2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones

Article abstract of DOI:10.1002/jhet.2744

Complementary strategies to 2,5-disubstituted pyrazolo[4,3-c]cinnolin-3-ones are reported herein, providing late stage substituent introduction at either the 2- or the 5-position. Treating a readily prepared 4-thiocinnoline ester with substituted hydrazines afforded late stage access to the 2-position, while late stage substituent introduction at the 5-position was achieved via two different strategies: alkylation of 4-hydrazonopyrazol-3-ones, followed by a ring-closing intramolecular S_NAr tactic and direct reaction of 5-(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-ones with aryl diazonium salts, followed by cyclization. The strategies described herein provide practical and general methods to prepare 2,5-disubstituted pyrazolo[4,3-c]cinnolin-3-ones.

Full text of DOI:10.1002/jhet.2744

Month 2016
2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones
*
Douglas C. Beshore, Adam W. Johnson, Robert M. DiPardo, Daniel R. Pitts, Victoria Cofre, and Scott D. Kuduk
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
*E-mail: douglas_beshore@merck.com
Additional Supporting Information may be found in the online version of this article.
Received May 5, 2016
DOI 10.1002/jhet.2744
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Complementary strategies to 2,5-disubstituted pyrazolo[4,3-c]cinnolin-3-ones are reported herein, provid-
ing late stage substituent introduction at either the 2- or the 5-position. Treating a readily prepared 4-
thiocinnoline ester with substituted hydrazines afforded late stage access to the 2-position, while late stage
substituent introduction at the 5-position was achieved via two different strategies: alkylation of 4-
hydrazonopyrazol-3-ones, followed by a ring-closing intramolecular SNAr tactic and direct reaction of 5-
(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-ones with aryl diazonium salts, followed by cyclization. The
strategies described herein provide practical and general methods to prepare 2,5-disubstituted pyrazolo
[4,3-c]cinnolin-3-ones.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
cyclization
provided
late-stage
introduction
of
substitution to the 5-position (R2).
During the course of a drug discovery project, access to
previously unreported 2,5-disubstituted pyrazolo[4,3-c]
cinnolin-3-ones was required [1]. While 2-substituted
pyrazolo[4,3-c]cinnolin-3-ones have been shown to
possess biological activity toward GABA-A [2] and
CD80 [3,4], the methods for their preparation rely on a
strategy in which 4-chlorocinnoline-carboxylate esters are
reacted with substituted hydrazines followed by
cyclization to generate the tricyclic ring system, which
represents a viable strategy for the preparation of 2-
substituted systems. However, this tactic is not applicable
to the preparation of 2,5-disubstituted pyrazolo[4,3-c]
cinnolin-3-ones because of the difficulty of generating an
unstable chloroquinolinium salt [5], and the preparation
of 5-substituted pyrazolo[4,3-c]cinnolin-3-ones has not
been reported to date.
RESULTS AND DISCUSSION
In order to access thioketone 2, a 1-substituted 4-oxo-
1,4-dihydrocinnoline-3-carboxylate ester (i.e., 8a, Scheme
2) was required. Intermediate 7 was prepared employing
the commercially available β-ketoester 4 [6,7], which was
readily converted to diazo compound 5. Partial reduction
with tri-n-butylphosphine, followed by heating at
elevated temperature to induce cyclization, provided
phosphonium salt 6. Direct purification via silica gel
chromatography afforded the phosphine-hydrolyzed 7 in
modest yield. Subsequent alkylation of 7 [8,9] with the
commercially available benzyl halide led to cinnolinone
8a in poor yield as a result of competitive formation of
O- and N2-alkylated isomers, the latter of which is
known to lead to the decomposition of the parent ring
system [7]. Although this sequence was capable of
delivering the requisite cinnolinone intermediate, the low-
yielding, non-selective alkylation of 7, coupled with the
modest overall yield for the 3-steps, led to the
Because we required access to substitution at both
the 2- and 5-positions of the pyrazolo[4,3-c]cinnolin-3-
one scaffold, two strategically different approaches
were developed to access 1 (Scheme 1) and are
described herein. Late-stage substituent introduction at
the 2-position (R1) was desired and envisioned to
occur by treating thioketone
2
with substituted
examination of
a
more robust strategy for the
hydrazines, in which imine formation followed by
cyclization would lead to formation of the tricyclic
ring system. As a complementary approach, treatment
of the 3-(2-fluorophenyl)-4-hydrazono-1H-pyrazol-5
construction of 1-substituted 4-oxo-1,4-dihydrocinnoline-
3-carboxylate esters.
As such, hydrazone 9 (Table 1), the initial product
derived from treatment of 5 with tri-n-butylphosphine,
was investigated as a substrate for alkylation; partial
(4H)-one
3
with electrophiles and subsequent
© 2016 Wiley Periodicals, Inc.

D. C. Beshore, A. W. Johnson, R. M. DiPardo, D. R. Pitts, V. Cofre, and S. D. Kuduk
Vol 000
Scheme 1. Complementary approaches to access 2,5-disubstituted pyrazole[4,3-c]cinnolin-3-ones.
Scheme 2. Preparation of ethyl 4-oxo-1-[4-(1H-pyrazol-1-yl)benzyl]-1,4-dihydrocinnoline-3-carboxylate.
Table 1
Preparation of 1-substituted ethyl 4-oxo-1,4-dihydrocinnoline-3-carboxylates 8a–h.
Entry
1
R2-X
Product
Yield (%)a
66
Entry
5
R2-X
Product
Yield (%)b
8a
8e
0b
2
3
BnBr
8b
8c
79
93
6
7
8f
40
50
8g
4
Bul
8d
42
8
8h
0b
aIsolated yield.
bNo N1-alkylation product 8 was obtained; rather exclusive formation of 7 was observed.
reduction of
5
with tri-n-butylphosphine afforded
of sodium hydride (2.2 equivalents) in N,N-
dimethylformamide at 0°C and the results are shown in
Table 1. Benzylic halides (entries 1–3) afforded
hydrazone 9 in excellent isolated yield [6,10]. Compound
9 was treated with various electrophiles in the presence
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2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones
cinnolines in good to excellent yields, while allyl (entry 7)
and propargyl (entry 6) halides afforded moderate yields of
substituted cinnolinones. Reactions with unactivated alkyl
halides were sensitive to steric effects; n-butyl iodide
(entry 4) afforded moderate yields of cinnolinone, while
β-branching inhibited product formation (entry 5).
Hydrazone 9 did not undergo SNAr reaction with 2-
fluoropyridine, as formation of 8h was not observed
under the reaction conditions (entry 8). All halides led to
exclusive N1-alkylation, and no O-alkylation products
were isolated or detected by LC/MS. In entries where
yields of 8 are lower, the mass balance was accounted for
by the formation of 7, the result of intramolecular SNAr
without alkylation. With an improved and scalable
procedure for the preparation of 1-substituted cinnolines
in hand, we turned our attention toward the preparation
of the tricyclic system.
the preparation of closely related 2,5-disubstituted
pyrazolo[4,3-c]quinolin-3-ones employing P2S5 [11], we
found that Lawesson’s reagent [12] provided superior
results, in which 10 (Table 2) was obtained in 95%
isolated yield. Thioketone 10 was treated with substituted
hydrazines and resulted in the formation of intermediate
imine 11, which was readily observed under basic
conditions at ambient temperature. Heating the reaction
mixture led to cyclization and formation of 2,5-
disubstituted
pyrazolo[4,3-c]cinnolin-3-ones
12a–g
(Table 2). Hydrazine (entry 1) led to near quantitative
formation of 12a in 1 h [13], while alkyl-substituted
hydrazines (entries 2–4) exhibited a range of isolated
yields and times required for reaction completion
(conditions A). N-Methyl pyrazolocinnolinone 12b was
prepared in 56% isolated yield after heating for 3 h, while
the tert-butyl 12c required 24h of heating to effect
complete conversion. Surprisingly, the benzyl hydrazine
product 12d (entry 4) was obtained in very low yield (3%
isolated yield). Employing aromatic hydrazines (entries
5–7) similarly led to little or no formation of the desired
tricyclic ring system. Analyses of reaction mixtures by
The introduction of substituents at N2 of the tricyclic
ring system via substituted hydrazines was examined.
Because ketone 8c does not directly react with
hydrazines, conversion to the more activated thioketone
was required. While this strategy has been exemplified in
Table 2
Construction of 2-substituted 5-(4-iodobenzyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-ones.
Entry
R1-NH-NH2
Product
Conditions A time (h)a
Yield (%)b
Conditions B time (h)c
Yield (%)b
1
2
3
4
5
6
Hd
12a
12b
12c
12d
12e
12f
1
3
24
24
24
24
97
56
46
3
NDe
3
NDe
52
37
60
30
Me
t-Bu
Bn
4
24
24
4
Phf
5
NRg
25
7
12g
24
NRg
4
45
aConditions A: hydrazine (1.5 equiv), K2CO3 (10 equiv), DME (0.1 M), 50°C.
bIsolated yield.
cConditions B: hydrazine (1.5 equiv), K2CO3 (10 equiv), HgCl2 (1 equiv), DME (0.1 M), 85°C.
dHydrazine (40 equiv), ethanol, 50°C.
eND = no data.
fEmploying conditions A at 85°C for 24 h provided 12f in 15% yield.
gNR = no reaction.
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D. C. Beshore, A. W. Johnson, R. M. DiPardo, D. R. Pitts, V. Cofre, and S. D. Kuduk
Vol 000
LC/MS revealed extensive decomposition under the
reaction conditions described, in which the only
identifiable side-product was a minor amount of the
hydrolyzed thioketone 8c. It was observed that the more
successful transformations (i.e., entries 1–3) were those in
which extensive imine formation (11) was observed prior
to heating. Additionally, if reaction mixtures were heated
immediately upon the combination of reagents, then
isolated yields of 12 diminished considerably. We
concluded from these observations that improving the
conversion of 10 to 11 was crucial to improve the overall
transformation.
Altering reaction concentration and/or time did not lead
to improved conversion of 11 [14], as such activation of
the thioketone were explored. Sulfur-mediated cleavage
of thioacetals is a well-exploited tactic for unmasking
Scheme 3. Compound 13 as a common intermediate in the preparation of pyrazolo[4,3-c]quinolin-3-ones and pyrazolo[4,3-c]cinnolin-3-ones.
Table 3
A two-step alkylation/cyclization protocol for the preparation of 5-substituted-2-phenylpyrazolo[4,3-c]cinnolin-3-ones 18a–f.
Entry
R2-X
Time (min)
Product
Yield (%)a
1
2
3
BnBr
Bul
60
60
120
18a
18b
18c
71
25
decomp.
4
5
120
120
18d
18e
21
13
6
18f
NRb
aIsolated yield.
bNR = no reaction.
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2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones
ketones and aldehydes [15,16] and as such direct
activation of thioketone 10 was examined. Toward this
end, the effect of stoiciometric mercuric chloride on this
transformation was explored, and the results are shown in
Table 2 (conditions B). While the presence of HgCl2 did
not have an effect on the rate or isolated yield of 12b
(entry 2), significant rate acceleration and a modest
improvement in isolated yield was observed for 12c
(entry 3). Improvements were also realized with respect
to reaction rate acceleration and product formation in
entries 4–7. Employing mercuric chloride significantly
increased the isolated yield of 12d (cf. 60% versus 3%
isolated yield) and as an additive in the presence of aryl
hydrazines (entries 5–7) had an overall increase in the
rate of reactions. Vastly improved isolated yields of 2-
aryl-5-substituted pyrazolo[4,3-c]cinnolin-3-ones 12e–g
were realized, of which 12f and 12g were previously
incompetent in the absence of HgCl2. Interestingly, after
both reverse and normal phase chromatography, the
pyrazolone ring system of compound 12f proved
unstable and decomposed slowly, presumably because
of the electron donating ability of the methoxyether.
Overall, stoichiometric mercuric chloride had a positive
effect on the transformation of thioketone 10 to tricycle
12, facilitating late-stage introduction of the 2-
substituent in good yields with a wide variety of
substrates to afford 2,5-disubstituted pyrazolo[4,3-c]
cinnolin-3-ones.
Complementary to the aforementioned strategy,
late-stage introduction of functionality at the 5-position of
2,5-disubstituted pyrazolo[4,3-c]cinnolin-3-ones required
an alternate strategy. Recently, it was reported that
5-(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-ones
13
(Scheme 3), readily prepared in a single step from
substituted hydrazines and β-ketoesters [17,18], were
useful intermediates in the preparation of 2,4,5-
trisubstituted pyrazolo[4,3-c]quinolin-3-ones (15) via a
two-step protocol [19]. Reaction of pyrazolone 13 with
orthoamides afforded the enamine 14, which was then
treated with substituted amines. Cyclization was then
promoted under basic conditions at elevated temperatures,
affording 2,4,5-trisubstituted pyrazolo[4,3-c]quinolin-3-
ones 15 in good to excellent yields. Employing the
pyrazolone 13, 2,5-disubstituted pyrazolo[4,3-c]cinnolin-
Table 4
A protective group strategy employed for the preparation of 5-substituted-2-phenylpyrazolo[4,3-c]cinnolin-3-ones 18a–i.
Method A
yield (%)a
Method B
yield (%)a
Method A
yield (%)a
Method B
yield (%)a
Entry
R2-X
BnBr
Product
Entry
R2-X
Product
1
18a
25
100
5
18e
10
20
52
14
32
13
2
Bul
18b
79
82
6
7
18g
18h
3
4
18c
18d
decomp.
14
78
30
8
9
18i
18f
30
14
NRb
NRb
aIsolated yield.
bNR = no reaction.
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D. C. Beshore, A. W. Johnson, R. M. DiPardo, D. R. Pitts, V. Cofre, and S. D. Kuduk
Vol 000
3-ones could be prepared via a modified strategy. Toward
this end, diazo transfer afforded 16 (R1 = Ph) [20], which
was reduced with tri-n-butylphosphine to afford the
hydrazinyl pyrazolone 3 in good yield [21]. With 3 in
hand, preparation of 1 via introduction of substituents at
R2, followed by ring closure, was examined.
Hydrazone 3a was reacted under similar conditions to
those previously described (NaH, DMF, 0°C) to afford
the alkylation products 17a–f (Table 3). After aqueous
work up, the unpurified mixture was added over 1 h via
syringe pump to a preheated 70°C mixture of potassium
carbonate in N,N-dimethylformamide to effect cyclization
to the tricycles 18a–f in modest yield with formation of
18a (entry 1) being most effective (71% yield). Allyl
bromide (entry 4) was significantly less compatible, while
butynyl bromide (entry 3) led only to decomposition.
Unactivated alkyl halides (entries 2 and 4) afforded the
tricycle in low yields, and 2-fluoropyridine was
unreactive under these conditions. During these studies,
two observations proved critical to improving heterocycle
synthesis (vida infra). First, the initial alkylation event of
3a was facile only with benzyl bromide; all other
electrophiles did not alkylate efficiently. Secondly, in the
latter circumstance when alkylation was sluggish,
competitive intramolecular cyclization without alkylation
(i.e., 18, R2 =H) and formation of diazo 16 (R1 = Ph)
were the major observed side products, the latter of
which represents an unexpected net oxidation.
In order to address the low efficiency of this two-step
protocol, suppression of the observed byproducts was
required, as well as improvement of the alkylation event.
One strategy to address the low efficiency of the
transformation
that
would
decrease
hydrazone
nucleophilicity and retard the non-productive cyclization
event would be to employ a protecting group; this would
also eliminate the potential for forming the diazo red-ox
Table 5
Diazonium strategy employed for the preparation of 5-aryl-2-phenylpyrazolo[4,3-c]cinnolin-3-ones 18j–o.
Entry
R2-N2
Product
Time (min)
Yield (%)a
1
18j
60
99
2
3
18k
18l
60
60
99
80
4
5
18m
18n
60
60
85
82
6
18o
120
89
aIsolated yield over the two-step sequence.
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2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones
byproduct that was observed. Toward this end, an N-Boc
protective group was introduced to afford 17g in 90% yield
(Table 4). A two-step sequence was then employed, which
included an alkylation step, followed by an aqueous
5-aryl-2-phenylpyrazolo[4,3-c]cinnolin-3-ones 18j–o in
good to excellent yields.
workup and subsequent treatment in
a
tandem
CONCLUSIONS
deprotection/cyclization step. N-Boc protective group
thermolysis [22] at 100°C in the presence of potassium
carbonate in N,N-dimethylformamide enabled cyclization
(method A) [23]. Isolated yields of 18a–f employing this
approach (method A) were comparable to results obtained
without a protective group strategy with some exceptions
(cf. 18a and 18b). However, a key observation was made
during the course of these studies, in that the first
alkylation step appeared to approach completion more
when employing the protective group strategy, while the
deprotection/cyclization strategy appeared to be
problematic (based on LC/MS analyses of reaction
mixtures).
Herein, we have described several methods for
constructing 2,5-disubstituted pyrazolo[4,3-c]cinnolin-3-
ones in which complimentary strategies have been
developed for late-stage introduction of functionality at
either N2 or N5, relying on the readily prepared β-
ketoester aryl fluorides 4. Additionally, strategies have
been outlined that allow for introduction of a wide array
of substituents at the 5-position employing both
alkylation- and diazonium-based chemistries. Together,
these methods provide a set of complementary strategies
that provide access to diversely substituted 2,5-
disubstituted pyrazolo[4,3-c]cinnolin-3-ones.
In order to address this, an alternate deprotection
cyclization strategy was employed in which the N-Boc
protective group was removed under acidic conditions
(TFA/CH2Cl2), followed by cyclization of the
deprotected material under conditions that were effective in
Table 3 (method B). Marrying these approaches resulted in
higher overall yields for the reaction sequence. In this case,
the N-benzylpyrazolocinnolinone 18a was obtained in
quantitative yield (entry 1), and the unactivated n-butyl
was obtained in an excellent yield 82% over the three-
step sequence. Previous attempts to install the propargylic
18c were unsuccessful; under these conditions, 18c was
obtained in modest isolated yield [24]. A marked
improvement in yield was realized with allyl 18d, which
was obtained in 78% isolated yield. No improvement in
isolated yield was realized to install the isobutyl group
(18e), regardless of method. However, some
improvements were realized with α-methylbenzyl 18g
(32% vs. 20%, method B vs. method A). Improved
results were obtained employing method A versus
method B with the β-substituted methoxy- and fluoro-
ethanes (entries 7 and 8), which may be the result of a
EXPERIMENTAL
General comments.
All reactions were performed
under nitrogen atmosphere in round bottomed flasks.
Proton NMR spectra were recorded on Varian Unity 400
or VRX-400 spectrometers (400MHz), or Varian Unity
or Varian Plus (500 MHz) spectrometers. Chemical shifts
are reported in parts per million (δ) downfield from
tetramethylsilane as an internal standard. High resolving
power accurate mass measurements were acquired by use
of a Bruker Daltonics 7 T Fourier transform ion cyclotron
resonance mass spectrometer. Samples were dissolved in
acetonitrile:water or used as provided and ionized by use
of electrospray ionization (ESI) yielding [M + H].
External calibration was accomplished with oligomers of
polypropylene glycol (average molecular weight 425 Da).
IR spectra were recorded on a Perkin Elmer Spectrum
100 FT-IR Spectrometer and are reported in cmÀ1
.
Column chromatography was performed on ISCO
Combiflash purification systems employing Silicycle
prepacked silica gel cartridges and analytical thin layer
chromatography was performed on EM Science Kieselgel
60F254 plates. Solvents and reagents were obtained from
commercial sources and used without further purification.
The reported yields are the actual isolated yields of
purified material and are not optimized.
competitive
β-elimination
pathway
leading
to
decomposition. Finally, all attempts at installing the
2-pyridyl via SNAr (entry 9) were unsuccessful.
The methods described so far have not provided a viable
way of installing an N-sp2-C bond (Table 1, entry 8;
Table 3, entry 6; Table 4, entry 9), including direct
SNAr-type reaction of fluoropyridine with hydrazone 3a.
Direct reaction of pyrazolone 13a with diazonium salts
was then examined to address this (Table 5). Treatment
of pyrazolone 13a with aryl diazonium salts [25] resulted
in the formation of the intermediates 17j–o. After
aqueous workup, the unpurified mixtures were treated
with potassium carbonate in N,N-dimethylformamide at
100°C [26], which resulted in cyclization to provide
(Z)-3-(2-Fluorophenyl)-4-hydrazono-1-phenyl-1H-pyrazol-
5(4H)-one
(3a).
3-(2-Fluorophenyl)-1-phenyl-1H-
pyrazol-5(4H)-one [27] (1.1g, 4.1mmol) was dissolved in
acetonitrile (41mL) and treated with triethylamine (0.52g,
5.2mmol). The mixture was cooled to 0°C, treated with 4-
acetamidobenzenesulfonyl azide (1.1g, 4.5mmol) and
stirred for 30m at 0°C. The mixture was treated with
sodium carbonate (saturated aqueous, 5mL), stirred for
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D. C. Beshore, A. W. Johnson, R. M. DiPardo, D. R. Pitts, V. Cofre, and S. D. Kuduk
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5min and then poured into water (50mL) and ethyl acetate
(100mL). The resulting mixture was filtered, and the solids
were discarded. The resulting biphasic mixture was
extracted with ethyl acetate (2×50mL), and the combined
organic extracts were dried with sodium sulfate, filtered,
and concentrated in vacuo. The residue was purified via
silica gel chromatography (100:0 to 50:50; hexanes:ethyl
acetate), affording 4-diazo-3-(2-fluorophenyl)-1-phenyl-1H-
pyrazol-5(4H)-one (16) (0.78g, 67 % yield).
(200mL) and extracted with ethyl acetate (3×250mL).
The combined organic extracts were dried with sodium
sulfate, filtered, and concentrated in vacuo. The residue
was purified via silica gel flash chromatography (100:0 to
85:15; hexanes:ethyl acetate) to afford the titled compound
(5.3g, 94% yield).
IR (thin film, neat): 2984, 2141, 1723, 1628, 1613,
1487, 1452, 1370, 1306, 1252, 1221, 1172, 1122, 1099,
1012, 934, 833, 752, 692cmÀ1
.
IR (thin film, neat): 3063, 2125, 1684, 1618, 1592,
1523, 1495, 1467, 1413, 1355, 1311, 1215, 1170, 1124,
1100, 1066, 1030, 969, 905, 834, 799, 744, 725, 709,
1H-NMR (400MHz, CDCl3) δ 7.51–7.42 (2H, m), 7.22
(1H, t, J =7.5 Hz), 7.08 (1H, t, J =9.2 Hz), 4.22 (2H, q,
J = 7.3 Hz), 1.21 (3H, t, J = 7.1 Hz) ppm.
691cmÀ1
.
13C-NMR (100MHz, CDCl3) δ 183.4, 160.5, 159.7 (d,
J = 251Hz), 133.1 (d, J= 8.6 Hz), 129.3 (d, J = 2.7Hz),
126.6 (d, J= 15.0 Hz), 124.2 (d, J= 3.4 Hz), 115.5 (d,
J = 21.7Hz), 78.0, 61.9, 14.3 ppm.
1H-NMR (400 MHz, CDCl3) δ 8.02–7.98 (3H, m), 7.51–
7.41 (3H, m), 7.32–7.16 (3H, m) ppm.
13C-NMR (100 MHz, CDCl3) δ 164.3, 160.1 (d,
J =251 Hz), 138.7, 138.1, 132.4 (d, J= 8.9 Hz), 129.1,
129.1, 129.1, 125.9, 125.4 (d, J = 3.2 Hz), 119.7, 117.7
(d, J = 13.0Hz), 116.4 (d, J =21.8 Hz) ppm.
HRMS calcd for C11H9FN2Na [M + Na]: 259.0500;
found 259.0489.
(E/Z)-Ethyl 3-(2-fluorophenyl)-2-hydrazono-3-oxopropanoate
HRMS calcd for C15H10FN4O [M+ H]: 281.0833; found
(9).
Ethyl 2-diazo-3-(2-fluorophenyl)-3-oxopropanoate
281.0833.
(5.1g, 22mmol) was dissolved in tetrahydrofuran (50mL),
cooled to 0°C, and treated with tri-n-butylphosphene (4.4g,
22mmol). After stirring for 30min, the mixture was
concentrated in vacuo, and the residue was purified via
silica gel chromatography (100:0 to 50:50; hexanes:ethyl
acetate) to afford the titled compound as a white solid
(5.0g, 97% yield).
4-Diazo-3-(2-fluorophenyl)-1-phenyl-1H-pyrazol-5(4H)-
one (16, 0.72g, 2.6mmol) was dissolved in tetrahydrofuran
(10mL), cooled to 0°C, and treated with tri-n-
butylphosphene (0.55g, 2.7mmol). After stirring for
30min, the mixture was concentrated in vacuo, and the
residue was purified via silica gel flash chromatography
(100:0 to 0:100; hexanes:ethyl acetate), providing (Z)-3-
(2-fluorophenyl)-4-hydrazono-1-phenyl-1H-pyrazol-5(4H)-
one (3) (0.71g, 98 % yield).
IR (thin film, neat): 3408, 3203, 2984, 1675, 1649,
1612, 1556, 1468, 1451, 1372, 1338, 1294, 1238, 1218,
1184, 1154, 1137, 1099, 1010, 931, 870, 844, 817, 752,
IR (thin film, neat): 3346, 3144, 1671, 1584, 1526,
684 cmÀ1
.
1494, 1364, 1282, 1226, 1180, 966, 756, 692cmÀ1
.
1H-NMR (400MHz, CDCl3, 3:1 mixture of E and Z
hydrazinylimines) δ 10.0 (br s), 7.62–7.53 (m), 7.50–7.42
(m), 7.25–7.17 (m), 7.09–7.01 (m), 4.29 (q, J =7.3Hz),
4.19 (q, J = 7.3 Hz), 1.28 (t, J = 7.2 Hz), 1.15 (t,
J = 7.2 Hz) ppm.
1H-NMR (400 MHz, CDCl3)
δ
11.79 (1H, d,
J =17.5 Hz), 8.16 (1H, d, J= 16.1 Hz), 8.01 (2H, d,
J =8.6 Hz), 7.78 (1H, t, J =6.9 Hz), 7.48–7.41 (3H, m),
7.28–7.16 (3H, m) ppm.
13C-NMR (100 MHz, CDCl3) δ 160.6 (d, J = 256Hz),
157.5, 145.4, 138.1, 131.7 (d, J = 8.6 Hz), 131.2
(d, J = 2.8 Hz), 129.2, 129.1, 125.8, 124.4 (d,
J = 3.6 Hz), 119.3, 118.4 (d, J = 14.5 Hz), 116.6 (d,
J = 21.9 Hz) ppm.
13C-NMR (100MHz, CDCl3) δ 188.1, 187.6, 167.2,
164.7, 162.9, 161.8, 161.2, 159.3, 158.7, 135.4, 135.3,
133.5, 133.4, 133.2, 133.1, 132.9, 130.9, 130.8, 129.9,
129.8, 129.7, 128.2, 128.1, 124.7, 124.6, 124.3, 124.2,
117.4, 117.2, 116.0, 115.8, 115.7, 115.5, 61.3, 61.1,
14.1, 14.1 ppm.
HRMS calcd for C15H12FN4O [M+ H]: 283.0990; found
283.0990.
HRMS calcd for C11H10FN2O3 [M + H]: 239.0826;
found 239.0826.
Ethyl 2-diazo-3-(2-fluorophenyl)-3-oxopropanoate (5). Ethyl
3-(2-fluorophenyl)-3-oxopropanoate (5.0g, 24mmol) was
dissolved in acetonitrile (70mL) and treated with
triethylamine (3.8mL, 27mmol). The mixture was cooled
to 0°C and then treated with 4-acetamidobenzenesulfonyl
azide (6.29g, 26.2mmol) and an additional volume of
acetonitrile (10mL). After stirring for 30min, the mixture
was warmed to ambient temperature and stirred for an
additional 1.5h, at which time the mixture was cooled to
0°C and treated with sodium bicarbonate (saturated
aqueous, 60mL). The mixture was poured into water
Ethyl 1-(4-iodobenzyl)-4-oxo-1,4-dihydrocinnoline-3-carbox-
ylate (8c). To a flame-dried flask were added (Z)-ethyl
3-(2-fluorophenyl)-2-hydrazono-3-oxopropanoate (5.9 g,
25mmol) and degassed N,N-dimethylformamide (49 mL).
The mixture was sparged under nitrogen (3×), treated
with 1-(bromomethyl)-4-iodobenzene (7.7 g, 26mmol),
and cooled to 0°C, to which sodium hydride (1g,
27mmol) was added portionwise over 0.5 h. The mixture
was stirred at 0°C for 3 h, treated with additional sodium
hydride (1 g, 27mmol), and stirred for an additional 2 h at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones
0°C. The mixture was treated with sodium bicarbonate
(saturated aqueous, 200 mL), poured into water (250 mL),
and then treated with ethyl acetate (400 mL). The
resulting precipitate was collected via filtration, and the
resulting filtrate was concentrated in vacuo. The residue
was suspended in hexanes (200 mL) and ethyl acetate
(20 mL), and the solids were collected via filtration,
rinsed with hexanes, and combined with the previously
isolated solid to afford the titled compound (9.9 g, 93%
yield).
Ethyl
(8d).
1-butyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate
IR (thin film, neat): 3072, 2956, 2870, 1718,
1619, 1603, 1499, 1476, 1449, 1433, 1400, 1372, 1345,
1299, 1249, 1228, 1204, 1172, 1147, 1133, 1107, 1091,
1031, 940, 923, 908, 879, 818, 792, 770, 731, 716,
685 cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 8.44 (1H, dd, J = 8.4,
1.6 Hz), 7.77 (1H, ddd, J= 9.2, 6.8, 1.5 Hz), 7.55–7.47
(2H, m), 4.50–4.44 (4H, m), 1.98–1.90 (2H, m), 1.43
(3H, t, J =7.3 Hz), 1.51–1.42 (2H, m), 1.00 (3H, t,
J = 7.1 Hz) ppm.
IR (thin film, neat): 2987, 1721, 1622, 1601, 1499,
1478, 1462, 1430, 1401, 1387, 1370, 1344, 1303, 1260,
1229, 1195, 1167, 1142, 1095, 1058, 1030, 1023, 1004,
13C-NMR (100MHz, CDCl3) δ 168.3, 163.7, 140.5,
139.1, 134.2, 127.4, 127.1, 126.2, 115.6, 62.0, 56.6,
30.7, 20.1, 14.5, 13.8 ppm.
980, 939, 919, 872, 832, 799, 777, 716, 685cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.41 (1H, d, J= 8.2 Hz),
7.68 (2H, d, J= 8.5 Hz), 7.69–7.63 (1H, m), 7.46 (1H, dd,
J =8.4, 7.2Hz), 7.36 (1H,d, J =8.4 Hz), 7.27 (1H, s), 7.00
(2H, d, J =8.3 Hz), 5.62 (2H, s), 4.49 (2H, q, J= 7.0 Hz),
1.44 (3H, t, J =7.4 Hz) ppm.
HRMS calcd for C18H15N4O [M + H]: 303.1240; found
303.1240.
Ethyl
1-(but-2-yn-1-yl)-4-oxo-1,4-dihydrocinnoline-3-car-
boxylate (8f).
IR (thin film, neat): 2994, 1721, 1620,
1605, 1509, 1476, 1398, 1372, 1337, 1297, 1234, 1198,
1145, 1098, 1018, 923, 866, 832, 809, 770, 711 cmÀ1
13C-NMR (100 MHz, CDCl3) δ 168.3, 163.4, 140.5,
139.7, 138.5, 134.6, 134.4, 128.7, 127.3, 127.0, 126.5,
116.0, 94.3, 62.2, 60.3, 14.5 ppm.
.
1H-NMR (400MHz, CDCl3) δ 8.40 (1H, dd, J = 8.1,
1.5 Hz), 7.81 (1H, ddd, J= 8.6, 7.1, 1.5 Hz), 7.71 (1H, d,
J = 8.6 Hz), 7.53–7.49 (1H, m), 5.17 (2H, q, J =2.3 Hz),
4.46 (2H, q, J= 7.1 Hz), 1.83 (3H, t, J = 2.4 Hz), 1.43
(3H, t, J = 7.0 Hz) ppm.
HRMS calcd for C18H16IN2O3 [M +H]: 435.0200;
found 435.0200.
Ethyl 1-(4-(1H-pyrazol-1-yl)benzyl)-4-oxo-1,4-dihydrocinnoline
-3-carboxylate (8a). IR (thin film, neat): 2990, 1724, 1620,
1602, 1524, 1498, 1465, 1442, 1391, 1365, 1338, 1317,
1298, 1252, 1228, 1193, 1167, 1141, 1094, 1042, 1028,
13C-NMR (100MHz, CDCl3) δ 168.3, 163.2, 139.9,
139.1, 134.1, 127.0, 126.5, 126.3, 116.2, 84.8, 71.1,
61.8, 47.9, 14.3, 3.7 ppm.
979, 935, 919, 869, 832, 792, 767, 740, 683, 662cmÀ1
.
HRMS calcd for C15H15N2O3 [M + H]: 271.1077; found
271.1076.
1H-NMR (400 MHz, CDCl3) δ 8.41 (1H, dd, J = 8.2,
1.6Hz), 7.89 (1H, d, J =2.5 Hz), 7.71–7.62 (4H, m), 7.45
(1H, t, J= 7.6Hz), 7.43 (1H, d, J = 8.8 Hz), 7.34 (2H, d,
J =8.6 Hz), 5.72 (2H, s), 4.50 (2H, q, J =7.2 Hz), 1.45
(3H, t, J = 7.4Hz) ppm.
Ethyl
(8g).
1-allyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate
IR (thin film, neat): 2982, 1718, 1621, 1602,
1498, 1475, 1461, 1434, 1389, 1372, 1339, 1296, 1257,
1226, 1191, 1170, 1144, 1093, 1023, 988, 969, 918, 869,
13C-NMR (100 MHz, CDCl3) δ 168.4, 163.5, 141.6,
140.5, 140.4, 139.6, 134.3, 132.9, 128.1, 127.3, 126.9,
126.9, 126.5, 119.9, 116.2, 108.2, 62.2, 60.4, 14.5ppm.
HRMS calcd for C21H19N4O3 [M + H]: 375.1452; found
375.1452.
813, 768, 714, 685cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 8.42 (1H, d, J =8.1 Hz),
7.75 (1H, ddd, J = 8.8, 7.0, 1.5 Hz), 7.52–7.47 (2H, m),
6.10–6.00 (1H, m), 5.36 (1H, d, J =10.7 Hz), 5.26 (1H, d,
J = 17.1Hz), 5.12 (2H, dt, J = 5.3, 1.6 Hz), 4.47 (2H, q,
J = 7.1 Hz), 1.43 (3H, t, J = 7.2 Hz) ppm.
Ethyl
(8b).
1-benzyl-4-oxo-1,4-dihydrocinnoline-3-carboxylate
IR (thin film, neat): 2964, 1715, 1621, 1601,
13C-NMR (100MHz, CDCl3) δ 168.4, 163.5, 140.7,
139.6, 134.2, 131.0, 127.2, 126.9, 126.3, 119.6, 116.1,
62.0, 59.6, 14.5 ppm.
1496, 1474, 1459, 1444, 1428, 1399, 1389, 1370, 1343,
1296, 1261, 1246, 1223, 1194, 1168, 1139, 1108, 1093,
1029, 974, 922, 908, 871, 810, 799, 769, 740, 702,
HRMS calcd for C14H15N2O3 [M + H]: 259.1077; found
259.1076.
684cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.41 (1H, d, J= 7.9 Hz),
7.67–7.61 (1H, m), 7.47–7.41 (2H, m), 7.38–7.28 (3H,
m), 7.25 (2H, d, J = 7.1 Hz), 5.70 (2H, s), 4.49 (2H, qd,
J =7.2, 1.2Hz), 1.45 (3H, td, J =7.2, 1.2 Hz) ppm.
13C-NMR (100 MHz, CDCl3) δ 168.4, 163.5, 140.7,
139.6, 134.9, 134.3, 129.4, 128.7, 127.4, 126.9, 126.8,
126.3, 116.3, 62.1, 60.9, 14.5ppm.
Ethyl 1-(4-iodobenzyl)-4-thioxo-1,4-dihydrocinnoline-3-car-
boxylate
(10).
Ethyl 1-(4-iodobenzyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxylate (3.0 g, 6.9 mmol) was
dissolved in dioxane (12 mL) and toluene (6 mL). The
mixture was heated at 110°C and then treated with
Lawesson’s Reagent (1.5 g, 3.8 mmol) portionwise over
10min. The mixture was stirred at 110°C for an
additional 30min, cooled to ambient temperature, and
then concentrated in vacuo. The residue was purified via
HRMS calcd for C18H17N2O3 [M + H]: 309.1234; found
309.1236.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. C. Beshore, A. W. Johnson, R. M. DiPardo, D. R. Pitts, V. Cofre, and S. D. Kuduk
Vol 000
silica gel chromatography (100:0 to 50:50; hexanes:ethyl
acetate) to afford the titled compound (2.9 g, 93% yield).
IR (thin film, neat): 2976, 1734, 1598, 1561, 1494,
1438, 1401, 1370, 1345, 1302, 1258, 1232, 1211, 1170,
HRMS calcd for C22H16IN4O [M + H]: 479.0363; found
479.0364.
5-(4-Iodobenzyl)-2H-pyrazolo[4,3-c]cinnolin-3(5H)-one
(12a). IR (thin film, neat): 2978, 2849, 2755, 1679, 1635,
1577, 1548, 1497, 1483, 1460, 1436, 1402, 1339, 1304,
1291, 1246, 1223, 1182, 1156, 1105, 1060, 1036, 1006,
968, 950, 937, 859, 832, 793, 781, 750, 730, 714, 699,
1132, 1033, 1004, 927, 826, 814, 769, 658cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.65 (1H, dd, J = 8.4,
1.3Hz), 7.68 (2H, d, J = 8.3 Hz), 7.70–7.63 (1H, m),
7.46–7.42 (1H, m), 7.38 (1H, d, J = 8.6 Hz), 7.02 (2H, d,
J =8.3 Hz), 5.56 (2H, s), 4.48 (2H, q, J =7.3 Hz), 1.43
(3H, t, J = 7.1Hz) ppm.
663cmÀ1
.
1H-NMR (400MHz, DMSO-d6) δ 12.02 (1H, s), 8.12
(1H, d, J = 8.5 Hz), 7.81 (1H, d, J =8.5 Hz), 7.71 (2H, d,
J = 7.7 Hz), 7.70–7.65 (1H, m), 7.60 (1H, t, J =7.7 Hz),
7.14 (2H, d, J= 8.5 Hz), 5.84 (2H, s) ppm.
13C-NMR (100 MHz, CDCl3) δ 185.7, 164.8, 151.2,
138.6, 136.3, 135.8, 135.0, 134.3, 129.2, 128.7, 127.7,
116.5, 94.4, 62.5, 60.4, 14.3 ppm.
13C-NMR (100 MHz, DMSO-d6) δ 162.3, 138.3, 136.4,
135.9, 133.3, 131.7, 129.9, 128.9, 122.6, 119.7, 118.1,
94.8, 59.8 ppm.
HRMS calcd for C18H16IN2O2S [M + H]: 450.9972;
found 450.9967.
HRMS calcd for C16H12IN4O [M + H]: 403.0050; found
403.0048.
2-Benzyl-5-(4-iodobenzyl)-2H-pyrazolo[4,3-c]cinnolin-3(5H)-
one (12e)
5-(4-Iodobenzyl)-2-methyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-
one (12b). IR (thin film, neat): 3336, 3055, 2928, 1715,
1673, 1636, 1584, 1555, 1510, 1483, 1461, 1430, 1401,
1366, 1313, 1287, 1265, 1242, 1224, 1173, 1119, 1090,
1039, 1023, 1004, 984, 965, 934, 878, 830, 793, 756, 745,
Method
A.
Ethyl
1-(4-iodobenzyl)-4-thioxo-1,4-
dihydrocinnoline-3-carboxylate (0.20 g, 0.44mmol) and
potassium carbonate (0.61 mg, 4.4 mmol) were combined
in dimethoxyethane (4.4 mL), and the mixture was treated
with benzylhydrazine hydrochloride (0.11 g, 0.67mmol).
The mixture was heated at 50°C for 16 h, cooled to
ambient temperature, and then poured into water (50 mL).
The mixture was extracted with ethyl acetate (3 × 50mL),
and the combined organic extracts were dried with
sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified via silica gel chromatography (100:0
to 0:100; hexanes:10% methanol in ethyl acetate) to
afford the titled compound (6mg, 3% yield).
711, 692cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 8.26–8.22 (1H, m), 7.66
(2H, d, J= 8.5 Hz), 7.68–7.63 (1H, m), 7.57–7.53 (1H, m),
7.49–7.44 (1H, m), 5.75 (2H, s), 3.71 (3H, s) ppm.
13C-NMR (100MHz, CDCl3) δ 160.0, 138.5, 135.7,
134.6, 132.1, 131.2, 129.5, 128.8, 128.4, 125.0, 123.2,
116.7, 94.4, 60.9, 32.9ppm.
HRMS calcd for C17H14IN4O [M + H]: 417.0207; found
417.0201.
Method
B.
Ethyl
1-(4-iodobenzyl)-4-thioxo-1,4-
2-(tert-Butyl)-5-(4-iodobenzyl)-2H-pyrazolo[4,3-c]cinnolin-
3(5H)-one (12c). IR (thin film, neat): 1664, 1589, 1447,
dihydrocinnoline-3-carboxylate (0.10 g, 0.22mmol) and
potassium carbonate (0.31 mg, 2.2 mmol) were combined
in dimethoxyethane (2.2 mL), and the mixture was treated
with benzylhydrazine hydrochloride (0.05 g, 0.33mmol)
and mercury(II) chloride (0.06 g, 0.22 mmol). The
mixture was heated at 50°C for 16 h, cooled to ambient
temperature, and then poured into water (60 mL). The
mixture was extracted with ethyl acetate (3 × 50 mL), and
the combined organic extracts were dried with sodium
sulfate, filtered, and concentrated in vacuo. The residue
was purified via silica gel chromatography (100:0 to
85:15; dichloromethane:methanol) to afford the titled
compound (65 mg, 60 % yield).
1357, 1279, 1238, 1039, 1000, 957, 791, 759, 731 cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 8.26–8.20 (1H, m), 7.65
(2H, d, J= 8.5 Hz), 7.52–7.45 (2H, m), 7.40–7.36 (1H, m),
7.02 (2H, d, J= 8.3 Hz), 5.69 (2H, s), 1.71 (9H, s) ppm.
13C-NMR (100MHz, CDCl3) δ 160.2, 138.4, 137.8,
135.7, 135.0, 130.8, 130.7, 128.8, 127.8, 123.2, 119.6,
116.4, 94.2, 60.5, 58.9, 28.6ppm.
HRMS calcd for C20H20IN4O [M + H]: 459.0676; found
459.0679.
2-Benzyl-5-(4-iodobenzyl)-2H-pyrazolo[4,3-c]cinnolin-3(5H)-
one (12d). IR (thin film, neat): 3329, 3062, 3029, 2964,
2925, 1959, 1670, 1590, 1555, 1483, 1458, 1405, 1364,
1346, 1327, 1288, 1260, 1240, 1201, 1120, 1093, 1059,
1025, 1004, 965, 933, 880, 857, 791, 749, 735, 703,
IR (thin film, neat): 1662, 1587, 1483, 1459, 1401,
1351, 1301, 1230, 1126, 790, 750, 728, 689 cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.38–8.33 (1H, m), 8.22
(2H, d, J= 7.8Hz), 7.68 (2H, d, J = 8.6 Hz), 7.60–7.54 (2H,
m), 7.51–7.46 (3H, m), 7.25 (1H, t, J= 7.2 Hz), 7.05 (2H,
d, J = 8.2Hz), 5.75 (2H, s) ppm.
667cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.25–8.22 (1H, m), 7.69–
7.65 (2H, m), 7.05–7.00 (2H, m), 7.55–7.42 (6H, m), 7.35–
7.24 (3H, m), 5.73 (2H, s), 5.26 (2H, s) ppm.
13C-NMR (100 MHz, CDCl3) δ 159.2, 139.5, 138.5,
136.4, 136.2, 134.6, 133.5, 131.6, 129.2, 128.8, 128.5,
125.7, 123.7, 120.0, 119.3, 116.8, 94.4, 60.9ppm.
13C-NMR (100MHz, CDCl3) δ 179.2, 154.6, 138.6,
138.5, 137.3, 135.8, 134.7, 131.3, 131.2, 128.8, 128.5,
128.3, 127.8, 123.5, 119.5, 116.6, 94.4, 60.9, 49.3ppm.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones
HRMS calcd for C23H18IN4O [M + H]: 493.0520; found
493.0516.
(d, J = 8.9 Hz), 131.3 (d, J =2.2 Hz), 129.3, 126.3, 124.5
(d, J = 4.2 Hz), 119.1, 117.3 (d, J = 12.3Hz), 116.9, 116.7,
84.5, 28.2 ppm.
HRMS calcd for C20H20FN4O3 [M + H]: 383.1514;
found 383.1509.
4-(5-(4-Iodobenzyl)-3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]cinnolin-
2-yl)benzonitrile (12g). IR (thin film, neat): 2217, 1688, 1589,
1486, 1462, 1438, 1402, 1348, 1317, 1242, 1197, 1173,
1125, 1099, 1006, 983, 956, 930, 838, 810, 784, 758, 738,
5-Benzyl-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-one
(18a). (Z)-3-(2-Fluorophenyl)-4-hydrazono-1-phenyl-1H-
pyrazol-5(4H)-one (0.21g, 0.74mmol) and benzyl bromide
(0.15g, 0.88mmol) were dissolved in degassed N,N-
dimethylformamide (2.5mL). The mixture was cooled to
0°C, treated with sodium hydride (0.06g, 1.5mmol), and
stirred for 3h 0°C. The mixture was poured into water
(10mL) and extracted with ethyl acetate (3×10mL). The
combined organic extracts were washed with water
(3×25mL) and brine (1×25mL), dried with sodium
sulfate, filtered, and concentrated in vacuo to afford the
titled compound. The resulting residue was used without
further purification.
(Z)-4-(2-Benzylhydrazono)-3-(2-fluorophenyl)-1-phenyl-
1H-pyrazol-5(4H)-one (0.27g, 0.74mmol) was dissolved in
degassed N,N-dimethylformamide (10mL), which was
slowly added via syringe pump over 1h to a suspension of
potassium carbonate (0.92g, 6.6mmol) in degassed N,N-
dimethylformamide (27mL) stirring at 70°C. The mixture
was stirred for an additional 2.5h at 70°C, cooled to
ambient temperature, and poured into water/brine (150mL,
3:1). The resulting mixture was extracted with ethyl acetate
(3×70mL), and the combined organic extracts were
combined, washed with water:brine (150mL, 3:1), dried
with sodium sulfate, filtered, and concentrated in vacuo.
The residue was purified via silica gel chromatography
(100:0 to 40:60; hexanes:ethyl acetate) to afford the titled
compound (0.18g, 71% yield).
692, 653cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.47 (2H, d, J= 9.2 Hz),
8.37–8.34 (1H, m), 7.75 (2H, d, J = 9.1 Hz), 7.69 (2H, d,
J =8.5 Hz), 7.66–7.59 (2H, m), 7.53–7.50 (1H, m), 7.05
(2H, d, J= 8.6Hz), 5.77 (2H, s) ppm.
13C-NMR (100 MHz, CDCl3) δ 159.8, 142.9, 138.6,
136.4, 135.8, 134.7, 134.3, 133.3, 132.2, 128.9, 128.8,
123.8, 119.3, 119.2, 119.1, 117.0, 108.2, 94.6, 61.2ppm.
HRMS calcd for C23H15IN5O [M + H]: 504.0316; found
504.0304.
3-(2-Fluorophenyl)-1-phenyl-1H-pyrazol-5(4H)-one (13a).
The preparation of compound 13a has been described in
the literature [19].
IR (thin film, neat): 3680, 2971, 2449, 1595, 1555, 1513,
1461, 1433, 1382, 1343, 1266, 1224, 1192, 1151, 1106,
1071, 1032, 1018, 967, 910, 822, 752, 687, 671cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.10 (1H, td, J = 7.7,
1.9Hz), 7.99–7.95 (2H, m), 7.46–7.40 (3H, m), 7.27–
7.20 (2H, m), 7.15 (1H, ddd, J = 11.3, 8.4, 0.9 Hz), 3.96
(2H, d, J= 3.0Hz) ppm.
13C-NMR (100 MHz, CDCl3) δ 170.8, 170.7, 161.1 (d,
J=255Hz), 150.9 (d, J=2.0Hz), 138.2, 132.5 (d, J=8.8Hz),
129.1, 127.8 (d, J=2.7 Hz), 125.6, 124.9 (d, J=3.4Hz),
119.3, 116.8 (d, J= 21.9 Hz), 42.7 (d, J= 8.8 Hz) ppm.
HRMS calcd forC15H12FN2O [M+ H]: 255.0928; found
255.0928.
(Z)-tert-Butyl
2-(3-(2-fluorophenyl)-5-oxo-1-phenyl-1H-
pyrazol-4(5H)-ylidene)hydrazinecarboxylate (17g).
Fluorophenyl)-4-hydrazono-1-phenyl-1H-pyrazol-5(4H)-one
(1.1g, 3.9mmol) was dissolved in dichloromethane (30mL),
(Z)-3-(2-
IR (thin film, neat): 3065, 1678, 1592, 1492, 1453,
1413, 1358, 1318, 1241, 1193, 1127, 1106, 1028, 978,
956, 906, 822, 745, 727, 692cmÀ1
.
treated
with
N,N-dimethylaminopyridine
(0.05g,
1H-NMR (400MHz, CDCl3) δ 8.35 (1H, d, J =8.3 Hz),
8.23 (2H, d, J =7.6 Hz), 7.58–7.52 (3H, m), 7.50–7.46
(2H, m), 7.37–7.28 (5H, m), 7.27–7.23 (1H, m), 5.82
(2H, s) ppm.
0.39mmol), cooled to 0°C, and treated with di-tert-butyl
dicarbonate (0.94g, 4.3mmol). The ice bath was removed,
and the mixture was stirred for an additional 16h at
ambient temperature. The mixture was diluted in
dichloromethane (100mL total) and washed with water
(2×40mL), and the organic extract was dried with sodium
sulfate, filtered, and concentrated in vacuo. The crude
residue was purified via silica gel chromatography (100:0 to
85:15; hexane:ethyl acetate) to afford the titled compound
as an orange solid (1.3g, 90% yield).
13C-NMR (100MHz, CDCl3) δ 159.3, 139.6, 136.3,
134.9, 133.6, 131.5, 129.4, 129.1, 128.8, 128.4, 126.9,
125.6, 123.5, 123.4, 119.9, 119.3, 117.1, 61.5 ppm.
HRMS calcd for C22H17N4O [M + H]: 353.1397; found
353.1395.
5-Butyl-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-one (18b)
Method A.
(Z)-tert-Butyl 2-(3-(2-fluorophenyl)-5-oxo-
IR (thin film, neat): 3226, 2980, 1762, 1673, 1597, 1568,
1542, 1485, 1462, 1394, 1368, 1328, 1252, 1229, 1210,
1-phenyl-1H-pyrazol-4(5H)-ylidene)hydrazinecarboxylate
(0.20 g, 0.52 mmol) was dissolved in degassed N,N-
dimethylformamide (11 mL) and then treated successively
with potassium carbonate (0.72mg, 5.2 mmol) and 1-
iodobutane (0.96 g, 5.2 mmol). The mixture was heated at
50°C for 20h, cooled to ambient temperature, and diluted
with ethyl acetate (100mL). The mixture was washed with
1124, 958, 896, 849, 819, 790, 755, 685, 671, 655 cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 12.81 (1H, s), 8.02–7.92 (3H,
m), 7.50–7.41 (3H, m), 7.30–7.17 (3H, m), 1.58 (9H, s) ppm.
13C-NMR (100 MHz, CDCl3) δ 160.8 (d, J = 256Hz),
156.2, 151.1, 145.5 (d, J= 2.8 Hz), 137.5. 133.2, 132.1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. C. Beshore, A. W. Johnson, R. M. DiPardo, D. R. Pitts, V. Cofre, and S. D. Kuduk
Vol 000
brine (2×150mL), dried with sodium sulfate, filtered, and
concentrated in vacuo to afford the titled compound. The
residue was used without further purification.
silica gel chromatography (100:0 to 50:50; hexanes:ethyl
acetate) to afford the titled compound as a red solid
(22 mg, 14% yield).
To
a
vigorously stirring mixture of potassium
IR (thin film, neat): 2919, 2234, 1677, 1587, 1489,
1459, 1352, 1309, 1235, 1194, 1125, 1104, 973, 949,
carbonate (0.72 g, 5.2 mmol, 10 equiv) in N,
N-dimethylformamide (46 mL) at 100°C was added a N,
N-dimethylformamide (6 mL) solution of tert-butyl 1-
butyl-2-(3-(2-fluorophenyl)-5-oxo-1-phenyl-1H-pyrazol-
4(5H)-ylidene)hydrazinecarboxylate (0.23 g, 0.52 mmol)
over 1 h via syringe pump. The mixture was stirred for
an additional hour at 100°C, cooled to ambient
temperature, and diluted with ethyl acetate (140 mL).
The mixture was washed with brine (3 × 90 mL), dried
with sodium sulfate, filtered, and concentrated in vacuo.
The residue was purified via silica gel chromatography
(100:0 to 50:50; hexanes:ethyl acetate) to afford the
titled compound as a red solid (130 mg, 79% yield).
IR (thin film, neat): 2926, 2867, 2952, 1669, 1586,
1545, 1486, 1455, 1414, 1352, 1297, 1239, 1202, 1125,
817, 750, 689cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 8.36 (1H, d, J =8.2Hz),
8.20 (2H, d, J = 8.2 Hz), 7.81 (1H, d, J = 8.6 Hz), 7.75–
7.71 (1H, m), 7.62 (1H, t, J = 8.2 Hz), 7.49–7.44 (2H, m),
7.27–7.21 (1H, m), 5.30 (2H, m), 1.82 (3H, m) ppm.
13C-NMR (100MHz, CDCl3) δ 159.0, 139.4, 135.9,
135.7, 133.6, 131.4, 12.9.0, 128.3, 125.5, 123.3, 119.8,
119.01, 117.0, 85.1, 71.2, 48.6, 3.7 ppm.
HRMS calcd for C19H15N4O [M + H]: 315.1240; found
315.1241.
5-Allyl-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-one
(18d). IR (thin film, neat): 1676, 1590, 1578, 1556, 1489,
1461, 1439, 1414, 1357, 1330, 1308, 1235, 1215, 1195,
1178, 1125, 1101, 1091, 1049, 991, 979, 951, 939, 915,
1089, 1052, 966, 910, 817, 753, 739, 691cmÀ1
.
846, 817, 767, 744, 726, 690, 670, 651cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, dd, J = 7.8,
1.4Hz), 8.24–8.19 (2H, m), 7.68–7.63 (1H, m), 7.60–
7.54 (2H, m), 7.45 (2H, m), 7.22 (1H, br t, J= 7.6 Hz),
4.59 (2H, t, J= 7.8 Hz), 2.00–1.92 (2H, m), 1.52–14.42
(2H, m), 0.99 (3H, t, J = 7.4 Hz) ppm.
1H-NMR (400MHz, CDCl3) δ 8.29–8.24 (1H, m), 8.19
(2H, d, J=8.7Hz), 7.63–7.50 (3H, m), 7.47–7.41 (2H, m),
7.24–7.19 (1H, m), 6.11–5.99 (1H, m), 5.35 (1H, d,
J=10.4Hz), 5.27 (1H, d, J=17.1Hz), 5.22–5.17 (2H, m)
ppm.
13C-NMR (100 MHz, CDCl3) δ 159.2, 139.7, 136.0,
135.5, 133.6, 131.5, 129.1, 128.3, 125.5, 123.6, 119.8,
119.2, 116.4, 57.4, 30.9, 20.1, 13.9ppm.
13C-NMR (100MHz, CDCl3) δ 159.1, 139.6, 136.2,
135.9, 133.5, 131.5, 131.0, 129.1, 128.4, 125.5, 123.4,
120.0, 119.7, 118.9, 116.9, 60.1ppm.
HRMS calcd for C19H19N4O [M + H]: 319.1553; found
319.1556.
HRMS calcd for C18H15N4O [M + H]: 303.1240; found
303.1240.
5-(But-2-yn-1-yl)-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-
one (18c)
5-Isobutyl-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-one
(18e).
IR (thin film, neat): 2948, 1669, 1585, 1490,
1452, 1413, 1393, 1340, 1305, 1216, 1174, 1152, 1123,
1088, 1057, 1025, 970, 900, 818, 743, 683 cmÀ1
Method
B.
t-Butyl
1-(but-2-ynyl)-2-(3-(2-
fluorophenyl)-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)
hydrazinecarboxylate, (0.23 g, 0.52 mmol) was dissolved in
dichloromethane (4.8 mL) and treated with trifluoroacetic
acid (0.48 mL). After stirring at ambient temperature for
4 h, the mixture was treated with sodium bicarbonate
(20 mL, saturated aqueous) and water (20 mL). The
mixture was extracted with ethyl acetate (3 × 50 mL), and
the combined organic extracts were dried with sodium
sulfate, filtered, and concentrated in vacuo to afford the
titled compound, which was used without purification.
To a vigorously stirring mixture of potassium carbonate
(0.72g, 5.2mmol, 10 equiv) in N,N-dimethylformamide
(46 mL) at 70°C was added a N,N-dimethylformamide
(6 mL) solution of 4-[2-(but-2-yn-1-yl)hydrazinylidene]-
5-(2-fluorophenyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-
one (16c, 0.18g, 0.52mmol, 1 equiv) over 1 h via syringe
pump. After stirring for an additional 1h at 70°C, the
mixture was cooled to ambient temperature and diluted
with ethyl acetate (140 mL). The mixture was washed
with brine (3 × 90 mL), dried with sodium sulfate, filtered,
and concentrated in vacuo. The residue was purified by
.
1H-NMR (400MHz, CDCl3) δ 8.33 (1H, d, J =8.6Hz),
8.22 (2H, d, J =8.2 Hz), 7.69–7.63 (1H, m), 7.61–7.54
(2H, m), 7.49–7.42 (2H, m), 7.26–7.20 (1H, m), 4.41
(2H, dd, J = 7.5, 2.9 Hz), 2.47–2.36 (1H, m), 1.02 (6H,
dd, J =6.5, 3.2 Hz) ppm.
13C-NMR (100MHz, CDCl3) δ 159.3, 139.7, 136.3,
135.4, 133.5, 131.4, 129.1, 128.3, 125.5, 123.5, 119.8,
119.1, 116.6, 64.2, 28.6, 20.2ppm.
HRMS calcd for C19H19N4O [M + H]: 319.1553; found
319.1555.
( )-2-Phenyl-5-(1-phenylethyl)-2H-pyrazolo[4,3-c]cinnolin-
3(5H)-one (18g). IR (thin film, neat): 2930, 2850, 1759,
1664, 1595, 1580, 1571, 1552, 1488, 1463, 1414, 1381,
1339, 1325, 1295, 1247, 1226, 1177, 1124, 1058, 1029,
997, 980, 955, 909, 839, 818, 757, 747, 724, 689, 671,
653 cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 8.36–8.33 (1H, m), 8.25
(2H, dd, J= 8.6, 1.3 Hz), 7.64–7.61 (1H, m), 7.57–7.44
(4H, m), 7.36–7.22 (6H, m), 6.05 (1H, q, J =6.9 Hz),
2.09 (3H, d, J= 6.7 Hz) ppm.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
2,5-Disubstituted Pyrazolo[4,3-c]cinnolin-3-ones
13C-NMR (100 MHz, CDCl3) δ 159.5, 141.0, 139.8,
136.6, 135.4, 133.5, 131.3, 129.4, 129.1, 128.5, 128.1,
126.0, 125.5, 123.5, 119.9, 119.5, 117.0, 64.8, 22.9ppm.
HRMS calcd for C23H19N4O [M + H]: 367.1553; found
367.1557.
aqueous). The mixture was extracted with ethyl acetate
(3×50mL), and the combined organic extracts were dried
with sodium sulfate, filtered, and concentrated in vacuo
and was used without further purification.
To
a vigorously stirring mixture of potassium
5-(2-Methoxyethyl)-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-
carbonate (0.64 g, 4.6 mmol) in N,N-dimethylformamide
(36 mL) at 100°C was added a N,N-dimethylformamide
(10 mL) solution of (Z)-3-(2-fluorophenyl)-1-phenyl-
4-(2-phenylhydrazono)-1H-pyrazol-5(4H)-one (0.17 g,
0.46 mmol) over 1 h via syringe pump. The mixture was
stirred for an additional 1 h at 100°C, cooled to
ambient temperature, and diluted with ethyl acetate
(100 mL). The mixture was washed with brine
(2 × 100 mL), dried with sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified via
3(5H)-one (18h).
IR (thin film, neat): 2918, 1672,
1589, 1489, 1453, 1410, 1363, 1317, 1246, 1192,
1114, 1086, 1048, 1018, 980, 907, 816, 754, 727,
689 cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.34 (1H, dd, J = 8.1,
1.6Hz), 8.23–8.20 (2H, m), 7.78 (1H, d, J = 9.0 Hz), 7.67
(1H, ddd, J = 8.5, 7.3, 1.7 Hz), 7.60–7.56 (1H, m), 7.46
(dd, J =8.6, 7.6Hz), 7.23 (1H, t, J= 7.6 Hz), 4.76 (2H, t,
J =5.5 Hz), 3.94 (2H, t, J =5.5 Hz), 3.33 (3H, s) ppm.
13C-NMR (100 MHz, CDCl3) δ 159.2, 139.6, 137.2,
136.0, 133.7, 131.4, 129.1, 128.3, 125.5, 123.3, 119.9,
118.9, 117.1, 70.8, 59.4, 56.5ppm.
silica
gel
chromatography
(100:0
to
98:2;
dichloromethane:methanol) to afford the titled
compound (0.15 g, 99% yield).
HRMS calcd for C18H17N4O2 [M + H]: 321.1346; found
321.1348.
IR (thin film, neat): 3048, 1677, 1575, 1486, 1455,
1406, 1342, 1303, 1237, 1172, 1147, 1110, 988, 940,
5-(2-Fluoroethyl)-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-
one (18i). IR (thin film, neat): 2956, 1674, 1591, 1491,
1463, 1414, 1354, 1313, 1257, 1241, 1129, 1088, 1015,
801, 763, 719, 694cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.41–8.36 (1H, m), 8.26–
8.21 (2H, m), 7.66–7.44 (9H, m), 7.34–7.28 (1H, m), 7.28–
7.21 (1H, m)ppm.
982, 947, 860, 813, 747, 728, 693 cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.38 (1H, d, J= 8.0 Hz),
8.21 (2H, d, J = 8.5 Hz), 7.72 (2H, d, J =3.8 Hz), 7.65–
7.59 (1H, m), 7.48 (2H, t, J =7.9 Hz), 7.27–7.22 (1H, m),
4.96 (2H, dt, J= 75.7, 4.9 Hz), 4.94 (2H, dt, J = 9.0,
4.6Hz), ppm.
13C-NMR (100MHz, CDCl3) δ 159.3, 142.1, 139.5,
137.5, 136.8, 133.4, 131.2, 130.2, 130.1, 129.1, 128.5,
127.4, 125.6, 123.2, 119.9, 118.7, 118.4 ppm.
HRMS calcd for C21H15N4O [M + H]: 339.1240; found
339.1243.
13C-NMR (100 MHz, CDCl3) δ 159.0, 139.5, 137.1,
133.5, 131.7, 129.1, 128.4, 125.7, 123.5, 120.0, 118.9,
116.5, 116.4, 82.0 (d, J =174 Hz), 56.5 (d, J = 20.1) ppm.
HRMS calcd for C17H14FN4O [M+ H]: 309.1146; found
309.1151.
5-(4-Bromophenyl)-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-3
(5H)-one (18k). IR (thin film, neat): 3059, 1673, 1592,
1553, 1480, 1455, 1409, 1340, 1304, 1276, 1236, 1193,
1171, 1148, 1107, 1066, 986, 903, 846, 827, 799, 763,
753, 727, 688, 653 cmÀ1
.
2,5-Diphenyl-2H-pyrazolo[4,3-c]cinnolin-3(5H)-one
1H-NMR (400 MHz, CDCl3) δ 8.46–8.35 (1H, m), 8.31–
8.19 (2H, m), 7.84–7.72 (2H, m), 7.69–7.42 (5H, m), 7.38–
7.23 (3H, m) ppm.
(18j).
Aniline (0.5g, 5.4mmol) was dissolved in
tetrahydrofuran (27mL) and treated with para-
toluenesulfonic acid (1.0g, 5.9mmol) and then acetic acid
(27mL). The mixture was cooled to À10°C, treated with
tert-butyl nitrite (0.83g, 8.1mmol), and stirred at À10°C
for an additional 30min. The mixture was warmed
to ambient temperature, stirred for 30min, and then cooled
to À10°C. The mixture was filtered, and the solids
were collected via filtration. The resulting solids were dried
13C-NMR (100MHz, CDCl3) δ 159.1, 141.2, 139.4,
137.2, 137.1, 133.4, 133.1, 131.3, 129.1, 129.0, 128.6,
125.7, 124.2, 123.4, 119.8, 118.6, 117.9 ppm.
HRMS calcd for C21H14BrN4O [M + H]: 417.0346;
found 417.0347.
5-(4-Methoxyphenyl)-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-
3(5H)-one (18l). IR (thin film, neat): 3048, 3003, 1677,
1592, 1575, 1552, 1504, 1487, 1456, 1438, 1406, 1343,
1298, 1250, 1237, 1191, 1176, 1148, 1110, 1090, 1026,
1000, 988, 941, 908, 844, 833, 810, 779, 767, 758, 731,
in
vacuo
to
afford
benzenediazonium
4-
methylbenzenesulfonate as white crystals, which were used
without further purification [26].
3-(2-Fluorophenyl)-1-phenyl-1H-pyrazol-5(4H)-one
(0.12g, 0.46mmol) was dissolved in acetonitrile (5.0mL)
and was treated with N-ethyl-N-isopropylpropan-2-amine
(0.07g, 0.55mmol), followed by benzenediazonium 4-
methylbenzenesulfonate (0.13g, 0.48mmol). The mixture
was stirred at ambient temperature for 15min and then
poured into sodium bicarbonate (30mL, saturated
715, 704, 691, 655 cmÀ1
.
1H-NMR (400MHz, CDCl3) δ 8.36 (1H, d, J =7.8 Hz),
8.23 (2H, d, J =8.5 Hz), 7.60–7.42 (6H, m), 7.32–7.21
(2H, m), 7.08 (2H, d, J = 8.8 Hz), 3.91 (3H, s) ppm.
13C-NMR (100MHz, CDCl3) δ 160.7, 159.3, 139.6,
137.8, 135.5, 135.0, 133.4, 131.1, 129.1, 128.6, 128.4,
125.5, 123.1, 119.9, 118.7, 118.5, 115.1, 55.9 ppm.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. C. Beshore, A. W. Johnson, R. M. DiPardo, D. R. Pitts, V. Cofre, and S. D. Kuduk
Vol 000
[2] Blurton, P.; Fletcher, S. R. Preparation of tricyclic pyrazolo-
pyridazinone analogs as GABAA receptor ligands. PCT Int Appl 1999,
WO 9900391 A1 19990107.
[3] Mathews, I. R. Preparation of oxopyrazolocinnolines as CD80
inhibitors useful as immunomodulators. PCT Int Appl 2004 WO
2004081011 A1 20040923.
[4] Huxley, P.; Sutton, D. H.; Debnam, P.; Matthews, I. R.;
Brewer, J. E.; Rose, J.; Trickett, M.; Williams, D. D.; Andersen, T. B.;
Classon, B. J. Chem Biol 2004, 11, 1651.
[5] Treatment of 8a with phosphorus oxychloride and subsequent
treatment with a substituted hydrazine did not lead to pyrazolo[4,3-c]
cinnolin-3-one formation; data not shown.
HRMS calcd for C22H17N4O2 [M + H]: 369.1346; found
369.1343.
5-(4-Fluorophenyl)-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-
3(5H)-one (18m). IR (thin film, neat): 3052, 1674, 1578,
1489, 1455, 1407, 1340, 1302, 1216, 1150, 1093, 988,
941, 910, 849, 818, 787, 755, 693cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.40 (1H, d, J=7.7Hz),
8.25–8.21 (2H, m), 7.63–7.45 (6H, m), 7.33–7.23 (4H, m) ppm.
13C-NMR (100 MHz, CDCl3) δ 164.5, 160.6 (d,
J =283 Hz), 139.5, 138.1 (d, J= 4.4 Hz), 137.5, 137.0,
133.2, 131.3, 129.4 (d, J = 8.9 Hz), 129.1, 128.6, 125.7,
123.3, 119.9, 118.6, 118.0, 117.2 (d, J= 23.2 Hz) ppm.
HRMS calcd forC21H14FN4O [M+ H]: 357.1142; found
357.1146.
[6] Miyamoto, T.; Matsumoto, J. Chem Pharm Bull 1988, 36,
1321.
[7] For a general review of cinnoline chemistry see: N. Haider and
W. Holzer, Sci Synth, Product Class 9: Cinnolines 16, 2004, p. 251.
[8] Dowlatshahi, H. A. Synth Commun 1985, 15, 1095.
[9] Gyorkos, A. C.; Corrette, C. P.; Cho, S. Y.; Turner, T. M.;
Aso, K.; Kori, M.; Gyoten, M.; Condroski, K. R.; Siedem, C. S.; Boyd,
S. A. PCT Int Appl, 2005, WO 2005099688 A2 20051027.
[10] Ohsumi, T.; Neuhoeffer, H. Tetrahedron 1992, 48, 651.
[11] Crespo, M. I.; Gràcia, J.; Puig, C.; Vega, A.; Bou, J.; Beleta, J.;
Doménech, T.; Ryder, H.; Segarra, V.; Palacios, J. Bioorg Med Chem Lett
2000, 10, 2661.
[12] Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S. O.
Bull Soc Chim Belg 1978, 87, 223.
[13] When Conditions A from Table 2 were employed, exclusive
formation of dimer was observed by LC/MS (see below). Employing
excess hydrazine (40 equiv) in ethanol suppressed dimer formation.
2-Phenyl-5-(o-tolyl)-2H-pyrazolo[4,3-c]cinnolin-3(5H)-one
(18n).
IR (thin film, neat): 3056, 1669, 1588, 1572,
1552, 1487, 1457, 1409, 1341, 1299, 1239, 1192, 1159,
1108, 1046, 989, 908, 813, 755, 732, 687 cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.41 (1H, d, J= 8.2 Hz),
8.25 (2H, d, J= 7.4 Hz), 7.63–7.35 (7H, m), 7.28–7.22
(2H, m), 7.03 (1H, d, J =8.9 Hz), 2.08 (3H, s) ppm.
13C-NMR (100 MHz, CDCl3) δ 159.3, 140.8, 139.6,
137.6, 136.9, 136.0, 133.4, 131.9, 131.5, 130.7, 129.1,
128.5, 128.2, 127.8, 125.6, 123.2, 120.0, 118.5, 117.9,
17.5ppm.
HRMS calcd for C22H16N4O [M + H]: 353.1397; found
353.1396.
Methyl
2-(3-oxo-2-phenyl-2H-pyrazolo[4,3-c]cinnolin-5
(3H)-yl)benzoate (18o). IR (thin film, neat): 3032, 1719,
1672, 1590, 1572, 1550, 1487, 1455, 1409, 1342, 1301,
1271, 1240, 1191, 1139, 1114, 1084, 1056, 991, 940,
906, 828, 800, 761, 719, 705, 689 cmÀ1
.
1H-NMR (400 MHz, CDCl3) δ 8.41 (1H, dd, J = 8.0,
1.2Hz), 8.27–8.22 (3H, m), 7.82 (1H, td, J =7.6, 1.6 Hz),
7.72 (1H, t, J= 7.9 Hz), 7.60–7.55 (2H, m), 7.53–7.45
(3H, m), 7.25 (t, J= 7.6 Hz), 7.00 (1H, d, J= 8.7Hz), 3.59
(3H, s) ppm.
[14] Data not shown.
[15] Satchell, D. P. N.; Satchell, R. S. Chem Soc Rev 1990, 19, 55.
[16] Corey, E. J.; Bock, M. G. Tetrahedron Lett 1975, 16, 2643.
[17] Bülow, C.; Göller, H. Ber 1911, 44, 2835.
13C-NMR (100 MHz, CDCl3) δ 164.3, 159.3, 141.6,
139.6, 138.3, 136.8, 134.2, 133.6, 132.7, 131.2, 130.8,
129.8, 128.5, 128.2, 125.6, 123.2, 120.0, 118.3, 117.5,
52.8ppm.
[18] Grob, C. A.; Rumpf, J. A. Helv Chim Acta 1954, 174, 1479.
[19] Beshore, D.; DiPardo, R.; Kuduk, S. Tetrahedron Lett 2010,
51, 970.
[20] Raushel, J.; Pitram, S. M.; Fokin, V. V. Org Lett 2008, 10,
3385.
[21] Schmitz, A.; Kraatz, U.; Korte, F. Heterocycles 1978, 10, 199.
[22] Rawal, V. H.; Jones, R. J.; Cava, M. P. J Org Chem 1987, 52,
19.
HRMS calcd for C23H17N4O3 [M + H]: 397.1295; found
397.1300.
[23] A one-pot protocol for this transformation was also attempted
without aqueous workup after the alkylation step. However, this protocol
afforded lower isolated yields of 18ai (yields not shown).
[24] The alkylation of 17g with propynylbromide proceeded well
(LC/MS analysis of the reaction mixture); however, the instability of the
deprotected homopropynyl amine to the cyclication conditions is likely
the reason for the low isolated yield of 18c.
Acknowledgments. The authors would like to thank Chuck W.
Ross for HRMS data and interpretation and Michael J. Bogusky
and Steven M Pitzenberger for NMR data and interpretation.
REFERENCES AND NOTES
[25] Aryl diazonium salts were prepared according to the proce-
dures described herein: Tang, Z.Y.; Zhang, Y.; Wang, T.; Wang, W.
Synlett 2010, 5, 0804.
[1] Preliminarily disclosure of this work has been reported: Pitts,
D. R.; DiPardo, R. M.; Johnson, A. W.; Cofre, V.; Beshore, D. C.
Abstracts of Papers, 240th ACS National Meeting, Boston, MA, United
States, August 22–26, 2010, ORGN-976.
[26] Lower temperatures (i.e., 70 °C) did not promote cyclization.
[27] Grob, C. A.; Rumpf, J. A. Ber 1911, 44, 2835.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet