Orthogonal Strapping of o-Haloaryl Ynones with Pyrazolones: A One-Pot, Domino Process toward Spiropyrazolones

Article abstract of DOI:10.1021/acs.joc.0c02087

A new class of spiroannulated pyrazolone scaffolds have been assembled from diverse o-haloaryl ynones and β-bromoalkenyl ynones via base mediated, one-pot, metal free, orthogonal strapping (tethering) mediated by the recursive anion(s) derived from pyrazolones. These convenient, preparatively useful transformations proceed through either a tandem Michael addition-intramolecular SNAr reaction or a tandem Michael addition-intramolecular AdNE process to furnish a range of pharmacophoric, diverse, spiroannulated pyrazolones from readily accessible precursors.

Full text of DOI:10.1021/acs.joc.0c02087

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Orthogonal Strapping of o‑Haloaryl Ynones with Pyrazolones: A
One-Pot, Domino Process toward Spiropyrazolones
Mallesh Beesu and Goverdhan Mehta*
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ABSTRACT: A new class of spiroannulated pyrazolone scaffolds have been assembled from diverse o-haloaryl ynones and β-
bromoalkenyl ynones via base mediated, one-pot, metal free, orthogonal strapping (tethering) mediated by the recursive anion(s)
derived from pyrazolones. These convenient, preparatively useful transformations proceed through either a tandem Michael
addition−intramolecular SNAr reaction or a tandem Michael addition−intramolecular AdNE process to furnish a range of
pharmacophoric, diverse, spiroannulated pyrazolones from readily accessible precursors.
pirocycles embodying different ring sizes and a diverse
Sdistribution and combination of heteroatoms are notable
for their scaffold diversity, and as a class, they are notable for
exhibiting a wide spectrum of biological activities.1 The
distinctive assembly of spirocyclics harboring a unique three
dimensionality, build around a quarternary sp3-carbon center
with a sprinkling of rings and heteroatoms, confers on them
spatial features amenable for engaging with varied biological
targets and receptors.2 Such spirocyclic constructs, in principle,
offer illimitable structural possibilities with significant oppor-
tunities for further expanding the chemical space and library
creation for mapping their bioactivity potential for pharma-
ceutical research and drug discovery.3
The heteroatom-embellished spirocyclic compounds are also
prevalent among many bioactive natural products, and owing
to their impressive collective attributes, they have been the
targets of both total synthesis and diversity creation
compaigns.4 Among the spirocyclic frameworks, those
embodying a pyrazolone segment are of special interest as
not only is this compact heterocyclic moiety embedded among
natural occurring compounds but also its synthetic variants
have applications in pharmaceuticals, agrochemicals, dyes, and
as chelating agents of strategic interest.5 These varied
characteristics of pyrazolones render derived spiro-pyrazolones
as highly privileged, three-dimensional structural motifs widely
encountered among a group of medicinally relevant com-
pounds with various biological activities.6 In particular, the
spiropyrazolones, harboring a spiro-fused six-membered ring
and additional appendages, are among well-recognized
constructs with a promising bioactivity profile and have
drawn considerable traction in recent years from synthetic
organic and medicinal chemistry communities.6,7 Representa-
tive examples of biologically active spiropyrazolones with six-
membered rings, exhibiting wide ranging biological activities
like antimicrobial (I),6a antitumor (II),6b,d insecticidal (III),6e
anti-inflammatory (IV),6f analgesic (V),6g and phosphodiester-
ase 4 (PDE4) inhibitor (VI)6h are displayed in Figure 1.
A confluence of uncommon structural features, possibilities
of creative diversification, and expectation of a new or
amplified bioactivity spectrum has fueled considerable interest
in exploring the chemical space around the six-membered-ring
bearing spiropyrazolone scaffold.5−7 As a result, several
synthetic routes, including enantioselective approaches to
access these spiropyrazolones motifs have been devised,
Received: August 29, 2020
https://dx.doi.org/10.1021/acs.joc.0c02087
© XXXX American Chemical Society
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A

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Figure 1. Representative bioactive compounds with a six-membered spiropyrazolone skeleton.
Scheme 1. Selection of Previous Approaches to Six-Membered-Ring Bearing Spiropyrazolones
particularly during the past decade.7−11 At a conceptual level,
the commonly pursed approach to spirocyclic pyrazolones has
been in the classical mold from readily accessible α-
arylidenepyrazolones involving variants of [4+2] cycloaddition
and formal [3+3] cycloaddition chemistry via a vinylogous
Michael−aldol sequence (Scheme 1a−d).7 On the other hand,
direct approaches toward spirocyclic pyrazolones from easily
accessible pyrazolones have received only limited attention,
and an assortment of representative efforts in this direction are
captured in Scheme 1e−h.8−11
reactive partners (double Michael or Michael−aldol acceptors)
and fancy bifunctional organocatalysts,7−11 which in a way,
could be self-limiting. Thus, new, practical approaches using
readily assembled precursors should be a welcome addition to
the repertoire of methods for the synthesis of these valuable
scaffolds. Conceptually, recursive anions B, sequentially
generated from pyrazolones, can be deployed to orthogonally
strap o-haloaryl ynones A through tandem Michael addition−
SNAr reactions, as indicated in Scheme 2, to install a
spirocarbon center and generate functionally embellished
spirocyclic pyrazolones C. An encouraging parallel to this
thought process can be found in our recent approach to
While the above-mentioned approaches (Scheme 1) have
met with some success, they also necessitate the use of highly
B
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tethered products 20k−p (Scheme 4). The structural integrity
of the new spiroannulated products 20a−p was established
through the internally consistent spectral data and single-
crystal X-ray structure determination of prototype 20a.
Encouraged by this outcome, it was decided to further
explore the generality and scope of this tandem Michael−SNAr
spiroannulation of pyrazolones with o-haloaryl ynones. To
reinforce confidence in the likely outcome, the first reaction
chosen for implementation was the strapping of 2-fluorophenyl
ynone 21a (with 2-fluoro substitution better poised for SNAr
substitution) and pyrazolone 11a. Indeed, under optimized
reaction conditions [Cs2CO3 (3.0 equiv), DMF, sealed tube,
110 °C, 36 h; see Table S2], with much longer reaction time,
the reaction between 2-fluorophenyl ynones 21a and
pyrazolone 11a afforded the 3′-methyl-1′,2-diphenyl-4H-spiro-
[naphthalene-1,4′-pyrazole]-4,5′(1′H)-dione 22a in 75% yield
(Scheme 5). It turned out that formation of 22a proceeded
with equal facility when other o-halogen-substituted aryl
ynones, 21g (X = Cl) and 21h (X = Br), were employed.
Recourse to bases like K2CO3 and solvents like DMF and
DMSO also worked, but less efficiently (see Table S2).
The generality of this one-pot spiroannulation of pyrazo-
lones with diverse o-haloaryl ynones, 21b−f (Figure S2), and
diverse pyrazolones 11c, 11d, and 11f (Figure S1) could be
readily demonstrated to furnish strapped products 22b−j in
moderate to good yields (Scheme 5, 10 examples). The
structure of one of them, 22g, was secured by a single-crystal
X-ray structure determination, and its diagnostic spectral
signature served as a benchmark for securing other
formulations in the series (Scheme 5).
A plausible reaction mechanism for the domino strapping
processes through a tandem Michael addition and nucleophilic
aromatic substitution (SNAr) reactions is shown in Scheme
6.12a An initial Michael addition of the pyrazolone derived
anion to ynone 19/21 affords the intermediate 23a, which
tautomerizes to 23b and in turn displaces the aromatic halide
in an SNAr fashion to deliver the spiroannulated product 20/
22 via intermediate 23c (Scheme 6).
Further scoping and contextual amplification of the results
displayed in Schemes 3−5 led us to explore strapping of o-halo
ynones derived from more dense architecture heterocyclic
scaffolds with pyrazolones through this tandem Michael−SNAr
protocol to furnish new functionally enriched entities. As an
example of this endeavor, we prepared two pyrazolyl ynones
24a and 24b following classical methods (Experimental
Section). Spiroannulation of 1-(5-chloro-3-methyl-1-phenyl-
1H-pyrazol-4-yl)-3-phenyl prop-2-yn-1-one (24a), and 1-(5-
chloro-1,3-dimethyl-1H-pyrazol-4-yl)-3-phenylprop-2-yn-1-
one (24b) with a model pyrazolone 11a was unexpectedly
smooth, and under the optimized reaction conditions [Cs2CO3
Scheme 2. Conceptualization of a New Strategy toward
Spiroannulated Pyrazolones through Aryl Ynone Strapping
by Pyrazolone Derived Recursive Anion(s)
spirooxindoles through insertion of oxindoles into o-haloaryl
ynones.12a
An efficient and successful realization of this objective
(Scheme 2), leading to an efficient and general method for the
spiroannulation of pyrazolones with o-haloaryl ynones, through
“one-pot” orthogonal strapping via a tandem Michael−
SNAr12,13 process to deliver a new class of quinolinone- and
naphthalenone-annulated spiropyrazolone scaffolds is de-
scribed here.
For an initial validation of the theme projected in Scheme 2,
reaction between N-phenyl pyrazolone 11a and o-haloaryl
ynone [1-(2-chloropyridin-3-yl)-3-phenylprop-2-yn-1-one]
19a was probed. The o-chloropyridyl ynone 19a was selected
in view of the known propensity of o-halopyridyl systems
toward facile SNAr reaction.12e,13a Several bases like NaOMe,
K2CO3, Cs2CO3, and DBU were explored for this purpose (see
Table S1), but under optimized reaction conditions [Cs2CO3
(2.0 equiv), DMF, sealed tube, 100 °C, 8 h], the reaction
afforded the expected pyrazolone strapped 3-methyl-1,7′-
diphenyl-5′H-spiro[pyrazole-4,8′-quinoline]-5,5′(1H)-dione
(20a) in 85% yield (Scheme 3). The structure of quinolone
spiropyrazolone 20a was confirmed unambiguously through a
single-crystal X-ray structure determination (Scheme 3).
With this pleasing outcome, we proceeded to demonstrate
the generality and scope of this tandem Michael−SNAr
reaction employing various pyrazolones (11a−f, see Figure
S1) and 2-chloropyridyl ynones (19a−j, see Figure S2) under
the optimized conditions (16 examples). Reaction between
pyrazolones 11a and various 2-chloropyridyl ynones with
donating and withdrawing group appendages (19b−e) led to
the formation of spiropyrazolones 20b−e, respectively, in good
yields (Scheme 4). Fine tuning of the steric environment, or
electronic modulation of the substituent on the ynone moiety,
did not have a major effect on the yields under the optimized
reaction protocol (20f−j, Scheme 4). Similarly, variation in the
substitution pattern on the pyrazolone moiety 11b−f (Figure
S1) had some, but not a profound, effect on the formation of
Scheme 3. Initial Experiment
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Scheme 4. Reaction of Various Substituted 2-Chloropyridyl Ynones with Pyrazolones
(2.0 equiv), DMF, 100 °C, 24 h] led to functionally
embellished spiroannulated pyrazolyl-pyrazolones 25a and
25b, respectively, in decent yield (Scheme 7). This brief
foray augurs well for further design of more complex and
functionally endowed heterocyclic systems based on spiropyr-
azolones through this “one-pot” Michael−SNAr protocol for
strapping of ynones.
At this stage, a curiosity driven question arose whether our
pyrazolone mediated ynone strapping protocol was well suited
only for o-haloaryl and heteroaryl ynone substrates or can it be
extended to nonaromatic β-haloalkenyl ynones as well, thereby
greatly enhancing the scope of our finding? To answer this
question and as a pilot, two carbocyclic β-bromoynones 26a
and 26b were readily assembled.12a Exposure of ynones 26a,b
to pyrazolone 11a under standard reaction conditions led to
facile orthogonal strapping to deliver spiroannulated carbocy-
clic pyrazolones 27a and 27b (65% and 75% yields,
respectively), embodying a p-benzoquinone moiety as well
(Scheme 8). The structure of 27a was established through
single-crystal X-ray structure determination, and its spectral
signature was used to secure the structure of 27b (Scheme 8).
A plausible mechanism for the above transformation can be
visualized through a tandem Michael addition, followed by
addition−elimination (AdNE) reactions (28a → 28b → 28c →
27a) (Scheme 9).12a,14 An initial Michael addition of the
pyrazolone derived anion to ynone 26a afforded the
intermediate 28a, which tautomerizes to 28b and in turn
displaces the aromatic halide in an AdNE fashion to deliver the
spiroannulated product 27a via intermediate 28c (Scheme
9).12a,14
In conclusion, we have outlined a one-pot, metal-free,
orthogonal spiroannulation strategy to conveniently access a
new class of quinolinone and naphthalenone annulated
spiropyrazolone motifs from readily accessible pyrazolones
and o-haloaryl ynones. This domino strapping protocol has
been further extended to o-chloropyrazolyl ynones and β-
bromocycloalkenyl ynones to deliver some novel heterocyclic
and carbocylic spiroannulated scaffolds. We believe that the
methodology reported here will enable access to a range of
spiroannulated pyrazolone scaffolds for potential biological
evaluation and applications.
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Scheme 5. Reaction of Various Substituted o-Haloaryl Ynones with Pyrazolones
Scheme 6. Proposed Reaction Mechanism
brine and dried over anhydrous Na2SO4 prior to concentration under
reduced pressure. Melting points were measured on a Buchi B-540
EXPERIMENTAL SECTION
■
General Experimental Details. Unless specified, all reagents
were used as obtained from commercial sources. All air and moisture
sensitive reactions were performed under N2 or a blanket in flame- or
oven-dried glassware under magnetic stirring. Tetrahydrofuran
(THF) was dried over sodium benzophenone ketyl and freshly
distilled. Reactions were monitored by TLC (silica gel 60 F254,
Merck) with visualization through UV light, iodine, and p-
anisaldehyde spray. Column chromatographies were on silica gel
(60−120 or 100−200 mesh). All solvent extracts were washed with
1
apparatus. H NMR and 13C NMR spectra were recorded in CDCl3
on a 400 or 500 MHz spectrometer at ambient temperature. The
coupling constants J are indicated in Hz, and the chemical shifts (δ)
are reported in ppm scale downfield from TMS with reference to
TMS (δ = 0.0) as internal standard. The signal patterns are indicated
as follows: s = singlet, d = doublet, dd = doublet of doublet, t = triplet,
q = quartet, m = multiplet. IR spectra were recorded on an FTIR
spectrophotometer. High-resolution mass spectra (HRMS) were
E
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Scheme 7. Spiroannulation of 5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one with o-Chloropyrazolyl Ynones
Scheme 8. Spiroannulation of β-Bromoalkenyl Ynones with Pyrazolones 11a
the spectral data were matched with the known data. Synthesis and
the corresponding spectral data for new compounds (21d,e and
24a,b) are summarized here.
Scheme 9. Proposed Reaction Mechanism via Michael−
AdNE Process
General Procedure for the Preparation of Ynones (21d,e
and 24a,b). To a stirred solution of alkyne (2.75 mmol) in
anhydrous THF (10 mL) at −78 °C was added n-BuLi (2.5 M, 2.75
mmol), and the resulting mixture was stirred at the same temperature
for 30 min. Aldehyde (2.5 mmol) in THF (2 mL) was dropwise
added, and the reaction temperature was allowed to warm to RT.
After completion (TLC), the reaction was quenched with an aq
NH4Cl (10 mL), and H2O (10 mL) and EtOAc (10 mL) were added.
The organic layer was separated and the aqueous layer further
extracted with EtOAc (3 × 10 mL). The combined organic phase was
washed and concentrated to afford the crude propargyl alcohol, which
was used as such for oxidation. To a stirred solution of propargyl
alcohol (2.5 mmol) in DMSO (6 mL) at room temperature was
added IBX (3 mmol), and the reaction mixture was stirred for 2 h.
After completion, the reaction mixture was filtered through a Celite
pad, diluted with water (10 mL), and extracted with EtOAc (10 mL ×
3). The combined organic layer was washed, dried, and concentrated
to furnish a crude product which was purified by column
chromatography (eluent, ethyl acetate/hexane, 1:4) to furnish the
substituted alkynones (21d,e and 24a,b).
recorded using ESI-TOF techniques. Single-crystal X-ray data were
collected on a Bruker D8 Quest CCD diffractometer or Oxford XT-
Lab Synergy Rigaku diffractometer using Mo Kα radiation at 298 K.
Data reduction was carried out with CrysAlispro version 171.33.55
software. Structure solution and refinements were performed with the
help of the SHELX2014/7program available in the WinGX package.
Preparation of Pyrazolone and Ynone Precursors. The
pyrazolones 11a−f were known and synthesized by using literature
procedures.15 Among the ynones synthesized by us, 19a−j, 21a−c,
21f−h, and 26a,b are known, and 21d,e and 24a,b are new. Ynones
19a−j12e and 21a−c,15d 21f−h,12c and 26a,b12c were synthesized by
following procedures previously reported by us12c,e and others,15d and
1-(2-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-yn-1-
1
one (21d). Pale yellow solid (629 mg, 80%); mp 166−168 °C; H
NMR (500 MHz, CDCl3) δ 8.10−8.07 (m, 1H), 7.60−7.56 (m, 1H),
7.29−7.26 (m, 1H), 7.20−7.16 (m, 1H), 6.89 (s, 2H), 3.89 (s, 3H),
3.88 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.2, 162.2 (d,
1JC‑F = 261.4 Hz), 153.4, 141.4, 135.7 (d, 2JC‑F = 9.2 Hz), 131.8, 125.8
3
4
2
(d, JC‑F = 7.8 Hz), 124.3 (d, JC‑F = 3.8 Hz), 117.2 (d, JC‑F = 21.9
Hz), 114.8, 110.7, 93.7 (d, 4JC‑F = 3.3 Hz), 88.2, 61.2, 56.4; IR (neat)
F
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vmax 2186, 1621, 1500 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C18H16FO4315.1027, found 315.1033.
7.27 (m, 2H), 7.26−7.22 (m, 1H), 6.87 (s, 1H), 1.86 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 183.7, 169.9, 159.0, 155.8,
1-(2,5-Difluorophenyl)-3-phenylprop-2-yn-1-one (21e).
White solid (454 mg, 75%); mp 75−77 °C; H NMR (500 MHz,
154.3, 150.7, 137.6, 136.7, 135.3, 134.8, 131.9, 129.6, 129.1, 128.3,
127.2, 126.0, 124.6, 119.5, 68.2, 15.0; IR (neat) vmax 1705, 1660, 1579
cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C24H16ClN3NaO2
436.0823, found 436.0825.
1
CDCl3) δ 7.77−7.73 (m, 1H), 7.66−7.65 (m, 2H), 7.50−7.47 (m,
1H), 7.42−7.39 (m, 2H), 7.29−7.25 (m, 1H), 7.18−7.13 (m, 1H);
13C{1H} NMR (126 MHz, CDCl3) δ 172.9, 158.3 (dd, 1JC‑F = 243.7,
4JC‑F = 0.9 Hz), 158.2 (dd, 1JC‑F = 260.6, 4JC‑F = 5.2 Hz), 133.4, 131.3,
128.8, 126.5 (dd, 2JC‑F = 10.1, 3JC‑F = 6.7 Hz), 122.4 (dd, 2JC‑F = 24.3,
Methyl 4-(3-Methyl-5,5′-dioxo-1-phenyl-1,5-dihydro-5′H-
spiro[pyrazole-4,8′-quinolin]-7′-yl)benzoate (20d). Yellow
solid (68 mg, 78%); mp 185−187 °C; 1H NMR (400 MHz,
CDCl3) δ 8.77 (dd, J = 4.7, 1.9 Hz, 1H), 8.53 (dd, J = 7.9, 1.9 Hz,
1H), 8.04−8.01 (m, 2H), 7.84−7.81 (m, 2H), 7.53−7.50 (m, 1H),
7.43−7.38 (m, 4H), 7.24−7.20 (m, 1H), 6.90 (s, 1H), 3.90 (s, 3H),
1.86 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 183.6, 169.7,
166.2, 158.7, 155.8, 154.3, 150.9, 140.6, 137.5, 135.2, 132.3, 131.8,
130.4, 129.1, 127.2, 127.1, 126.0, 124.6, 119.5, 68.1, 52.5, 14.9; IR
(neat) vmax 1712, 1663, 1579 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C26H20N3O4 438.1448, found 438.1451.
2
3
3JC‑F = 9.3 Hz), 119.9, 118.7 (dd, JC‑F = 24.9, JC‑F = 7.9 Hz), 117.5
2
4
(d, JC‑F = 25.0 Hz), 94.0 (d, JC‑F = 3.5 Hz), 88.33; IR (neat) vmax
2185, 1616, 1484 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C15H9F2O243.0616, found 243.0615.
1-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-3-phenyl-
prop-2-yn-1-one (24a). Yellow solid (624 mg, 78%); mp 77−79
1
°C; H NMR (500 MHz, CDCl3) δ 7.64−7.62 (m, 2H), 7.56−7.49
(m, 4H), 7.48−7.44 (m, 2H), 7.40−7.37 (m, 2H), 2.64 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 170.4, 152.5, 137.3, 132.9,
131.7, 130.8, 129.29, 129.27, 128.7, 125.7, 120.3, 118.3, 92.6, 88.4,
15.2; IR (neat) vmax 2198, 1618, 1519, 1489 cm−1; HRMS (ESI) m/z
[M + Na]+ calcd for C19H13ClN2NaO343.0609, found 343.0628.
1-(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)-3-phenylprop-2-
7′-(2-Methoxyphenyl)-3-methyl-1-phenyl-5′H-spiro-
[pyrazole-4,8′-quinoline]-5,5′(1H)-dione (20e). Yellow solid (57
1
mg, 70%); mp 152−154 °C; H NMR (500 MHz, CDCl3) δ 8.74
(dd, J = 4.7, 1.9 Hz, 1H), 8.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.81−7.79
(m, 2H), 7.51−7.48 (m, 1H), 7.38−7.31 (m, 3H), 7.21−7.16 (m,
2H), 6.91−6.88 (m, 2H), 6.78 (s, 1H), 3.65 (s, 3H), 1.88 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 184.2, 169.9, 159.5, 156.6,
1
yn-1-one (24b). Yellow solid (517 mg, 80%); mp 87−89 °C; H
NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.7 Hz, 2H), 7.47−7.44 (m,
1H), 7.40−7.37 (m, 2H), 3.82 (s, 3H), 2.54 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 170.1, 151.5, 132.9, 131.9, 130.7, 128.8, 120.4,
117.1, 92.0, 88.2, 36.4, 15.1; IR (neat) vmax 2197, 1606, 1509, 1464
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H12ClN2O259.0633,
found 259.0632.
156.1, 153.7, 149.7, 137.9, 135.2, 133.4, 131.2, 129.7, 129.0, 127.6,
125.5, 125.2, 124.3, 120.8, 119.2, 111.1, 69.1, 55.4, 15.2; IR (neat)
vmax 1712, 1655, 1583 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C25H20N3O3410.1499, found 410.1480.
7′-(3,5-Dimethoxyphenyl)-3-methyl-1-phenyl-5′H-spiro-
[pyrazole-4,8′-quinoline]-5,5′(1H)-dione (20f). Yellow solid (68
3-Methyl-1,7′-diphenyl-5′H-spiro[pyrazole-4,8′-quinoline]-
5,5′(1H)-dione (20a). To an oven-dried sealed tube were added
ynone 19a (0.2 mmol, 48.3 mg) and pyrazolone 11a (0.2 mmol, 35
mg), followed by DMF (2 mL) and Cs2CO3 (0.4 mmol, 130 mg).
The reaction mixture was placed in a preheated oil bath at 100 °C,
and stirred for 8 h. After the consumption of the starting material
(TLC), the reaction was quenched with a saturated solution of aq
NH4Cl (10 mL), extracted with EtOAc (3 × 20 mL), worked up, and
concentrated. The crude material was purified through silica gel
column chromatography (eluent, 60% EtOAC/hexane) to obtain the
20a as a yellow solid (65 mg, 85%); mp 176−178 °C; 1H NMR (500
MHz, CDCl3) δ 8.76 (dd, J = 4.7, 1.9 Hz, 1H), 8.53 (dd, J = 7.9, 1.9
Hz, 1H), 7.84 (dd, J = 8.7, 1.1 Hz, 2H), 7.50 (dd, J = 7.9, 4.7 Hz,
1H), 7.42−7.39 (m, J = 9.1, 5.4, 1.8 Hz, 3H), 7.38−7.33 (m, 4H),
7.24−7.21 (m, 1H), 6.90 (s, 1H), 1.86 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 183.9, 170.0, 159.2, 155.9, 154.1, 152.1, 137.7, 136.4,
135.2, 131.6, 130.4, 129.2, 129.1, 127.3, 126.9, 125.9, 124.5, 119.5,
68.3, 14.9; IR (neat) vmax 1706, 1663, 1578 cm−1; HRMS (ESI) m/z
[M + Na]+ calcd for C24H17N3NaO2402.1213, found 402.1210.
Larger-Scale Synthesis of 20a. By following the general
procedure, using ynone 19a (1.5 mmol, 362 mg), pyrazolone 11a
(1.5 mmol, 261 mg), and Cs2CO3 (3 mmol, 977 mg), compound 20a
was prepared (470 mg, 83%).
1
mg, 77%); mp 189−191 °C; H NMR (400 MHz, CDCl3) δ 8.76
(dd, J = 4.6, 1.8 Hz, 1H), 8.52 (dd, J = 7.9, 1.8 Hz, 1H), 7.92−7.90
(m, 2H), 7.52−7.48 (m, 1H), 7.42−7.38 (m, 2H), 7.23−7.19 (m,
1H), 6.91 (s, 1H), 6.47 (s, 3H), 3.60 (s, 6H), 1.86 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 183.9, 170.1, 161.2, 159.5, 156.0, 154.1,
152.0, 138.3, 137.8, 135.2, 131.4, 129.1, 127.3, 125.8, 124.5, 119.1,
104.7, 102.7, 68.3, 55.4, 15.0; IR (neat) vmax 1700, 1657, 1583 cm−1;
HRMS (ESI) m/z [M + H]+ calcd for C26H22N3O4 440.1605, found
440.1606.
3-Methyl-1-phenyl-7′-(3,4,5-trimethoxyphenyl)-5′H-spiro-
[pyrazole-4,8′-quinoline]-5,5′(1H)-dione (20g). Yellow solid (70
1
mg, 75%); mp 166−168 °C; H NMR (500 MHz, CDCl3) δ 8.77
(dd, J = 4.7, 1.9 Hz, 1H), 8.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.95−7.92
(m, 2H), 7.53−7.50 (m, 1H), 7.42−7.38 (m, 2H), 7.23−7.20 (m, J =
7.4 Hz, 1H), 6.95 (s, 1H), 6.57 (s, 2H), 3.84 (s, 3H), 3.64 (s, 6H),
1.86 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 183.9, 170.3,
159.9, 156.0, 154.2, 153.6, 151.8, 139.9, 137.9, 135.2, 131.7, 131.0,
129.2, 127.2, 125.8, 124.6, 118.9, 104.0, 68.3, 61.1, 56.2, 15.0; IR
(neat) vmax 1701, 1664, 1575 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C27H24N3O5 470.1710, found 470.1718.
3-Methyl-7′-pentyl-1-phenyl-5′H-spiro[pyrazole-4,8′-qui-
noline]-5,5′(1H)-dione (20h). Pale brown liquid (54 mg, 72%); 1H
NMR (500 MHz, CDCl3) δ 8.73 (dd, J = 4.7, 1.9 Hz, 1H), 8.47 (dd, J
= 7.9, 1.9 Hz, 1H), 7.98−7.96 (m, 2H), 7.48−7.42 (m, 3H), 7.25−
7.22 (m, 1H), 6.72 (s, 1H), 2.29−2.22 (m, 1H), 2.19−2.12 (m, 1H),
1.87 (s, 3H), 1.68−1.62 (m, 2H), 1.34−1.28 (m, 4H), 0.87 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 183.9, 170.4, 159.4,
156.0, 154.3, 154.0, 137.8, 135.0, 129.1, 128.7, 127.5, 125.7, 124.4,
119.2, 68.9, 32.3, 31.3, 26.3, 22.5, 14.6, 14.0; IR (neat) vmax 1715,
1661, 1582 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H24N3O2
374.1863, found 374.1855.
Compounds 20b−p were synthesized following the procedure for
compound 20a, and their characterization is detailed below.
3-Methyl-1-phenyl-7′-(p-tolyl)-5′H-spiro[pyrazole-4,8′-qui-
noline]-5,5′(1H)-dione (20b). Yellow solid (63 mg, 80%): mp
1
174−176 °C; H NMR (400 MHz, CDCl3) δ 8.76 (dd, J = 4.7, 1.9
Hz, 1H), 8.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.88−7.86 (m, 2H), 7.51−
7.48 (m, 1H), 7.44−7.40 (m, 2H), 7.25−7.21 (m, 3H), 7.17−7.15
(m, 2H), 6.90 (s, 1H), 2.34 (s, 3H), 1.84 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 183.9, 170.2, 159.5, 156.1, 154.1, 152.2, 140.8,
137.8, 135.2, 133.6, 131.1, 130.0, 129.1, 127.3, 126.8, 125.8, 124.5,
119.5, 68.3, 21.4, 14.9; IR (neat) vmax 1704, 1660, 1579 cm−1; HRMS
(ESI) m/z [M + H]+ calcd for C25H20N3O2394.1550, found
394.1543.
3-Methyl-7′-octyl-1-phenyl-5′H-spiro[pyrazole-4,8′-quino-
1
line]-5,5′(1H)-dione (20i). Pale brown liquid (62 mg, 75%); H
NMR (500 MHz, CDCl3) δ 8.73 (dd, J = 4.7, 1.9 Hz, 1H), 8.47 (dd, J
= 7.9, 1.9 Hz, 1H), 7.98−7.96 (m, 2H), 7.48−7.42 (m, 3H), 7.25−
7.22 (m, 1H), 6.71 (s, 1H), 2.29−2.22 (m, 1H), 2.19−2.12 (m, 1H),
1.87 (s, 3H), 1.69−1.58 (m, 2H), 1.33−1.22 (m, 10H), 0.86 (t, J =
7.0 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 183.9, 170.4,
159.4, 155.9, 154.3, 153.9, 137.8, 135.0, 129.1, 128.8, 127.5, 125.7,
124.4, 119.2, 68.9, 32.3, 31.8, 29.4, 29.2, 29.1, 26.7, 22.7, 14.6, 14.2;
7′-(4-Chlorophenyl)-3-methyl-1-phenyl-5′H-spiro[pyrazole-
4,8′-quinoline]-5,5′(1H)-dione (20c). Yellow solid (62 mg, 75%);
1
mp 180−182 °C; H NMR (500 MHz, CDCl3) δ 8.77 (dd, J = 4.7,
1.9 Hz, 1H), 8.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.85−7.83 (m, 2H),
7.53−7.50 (m, 1H), 7.44−7.40 (m, 2H), 7.35−7.33 (m, 2H), 7.30−
G
https://dx.doi.org/10.1021/acs.joc.0c02087
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
IR (neat) vmax 1717, 1664, 1585 cm−1; HRMS (ESI) m/z [M + Na]+
calcd for C26H29N3NaO2 438.2152, found 438.2152.
154.6, 153.9, 135.0, 128.6, 127.7, 124.3, 67.4, 32.1, 32.0, 31.4, 26.3,
22.5, 14.4, 14.0; IR (neat) vmax 1707, 1662, 1580 cm−1; HRMS (ESI)
m/z [M + H]+ calcd for C18H22N3O2 312.1707, found 312.1703.
3′-Methyl-1′,2-diphenyl-4H-spiro[naphthalene-1,4′-pyra-
zole]-4,5′(1′H)-dione (22a). To an oven-dried sealed tube were
added ynone 21a (0.2 mmol, 45 mg) and pyrazolone 11a (0.2 mmol,
35 mg), followed by DMF (2 mL) and Cs2CO3 (0.6 mmol, 195 mg).
The reaction mixture was placed in a preheated oil bath at 110 °C and
stirred for 36 h. After the consumption of the starting material (TLC),
the reaction was quenched with a saturated solution of aq NH4Cl (10
mL), extracted with EtOAc (3 × 20 mL), worked up, and
concentrated. The crude material was purified by silica gel column
chromatography (eluent, 60% EtOAC/hexane) to obtain 22a as a
2′,3-Dimethyl-1,7′-diphenyl-5′H-spiro[pyrazole-4,8′-quino-
line]-5,5′(1H)-dione (20j). Yellow solid (63 mg, 80%); mp 192−
1
194 °C; H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 8.1 Hz, 1H),
7.83−7.81 (m, 2H), 7.43−7.38 (m, 3H), 7.35−7.32 (m, 5H), 7.25−
7.22 (m, 1H), 6.86 (s, 1H), 2.55 (s, 3H), 1.85 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 184.1, 170.4, 164.4, 159.2, 155.6, 151.7, 137.8,
136.6, 135.0, 131.7, 130.2, 129.2, 129.1, 127.0, 125.9, 124.9, 124.4,
119.8, 68.3, 25.2, 14.9; IR (neat) vmax 1717, 1655, 1590 cm−1; HRMS
(ESI) m/z [M + Na]+ calcd for C25H19N3NaO2 416.1369, found
416.1371.
1-(4-Chlorophenyl)-3-methyl-7′-phenyl-5′H-spiro[pyrazole-
1
4,8′-quinoline]-5,5′(1H)-dione (20k). Yellow solid (68 mg, 82%);
pale yellow solid (57 mg, 75%); mp 158−160 °C; H NMR (500
1
mp 188−190 °C; H NMR (500 MHz, CDCl3) δ 8.76 (dd, J = 4.7,
MHz, CDCl3) δ 8.34−8.32 (m, 1H), 7.84−7.82 (m, 2H), 7.62−7.56
(m, 2H), 7.45−7.41 (m, 2H), 7.40−7.38 (m, 1H), 7.36−7.33 (m,
2H), 7.32−7.29 (m, 2H), 7.27−7.24 (m, 1H), 7.12−7.11 (m, 1H),
6.88 (s, 1H), 1.85 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
184.0, 170.8, 160.9, 150.9, 137.6, 136.7, 135.7, 134.0, 132.2, 131.2,
130.2, 129.6, 129.2, 127.7, 126.9, 126.1, 125.4, 119.5, 65.6, 14.7; IR
(neat) vmax 1711, 1656, 1591 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C25H19N2O2 379.1441, found 379.1438.
1.9 Hz, 1H), 8.53 (dd, J = 7.9, 1.9 Hz, 1H), 7.83−7.80 (m, 2H),
7.53−7.50 (m, 1H), 7.43−7.39 (m, 1H), 7.37−7.34 (m, 4H), 7.32−
7.30 (m, 2H), 6.89 (s, 1H), 1.86 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 183.8, 170.0, 159.5, 155.8, 154.1, 151.9, 136.3, 136.2, 135.3,
131.7, 130.9, 130.4, 129.3, 129.1, 127.3, 126.9, 124.6, 120.5, 68.3,
15.0; IR (neat) vmax 1710, 1660, 1580 cm−1; HRMS (ESI) m/z [M +
H]+ calcd for C24H17ClN3O2 414.1004, found 414.1043.
1,7′-Diphenyl-3-propyl-5′H-spiro[pyrazole-4,8′-quinoline]-
5,5′(1H)-dione (20l). Yellow solid (59 mg, 72%); mp 134−136 °C;
1H NMR (400 MHz, CDCl3) δ 8.76 (dd, J = 4.7, 1.9 Hz, 1H), 8.53
Compounds 22b−j were synthesized following the procedure for
compound 22a, and their characterization is detailed below.
3′-Methyl-1′-phenyl-2-(p-tolyl)-4H-spiro[naphthalene-1,4′-
pyrazole]-4,5′(1′H)-dione (22b). Pale yellow solid (49 mg, 62%);
mp 172−174 °C; 1H NMR (500 MHz, CDCl3) δ 8.33−8.31 (m, 1H),
7.86 (dd, J = 8.7, 1.0 Hz, 2H), 7.61−7.55 (m, 2H), 7.46−7.42 (m,
2H), 7.28−7.24 (m, 1H), 7.21−7.19 (m, 2H), 7.15−7.10 (m, 3H),
6.88 (s, 1H), 2.33 (s, 3H), 1.84 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 183.9, 171.0, 161.2, 150.9, 140.5, 137.7, 135.8, 133.9, 133.8,
131.8, 131.2, 129.9, 129.5, 129.2, 127.7, 126.8, 126.0, 125.3, 119.4,
65.5, 21.4, 14.6; IR (neat) vmax 1713, 1656, 1591 cm−1; HRMS (ESI)
m/z [M + H]+ calcd for C26H21N2O2 393.1598, found 393.1586.
2-(4-Fluorophenyl)-1′,3′-dimethyl-4H-spiro[naphthalene-
1,4′-pyrazole]-4,5′(1′H)-dione (22c). Pale yellow solid (43 mg,
65%); mp 118−120 °C; 1H NMR (500 MHz, CDCl3) δ 8.29 (dd, J =
7.7, 1.1 Hz, 1H), 7.62−7.54 (m, 2H), 7.27−7.24 (m, 2H), 7.10−7.07
(m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 6.78 (s, 1H), 3.36 (s, 3H), 1.76 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 183.7, 172.7, 163.8 (d,
(dd, J = 7.9, 1.9 Hz, 1H), 7.88−7.85 (m, 2H), 7.52−7.48 (m, 1H),
7.43−7.38 (m, 3H), 7.36−7.34 (m, 4H), 7.25−7.21 (m, 1H), 6.91 (s,
1H), 2.15−2.07 (m, 1H), 2.04−1.96 (m, 1H), 1.50−1.37 (m, 2H),
0.76 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 184.0,
170.2, 162.1, 156.4, 154.0, 152.4, 137.8, 136.5, 135.1, 131.5, 130.4,
129.2, 129.0, 127.2, 127.0, 125.8, 124.5, 119.6, 68.4, 31.3, 18.5, 13.7;
IR (neat) vmax 1700, 1657, 1576 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C26H22N3O2408.1707, found 408.1697.
1,3-Dimethyl-7′-phenyl-5′H-spiro[pyrazole-4,8′-quinoline]-
5,5′(1H)-dione (20m). Yellow solid (51 mg, 80%); mp 158−160 °C;
1H NMR (400 MHz, CDCl3) δ 8.77 (dd, J = 4.7, 1.9 Hz, 1H), 8.50
(dd, J = 7.9, 1.9 Hz, 1H), 7.50−7.47 (m, 1H), 7.43−7.36 (m, 3H),
7.30−7.27 (m, 2H), 6.82 (s, 1H), 3.36 (s, 3H), 1.76 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 183.9, 171.9, 158.3, 156.0, 154.0, 152.3,
136.5, 135.2, 131.6, 130.2, 129.1, 127.4, 126.9, 124.4, 66.9, 31.9, 14.7;
IR (neat) vmax 1700, 1655, 1584 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C19H16N3O2 318.1237, found 318.1230.
4
1JC‑F = 250.9 Hz), 159.8, 149.9, 135.7, 134.0, 132.9 (d, JC‑F = 3.6
Hz), 132.5, 131.3, 129.5, 129.1 (d, 3JC‑F = 8.4 Hz), 127.7, 125.4, 116.2
(d, 2JC‑F = 21.7 Hz), 64.4, 31.9, 14.4; IR (neat) vmax 1713, 1659, 1599
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C20H16FN2O2 335.1190,
found 335.1195.
1-Methyl-7′-phenyl-3-propyl-5′H-spiro[pyrazole-4,8′-qui-
noline]-5,5′(1H)-dione (20n). Yellow solid (47 mg, 68%); mp
1
160−162 °C; H NMR (500 MHz, CDCl3) δ 8.76 (dd, J = 4.7, 1.9
Hz, 1H), 8.49 (dd, J = 7.9, 1.9 Hz, 1H), 7.49−7.46 (m, 1H), 7.42−
7.37 (m, 3H), 7.31−7.29 (m, 2H), 6.84 (s, 1H), 3.38 (s, 3H), 2.06−
2.00 (m, 1H), 1.93−1.87 (m, 1H), 1.40−1.29 (m, 2H), 0.71 (t, J =
7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 184.0, 172.0,
161.3, 156.4, 153.9, 152.6, 136.7, 135.1, 131.5, 130.2, 129.0, 127.4,
127.0, 124.3, 67.0, 32.0, 31.1, 18.6, 13.7; IR (neat) vmax 1700, 1664,
1578 cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C21H19N3NaO2
368.1369, found 368.1332.
1-Methyl-3,7′-diphenyl-5′H-spiro[pyrazole-4,8′-quinoline]-
5,5′(1H)-dione (20o). Pale yellow solid (49 mg, 65%); mp 232−234
°C; 1H NMR (400 MHz, CDCl3) δ 8.68−8.66 (m, 1H), 8.57 (dd, J =
7.9, 1.9 Hz, 1H), 7.47−7.43 (m, 1H), 7.40−7.37 (m, 2H), 7.33−7.30
(m, 1H), 7.27−7.18 (m, 5H), 7.12−7.09 (m, 2H), 6.86 (s, 1H), 3.44
(s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 184.1, 171.2, 157.0,
156.6, 154.3, 154.1, 136.3, 135.5, 131.2, 130.6, 130.4, 129.9, 128.9,
128.7, 127.1, 127.0, 125.8, 124.4, 65.6, 32.4; IR (neat) vmax 1700,
1656, 1582 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C24H18N3O2380.1394, found 380.1392.
1′,3′-Dimethyl-2-(3,4,5-trimethoxyphenyl)-4H-spiro-
[naphthalene-1,4′-pyrazole]-4,5′(1′H)-dione (22d). Pale yellow
solid (63 mg, 77%); mp 193−195 °C; 1H NMR (500 MHz, CDCl3) δ
8.28 (d, J = 7.7 Hz, 1H), 7.61−7.53 (m, 2H), 7.01 (d, J = 7.7 Hz,
1H), 6.85 (s, 1H), 6.51 (s, 2H), 3.87 (s, 3H), 3.83 (s, 6H), 3.40 (s,
3H), 1.77 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 184.0, 173.0,
160.6, 153.6, 150.7, 139.7, 135.7, 133.9, 132.2, 131.7, 131.2, 129.4,
127.6, 125.2, 104.3, 64.1, 61.1, 56.3, 32.0, 14.4; IR (neat) vmax 1707,
1658, 1580 cm−1; HRMS (ESI) m/z [M + Na]+ calcd for
C23H22N2NaO5429.1421, found 429.1428.
6-Fluoro-3′-methyl-1′,2-diphenyl-4H-spiro[naphthalene-
1,4′-pyrazole]-4,5′(1′H)-dione (22e). Pale yellow solid (57 mg,
72%); mp 125−127 °C; 1H NMR (500 MHz, CDCl3) δ 7.98 (dd, J =
8.6, 2.8 Hz, 1H), 7.83−7.81 (m, 2H), 7.45−7.39 (m, 3H), 7.37−7.33
(m, 2H), 7.32−7.24 (m, 4H), 7.12 (dd, J = 8.7, 4.7 Hz, 1H), 6.88 (s,
1H), 1.86 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 182.8, 170.4,
163.1 (d, 1JC‑F = 251.5 Hz), 160.5, 151.4, 137.5, 136.4, 133.5 (d, 3JC‑F
= 7.1 Hz), 131.8, 131.5 (d, 4JC‑F = 3.2 Hz), 130.3, 129.3, 129.2, 127.8
3
2
1,3-Dimethyl-7′-pentyl-5′H-spiro[pyrazole-4,8′-quinoline]-
5,5′(1H)-dione (20p). Yellow solid (44 mg, 70%); mp 130−132 °C;
1H NMR (400 MHz, CDCl3) δ 8.74 (dd, J = 4.7, 1.9 Hz, 1H), 8.45
(d, JC‑F = 7.9 Hz), 126.9, 126.2, 121.7 (d, JC‑F = 23.0 Hz), 119.4,
113.9 (d, 2JC‑F = 22.8 Hz), 65.2, 14.6; IR (neat) vmax 1716, 1661, 1593
c m − 1
;
H R M S ( ES I ) m /z [ M
+
N a ] + c a l c d f o r
(dd, J = 7.9, 1.9 Hz, 1H), 7.46 (dd, J = 7.9, 4.7 Hz, 1H), 6.68 (s, 1H),
3.46 (s, 3H), 2.22−2.13 (m, 1H), 2.10−2.01 (m, 1H), 1.76 (s, 3H),
1.64−1.59 (m, 2H), 1.35−1.31 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 184.0, 172.4, 158.8, 156.0,
C25H17FN2NaO2419.1166, found 419.1142.
7-Chloro-3′-methyl-1′,2-diphenyl-4H-spiro[naphthalene-
1,4′-pyrazole]-4,5′(1′H)-dione (22f). Pale yellow solid (56 mg,
68%); mp 172−174 °C; 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J =
H
https://dx.doi.org/10.1021/acs.joc.0c02087
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
8.5 Hz, 1H), 7.84−7.82 (m, 2H), 7.55 (dd, J = 8.5, 1.9 Hz, 1H),
7.46−7.38 (m, 3H), 7.36−7.33 (m, 2H), 7.30−7.26 (m, 3H), 7.08 (d,
J = 1.9 Hz, 1H), 6.86 (s, 1H), 1.88 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 182.7, 170.2, 160.2, 150.9, 140.6, 137.4, 137.2, 136.4,
132.0, 130.3, 130.2, 129.7, 129.3, 129.2, 126.9, 126.3, 125.4, 119.5,
65.4, 14.7; IR (neat) vmax 1716, 1658, 1590 cm−1; HRMS (ESI) m/z
[M + H]+ calcd for C25H18ClN2O2413.1051, found 413.1059.
1′,3′-Dimethyl-2-phenyl-4H-spiro[naphthalene-1,4′-pyra-
zole]-4,5′(1′H)-dione (22g). Pale yellow solid (44 mg, 70%); mp
13.3; IR (neat) vmax 1718, 1661, 1498 cm−1; HRMS (ESI) m/z [M +
H]+ calcd for C24H21N4O2 397.1659, found 397.1662.
3′-Methyl-1′,5-diphenyl-2,3-dihydrospiro[indene-4,4′-pyra-
zole]-5′,7(1H,1′H)-dione (27a). Brown solid (48 mg, 65%); mp
1
128−130 °C; H NMR (400 MHz, CDCl3) δ 7.79−7.77 (m, 2H),
7.44−7.40 (m, 2H), 7.36−7.29 (m, 3H), 7.27−7.25 (m, 3H), 6.71 (s,
1H), 2.83−2.78 (m, 2H), 2.61−2.52 (m, 1H), 2.45−2.35 (m, 1H),
2.13−1.98 (m, 2H), 1.91 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 184.2, 168.9, 158.1, 152.2, 150.4, 142.5, 137.4, 136.5, 132.8,
130.1, 129.3, 129.2, 126.8, 126.2, 119.5, 66.4, 33.0, 29.6, 21.9, 14.6; IR
(neat) vmax 1711, 1653, 1593 cm−1; HRMS (ESI) m/z [M + H]+
calcd for C24H21N2O2 369.1598, found 369.1557.
1
143−145 °C; H NMR (500 MHz, CDCl3) δ 8.29 (dd, J = 7.8, 1.4
Hz, 1H), 7.62−7.53 (m, 2H), 7.44−7.37 (m, 3H), 7.27−7.25 (m,
2H), 7.01 (dd, J = 7.7, 0.7 Hz, 1H), 6.81 (s, 1H), 3.36 (s, 3H), 1.76
(s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 183.9, 172.8, 160.0,
151.1, 136.8, 135.7, 133.9, 132.2, 131.2, 130.0, 129.4, 129.0, 127.6,
126.9, 125.3, 64.2, 31.9, 14.4; IR (neat) vmax 1702, 1656, 1595 cm−1;
HRMS (ESI) m/z [M + Na]+ calcd for C20H16N2NaO2339.1104,
found 339.1088.
7-Chloro-1′,3′-dimethyl-2-phenyl-4H-spiro[naphthalene-
1,4′-pyrazole]-4,5′(1′H)-dione (22h). Pale yellow solid (54 mg,
77%); mp 179−181 °C; 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J =
8.5 Hz, 1H), 7.52 (dd, J = 8.5, 1.9 Hz, 1H), 7.44−7.37 (m, 3H),
7.24−7.22 (m, 2H), 6.97 (d, J = 1.9 Hz, 1H), 6.79 (s, 1H), 3.37 (s,
3H), 1.78 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 182.8, 172.2,
159.4, 151.0, 140.4, 137.2, 136.5, 132.1, 130.2, 130.0, 129.8, 129.2,
129.1, 126.9, 125.4, 64.0, 32.0, 14.5; IR (neat) vmax 1709, 1660, 1588
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C20H16ClN2O2351.0895,
found 351.0896.
3′-Methyl-1′,2-diphenyl-6,7,8,9-tetrahydrospiro[benzo[7]-
annulene-1,4′-pyrazole]-4,5′(1′H,5H)-dione (27b). Brown liquid
1
(55 mg, 70%); H NMR (500 MHz, CDCl3) δ 7.71−7.69 (m, 2H),
7.41−7.38 (m, 2H), 7.35−7.31 (m, 1H), 7.29−7.26 (m, 2H), 7.25−
7.20 (m, 3H), 6.62 (s, 1H), 2.94−2.89 (m, 1H), 2.69−2.63 (m, 1H),
2.28−2.23 (m, 1H), 2.20−2.15 (m, 1H), 1.95 (s, 3H), 1.89−1.83 (m,
1H), 1.81−1.74 (m, 1H), 1.62−1.53 (m, 4H); 13C{1H} NMR (126
MHz, CDCl3) δ 184.8, 169.2, 158.0, 149.6, 149.5, 143.1, 137.3, 136.4,
131.9, 129.8, 129.2, 129.0, 127.1, 126.2, 119.6, 69.1, 32.4, 31.2, 25.5,
25.4, 24.5, 14.9; IR (neat) vmax 1714, 1651, 1595 cm−1; HRMS (ESI)
m/z [M + Na]+ calcd for C26H24N2NaO2 419.1730, found 419.1709.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02087.
■
sı
1′,2-Diphenyl-3′-propyl-4H-spiro[naphthalene-1,4′-pyra-
zole]-4,5′(1′H)-dione (22i). Pale yellow solid (53 mg, 65%); mp
Control experiments, and spectra for all new compounds
(PDF)
1
148−150 °C; H NMR (500 MHz, CDCl3) δ 8.33−8.31 (m, 1H),
7.86 (dd, J = 8.7, 1.0 Hz, 2H), 7.61−7.55 (m, 2H), 7.45−7.42 (m,
2H), 7.39−7.37 (m, 1H), 7.36−7.30 (m, 4H), 7.27−7.24 (m, 1H),
7.13−7.12 (m, 1H), 6.89 (s, 1H), 2.14−2.07 (m, 1H), 2.05−1.98 (m,
1H), 1.52−1.45 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 183.9, 170.9, 163.9, 151.1, 137.7, 136.8, 136.1,
133.9, 132.1, 131.1, 130.2, 129.5, 129.2, 127.7, 127.0, 126.0, 125.5,
119.5, 65.6, 30.9, 18.5, 13.7; IR (neat) vmax 1714, 1657, 1594 cm−1;
HRMS (ESI) m/z [M + H]+ calcd for C27H23N2O2 407.1754, found
407.1734.
Single-crystal X-ray diffraction data and files for
compound 20a (CCDC 1990420) (CIF)
Single-crystal X-ray diffraction data and files for
compound 22g (CCDC 1990419) (CIF)
Single-crystal X-ray diffraction data and files for
compound 25b (CCDC 1990423) (CIF)
Single-crystal X-ray diffraction data and files for
compound 27a (CCDC 1990425) (CIF)
1′-Methyl-2,3′-diphenyl-4H-spiro[naphthalene-1,4′-pyra-
zole]-4,5′(1′H)-dione (22j). Pale yellow solid (45 mg, 60%); mp
1
228−230 °C; H NMR (500 MHz, CDCl3) δ 8.38−8.36 (m, 1H),
AUTHOR INFORMATION
Corresponding Author
■
7.55−7.48 (m, 2H), 7.38−7.36 (m, 2H), 7.32−7.27 (m, 2H), 7.24−
7.18 (m, 4H), 7.06−7.01 (m, 3H), 6.82 (s, 1H), 3.44 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 184.1, 171.9, 157.6, 153.2,
Goverdhan Mehta − School of Chemistry, University of
Hyderabad, Hyderabad 500 046, India; orcid.org/0000-
0001-6841-4267; Email: gmehta43@gmail.com
136.9, 136.6, 133.9, 131.7, 130.8, 130.7, 129.9, 129.6, 129.3, 128.9,
128.6, 127.9, 127.1, 126.1, 125.6, 62.9, 32.4; IR (neat) vmax 1715,
1657, 1596 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C25H19N2O2
379.1441, found 379.1441.
Compounds 25a, 25b, 27a, and 27b were synthesized following the
procedure for compound 20a. The reaction time for 27a was 12 h and
25a, 25b, and 27b was 24 h. Characterization of all compounds is
detailed below.
Author
Mallesh Beesu − School of Chemistry, University of Hyderabad,
Hyderabad 500 046, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02087
3,3′-Dimethyl-1,1′,6-triphenylspiro[indazole-7,4′-pyra-
zole]-4,5′(1H,1′H)-dione (25a). Yellow solid (60 mg, 65%); mp
1
Notes
166−168 °C; H NMR (500 MHz, CDCl3) δ 7.31−7.23 (m, 10H),
7.21−7.16 (m, 5H), 6.56 (s, 1H), 2.68 (s, 3H), 1.91 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 181.3, 168.1, 155.2, 149.3, 147.3, 142.3,
137.2, 136.7, 135.3, 134.0, 130.4, 129.8, 129.3, 128.8, 128.7, 127.7,
127.2, 126.1, 119.4, 117.4, 62.3, 14.8, 13.4;IR (neat) vmax 1716, 1661,
1493 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C29H23N4O2
459.1816, found 459.1811.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.B. thanks the University Grants Commission in India for the
award of a Dr. D. S. Kothari postdoctoral fellowship. We
appreciate the help from G. Anilkumar and Ankit Kumar
Srivastava in determining the X-ray crystal structures. G.M.
acknowledges the generous research support from Dr. Reddy’s
Laboratories and the award of the Dr. Kallam Anji Reddy
Chair Professorship at the University of Hyderabad. We also
thank Dr. P. Srihari, IICT, Hyderabad, for his interest in this
work.
1,3,3′-Trimethyl-1′,6-diphenylspiro[indazole-7,4′-pyra-
zole]-4,5′(1H,1′H)-dione (25b). Yellow solid (55 mg, 70%); mp
1
185−187 °C; H NMR (500 MHz, CDCl3) δ 7.66−7.64 (m, 2H),
7.42−7.34 (m, 3H), 7.32−7.29 (m, 2H), 7.27−7.23 (m, 3H), 6.54 (s,
1H), 3.62 (s, 3H), 2.58 (s, 3H), 1.96 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 181.0, 167.5, 155.7, 148.3, 146.5, 140.9, 136.9, 135.4,
134.1, 129.9, 129.3, 128.9, 127.6, 126.6, 119.5, 117.1, 62.1, 36.3, 14.6,
I
https://dx.doi.org/10.1021/acs.joc.0c02087
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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