5 (d, J = 9 Hz). HRMS (ESI) calculated for C15H8ClF2NOS (M+H)+
324.0062, found 324.0046.
Acknowledgments
We would like to thank the following individuals from Merck
Research Laboratories: Mr. Robert A. Reamer (NMR) and Drs. Greg
L. Beutner, Paul G. Bulger, David L. Hughes, Jeff T. Kuethe, and Jing-
jun Yin for helpful scientific discussions.
9. Methylamine substitution of 2,6-difluoropyridine-3-carboxylic esters gave a
mixture of methyl 2-fluoro-6-methylaminopyridine-3-carboxylate and
methyl-6-fluoro-2-methylaminopyridine-3-carboxylate in a ratio of 1.8:1–1:3
depending on the solvent used. Please see: (a) Hirokawa, Y.; Horikawa, T.; Kato,
S. Chem. Pharm. Bull. 2000, 48, 1847; (b) Hirokawa, Y.; Yoshida, N.; Kato, S.
Bioorg. Med. Chem. Lett. 1998, 8, 1551; (c) Hirokawa, Y.; Fujiwara, I.; Suzuki, K.;
Harada, H.; Yoshikawa, T.; Yoshida, N.; Kato, S. J. Med. Chem. 2003, 46, 702.
10. 35 wt% of hydrazine aqueous also worked well.
11. The 6-N-tert-butyl group of 6-tert-butylamino-3-substituted-1H-pyrazolo[3,4-
b]pyridines 5a–k could be easily removed to generate the corresponding 6-
amino-3-substituted-1H-pyrazolo[3,4-b]pyridines by TFA treatment. Please
see: Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W. J. Org. Chem.
2007, 72, 4554.
12. General procedure for the preparation of 3,6-disubstituted-1H-Pyrazolo[3,4-
b]pyridines 5. To a solution of 2,6-difluoro-3-ketopyridine (3.00 mmol) in
DMAc (5 mL) was slowly added nucleophile (9.00 mmol) at 0–5 °C
(exothermic), and stirred at the same temperature for 0.5–3 h. Then,
hydrazine monohydrate (12.0 mmol) was slowly added at 0–5 °C
(exothermic). After complete addition, the reaction mixture was stirred at 0–
5 °C for 1 h, and at rt for 1–5 h. The reaction mixture was cooled to 0 °C, and
adjusted to pH 5 by 5 N sulfuric acid at <20 °C. Water (10 mL) and EtOAc
(10 mL) were charged, respectively. After phase separation, the aqueous layer
was extracted with EtOAc (10 mL). The combined organic layers were washed
with water (10 mL), brine (10 mL), and concentrated. The residue was purified
by chromatography on silica gel (hexane/EtOAc = 10:1, 5:1) to afford desired
product 3,6-dibstituted-1H-pyrazolo[3,4-b]pyridines 5. Selected example 5a
was isolated as an off-white crystalline solid, m.p. 203.8–203.6 °C. 1H NMR
(400 MHz, CDCl3) d: 10.95 (br s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz,
1 H), 7.62 (s, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 6.31 (d, J = 8.0 Hz, 1 H), 4.79 (s, 1 H),
2.50 (s, 3 H), 1.53 (s, 9 H). 13C NMR (100 MHz, CDCl3) d 157.9, 152.8, 137.9,
137.7, 135.8, 135.4, 131.5, 128.7, 126.7, 122.2, 121.8, 117.5, 108.1, 105.7, 51.7,
29.2, 21.6.
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