Enantioselective Synthesis of Spiropyrazolone-Fused Cyclopenta[ c]chromen-4-ones Bearing Five Contiguous Stereocenters via (3+2) Cycloaddition

Article abstract of DOI:10.1021/acs.joc.1c01215

An enantioselective synthesis of spiropyrazolone-fused cyclopenta[c]chromen-4-ones is demonstrated via a (3+2) cycloaddition reaction. The reactions of 3-homoacylcoumarins and α,β-unsaturated pyrazolones in the presence of the cinchona-alkaloid derived hy

Full text of DOI:10.1021/acs.joc.1c01215

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Enantioselective Synthesis of Spiropyrazolone-Fused
Cyclopenta[c]chromen-4-ones Bearing Five Contiguous
Stereocenters via (3+2) Cycloaddition
Pankaj V. Khairnar,† Yin-Hsiang Su,† Athukuri Edukondalu, and Wenwei Lin*
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ABSTRACT: An enantioselective synthesis of spiropyrazolone-fused cyclopenta[c]chromen-4-ones is demonstrated via a (3+2)
cycloaddition reaction. The reactions of 3-homoacylcoumarins and α,β-unsaturated pyrazolones in the presence of the cinchona-
alkaloid derived hydrogen-bonding catalyst provide aforementioned spiropyrazolone-chromenone adducts bearing five contiguous
stereocenters, of which one is the spiro all-carbon quaternary stereocenter in high yields (up to 98%) with good to excellent
stereoselectivities (>25:1 dr and up to 99% ee). This one-pot methodology could also be practically demonstrated on a gram-scale
with similar efficacy.
yrazolones are important structural motifs that are widely
Pfound in natural products and medicinally important
compounds exhibiting a wide range of biological and
pharmacological activities.1 Specifically, 4-spiro-5-pyrazolones
have emerged as promising pharmacophores in medicinal
chemistry.2 Consequently, significant efforts have been focused
on the catalytic asymmetric synthesis of chiral spiro six-
membered rings over the past few decades.3 However, the
methods to construct spiro five-membered ring bearing spiro-
pyrazolones were rarely explored.4 On the other hand,
coumarin derivatives are privileged heterocyclic scaffolds in
medicinal and materials science; recently, they have attracted
more attention from synthetic chemists because of their utility
for the construction of complex structures and bioactive
skeletons.5 In particular, cyclopentane-fused coumarin deriva-
tives are important scaffolds found in many alkaloids and
sesquiterpenes.6 Owing to their medicinal properties (Figure
1),7 the development of methods to construct new fused-ring
tetracyclic frameworks of these systems would have shown
more potentiality in the area of drug discovery.
architectures,9 we were interested in developing a (3+2)
cycloaddition reaction for the synthesis of spiropyrazolones,
using 3-homoacylcoumarins and α,β-unsaturated pyrazolones.
This asymmetric methodology would access the hybrid chiral
complex skeletons bearing five contiguous stereocenters
including a quaternary stereogenic center at the C-4 position
of pyrazolones. Herein, we report a method for the
enantioselective construction of spiropyrazolone-fused
cyclopenta[c]chromen-4-ones in high yields and good to
excellent enantioselectivities via a (3+2) cycloaddition reaction
(Scheme 1).
We started our investigation to examine a model reaction
between 3-homoacylcoumarin 1a and α,β-unsaturated pyr-
azolone 2a with 20 mol % of 1,4-diazabicyclo[2.2.2]octane
(DABCO) in CH2Cl2 at 30 °C. Delightfully, the spiropyr-
azolone-fused cyclopenta[c]chromen-4-one derivative 3aa was
successfully produced in 99% yield after 16 h (entry 1, Table
1). The result from the racemic version enforced us to screen
different tertiary amine hydrogen bond donor bifunctional
Earlier, our group developed a new type of all-carbon 1,3-
dipolar precursor such as 3-homoacylcoumarin, and it was
utilized to prepare a series of five-membered coumarin-fused
spirocyclopentanes in high yields and excellent stereo-
selectivities via the (3+2) cycloaddition reaction.8 In
continuation of our effort toward the exploration of organo-
catalytic cascade reactions to construct the complex molecular
Received: May 25, 2021
https://doi.org/10.1021/acs.joc.1c01215
J. Org. Chem. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Note
Figure 1. Selected biological active spiropyrazolones and coumarin-fused cyclopentanes.
Scheme 1. Design for the Construction of Spiropyrazolone-Fused Cyclopenta[c]chromen-4-ones via (3+2) Cycloaddition
a
Table 1. Optimization of Reaction Conditions
b
c
entry
catalyst
solvent
t (h)
3aa (%)
ee (%)
1
2
3
4
5
6
7
8
DABCO
I
II
III
IV
V
III
III
III
III
III
III
III
III
III
III
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
16
24
22
24
18
15
24
24
16
16
16
72
192
36
72
72
99
99
53
91
84
92
73
93
98
86
84
92
85
95
96
97
racemic
53
68
71
70
37
61
71
15
75
75
87
87
75
87
85
DCE
9
10
11
CH3CN
toluene
o-xylene
toluene
toluene
toluene
toluene
toluene
d
12
de
,
13
14
15
16
df
,
dg
,
dh
,
a
Unless otherwise specified, all reactions were carried out with 1a (0.2 mmol, 1.0 equiv), 2a (0.2 mmol, 1.0 equiv), and catalyst (20 mol %) in a
b
1
given solvent (1.0 mL) at 30 °C. The yield of the product 3aa was determined by H NMR analysis using Ph3CH as an internal standard.
c
d
e
f
Enantiomeric excess was determined by chiral HPLC analysis. Benzoic acid (20 mol %) was used. Catalyst III (10 mol %) was used. Toluene
g
h
(0.5 mL) was used. 1.1 equiv of 2a was used. 1.2 equiv of 2a was used.
B
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Note
a b c
, ,
Scheme 2. Substrate Scope of the (3+2) Cycloaddition Reaction
a
Unless otherwise specified, all reactions were carried out using 1 (0.2 mmol), 2 (1.1 equiv), benzoic acid (20 mol %), and catalyst III (20 mol %)
b
c
in toluene (1.0 mL) at 30 °C. Isolated yield. Enantiomeric excess was determined by HPLC analysis on a chiral stationary phase.
organocatalysts for the optimal reaction conditions of an
asymmetric (3+2) cycloaddition reaction.
a (3+2) cycloaddition product 3aa in 86% yield and 75% ee
within 16 h (entry 10). Under the same conditions, the use of
PhCO2H as the additive uplifted the yield and selectivity of the
product 3aa to 92% yield and 87% ee, albeit after a longer
reaction time (entry 12). It is worthy to note that, in all cases,
excellent diastereoselectivity of 3aa was found (>25:1 dr).
Furthermore, we attempted to investigate other reaction
parameters, such as catalyst loading, the concentration of the
reaction, and equivalents of substrates. It should be noticed
that decreasing the catalyst loading to 10 mol % resulted in a
lower yield of 3aa to 85%, but the enantioselectivity was
retained as 87% ee (entry 13). Finally, increasing the ratio of
substrate 2a improved the yield of the product 3aa up to 97%
(entries 15 and 16). Thus, the optimal conditions for 3aa were
established with 1a (0.2 mmol), 2a (1.1 equiv), catalyst III (20
Accordingly, the effect of commercially available catalyst I
was examined in CH2Cl2 at 30 °C. The spiropyrazolone-fused
cyclopenta[c]chromen-4-one derivative 3aa was obtained in
excellent yield (99%) with moderate enantioselectivity (53%
ee) within 24 h (entry 2). To improve the enantioselectivity of
the product, other catalysts were evaluated (entries 3−6, see
Supporting Information for detailed optimization). Among
them, the thiourea derivative III was selected as the better
catalyst for the (3+2) cycloaddition reaction to afford the
desired product 3aa in 91% yield with 71% enantioselectivity
(entry 4). Next, various solvents such as THF, 1,2-dichloro-
ethane (DCE), MeCN, toluene, and o-xylene were screened
(entries 7−11). Gratefully, toluene was found to be a suitable
solvent in terms of both yield and enantioselectivity, providing
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Scheme 3. Gram-Scale Reactions for the Synthesis of Spiropyrazolones 3aa and 3ad
mol %), and PhCO2H (20 mol %) in toluene (1.0 mL) at 30
°C as shown in entry 15.
To demonstrate the synthetic utility of our protocol, we
selected two substrates of α,β-unsaturated pyrazolones 2 for
the gram-scale reactions with 3-homoacylcoumarin 1a. Both
substrates 2a and 2d furnished the desired spiropyrazolone-
fused cyclopenta[c]chromen-4-one derivatives 3aa and 3ad in
up to 92% yields and 99% ee with similar efficacy in substantial
quantities under the standard conditions (Scheme 3).
The absolute stereochemistry of spiropyrazolone-fused
cyclopenta[c]chromen-4-one derivative 3ea was assigned
unambiguously by single-crystal X-ray diffraction analysis and
that of the other derivatives were assigned by analogy.10 The
ORTEP diagram for 3ea was shown in Figure 2.
Once the optimal reaction conditions were established
(Table 1, entry 15), the scope and generality of the (3+2)
cycloaddition reaction with the variety of reactants 1 and 2
were investigated (Scheme 2). At first, the scope of 3-
homoacylcoumarin 1 bearing various R1 and R2 substituents
was tested. The substrate 1 with different R1 substitutions
reacted smoothly with 2a to afford the products 3aa−3ha in
high yields and good enantioselectivities (up to 98% and 94%
ee), regardless of the electronic nature of the substituent.
When the substrate contains the OMe (R1) group at different
positions (3ba, 3ca and 3fa, 3ga), the significant positional
effect was found in the reaction outcome in terms of
enantioselectivities, but the excellent yields were maintained.
Notably, substrate 1h bearing a 6,8-dichloro substituent also
furnished the desired product 3ha in 97% yield, albeit
providing only moderate enantioselectivity. Furthermore, the
3-homoacylcoumarin with different R2 substituents 1i and 1j
also reacted well with 2a to provide the spiropyrazolone
derivatives 3ia and 3ja in 91% and 94% yields and 95% and
96% enantioselectivities, respectively. We have also tested the
substrate bearing R2 as an aliphatic CH3 group with 2a, but the
corresponding product could not be found in the reaction,
even prolonging the reaction time up to 24 h.
Figure 2. ORTEP diagram of 3ea (CCDC 1992666).
Next, we turned our attention toward the substitution effect
of α,β-unsaturated pyrazolones 2 bearing different R3, R4, and
R5 groups to test with 3-homoacylcoumarin 1a. The substrate
Furthermore, to demonstrate the reaction pathway, we have
carried out several control experiments at lower reaction
temperatures (0 °C to −10 °C), and the progress of the
i
2b containing the Pr group as an R3 substitution afforded the
1
reactions was monitored by H NMR analysis. However, we
corresponding product 3ab in 89% yield with moderate
enantioselectivity. Furthermore, the effect of various R4
substituents on amide functionality was also investigated. It
was delightful to find that the corresponding products 3ac and
3ad were obtained in high yields and excellent enantiose-
lectivities (up to 99% ee), irrespective of the electronic nature
of the substituent. Finally, substrates with different R5 groups
were also tested under the standard reaction conditions. All
substrates were well-tolerated to afford the corresponding
products 3ae−3ai in good yields and enantioselectivities.
Interestingly, the substrates 2g and 2h bearing heteroaryl (R5 =
2-furyl and 2-thienyl) substituents also furnished the desired
products 3ag and 3ah in up to 95% yields with up to 92% ee. It
is worth noting that the sterically hindered substrate 2i (R5 =
2-naphthyl) also smoothly reacted with 1a to provide the
spiropyrazolone derivative 3ai in excellent yield and good
enantioselectivity. We have also attempted to prepare substrate
2 bearing R4 and R5 as an aliphatic group, to test in the
reaction with 1a under our standard conditions. Unfortunately,
our efforts to prepare the substrate 2 bearing R4 and R5 as an
aliphatic group such as methyl, ethyl, or tbutyl were
unsuccessful.
could not find the Michael adduct intermediate in any of the
reactions. On the basis of our previous reports,8 we imagined
that Michael−Michael addition may be less efficient, and the
reaction more likely proceeds through a (3+2) cycloaddition.
It was also noticed that the reaction was promoted effectively
by the combined use of a bifunctional thiourea catalyst with a
Brønsted acid as an additive. Eventually, the formation of
possible intermediates or transition states had a different fate
under the addition of the additive and thus significantly
improved the yields and enantioselectivities of the formation of
products, although the acid additive showed no effects in
enantioselectivities of products in our previous studies.8,9b
Therefore, we assume that the double activation of both the
substrates through hydrogen bond involvements may be
possible for the reaction mechanism.
Based on analyzing the experimental data, the screening of
catalysts, and the absolute configurations of the products, a
stereochemical model for the (3+2) cycloaddition reaction is
depicted in Figure 3. The significance of catalyst III to achieve
the high enantioselectivities in the (3+2) cycloaddition asserts
the possibility of the proposed model. Furthermore, the role of
the thiourea-derivatization of the cinchona catalyst for a
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Note
over anhydrous MgSO4 and concentrated under reduced pressure.
The crude residue was recrystallized from ethanol to give pure 3-
homoacylcoumarin 1.
General Procedure for the Preparation of Starting Materials 2.12
A round-bottomed flask equipped with a magnetic stir bar was
charged with b-keto ethyl ester derivative (10.0 mmol), and hydrazine
derivative (1.1 equiv) in acetic acid (20.0 mL) was refluxed for 6−8 h
in an oil bath. After the completion of the reaction, the crude mixture
was left to cool. The crude pyrazolone product was obtained by
recrystallization from acetic acid as a yellow solid and directly
subjected to the next step without further purification. To a solution
of crude pyrazolone (8.0 mmol) in acetic acid (20.0 mL) were added
aldehyde (1.1 equiv) and sodium acetate (1.1 equiv). The mixture
was stirred at 30 °C for 1−3 h. After the completion of the reaction,
H2O (50 mL) was added to the reaction mixture, and the aqueous
phase was extracted with EtOAc (20 mL × 3). The combined organic
layer was dried over anhydrous Na2SO4 and concentrated in vacuo.
The crude residue was further subjected to flash column
chromatography (hexanes/EtOAc = 10:1 as an eluent) to afford
pure α,β-unsaturated pyrazolone derivative 2.
Typical Procedure for the Synthesis of Spiropyrazolone-Fused
Cyclopenta[c]chromen-4-ones 3. A capped glass vial equipped with
a magnetic stir bar was charged with 1 (0.2 mmol), 2 (1.1 equiv),
catalyst III (20 mol %), and benzoic acid (20 mol %) in toluene (1.0
mL), and the mixture was stirred at 30 °C in a water bath. The
progress of the reaction was monitored by TLC analysis and 1H NMR
data analysis until the complete consumption of 3-homoacylcoumarin
1. After the reaction was complete, the solvent was removed under
reduced pressure. The crude residue was subjected by column
chromatography over silica gel (hexanes/EtOAc as an eluent) to
afford pure product 3.
Figure 3. Stereochemical model for (3+2) cycloaddition of 3-
homoacylcoumarin 1e and α,β-unsaturated pyrazolone 2a.
hydrogen-bond donor is crucial to afford the desired products
with high stereoselectivities (Table 1, entries 2−6).
In conclusion, we have developed an efficient protocol for
the construction of highly stereoselective spiropyrazolone-
fused cyclopenta[c]chromen-4-ones from 3-homoacylcoumar-
ins and α,β-unsaturated pyrazolones catalyzed by a cinchona-
based chiral amine catalyst via a (3+2) cycloaddition reaction.
The cascade products are obtained in high yields with excellent
diastreo and enantioselectivities under mild and one-pot
reaction conditions. In addition, the reaction could also be
performed on a gram scale with similar efficacy. Further
exploration of the substrate scope of this catalytic system and
the biological evaluations of the resulting spiro compounds are
in progress in our laboratory.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-3′-methyl-1′,2-diphenyl-
2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyra-
zole]-4,5′(1′H)-dione (3aa). Following the typical procedure, 3aa was
obtained from 1a (52.9 mg, 0.2 mmol) and 2a (57.7 mg, 1.1 equiv)
using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99 mg, 0.2
equiv) in toluene (1.0 mL) at 30 °C for 3 days. Purification by flash
chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3aa as a
white solid (101.1 mg, 96%). Mp: 221.8−222.2 °C. Rf = 0.25
(hexanes/EtOAc = 4:1). [α]2D5 = +150.43 (c = 0.25 in CH2Cl2).
HPLC: 87% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 21.36 min (major), 18.84 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.08 (d, J = 7.5 Hz, 2H),
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out in oven-
dried glassware with a magnetic stir bar. Unless otherwise stated, all
reagents were used as purchased from commercial suppliers without
further purification. Analytical thin-layer chromatography (TLC) was
performed on precoated, alumina-backed silica gel plates (Merck 60
F254, 0.2 mm thickness), which were developed using UV irradiation
at 254 nm. Flash column chromatography was performed using silica
gel (Silicycle SiliaFlash P60, 230−400 mesh). Melting points were
measured on a Fargo melting point apparatus and were uncorrected.
IR spectra were recorded on a PerkinElmer 500 spectrometer, and
only selected peaks were mentioned. 1H NMR spectra were recorded
on either a Bruker AV-400 spectrometer or a Bruker AV-III HD-400
spectrometer. Chemical shifts were reported in δ ppm and referenced
to the following internal standards: TMS (δ = 0.00 ppm for 1H
NMR), chloroform-d (δ = 77.00 ppm for 13C NMR), and DMSO-d6
(δ = 2.50 ppm for 1H NMR and 39.5 ppm for 13C NMR). The
following abbreviations (or any combinations thereof) were used to
explain the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, dd = doublet of doublet, td = triplet of
doublet, qd = quartet of doublet, pt = pseudo triplet, br = broad.
High-resolution mass spectra were recorded on a JEOL MStation
JMS-700 (2) using EI (Magnetic sector analyzer) or on a Waters
Xevo G2-S Tof using ESI (TOF analyzer). The X-ray diffraction
measurements were carried out at 200 K on a Bruker KAPPA APEX II
CCD area detector system equipped with a graphite monochromator
and a Mo Kα fine-focus sealed tube (k = 0.71073 Å). Optical
rotations were measured in CH2Cl2 on a Polarimeter with a 50 mm
cell (c given in g/100 mL) operated at λ = 589 nm, corresponding to
the sodium D line, at the indicated temperatures.
7.49 (t, J = 7.5 Hz, 1H), 7.41−7.30 (m, 4H), 7.28 (d, J = 7.5 Hz, 2H),
7.25−7.08 (m, 6H), 7.08−6.96 (m, 3H), 6.91 (d, J = 7.7 Hz, 1H),
5.63 (dd, J = 10.2, 4.4 Hz, 1H), 4.13 (d, J = 10.6 Hz, 1H), 4.07 (d, J =
10.2 Hz, 1H), 3.83 (dd, J = 10.6, 4.4 Hz, 1H), 2.46 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.5, 172.3, 167.4, 157.6,
151.2, 136.7, 135.9, 134.0, 133.8, 129.9, 129.3, 128.8, 128.5, 128.4,
128.1, 127.3, 125.4, 1∼24.3, 119.4, 117.8, 116.2, 72.2, 56.1, 52.7, 46.0,
44.3, 13.8. IR (KBr) v (cm−1): 3061, 1637, 1456, 1373, 1312, 1279,
1237, 703. HRMS (ESI) m/z: [M + H]+ calcd for C34H27N2O4,
527.1969; found, 527.1971.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-9-methoxy-3′-methyl-1′,2-diphen-
yl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyr-
azole]-4,5′(1′H)-dione (3ba). Following the typical procedure, 3ba
was obtained from 1b (60.1 mg, 0.2 mmol) and 2a (57.7 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 3 days. Purification by
flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ba as
a white solid (109.1 mg, 98%). Mp: 207.5−208.6 °C. Rf = 0.20
(hexanes/EtOAc = 4:1). [α]2D5 = +259.60 (c = 0.25 in CH2Cl2).
HPLC: 94% ee, (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 21.65 min (major), 18.93 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.04 (d, J = 8.4 Hz, 2H),
7.46 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.35−7.26 (m, 4H),
7.20−7.05 (m, 6H), 7.02 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H),
6.50 (d, J = 8.5 Hz, 1H), 5.54 (dd, J = 10.2, 4.0 Hz, 1H), 4.30 (d, J =
10.6 Hz, 1H), 4.09 (d, J = 10.2 Hz, 1H), 3.75 (s, 3H), 3.72 (dd, J =
10.6, 4.0 Hz, 1H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25
Experimental Procedures. General Procedure for the Prepara-
tion of Starting Materials 1..8,9b,11 A round-bottomed flask equipped
with a magnetic stir bar was charged with lactone derivative (1.0
mmol), salicylaldehyde derivative (1.1 equiv), Et3N (1.0 mL), and
CH2Cl2 (30.0 mL), and the mixture was stirred at 30 °C in a water
bath. After the completion of the reaction as monitored by TLC, the
reaction mixture was quenched with 1 M HCl, extracted with CH2Cl2,
and washed with brine. The combined organic layers were then dried
E
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Note
°C) δ/ppm: 201.2, 172.4, 167.7, 159.8, 157.1, 152.3, 137.0, 135.8,
166.8, 157.2, 150.4, 136.6, 135.8, 133.9, 133.7, 133.0, 130.0, 129.3,
134.4, 133.6, 130.1, 129.2, 128.7, 128.4, 128.2, 128.1, 125.0, 119.1,
128.8, 128.6, 128.54, 128.52, 128.0, 125.6, 119.6, 119.4, 118.4, 116.6,
∼
∼
110.1, 105.8, 71.1, 56.1, 55.0, 52.9, 44.7, 42.2, 14.1. IR (KBr) v
72.1, 56.2, 52.6, 45.4, 44.0, 13.7. IR (KBr) v (cm−1): 2923, 2848,
(cm−1): 2919, 2853, 1756, 1643, 1500, 1367, 1239, 1160, 751. HRMS
(ESI) m/z: [M + H]+ calcd for C35H29N2O5, 557.2075; found,
557.2076.
1752, 1639, 1483, 1369, 1336, 1215, 1077, 751, 667. HRMS (ESI) m/
z: [M + H]+ calcd for C34H2679BrN2O4 605.1077; found, 605.1076.
HRMS (ESI) m/z: [M + H]+ calcd for C34H2681BrN2O4, 607.1064;
found, 607.1050.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-8-methoxy-3′-methyl-1′,2-diphen-
yl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyr-
azole]-4,5′(1′H)-dione (3ca). Following the typical procedure, 3ca
was obtained from 1c (60.1 mg, 0.2 mmol) and 2a (57.7 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 7 days. Purification by
flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ca as
a white solid (100.2 mg, 90%). Mp: 221.1−221.6 °C. Rf = 0.10
(hexanes/EtOAc = 4:1). [α]2D5 = +206.93 (c = 0.25 in CH2Cl2).
HPLC: 86% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 32.40 min (major), 24.68 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.07 (dd, J = 7.9 Hz,
2H), 7.46 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5
Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.5 Hz, 2H), 7.14−6.99
(m, 4H), 6.96 (d, J = 8.8 Hz, 1H), 6.72 (dd, J = 8.8, 2.8 Hz, 1H), 6.40
(d, J = 2.8 Hz, 1H), 5.62 (dd, J = 10.2, 4.4 Hz, 1H), 4.08 (d, J = 10.6
Hz, 1H), 4.05 (d, J = 10.2 Hz, 1H), 3.79 (dd, J = 10.6, 4.3 Hz, 1H),
3.66 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C)
δ/ppm: 201.5, 172.2, 167.6, 157.5, 155.7, 145.1, 136.8, 135.9, 133.9,
(1R,2S,3R,3aR,9bR)-3-Benzoyl-7-methoxy-3′-methyl-1′,2-diphen-
yl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyr-
azole]-4,5′(1′H)-dione (3fa). Following the typical procedure, 3fa
was obtained from 1f (60.1 mg, 0.2 mmol) and 2a (57.7 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 12 days. Purification
by flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3fa
as a white solid (99.1 mg, 89%). Mp: 180.7−181.4 °C. Rf = 0.15
(hexanes/EtOAc = 4:1). [α]2D5 = +214.45 (c = 0.25 in CH2Cl2).
HPLC: 76% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 22.99 min (major), 25.02 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.08 (d, J = 8.5 Hz, 2H),
7.47 (t, J = 7.5 Hz, 1H), 7.41−7.31 (m, 4H), 7.31−7.25 (m, 2H),
7.19 (t, J = 7.5 Hz, 2H), 7.15−6.99 (m, 4H), 6.81 (d, J = 8.3 Hz, 1H),
6.60−6.50 (m, 2H), 5.61 (dd, J = 10.2, 4.3 Hz, 1H), 4.08 (d, J = 10.8
Hz, 1H), 4.05 (d, J = 10.2 Hz, 1H), 3.79 (dd, J = 10.8, 4.3 Hz, 1H),
3.68 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C)
δ/ppm: 201.5, 172.4, 167.5, 160.5, 157.7, 152.1, 136.8, 135.9, 134.1,
133.7, 129.2, 128.7, 128.5, 128.4, 128.3, 128.0, 125.2, 119.2, 118.4,
133.7, 129.2, 128.7, 128.5, 128.4, 128.3, 128.0, 125.3, 119.2, 111.2,
∼
∼
116.9, 114.7, 112.5, 72.1, 56.1, 55.5, 52.5, 46.0, 44.0, 13.7. IR (KBr) v
107.9, 102.4, 72.1, 56.0, 55.4, 52.5, 45.5, 44.3, 13.7. IR (KBr) v
(cm−1): 2972, 2834, 1639, 1498, 1377, 1295, 1090, 700. HRMS (ESI)
m/z: [M + H]+ calcd for C35H29N2O5, 557.2075; found, 557.2076.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-8-chloro-3′-methyl-1′,2-diphenyl-
2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyra-
zole]-4,5′(1′H)-dione (3da). Following the typical procedure, 3da was
obtained from 1d (61.2 mg, 0.2 mmol) and 2a (57.7 mg, 1.1 equiv)
using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99 mg, 0.2
equiv) in toluene (1.0 mL) at 30 °C for 4 days. Purification by flash
chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3da as
yellow solid (106.6 mg, 95%). Mp: 208.7−209.1 °C. Rf = 0.25
(hexanes/EtOAc = 4:1). [α]2D5 = +114.11 (c = 0.25 in CH2Cl2).
HPLC: 90% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 21.09 min (major), 17.37 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.05 (d, J = 8.4 Hz, 2H),
(cm−1): 2988, 2857, 1637, 1498, 1275, 1155, 1073, 685. HRMS (ESI)
m/z: [M + H]+ calcd for C35H29N2O5, 557.2078; found, 557.2076.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-6-methoxy-3′-methyl-1′,2-diphen-
yl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyr-
azole]-4,5′(1′H)-dione (3ga). Following the typical procedure, 3ga
was obtained from 1g (60.1 mg, 0.2 mmol) and 2a (57.7 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL). at 30 °C for 10 days. Purification
by flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ga
as a white solid (103.5 mg, 93%). Mp: 136.7−137.5 °C. Rf = 0.13
(hexanes/EtOAc = 4:1). [α]2D5 = +219.09 (c = 0.25 in CH2Cl2).
HPLC: 62% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 27.69 min (major), 23.97 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.05 (d, J = 8.5 Hz, 2H),
7.49 (t, J = 7.5 Hz, 1H), 7.39−7.31 (m, 4H), 7.30−7.25 (m, 2H),
7.24−7.03 (m, 7H), 6.99 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 2.3 Hz,
1H), 5.60 (dd, J = 10.2, 4.2 Hz, 1H), 4.06 (d, J = 10.8 Hz, 1H), 4.03
(d, J = 10.2 Hz, 1H), 3.82 (dd, J = 10.8, 4.2 Hz, 1H), 2.45 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.3, 172.1,
166.9, 157.2, 149.8, 136.6, 135.7, 133.9, 133.7, 130.1, 129.3, 128.9,
7.44 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.35−7.25 (m, 4H),
7.17 (t, J = 8.3 Hz, 2H), 7.13−6.98 (m, 4H), 6.90 (t, J = 8.0 Hz, 1H),
6.74 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 7.5 Hz, 1H), 5.63 (dd, J = 10.3,
4.3 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 4.04 (d, J = 10.3 Hz, 1H),
3.83 (dd, J = 10.6, 4.3 Hz, 1H), 3.75 (s, 3H), 2.43 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.4, 172.2, 166.8, 157.2,
147.7, 140.8, 136.8, 135.8, 133.9, 133.7, 129.2, 128.7, 128.42, 128.39,
128.6, 128.5, 128.0, 127.0, 125.6, 119.3, 119.2, 117.9, 72.1, 56.2, 52.5,
∼
45.5, 44.0, 13.8. IR (KBr) v (cm−1): 3078, 1759, 1640, 1486, 1375,
128.26, 128.0, 125.1, 124.1, 119.1, 118.4, 117.0, 112.3, 72.0, 56.0,
∼
1307, 1238, 1159, 1090, 749, 689. HRMS (ESI) m/z: [M + H]+ calcd
for C34H2635ClN2O4 561.1578; found, 561.1581. HRMS (ESI) m/z:
[M + H]+ calcd for C34H2637ClN2O4, 563.1567; found, 563.1552.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-8-bromo-3′-methyl-1′,2-diphenyl-
2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyra-
zole]-4,5′(1′H)-dione (3ea). Following the typical procedure, 3ea was
obtained from 1e (70.0 mg, 0.2 mmol) and 2a (57.7 mg, 1.1 equiv)
using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99 mg, 0.2
equiv) in toluene (1.0 mL) at 30 °C for 5 days. Purification by flash
chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ea as a
white solid (112.6 mg, 93%). Mp: 212.6−213.2 °C. Rf = 0.35
(hexanes/EtOAc = 4:1). [α]2D5 = +214.45 (c = 0.25 in CH2Cl2).
HPLC: 90% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 19.85 min (major), 16.64 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.05 (d, J = 8.5 Hz, 2H),
55.9, 52.6, 45.9, 44.0, 13.7. IR (KBr) v (cm−1): 2987, 1638, 1483,
1336, 1279, 1152, 689. HRMS (ESI) m/z: [M + H]+ calcd for
C35H29N2O5, 557.2076; found, 557.2076.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-6,8-dichloro-3′-methyl-1′,2-di-
phenyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-
1,4′-pyrazole]-4,5′(1′H)-dione (3ha). Following the typical proce-
dure, 3ha was obtained from 1h (68.0 mg, 0.2 mmol) and 2a (57.7
mg, 1.1 equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid
(4.99 mg, 0.2 equiv) in toluene (1.0 mL). at °C for 5 days.
Purification by flash chromatography (SiO2, hexanes/EtOAc = 4:1)
furnished 3ha as a white solid (115.5 mg, 97%). Mp: 213.5−214.3 °C.
Rf = 0.25 (hexanes/EtOAc = 4:1). [α]2D5 = +216.50 (c = 0.25 in
CH2Cl2). HPLC: 64% ee (Chiralpak IA, n-hexane/EtOH = 85:15,
flow rate = 1.0 mL/min, λ= 250 nm) tR = 12.30 min (major), 13.58
min (minor). 1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.00 (d, J
= 7.6 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H),
7.34−7.24 (m, 5H), 7.21 (t, J = 7.8 Hz, 2H), 7.16−7.00 (m, 4H),
6.77 (d, J = 2.5 Hz, 1H), 5.60 (dd, J = 10.2, 4.2 Hz, 1H), 4.09 (d, J =
10.9 Hz, 1H), 4.02 (d, J = 10.2 Hz, 1H), 3.85 (dd, J = 10.9, 4.2 Hz,
1H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm:
7.48 (t, J = 7.5 Hz, 1H), 7.42−7.25 (m, 7H), 7.21 (t, J = 8.0 Hz, 2H),
7.17−7.03 (m, 4H), 7.00 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.5 Hz,
1H), 5.60 (dd, J = 10.2, 4.2 Hz, 1H), 4.06 (d, J = 10.8 Hz, 1H), 4.03
(d, J = 10.2 Hz, 1H), 3.82 (dd, J = 10.8, 4.2 Hz, 1H), 2.44 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.3, 172.1,
F
https://doi.org/10.1021/acs.joc.1c01215
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
200.8, 172.0, 165.8, 157.1, 146.2, 136.6, 135.6, 133.9, 133.4, 130.5,
6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.6, 172.7,
167.3, 165.0, 151.3, 136.9, 135.9, 135.1, 133.7, 129.8, 129.2, 128.7,
129.2, 129.0, 128.8, 128.6, 128.55, 128.50, 128.0, 125.6, 125.5, 123.5,
∼
119.4, 119.2, 72.0, 56.1, 52.4, 45.4, 43.8, 13.7. IR (KBr) v (cm−1):
128.50, 128.47, 128.41, 128.3, 128.1, 127.5, 125.3, 124.1, 119.4, 117.7,
3072, 2914, 1763, 1643, 1499, 1375, 1307, 1146, 749, 689, 663.
HRMS (ESI) m/z: [M + H]+ calcd for C34H2635Cl35ClN2O4
595.1188; found, 595.1191. HRMS (ESI) m/z: [M + H]+ calcd for
C34H2635Cl37ClN2O4, 597.1162; found, 597.1166. HRMS (ESI) m/z:
[M + H]+ calcd for C34H2637Cl37ClN2O4, 599.1132; found, 599.1156.
(1R,2S,3R,3aR,9bR)-3-(4-Methoxybenzoyl)-3′-methyl-1′,2-di-
phenyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-
1,4′-pyrazole]-4,5′(1′H)-dione (3ia). Following the typical procedure,
3ia was obtained from 1i (60.1 mg, 0.2 mmol) and 2a (57.7 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL). at 30 °C for 8 days. Purification
by flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ia
as yellow solid (104.5 mg, 91%). Mp: 125.3−126.5 °C. Rf = 0.13
(hexanes/EtOAc = 4:1). [α]2D5 = +299.76 (c = 0.25 in CH2Cl2).
HPLC: 95% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 41.76 min (major), 49.24 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.09 (d, J = 8.6 Hz, 2H),
∼
116.3, 72.1, 55.4, 54.0, 46.2, 44.4, 27.8, 22.2, 21.9. IR (KBr) v (cm−1):
3075, 2977, 1637, 1599, 1521, 1152, 692. HRMS (ESI) m/z: [M +
H]+ calcd for C36H31N2O4, 555.2281; found, 555.2284.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-1′-(4-methoxyphenyl)-3′-methyl-
2-phenyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-
1,4′-pyrazole]-4,5′(1′H)-dione (3ac). Following the typical proce-
dure, 3ac was obtained from 1a (52.9 mg, 0.2 mmol) and 2c (64.3
mg, 1.1 equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid
(4.99 mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 12 days.
Purification by flash chromatography (SiO2, hexanes/EtOAc = 4:1)
furnished 3ac as an orange solid (101.2 mg, 91%). Mp: 240.5−241.2
°C. Rf = 0.13 (hexanes/EtOAc = 4:1). [α]2D5 = +74.13 (c = 0.25 in
CH2Cl2). HPLC: 92% ee (Chiralpak IA, n-hexane/EtOH = 85:15,
flow rate = 1.0 mL/min, λ = 250 nm) tR = 25.79 min (major), 22.98
min (minor). 1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.07 (d, J
= 8.3 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.28
(d, J = 7.6 Hz, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.17−7.07 (m, 5H), 7.04
(d, J = 8.4 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H),
6.69 (d, J = 8.5 Hz, 2H), 5.62 (dd, J = 10.3, 4.3 Hz, 1H), 4.11 (d, J =
10.9 Hz, 1H), 4.05 (d, J = 10.3 Hz, 1H), 3.83 (dd, J = 10.9, 4.3 Hz,
1H), 3.68 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
25 °C) δ/ppm: 201.5, 172.0, 167.4, 157.4, 157.3, 151.2, 135.9, 134.1,
133.7, 129.9, 129.8, 129.2, 128.7, 128.5, 128.3, 128.1, 127.3, 124.2,
7.36−7.26 (m, 4H), 7.22−7.08 (m, 6H), 7.06−6.95 (m, 3H), 6.90 (d,
J = 7.8 Hz, 1H), 6.82 (t, J = 8.6 Hz, 2H), 5.57 (dd, J = 10.2, 4.3 Hz,
1H), 4.12 (d, J = 10.6 Hz, 1H), 4.09 (d, J = 10.2 Hz, 1H), 3.79 (s,
3H), 3.78 (dd, J = 10.6, 4.3 Hz, 1H), 2.44 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3, 25 °C) δ/ppm: 199.5, 172.4, 167.5, 164.2, 157.7,
151.2, 136.8, 134.2, 131.8, 129.8, 128.8, 128.7, 128.5, 128.3, 128.0,
127.3, 125.3, 124.3, 119.3, 117.7, 116.2, 113.7, 72.2, 55.9, 55.4, 52.2,
∼
121.5, 117.7, 116.3, 113.7, 72.0, 55.9, 55.3, 52.7, 45.8, 44.2, 13.7. IR
46.0, 44.4, 13.7. IR (KBr) v (cm−1): 2876, 1636, 1508, 1454, 1233,
∼
(KBr) (cm−1): 3147, 2986, 1639, 1512, 1454, 1245, 1167, 742.
v
1175, 687. HRMS (ESI) m/z: [M + H]+ calcd for C35H29N2O5,
557.2076; found, 557.2076.
HRMS (ESI) m/z: [M + H]+ calcd for C35H29N2O5, 557.2075; found,
557.2076.
(1R,2S,3R,3aR,9bR)-3-(4-Chlorobenzoyl)-3′-methyl-1′,2-diphen-
yl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyr-
azole]-4,5′(1′H)-dione (3ja). Following the typical procedure, 3ja was
obtained from 1j (61.2 mg, 0.2 mmol) and 2a (57.7 mg, 1.1 equiv)
using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99 mg, 0.2
equiv) in toluene (1.0 mL). at 30 °C for 5 days. Purification by flash
chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ja as a
white solid (105.5 mg, 94%). Mp: 198.1−198.6 °C. Rf = 0.20
(hexanes/EtOAc = 4:1). [α]2D5 = +253.97 (c = 0.25 in CH2Cl2).
HPLC: 96% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 25.17 min (major), 16.00 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.01 (d, J = 8.5 Hz, 2H),
7.37−7.24 (m, 6H), 7.23−7.08 (m, 6H), 7.07−6.95 (m, 3H), 6.90 (d,
J = 7.8 Hz, 1H), 5.57 (dd, J = 10.4, 4.4 Hz, 1H), 4.12 (d, J = 10.9 Hz,
1H), 4.03 (d, J = 10.4 Hz, 1H), 3.82 (dd, J = 10.9, 4.4 Hz, 1H), 2.43
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 200.4,
172.3, 167.5, 157.5, 151.1, 140.4, 136.7, 134.2, 133.8, 130.6, 129.9,
(1R,2S,3R,3aR,9bR)-3-Benzoyl-1′-(4-fluorophenyl)-3′-methyl-2-
phenyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-
1,4′-pyrazole]-4,5′(1′H)-dione (3ad). Following the typical proce-
dure, 3ad was obtained from 1a (52.9 mg, 0.2 mmol) and 2d (61.7
mg, 1.1 equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid
(4.99 mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 8 days.
Purification by flash chromatography (SiO2, hexanes/EtOAc = 4:1)
furnished 3ad as an orange solid (96.9 mg, 89%). Mp: 210.9−211.5
°C. Rf = 0.25 (hexanes/EtOAc = 4:1). [α]2D5 = +251.81 (c = 0.25 in
CH2Cl2). HPLC: 99% ee (Chiralpak IA, n-hexane/EtOH = 85:15,
flow rate = 1.0 mL/min, λ= 250 nm) tR = 20.87 min (major), 19.42
min (minor). 1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.07 (d, J
= 8.4 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H),
7.30−7.24 (m, 3H), 7.23−7.18 (m, 1H), 7.17−7.07 (m, 3H), 7.04 (d,
J = 8.5 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H),
6.85 (t, J = 8.5 Hz, 2H), 5.62 (dd, J = 10.2, 4.2 Hz, 1H), 4.12 (d, J =
10.8 Hz, 1H), 4.07 (d, J = 10.2 Hz, 1H), 3.82 (dd, J = 10.8, 4.2 Hz,
1H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm:
201.3, 172.2, 167.3, 161.2, 158.8, 157.8, 151.1, 135.8, 133.9, 133.8,
132.78, 132.75, 129.9, 129.2, 128.8, 128.5, 128.4, 128.0, 127.3, 124.3,
128.9, 128.8, 128.5, 127.9, 127.3, 125.4, 124.4, 119.3, 117.7, 116.0,
∼
72.1, 56.2, 52.7, 45.8, 44.1, 13.7. IR (KBr) v (cm−1): 2985, 1638,
1454, 1237, 1211, 1163, 707, 690. HRMS (ESI) m/z: [M + H]+ calcd
for C34H2635Cl35ClN2O4, 561.1580; found, 561.1581. HRMS (ESI)
m/z: [M + H]+ calcd for C34H2635Cl37ClN2O4, 563.1552; found,
563.1565.
121.2, 121.1, 117.7, 116.1, 115.4, 115.1, 72.2, 55.9, 52.6, 45.9, 44.2,
∼
13.7. IR (KBr) v (cm−1): 3079, 1748, 1637, 1510, 1373, 1283, 1161,
751, 702. HRMS (ESI) m/z: [M + H]+ calcd for C34H26N2O4F,
545.1877; found, 545.1877.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-3′-isopropyl-1′,2-diphenyl-
2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-pyra-
zole]-4,5′(1′H)-dione (3ab). Following the typical procedure, 3ab was
obtained from 1a (52.9 mg, 0.2 mmol) and 2b (63.9 mg, 1.1 equiv)
using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99 mg, 0.2
equiv) in toluene (1.0 mL) at 30 °C for 6 days. Purification by flash
chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ab as a
white solid (98.7 mg, 89%). Mp: 103.5−104.3 °C. Rf = 0.25
(hexanes/EtOAc = 4:1). [α]2D5 = +169.36 (c = 0.25 in CH2Cl2).
HPLC: 71% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 16.55 min (major), 17.57 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.01 (d, J = 8.5 Hz, 2H),
(1R,2S,3R,3aR,9bR)-3-Benzoyl-2-(4-methoxyphenyl)-3′-methyl-
1′-phenyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-
1,4′-pyrazole]-4,5′(1′H)-dione (3ae). Following the typical proce-
dure, 3ae was obtained from 1a (52.9 mg, 0.2 mmol) and 2e (64.3
mg, 1.1 equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid
(4.99 mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 7 days.
Purification by flash chromatography (SiO2, hexanes/EtOAc = 4:1)
furnished 3ae as a white solid (104.6 mg, 94%). Mp: 244.7−245.5 °C.
Rf = 0.10 (hexanes/EtOAc = 4:1). [α]2D5 = +207.35 (c = 0.25 in
CH2Cl2). HPLC: 90% ee (Chiralpak IA, n-hexane/EtOH = 85:15,
flow rate = 1.0 mL/min, λ= 250 nm) tR = 19.35 min (major), 17.60
min (minor). 1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.07 (d, J
= 8.4 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.40−7.31 (m, 4H), 7.23−
7.15 (m, 5H), 7.07−7.01 (m, 2H), 6.98 (td, J = 7.5, 1.2 Hz, 1H), 6.90
(dd, J = 7.65 1.2 Hz, 1H), 6.63 (d, J = 8.5 Hz, 2H), 5.58 (dd, J = 10.4,
7.47 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 7.5 Hz,
2H), 7.24−7.14 (m, 5H), 7.13−7.01 (m, 6H), 6.97 (t, J = 7.5 Hz,
1H), 5.54 (dd, J = 10.2, 4.4 Hz, 1H), 4.25 (d, J = 10.6 Hz, 1H), 4.24
(d, J = 10.2 Hz, 1H), 3.83 (dd, J = 10.6, 4.4 Hz, 1H), 3.13 (septet, J =
G
https://doi.org/10.1021/acs.joc.1c01215
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The Journal of Organic Chemistry
pubs.acs.org/joc
Note
4.3 Hz, 1H), 4.10 (d, J = 10.9 Hz, 1H), 4.01 (d, J = 10.4 Hz, 1H),
3.81 (dd, J = 10.9, 4.3 Hz, 1H), 3.61 (s, 3H), 2.43 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.7, 172.4, 167.5, 159.4,
157.7, 151.2, 136.8, 136.0, 133.7, 129.8, 129.3, 129.2, 128.51, 128.50,
127.3, 125.8, 125.3, 124.3, 119.3, ∼117.7, 116.2, 114.1, 72.3, 55.6, 55.0,
1H), 4.09 (d, J = 10.6 Hz, 1H), 3.76 (dd, J = 10.6, 4.4 Hz, 1H), 2.45
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.4,
172.1, 167.1, 157.4, 151.0, 136.9, 136.4, 136.0, 134.0, 130.0, 129.3,
128.59, 128.58, 127.3, 127.1, 126.2, 125.4, 125.3, 124.4, 119.2, 117.8,
∼
115.9, 71.8, 54.0, 50.7, 45.7, 44.0, 13.6. IR (KBr) v (cm−1): 3079,
52.9, 45.8, 44.2, 13.7. IR (KBr) v (cm−1): 3027, 2857, 1637, 1516,
1399, 1172, 682. HRMS (ESI) m/z: [M + H]+ calcd for C35H29N2O5,
557.2076; found, 557.2076.
2919, 1639, 1498, 1307, 1277, 1031, 746. HRMS (ESI) m/z: [M +
H]+ calcd for C32H25SN2O4, 533.1535; found, 533.1534.
(1R,2S,3R,3aR,9bR)-3-Benzoyl-3′-methyl-2-(naphthalen-2-yl)-1′-
phenyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-
1,4′-pyrazole]-4,5′(1′H)-dione (3ai). Following the typical procedure,
3ai was obtained from 1a (52.9 mg, 0.2 mmol) and 2i (68.7 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 4 days. Purification by
flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ai as
an orange solid (110.6 mg, 96%). Mp: 250.7−251.6 °C. Rf = 0.18
(hexanes/EtOAc = 4:1). [α]2D5 = +324.10 (c = 0.25 in CH2Cl2).
HPLC: 87% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 19.35 min (major), 17.60 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.09 (d, J = 8.5 Hz, 2H),
7.71−7.57 (m, 4H), 7.51 (dd, J = 8.6, 1.2 Hz, 1H), 7.44−7.34 (m,
3H), 7.34−7.26 (m, 4H), 7.22 (td, J = 7.5, 1.2 Hz, 1H), 7.14 (t, J =
7.6 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 7.04−6.91 (m, 2H), 6.93 (dd, J
= 8.0, 1.0 Hz, 1H), 5.75 (dd, J = 10.4, 4.3 Hz, 1H), 4.26 (d, J = 10.4
Hz, 1H), 4.18 (d, J = 10.6 Hz, 1H), 3.86 (dd, J = 10.6, 4.3 Hz, 1H),
2.49 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm:
201.7, 172.4, 167.5, 157.6, 151.2, 136.7, 135.9, 133.8, 133.1, 133.0,
131.5, 129.9, 129.3, 128.8, 128.5, 127.8, 127.5, 127.4, 126.25, 126.23,
(1R,2S,3R,3aR,9bR)-3-Benzoyl-2-(4-bromophenyl)-3′-methyl-1′-
phenyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-
1,4′-pyrazole]-4,5′(1′H)-dione (3af). Following the typical proce-
dure, 3af was obtained from 1a (52.9 mg, 0.2 mmol) and 2f (52.9 mg,
1.1 equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid
(4.99 mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 4 d. Purification
by flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3af
as a white solid (117.2 mg, 97%). Mp: 229.3−229.7 °C. Rf = 0.10
(hexanes/EtOAc = 4:1). [α]2D5 = +229.65 (c = 0.25 in CH2Cl2).
HPLC: 90% ee (Chiralpak IA, n-hexane/EtOH = 85:15, flow rate =
1.0 mL/min, λ= 250 nm) tR = 19.76 min (major), 17.20 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.09 (d, J = 7.8 Hz, 2H),
7.50 (t, J = 7.4 Hz, 1H), 7.43−7.29 (m, 4H), 7.25 (d, J = 6.3 Hz, 1H),
7.22−7.10 (m, 5H), 7.10−7.00 (m, 2H), 6.98 (t, J = 7.5 Hz, 1H),
6.89 (d, J = 7.8 Hz, 1H), 5.57 (dd, J = 10.2, 4.2 Hz, 1H), 4.10 (d, J =
10.8 Hz, 1H), 4.08 (d, J = 10.2 Hz, 1H), 3.78 (dd, J = 10.8, 4.2 Hz,
1H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm:
201.0, 172.1, 167.2, 157.4, 151.0, 136.6, 135.7, 133.9, 133.2, 131.9,
129.9, 129.7, 129.2, 128.6, 128.5, 127.3, 125.5, 124.3, 122.4, 119.2,
∼
125.4, 125.1, 124.4, 119.3, 117.8, 116.1, 72.2, 56.3, 52.8, 46.1, 44.4,
117.7, 115.9, 71.9, 54.9, 52.6, 45.9, 44.2, 13.7. IR (KBr) v (cm−1):
∼
13.8. IR (KBr) v (cm−1): 3227, 3047, 1637, 1499, 1373, 1310, 1165,
3092, 2932, 1638, 1494, 1285, 751, 689. HRMS (ESI) m/z: [M + H]+
calcd for C34H2679BrN2O4, 605.1076; found, 605.1076. HRMS (ESI)
m/z: [M + H]+ calcd for C34H2681BrN2O4, 607.1055; found,
607.1061.
751. HRMS (ESI) m/z: [M + H]+ calcd for C38H29N2O4, 557.2127;
found, 557.2127.
ASSOCIATED CONTENT
(1S,2R,3R,3aR,9bR)-3-Benzoyl-2-(furan-2-yl)-3′-methyl-1′-phe-
nyl-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-
pyrazole]-4,5′(1′H)-dione (3ag). Following the typical procedure,
3ag was obtained from 1a (52.9 mg, 0.2 mmol) and 2g (55.5 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 6 days. Purification by
flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ag as
a white solid (98.1 mg, 95%). Mp: 248.7−249.3 °C. Rf = 0.20
(hexanes/EtOAc = 4:1). [α]2D5 = +196.45 (c = 0.25 in CH2Cl2).
HPLC: 86% ee (Chiralpak AD-H, n-hexane/EtOH = 85:15, flow rate
= 1.0 mL/min, λ= 250 nm) tR = 13.51 min (major), 11.02 min
(minor). 1H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.20 (d, J = 8.3
Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.50−7.38 (m, 4H), 7.24−7.17 (m,
3H), 7.12−6.97 (m, 4H), 6.92 (d, J = 7.6 Hz, 1H), 6.21−5.90 (m,
2H), 5.59 (dd, J = 10.2, 4.3 Hz, 1H), 4.22 (d, J = 10.2 Hz, 1H), 4.08
(d, J = 10.6 Hz, 1H), 3.77 (dd, J = 10.6, 4.3 Hz, 1H), 2.45 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ/ppm: 201.1, 171.9,
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01215.
Copies of the 1H and 13C NMR spectra of the products,
HPLC analysis profiles, X-ray data, and ORTEP
diagrams for compounds 3aa and 3ea (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3aa−3ja and 3ab−3ai (ZIP)
Accession Codes
CCDC 1990595 (3aa) and CCDC 1992666 (3ea) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223
336033.
167.1, 157.5, 151.0, 148.5, 142.5, 136.9, 135.9, 134.0, 130.0, 129.3,
128.7, 128.6, 127.3, 125.3, 124.3, 119.2, 117.7, 115.8, 110.4, 107.8,
∼
70.1, 51.1, 48.6, 45.6, 43.8, 13.5. IR (KBr) v (cm−1): 3152, 2917,
1638, 1507, 1459, 1305, 1279, 1075, 700. HRMS (ESI) m/z: [M +
H]+ calcd for C32H25N2O5, 517.1763; found, 517.1763.
(1S,2R,3R,3aR,9bR)-3-Benzoyl-3′-methyl-1′-phenyl-2-(thiophen-
2-yl)-2,3,3a,9b-tetrahydro-4H-spiro[cyclopenta[c]chromene-1,4′-
pyrazole]-4,5′(1′H)-dione (3ah). Following the typical procedure,
3ah was obtained from 1a (52.9 mg, 0.2 mmol) and 2h (59.0 mg, 1.1
equiv) using catalyst III (24.3 mg, 0.2 equiv) and benzoic acid (4.99
mg, 0.2 equiv) in toluene (1.0 mL) at 30 °C for 10 days. Purification
by flash chromatography (SiO2, hexanes/EtOAc = 4:1) furnished 3ah
as a white solid (91.6 mg, 86%). Mp: 238.5−239.2 °C. Rf = 0.20
(hexanes/EtOAc = 4:1). [α]2D5 = +256.82 (c = 0.25 in CH2Cl2).
HPLC: 92% ee (Chiralpak AD-H, n-hexane/EtOH = 85:15, flow rate
= 1.0 mL/min, λ= 250 nm) tR = 33.92 min (major), 22.76 min
AUTHOR INFORMATION
■
Corresponding Author
Wenwei Lin − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan R.O.C;
orcid.org/0000-0002-1121-072X; Email: wenweilin@
ntnu.edu.tw
Authors
Pankaj V. Khairnar − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan R.O.C;
orcid.org/0000-0001-8352-3314
Yin-Hsiang Su − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan R.O.C
1
(minor). H NMR (400 MHz, CDCl3, 25 °C) δ/ppm: 8.17 (dd, J =
8.5 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.48−7.34 (m, 4H), 7.24−7.15
(m, 3H), 7.15−6.94 (m, 4H), 6.94−6.88 (m, 2H), 6.72 (dd, J = 5.1,
3.8 Hz, 1H), 5.60 (dd, J = 10.2, 4.4 Hz, 1H), 4.37 (d, J = 10.2 Hz,
H
https://doi.org/10.1021/acs.joc.1c01215
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Chem. 2011, 9, 6519−6523. (f) Companyó, X.; Zea, A.; Alba, A.-N.
R.; Mazzanti, A.; Moyano, A.; Rios, R. Organocatalytic synthesis of
spiro compounds via a cascade Michael−Michael-aldol reaction.
Chem. Commun. 2010, 46, 6953−6955.
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Asymmetric Organocatalytic [4 + 1] Annulations Involving a Polarity
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alized Spiropyrazolone Derivatives. J. Org. Chem. 2020, 85, 594−602.
(b) Khairnar, P. V.; Wu, C.-Y.; Lin, Y.-F.; Edukondalu, A.; Chen, Y.-
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Pyrazolones and 1H-Oxepino[2,3-c]pyrazoles from Doubly Con-
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Athukuri Edukondalu − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan R.O.C;
orcid.org/0000-0003-4593-3843
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01215
Author Contributions
†P.V.K. and Y.-H.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
2020, 22, 4760−4765. (c) Hack, D.; Du
̈
rr, A. B.; Deckers, K.;
ACKNOWLEDGMENTS
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Chauhan, P.; Seling, N.; Rubenach, L.; Mertens, L.; Raabe, G.;
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for financial support.
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