Selective N7 Alkylation of 7-Azaindazoles

Article abstract of DOI:10.1021/acs.joc.0c00722

A general and mild procedure for alkylation of 7-azaindazoles at the N7 position using alkyl halides in butanone is reported, which requires no additives such as acids or bases. The scope of the reaction regarding substituents on 7-azaindazoles and the alkyl electrophiles is presented.

Full text of DOI:10.1021/acs.joc.0c00722

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Note
Selective N7 Alkylation of 7-Azaindazoles
Zhiyu Lei, Jianming Bao, Chen Cheng, Wensheng Yu, Bin Hu, Weichen Jin,
Salman Jabri, Song Yang, Lianyun Zhao, Christopher J Sinz, and Joseph L Duffy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00722 • Publication Date (Web): 04 May 2020
Downloaded from pubs.acs.org on May 11, 2020
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The Journal of Organic Chemistry
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Selective N7 Alkylation of 7-Azaindazoles
†
§
§
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†
†
§
Zhiyu Lei , Jianming Bao* , Chen Cheng* , Wensheng Yu , Bin Hu , Weichen Jin , Salman Jabri ,
§
§
§
§
Song Yang , Lianyun Zhao , Christopher J. Sinz , Joseph L. Duffy
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†IDSU, Wuxi AppTec Co., Ltd, Shanghai 200131, China
§Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
Supporting Information Placeholder
ABSTRACT: A general and mild procedure for alkylation of 7-azaindazole at the N7 position using alkyl halides in butanone is
reported, which requires no additives such as acids or bases. The scope of the reaction regarding substituents on 7-azaindazoles and
the alkyl electrophiles is presented.
7-Azaindazoles are important building blocks for pharma-
ceuticals and bioactive agents (Figure 1). Examples of unsub-
stituted 7-azaindazoles include non-nucleoside reverse tran-
scriptase inhibitors (NNTRIs, 1a), c-Met inhibitors (1b),
and fibroblast growth factor receptor (FGFR) kinase inhibitors
ed through hydrazone formation and subsequent ring closure
using POCl from a ketone intermediate 3 in < 30% total yield
3
(2 to 1f, Figure 3). A plausible reason for the scarcity of N7
substituted azaindazoles in literature could be the lack of effi-
cient methods for the synthesis of these compounds. We sur-
mised that a methodology for direct alkylation of 7-
azaindazoles at the N7 position would be of great synthetic
utility for medicinal chemistry.
1
,2
3
4
(
1c). There are also multiple examples of N1 substituted
agents, including the dual orexin receptor antagonists (DO-
RAs, 1d) and the approved pulmonary hypertension drug
riociguat (1e), which is a stimulator of soluble guanylate
Baelen et al. reported that direct N7 alkylation of 7-
azaindole 4 with iodomethane in THF upon heating afforded
nearly quantitative yield of the N7 methylated product 5 (Fig-
5
,6
cyclase (sGC). Much less common, however are examples of
N7 substituted species, which includes the γ-secretase modula-
7
tor (1f) for potential treatment of Alzheimer's disease.
8
ure 3). However, the additional N2 nitrogen in the 7-
Recently, we became interested in synthesizing structures
with N7 alkylated azaindazoles due to their potentially favora-
ble physicochemical properties as compared to the corre-
sponding N1 substituted azaindazoles. As shown in Figure 2,
regioisomers A and B share the same molecular weight and
similar topography, but isomer B has lower cLogP and is more
basic than A. We believe that N7 alkylated azaindazoles offer
a potentially useful alternative scaffold to modulate the phar-
macologic properties of compounds of medicinal interest.
azaindazole core significantly alters this reactivity. There is
limited precedent for direct alkylation of 7-azaindazoles at the
N7 position. Wu and coworkers reported, as the only example
of direct N7 alkylation of 7-azaindazole, that reaction of 6
with iodomethane under similar conditions gave 7 in only 15%
yield (Figure 3). Herein, we report a mild, general, and selec-
tive method for the direct alkylation of readily available 7-
azaindazoles at the N7 position.
9
There is an abundance of reports detailing the synthesis of
N1 substituted 7-azaindazoles. Indeed, using CAS SciFinder,
we identified over 2,000 publications for the preparation of
over 30,000 such derivatives. However, there are significantly
fewer methods focusing on the synthesis of N7 alkylated 7-
azaindazoles. Qin and coworkers reported the synthesis of
compound 1f (Figure 1) and provided a general method for the
7
syntheses of this regioisomer. All compounds in that study
were synthesized from a pyridone precursor 2 via a multi-step
synthetic route in which the 7-azaindazole core was construct-
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FIGURE 1. 7-Azaindazoles in Compounds of Medicinal Inter-
est
We used 3-bromo-1H-pyrazolo[3,4-b]pyridine 8 and 4-
fluorobenzyl bromide 9 as model substrates due to the specific
need of a medicinal chemistry project. The parameters ex-
plored during the optimization included solvent, acid or base
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
4
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5
5
5
5
5
5
5
5
5
5
6
additive, and temperature (Table 1). In THF at 80 °C for 16 h
8
(conditions reported by Wu and co-workers), the reaction of 8
and 9 (2 equiv) gave 16% isolated yield of 10a (N7) and 15%
isolated yield of dialkylated product 10c with 20% of unreact-
1
0
ed starting material 9 (entry 1). The dialkylated product 10c
was also formed from 10a by treating isolated 10a with 9 un-
der the same reaction conditions, suggesting that 10c may be
formed sequentially from 10a. In dioxane, the selectivity for
10a over 10c (1:1) was higher than reaction in THF (entry 2).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Using inorganic bases such as K
tive, the reaction afforded exclusively the N1 product 10b
entries 3 & 4). With addition of 1 equivalent of trifluoroacetic
2 3 3
CO or NaHCO as an addi-
(
acid (TFA), good regioselectivity for 10a (N7 alkylation) was
achieved, although the conversion was low (entry 5). Addi-
tional solvents were screened to optimize the yield of 10a (en-
try 6–15). We were pleased to find that the reaction in buta-
none gave 54% yield of 10a with only negligible amount of
1
0b and a small amount (~5%, not isolated) 10c (entry 15).
The yield of 10a was improved to 78% yield by extending the
reaction time to 3 days (entry 16). The addition of TFA (1
equiv) in butanone did not increase the rate of reaction and
gave 10a in 61% yield in 64 h (entry 17). The yield of 10a was
lower at 60 °C in butanone compared with that of at 80 °C
(60%, entry 18). Finally, the reaction was conducted with oth-
FIGURE 2. Calculated LogP and pKa of N1 and N7 Benzylat-
ed 7-Azaindazoles
er benzyl halides. Whereas reaction with 4-fluorobenzyl chlo-
ride did not give any desired product (entry 20), reaction with
a
4
-fluorobenzyl iodide gave 10a in a low yield (13%) due to
significant bis-alkylation (10c, entry 21).
TABLE 1. Optimization of Reaction Conditions for N7
a
Alkylation of 8
aCalculated using ACD/Percepta. pKa refers to the pKa of the most acidic N.
FIGURE 3. Reported Methods for the Synthesis of 7-
Azaind(az)oles
a
Reaction conditions: All reactions were performed with 8 (0.5 mmol), 9 (1.0 mmol),
b
and the additive in 2.0 mL of solvent at 80 °C for 16 h unless otherwise noted. Y-
4
ields of products isolated by NH OH workup followed up either prep. TLC or silica
gel flash chromatography to a purity of ≥ 95%. n.i.: not isolated and estimated to be
c
<
2
5% by crude LCMS. Determined on crude samples by LCMS using UV area at
d e
20 nM. n.d.: not determined. The reaction time was 64 h. The reaction temperature
was 60 °C. Reaction conducted with 1.0 mmol of 8 and 2.0 mmol of 9 in 4 mL of
f
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butanone. gReaction conducted with 4-fluorobenzyl chloride as the electrophile.
Reaction conducted with 4-fluorobenzyl iodide as the electrophile.
products in lower yields (12n-12q), presumably because of the
reduced nucleophilicity of the N7.
h
1
2
3
4
5
6
7
8
9
We hypothesized that the distribution of alkylation products
FIGURE 4. Alkylation of 7-Azaindazoles by 4-Fluorobenzyl
Bromide - Scope of Substitutions on 7-Azaindazole Core
depends on the nucleophilicity of each N atom: with inorganic
bases as additive in dioxane, the nucleophile is the anionic
form of 8, with the negative charge mainly localized on N1,
whereas with TFA or without additive (the alkylation gener-
ates 1 equivalent of acid) in butanone, the nucleophile is the
neutral form of 8 with N7 atom being the most nucleophilic N
atom. The above rationale is supported by electron density
calculation on 8 (Table 2), which indicates that N1 is the most
electron-rich N-atom in the anion form and N7 is the most
electron-rich N-atom in the neutral form.
a,b
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TABLE 2. Calculated Electron Densities of N atoms of 8 in
a
Neutral and Anion Forms
Natural bond orbital (NBO) charges
N1
N2
N7
Neutral
Anion
-0.358
-0.498
-0.271
-0.277
-0.466
-0.383
aElectron density of the nitrogen atoms of 8 are computed with b3lyp/6-311+G**
basis set for the neutral form and anion with -1 charge. The electron density at N2
position is almost identical in the two forms. N7 has the largest electron density in
the neutral form while in the anion form, deprotonated N1 is the most negatively
charged.
With the optimal reaction conditions in hand, we next exam-
ined the scope of the N7 selective alkylation reaction with
respect to various substituted 7-azaindazoles. As summarized
in Figure 4, N7 alkylated products were obtained in excellent
yields from a diverse set of substituted 7-azaindazoles under
the optimized reaction conditions. For 3-aryl-7-azaindazoles
substrates 11a–11d), neither electronic nature of the substitu-
ents (electron-donating or electron-withdrawing groups) nor
steric hindrance (Cl group at the 2-position of the phenyl ring,
(
a
Reaction conditions: All reactions were performed with 11a-m (0.25 mmol) and 9
b
(
0.5 mmol) in 1.0 mL of butanone at 80 °C for 16 h unless otherwise noted. Yields
of products isolated by NH OH workup followed by column chromatography to ≥
5% purity, as illustrated in the SI. The reaction time was 32 h. The major product
4
c
d
9
e
f
1
1d) impacted the reaction yields (compounds 12a−12d).
(40%) was the N2 alkylation product. The reaction time was 3 h. The reaction time
was 24 h. The reaction time was 60 h. The reaction time was 120 h.
i
g
h
With Me, Pr and Cl as substituents at the C3 position, the
alkylation reaction produced 12f, 12g, and 12h in 77%, 85%,
and 74% yields, respectively. A lower yield (12i, 48%) was
obtained for C3 unsubstituted 7-azaindazole due to formation
of the dialkylated byproduct. Whereas reaction of a 4-
substituted substrate (11j) gave the desired regioisomer in a
good yield (72%), reaction of a 5-substitued substrate (11k)
proceeded more slowly with the starting material remaining
after 16 h (presumably due to the electron-withdrawing effect
of Cl). Reaction of a 6-substituted azaindazole (11l) proceeded
with poor selectivity, with the major product being the N2
alkylated product, presumably due to the steric effect of the
methyl group at the C6 position. Interestingly, alkylation of 7-
azaindole under the standard conditions was faster than alkyla-
tion of 7-azaindazole and completed in 3 h with 75% yield
Next, we examined the N7 alkylation with respect to differ-
ent types of electrophiles (R-X) as depicted in Figure 5. For
substituted benzyl bromides, the reactions gave N7 alkylated
products in >80% yields regardless of the substitution pattern
of the electrophiles (14a–14f). For other reactive electrophiles
3 2
(MeI, allyl bromide, ethyl bromoacetate and CF CH OTf), the
yields were >70%. For less reactive alkyl halides, the rate of
reactions decreased substantially, but synthetically useful
yields (>60%) were obtained with increased amounts of elec-
trophiles and extended reaction time (14g, 14h, and 14m).
(
compound 12m), which is most likely due to the stronger
nucleophilicity of the N7 atom in 7-azaindole compared to 7-
azaindazole (7-azaindole is more electron-rich than 7-
azaindazole). In contrast, reactions of substrates with strongly
electron-withdrawing groups were slower and gave the desired
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FIGURE 5. Scope of Electrophiles for N7 Alkylationa,b
added K
CO
(2 eq) and Pd(dppf)Cl
(0.1 eq). The mixture was
2
for 16 h. After finished, the
2
3
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stirred in an oil bath at 90 °C under N
mixture was diluted with EtOAc (15 mL), the organic layer was
washed with water (10 mL) and brine (10 mL), dried over
Na SO , filtered and concentrated in vacuum. The residue was
2 4
purified by silica gel chromatography with petroleum ether /ethyl
acetate (PE/EA) as the eluent to afford the desired product.
3-phenyl-1H-pyrazolo[3,4-b]pyridine (11a) Colorless solid,
1
PE/EA (1/1), 58% (171 mg). H NMR (400 MHz, DMSO-d
6
) δ
1
3.82 (s, 1H), 8.58 - 8.56 (m, 2H), 8.03 - 8.02 (m, 2H), 7.53 (t, J
=
7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.28 (dd, J = 4.8, 7.6 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
H). The NMR data agree with the literature data.
3
-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine
1
(11b) Colorless solid, PE/EA (2/1), 39% (105 mg). H NMR (400
MHz, CDCl ) δ 12.51 (br s, 1H), 8.73 (dd, J = 1.6, 4.4 Hz, 1H),
.44 (dd, J = 1.6, 8.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.81 (d, J
3
8
=
1
3
1
7.6 Hz, 2H), 7.33 (dd, J = 4.8, 8.0 Hz, 1H). C{ H} NMR (100
) δ 152.3, 148.4, 143.3, 133.6, 131.2, 130.4 (q, J =
2 Hz), 127.3, 126.0 (q, J = 3.7 Hz), 124.1 (q, J = 271 Hz),
MHz, CDCl
3
1
3
19
17.7, 113.8. F NMR (470 MHz, CDCl
3
) δ -62.57. HRMS (ESI)
+
+
m/z: [M+H] Calcd for C13
H
9
F
3
N
3
264.0743; Found 264.0741.
3
-(4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine (11c) Color-
a
Reaction conditions: All reactions were performed with 11g (0.25 mmol) and 13a-n
1
less solid, PE/EA (1/1), 50% (173 mg). H NMR (400 MHz,
DMSO-d ) δ 13.68 (br s, 1H), 8.55 - 8.51 (m, 2H), 7.95 (d, J = 8.8
Hz, 2H), 7.25 (dd, J = 4.4, 8.0 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H),
(0.5 mmol) in 1.0 mL of butanone at 80 °C for 16 h unless otherwise noted. bYields
of products isolated by NH
9
was stirred at 80 °C for 48 h. 6 equiv of alkyl bromide was used and the reaction
was stirred at 80 °C for 72 h. 10 equiv of alkyl iodide was used and the reaction was
stirred at 80 °C for 96 h.
6
4
OH workup followed by column chromatography to ≥
c
5% purity, as illustrated in the SI. 3 Equiv of alkyl iodide was used and the reaction
d
13
1
3
6
.83 (s, 3H). C{ H} NMR (100 MHz, DMSO-d ) δ 159.2,
e
152.8, 148.7, 142.5, 130.3, 127.8, 125. 8, 117.0, 114.4, 111.8,
+
+
55.2. HRMS (ESI) m/z: [M+H] Calcd for C13
H
12
N
3
O 226.0975;
Found 226.0975.
CONCLUSIONS
3
-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyridine (11d) Colorless
In conclusion, we developed a general and operationally
simple protocol for the synthesis of N7 substituted 7-
azaindazoles through direct alkylation of 7-azaindazoles with
various electrophiles in butanone. Compared to the previously
reported ring forming strategy, the current method offers di-
rect access to this structural motif, allowing rapid SAR explo-
ration at the N7 position of 7-azaindazoles. The method af-
fords products in high yields for 1° and 2° alkyl electrophiles
irrespective of the substitutions at C3, C4, and C5 on the 7-
azaindazole core (except when C3 is unsubstituted).
1
solid, PE/EA (1/1), 41% (143 mg). H NMR (400 MHz, DMSO-
) δ 13.96 (br s, 1H), 8.58 (dd, J = 1.6, 4.4 Hz, 1H), 8.12 (dd, J =
1.2, 8.0 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.52 - 7.49 (m, 2H), 7.25
d
6
1
3
1
6
(dd, J = 4.4, 8.0 Hz, 1H). C{ H} NMR (100 MHz, DMSO-d ) δ
1
1
C
52.1, 149.0, 141.7, 132.2, 132.2, 131.8, 130.4, 130.3, 130.0,
+
27.5, 117.1, 113.2. HRMS (ESI) m/z: [M+H] Calcd for
+
12
H
9
ClN
3
230.0480 found: 230.0480.
3
-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridine
1
(11e) Colorless solid, PE/EA (3/1), 22% (66 mg). H NMR (400
MHz, CDCl ) δ 12.50 (br s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.28
dd, J = 1.2, 8.0 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.31 (dd, J =
3
(
4
1
3
1
.8, 8.4 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 4.28 (s, 3H). C{ H}
) δ 152.3, 149.2, 138.6, 136.0, 134.2,
EXPERIMENTAL SECTION
NMR (100 MHz, CDCl
1
for C10H N 200.0931; Found 200.0932.
10 5
3
+
30.5, 117.6, 114.2, 106.4, 39.0. HRMS (ESI) m/z: [M+H] Calcd
General Information: All reagents and solvents were obtained
from commercial suppliers and used without further purification
unless stated otherwise. All experiments were carried out under
+
Procedure for 3-isopropyl-1H-pyrazolo[3,4-b]pyridine (11g):
Step 1: To a solution of 2-fluoropyridine (5 g, 51.5 mmol) in THF
2
N , and oven-dried glassware was used in all cases. For thin layer
chromatography (TLC), Liang Chen Gui Yuan precoated TLC
plates were used, and compounds were visualized with a UV light
at 254 nm. Column chromatography separations were performed
on silica gel (200−300 mesh). H and C{ H} NMR spectra were
recorded on a Varian spectrometer at 400 MHz for H and 100
(
60 mL) was added LDA (25.7 mL, 51.5 mmol) at 0 °C under N
The mixture was stirred at 0°C for 30 min. Then isobutyraldehyde
7.43 g, 103 mmol) was added by dropwise. The mixture was
2
.
(
1
13
1
stirred at 0°C for 2 hours. TLC showed the starting material was
consumed. The mixture was quenched with water (50 mL), ex-
tracted with EtOAc (50 mL×3). The combined organic layers
1
1
3
MHz for C or a Bruker Avance III spectrometer at 500 MHz for
1
13
H and 125 MHz for C. High-resolution mass spectra (HRMS)
2 4
were washed with brine (20 mL), dried over Na SO , filtered and
were recorded with an Agilent G6230B instrument and were per-
formed in positive mode with an ESI source on a TOF mass spec-
trometer.
concentrated in vacuum. The residue was purified by silica gel
chromatography with (PE/EA 5:1) to give 1-(2-fluoropyridin-3-
1
yl)-2-methylpropan-1-ol (2.5 g, 29% yield) as a colorless oil. H
NMR (400 MHz, CDCl
3
) δ 8.08 (d, J = 4.8 Hz, 1H), 7.92-7.89 (m,
General Procedure for Azaindazoles Synthesis 11a-11e: To a
solution of 3-bromo-1H-pyrazolo[3,4-b]pyridine (1.5 mmol, 1 eq)
and Ar-B(OH) (1.5 eq) in Dioxane (3 mL)/Water (0.6 mL) was
2
1
H), 7.20 - 7.17 (m, 1H), 4.71 (d, J = 5.6 Hz, 1H), 2.32 (br s, 1H),
2.01 - 1.96 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz,
3H).
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The Journal of Organic Chemistry
Step 2: To a solution of 1-(2-fluoropyridin-3-yl)-2-methylpropan-
1-ol (2.5 g, 14.78 mmol) in DCM (50 mL) was added 4Å MS
500 mg) and NMO (2.60 g, 22.16 mmol), the mixture was stirred
δ 8.89 (d, J = 7.6 Hz, 1H), 8.51 (d, J = 6.4 Hz, 1H), 8.14 (d, J =
8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 5.2, 8.4 Hz,
2H), 7.28 (dd, J = 6.0, 7.6 Hz, 1H), 7.09 (t, J = 8.8 Hz, 2H), 5.95
1
2
3
4
5
6
7
8
9
(
1
3
1
at 20 °C for 15 min, then TPAP (0.104 g, 0.296 mmol) was added.
The resulting mixture was stirred at 20 °C for 3h. Then filtered
and the filtrate was concentrated, the residue was purified by sili-
ca gel chromatography (PE/EA 2:1) to give 1-(2-fluoropyridin-3-
4
(s, 2H). C{ H} NMR (100 MHz, MeOH-d ) δ 164.6 (d, J =
245.9 Hz), 152.3, 147.6, 139.7, 139.6, 138.6, 132.2 (d, J = 3.8
Hz), 132.1 (d, J = 8.3 Hz), 130.8 (q, J = 33 Hz), 128.5, 127.1 (q,
J = 3.8 Hz), 125.9 (q, J = 269.4 Hz), 122.2, 117.0 (d, J = 22 Hz),
1
19
yl)-2-methylpropan-1-one (2 g, 81% yield) as a colorless oil. H
NMR (400 MHz, CDCl ) δ 8.36 - 8.35 (m, 1H), 8.28 - 8.23 (m,
1H), 7.33 - 7.29 (m, 1H), 3.48 - 3.41 (m, 1H), 1.20 (d, J = 6.8 Hz,
H).
114.1, 57.2. F NMR (470 MHz, CDCl
3
) δ -62.42, -111.48.
+
+
3
HRMS (ESI) m/z: [M+H] Calcd for C20
Found 372.1122.
H
14
F
4
N
3
372.1118;
6
7
-(4-Fluorobenzyl)-3-(4-methoxyphenyl)-7H-pyrazolo[3,4-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Step 3: To a solution of 1-(2-fluoropyridin-3-yl)-2-methylpropan-
-one (2 g, 11.96 mmol) in EtOH (20 mL) was added hydrazine
hydrate (5 mL, 98 mmol). The mixture was stirred in an oil bath at
80 °C for 16 h. TLC showed starting material was consumed. The
mixture was concentrated in vacuum. The residue was diluted
with EtOAc (30 mL), washed with water (10 mL) and brine (10
b]pyridine (12c) Yellow solid, EA/MeOH (10/1), 84% (70 mg).
H NMR (400 MHz, MeOH-d ) δ 8.77 (d, J = 7.6 Hz, 1H), 8.42
4
1
1
(d, J = 5.6 Hz, 1H), 7.86 (d, J = 9.2 Hz, 2H), 7.55 (dd, J = 5.2,
8.4 Hz, 2H), 7.19 (dd, J = 6.4, 7.6 Hz, 1H), 7.11 - 7.04 (m, 4H),
1
3
1
4
5.91 (s, 2H), 3.84 (s, 3H). C{ H} NMR (100 MHz, MeOH-d ) δ
164.5 (d, J = 245.0 Hz), 161.5, 152.0, 149.4, 139.6, 139.4, 132.3
(d, J = 3.6 Hz), 132.0 (d, J = 8.1 Hz), 129.6, 127.3, 122.5, 117.0
(d, J = 21.8 Hz), 115.7, 113.1, 56.9, 56.0. HRMS (ESI) m/z:
2 4
mL). The organic layer was dried over Na SO , filtered and con-
centrated in vacuum. The residue was purified by silica gel chro-
matography (PE/EA 3:1) to give 3-isopropyl-1H-pyrazolo[3,4-
+
+
3
[M+H] Calcd for C20H17FN O 334.1350; Found 334.1355.
1
b]pyridine (1.5 g, 78% yield) as a colorless oil. H NMR (400
MHz, CDCl ) δ 12.00 (br s, 1H), 8.59 (dd, J = 1.2, 4.4 Hz, 1H),
8.15 (dd, J = 1.2, 8.0 Hz, 1H), 7.13 (dd, J = 4.4, 8.0 Hz, 1H), 3.46
3
3-(2-Chlorophenyl)-7-(4-fluorobenzyl)-7H-pyrazolo[3,4-
b]pyridine (12d) Yellow solid, EA/MeOH (10/1), 75% (63 mg).
1
-
3.40 (m, 1H), 1.49 (d, J = 6.8 Hz, 6H). The NMR data agree
4
H NMR (400 MHz, MeOH-d ) δ 8.54 (d, J = 7.6 Hz, 1H), 8.51
1
2
with the literature data.
(d, J = 6.4 Hz, 1H), 7.61 - 7.57 (m, 4H), 7.46 - 7.43 (m, 2H), 7.24
dd, J = 6.4, 7.6 Hz, 1H), 7.12 (t, J = 8.8 Hz, 2H), 5.97 (s, 2H).
(
13
1
General Procedure for Alkylation: A solution of azaindazole
0.25 mmol) and halogenoalkane 2 (0.5 mmol) in butanone (1
mL) in a sealed tube was stirred in an oil bath at 80 °C for 16 h.
Then NH O (28–30% ammonia in water, 1 mL) was added and
4
C{ H} NMR (100 MHz, MeOH-d ) δ 164.5 (d, J = 245.2 Hz),
(
151.7, 147.8, 140.1, 139.6, 134.3, 133.7, 133.6, 132.2, 132.2 (d, J
= 8.4 Hz), 131.3, 128.4, 123.0, 117.1 (d, J = 22.0 Hz), 116.2,
+
+
3
H
2
113.4, 57.2. HRMS (ESI) m/z: [M+H] Calcd for C19
H
14ClFN
3
the mixture was stirred at room temperature for 15 min. The re-
sulting mixture was diluted with EtOAc (10 mL) and water (5
mL). The organic layer was washed with brine (5 mL), dried over
Na SO , filtered and concentrated in vacuum. The residue was
2 4
purified by preparative TLC (with EA/MeOH 10/1 as eluent un-
less otherwise stated) to give the desired product.
338.0855; Found 338.0859.
7-(4-Fluorobenzyl)-3-(1-methyl-1H-pyrazol-5-yl)-7H-
pyrazolo[3,4-b]pyridine (12e) Yellow solid, EA/MeOH (10/1),
1
4
72% (55 mg). H NMR (400 MHz, MeOH-d ) δ 8.67 (d, J = 7.6
Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.59 - 7.55 (m, 3H), 7.27 (dd, J
= 6.0, 7.6 Hz, 1H), 7.08 (t, J = 8.8 Hz, 2H), 6.70 (d, J = 2.0 Hz,
1
3
1
3
-Bromo-7-(4-fluorobenzyl)-7H-pyrazolo[3,4-b]pyridine (10a)
1H), 5.95 (s, 2H), 4.14 (s, 3H). C{ H} NMR (100 MHz, MeOH-
4
d ) δ 164.5 (d, J = 245.5 Hz), 151.6, 140.1, 139.9, 139.8, 139.0,
Synthesized according to the general procedure on a 1-mmol scale
and the reaction time was 64 h. Yellow solid, mp 221-223 °C,
136.8, 132.1 (d, J = 3.0 Hz), 132.1 (d, J = 9.0 Hz), 123.3, 117.0
(d, J = 22.4 Hz), 114.0, 107.2, 57.3, 38.9. HRMS (ESI) m/z:
1
EA/MeOH (10/1), 75% (231 mg). H NMR (400 MHz, MeOH-d
4
)
+
+
δ 8.58 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 7.6 Hz, 1H), 7.55 (dd, J =
.2, 8.0 Hz, 2H), 7.27 (t, J = 6.8 Hz, 1H), 7.10 (t, J = 8.8 Hz, 2H),
5
[M+H] Calcd for C17H15FN 308.1306; Found 308.1310.
5
1
3
1
5.91 (s, 2H). C{ H} NMR (100 MHz, MeOH-d
4
) δ 164.6 (d, J =
7-(4-Fluorobenzyl)-3-methyl-7H-pyrazolo[3,4-b]pyridine (12f)
1
2
=
45.9 Hz), 151.5, 141.1, 138.8, 132.2 (d, J = 8.4 Hz), 131.9 (d, J
Yellow solid, EA/MeOH (10/1), 77% (46 mg). H NMR (400
1
9
2.9 Hz), 123.4, 122.6, 117.1 (d, J = 22.1 Hz), 113.8, 56.8.
F
MHz, MeOH-d
4
) δ 8.54 (dd, J = 1.2, 7.6 Hz, 1H), 8.36 (d, J = 5.6
NMR (470 MHz, MeOH-d
4
) δ -114.68. HRMS (ESI) m/z: Calcd
Hz, 1H), 7.50 (dd, J = 5.2, 8.8 Hz, 2H), 7.11 - 7.05 (m, 3H), 5.83
7
9
+
+
13
1
for C13
H
10 BrFN
3
[M + H] = 306.0037; Found 306.0040;
4
(s, 2H), 2.63 (s, 3H). C{ H} NMR (100 MHz, MeOH-d ) δ
+
81
+
HRMS (ESI) m/z: [M + H] Calcd for C13
Found 308.0020.
H
10 BrFN
3
308.0016;
164.5 (d, J = 245.2 Hz), 151.4, 146.7, 139.3, 138.4, 132.4, 131.9
(d, J = 8.4 Hz), 124.2, 117.0 (d, J = 21.3 Hz), 111.9, 56.7, 12.3.
+
+
HRMS (ESI) m/z: [M+H] Calcd for C14
H13FN
3
242.1088;
7
-(4-Fluorobenzyl)-3-phenyl-7H-pyrazolo[3,4-b]pyridine (12a)
Found 242.1092.
1
Yellow solid, EA/MeOH (10/1), 85% (64 mg). H NMR (400
MHz, MeOH-d ) δ 8.79 (d, J = 7.6 Hz, 1H), 8.43 (d, J = 5.6 Hz,
H), 7.92 (d, J = 7.2 Hz, 2H), 7.55 (dd, J = 5.2, 8.4 Hz, 2H), 7.49
t, J = 7.6 Hz, 2H), 7.42 - 7.35 (m, 1H), 7.20 (dd, J = 6.0, 7.2 Hz,
4
7-(4-Fluorobenzyl)-3-isopropyl-7H-pyrazolo[3,4-b]pyridine
1
1
(
(12g) Yellow solid, EA/MeOH (10/1), 85% (57 mg). H NMR
(400 MHz, MeOH-d
4
) δ 8.63 (d, J = 7.2 Hz, 1H), 8.35 (d, J = 6.0
13
1
1
H), 7.08 (t, J = 8.8 Hz, 2H), 5.91 (s, 2H). C{ H} NMR (100
) δ 164.5 (d, J = 245.9 Hz), 152.1, 149.3, 139.6,
139.5, 134.7, 132.27 (d, J = 3.1 Hz), 132.0 (d, J = 8.4 Hz), 130.2,
29.4, 128.3, 122.3, 117.0 (d, J = 22.0 Hz), 113.5, 57.0. HRMS
Hz, 1H), 7.51 (dd, J = 5.2, 7.6 Hz, 2H), 7.10 - 7.04 (m, 3H), 5.84
1
3
1
MHz, MeOH-d
4
(s, 2H), 3.51 - 3.44 (m, 1H), 1.45 (d, J = 7.2 Hz, 6H). C{ H}
NMR (100 MHz, MeOH-d ) δ 164.3 (d, J = 244.7 Hz), 156.0,
4
1
151.3, 138.9, 138.6, 132.2 (d, J = 3 Hz), 131.7 (d, J = 8.9 Hz),
122.3, 116.7 (d, J = 22.3 Hz), 111.6, 56.5, 29.7, 23.0. HRMS
+
+
(ESI) m/z: [M+H] Calcd for C19
H
15FN
3
304.1245; Found
+
+
3
04.1245.
(ESI) m/z: [M+H] Calcd for C16
70.1403.
H17FN
3
270.1401; Found
2
7
-(4-Fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)-7H-
pyrazolo[3,4-b]pyridine (12b) Yellow solid, mp 332-334 °C,
3-Chloro-7-(4-fluorobenzyl)-7H-pyrazolo[3,4-b]pyridine (12h)
Synthesized according to the general procedure and the reaction
1
EA/MeOH (10/1), 86% (80 mg). H NMR (400 MHz, MeOH-d
4
)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 8
time was 32 h. Yellow solid, mp 282-284 °C, EA/MeOH (10/1),
dure and the reaction time was 24 h. Yellow solid, mp 199−201
°C, EA/MeOH (10/1), 55% (39 mg). H NMR (400 MHz, MeOH-
1
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
74% (48 mg). H NMR (400 MHz, DMSO-d
6
) δ 8.75 (d, J = 6.0
Hz, 1H), 8.53 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 5.6, 7.6 Hz, 2H),
d
4
) δ 8.94 (d, J = 7.6 Hz, 1H), 8.62 (d, J = 6.0 Hz, 1H), 7.58 (dd, J
1
3
1
7
.22 - 7.17 (m, 3H), 5.88 (s, 2H). C{ H} NMR (125 MHz,
DMSO-d ) δ 161.6 (d, J = 243.7 Hz), 148.7, 138.6, 135.4, 132.1,
30.9 (d, J = 3.7 Hz), 130.6 (d, J = 8.1 Hz), 118.2, 115.1 (d, J =
= 8.4, 5.6 Hz, 2H), 7.44 (dd, J = 7.6, 6.0 Hz, 1H), 7.10 (t, J = 8.4
1
3
1
6
Hz, 2H), 6.03 (s, 2H), 4.00 (s, 3H). C{ H} NMR (100 MHz,
MeOH-d ) δ 164.6 (d, J = 245.9 Hz), 164.3, 151.8, 140.4, 140.1,
139.9, 132.2 (d, J = 8.3 Hz), 131.9 (d, J = 3.0 Hz), 123.6, 117.1
(d, J = 22.0 Hz), 116.3, 57.6, 52.4. F NMR (376 MHz, MeOH-
d
1
2
4
19
3
0.7 Hz), 110.9, 54.1. F NMR (470 MHz, CDCl ) δ -111.35.
+
+
19
HRMS (ESI) m/z: [M+H] Calcd for C13
Found 262.0545.
H
10ClFN
3
262.0542;
+
+
4
) δ -114.5. HRMS (ESI) m/z: [M+H] Calcd for C15
3 2
H13FN O
286.0986; Found 286.0985.
7
-(4-Fluorobenzyl)-7H-pyrazolo[3,4-b]pyridine (12i) Yellow
1
solid, EA/MeOH (8/1), 48% (27 mg). H NMR (400 MHz,
MeOH-d ) δ 8.66 (d, J = 7.6 Hz, 1H), 8.49 (s, 1H), 8.45 (d, J =
.0 Hz, 1H), 7.53 (dd, J = 5.2, 8.4 Hz, 2H), 7.19 (dd, J = 6.0, 7.6
7-(4-Fluorobenzyl)-3-(trifluoromethyl)-7H-pyrazolo[3,4-
b]pyridine (12o) Synthesized according to the general procedure
and the reaction time was 60 h. Yellow solid, mp 266−268 °C,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
6
13
1
1
Hz, 1H), 7.08 (t, J = 8.8 Hz, 2H), 5.91 (s, 2H). C{ H} NMR
(100 MHz, MeOH-d ) δ 164.5 (d, J = 244 Hz), 151.0, 139.5,
139.3, 137.8, 132.3 (d, J = 3.6 Hz), 132.0 (d, J = 8.0 Hz), 124.7,
4
EA/MeOH (10/1), 40% (30 mg). H NMR (400 MHz, MeOH-d )
4
δ 8.74 (d, J = 7.6 Hz, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.58 - 7.60
(m, 2H), 7.42-7.45 (m, 1H), 7.11 (t, J = 8.0 Hz, 2H), 6.04 (s, 2H).
+
13
1
1
17.0 (d, J = 21.8 Hz), 113.2, 57.2. HRMS (ESI) m/z: [M+H]
C{ H} NMR (100 MHz, MeOH-d
151.4, 140.8, 138.7, 138.5 (q, J = 36.4 Hz), 132.3 (d, J = 7.4 Hz),
31.8 (d, J = 3.0 Hz), 123.8 (q, J = 265.6 Hz), 120.4, 117.1 (d, J
4
) δ 164.7 (d, J = 245.5 Hz),
+
3
Calcd for C13H11FN = 228.0932; Found 228.0936.
1
19
3
-Bromo-7-(4-fluorobenzyl)-4-methyl-7H-pyrazolo[3,4-
4
= 21.5 Hz), 115.7, 57.7. F NMR (376 MHz, MeOH-d ) δ -61.2,
-114.5. HRMS (ESI) m/z: [M+H] Calcd for C14
296.0805; Found 296.0813.
+
+
b]pyridine (12j) Yellow solid, mp 241-243 °C, EA/MeOH
10 4 3
H F N
1
(10/1), 72% (57 mg). H NMR (400 MHz, MeOH-d
4
) δ 8.34 (d, J
= 6.0 Hz, 1H), 7.51 (dd, J = 5.2, 8.8 Hz, 2H), 7.09 (t, J = 8.8 Hz,
1
3
1
2
H), 7.03 (d, J = 6.4 Hz, 1H), 5.80 (s, 2H), 2.93 (s, 3H). C{ H}
NMR (125 MHz, MeOH-d ) δ 164.6 (d, J = 145.5 Hz), 155.0,
51.1, 140.5, 132.1 (d, J = 3.6 Hz), 132.0 (d, J = 9.0 Hz), 121.6,
7-(4-Fluorobenzyl)-7H-pyrazolo[3,4-b]pyridine-3-carbonitrile
(12p) Synthesized according to the general procedure and the
reaction time was 120 h. Yellow solid, mp 275−276 °C,
EA/MeOH (10/1), 8% (5 mg). H NMR (500 MHz, Chloroform-
d) δ 8.62 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 6.0 Hz, 1H), 7.58 - 7.55
(m, 2H), 7.28 (dd, J = 8.0, 6.0 Hz, 1H), 7.10 (t , J = 8.5, 2H), 6.06
4
1
1
19
1
20.6, 117.0 (d, J = 21.8 Hz), 115.9, 56.3, 19.1. F NMR (470
+
MHz, MeOH-d
C
[M+H] Calcd for C14
4
) δ -114.89. HRMS (ESI) m/z: Calcd for [M+H]
322.0193; Found 320.0189; HRMS (ESI) m/z:
7
9
+
14
H
12 BrFN
3
+
81
+
13
1
H
12 BrFN
3
322.0173; Found 322.0170.
(s, 2H). C{ H} NMR (100 MHz, Chloroform-d) δ 163.4 (d, J =
48.4 Hz), 149.4, 135.8, 135.7, 131.4 (d, J = 9.0 Hz), 128.7 (d, J
= 3.0 Hz), 124.7, 121.9, 116.6 (d, J = 21.5 Hz), 114.4, 113.6,
2
5
-Chloro-7-(4-fluorobenzyl)-3-methyl-7H-pyrazolo[3,4-
1
9
b]pyridine (12k) Yellow solid, EA/MeOH (10/1), 45% (31 mg).
56.8. F NMR (471 MHz, Chloroform-d) δ -110.5. HRMS (ESI)
m/z: [M+H] Calcd for C14H10FN 253.0884; Found 253.0897.
4
1
+
+
H NMR (400 MHz, MeOH-d
4
) δ 8.65 (d, J = 2.0 Hz, 1H), 8.61
(
d, J = 1.4 Hz, 1H), 7.55 (dd, J = 5.2, 8.8 Hz, 2H), 7.10 (t, J = 8.8
1
3
1
Hz, 2H), 5.83 (s, 2H), 2.62 (s, 3H). C{ H} NMR (100 MHz,
MeOH-d ) δ 164.6 (d, J = 245.5 Hz), 150.2, 146.9, 138.1, 137.7,
32.1 (d, J = 8.2 Hz), 131.9 (d, J = 3.0 Hz), 124.6, 118.4, 117.0
7-Benzyl-3-isopropyl-7H-pyrazolo[3,4-b]pyridine (14a) Yellow
solid, EA/MeOH (10/1), 85% (53 mg). H NMR (400 MHz,
MeOH-d ) δ 8.62 (d, J = 7.2 Hz, 1H), 8.32 (d, J = 6.4 Hz, 1H),
4
7.42 (d, J = 6.0 Hz, 2H), 7.31 (d, J = 6.8 Hz, 3H), 7.07 (t, J = 6.8
Hz, 1H), 5.85 (s, 2H), 3.51 - 3.44 (m, 1H), 1.44 (d, J = 6.8 Hz,
1
4
1
+
(d, J = 22.4 Hz), 57.2, 12.2. HRMS (ESI) m/z: [M+H] Calcd for
+
C
14
H
12ClFN
3
276.0698; Found 276.0699.
1
3
1
6
4
H). C{ H} NMR (100 MHz, MeOH-d ) δ 156.1, 151.6, 139.3,
7
-(4-Fluorobenzyl)-6-methyl-7H-pyrazolo[3,4-b]pyridine (12l)
138.8, 136.3, 130.2, 130.0, 129.7, 122.4, 111.8, 57.5, 29.7, 23.3.
HRMS (ESI) m/z: [M+H] Calcd for C16
252.1496.
+
+
Synthesized according to the general procedure except that the
reaction time was 32 h. Yellow solid, EA/MeOH (10/1), 9% (5.5
H
18
N
3
252.1495; Found
1
mg). H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.28 (d, J
=
7.6 Hz, 1H), 7.31 – 7.25 (m, 2H), 6.99 (t, J = 8.6 Hz, 2H), 6.80
7-(4-Chlorobenzyl)-3-isopropyl-7H-pyrazolo[3,4-b]pyridine
(14b) Yellow solid, EA/MeOH (10/1), 86% (61 mg). H NMR
(400 MHz, MeOH-d ) δ 8.62 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 6.0
4
Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.08
(t, J = 6.8 Hz, 1H), 5.83 (s, 2H), 3.49 - 3.42 (m, 1H), 1.43 (d, J =
7.2 Hz, 6H). C{ H} NMR (100 MHz, MeOH-d
1
23.3. HRMS (ESI) m/z: [M+H] Calcd for C16
Found 286.1109.
1
3
1
1
(d, J = 7.6 Hz, 1H), 6.08 (s, 2H), 2.67 (s, 3H). C{ H} NMR (151
MHz, Chloroform-d) δ 162.8 (d, J = 247.9 Hz), 152.1, 146.3,
1
2
C
37.1, 136.2, 130.0, 129.6 (d, J = 8.3 Hz), 121.8, 116.3 (d, J =
+
1.8 Hz), 113.0, 52.0, 20.0. HRMS (ESI) m/z: [M+H] Calcd for
+
13
1
14
H13FN
3
242.1093; Found 242.1101.
4
) δ 156.2, 151.5,
39.3, 138.9, 135.8, 135.1, 131.2, 130.2, 122.5, 111.8, 56.8, 29.7,
+
+
3
-Bromo-7-(4-fluorobenzyl)-7H-pyrrolo[2,3-b]pyridine (12m)
H
3
17ClN 286.1106;
Synthesized according to the general procedure and the reaction
1
time was 3 h. Yellow solid, PE/EA (1/1), 75% (57 mg). H NMR
(400 MHz, MeOH-d
4
) δ 8.08 (d, J = 7.2 Hz, 2H), 7.64 (s, 1H),
4-((3-Isopropyl-7H-pyrazolo[3,4-b]pyridin-7-
yl)methyl)benzonitrile (14c) Yellow solid, EA/MeOH (10/1),
88% (61 mg). H NMR (400 MHz, MeOH-d ) δ 8.70 (d, J = 7.6
4
Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.54
(d, J = 8.4 Hz, 2H), 7.15 (dd, J = 6.0, 7.2 Hz, 1H), 5.95 (s, 2H),
3.52 - 3.45 (m, 1H), 1.44 (d, J = 7.2 Hz, 6H). C{ H} NMR (100
MHz, MeOH-d ) δ 156.3, 151.4, 141.7, 139.9, 139.5, 134.0,
130.1, 122.6, 119.4, 113.6, 112.04, 57.1, 29.6, 23.2. HRMS (ESI)
7
.39 (dd, J = 5.2, 8.4 Hz, 2H), 7.07 - 7.00 (m, 3H), 5.81 (s, 2H).
1
3
1
1
C{ H} NMR (100 MHz, MeOH-d
148.1, 143.4, 133.4, 132.8 (d, J = 3.0 Hz), 132.3, 131.5 (d, J =
.2 Hz), 129.6, 116.9 (d, J = 21.6 Hz), 112.2, 89.0, 57.8. HRMS
4
) δ 164.3 (d, J = 244.7 Hz),
8
7
9
+
+
13
1
(ESI) m/z: Calcd for C14
H
11 BrFN
2
[M+H] = 305.0084; Found
+
81
+
3
3
05.0082; HRMS (ESI) m/z: [M+H] Calcd for C14
07.0064; Found 307.0063.
H
11 BrFN
2
4
+
+
17 4
m/z: [M+H] Calcd for C17H N 277.1448; Found 277.1449.
Methyl
7-(4-fluorobenzyl)-7H-pyrazolo[3,4-b]pyridine-3-
carboxylate (12n) Synthesized according to the general proce-
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The Journal of Organic Chemistry
3
-Isopropyl-7-(4-methylbenzyl)-7H-pyrazolo[3,4-b]pyridine
121.0, 111.8 (d, J = 9.7 Hz), 56.6, 29.7, 29.6, 23.3. HRMS (ESI)
m/z: [M+H] Calcd for C12H N 202.1339; Found 202.1337.
16 3
1
+
+
1
2
3
4
5
6
7
8
9
(14d) Yellow solid, EA/MeOH (10/1), 91% (60 mg). H NMR
400 MHz, MeOH-d ) δ 8.59 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 6.0
Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.04
(
4
Ethyl 2-(3-isopropyl-7H-pyrazolo[3,4-b]pyridin-7-yl)acetate
1
(t, J = 6.8 Hz, 1H), 5.78 (s, 2H), 3.50 - 3.43 (m, 1H), 2.24 (s, 3H),
(14j) Yellow solid, EA/MeOH (10/1), 81% (50 mg). H NMR
1
3
1
1
1
1
.43 (d, J = 7.2 Hz, 6H). C{ H} NMR (100 MHz, MeOH-d
4
) δ
(500 MHz, CHLOROFORM-d) δ 8.34 (d, J = 7.5 Hz, 1H), 7.83
(d, J = 6.0 Hz, 1H), 6.86 (dd, J = 6.5, 7.5 Hz, 1H), 5.44 (s, 2H),
4.22 (q, J = 7.0 Hz, 2H), 3.51 - 3.44 (m, 1H), 1.45 (d, J = 7.0 Hz,
56.1, 151.6, 140.2, 139.1, 138.6, 133.2, 130.8, 129.8, 122.4,
+
11.8, 57.2, 29.7, 23.3, 21.3. HRMS (ESI) m/z: [M+H] Calcd for
+
13
1
C
17
H
20
N
3
266.1652; Found 266.1650.
6H), 1.26 (t, J = 7.5 Hz, 3H). C{ H} NMR (125 MHz, MeOH-
) δ 166.5, 155.6, 150.3, 136.2, 136.0, 122.3, 108.4, 62.5, 52.7,
d
4
+
7
-(2-Chlorobenzyl)-3-isopropyl-7H-pyrazolo[3,4-b]pyridine
28.6, 22.7, 14.0. HRMS (ESI) m/z: [M+H] Calcd for
C
1
+
(
(
=
8
14e) Yellow solid, EA/MeOH (10/1), 83% (59 mg). H NMR
400 MHz, MeOH-d ) δ 8.68 (dd, J = 0.8, 7.6 Hz, 1H), 8.14 (d, J
6.0 Hz, 1H), 7.50 (dd, J = 0.8, 8.0 Hz, 1H), 7.37 (dt, J = 1.6,
.4 Hz, 1H), 7.28 (dt, J = 1.2, 7.6 Hz, 1H), 7.18 - 7.16 (m, 1H),
7.09 (dd, J = 6.4, 7.6 Hz, 1H), 5.98 (s, 2H), 3.55 - 3.45 (m, 1H),
13
H
18
N
3
O
2
248.1394; Found 248.1396.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
3-Isopropyl-7-methyl-7H-pyrazolo[3,4-b]pyridine (14k) Yel-
1
low solid, EA/MeOH (10/1), 90% (39 mg). H NMR (400 MHz,
MeOH-d ) δ 8.86 (d, J = 7.6 Hz, 1H), 8.58 (d, J = 5.6 Hz, 1H),
7.30 (dd, J = 6.0, 7.6 Hz, 1H), 4.37 (s, 3H), 3.63 - 3.54 (m, 1H),
4
1
3
1
1.46 (d, J = 6.8 Hz, 6H). C{ H} NMR (100 MHz, MeOH-d
1
1
4
) δ
1
3
1
56.3, 151.7, 139.2, 138.9, 135.2, 133.1, 131.8, 131.8, 131.3,
1.49 (d, J = 7.2 Hz, 6H). C{ H} NMR (100 MHz, MeOH-d
4
) δ
+
28.9, 122.5, 111.7, 55.2, 29.7, 23.3. HRMS (ESI) m/z: [M+H]
154.5, 150.9, 143.6, 140.7, 120.5, 113.8, 41.9, 29.2, 22.9. HRMS
+
+
+
Calcd for C16
H17ClN
3
286.1106; Found 286.1110.
(ESI) m/z: [M+H] Calcd for C10
76.1182.
H
14
N
3
176.1182; Found
1
7
-(2,4-Difluorobenzyl)-3-isopropyl-7H-pyrazolo[3,4-
b]pyridine (14f) Yellow solid, EA/MeOH (10/1), 84% (60 mg).
7-Ethyl-3-isopropyl-7H-pyrazolo[3,4-b]pyridine (14l) Yellow
solid, EA/MeOH (10/1), 81% (38 mg). H NMR (400 MHz,
1
1
H NMR (400 MHz, MeOH-d
4
) δ 8.64 (d, J = 7.6 Hz, 1H), 8.29
(
d, J = 6.0 Hz, 1H), 7.56 - 7.53 (m, 1H), 7.11-7.09 (m, 1H), 7.05 -
4
MeOH-d ) δ 8.64 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 6.4 Hz, 1H),
6
1
d
.99 (m, 1H), 7.02 - 6.94 (m, 1H), 5.89 (s, 2H), 3.52 - 3.41 (m,
7.11 (dd, J = 6.0, 7.2 Hz, 1H), 4.73 (q, J = 7.2 Hz, 2H), 3.54 -
3.45 (m, 1H), 1.62 (t, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 6H).
1
3
1
H), 1.44 (d, J = 7.2 Hz, 6H). C{ H} NMR (100 MHz, MeOH-
) δ 165.0 (dd, J = 248.5, 11.9 Hz), 162.8 (dd, J = 248.4, 11.9
13
1
4
C{ H} NMR (100 MHz, MeOH-d
4
) δ 155.7, 151.0, 139.1,
Hz), 156.3, 151.5, 139.3, 139.1, 133.9, 122.6, 119.2 (dd, J = 14.6,
4.1 Hz), 113.0 (dd, J = 21.7, 3.7 Hz), 111.7, 105.4 (t, J = 25.6
138.4, 121.9, 111.8, 50.5, 29.5, 23.2, 15.2. HRMS (ESI) m/z:
+
+
[M+H] Calcd for C11
16 3
H N 190.1339; Found 190.1337.
+
Hz), 51.4, 29.7, 23.2. HRMS (ESI) m/z: [M+H] Calcd for
+
C
16
H
16
F
2
N
3
288.1307; Found 288.1305.
3,7-Diisopropyl-7H-pyrazolo[3,4-b]pyridine (14m) Ten equiv
o
2
-iodopropane was used and the reaction was stirred at 80 C for
1
7
-(1-(4-Fluorophenyl)ethyl)-3-isopropyl-7H-pyrazolo[3,4-
96 h. Yellow solid, EA/MeOH (10/1), 79% (40 mg). H NMR
(400 MHz, MeOH-d ) δ 8.78 (d, J = 7.6 Hz, 1H), 8.70 (d, J = 6.0
b]pyridine (14g) Three equivalents of 1-fluoro-4-(1-
4
o
iodoethyl)benzene was used and the reaction was stirred at 60 C
Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 5.64 - 5.53 (m, 1H), 3.61 - 3.48
(m, 1H), 1.72 (d, J = 6.4 Hz, 6H), 1.48 (d, J = 7.2 Hz, 6H).
1
for 48 h. Yellow solid, EA/MeOH (10/1), 65% (46 mg). H NMR
1
3
1
(500 MHz, MeOH-d
4
) δ 8.65 (dd, J = 1.0, 7.5 Hz, 1H), 8.33 -
4
C{ H} NMR (100 MHz, MeOH-d ) δ 154.7, 150.4, 139.7 (d, J
8
=
.32 (m, 1H), 7.55 - 7.53 (m, 2H), 7.14 - 7.12 (m, 3H), 6.73 (q, J
= 7.5 Hz), 138.0 (d, J = 8.2 Hz), 121.1, 113.6 (d, J = 10.4 Hz),
+
7.0 Hz, 1H), 3.55 - 3.46 (m, 1H), 2.05 (d, J = 7.0 Hz, 3H), 1.47
56.7, 29.3, 29.2, 23.1, 23.1, 22.2. HRMS (ESI) m/z: [M+H]
1
3
1
+
(d, J = 7.0 Hz, 6H). C{ H} NMR (100 MHz, MeOH-d
4
) δ 164.4
Calcd for C12
H
18
N
3
204.1495; Found 204.1495.
(
2
1
d, J = 245.5 Hz), 156.0, 151.4, 138.8, 138.7, 136.6, 136.0 (d, J =
.9 Hz), 130.9 (t, J = 7.8 Hz), 122.2, 117.1 (d, J = 22.4 Hz),
3-Isopropyl-7-(2,2,2-trifluoroethyl)-7H-pyrazolo[3,4-
17.0 (d, J = 21.6 Hz), 112.3 (d, J = 6.0 Hz), 61.1, 29.6, 23.2,
b]pyridine (14n) Yellow solid, EA/MeOH (10/1), 75% (46 mg).
+
1
20.1. HRMS (ESI) m/z: [M+H] Calcd for C17
Found 284.1559.
H19FN
3
284.1558;
4
H NMR (400 MHz, MeOH-d ) δ 8.75 (d, J = 7.6 Hz, 1H), 8.36
(d, J = 6.4 Hz, 1H), 7.16 (dd, J = 6.4, 7.6 Hz, 1H), 5.52 (q, J =
.8 Hz, 2H), 3.52 - 3.45 (m, 1H), 1.46 (d, J = 7.2 Hz, 6H).
8
1
3
1
7
-(4-Fluorophenethyl)-3-isopropyl-7H-pyrazolo[3,4-
4
C{ H} NMR (100 MHz, MeOH-d ) δ 157.0, 151.7, 140.5,
b]pyridine (14h) Six equivalents of 1-(2-bromoethyl)-4-
140.2, 125.0 (q, J = 278.2 Hz), 123.3, 111.6, 53.3 (q, J = 35.0
o
+
+
fluorobenzene was used and the reaction was stirred at 80 C for
Hz), 29.7, 23.2. HRMS (ESI) m/z: [M+H] Calcd for C11
H
13
F
3
N
3
1
7
2 h. Yellow solid, EA/MeOH (10/1), 71% (50 mg). H NMR
244.1056; Found 244.1060.
(500 MHz, MeOH-d ) δ 8.62 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 6.0
4
Hz, 1H), 7.13 - 7.10 (m, 2H), 6.98 - 6.94 (m, 3H), 4.89 (t, J = 7.5
Hz, 2H), 3.54 - 3.48 (m, 1H), 3.36 - 3.28 (m, 2H), 1.48 (d, J = 7.0
1
3
1
Hz, 6H). C{ H} NMR (100 MHz, MeOH-d
4
) δ 163.4 (d, J =
ASSOCIATED CONTENT
Supporting Information
2
1
3
42.5 Hz), 156.0, 151.0, 139.7, 138.7, 134.4 (d, J = 3.7 Hz),
31.9 (d, J = 7.4 Hz), 122.1, 116.5 (d, J = 21.5 Hz), 111.2, 59.8,
+
5.1, 29.7, 29.6, 23.3. HRMS (ESI) m/z: [M+H] Calcd for
+
C
17
H19FN
3
284.1558; Found 284.1558.
The Supporting Information is available free of charge on the
ACS Publications website.
7
-Allyl-3-isopropyl-7H-pyrazolo[3,4-b]pyridine (14i) Yellow
1
solid, EA/MeOH (10/1), 94% (47 mg). H NMR (400 MHz,
MeOH-d ) δ 8.67 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 6.4 Hz, 1H),
.13 (dd, J = 6.4, 7.6 Hz, 1H), 6.24 - 6.17 (m, 1H), 5.38 - 5.29 (m,
NMR spectra for all products (PDF)
4
7
4
AUTHOR INFORMATION
Corresponding Authors
13
1
H), 3.55 - 3.42 (m, 1H), 1.47 (d, J = 6.8 Hz, 6H). C{ H} NMR
) δ 156.0, 151.3, 139.3, 138.8, 132.3, 122.2,
(100 MHz, MeOH-d
4
*
Email: jianming.bao@merck.com; chen.cheng1@merck.com.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 8
ceptor antagonists (DORAs). Bioorg. Med. Chem. Lett. 2015, 25,
5555−5560.
6) Mittendorf, J.; Weigand, S.; Alonso-Alija, C.; Bischoff, E.;
Feurer, A.; Gerisch, M.; Kern, A.; Knorr, A.; Lang, D.; Muenter, K.;
Radtke, M.; Schirok, H.; Schlemmer, K. H.; Stahl, E.; Straub, A.;
Wunder, F.; Stasch, J. P. Discovery of Riociguat (BAY 63‐2521): A
Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treat-
ment of Pulmonary Hypertension. ChemMedChem. 2009, 4, 853−865.
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
Mengfen Lin of MRL South San Francisco for NMR support.
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