Palladium-Catalyzed Construction of Tetracyclic Scaffolds via the 1,7-Enyne Carbocyclization/Iodophenol Dearomatization Cascade

Article abstract of DOI:10.1021/acs.joc.7b02196

An efficient palladium-catalyzed dearomatizing [2+2+1] carbocyclization of 1,7-enynes with iodophenols has been developed. A type of tetracyclic scaffold was built in this reaction, exhibiting a broad substrate scope with moderate to excellent yields. More importantly, this method provides a potential strategy for the synthesis of tetracyclic skeleton natural products.

Full text of DOI:10.1021/acs.joc.7b02196

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Article
Palladium-Catalyzed Construction of Tetracyclic Scaffolds via 1,7-
Enynes Carbocyclization/Iodophenol Dearomatization Cascade
Yu Xia, Li-Jing Wang, Jia Wang, Si Chen, Yi Shen, Chun-Huan Guo, and Yong-Min Liang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02196 • Publication Date (Web): 30 Oct 2017
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Palladium-Catalyzed Construction of Tetracyclic Scaffolds via
1,7-Enynes Carbocyclization/Iodophenol Dearomatization
Cascade
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Yu Xia,† Li-Jing Wang,‡ Jia Wang,† Si Chen,† Yi Shen,† Chun-Huan Guo† and
Yong-Min Liang*,†
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, People’s Republic of China
‡
College of Chemistry & Environmental Science, HeBei University, 180 Wusi
Donglu, Baoding 071002, People’s Republic of China
liangym@lzu.edu.cn
ABSTRACT
An efficient palladium-catalyzed dearomatizing [2+2+1] carbocyclization of
1,7-enynes with iodophenols has been developed. A type of tetracyclic
scaffolds was built in this reaction, exhibiting a broad substrate scope with
moderate to excellent yields. More importantly, this method provides a
potential strategy for the synthesis of tetracyclic skeleton natural products.
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INTRODUCTION
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Diverse polycyclic frameworks with spirocyclic units are attractive scaffolds
that are present a large number of natural products, bioactive molecules and
useful chemical structures.1 For example, the komarovispirone containing
tetracyclic scaffold has trypanocidal activity to against epimastigotes of T.
cruzi.1e As a result of their remarkable pharmacological activities, chemists
continues to pay much attention to the ubiquity of many polycyclic frameworks
to develop new methods. The traditional strategies of the polycyclic molecules
rely on multistep reactions and the synthesis of complex substrates.2 Recent
studies have shown that transition-metal-catalyzed (1, n)-enynes cascade
reactions have proven to be a powerful and efficient method for building highly
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functionalized
polycyclic
molecules.3 Specially,
palladium-catalyzed
transformations with (1, n)-enynes have exhibited fascinating progress in
recent years. Including our group4, various groups5 have reported great efforts
towards characterizing these approaches. In 2017, Li and co-workers5f
reported a palladium-catalyzed carboannulation of 1,7-enynes with aryl
diazonium salts and H2O to synthesize the polycyclic compounds. The crucial
mechanism is that the oxygen atom of carbonyl group is formed by H2O attack.
Because of the highly reactive activity of palladium and the simplicity of (1,
n)-enynes, we easily realize designs that could not be achieved through
traditional methods. Thus, the development of palladium-catalyzed (1,
n)-enynes tandem methods for the construction of polycyclic compounds is still
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in great demand.
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Dearomatization reactions have proven to be an efficient strategy for the
construction of spirocyclic structures from readily available aromatic
compounds.6 Although eminent dearomatization approaches7 have been
realized, including oxidation, cycloaddition, halogenation, allylation and C-H
activation, dearomative cascade reactions are still highly desirable due to their
significant value in the synthesis of spirocyclic and polycyclic molecules.
Phenols and their derivatives are a class of widely distributed chemical starting
materials in nature and play an important role in dearomatization
transformations. The diversified functionalization of phenol and naphthol
derivatives provide a convenient and straightforward way to access the
challenging but synthetically valuable dearomative spirocarbocycles,8 which
have already attracted extensive attention with the development of
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multifariousness
of
synthetic
methods.
Very
recently,
transition-metal-catalyzed tandem reactions as a potent tool has enabled
highly efficient construction of dearomatization of indoles, anilines, pyrroles,
furans, isoquinolines, especially phenols and so on.6d, 9 The pioneering
dearomatization approaches of phenols which were reported by the groups of
Buchwald,10 You,11 Hamada,12 Luan,13 and others14 have demonstrated the
ability of transition-metal-catalyzed strategies to produce polycyclic
frameworks with spirocyclic units. In 2011, Buchwald et al.10 used
[Pd(C3C5)Cl]2/L1 catalyst system to realize an intramolecular dearomatization
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of phenols with excellent yields and chemoselectivity (Scheme 1, 1a). Recently,
Luan and co-workers13a employed palladium-catalyzed to access a series of
spirocyclic compounds through the vinylative dearomatization reaction of
β-naphthol with alkyne migratory insertion (Scheme 1, 1b). Soon after, Luan et
al.13b further developed a palladium-catalyzed dearomatizing [2+2+x] (x=1 or 2)
carbocyclization of tethered diynes with different bromophenols to afford a
class of novel tricyclic compounds (Scheme 1, 1c). Although significant
advances have been reported towards producing these eminent methods, few
examples of the palladium-catalyzed intermolecular dearomatization of enynes
with phenols have been reported. Inspired by these studies, we decided to
attempt whether palladium can catalyze the cyclization of 1,7-enynes and the
dearomatization of phenols to form the corresponding dearomative tetracyclic
scaffolds with spirocyclic units. Herein, we describe the successful execution
of our design which employed 1,7-enynes and phenols in a one-pot
palladium-catalyzed reaction (Scheme 1, 1d).
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Scheme 1. Methods toward Diverse Phenols via Palladium-Catalyzed
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Dearomatization
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RESULTS AND DISCUSSION
The initial exploration began by employing the classical compound
1,7-enyne 1a and commercially available 4-iodophenol 2a as the standard
coupling partners to optimize the reaction conditions. The results are
summarized in Table 1. Much to our delight, our anticipated reaction was first
realized to obtain the desired product 3a with a 36% yield using Pd(OAc)2
(10.0 mol %), PPh3 (20.0 mol %), and Cs2CO3 (2.0 equiv) in MeCN at 100 oC
for 12 h (Table 1, entry 1). Subsequently, various solvents were executed
(entries 2-5), and the condition was dramatically improved following the use of
DMSO as the solvent, providing 3a in 83% yield. No better results were
obtained after further screening on the effect of the base (entries 6-8). Next,
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ligands such as XPhos, PCy3 and P(2-furyl)3 did not give a superior yield
(entries 9-11). Other palladium catalysts were investigated along with PPh3 as
the ligand (entries 12-14), but inferior performance was observed in contrast
with Pd(OAc)2. The subsequent adjustment of the catalyst/ligand loading ratio
and the reaction temperature produced lower yields for the formation of
product 3a (entries 15-16). Finally, we changed 2a to 4-bromophenol. However,
the reaction failed to obtain the product 3a (entry 17). The optimized reaction
conditions were characterized as follows: 10.0 mol % Pd(OAc)2, 20.0 mol %
PPh3 and 2.0 equivalents of Cs2CO3 in DMSO at 100 oC for 12 h.
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Table 1. Optimization of the Reaction Conditionsa
entry
[Pd]
ligand
base
solvent
yieldb
(%)
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30
71
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83
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32
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nr
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15c
16d
17e
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(MeCN)2Cl2
Pd(PPh3)2Cl2
[Pd(allyl)Cl]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
XPhos
PCy3
Cs2CO3
Cs2CO3
Cs2CO3 1,4-dioxane
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
MeCN
Toluene
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
P(2-furyl)3 Cs2CO3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
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aReactions were carried out using 1a (0.2 mmol), 2a (0.4 mmol), [Pd] (10.0 mol %), ligand
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(20.0 mol %), Cs2CO3 (2.0 equiv), solvent (0.1 M), 100 °C, 12 h. Isolated yields.
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cPd(OAc)2 (5 mol %), PPh3 (10.0 mol %). dAt 120 oC. e2a was changed to 4-bromophenol.
Firstly, a series of 1,7-enynes with a terminal alkyne of alkyl groups were
tested under the optimized reaction conditions, thus affording the
corresponding products (3a-3l) in moderate to excellent yields (Scheme 2).
The terminal alkyne of n-alkyl groups (1a-1c) could be achieved smoothly with
yields of 75-83%. Moreover, various alkyl groups, which possess the
cyclohexyl, cyclopropyl, cyclopentyl, and iospentyl substituents on the alkyne
termini were employed for the desired cyclization to successfully form the
products 3d-3g. Several substituents, such as methyl and fluoro on the aryl of
aniline were well-tolerated and provided the tetracyclic compounds with
acceptable yields (3h and 3i). In addition, R4 was changed to phenyl group,
corresponding product was obtained in 58% yield (3j). Unfortunately, substrate
1l failed to give the corresponding product 3l. But gratifyingly, nitrogen with
benzyl protection carried out the desired product (3k) in moderate yield.
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Scheme 2. Substrate Scope with Respect to the 1,7-enynes of alkyl
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groupa
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aReaction conditions unless otherwise noted: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (10
mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv), DMSO (0.1 M), 100 °C, 12 h. Isolated
yields are shown.
To further ascertain the scope of the chosen reaction conditions, a variety of
1,7-enynes with a terminal alkyne of aryl groups were also evaluated (Scheme
3). The fundamental structure of the 1,7-enyne substrate (1m) was tested at
once, thus affording corresponding product in 65% yield (3m). The structure of
3m was confirmed by X-ray crystal structure analysis (see the Supporting
Information). A comparison of the current results with our previous experiments
indicated that the alkyl groups on the alkyne termini were more active than the
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aryl groups. The presence of electron-donating groups at the para- and
meta-positions, such as methyl, methoxy, tert-butyl were tolerated and gave
rise to the production of 3n-3r in 57-65% yields. Satisfactorily, various
electron-withdrawing groups were also applied at the para-, meta-positons to
afford 3s-3w in 38-55% yields. It is worth mentioning that trifluoromethyl and
nitro groups were compatible with this transformation. Furthermore, we tested
the electronic effect on the R2, corresponding reactions proceeded to provide
the anticipated products in moderate yield (3x-3z). Gratifyingly, the novel
tetracyclic scaffolds of naphthyridine and chroman were synthesized in 33-35%
yields (3aa and 3ab).
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Scheme 3. Substrate Scope with Respect to the 1,7-Enynes of Aryl
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Groupsa
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aReaction conditions unless otherwise noted: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (10.0
mol %), PPh3 (20.0 mol %), Cs2CO3 (2.0 equiv), DMSO (0.1 M), 100 °C, 12 h. Isolated
yields are shown.
Finally, to test the electronic effect of the 4-iodophenols, substrates 2ac-2af
were synthesized and subjected to the optimized conditions (Scheme 4).
Electron-withdrawing groups were tolerated, such as fluoro and ester, giving
3ac-3ae in 52-60% yields with 5:1-7:1 dr. Electron-donating groups also could
be achieved (3af), but in a lower yield with 7:1 dr.
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Scheme 4. Substrate Scope with Respect to the Iodophenolsa, b
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aReaction conditions unless otherwise noted: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (10
mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv), DMSO (0.1 M), 100 °C, 12 h. Isolated
b
1
yields are shown. The dr values were determined by H NMR analysis of the crude
reaction mixture.
A plausible mechanism for the formation of 3a is depicted in Scheme 5.10,
11a, 13b, 15 The catalytic cycle is initiated that the in situ formed Pd(0) undergoes
oxidative addition with C-I bond of 4-iodophenol (2a). Subsequently, the
intermediate A is preferred to react with carbon-carbon double bonds in
1,7-enyne (1a) to afford the intermediate B. The intermediate B, which
undergoes intramolecular coordination of the alkyne unit to the Pd center,
could follow cyclization with alkyne to form vinylpalladium C. Under the action
of base, the deprotonation reaction is carried out on the hydroxyl group of C,
the dearomatization occurs at the ipso-position and nucleophilic immediately
attacks to the Pd (II) center, producing the cyclicpalladium D. Finally, the
reaction delivered the product 3a via reductive elimination, meanwhile
released the Pd(0) to the next reaction cycle.
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Scheme 5. Proposed Mechanism
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CONCLUSION
In summary, we developed an efficient palladium-catalyzed dearomatizing
[2+2+1] carbocyclization of 1,7-enynes with 4-iodophenols to build novel
tetracyclic compounds. The 1,7-enynes tolerated both alkyl and aryl groups in
the method. Moreover, some heterocycles in tetracyclic scaffolds are also
synthesized smoothly, showing a wide application prospects in the synthesis of
natural products. More importantly, this method provided a new strategy of
transition-metal-catalyzed dearomatization reaction to construct the
less-common tetracyclic frameworks.
EXPERIMENTAL SECTION
General Remarks
1
Column chromatography was carried out on silica gel. H NMR spectra were
recorded on 400 MHz in CDCl3, 13C NMR spectra were recorded on 100 MHz
19
in CDCl3 and F NMR spectra were recorded on 376 MHz in in CDCl3. IR
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spectra were recorded on a FT-IR spectrometer and only major peaks are
reported in cm-1. All products were further characterized by high resolution
mass spectra (HRMS), the HRMS was obtained on a Q-Exactive Hybrid
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1
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Quadrupole-Orbitrap Mass Sepctrometer. Copies of their H NMR, C NMR
spectra and 19F NMR are provided in the Supporting Information. Room
temperature is 23-25°C. MeCN, toluene, 1,4-dioxane were distilled over CaH2
and DMF, DMSO were reduced pressure distillation over CaH2.
General Procedure for Synthesis of 1,7-enynes
To a mixture of 2-iodoanilines (12 mmol), PdCl2(PPh3)2 (1 mol %) and CuI (2
mol %) in Et3N (20 ml) were added ethynylbenzene derivatives (1.2 equiv) or
alkyl acetylenes (1.2 equiv) under argon atmosphere. The reaction was
performed at room temperature overnight. Saturated NH4Cl solution was
added to mixture and extracted with ethyl acetate twice. The combined organic
phase was washed with brine and dried over Na2SO4. The concentrated
residue was purified by column chromatography over silica gel using
petroleum ether/ethyl acetate 20:1 to get the anilines.
Next, Methacryloyl chloride (1.2 equiv), was added to a mixture of anilines (1.0
o
equiv), DMAP (5 mol %), Et3N (2 equiv) in CH2Cl2 (20 ml) at 0 C dropwise.
o
After stirring at 0 C for 30 min and room temperature overnight, the mixture
was quenched with saturated NaHCO3. The mixture was extracted with CH2Cl2,
washed with brine, and dried over Na2SO4. After filtration and concentration,
the obtained crude amide was used in next step without purification. NaH
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(60 %, in mineral oil, 2.0 equiv) was added to a solution of above crude amide
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o
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in THF (20 ml) at 0 C in portions. After stirring for 30 min at 0 C, MeI (3.0
equiv) added dropwise and the reaction mixture was allowed to warm to room
temperature and stirred for another 2 h. The reaction was quenched with water
and the resulting mixture was extracted with ethyl acetate twice. The combined
organic phase was washed with brine and dried over Na2SO4. The
concentrated residue was purified by column chromatography over silica gel
using petroleum ether/ethyl acetate 10:1 to get the 1,7-enynes.16a
N-(2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1l) was synthesized refer
to the reference.16b
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General Procedure for Synthesis of 3
To a Schlenk tube were added 1,7-enynes 1 (0.20 mmol), phenols 2 (0.4
mmol), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cs2CO3 (2 equiv) and DMSO
(0.1 M). Then the tube was charged by argon, and was stirred at 100 oC for 12
h. After the reaction was finished, the mixture was quenched by water and
extracted with ethyl acetate twice. The combined organic phase was washed
with brine and dried over Na2SO4. The concentrated residue was purified by
column chromatography over silica gel using petroleum ether/ethyl acetate 4:1
to afford the desired products 3.
Characterization Data of Products 3a-3af
3a',5'-dimethyl-1'-propyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclopent
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a[c]quinoline]-4,4'(5'H)-dione (3a). Yellow oil (55.4 mg, 83%). H NMR (400
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MHz, CDCl3; δ, ppm): 7.42 (dd, J =7.6 Hz, 1.3 Hz, 1H), 7.39-7.34 (m, 1H),
7.16-7.12 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 9.9 Hz, 3.0 Hz, 1H),
6.69 (dd, J = 9.8 Hz, 2.8 Hz, 1H), 6.32 (dd, J = 10.0 Hz, 1.9 Hz, 1H), 6.29 (dd, J
= 9.9 Hz, 1.8 Hz, 1H), 3.41 (s, 3H), 2.90 (d, J = 14.5 Hz, 1H), 2.12 (d, J = 14.5
Hz, 1H), 2.07-2.02 (m, 2H), 1.51-1.36 (m, 2H), 1.31 (s, 3H), 0.87 (t, J = 7.3 Hz,
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3H). C NMR (100 MHz, CDCl3; δ, ppm): 185.7, 174.7, 153.9, 153.5, 140.4,
139.4, 137.2, 129.1, 128.9, 128.1, 126.8, 122.9, 121.7, 115.1, 57.2, 53.4, 43.5,
30.0, 29.2, 26.1, 23.3, 14.3. IR (neat, cm−1): 2962, 2929, 1665, 1599, 1102,
861, 756. HRMS (ESI): m/z calcd for C22H24NO2 [M+H]+ 334.1802, found
334.1789.
1'-butyl-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclopenta
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[c]quinoline]-4,4'(5'H)-dione (3b). Yellow oil (55.5 mg, 75%). H NMR (400
MHz, CDCl3; δ, ppm): 7.43 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.39-7.34 (m, 1H),
7.14 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 8.3, 1H), 6.92 (dd, J = 9.9 Hz, 3.0 Hz, 1H),
6.69 (dd, J = 9.8 Hz, 2.8 Hz, 1H), 6.33 (dd, J = 10.0 Hz, 1.8Hz, 1H), 6.30 (dd, J
= 9.9 Hz, 1.8 Hz, 1H), 3.41 (s, 3H), 2.90 (d, J = 14.5 Hz, 1H), 2.12 (d, J = 14.5
Hz, 1H), 2.07 (t, J = 7,2 Hz, 2H), 1.45-1.37 (m, 2H), 1.31 (s, 3H), 1.29-1.23 (m,
2H), 0.85 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3; δ, ppm): 185.8, 174.8,
154.1, 153.7, 140.6, 139.4, 137.0, 129.1, 128.9, 128.1, 126.9, 123.0, 121.7,
115.2, 57.2, 53.4, 43.5, 32.1, 30.1, 26.8, 26.1, 23.0, 13.7. IR (neat, cm−1): 2959,
2929, 1665, 1599, 1103, 861, 755. HRMS (ESI): m/z calcd for C23H25NO2Na
[M+Na]+ 370.1778, found 370.1774.
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a[c]quinoline]-4,4'(5'H)-dione (3c). Yellow oil (57.6 mg, 75%). H NMR (400
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MHz, CDCl3; δ, ppm): 7.43 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.39-7.34 (m, 1H),
7.17-7.12 (m, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 10.0 Hz, 2.9 Hz, 1H),
6.69 (dd, J = 9.8 Hz, 2.9 Hz, 1H), 6.33 (dd, J = 10.0 Hz, 1.8Hz, 1H), 6.30 (dd, J
= 9.9 Hz, 1.8 Hz, 1H), 3.41 (s, 3H), 2.90 (d, J = 14.5 Hz, 1H), 2.12 (d, J = 14.5
Hz, 1H), 2.07 (t, J = 7,2 Hz, 2H), 1.49-1.36 (m, 2H), 1.31 (s, 3H), 1.28-1.23 (m,
4H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3; δ, ppm): 185.8, 174.7,
154.0, 153.6, 140.5, 139.4, 137.0, 129.0, 128.9, 128.0, 126.8, 122.9, 121.7,
115.1, 57.2, 53.4, 43.5, 32.0, 30.0, 29.5, 27.0, 26.1, 22.1, 13.8. IR (neat, cm−1):
2957, 2929, 1665, 1599, 1103, 861, 754. HRMS (ESI): m/z calcd for
C24H27NO2Na [M+Na]+ 384.1934, found 384.1930.
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1'-isopentyl-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclop
enta[c]quinoline]-4,4'(5'H)-dione (3d). Yellow soild (63.0 mg, 87%). mp:
135-137 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.44 (dd, J = 7.6 Hz, 1.2 Hz,
1H), 7.39-7.34 (m, 1H), 7.16-7.12 (m, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.92 (dd, J
= 10.0 Hz, 2.9 Hz, 1H), 6.69 (dd, J = 9.8 Hz, 2.9 Hz, 1H), 6.33 (dd, J = 10.0 Hz,
1.8Hz, 1H), 6.30 (dd, J = 9.9 Hz, 1.8 Hz, 1H), 3.41 (s, 3H), 2.90 (d, J = 14.5 Hz,
1H), 2.12 (d, J = 14.5 Hz, 1H), 2.08 (t, J = 7,2 Hz, 2H), 1.52-1.44 (m, 1H), 1.31
(s, 3H), 1.27-1.18 (m, 2H), 0.85 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H).
13C NMR (100 MHz, CDCl3; δ, ppm): 185.7, 174.7, 154.0, 153.5, 140.6, 139.4,
136.9, 129.1, 128.9, 128.1, 126.8, 122.9, 121.7, 115.1, 57.2, 53.4, 43.5, 38.8,
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30.0, 28.6, 26.1, 24.9, 22.2, 22.0. IR (neat, cm−1): 2956, 2937, 1661, 1599,
1106, 859, 755. HRMS (ESI): m/z calcd for C24H28NO2 [M+H]+ 362.2115, found
362.2113.
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1'-cyclohexyl-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclo
penta[c]quinoline]-4,4'(5'H)-dione (3e). Yellow soild (30.0 mg, 40%). mp:
168-170 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.39 (d, J = 8.4 Hz, 2H), 7.16
(t, J = 7.5 Hz, 1H), 7.11 (d, J = 8 Hz, 1H), 6.98 (dd, J = 9.9 Hz, 2.8 Hz, 1H),
6.87 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.32 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.24 (dd,
J = 10.0 Hz, 2.9 Hz, 1H), 3.41 (s, 3H), 2.91 (d, J = 14.5 Hz, 1H), 2.69-2.63 (m,
1H), 2.00 (d, J = 14.5 Hz, 1H), 1.76-1.73 (m, 1H), 1.61 (s, 3H), 1.49-1.42 (m,
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2H), 1.34-1.28 (m, 2H), 1.21 (s, 3H), 1.1-1.02 (m, 2H). C NMR (100 MHz,
CDCl3; δ, ppm): 185.8, 174.7, 155.2, 155.0, 146.0, 139.6, 136.5, 128.8, 127.7,
127.6, 126.8, 122.8, 122.4, 115.2, 56.6, 52.7, 44.4, 39.4, 32.6, 32.5, 30.1, 26.7,
26.4, 25.5, 25.2. IR (neat, cm−1): 2924, 2852, 1662, 1597, 1106, 862, 753.
HRMS (ESI): m/z calcd for C25H28NO2 [M+H]+ 374.2115, found 374.2113.
1'-(cyclopentylmethyl)-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-
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1,2'-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3f). Yellow oil (59.8 mg, 80%). H
NMR (400 MHz, CDCl3; δ, ppm): 7.55 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.38-7.34
(m, 1H), 7.15-7.09 (m, 2H), 6.93 (dd, J = 9.9 Hz, 2.9 Hz, 1H), 6.76 (dd, 9.8 Hz,
2.9 Hz, 1H), 6.33 (dd, J = 10.0 Hz, 1.8Hz, 1H), 6.30 (dd, J = 9.9 Hz, 1.8 Hz,
1H), 3.41 (s, 3H), 2.89 (d, J = 14.5 Hz, 1H), 2.41-2.36 (m, 1H), 2.12 (d, J = 14.5
Hz, 1H), 2.04-1.95 (m, 1H), 1.92-1.85 (m, 1H), 1.60-1.40 (m, 6H), 1.30 (s, 3H),
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1.15-1.10 (m, 1H), 0.94-0.88 (m, 1H). C NMR (100 MHz, CDCl3; δ, ppm):
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185.8, 174.9, 154.1, 153.9, 140.0, 139.4, 137.4, 128.9, 128.8, 128.1, 127.0,
122.8, 122.0, 115.2, 57.2, 53.4, 43.7, 38.7, 33.0, 32.4, 32.1, 30.0, 25.5, 24.8,
24.7. IR (neat, cm−1): 2952, 2868, 1665, 1599, 1105, 861, 755. HRMS (ESI):
m/z calcd for C25H28NO2 [M+H]+ 374.2115, found 374.2110.
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1'-cyclopropyl-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cycl
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openta[c]quinoline]-4,4'(5'H)-dione (3g). Yellow oil (29.9 mg, 45%). H NMR
(400 MHz, CDCl3; δ, ppm): 7.70 (dd, J = 7.5 Hz, 1.0 Hz, 1H), 7.38-7.34 (m, 1H),
7.14 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 10.4 Hz, 3.1Hz,
1H), 6.85 (dd, J = 9.8 Hz, 2.6 Hz, 1H), 6.32-6.28 (m, 2H), 3.40 (s, 3H), 2.86 (d,
J = 14.4 Hz, 1H), 2.08 (d, J = 14.4 Hz, 1H), 1.45-1.40 (m, 1H), 1.29 (s, 3H),
0.80-0.73 (m, 1H), 0.67-0.60 (m, 1H), 0.48-0.43 (m, 1H), 0.39-0.33 (m, 1H).
13C NMR (100 MHz, CDCl3; δ, ppm): 185.9, 174.8, 155.4, 153.7, 139.7, 139.5,
137.9, 128.9, 128.8, 128.2, 127.9, 122.5, 121.3, 114.9, 57.2, 52.9, 44.1, 30.0,
25.5, 10.0, 9.6, 6.0. IR (neat, cm−1): 3042, 2968, 1664, 1599, 1105, 861, 756.
HRMS (ESI): m/z calcd for C22H22NO2 [M+H]+ 332.1645, found 332.1635.
3a',5',8'-trimethyl-1'-propyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclop
enta[c]quinoline]-4,4'(5'H)-dione (3h). Yellow oil (46.6 mg, 67%). 1H NMR (400
MHz, CDCl3; δ, ppm): 7.21 (s, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.4 Hz,
1H), 6.91 (dd, J = 10.0 Hz, 3.0 Hz, 1H), 6.69 (dd, J = 9.9 Hz, 2.8 Hz, 1H),
6.35-6.28 (m, 2H), 3.38 (s, 3H), 2.89 (d, J = 14.5 Hz, 1H), 2.37 (s, 3H), 2.11 (d,
J = 14.4 Hz, 1H), 2.08-2.01 (m, 2H), 1.51-1.43 (m, 2H), 1.30 (s, 3H), 0.88 (t, J
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= 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3; δ, ppm): 185.8, 174.7, 154.0, 153.7,
140.1, 137.4, 137.1, 132.4, 129.4, 129.1, 128.1, 127.5, 121.6, 115.0, 57.2,
53.4, 43.5, 30.0, 29.1, 26.1, 23.3, 20.8, 14.3. IR (neat, cm−1): 2961, 2927, 1666,
1613, 1109, 860, 813. HRMS (ESI): m/z calcd for C23H26NO2 [M+H]+ 348.1958,
found 348.1957.
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8'-fluoro-3a',5'-dimethyl-1'-propyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-
cyclopenta[c]quinoline]-4,4'(5'H)-dione (3i). Yellow oil (45.8 mg, 65%). 1H NMR
(400 MHz, CDCl3; δ, ppm): 7.12 (dd, J = 9.1 Hz, 2.4 Hz, 1H), 7.07-7.05 (m, 2H),
6.89 (dd, J = 9.9 Hz, 3.0 Hz, 1H), 6.68 (dd, J = 9.8 Hz, 2.9 Hz, 1H), 6.35-6.29
(m , 2H), 3.39 (s, 3H), 2.90 (d, J = 14.5 Hz, 1H), 2.12 (d, J = 14.5 Hz, 1H),
2.07-2.00 (m, 2H), 1.50-1.42 (m, 2H), 1.31 (s, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3; δ, ppm): 185.6, 174.3, 158.4 (d, J = 242.0 Hz), 153.4,
153.1, 142.0, 136.3 (d, J = 2.2 Hz), 135.8, (d, J = 2.9 Hz), 129.2, 128.3, 123.2
(d, J = 7.3 Hz), 116.4 (d, J = 8.0 Hz) 115.2 (d, J = 22.5 Hz), 113.6 (d, J = 23.3
Hz), 57.1, 53.2, 43.5, 30.3, 29.0, 26.0, 23.3, 14.3. 19F NMR (376 MHz, CDCl3):
δ -119.71. IR (neat, cm−1): 2962, 2928, 1666, 1108, 860, 815, 735. HRMS
(ESI): m/z calcd for C22H23FNO2 [M+H]+ 352.1707, found 352.1702.
5'-methyl-3a'-phenyl-1'-propyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cycl
openta[c]quinoline]-4,4'(5'H)-dione (3j). Yellow soild (45.9 mg, 58%). mp:
204-206 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.57 (dd, J = 7.6 Hz, 1.2 Hz,
1H), 7.32-7.25 (m, 3H), 7.23-7.19 (m, 2H), 7.18-7.13 (m, 2H), 6.93 (d, J = 8.1
Hz, 1H), 6.74 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.58 (dd, J = 10.0 Hz, 2,9 Hz, 1H),
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6.35, (dd, J = 10.0 Hz, 2.9Hz, 1H), 6.11 (dd, J = 10 Hz, 2.9 Hz, 1H), 3.37 (s,
3H), 3.26 (d, J = 14.2 Hz, 1H), 2.36 (d, J = 14.2 Hz, 1H), 2.26-2.20 (m, 2H),
1.55-1.42 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3; δ, ppm):
185.8, 172.2, 153.0, 152.8, 144.5, 142.0, 139.4, 134.5, 129.7, 129.0, 128.7,
128.0, 127.4, 126.5, 126.4, 123.2, 122.6, 115.5, 61.0, 57.4, 47.3, 30.4, 29.7,
29.6, 23.4, 14.4. IR (neat, cm−1): 2955, 2926, 1665, 1598, 867, 761, 707.
HRMS (ESI): m/z calcd for C27H26NO2 [M+H]+ 396.1958, found 396.1957.
5'-benzyl-3a'-methyl-1'-propyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cycl
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openta[c]quinoline]-4,4'(5'H)-dione (3k). Yellow oil (41.8 mg, 51%). H NMR
(400 MHz, CDCl3; δ, ppm): 7.44 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.34-7.30 (m, 2H),
7.25 (d, J = 6.4 Hz, 1H), 7.20 (d, J = 7.0 Hz, 3H), 7.11-7.08 (m, 1H), 6.98 (d, J
= 8.2 Hz, 1H), 6.94 (dd, J = 10.0 Hz, 3 Hz, 1H), 6.73 (dd, J = 9.8 Hz, 2.8 Hz,
1H), 6.36-6.30 (m, 2H), 5.62 (d, J = 16.3 Hz, 1H), 4.75 (d, J = 16.3 Hz, 1H),
2.99 (d, J = 14.6 Hz, 1H), 2.16 (d, J = 14.5 Hz, 1H), 2.11-2.04 (m, 2H),
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1.49-1.32 (m, 2H),1.44 (s, 3H), 0.88 (t, J = 7.3 Hz, 3H). C NMR (100 MHz,
CDCl3; δ, ppm): 185.8, 174.9, 154.0, 153.6, 140.6, 138.9, 137.1, 136.9, 129.1,
128.9, 128.2, 127.1, 126.9, 126.0, 123.1, 121.9, 116.0, 57.3, 53.5, 46.7, 43.3,
29.1, 26.1, 23.3, 14.3. IR (neat, cm−1): 2961, 2928, 1665, 1599, 860, 754, 734,
698. HRMS (ESI): m/z calcd for C28H28NO2 [M+H]+ 410.2115, found 410.2112.
3a',5'-dimethyl-1'-phenyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclopen
ta[c]quinoline]-4,4'(5'H)-dione (3m). Yellow solid (47.8 mg, 65%). mp: 142-144
oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.27-7.21 (m, 5H), 7.09-7.05 (m, 3H),
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6.87 (dd, J = 7.7 Hz, 1.5 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.66 (dd, J = 10.0 Hz,
2,9 Hz, 1H), 6.38 (dd, J = 10.0 Hz, 1.9 Hz, 1H), 6.09 (dd, J = 10.0 Hz, 1.8 Hz,
1H), 3.45 (s, 3H), 3.01 (d, J = 14.3 Hz, 1H), 2.29 (d, J = 14.4 Hz, 1H), 1.46 (s,
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3H). C NMR (100 MHz, CDCl3; δ, ppm): 185.5, 174.4, 153.4, 153.2, 139.9,
138.7, 134.4, 129.3, 128.9, 128.6, 128.5, 128.2, 128.1, 128.0, 122.7, 120.5,
115.2, 57.3, 53.5, 44.7, 30.0, 25.9. IR (neat, cm−1): 2966, 2926, 1665, 1599,
1105, 861, 754, 731. HRMS (ESI): m/z calcd for C25H22NO2 [M+H]+ 368.1645,
found 368.1643.
3a',5'-dimethyl-1'-(p-tolyl)-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclope
nta[c]quinoline]-4,4'(5'H)-dione (3n). Yellow solid (45.8 mg, 60%). mp: 138-140
oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.29-7.23 (m, 2H), 7.07 (d, J = 8.2 Hz,
1H), 7.01 (d, J = 8.0 Hz, 2H), 6.95-6.92 (m, 3H), 6.81 (t, J = 7.4 Hz, 1H), 6.65
(dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.38 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 6.09 (dd, J =
10.0 Hz, 1.8 Hz, 1H), 3.45 (s, 3H), 3.00 (d, J = 14.5 Hz, 1H), 2.29 (s, 3H), 2.27
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(d, J = 14.5, 1H), 1.44 (s, 3H). C NMR (100 MHz, CDCl3; δ, ppm): 185.6,
174.5, 153.7, 153.5, 139.8, 138.8, 138.2, 138.0, 131.3, 129.2, 129.1, 128.9,
128.5, 128.0, 127.9, 122.6, 120.7, 115.1, 57.3, 53.4, 44.7, 30.0, 25.8, 21.2. IR
(neat, cm−1): 2966, 2926, 1665, 1599, 1105, 862, 746, 731. HRMS (ESI): m/z
calcd for C26H24NO2 [M+H]+ 382.1802, found 382.1789.
1'-(4-methoxyphenyl)-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1
,2'-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3o). Yellow solid (51.7 mg, 65%).
mp: 178-180 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.28-7.24 (m, 2H), 7.08
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(d, J = 8.2Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 7.1 Hz, 1H), 6.83 (t, J =
7.4 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.66 (dd, J = 10.0 Hz, 2.8 Hz, 1H), 6.39
(dd, J = 10.0 Hz, 1.5 Hz, 1H), 6.11 (dd, J = 10.0 Hz, 1.5 Hz, 1H), 3.76 (s, 3H),
3.45 (s, 3H), 3.00 (d, J = 14.3 Hz, 1H), 2.26 (d, J = 14.3 Hz, 1H), 1.43 (s, 3H).
13C NMR (100 MHz, CDCl3; δ, ppm): 185.6, 174.5, 159.3, 153.9, 153.6, 139.9,
138.3, 137.9, 129.3, 129.2, 128.9, 128.5, 127.9, 126.5, 122.6, 120.8, 115.1,
113.9, 57.2, 55.1, 53.2, 44.8, 30.0, 25.7. IR (neat, cm−1): 2963, 2930, 1664,
1598, 862, 830, 754. HRMS (ESI): m/z calcd for C26H24NO3 [M+H]+ 398.1751,
found 398.1737.
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1'-(4-(tert-butyl)phenyl)-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene
-1,2'-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3p). Yellow solid (49.2 mg, 58%).
mp: 105-107 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.28-7.25 (m, 2H), 7.20
(d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.93 (d, J
= 6.6 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.67 (dd, J = 10.0 Hz, 2.8 Hz, 1H), 6.39
(dd, J = 10.0 Hz, 1.7 Hz, 1H), 6.11 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.46 (s, 3H),
3.00 (d, J = 14.3 Hz, 1H), 2.26 (d, J = 14.2 Hz, 1H), 1.44 (s, 3H), 1.27 (s, 9H).
13C NMR (100 MHz, CDCl3; δ, ppm): 185.8, 174.6, 153.9, 153.7, 151.1, 139.8,
138.7, 138.1, 129.2, 128.9, 128.5, 128.0, 127.6, 125.3, 122.6, 120.8, 115.1,
57.3, 53.4, 44.8, 34.5, 31.1, 30.0, 25.7. IR (neat, cm−1): 2963, 1665, 1599,
1105, 857, 754, 730. HRMS (ESI): m/z calcd for C29H30NO2 [M+H]+ 424.2271,
found 424.2259.
3a',5'-dimethyl-1'-(m-tolyl)-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclope
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nta[c]quinoline]-4,4'(5'H)-dione (3q). Yellow solid (48.1 mg, 63%). mp: 192-194
oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.28-7.22 (m, 2H), 7.12-7.04 (m, 3H),
6.89 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 6.80 (t, J = 7.6 Hz,
1H), 6.66 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.38 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 6.09
(dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.45 (s, 3H), 3.00 (d, J = 14.3 Hz, 1H), 2.28 (d, J
= 14.3 Hz, 1H), 2.22 (s, 3H), 1.45 (s, 3H). 13C NMR (100 MHz, CDCl3; δ, ppm):
185.5, 174.4, 153.6, 153.3, 139.8, 138.9, 138.4, 138.0, 134.3, 129.2, 128.9,
128.8, 128.6, 128.5, 128.3, 128.0, 125.1, 122.6, 120.6, 115.1, 57.3, 53.4, 44.7,
30.0, 25.9, 21.3. IR (neat, cm−1): 2975, 2931, 1664, 1597, 1104, 867, 769, 758.
HRMS (ESI): m/z calcd for C26H24NO2 [M+H]+ 382.1802, found 382.1796.
1'-(3-methoxyphenyl)-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1
,2'-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3r). Yellow solid (45.4 mg, 57%).
mp: 84-86 oC.1H NMR (400 MHz, CDCl3; δ, ppm): 7.29-7.23 (m ,2H), 7.12 (t, J
= 8.0 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.94 (dd, J = 7.7 Hz, 1.3 Hz, 1H), 6.83
(d, J = 7.2 Hz, 1H), 6.78 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 6.68-6.60 (m, 3H), 6.38
(dd, J = 10.0 Hz, 1.8 Hz, 1H), 6.10 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.67 (s, 3H),
3.45 (s, 3H), 3.00 (d, J = 14.3 Hz, 1H), 2.28 (d, J = 14.3 Hz, 1H), 1.45 (s, 3H).
13C NMR (100 MHz, CDCl3; δ, ppm): 185.5, 174.4, 159.4, 153.4, 153.3, 139.8,
138.8, 138.4, 135.7, 129.6, 129.4, 128.9, 128.6, 128.1, 122.7, 120.5, 120.4,
115.1, 113.6, 57.2, 55.1, 53.4, 44.7, 30.0, 25.9. IR (neat, cm−1): 2975, 2930,
1664, 1597, 1105, 867, 769, 758. HRMS (ESI): m/z calcd for C26H24NO3
[M+H]+ 398.1751, found 398.1736.
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1'-(4-chlorophenyl)-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'
-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3s). Yellow solid (44.2 mg, 55%). mp:
204-206 oC.1H NMR (400 MHz, CDCl3; δ, ppm): 7.32-7.27 (m, 1H), 7.23 (dd, J
= 10.0 Hz, 2.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.2 Hz, 1H), 7.01
(d, J = 8.4 Hz, 2H), 6.89-6.82 (m, 2H), 6.63 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.39
(dd, J = 10.0 Hz, 1.7 Hz, 1H), 6.11 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.45 (s, 3H),
3.01 (d, J = 14.4 Hz, 1H), 2.29 (d, J = 14.4 Hz, 1H), 1.45 (s, 3H). 13C NMR (100
MHz, CDCl3; δ, ppm): 185.3, 174.2, 153.1, 153.0, 139.9, 139.5, 137.1, 134.1,
132.9, 129.6, 129.4, 129.1, 128.8, 128.7, 127.9, 122.8, 120.2, 115.3, 57.1,
53.5, 44.7, 30.0, 25.8. IR (neat, cm−1): 2966, 2944, 1662, 1600, 1105, 861, 828,
752. HRMS (ESI): m/z calcd for C25H21ClNO2 [M+H]+ 402.1255, found
402.1245.
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1'-(4-bromophenyl)-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'
-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3t). Yellow solid (44.9 mg, 48%). mp:
o
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101-103 C. H NMR (400 MHz, CDCl3; δ, ppm): 7.34 (d, J = 8.4 Hz, 2H),
7.30-7.27 (m, 1H), 7.22 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H),
6.95 (d, J = 8.4 Hz, 2H), 6.89-6.84 (m, 2H), 6.62 (dd, J = 10.0 Hz, 2.8 Hz, 1H),
6.39 (dd, J = 10.0 Hz, 1.7 Hz, 1H), 6.12 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.45 (s,
3H), 3.00 (d, J = 14.4 Hz, 1H), 2.29 (d, J = 14.3 Hz, 1H), 1.45 (s ,3H). 13C NMR
(100 MHz, CDCl3; δ, ppm): 185.3, 174.2, 153.1, 153.0, 139.9, 139.5, 137.2,
133.3, 131.8, 129.7, 129.6, 129.2, 128.8, 127.9, 122.8, 122.4, 120.2, 115.3,
57.0, 53.5, 44.7, 30.1, 25.8. IR (neat, cm−1): 2962, 2926, 1664, 1599, 1104,
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857, 821, 753. HRMS (ESI): m/z calcd for C25H20BrNO2Na [M+Na]+ 468.0570,
found 468.0553.
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diene-1,2'-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3u). Yellow solid (33.1 mg,
38%). mp: 81-83 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.49 (d, J = 8.2 Hz,
2H), 7.33-7.29 (m, 1H), 7.26-7.24 (m, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.11 (d, J =
8.2 Hz, 1H), 6.86-6.80 (m, 2H), 6.64 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.43 (dd, J =
10.0 Hz, 1.8 Hz, 1H), 6.13 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.46 (s, 3H), 3.05 (d, J
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= 14.4 Hz, 1H), 2.34 (d, J = 14.4 Hz, 1H), 1.47 (s, 3H). C NMR (100 MHz,
CDCl3; δ, ppm): 185.2, 174.2, 152.8 (d, J = 1.45 Hz), 140.5, 140.0, 138.3,
136.9, 130.2 (q, J = 32.1 Hz), 130.0, 129.3, 128.9, 128.5, 127.9, 126.5 (q, J =
269.6 Hz), 125.5 (q, J = 3.6 Hz), 119.9, 115.4, 57.1, 53.7, 44.8, 30.1, 25.8. 19F
NMR (376 MHz, CDCl3): δ -62.7. IR (neat, cm−1): 2976, 2929, 1666, 1599,
1106, 857, 754. HRMS (ESI): m/z calcd for C26H21F3NO2 [M+H]+ 436.1519,
found 436.1502.
3a',5'-dimethyl-1'-(3-nitrophenyl)-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-c
yclopenta[c]quinoline]-4,4'(5'H)-dione (3v). Yellow solid (34.7 mg, 42%). mp:
198-200 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 8.14-8.11 (m, 1H), 7.95 (t, J =
1.6 Hz, 1H), 7.47-7.41 (m, 2H), 7.34-7.29 (m, 1H), 7.28-7.24 (m, 1H), 7.12 (d, J
= 8.2 Hz, 1H), 6.83-6.79 (m, 1H), 6.76 (q, J = 7.7 Hz, 1.6 Hz, 1H), 6.65 (dd, J =
10.0 Hz, 3.0 Hz, 1H), 6.43 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 6.11 (dd, J = 10.0 Hz,
1.9 Hz, 1H), 3.47 (s, 3H), 3.05 (d, J = 14.5 Hz, 1H), 2.35 (d, J = 14.4 Hz, 1H),
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1.49 (s, 3H). C NMR (100 MHz, CDCl3; δ, ppm): 184.9, 173.9, 152.4, 152.3
148.2, 141.4, 140.0, 136.2, 135.5, 134.2, 130.2, 129.7, 129.4, 129.1, 127.5,
123.4, 123.1, 122.9, 119.5, 115.6, 57.0, 53.8, 44.6, 30.1, 26.0. IR (neat, cm−1):
2979, 2934, 1665, 1597, 1105, 869, 782, 760. HRMS (ESI): m/z calcd for
C25H21N2O4 [M+H]+ 413.1496, found 413.1485.
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1'-(3-chlorophenyl)-3a',5'-dimethyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'
-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3w). Yellow solid (40.2 mg, 50%). mp:
200-202 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.32-7.27 (m, 1H), 7.24-7.14
(m, 3H), 7.08 (d, J = 8.3 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H),
6.87-6.81 (m, 2H), 6.64 (dd, J = 10.0 Hz, 2.8 Hz, 1H), 6.39 (dd, J = 10.0 Hz,
1.6 Hz, 1H), 6.11 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 3.45 (s, 3H), 3.01 (d, J = 14.4
Hz, 1H), 2.29 (d, J = 14.4Hz, 1H), 1.46 (s, 3H). 13C NMR (100 MHz, CDCl3; δ,
ppm): 185.2, 174.2, 152.9, 152.7, 140.0, 139.9, 136.9, 134.3, 129.8, 129.7,
129.2, 128.9, 128.4, 128.2, 127.9, 126.3, 122.8, 120.0, 115.3, 57.1, 53.6, 44.7,
30.1, 25.9. IR (neat, cm−1): 2976, 2931, 1663, 1596, 1105, 863, 760, 685.
HRMS (ESI): m/z calcd for C25H21ClNO2 [M+H]+ 402.1255, found 402.1253.
3a',5',7'-trimethyl-1'-phenyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-cyclop
enta[c]quinoline]-4,4'(5'H)-dione (3x). Yellow solid (42.0 mg, 55%). mp:
166-168 oC. 1H NMR (400 MHz, CDCl3; δ, ppm): 7.27-7.18 (m, 4H), 7.05 (dd, J
= 7.6 Hz, 1.4 Hz, 2H), 6.88 (s, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.67-6.60 (m, 2H),
6.37 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 6.08 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.44 (s,
3H), 2.99 (d, J = 14.3 Hz, 1H), 2.34 (s, 3H), 2.27 (d, J = 14.3 Hz, 1H), 1.45 (s,
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3H). C NMR (100 MHz, CDCl3; δ, ppm): 185.5, 174.6, 153.6, 153.4, 139.9,
139.6, 138.8, 137.6, 134.6, 128.9, 128.5, 128.4, 128.1, 128.0, 127.8, 123.5,
117.8, 115.9, 57.2, 53.5, 44.7, 30.0, 25.9, 21.8. IR (neat, cm−1): 2996, 2927,
1662, 1607, 1104, 860, 818, 695. HRMS (ESI): m/z calcd for C26H24NO2
[M+H]+ 382.1802, found 382.1793.
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7'-chloro-3a',5'-dimethyl-1'-phenyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'
-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3y). Yellow solid (46.6 mg, 58%). mp:
o
180-182 C.1H NMR (400 MHz, CDCl3; δ, ppm): 7.27-7.20 (m, 4H), 7.07 (s,
1H), 7.03 (dd, J = 7.6 Hz, 1.2 Hz, 2H), 6.68 (s, 2H), 6.64 (dd, J = 10.0 Hz, 2.9
Hz, 1H), 6.39 (dd, J =10.0 Hz, 1.8 Hz, 1H), 6.09 (dd, J = 10.0 Hz, 1.8 Hz, 1H),
3.43 (s, 3H), 2.99 (d, J = 14.3 Hz, 1H), 2.29 (d, J = 14.3 Hz, 1H), 1.45 (s, 3H).
13C NMR (100 MHz, CDCl3; δ, ppm): 185.4, 174.3, 153.1, 152.8, 141.0, 139.4,
137.5, 135.0, 134.0, 129.0, 128.9, 128.7, 128.6, 128.3, 122.7, 118.9, 115.5,
57.2, 53.3, 44.6, 30.1, 25.9. IR (neat, cm−1): 2966, 2926, 1664, 1593, 1094,
863, 850, 729, 700. HRMS (ESI): m/z calcd for C25H21ClNO2 [M+H]+ 402.1255,
found 402.1240.
8'-fluoro-3a',5'-dimethyl-1'-phenyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-
cyclopenta[c]quinoline]-4,4'(5'H)-dione (3z). Yellow solid (23.9 mg, 31%). mp:
o
165-167 C.1H NMR (400 MHz, CDCl3; δ, ppm): 7.28-7.20 (m, 4H), 7.06-7.01
(m, 3H), 6.99-6.94 (m, 1H), 6.65 (dd, J = 10.0 Hz, 3.0 Hz, 1H), 6.54 (dd, J =
10.0 Hz, 2.8 Hz, 1H), 6.39 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 6.09 (dd, J = 10.0 Hz,
1.8 Hz, 1H), 3.44 (s, 3H), 3.01 (d, J = 14.4 Hz, 1H), 2.30 (d, J = 14.3 Hz, 1H),
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1.46 (s, 3H). C NMR (100 MHz, CDCl3; δ, ppm): 185.3, 173.9, 158.0 (d, J =
241.6 Hz), 153.0, 152.7, 140.3, 137.7 (d, J = 1.8 Hz), 136.2 (d, J = 2.6 Hz),
133.7, 129.0, 128.8, 128.6, 128.5, 127.9, 122.0 (d, J = 8.3 Hz), 116.4 (d, J =
8.3 Hz), 115.9 (d, J = 22.8 Hz), 114.4 (d, J = 23.8 Hz), 57.2, 53.2, 44.6, 30.3,
25.8. 19F NMR (376 MHz, CDCl3): δ -119.8. IR (neat, cm−1): 2968, 2927, 1690,
1664, 1109, 868, 813, 699. HRMS (ESI): m/z calcd for C25H21FNO2 [M+H]+
386.1551, found 386.1537.
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5',6a'-dimethyl-9'-phenyl-6a',7'-dihydrospiro[cyclohexa[2,5]diene-1,8'-cyclopen
ta[c][1,8]naphthyridine]-4,6'(5'H)-dione (3aa). Yellow solid (24.4 mg, 33%). mp:
o
178-180 C.1H NMR (400 MHz, CDCl3; δ, ppm): 8.26 (dd, J = 4.9 Hz, 1H),
7.29-7.21 (m, 4H), 7.11 (dd, J = 7.6 Hz, 1.8 Hz, 1H), 7.03 (m, 2H), 6.73 (dd, J =
7.6 Hz, 4.9 Hz, 1H), 6.65 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 6.39 (dd, J = 10.0 Hz,
1.8 Hz, 1H), 6.10 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 3.56 (s, 3H), 3.03 (d, J = 14.4
Hz, 1H), 2.33 (d, J = 14.4 Hz, 1H), 1.50 (s, 3H). 13C NMR (100 MHz, CDCl3; δ,
ppm): 185.4, 174.9, 152.9, 152.5, 151.4, 147.8, 141.1, 136.7, 135.5, 133.7,
129.2, 128.9, 128.7, 128.5, 127.9, 118.0, 115.7, 57.2, 53.7, 44.6, 28.9, 26.6. IR
(neat, cm−1): 2970, 2948, 1672, 1663, 1106, 864, 776, 702. HRMS (ESI): m/z
calcd for C24H21N2O2 [M+H]+ 369.1598, found 369.1584.
3a'-methyl-1'-phenyl-3a',4'-dihydro-3'H-spiro[cyclohexa[2,5]diene-1,2'-cyclope
nta[c]chromen]-4-one (3ab). Yellow solid (25.4 mg, 35%). mp: 198-200 oC. 1H
NMR (400 MHz, CDCl3; δ, ppm): 7.33 (dd, J = 10.0 Hz, 2.9 Hz, 1H), 7.27-7.25
(m, 3H), 7.12-7.09 (m, 3H), 6.89 (d, J = 8.2 Hz, 1H), 6.74 (dd, J = 7.9 Hz, 1.3
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The Journal of Organic Chemistry
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Hz, 1H), 6.65-6.56 (m, 2H), 6.33 (dd, J = 10.0 Hz, 1.7 Hz, 1H), 10.0 Hz, 1.7 Hz,
1H), 4.29 (d, J = 10.2 Hz, 1H), 4.02 (d, J = 10.2 Hz, 1H), 2.13 (s, 2H), 1.43 (s,
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3H). C NMR (100 MHz, CDCl3; δ, ppm): 185.7, 154.2, 153.6, 153.4, 139.2,
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135.3, 134.0, 129.9, 129.0, 128.6, 128.2, 128.1, 127.9, 120.3, 117.9, 116.9,
77.2, 57.6, 45.4, 44.3, 23.2. IR (neat, cm−1): 3036, 2964, 2925, 1660, 1617,
1242, 867, 751, 696. HRMS (ESI): m/z calcd for C24H20O2Na [M+Na]+
363.1356, found 363.1340.
3,5-difluoro-3a',5'-dimethyl-1'-propyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,
1
2'-cyclopenta[c]quinoline]-4,4'(5'H)-dione (3ac). Yellow oil (38.5 mg, 52%). H
NMR (400 MHz, CDCl3; δ, ppm): 7.42-7.37 (m, 2H), 7.18-7.14 (m, 1H), 7.11 (d,
J = 8.2 Hz, 1H), 6.51 (dd, J = 11.5 Hz, 2.5 Hz, 1H), 6.33 (dd, J = 11.6 Hz, 2.4
Hz, 1H), 3.41 (s, 3H), 3.01 (d, J = 14.6 Hz, 1H), 2.22 (d, J = 14.6 Hz, 1H),
2.11-1.98 (m, 2H), 1.45-1.34 (m, 2H), 1.31 (s, 3H), 0.91 (t, J = 7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3; δ, ppm): 174.2, 171.8 (t, J = 24.1 Hz), 154.1 (dd, J =
84.7 Hz, 8.0 Hz), 151.5 (dd, J = 84.7 Hz, 8.1 Hz), 139.5, 138.7, 137.9, 130.1
(dd, J = 10.9 Hz, 2.1 Hz), 129.9 (dd, J = 11.0 Hz, 1.6 Hz), 129.3, 126.9, 123.2,
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121.3, 115.3, 54.6 (t, J = 5.5 Hz), 53.5, 43.7, 30.1, 28.9, 25.8, 23.6, 14.3. F
NMR (376 MHz, CDCl3): δ – 129.26 (d, J =15.1 Hz) -130.02 (d, J = 15.0 Hz). IR
(neat, cm−1): 2964, 2932, 1687, 1669, 1599, 1002, 756. HRMS (ESI): m/z
calcd for C22H22F2NO2 [M+H]+ 370.1613, found 370.1613.
3-fluoro-3a',5'-dimethyl-1'-propyl-3',3a'-dihydrospiro[cyclohexa[2,5]diene-1,2'-c
1
yclopenta[c]quinoline]-4,4'(5'H)-dione (3ad). Yellow oil (44.9 mg, 60%). H
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