Gas-phase synthesis of pyrazolo[3,4- b ]pyridin-4-ones

Article abstract of DOI:10.1055/s-0034-1378666

Flash vacuum pyrolysis (FVP) at 500-600 °C of 1-substituted pyrazolylaminomethylene derivatives of Meldrum's acid provides 1-substituted pyrazolo[3,4-b]pyridin-4-ones in high yields. If the 1-substituent is a tert-butyl group, FVP at 750-850 °C causes elimination of 2-methyl-1-propene to give the parent pyrazolo[3,4-b]pyridin-4-one.

Full text of DOI:10.1055/s-0034-1378666

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 242–248
paper
242
M. Mackay et al.
Paper
Synthesis
Gas-Phase Synthesis of Pyrazolo[3,4-b]pyridin-4-ones
Pyrazolo[3,4-b]pyridin-4-ones
Martha Mackay
Andrew Nortcliffe
Hamish McNab1
O
N
O
H
N
FVP
500 °C
Alison N. Hulme*
N
N
H
tBu
O
NtBu
O
EastCHEM School of Chemistry, The University of Edinburgh,
West Mains Road, Edinburgh EH9 3JJ, UK
Alison.Hulme@ed.ac.uk
N
O
O
FVP
750 °C
N
N
N
H
H
Received: 18.06.2014
Accepted after revision: 18.08.2014
Published online: 02.10.2014
trogen atom to provide a useful route to the pyrazolo[1,5-
a]pyrimidine system 5 (Scheme 1).5 Clearly this route must
be blocked to provide pyrazolo[3,4-b]pyridin-4-ones.
DOI: 10.1055/s-0034-1378666; Art ID: ss-2014-n0372-op
O
H
H
N
N
FVP
Abstract Flash vacuum pyrolysis (FVP) at 500–600 °C of 1-substituted
pyrazolylaminomethylene derivatives of Meldrum’s acid provides 1-sub-
stituted pyrazolo[3,4-b]pyridin-4-ones in high yields. If the 1-substitu-
ent is a tert-butyl group, FVP at 750–850 °C causes elimination of 2-
methyl-1-propene to give the parent pyrazolo[3,4-b]pyridin-4-one.
O
NR1
NR1
N
N
O
O
3
O
O
N
N
Key words gas-phase reactions, pericyclic reactions, heterocycles,
Meldrum’s acid, medicinal chemistry
NR1
N
N
N
N
R1
4
4
O
R1 = alkyl
or aryl
O
R1 = H
There are very few references to 1-unsubstituted pyra-
zolo[3,4-b]pyridin-4-ones 1 in the literature2 and all known
derivatives except the parent compound 1 (R = R′ = H) have
a substituent in the 6-position. Potential functionalization
of the 4-position (e.g., via the triflate or the 4-chloro com-
pound) would provide 4-substituted pyrazolo[3,4-b]pyri-
dines 2 (Figure 1), which have shown diverse application in
medicinal chemistry.3 On the other hand, substitution at
the 1-position generally results in loss of biological activity
due to the disruption of the hydrogen bonding regime.4
H
N
N
N
N
N
H
5
O
R1
1 (R1 = alkyl or aryl)
Scheme 1
The present work therefore had a range of objectives.
First, 3 (R1 = alkyl or aryl) were synthesized and pyrolyzed
to ensure that, in the absence of the pyrazole NH, cycliza-
tion onto the adjacent carbon atom to give 1 (R = 1-alkyl or
1-aryl) would take place (Scheme 1), as observed in many
related systems.6 Second, we explored the design of a ther-
mal N-protecting group, which would remain at low fur-
nace temperatures, but be selectively removed at higher
furnace temperatures to provide N-unsubstituted pyrazol-
opyridinones 1 (R1 = H). If the previous stages were success-
ful, we aimed finally to functionalize the 4-position of the
pyrazolo[3,4-b]pyridin-4-ones to establish that the route
has significant potential for the synthesis of pyrazolo[3,4-
b]pyridines 2.
O
X
3
4
R
R
5
6
2
R′
N
R′
N
N
H
N
1
N
H
N
7
H
1
2
Figure 1 1-Unsubstituted pyrazolo[3,4-b]pyridin-4-ones 1 and 4-sub-
stituted pyrazolo[3,4-b]pyridines 2
In earlier work, we explored a potential route to 1 by
flash vacuum pyrolysis (FVP) of Meldrum’s acid derivatives
[e.g., 3 (R1 = H)], but cyclization of the imidoylketene inter-
mediate 4 (R1 = H) occurred exclusively at the adjacent ni-
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M. Mackay et al.
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Synthesis
The 1-substituted and 1,3-disubstituted 3-aminopyra-
zoles 6a–f (Figure 2) were either commercially available or
were synthesized by known methods. Compounds 6c,7 6e,8
and 6f9a are known only in patents or are formed in poor
yield;9b their full characterization data are given here. Com-
pound 6c was formed as a 5:1 mixture of 6c and its 1-tert-
butyl-3-amino isomer, which was taken on to the next
stage without purification. Reaction of 6a–f with meth-
oxymethylene Meldrum’s acid in acetonitrile gave the ami-
nomethylene derivatives 3a–f (Figure 2) in 89–99% yield
and (generally) high purity. Compound 3c was purified by
recrystallization before pyrolysis.
N
+
HN
H
N
N
8
7
Scheme 2
R2
R2
O
O
O
O
N
N
N
R1
N
R1
NH2
N
H
6a R1 = Me, R2 = H
6b R1 = Ph, R2 = Me
6c R1 = t-Bu, R2 = H
6d R1 = t-Bu, R2 = Me
6e R1 = t-Bu, R2 = Ph
6f R1 = R2 = t-Bu
3a R1 = Me, R2 = H
3b R1 = Ph, R2 = Me
3c R1 = t-Bu, R2 = H
3d R1 = t-Bu, R2 = Me
3e R1 = t-Bu, R2 = Ph
3f R1 = R2 = t-Bu
Figure 3 Temperature-conversion plot for FVP of 7
Figure 2 1,3-Disubstituted 3-aminopyrazoles 6 and aminomethylene
derivatives 3
obtained as more complex mixtures.12 N-Unsubstituted
pyrazolopyridinones show exceptionally broad peaks in
their NMR spectra due to tautomerization, but the two NH
resonances at ca. δH = 12.8–13.8 and 11.5–11.8 are charac-
teristic, as previously reported.2a
FVP of 3a and 3b at 600 °C (0.03 Torr) gave 1-methylpyr-
azolo[3,4-b]pyridin-4-one (1aa) (92%) and its 3-methyl-1-
phenyl analogue 1ba (95%), respectively, as involatile solids
that crystallized at the exit point of the furnace. It is clear,
therefore, that blocking the 1-position of the pyrazole has
the effect of diverting the cyclization to the adjacent carbon
atom to provide the target pyrazolopyridinones.
O
R2
N
N
N
H
R1
In order to access the 1-unsubstituted pyrazolo[3,4-
b]pyridines 1 (R1 = H), a thermally removable N-protecting
group was required. If a retro-ene reaction is possible, an N-
tert-butyl group is ideal because the only co-product is 2-
methyl-1-propene. We have exploited this in the pyridazin-
3-one series10 and it is also known that N-tert-butylpyra-
zole (7) loses 2-methyl-1-propene at high temperatures
(Scheme 2).11 A temperature profile of this reaction (Figure
3) shows that, in our apparatus, at temperatures below
600 °C the N-alkyl product 7 is formed exclusively whereas
at temperatures above 850 °C, only the deprotected product
8 was formed. It was therefore anticipated that FVP of 3c–f
in the range 500–600 °C should provide the N-tert-butyl
products 1 (R1 = t-Bu) whereas FVP in the range 750–850 °C
should provide the deprotected products 1 (R1 = H).
1aa R1 = Me, R2 = H
1ba R1 = Ph, R2 = Me
1ca R1 = t-Bu, R2 = H
1da R1 = t-Bu, R2 = Me
1ea R1 = t-Bu, R2 = Ph
1fa R1 = R2 = t-Bu
1cb R1 = H, R2 = H
1db R1 = H, R2 = Me
1eb R1 = H, R2 = Ph
1fb R1 = H, R2 = t-Bu
Figure 4 Pyrazolopyridinones 1
As an alternative to the one-pass cyclization-deprotec-
tion described above, the protecting group can be retained
prior to functionalization of the 4-oxo substituent. This
strategy is illustrated for the 3-phenyl series 1e, which was
chosen as it might prove unreactive owing to peri interac-
tions with the 3-substituent.
Thus, treatment of 1ea with phosphoryl chloride gave
the 4-chloro compound 9 (99%), which could either be ther-
mally deprotected to 10 (87%), or reacted further. For exam-
ple, reaction of 9 with pyrrolidine in the absence of a cata-
lyst provided a low yield of the pyrrolidino compound 11
(37%); alternatively, reaction with aniline under Buchwald–
These predictions were borne out in practice. FVP of 3c–
f at 500 °C gave the pyrazolopyridinones 1ca, 1da, 1ea, and
1fa (Figure 4) in 83–97% yields and at 750–850 °C gave the
deprotected products 1cb and 1db in 67–82% yields whilst
the more highly substituted derivatives 1eb and 1fb were
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M. Mackay et al.
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Synthesis
Hartwig conditions gave the anilino compound 12 (87%),
HRMS: m/z calcd for C7H13N3 (M+): 139.1104; found: 139.1103.
which could be thermally deprotected to 13 (72%) (Scheme
3).
5-Amino-1-tert-butyl-3-phenyl-1H-pyrazole (6e)8
A solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) in
EtOH (10 mL) was added to a slurry of tert-butylhydrazine hydrochlo-
ride (2.6 g, 20.7 mmol) in EtOH (35 mL) and the solution was heated
to reflux with stirring for 18 h. The solution was cooled, concentrated
and the residue was partitioned between sat. aq NaHCO3 (30 mL) and
EtOAc (30 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (2 × 20 mL). The organic layers were com-
bined, washed with brine (20 mL), dried (MgSO4), and the solvent re-
moved in vacuo to give 6e as a pale yellow solid; yield: 2.2 g (97%);
mp 100–102 °C.
O
Cl
N
NHPh
N
Ph
N
Ph
N
Ph
N
PhNH2
t-BuONa
POCl3
Pd2(dba)3
dppp
N
N
N
N
H
t-Bu
t-Bu
t-Bu
9
1ea
12
FVP
FVP
Cl
Ph
N
NHPh
H
Ph
N
1H NMR (DMSO-d6): δ = 7.64 (d, 3J = 7.4 Hz, 2 H), 7.33 (t, 3J = 7.4 Hz, 2
H), 7.22 (t, 3J = 7.4 Hz, 1 H), 5.79 (s, 1 H), 4.97 (s, 2 H), 1.58 (s, 9 H).
N
N
N
N
H
N
Ph
N
13C NMR (DMSO-d6): δ = 148.1 (Cq), 146.1 (Cq), 135.0 (Cq), 128.8 (2
CH), 127.1 (CH), 125.0 (2 CH) 89.2 (CH), 58.3 (Cq), 40.1 (3 CH3).
MS: m/z (%) = 215 (M+, 25), 159 (100).
HRMS: m/z calcd for C13H17N3 (M+): 215.1417; found: 215.1416.
N
10
H
13
N
N
t-Bu
11
5-Amino-1,3-di-tert-butyl-1H-pyrazole (6f)9
Scheme 3
A solution of 4,4-dimethyl-3-oxovaleronitrile (1.75 g, 14.0 mmol) in
EtOH (10 mL) was added to a slurry of tert-butylhydrazine hydrochlo-
ride (3.5 g. 28.1 mmol) in EtOH (35 mL) and the solution was heated
to reflux with stirring for 18 h. The solution was cooled, concentrated,
and the residue was partitioned between sat. aq NaHCO3 (30 mL) and
EtOAc (30 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (2 × 20 mL). The organic layers were com-
bined, washed with brine (20 mL), dried (MgSO4), and the solvent re-
moved to give 6f as a pale orange solid; yield: 1.8 g (66%); mp 67–
69 °C (Lit.9a mp 64–66 °C).
In conclusion, the work described here has provided a
flexible gas-phase route to pyrazolo[3,4-b]pyridin-4-ones
and pyrazolo[3,4-b]pyridines. An important feature of the
strategy is the use of an N-tert-butyl group, which may be
retained at low furnace temperatures (allowing functional-
ization of the 4-oxo group) or removed at high furnace tem-
peratures to provide a one-pass route to N-unsubstituted
analogues.
1H NMR (CDCl3): δ = 5.48 (s, 1 H), 3.46 (s, 2 H), 1.27 (s, 18 H).
13C NMR (CDCl3): δ = 157.8 (Cq), 144.1 (Cq), 90.2 (CH), 58.2 (Cq), 44.7
(Cq), 30.4 (3 CH3), 29.5 (3 CH3).
1H and 13C NMR spectra were recorded at 500 or 250 MHz and 125 or
63 MHz, respectively, unless otherwise stated. Chemical shifts are
given in ppm relative to TMS. Mass spectra were recorded under elec-
tron impact conditions.
Spectra differ significantly from those reported,9b but were recorded
in a different solvent.
MS: m/z (%) = 195 (M+, 29), 139 (63), 124 (100).
HRMS: m/z calcd for C11H21N3 (M+): 195.1730; found: 175.1728.
5-Amino-1-tert-butyl-1H-pyrazole (6c)7
Meldrum’s Acid Derivatives; General Procedure
tert-Butylhydrazine hydrochloride (5.99 g, 48.1 mmol) was added to
EtOH (60 mL) to form a slurry. To this was added NaOAc (7.93 g, 96.7
mmol) and 2-chloroacrylonitrile (5 mL, 62.6 mmol). The solution was
heated to 80 °C for 18 h, cooled, and the solvent removed in vacuo.
The residue was slowly diluted with distilled H2O (35 mL) and parti-
tioned between sat. aq NaHCO3 (40 mL) and EtOAc (40 mL). The or-
ganic layer was separated and the aqueous layer was extracted with
EtOAc (2 × 20 mL). The organic layers were combined, washed with
brine (20 mL), dried (MgSO4), and the solvent removed in vacuo to af-
ford a red oil; yield: 7.95 g (91%); bp 93–94 °C/0.9 Torr (yellow liquid).
The product was a 5:1 mixture of the title compound 6c and its 1-
tert-butyl-3-amino isomer. The crude product was used to prepare
the Meldrum’s acid derivative 3c, which was purified by recrystalliza-
tion (see below).
5-(Methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.5 g,
2.9 mmol) was added to a stirred solution of the 5-aminopyrazole 6
(2.9 mmol) in MeCN (10 mL). After stirring for 1 h, the solvent was
removed in vacuo to complete the precipitation of the product.
5-(1-Methyl-1H-pyrazol-5-ylaminomethylene)-2,2-dimethyl-1,3-
dioxane-4,6-dione (3a)
Treatment of 6a using the general procedure gave 3a; yield: 0.71 g
(98%); yellow solid; mp 144 °C (MeOH).
1H NMR (CDCl3): δ = 11.28 (d, 3J = 13.3 Hz, 1 H), 8.34 (d, 3J = 13.3 Hz, 1
H), 7.34 (d, 3J = 2.1 Hz, 1 H), 6.18 (d, 3J = 2.1 Hz, 1 H), 3.85 (s, 3 H), 1.75
(s, 6 H).
13C NMR (CDCl3): δ = 165.7 (Cq), 162.6 (Cq), 154.7 (CH), 139.1 (CH),
138.0 (Cq), 105.6 (Cq), 95.3 (CH), 88.9 (Cq), 35.4 (CH3), 27.1 (2 CH3).
MS: m/z (%) = 251 (M+, 16), 193 (100), 149 (14), 122 (40).
1H NMR (CDCl3): δ = 7.21 (d, 3J = 1.8 Hz, 1 H), 5.57 (d,3J = 1.8 Hz, 1 H),
3.60 (br s, 2 H), 1.65 (s, 9 H).
13C NMR (CDCl3): δ = 144.5 (Cq), 136.6 (CH), 94.1 (CH), 58.5 (Cq), 29.3
(3 CH3).
Anal. Calcd for C11H13N3O4: C, 52.6; H, 5.2; N, 16.75. Found: C, 52.65;
H, 5.35; N, 16.8.
MS: m/z (%) = 139 (M+, 45), 83 (M – C4H10, 100).
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M. Mackay et al.
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Synthesis
5-(3-Methyl-1-phenyl-1H-pyrazol-5-ylaminomethylene)-2,2-di-
1H NMR (CDCl3): δ = 11.47 (d, 3J = 13.1 Hz, 1 H), 8.35 (d, 3J = 13.1 Hz, 1
methyl-1,3-dioxane-4,6-dione (3b)
H), 6.08 (s, 1 H), 1.78 (s, 6 H), 1.67 (s, 9 H), 1.28 (s, 9 H).
13C NMR (CDCl3): δ = 165.9 (Cq), 163.1 (Cq), 158.9 (Cq), 154.6 (CH),
137.0 (Cq), 105.5 (Cq), 94.0 (CH), 87.8 (Cq), 59.8 (Cq), 32.3 (Cq), 30.3 (3
CH3), 29.9 (3 CH3), 27.1 (2 CH3).
Treatment of 6b using the general procedure gave 3b; yield: 0.90 g
(95%); yellow solid; mp 167 °C (MeOH).
1H NMR (CDCl3): δ = 11.45 (d, 3J = 13.4 Hz, 1 H), 8.38 (d, 3J = 13.4 Hz, 1
MS: m/z (%) = 349 (M+, 24), 291 (100), 217 (27), 202 (45), 176 (56).
HRMS: m/z calcd for C18H27N3O4 (M+): 349.1996; found: 349.2000.
H), 7.56–7.42 (m, 5 H), 6.17 (s, 1 H), 2.34 (s, 3 H), 1.71 (s, 6 H).
13C NMR (CDCl3): δ = 165.3 (Cq), 162.7 (Cq), 153.1 (CH), 150.1 (Cq),
138.3 (Cq), 136.8 (Cq), 130.0 (2 CH), 128.8 (CH), 124.8 (2 CH), 105.5
(Cq), 94.3 (CH), 88.8 (Cq), 27.1 (2 CH3), 14.0 (CH3).
FVP Reactions
MS: m/z (%) = 327 (M+, 23), 269 (100), 225 (22), 184 (74), 156 (22).
Flash vacuum pyrolysis reactions were carried out by distillation of
the substrate in vacuo through an electrically heated silica furnace
tube (35 × 2.5 cm). Products were trapped in a U-tube situated at the
exit point of the furnace and cooled with liquid N2. Conditions were
first established on a small scale (20 mg) where the product(s) were
dissolved in a deuterated solvent and analyzed directly by 1H NMR
spectroscopy. Larger-scale pyrolyses, involving 0.1 g or more of sub-
strate, were usually removed from the trap by solution in CH2Cl2 (30
mL). The precursors and pyrolysis conditions [quantity of precursor,
inlet temperature (Ti), furnace temperature (Tf), pressure range (P),
and pyrolysis time (t)] and yields are stated.
Anal. Calcd for C17H17N3O4: C, 62.4; H, 5.25; N, 12.85. Found: C, 62.3;
H, 5.15; N, 12.75.
5-(1-tert-Butyl-1H-pyrazol-5-ylamino)methylene-2,2-dimethyl-
1,3-dioxane-5,6-dione (3c)
Treatment of 6c using the general procedure gave 3c; yield: 0.985 g
(97%); yellow solid; mp 84 °C.
1H NMR (CDCl3): δ = 11.53 (d, 3J = 13.4 Hz, 1 H), 8.33 (d, 3J = 13.4 Hz, 1
H), 7.41 (d, 3J = 1.9 Hz, 1 H), 6.23 (d,3J = 1.9 Hz, 1 H), 1.77 (s, 6 H), 1.70
(s, 9 H).
13C NMR (CDCl3): δ = 165.6 (Cq), 162.9 (Cq), 154.7 (CH), 137.5 (Cq),
137.3 (CH), 105.6 (Cq), 97.8 (CH), 88.4 (Cq), 60.3 (Cq), 29.8 (3 CH3), 27.3
(2 CH3).
MS: m/z (%) = 293 (M+, 21), 235 (47), 179 (59), 161 (100).
HRMS: m/z calcd for C14H19N3O4 (M+): 293.1381; found: 293.1384.
FVP of 1-tert-Butylpyrazole (7)
This compound was too volatile for normal inlet conditions. It was
therefore cooled in an acetone-dry ice bath, which was slowly re-
moved to allow sublimation (20 mg, Ti acetone/dry ice bath, Tf 600–
850 °C, P 0.03 Torr, t 15 min).
1-Methyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1aa)
5-(1-tert-Butyl-3-methyl-1H-pyrazol-5-ylamine)-2,2-dimethyl-
FVP of 3a (recrystallized from MeOH, 203 mg, 0.81 mmol, Ti 199 °C, Tf
600 °C, P 0.03 Torr, t 30 min) gave 1aa; yield: 111 mg (92%); off-white
solid; mp 164 °C (Lit.13 mp 165–168 °C).
1H NMR (DMSO-d6): δ = 8.37 (d, 3J = 4.0 Hz, 1 H), 8.30 (s, 1 H), 6.65 (br
s, 1 H), 4.22 (s, 3 H).
13C NMR (DMSO-d6): δ = 162.4 (br Cq), 150.7 (br Cq), 148.1 (br CH),
1,3-dioxane-4,6-dione (3d)
Treatment of 6d using the general procedure gave 3d; yield: 0.88 g
(99%); yellow solid; mp 82 °C.
1H NMR (CDCl3): δ = 11.47 (br d, 3J = 13.4 Hz, 1 H), 8.29 (d, 3J = 13.4 Hz,
1 H), 6.00 (s, 1 H), 2.23 (s, 3 H), 1.75 (s, 6 H), 1.66 (s, 9 H).
13C NMR (CDCl3): δ = 165.9 (Cq), 162.9 (Cq), 154.4 (CH), 146.2 (Cq),
137.7 (Cq), 105.5 (Cq), 97.1 (CH), 88.1 (Cq), 59.7 (Cq), 29.8 (3 CH3), 27.1
(2 CH3), 13.9 (CH3).
130.6 (CH), 107.9 (br Cq), 104.4 (CH), 33.9 (CH3).
MS: m/z (%) = 149 (M+, 100), 95 (12), 78 (14), 63 (13).
MS: m/z (%) = 307 (M+, 21), 249 (100), 175 (68).
HRMS: m/z calcd for C7H7N3O (M+): 149.0584; found: 149.0584.
HRMS: m/z calcd for C15H21N3O4 (M+): 307.1527; found: 307.1533.
3-Methyl-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-4-one
(1ba)
5-(1-tert-Butyl-3-phenyl-1H-pyrazol-5-ylamino)methylene-2,2-
FVP of 3b (recrystallized from MeOH, 195 mg, 0.60 mmol, Ti 170 °C, Tf
600 °C, P 0.03 Torr, t 45 min) gave 1ba; yield: 0.129 mg (95%); off-
white solid; mp 195 °C.
1H NMR (DMSO-d6): δ = 11.76 (s, 1 H), 8.31 (br m, 3 H), 7.57 (app t,
3J = 7.8 Hz, 2 H), 7.32 (d, 3J = 7.3 Hz, 1 H), 6.66 (br s, 1 H), 2.68 (s, 3 H).
13C NMR (DMSO-d6): δ = 160.6 (Cq), 153.1 (Cq), 150.9 (CH), 142.0 (Cq),
139.5 (Cq), 128.9 (2 CH), 124.9 (CH), 119.7 (2 CH), 107.4 (Cq), 103.2
(CH), 14.3 (CH3).
dimethyl-1,3-dioxane-4,6-dione (3e)
Treatment of 6e using the general procedure gave 3e; yield: 0.97 g
(98%); yellow solid; mp 152 °C.
1H NMR (CDCl3): δ = 11.59 (d, 3J = 13.4 Hz, 1 H), 8.43 (d, 3J = 13.4 Hz, 1
H), 7.80 (d, 3J = 7.3 Hz, 2 H), 7.44 (t, 3J = 7.3 Hz, 2 H), 7.35 (t, 3J = 7.3 Hz,
1 H), 6.75 (s, 1 H), 1.81 (s, 6 H), 1.77 (s, 9 H).
13C NMR (CDCl3): δ = 166.0 (Cq), 162.9 (Cq), 154.4 (CH), 148.5 (Cq),
138.8 (Cq), 132.8 (Cq), 128.7 (2 CH), 128.1 (CH), 125.3 (2 CH), 105.7
(Cq), 94.5 (CH), 88.5 (Cq), 60.6 (Cq), 29.9 (3 CH3), 27.2 (2 CH3).
MS: m/z (%) = 226 (M+, 30), 225 (100), 79 (15), 78 (39).
MS: m/z (%) = 369 (M+, 33), 311 (100), 237 (58), 211 (57), 183 (44),
HRMS: m/z calcd for C13H11N3O (M+): 225.0897; found: 225.0896.
108 (45).
HRMS: m/z calcd for C20H23N3O4 (M+): 369.1683; found: 369.1690.
1-tert-Butyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1ca)
FVP of 3c (recrystallized from cyclohexane, 300 mg, 1.02 mmol, Ti
210 °C, Tf 500 °C, P 0.03 Torr, t 0.5 h) gave 1ca; yield: 185 mg (95%);
yellow solid; mp 189–191 °C.
5-(1,3-Di-tert-butyl-1H-pyrazol-5-ylamino)methylene-2,2-di-
methyl-1,3-dioxane-5,6-dione (3f)
Treatment of 6f using the general procedure gave 3f, yield: 0.83 g
(89%); yellow solid; mp 105 °C.
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1H NMR (DMSO-d6): δ = 11.40 (s, 1 H), 8.12 (br s, 1 H), 8.02 (s, 1 H),
6.49 (br s, 1 H), 1.74 (s, 9 H). 13C NMR (DMSO-d6): δ = 159.3 (Cq), 152.9
(Cq), 149.7 (CH), 128.5 (CH), 108.9 (Cq), 102.2 (CH), 59.6 (Cq), 29.2 (3
CH3).
1,7-Dihydro-3-phenylpyrazolo[3,4-b]pyridin-4-one (1eb)
FVP of 3e (500 mg, 1.36 mmol, Ti 220 °C, Tf 750 °C, P 0.03 Torr, t 0.5 h)
was followed by distillation of CH2Cl2 into the U-tube trap. The solu-
tion was removed and the insoluble product filtered under vacuum to
give 1eb; yield: 275 mg (96% mix12); off-white solid; mp 298 °C.
MS: m/z (%) = 191 (M+, 24), 135 (56).
1H NMR (DMSO-d6): δ (major tautomer) = 13.85 (br s, 1 H), 11.74 (br
s, 1 H), 8.29 (br s, 1 H), 8.05 (br d, 3J = 4.9 Hz, 1 H), 7.63 (m, 2 H), 7.47
(m, 2 H), 5.71 (br s, 1 H).
MS: m/z (%) = 211 (M+, 34), 183 (100).
HRMS: m/z calcd for C12H9N3O (M+): 211.0751; found: 211.0751.
HRMS: m/z calcd for C10H13N3O (M+): 191.1064; found: 191.1060.
1,7-Dihydropyrazolo[3,4-b]pyridin-4-one (1cb)
FVP of 3c (recrystallized from cyclohexane, 50 mg, 0.17 mmol, Ti
210 °C, Tf 750 °C, P 0.03 Torr, t 0.5 h) was followed by distillation of
CH2Cl2 into the U-tube trap. The solvent was removed in vacuo to af-
ford a yellow solid, which was triturated with Et2O and filtered under
vacuum. The filtrate was further washed with Et2O to yield 1cb; yield:
24 mg (67%); pale brown solid; mp 327–330 °C (Lit.2d mp 328–
330 °C).
1H NMR (DMSO-d6): δ (major tautomer) = 13.54 (s, 1 H), 11.71 (s, 1
H), 8.28 (br s, 1 H), 7.62 (br s, 1 H), 5.66 (br s, 1 H).
13C NMR (DMSO-d6): δ (major tautomer) = 177.1 (Cq), 151.2 (Cq),
139.2 (CH), 125.8 (CH), 113.4 (Cq), 107.3 (CH).
1,3-Di-tert-butyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1fa)
FVP of 3f (500 mg, 1.43 mmol, Ti 200 °C, Tf 500 °C, P 0.03 Torr, t 0.5 h)
was followed by distillation of CH2Cl2 into the U-tube trap. The solu-
tion was removed and solvent removed in vacuo to afford 1fa; yield:
345 mg (97%); yellow solid; mp 264–266 °C.
3
1H NMR (CDCl3): δ = 11.39 (s, 1 H), 8.13 (d, J = 4.7 Hz, 1 H), 6.50 (d,
3J = 4.7 Hz, 1 H), 1.71 (s, 9 H), 1.43 (s, 9 H).
13C NMR (CDCl3): δ = 159.3 (Cq), 154.4 (Cq), 148.9 (CH), 139.4 (Cq),
105.7 (Cq), 101.9 (CH), 59.0 (Cq), 33.7 (Cq), 29.1 (3 CH3), 26.1 (3 CH3).
MS: m/z (%) = 135 (M+, 100).
MS: m/z (%) = 247 (M+, 29), 232 (54), 232 (100).
HRMS: m/z calcd for C14H21N3O (M+): 247.1685; found: 247.1690.
1-tert-Butyl-1,7-dihydro-3-methylpyrazolo[3,4-b]pyridin-4-one
(1da)
FVP of 3d (125 mg, 0.41 mmol, Ti 160 °C, Tf 500 °C, P 0.03 Torr, t 1 h)
gave 1da; yield: 0.70 g (83%); off-white solid; mp 158 °C.
1H NMR (DMSO-d6): δ = 11.17 (br s, 1 H), 8.01 (d, 3J = 4.7 Hz, 1 H), 6.34
(d, 3J = 4.7 Hz, 1 H), 2.45 (s, 3 H), 1.63 (s, 9 H).
13C NMR (DMSO-d6): δ = 160.7 (br Cq), 152.2 (br Cq), 147.5 (CH), 137.4
(br Cq), 107.2 (br Cq), 101.5 (CH), 58.5 (Cq), 28.8 (3 CH3), 14.3 (CH3).
3-tert-Butyl-1,7-dihydropyrazolo[3,4-b]pyridin-4-one (1fb)
FVP of 3f (500 mg, 1.43 mmol, Ti 200 °C, Tf750 °C, P 0.03 Torr, t 0.5 h)
was followed by distillation of CH2Cl2 into the U-tube trap. The solu-
tion was removed and the insoluble product 1fb was filtered under
vacuum; yield: 374 mg (95% mix12); off-white solid; mp 265–266 °C.
1H NMR (DMSO-d6): δ (major tautomer) = 12.88 (br s, 1 H), 11.56 (br
s, 1 H), 7.59 (br s, 1 H), 5.63 (br s, 1 H), 1.44 (s, 9 H).
MS: m/z (%) = 205 (M+, 48), 150, (22), 149 (100), 148 (26).
HRMS: m/z calcd for C11H15N3O (M+): 205.1210; found: 205.1210.
MS: m/z (%) = 191 (M+, 28), 176 (100), 149 (27).
HRMS: m/z calcd for C10H13N3O (M+): 191.1059; found: 191.1063.
3-Methyl-1,7-dihydropyrazolo[3,4-b]pyridin-3-one (1db)
FVP of 3d (100 mg, 0.33 mmol, Ti 160 °C, Tf 850 °C, P 0.03 Torr, t 45
min) gave 1db; yield: 0.40 g (82%); off-white solid; mp 254 °C.
1H NMR (DMSO-d6): δ (major tautomer) = 13.11 (s, 1 H), 11.51 (s, 1
H), 7.50 (t, 3J = 6.3 Hz, 1 H), 5.55 (d, 3J = 6.3 Hz, 1 H), 2.53 (s, 3 H).
13C NMR (DMSO-d6, 600 MHz): δ (major tautomer) = 178.1 (br Cq),
151.5 (br Cq), 141.5 (br Cq), 138.6 (CH), 110.2 (Cq), 107.1 (CH), 11.0
(CH3).
1-tert-Butyl-4-chloro-3-phenyl-1H-pyrazolo[3,4-b]pyridine (9)
Compound 1ea (1.00 g, 3.74 mmol) was dissolved in POCl3 (18 mL,
197 mmol) and heated to reflux for 4 h. The solution was cooled, and
the volume reduced in vacuo. H2O (40 mL) was added slowly to the
dark residue followed by sat. aq NaHCO3 (40 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 30 mL), the combined organic layers
were washed with brine (30 mL), dried (MgSO4), and the solvent re-
moved in vacuo to afford 9; yield: 1.06 g (99%); brown solid; mp 123–
125 °C.
1H NMR (CDCl3): δ = 8.41 (d, 3J = 5.0 Hz, 1 H), 7.77 (m, 2 H), 7.48 (m, 3
H), 7.14 (d, 3J = 5.0 Hz, 1 H), 1.91 (s, 9 H).
13C NMR (CDCl3): δ = 151.9 (Cq), 147.3 (CH), 141.6 (Cq), 137.7 (Cq),
133.1 (Cq), 130.5 (2 CH), 128.2 (CH), 127.9 (2 CH), 117.2 (CH), 113.5
(Cq), 60.7 (Cq), 29.2 (3 CH3).
MS: m/z (%) = 149 (M+, 80), 78 (100).
HRMS: m/z calcd for C7H7N3O (M+): 149.0584; found: 149.0583.
1-tert-Butyl-1,7-dihydro-3-phenylpyrazolo[3,4-b]pyridin-4-one
(1ea)
FVP of 3e (500 mg, 1.36 mmol, Ti 220 °C, Tf 500 °C, P 0.03 Torr, t 0.5 h)
gave 1ea; yield: 358 mg (96%); yellow solid; mp 295–298 °C.
MS: m/z (%) = 287 [M+(37Cl), 10], 285 [M+(35Cl), 31], 231 (32), 229
(100).
HRMS: m/z calcd for C16H1635ClN3 (M+): 285.1038; found: 285.1039.
3
1H NMR (CDCl3): δ = 11.51 (s, 1 H), 8.23 (d, J = 5.4 Hz, 1 H), 8.00 (d,
3J = 7.3 Hz, 2 H), 7.45 (t, 3J = 7.3 Hz, 2 H), 7.36 (t, 3J = 7.3 Hz, 1 H), 6.60
(d, 3J = 5.4 Hz, 1 H), 1.80 (s, 9 H).
13C NMR (CDCl3): δ = 160.0 (Cq), 154.1 (Cq), 149.6 (CH), 140.7 (Cq),
134.1 (Cq), 129.0 (2 CH), 128.4 (2 CH), 128.0 (CH), 105.8 (Cq), 102.6
(CH), 59.9 (Cq), 29.2 (3 CH3).
MS: m/z (%) = 267 (M+, 33), 211 (100).
HRMS: m/z calcd for C16H17N3O (M+): 267.1366; found: 267.1367.
4-Chloro-3-phenyl-1H-pyrazolo[3,4-b]pyridine (10)
FVP of 9 (50 mg, 0.18 mmol, Ti 300 °C, Tf 750 °C, P 0.033 Torr, t 0.5 h)
was followed by distillation of CH2Cl2 into the U-tube trap. The sol-
vent was removed in vacuo to afford 10; yield: 35 mg (87%); pale
brown solid; mp 274–277 °C.
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1H NMR (CDCl3): δ (major tautomer) = 12.85 (s, 1 H), 8.57 (d, 3J = 5.2
1H NMR (CDCl3): δ (major tautomer) = 12.92 (br s, 1 H), 8.33 (d, 3J =
5.7 Hz, 1 H), 7.81 (d, 3J = 7.3 Hz, 2 H), 7.58 (t, 3J = 7.4 Hz, 2 H), 7.52 (t,
3J = 7.4 Hz, 1 H), 7.41 (t, 3J = 7.9 Hz, 2 H), 7.23 (m, 3 H), 6.76 (d, 3J = 5.7
Hz, 1 H), 6.74 (s, 1 H).
13C NMR (CDCl3): δ (major tautomer) = 154.7 (Cq), 150.3 (Cq), 146.8
(CH), 144.5 (Cq) 138.7 (Cq), 134.4 (Cq), 129.6 (2 CH), 129.3 (2 CH),
129.0 (2 CH), 128.9 (CH), 125.1 (CH), 122.8 (2 CH), 102.8 (Cq), 98.3
(CH).
Hz, 1 H), 7.81 (d, 3J = 6.2 Hz, 2 H), 7.52 (m, 3 H), 7.26 (d, 3J = 5.2 Hz, 1
H).
13C NMR (CDCl3): δ (major tautomer) = 153.7 (Cq), 149.1 (CH), 145.8
(Cq), 139.2 (Cq), 132.4 (Cq), 130.3 (2 CH), 128.7 (CH), 128.1 (2 CH),
118.3 (CH), 112.4 (Cq).
MS: m/z (%) = 231 [M+(37Cl), 30], 229 [M+(35Cl), 100], 166 (50).
HRMS: m/z calcd for C12H835ClN3 (M+): 229.0412; found: 229.0414.
MS: m/z (%) = 286 (M+, 100), 285 (58), 258 (58).
HRMS: m/z calcd for C18H14N4 (M+): 286.1224; found: 286.1218.
1-tert-Butyl-3-phenyl-4-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyri-
dine (11)
Pyrrolidine (1.0 mL, 11 mmol) was added to a solution of 9 (250 mg,
0.877 mmol) in 1,2-dimethoxyethane (15 mL) and the mixture was
heated at reflux with stirring for 18 h. The solvent was removed and
the residue was partitioned between sat. aq NaHCO3 (25 mL) and
EtOAc (25 mL). The organic layer was separated and the solvent re-
moved in vacuo to yield an orange residue, which was purified by dry
flash chromatography eluting with hexane–EtOAc (20:1). Product
containing fractions were combined and solvent removed in vacuo to
give 11 as a yellow gum, which crystallized on standing; yield: 87 mg
(37%); mp 122–123 °C.
1H NMR (CDCl3): δ = 8.18 (d, 3J = 5.5 Hz, 1 H), 7.66 (d, 3J = 6.9 Hz, 2 H),
7.42 (t, 3J = 7.6 Hz, 2 H), 7.35 (t, 3J = 8.6 Hz, 1 H), 6.28 (d, 3J = 5.5 Hz, 1
H), 3.06 (t, 3J = 6.5 Hz, 4 H), 1.89 (s, 9 H), 1.73 (t, 3J = 6.5 Hz, 4 H).
13C NMR (CDCl3): δ = 153.3 (Cq), 151.5 (Cq), 147.4 (CH), 141.8 (Cq),
136.7 (Cq), 129.2 (2 CH), 128.4 (2 CH), 127.6 (CH), 106.0 (Cq), 99.6
(CH), 59.7 (Cq), 51.5 (2 CH2), 29.1 (3 CH3), 25.2 (2 CH2).
Acknowledgment
We thank Cancer Research UK (studentships to AN and MM; Grant
Ref C21383/A6950) for financial support and Lorna Murray for assis-
tance with NMR data.
References
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Kimball, S. D.; Webster, K. R. Bioorg. Med. Chem. Lett. 2003, 13,
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Bondavalli, F.; Brullo, C.; Bruno, O.; Mosti, L.; Zizzari, A. T.;
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Martinelli, A.; Botta, M. ChemMedChem 2008, 3, 898. CDK1 and
CDK4 inhibitors: (d) Sielecki, T. M.; Boylan, J. F.; Benfield, P. A.;
Trainor, G. L. J. Med. Chem. 2000, 43, 1. GSK3 inhibitors:
(e) Witherington, J.; Bordas, V.; Gaiba, A.; Naylor, A.; Rawlings,
A. D.; Slingsby, B. P.; Smith, D. G.; Takle, A. K.; Ward, R. W.
Bioorg. Med. Chem. Lett. 2003, 13, 3059. CHK1 inhibitors:
(f) Matthews, T. P.; Klair, S.; Burns, S.; Boxall, K.; Cherry, M.;
Fisher, M.; Westwood, I. M.; Walton, M. I.; McHardy, T.; Cheung,
K. M.; Van Montfort, R.; Williams, D.; Aherne, G. W.; Garrett, M.
D.; Reader, J.; Collins, I. J. Med. Chem. 2009, 52, 4810.
MS: m/z (%) = 320 (M+, 54), 264 (100), 263 (M – C3H6O, 38).
HRMS: m/z calc for C20H24N4 (M+): 320.2007; found: 320.2005.
4-Anilino-1-tert-butyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine (12)
A solution of 9 (285 mg, 1.00 mmol), aniline (0.1 mL, 1.1 mmol),
Pd2(dba)3 (18 mg, 0.02 mmol), dppp (16 mg, 0.04 mmol), and t-
BuONa (134 mg, 1.4 mmol) in toluene (10 mL) contained in an oven-
dried flask purged with N2, was heated to 70 °C for 72 h. The mixture
was cooled, taken up in Et2O (10 mL), washed with brine (3 × 5 mL),
and concentrated in vacuo to give the crude product, which was puri-
fied by dry flash chromatography eluting with hexane–EtOAc (20:1).
Product containing fractions were combined and solvent removed in
vacuo to afford 12 as a yellow gum, which crystallized on standing;
yield: 280 mg (87%); mp 116–118 °C.
1H NMR (CDCl3): δ = 8.23 (d, 3J = 5.5 Hz, 1 H), 7.68 (d, 3J = 6.9 Hz, 2 H),
7.77 (t, 3J = 7.5 Hz, 2 H), 7.55 (t, 3J = 7.4 Hz, 1 H), 7.38 (dd, 3J = 8.4, 7.4
Hz, 2 H), 7.17 (m, 3 H), 6.72 (d, 3J = 5.5 Hz, 1 H), 6.62 (br s, 1 H), 1.91 (s,
9 H).
13C NMR (CDCl3): δ = 152.8 (Cq), 148.8 (CH), 145.9 (Cq), 140.5 (Cq),
139.2 (Cq), 134.9 (Cq), 129.5 (2 CH), 129.3 (2 CH), 129.1 (2 CH), 128.6
(CH), 124.5 (CH), 122.3 (2 CH), 104.5 (Cq), 97.7 (CH), 60.0 (Cq), 29.2 (3
CH3).
MS: m/z (%) = 342 (M+, 42), 286 (100).
HRMS: m/z calcd for C22H22N4 (M+): 342.1850; found: 342.1852.
(4) Fischmann, T. O.; Hurza, A.; Duca, J. S.; Ramanathan, L.;
Mayhood, T.; Windsor, W. T.; Le, H. V.; Guzi, T. J.; Dwyer, M. P.;
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V. Biopolymers 2007, 89, 372.
(5) Clarke, D.; Mares, R. W.; McNab, H. J. Chem. Soc., Perkin Trans. 1
1997, 1799.
4-Anilino-3-phenyl-1H-pyrazolo[3,4-b]pyridine (13)
FVP of 12 (30 mg, 0.88 mmol, Ti 235 °C, Tf 750 °C, P 0.03 Torr, t 0.5 h)
was followed by distillation of CH2Cl2 into the U-tube trap. The sol-
vent was removed in vacuo to afford 13; yield: 18 mg (72%); pale yel-
low solid; mp 216–217 °C.
(6) Review:Gaber, A. M.; McNab, H. Synthesis 2001, 2059.
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(7) Iwasawa, Y.; Kato, T.; Kawanishi, N.; Masutani, K.; Kouta, M.;
Mita, T.; Nonoshita, K.; Ohkubo, M. Patent PCT Int. Appl. WO
2008026769, 2008; Chem. Abstr. 2008, 148, 331690
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2005; Chem. Abstr. 2005, 142, 114054
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1986, 129.
(12) For 1eb and 1fb, the product was contaminated with unreacted
starting material as well as the pyrazolo[1,5-a]pyrimidine
isomer, indicating competing N-tert-butyl deprotection prior to
ring formation, and hence cyclization via pathway 4 to 5 in
Scheme 1 rather than 4 to 1.
(9) (a) Adapted from:Niculescu-Duvaz, D.; Springer, C. J.; Gill, A. L.;
Taylor, R. D.; Marais, R. M.; Dijkstra, H.; Gaulon, C.; Menard, D.;
Roman Vela, E. Patent PCT Int. Appl. WO 2006043090, 2006;
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Niculescu-Duvaz, I.; Gaulon, C.; Dijkstra, H. P.; Niculescu-Duvaz,
D.; Menard, D.; Zambon, A.; Nourry, A.; Davies, L.; Manne, H. A.;
(13) Chu, I.; Lynch, B. M. J. Med. Chem. 1975, 18, 161.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 242–248