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D. C. Beshore et al. / Tetrahedron Letters 51 (2010) 970–973
Table 2
Effect of substitution at N2, C6, and C9 on the formation of substituted pyrazolo[4,3-c]quinolinones 1k–n
R1
R1
R1
N
N
F
N
N
Y
N
F
N
O
O
DMF•DMA
THF, 23 °C
O
H2N
Bn
X
X
K2CO3, DMSO
See Table
Y
X
N
Y
NMe2
Bn
8
9
1
Entry
1
X
Y
R1
Time (min)
90
Temp (°C)
Product
Yield (%)
66
Me
Me
Me
CH
H
H
100
1m
2
3
N
CH
Ph
Ph
60
90
23
100
1n
1p
77
37
OMe
(entries 1–5) afforded pyrazolo[4,3-c]quinolinones 1 in moderate
to excellent yields. With an increase in steric demand at the -car-
during the formation of the high energy Meisenheimer complex.13
The electron donating methoxy group was tolerated at C9 (entry 3),
providing 1p in moderate yields.
a
bon of the amine, a corresponding increase in reaction time was re-
quired (cf. entries 1–4). In an effort to shorten the reaction time,
the reaction temperature was increased from 100 °C to 130 °C (en-
try 4), affording similar yields. Enantiopure amino acid esters
(>98% ee) were competent in the reaction as substrates (entries 4
and 5). However, complete racemization was observed for 1d
and 1e at both 100 °C and 130 °C, which may be due to enhanced
methine acidity of the resulting pyrazolo[4,3-c]quinolinone prod-
ucts. When employing tert-butylamine (entry 6) as a substrate,
cyclization of 10 was not observed at 100 °C and required heating
the mixture to higher temperature (130 °C) for the SNAr-cyclization
to proceed, providing 1f in fair yield. By further increasing the tem-
perature to 150 °C, the desired pyrazolo[4,3-c]quinolinone was ob-
tained in shorter reaction time (60 min) and higher isolated yield
(77%).12 This sequence was also amenable to substitution of the
orthoamide, as N,N-dimethylacetamide dimethylacetal (entry 7)
was competent in this sequence, providing the corresponding
4-methylpyrazolo[4,3-c]quinolinone in shorter reaction time
(cf. entries 7 and 2), albeit in somewhat decreased yield.
Aromatic amines were also examined (entries 8–11), affording
pyrazolo[4,3-c]quinolinones, and yields were dependent on the
steric and electronic nature of the aniline. As was observed for ste-
rically encumbered aliphatic amines, SNAr-cyclization of the puta-
tive intermediate 10 was not observed for aromatic amines at
100 °C. Rather, cyclization was only observed at temperatures
P130 °C. In addition, shorter reaction times at higher tempera-
tures provided pyrazolo[4,3-c]quinolinones in higher isolated
yields, as was observed in entry 6. Notably, both electron-rich
and electron-deficient aromatic amines (entries 9 and 10) required
longer reaction times than aniline (entry 8) and afforded product in
lower yields, 52% and 11%, respectively. The sterically encumbered
2-bromoaniline (entry 11) also provided the corresponding
4-methylpyrazolo[4,3-c]quinolinone after 90 min at 150 °C in good
yield.
In summary, an alternative strategy for the construction of 2,5-
disubstituted pyrazolo[4,3-c]quinolinones has been developed.
(2-Fluorophenyl)-3-oxo-2,4-dihydro-3H-pyrazol-3-ones (8) were
prepared from 3-(2-fluorophenyl)-3-oxopropanoates esters (7)
and served as a key building block. A protocol was developed in
which facile condensation with an orthoamide, followed by substi-
tution with a primary amine and subsequent SNAr-cyclization,
provide rapid access to 4- and 5-substituted pyrazolo[4,3-
c]quinolinones.
Representative procedure: 2-Phenyl-5-(phenylmethyl)-2,5-dihy-
dro-3H-pyrazolo[4,3-c]quinolin-3-one (1a): 5-(2-Fluorophenyl)-2-
phenyl-2,4-dihydro-3H-pyrazol-3-one (200 mg, 0.787 mmol) was
dissolved in tetrahydrofuran (3 mL) and treated with N,N-dimeth-
ylformamide dimethylacetal (0.126 mL, 0.944 mmol, 1.2 equiv).
After stirring for 30 min at ambient temperature, the mixture
was concentrated in vacuo. The resulting 4-[(dimethylamino)-
methylidene]-5-(2-fluorophenyl)-2-phenyl-2,4-dihydro-3H-pyraz-
olo-3-one residue was dissolved in dimethylsulfoxide (3 mL),
treated with benzylamine (0.129 mL, 1.18 mmol, 1.5 equiv) and
potassium carbonate (326 mg, 2.36 mmol, 3 equiv) and then stir-
red at ambient temperature for 30 min. The mixture was placed
into a preheated oil bath at 100 °C for 1 h, cooled to ambient tem-
perature, poured into water (50 mL) and extracted with ethyl ace-
tate containing 5% methanol (3 Â 150 mL). The combined organic
extracts were dried with sodium sulfate, filtered and concentrated
in vacuo. The residue was treated with ethyl acetate (20 mL) and
hexanes (75 mL), aged for 30 min and then filtered. The solid was
collected and dried in vacuo, providing the titled compound as a
bright yellow solid (256 mg, 93% yield): IR (thin film, neat): 3032
(w), 1638 (s), 1614 (m), 1592 (m), 1488 (m), 1460 (m), 1397 (m),
1371 (m), 1325 (m), 1308 (m), 1233 (m), 1184 (w), 1165 (w),
1126 (m), 1054 (w), 1027 (w), 970 (m), 984 (w), 855 (w), 816
(w), 719 (s), 653 (m), 536 (m) cmÀ1
;
1H NMR (400 MHz, DMSO-
The effect of substitution at N2, C6, and C9 was also evaluated
(Table 2). Introduction of an aliphatic tert-butyl group at N2 (entry
1), afforded the pyrazolo[4,3-c]quinolinone 1m in good yield with
a slightly decreased yield and increased reaction time, presumably
a result of increased electron density in the pyrazolone ring (cf.
Table 1, entry 2). Introduction of a nitrogen atom was well-toler-
ated at the 6-position (entry 2), providing the desired pyrazol-
o[4,3-c]-1,8-naphthyridin-3-one 1n in good yield after 60 min at
ambient temperature. The decrease in required temperature is
presumably due to the stabilizing nature of the adjacent nitrogen
d6) d 9.14 (1H, s), 8.30 (1H, d, J = 6.6 Hz), 8.21 (2H, d, J = 8.6 Hz),
7.76 (1H, d, J = 8.7 Hz), 7.64–7.61 (1H, m), 7.56 (1H, t, J = 7.4 Hz),
7.46 (2H, t, J = 8.0 Hz), 7.38–7.35 (2H, m), 7.34–7.28 (3H, m), 7.20
(1H, t, J = 7.5 Hz), 5.76 (2H, s) ppm; high resolution mass spectrom-
etry (ES+) m/z 352.1444 [(M+H)+; calcd C23H18N3O: 352.1444].
Acknowledgments
We thank analytical chemistry, mass spectroscopy and NMR
analysis groups for their assistance.
Beshore, Douglas C.
