Redox-Neutral Cascade Dearomatization of Indoles via Hydride Transfer: Divergent Synthesis of Tetrahydroquinoline-Fused Spiroindolenines

Article abstract of DOI:10.1021/acs.joc.9b02110

The redox-neutral cascade dearomatization of indoles with o-aminobenzaldehydes has been realized via the hydride transfer strategy, achieving the condition- A nd substrate-controlled divergent synthesis of tetrahydroquinoline-fused spiroindolenines. The integration of hydride transfer-involved C(sp³)-H functionalization with dearomatization provides a promising platform for the construction of structurally diverse molecules.

Full text of DOI:10.1021/acs.joc.9b02110

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Article
Redox-Neutral Cascade Dearomatization of Indoles via Hydride Transfer:
Divergent Synthesis of Tetrahydroquinoline-Fused Spiroindolenines
Yao-Bin Shen, Long-Fei Li, Ming-Yan Xiao, Jian-Ming Yang, Qing Liu, and Jian Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02110 • Publication Date (Web): 19 Sep 2019
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Redox-Neutral Cascade Dearomatization of Indoles via Hydride
Transfer: Divergent Synthesis of Tetrahydroquinoline-Fused
Spiroindolenines
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Yao-Bin Shen,†, ∥Long-Fei Li,†, ∥Ming-Yan Xiao,† Jian-Ming Yang,§ Qing Liu,┴ Jian Xiao*,†,‡
† College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
‡ College of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.
§ College of Life Sciences, Qingdao Agricultural University, Qingdao 266109, China
┴ College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao
266590, China.
Corresponding author: Jian Xiao
E-mail address: chemjianxiao@163.com
Graphic Abstract
Abstract: The redox-neutral cascade dearomatization of indoles with o-aminobenzaldehydes has
been realized via hydride transfer strategy, achieving the condition- and substrate-controlled
divergent synthesis of tetrahydroquinoline-fused spiroindolenines. The integration of hydride
transfer-involved C(sp3)‒H functionalization with dearomatization provides a promising platform
for the construction of structurally diverse molecules.
INTRODUCTION
Spiroindolenines are not only the core structures of naturally occurring products and
pharmaceutically relevant molecules (Figure 1),1 but also the versatile synthetic intermediates
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Figure 1. Natural products and bioactive molecules containing spiroindolenine skeleton.
for the syntheses of tetrahydrocarbolines, tetrahydrocarbazoles as well as spiroindolines.2
Consequently, tremendous efforts have focused on the development of effective strategies to
access these attractive scaffolds,3 wherein the transition-metal (TM)-catalyzed intramolecular
dearomatization of indoles have proved to be the robust way (Scheme 1, a).2, 4‒5 Despite the
advances, these methods generally suffer from the substrate engineering, namely the complicated
pre-preparation of C3-functionalized indole precursors, which contradicts the principle of
step-economy. Moreover, this type of reactions has been restrained by the intramolecular versions,
and the dearomatization reactions between independent indoles and dearomatizing spiroannulation
reagents are underdeveloped. At the same time, the synthesis of tetrahydroquinoline(THQ)-fused
spiroindolenines remains elusive, in spite of the vital role of THQ skeletons in pharmaceutical and
agrochemical industries.6 Therefore, it is highly appealing to explore an efficient intermolecular
methodology for the rapid, divergent assembly of THQ-fused spiroindolenines from readily
accessible indole feedstocks and dearomatizing spiroannulation reagents.
The cascade [1,5]-hydride transfer/cyclization represents a powerful redox-neutral strategy for
the direct functionalization of inert C(sp3)‒H bonds, allowing the rapid generation of polycyclic
and spirocyclic architectures.7 Owing to its high efficiency and atom-economy in building
molecular complexity, a plethora of protocols have been developed by employing various types of
hydride acceptors beforehand or in situ.8‒13 Although great achievements have been made in this
area, the reaction modes are still relatively limited. To the best of our knowledge, there are only
sporadic reports combining hydride transfer with dearomatization process.14 In this regard, our
group recently disclosed
a
redox-neutral dearomative cyclization of phenols with
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o-aminobenzaldehydes, affording an array of highly functionalized THQ scaffolds (Scheme 1,
b).14a Inspired by this exciting result, we hypothesized that the dearomatization of simple indoles
could also be realized by using readily available o-aminobenzaldehydes as the dearomatizing
spiroannulation reagents. As our continuing interest in the one-step assembly of biologically
important molecules, herein, we reported the redox-neutral cascade dearomatization of simple
indoles with o-aminobenzaldehydes through hydride transfer strategy, furnishing two kinds of
THQ-fused spiroindolenines in good yields with moderate diastereoselectivities (Scheme 1, c).
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Scheme 1. Redox-Neutral Cascade Dearomatization of Indoles through [1,5]-Hydride
Transfer
RESULTS AND DISCUSSION
To verify the feasibility of our hypothesis, 2-(pyrrolidin-1-yl)benzaldehyde 1a and
2-methylindole 2a were chosen as the model substrates to optimize the reaction conditions (Table
1). Given the unique characteristics of fluorinated alcohols15 as well as our recent success in
HFIP-promoted hydride transfer reactions9b, 14a, HFIP was initially investigated as both promoter
and solvent in the absence of any catalyst (Table 1, entry 1). Gratifyingly, the reaction proceeded
efficiently to provide the desired THQ-fused spiroindolenine 3a in 96% yield with moderate
diastereoselectivity (Table 1, entry 1). In comparison, the employment of other alcohols and H2O
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exhibited inferior outcomes (Table 1, entries 2‒5). Afterwards, the screening of various Brønsted
acids and Lewis acids failed to produce a superior result (Table 1, entries 6‒10). However, it was
exciting that an intriguing product 4a was isolated in 12% yield when Sc(OTf)3 was used as a
catalyst (Table 1, entry 9). The structure of 4a has been confirmed undoubtedly by NMR and
HRMS analysis. To improve the reaction efficiency, the molar ratio of starting materials was
adjusted from 1.2:1 to 2.5:1, which resulted in an enhanced yield of 66%, albeit with low
diastereoselectivity (Table 1, entry 11). Further evaluation of other solvents indicated that DCE
was the best solvent (Table 1, entries 12‒14). Finally, the elevation of temperature led to a lower
yield (Table 1, entry 15).
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Table 1. Optimization of the Reaction Conditionsa
yield (%)b/drc
entry
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2
3
4
5
6
7
8
catalyst
-
solvent
HFIP
TFE
i-PrOH
EtOH
H2O
DCE
DCE
DCE
DCE
DCE
DCE
DCM
toluene
DMF
DCE
time (h)
0.2
24
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24
3
3a
96/3.3:1
53/2.6:1
0
4a
0
0
0
0
-
-
-
-
0
0
0
TfOH
TsOH·H2O
PhCO2H
Sc(OTf)3
Zn(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
45/2.8:1
52/2.6:1
23/3:1
47/2:1
30/2.3:1
trace
trace
25/2:1
0
trace
trace
0
12/1.8:1
trace
66/2:1
54/2:1
19/2.2:1
0
9
10
11d
12d
13d
14d
15d, e
3
72
72
72
72
72
trace
51/1.8:1
aReaction conditions (unless other indicated): 1a (0.12 mmol), 2a (0.1 mmol), and catalyst (20 mol %) in 1 mL of
b
c
1
d
solvent at room temperature. Isolated yield. Determined by H NMR analysis. 1a (0.25 mmol), 2a (0.1 mmol).
eAt 60 °C .
After the optimized reaction conditions established, the substrate scope for the synthesis of
THQ-fused spiroindolenines 3 was explored by using a variety of o-aminobenzaldehydes and
2-methylindoles (Table 2). Regarding the substituents (R1) on the phenyl ring of
2-(pyrrolidin-1-yl)benzaldehydes, the electron-donating groups (-MeO and -Me) were fully
compatible, giving the corresponding products 3b‒d in 82‒93% yields. Satisfyingly, various
electron-withdrawing groups (-CF3, -F, -Cl, -Br, -CN, and 4-Ac-Ph) were also well-tolerated to
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afford 3e‒m in 53‒97% yields, which demonstrated the excellent functional group tolerance of
this methodology. Notably, the position of substituents on the phenyl rings had little influence on
these transformations. When the hydride donors varied from pyrrolidine to octahydroisoindole or
seven-membered hexamethyleneimine, the reactions still proceeded smoothly and furnished the
desired spiroindolenines 3n and 3o in 90% and 79% yields, respectively. Remarkably, the less
reactive 2-(dimethylamino)benzaldehyde was also a competent dearomatizing spiroannulation
reagent, providing product 3p in 49% yield. Furthermore, 2-methylindoles bearing
electron-donating and electron-withdrawing groups could be readily converted into the
corresponding adducts 3q and 3r in 90% and 92% yields.
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According to the previous reports,2 it was difficult to synthesize the C2-unsubstituted
spiroindolenines under the acidic conditions due to their propensity for rearomatization to undergo
intramolecular 1,2-migration to afford C2-alkylated indole derivatives. Thus, the more challenging
dearomatization reactions of o-aminobenzaldehydes with C2-unsubstituted indoles were
investigated. To our delight, an array of indoles incorporating multifarious electron-donating or
electron-withdrawing substituents were totally amenable to the reaction and provided THQ-fused
spiroindolenines 3s‒za in 65‒82% yields, albeit with poor diastereoselectivities. Obviously, the
electronic effect of substituents had marginal impacts on the transformations. It was worth
mentioning that the C4-substituted indole could furnish product 3z with excellent
diastereoselectivity (dr >20:1), which might be attributed to the steric hindrance of the bromo
group.
Subsequently, we continue to investigate the substrate scope of the three-component reactions
for the assembly of THQ-fused indolenines 4 (Table 3). With respect to o-aminobenzaldehydes,
the fluro (-F) and bromo (-Br) substituents were well-tolerated, and the corresponding products 4b
and 4c were delivered in 59% and 63% yields with relatively lower diastereoselectivities.
Moreover, 2-methylindoles incorporating methoxy (-MeO) and fluro (-F) groups were proved to
be ideal candidates for this reaction, giving adducts 4d and 4e in good yields.
Table 2. Scope for Reactions of o-Aminobenzaldehydes with 2-Alkylindolesa
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aReaction conditions: 1 (0.12 mmol) and 2 (0.1 mmol) in 1 mL of HFIP at room temperature. Isolated yields after
4
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column chromatography, dr was determined by 1H NMR analysis.
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Table 3. Scope for the Three-Component Reactionsa
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aReaction conditions: 1 (0.25 mmol), 2 (0.1 mmol), and Sc(OTf)3 (20 mol %) in 1 mL of DCE at room temperature
for 72 h. Isolated yields after column chromatography, dr was determined by 1H NMR analysis.
To illustrate the practical utility of this protocol, the large-scale reactions of
2-(pyrrolidin-1-yl)benzaldehyde 1a and 2-methylindole 2a were conducted (Scheme 2). The
reactions proceeded smoothly and furnished products 3a and 4a in 95% and 58% yields,
respectively. Furthermore, the derivatization of THQ-fused spiroindolenine 3t was performed
under the acidic conditions (Scheme 3).2a Delightedly, the acid-catalyzed ring expansion occurred
via an 1,2-migration process to afford the indole-fused benzazepine 5 in 60% yield, which was
difficult to realize in previous report.11f
Scheme 2. Large-Scale Synthesis of Products 3a and 4a.
Scheme 3. Transformation of Product 3t.
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To get insights into the mechanism, the isotopic experiment between the deuterium substrate
[D]-1a and 2-methylindole 2a was performed under the optimized conditions (Scheme 4). The
corresponding product [D]-3a was isolated in 87% yield and the observation of >99% deuterium
at the benzyl position fully demonstrated the intramolecular hydride transfer process.
Scheme 4. Deuterium Labeling Experiment.
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On the basis of the above experimental results and literature precedents, the plausible
mechanisms were proposed as shown in Scheme 5. With respect to the HFIP-mediated
two-component reaction, HFIP initially aggregates both substrates 1a and 2a via the double
hydrogen-bonding activation mode to generate the transition state A, which subsequently
undergoes the Friedel‒Crafts alkylation to form 3-indolylmethanol B.14a Afterwards, with the
assistance of the hydrogen-bonding cluster of HFIP, the dehydration of 3-indolylmethanol B
affords the dearomatized vinylimine species C. Then the rearomatization-driven [1,5]-hydride
transfer occurs to give the iminium intermediate D, which is stabilized by the HFIP counteranion.
Finally, the cascade dearomatization/spirocyclization occurs to provide the THQ-fused
spiroindolenine 3a (Scheme 5, I). However, owing to the weak acidity of HFIP, the activation of
3a to undergo condensation with 1a is prohibited. In contrast, Sc(OTf)3 could push forward this
process, affording the α,β-unsaturated indolenine intermediate E.9e Then the Sc(OTf)3-catalyzed
[1,5]-hydride transfer operates and gives rise to the iminium intermediate F, which is followed by
the 6-endo cyclization to furnish the desired product 4a. It is worth mentioning that Sc(OTf)3
could produce the product 4a due to its strong Lewis acidity. Compared with various Brønsted
acids and Lewis acids, HFIP exhibits excellent efficiency in the two-component reaction, thanks
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to its inherent properties of strong hydrogen bond donor ability and the cationic species
stabilization ability.16
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Scheme 5. Proposed Mechanism
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CONCLUSION
In summary, we developed the redox-neutral cascade dearomatization of indoles with
o-aminobenzaldehydes via hydride transfer strategy, accomplishing the condition- and
substrate-controlled divergent synthesis of THQ-fused spiroindolenines. This method featured
mild reaction conditions, wide substrate scope, and good functional group tolerance.
Mechanistically, the key step of intramolecular [1, 5]-hydride transfer has been fully confirmed by
the isotope experiment. We were optimistic that the strategy merging hydride transfer with
dearomatization would provide a straightforward avenue for the assembly of bioactive spirocyclic
molecules in drug discovery.
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Experimental Section
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All commercially available reagents, unless otherwise indicated, were used without further
purification. All solvents were purified and dried according to standard methods prior to use.
Reactions were monitored by thin layer chromatography (TLC) with 0.2 mm silica gel-coated
HSGF 254 plates, visualized by UV light at 254 or 365 nm. Products were isolated and purified by
column chromatography on 200‒300 mesh silica gel. 1H, 13C, and 19F NMR spectra were recorded
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1
on a Bruker AMX 500 (500 MHz for H NMR, 125 MHz for 13C NMR and 470 MHz for 19F
NMR) spectrometer at room temperature. The chemical shifts (δ) were reported in ppm with
1
respect to an internal standard, tetramethylsilane (0 ppm), and the solvent (CDCl3, H: δ = 7.26
ppm, 13C: δ = 77.16 ppm). Coupling constants (J) are given in Hertz. Splitting patterns of apparent
multiplets associated with an averaged coupling constants were designated as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) and br (broadened). All
13C spectra were recorded with broadband proton decoupling. HRMS were performed on a Waters
XEVO QTOF mass spectrometer.
General Procedure for the Synthesis of o-Aminobenzaldehydes 1.8a, 12c, 13a, 14b
An oven-dried round-bottomed flask was charged with 2-chloro/fluorobenzaldehydes (1.0 equiv,
10 mmol), secondary amines (1.2 equiv, 12 mmol), K2CO3 (2.0 equiv, 20 mmol), and DMF (50
mL). The reaction mixture was stirred vigorously and refluxed in oil bath for 12 h and monitored
by TLC. Upon consumption, the mixture was cooled to room temperature and diluted with water
(100 mL), and extracted with EtOAc (3 x 100 mL). The combined extracts were washed with
brine (3 x 50 mL), dried by anhydrous Na2SO4, filtered, and concentrated under reduced pressure
and the residue was purified by flash column chromatography (column chromatography eluent,
petroleum
ether/EtOAc)
to
afford
o-aminobenzaldehydes
1.
2-Methoxy-6-(pyrrolidin-1-yl)benzaldehyde 1b was a new compound and characterized as
follows.
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Procedure for the Synthesis of Deuterated Substrate [D]-1a.
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To a solution of pyrrolidine-2,5-dione (3.6 mmol, 357 mg) in THF (15 mL) was added LiAlD4
(18 mmol, 756 mg) in portions in ice bath (0 °C ). After stirring at 40 °C in oil bath for 12 h,
Na2SO4·10H2O was added until no bubbles appeared. Then DMF (15 mL), K2CO3 (4.5 mmol, 622
mg), and 2-fluorobenzaldehyde (3 mmol, 372 mg) were added in sequence. The mixture was
heated to 120 °C in oil bath and monitored by TLC. After the consumption of
2-fluorobenzaldehyde, the mixture was cooled to room temperature and diluted with water (40
mL), and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with brine (3 x
30 mL), dried by anhydrous Na2SO4, filtered, and concentrated under reduced pressure and the
residue was purified by flash column chromatography (column chromatography eluent, petroleum
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ether/EtOAc) to afford the deuterated substrate [D]-1a as colorless oil in 76% yield (408 mg).
General Procedure for the Synthesis of Products 3.
An oven-dried reaction tube was charged with o-aminobenzaldehydes 1 (1.2 equiv, 0.12 mmol),
indoles 2 (1.0 equiv, 0.1 mmol), and HFIP (1 mL). The reaction mixture was stirred vigorously at
room temperature and monitored by TLC. After the consumption of 2, the reaction mixture was
concentrated under reduced pressure and then purified by flash column chromatography (column
chromatography eluent, petroleum ether/EtOAc) to afford products 3.
General Procedure for the Synthesis of Products 4.
An oven-dried reaction tube was charged with o-aminobenzaldehydes 1 (2.5 equiv, 0.25 mmol),
2-methylindoles 2 (1.0 equiv, 0.1 mmol), DCE (1 mL), and Sc(OTf)3 (20 mol %, 9.8 mg). The
reaction mixture was stirred vigorously at room temperature for 72 h and monitored by TLC. After
the completion of the reaction, the reaction mixture was concentrated under reduced pressure and
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then purified by flash column chromatography (column chromatography eluent, petroleum
ether/EtOAc) to afford products 4.
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Procedure for the Large-Scale Synthesis of 3a.
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An oven-dried round-bottomed flask was charged with 2-(pyrrolidin-1-yl)benzaldehyde 1a (6
mmol, 1050 mg), 2-methylindole 2a (5 mmol, 655 mg), and HFIP (50 mL). The reaction mixture
was stirred vigorously at room temperature for 0.2 h and monitored by TLC. After the
consumption of 2a, the reaction mixture was concentrated under reduced pressure and then
purified by flash column chromatography (column chromatography eluent, petroleum
ether/EtOAc = 5:1) to afford product 3a as white solid in 95% yield (1368 mg) with moderate
diastereoselectivity (3.2:1 dr).
Procedure for the Large-Scale Synthesis of 4a.
An oven-dried round-bottomed flask was charged with 2-(pyrrolidin-1-yl)benzaldehyde 1a (7.5
mmol, 1313 mg), 2-methylindole 2a (3 mmol, 393 mg), DCE (30 mL), and Sc(OTf)3 (0.6 mmol,
295 mg). The reaction mixture was stirred vigorously at room temperature for 72 h and monitored
by TLC. After the completion of the reaction, the reaction mixture was concentrated under
reduced pressure and then purified by flash column chromatography (column chromatography
eluent, petroleum ether/EtOAc = 20:1) to afford product 4a as yellow solid in 58% yield (774 mg)
with moderate diastereoselectivity (2:1 dr).
Procedure for the Deuterium Labeling Experiment.
An oven-dried reaction tube was charged with [D]-1a (0.12 mmol, 21.5 mg), 2-methylindole 2a
(0.1 mmol, 13.1 mg), and HFIP (1 mL). The reaction mixture was stirred vigorously at room
temperature for 0.2 h and monitored by TLC. After the consumption of 2a, the reaction mixture
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was concentrated under reduced pressure and then purified by flash column chromatography
(column chromatography eluent, petroleum ether/EtOAc = 5:1) to afford product [D]-3a as white
solid in 87% yield (25.4 mg) with moderate diastereoselectivity (3.3:1 dr).
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Procedure for the Transformation of Product 3t.
An oven-dried reaction tube was charged with 3t (0.1 mmol, 30.4 mg), TsOH·H2O (0.03 mmol,
5.7 mg), and THF (1 mL). The reaction mixture was stirred vigorously at room temperature for 5
min and monitored by TLC. After the consumption of 3t, the reaction mixture was concentrated
under reduced pressure and then purified by flash column chromatography (column
chromatography eluent, petroleum ether/EtOAc = 10:1) to afford product 5 as white solid in 60%
yield (18.3 mg).
2-methoxy-6-(pyrrolidin-1-yl)benzaldehyde (1b). Yellow solid; 1.78 g, 87% yield; mp
50–52 °C; column chromatography eluent, petroleum ether/EtOAc = 20:1; 1H NMR (500 MHz,
CDCl3) δ 10.44 (s, 1H), 7.27 (t, J = 8.4 Hz, 1H), 6.46 (d, J = 8.7 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H),
3.86 (s, 3H), 3.23–3.16 (m, 4H), 1.97–1.91 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 189.0,
164.0, 150.3, 134.3, 112.3, 107.3, 98.0, 55.8, 52.4 (2C), 25.9 (2C); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C12H16NO2 206.1176; found 206.1175.
2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3a). White
solid; 27.6 mg, 96% yield, dr 3.3:1; mp 246–248 °C; column chromatography eluent, petroleum
ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.7 Hz, 1H), 7.28–7.21 (m, 2H),
6.97 (d, J = 7.4 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.64 (t, J = 7.2 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H),
6.53 (d, J = 7.0 Hz, 1H), 3.95 (dd, J = 10.2, 5.8 Hz, 1H), 3.58–3.49 (m, 1H), 3.43 (d, J = 15.4 Hz,
1H), 3.23 (dd, J = 16.4, 8.9 Hz, 1H), 2.44 (d, J = 15.4 Hz, 1H), 2.32 (s, 3H), 1.90–1.82 (m, 1H),
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1.82–1.74 (m, 1H), 1.67–1.58 (m, 1H), 0.64 (tdd, J = 11.7, 9.9, 7.9 Hz, 1H); 13C{1H} NMR (125
MHz, CDCl3) δ 184.2, 154.9, 144.0, 139.0, 129.6, 128.1, 127.8, 125.2, 123.9, 119.7, 117.9, 115.8,
110.2, 61.3, 56.5, 47.3, 35.7, 26.8, 23.3, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H21N2 289.1699; found 289.1697.
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6'-methoxy-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline]
(3b). White solid; 29.6 mg, 93% yield, dr 3.7:1; mp 194‒196 °C; column chromatography eluent,
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petroleum ether/EtOAc = 5:1; H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.27–7.24
(m, 1H), 7.24–7.11 (m, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.36–6.22 (m, 2H),
3.92–3.82 (m, 1H), 3.72 (s, 3H), 3.49 (td, J = 8.8, 2.3 Hz, 1H), 3.27 (dd, J = 16.4, 8.5 Hz, 1H),
3.02 (d, J = 16.3 Hz, 1H), 2.72 (d, J = 16.3 Hz, 1H), 2.33 (s, 3H), 1.90–1.78 (m, 1H), 1.77–1.70
(m, 1H), 1.68–1.58 (m, 1H), 0.68–0.57 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 184.5, 158.1,
155.0, 144.9, 139.6, 127.9, 127.7, 125.1, 123.9, 119.6, 106.0, 104.0, 98.5, 60.6, 56.5, 55.3, 47.5,
29.2, 26.8, 23.3, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H23N2O 319.1805; found
319.1809.
7'-methoxy-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline]
(3c). White solid; 26.1 mg, 82% yield, dr 3.3:1; mp 238‒240 °C; column chromatography eluent,
1
petroleum ether/EtOAc = 5:1; H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.7 Hz, 1H), 7.28–7.25
(m, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.83 (dd, J = 8.7, 2.7 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.58 (d,
J = 7.4 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 3.94–3.86 (m, 1H), 3.74 (s, 3H), 3.51–3.38 (m, 2H),
3.22 (dd, J = 16.2, 8.5 Hz, 1H), 2.42 (d, J = 15.6 Hz, 1H), 2.31 (s, 3H), 1.91–1.80 (m, 1H), 1.76
(ddd, J = 7.3, 6.2, 2.3 Hz, 1H), 1.66–1.58 (m, 1H), 0.69–0.55 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 184.2, 155.0, 150.7, 139.1, 138.8, 127.8, 125.1, 124.1, 119.7, 119.0, 115.7, 113.6, 111.0,
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61.4, 56.8, 55.8, 47.7, 35.9, 26.7, 23.3, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C21H23N2O 319.1805; found 319.1811.
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2,8'-dimethyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline]
(3d).
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Faint yellow solid; 26.3 mg, 87% yield, dr 3.7:1; mp 125–127 °C; column chromatography eluent,
petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.7 Hz, 1H), 7.24 (t, J =
7.7 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.56 (d, J = 7.4 Hz, 1H), 6.46 (d, J
= 7.0 Hz, 1H), 6.40 (s, 1H), 3.91 (dd, J = 10.0, 5.5 Hz, 1H), 3.49 (td, J = 8.8, 2.2 Hz, 1H), 3.36 (d,
J = 15.3 Hz, 1H), 3.21 (dd, J = 16.4, 8.8 Hz, 1H), 2.39 (d, J = 15.3 Hz, 1H), 2.36 (s, 3H), 2.30 (s,
3H), 1.96–1.72 (m, 2H), 1.63–1.57 (m, 1H), 0.67–0.56 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 184.2, 154.9, 143.8, 139.1, 137.7, 129.4, 127.7, 125.1, 123.9, 119.6, 116.7, 115.0, 111.0, 61.3,
56.7, 47.3, 35.4, 26.7, 23.3, 21.7, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H23N2
303.1856; found 303.1855.
2-methyl-8'-(trifluoromethyl)-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quin
oline] (3e). Yellow solid; 18.9 mg, 53% yield, dr 4:1; mp 170–172 °C; column chromatography
eluent, petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz, 1H), 7.28
(t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H),
6.76 (s, 1H), 6.48 (d, J = 7.4 Hz, 1H), 3.95 (dd, J = 10.0, 6.0 Hz, 1H), 3.62–3.51 (m, 1H), 3.42 (d,
J = 15.7 Hz, 1H), 3.25 (dd, J = 16.5, 9.0 Hz, 1H), 2.49 (d, J = 15.7 Hz, 1H), 2.33 (s, 3H),
2.06–1.78 (m, 2H), 1.65 (ddd, J = 12.5, 7.2, 1.6 Hz, 1H), 0.73–0.59 (m, 1H); 13C{1H} NMR (125
MHz, CDCl3) δ 183.5, 155.0, 144.1, 138.6, 130.4 (q, J = 31.5 Hz), 129.7, 128.2, 125.4, 124.6 (q, J
= 270.6 Hz), 123.6, 121.6 (q, J = 1.0 Hz), 120.0, 112.3 (q, J = 3.9 Hz), 106.4 (q, J = 3.9 Hz), 61.4,
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55.8, 47.5, 35.6, 26.8, 23.3, 16.2; 19F NMR (470 MHz, CDCl3) δ ‒62.4; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C21H20F3N2 357.1573; found 357.1573.
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6'-fluoro-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3f).
White solid; 28.5 mg, 93% yield, dr 4.2:1; mp 156–158 °C; column chromatography eluent,
petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz, 1H), 7.29 (t, J =
7.6 Hz, 1H), 7.19–7.09 (m, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 6.45–6.34 (m,
2H), 3.90 (dd, J = 9.5, 6.0 Hz, 1H), 3.57–3.48 (m, 1H), 3.24 (dd, J = 16.5, 8.9 Hz, 1H), 3.12 (d, J
= 16.1 Hz, 1H), 2.71 (d, J = 15.8 Hz, 1H), 2.34 (s, 3H), 2.02–1.74 (m, 2H), 1.68–1.62 (m, 1H),
0.71–0.57 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 183.8, 161.8 (d, J = 240.4 Hz), 155.0,
145.4 (d, J = 7.6 Hz), 138.9, 128.5 (d, J = 10.8 Hz), 128.0, 125.3, 123.6, 119.9, 106.0 (d, J = 2.3
Hz), 105.2 (d, J = 20.1 Hz), 102.6 (d, J = 22.5 Hz), 60.8, 55.8, 47.7, 28.4 (d, J = 4.4 Hz), 26.8,
23.3, 16.3; 19F NMR (470 MHz, CDCl3) δ ‒117.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H20FN2 307.1605; found 307.1614.
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7'-chloro-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3g).
Yellow solid; 29.0 mg, 90% yield, dr 3.3:1; mp 124–126 °C; column chromatography eluent,
petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz, 1H), 7.29 (td, J =
7.6, 1.1 Hz, 1H), 7.17 (dd, J = 8.6, 1.9 Hz, 1H), 7.00–6.87 (m, 2H), 6.59–6.46 (m, 2H), 3.99–3.84
(m, 1H), 3.54–3.46 (m, 1H), 3.38 (d, J = 15.5 Hz, 1H), 3.19 (dd, J = 16.4, 9.0 Hz, 1H), 2.40 (d, J =
15.6 Hz, 1H), 2.31 (s, 3H), 2.05–1.84 (m, 1H), 1.83–1.75 (m, 1H), 1.63 (ddd, J = 12.8, 7.5, 1.9 Hz,
1H), 0.64 (tdd, J = 11.8, 9.9, 7.9 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 183.7, 154.9, 142.6,
138.6, 129.2, 128.1, 127.9, 125.3, 123.9, 120.3, 119.9, 119.5, 111.2, 61.3, 56.1, 47.6, 35.5, 26.8,
23.3, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20ClN2 323.1310; found 323.1316.
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8'-chloro-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3h).
White solid; 30.6 mg, 95% yield, dr 4:1; mp 176–178 °C; column chromatography eluent,
petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.7 Hz, 1H), 7.27 (t, J =
7.3 Hz, 1H), 6.95 (t, J = 7.7 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.66–6.56 (m, 1H), 6.55 (d, J = 1.5
Hz, 1H), 6.51 (d, J = 7.5 Hz, 1H), 3.97–3.86 (m, 1H), 3.52–3.45 (m, 1H), 3.33 (d, J = 15.4 Hz,
1H), 3.18 (dd, J = 16.6, 9.0 Hz, 1H), 2.40 (d, J = 15.4 Hz, 1H), 2.31 (s, 3H), 1.94–1.84 (m, 1H),
1.83–1.76 (m, 1H), 1.66–1.58 (m, 1H), 0.69–0.58 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
183.7, 154.9, 144.9, 138.6, 133.5, 130.4, 128.0, 125.3, 123.7, 119.8, 116.4, 115.5, 109.9, 61.2,
56.1, 47.4, 35.2, 26.7, 23.3, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20ClN2
323.1310; found 323.1310.
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8'-bromo-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3i).
Yellow solid; 34.0 mg, 93% yield, dr 1.5:1; mp 138–140 °C; column chromatography eluent,
petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz, 1H), 7.28 (t, J =
7.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.70 (s,
1H), 6.52 (d, J = 7.4 Hz, 1H), 4.01–3.87 (m, 1H), 3.54–3.45 (m, 1H), 3.33 (d, J = 15.5 Hz, 1H),
3.19 (dd, J = 16.9, 8.4 Hz, 1H), 2.40 (d, J = 15.4 Hz, 1H), 2.31 (s, 3H), 1.95–1.83 (m, 1H),
1.83–1.77 (m, 1H), 1.63 (dt, J = 12.4, 6.3 Hz, 1H), 0.69–0.58 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 183.6, 155.0, 145.1, 138.6, 130.7, 128.1, 125.3, 123.7, 121.7, 119.9, 118.5, 116.9, 112.8,
61.2, 56.0, 47.4, 35.3, 26.7, 23.3, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20BrN2
367.0804; found 367.0811.
7'-bromo-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3j).
White solid; 35.5 mg, 97% yield, dr 4:1; mp 130–132 °C; column chromatography eluent,
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petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.7 Hz, 1H), 7.32–7.21
(m, 2H), 7.06 (s, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.51 (d, J = 7.4 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H),
3.97–3.84 (m, 1H), 3.53–3.45 (m, 1H), 3.37 (d, J = 15.5 Hz, 1H), 3.18 (dd, J = 16.5, 8.9 Hz, 1H),
2.38 (d, J = 15.6 Hz, 1H), 2.31 (s, 3H), 1.91–1.83 (m, 1H), 1.82–1.74 (m, 1H), 1.66–1.59 (m, 1H),
0.68–0.58 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 183.6, 155.0, 143.0, 138.6, 132.0, 130.8,
128.1, 125.3, 123.8, 120.0, 119.9, 111.7, 107.4, 61.3, 56.0, 47.5, 35.5, 26.8, 23.3, 16.3; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C20H20BrN2 367.0804; found 367.0807.
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6'-bromo-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3k).
White solid; 34.4 mg, 94% yield, dr 3.8:1; mp 148–150 °C; column chromatography eluent,
petroleum ether/EtOAc = 15:1; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.5 Hz, 1H), 7.28 (t, J =
7.6 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.61 (d, J
= 7.4 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 3.86 (dd, J = 9.1, 6.3 Hz, 1H), 3.48 (t, J = 7.9 Hz, 1H),
3.28–3.22 (m, 1H), 3.16 (d, J = 16.3 Hz, 1H), 2.76 (d, J = 16.3 Hz, 1H), 2.34 (s, 3H), 2.02–1.73
(m, 2H), 1.69–1.60 (m, 1H), 0.70–0.55 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 183.4, 154.9,
145.3, 139.0, 128.8, 128.0, 126.0, 125.3, 123.6, 119.8 (2C), 117.6, 109.4, 60.8, 56.8, 47.5, 36.0,
26.6, 23.3, 16.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20BrN2 367.0804; found
367.0803.
2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline]-8'-carbonitril
e (3l). White solid; 28.2 mg, 90% yield, dr 4.3:1; mp 309–311 °C; column chromatography eluent,
petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 7.7 Hz, 1H), 7.29 (td, J =
7.6, 1.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.99–6.94 (m, 1H), 6.92 (dd, J = 7.2, 1.3 Hz, 1H), 6.78
(d, J = 1.1 Hz, 1H), 6.44 (d, J = 7.4 Hz, 1H), 4.02–3.94 (m, 1H), 3.57–3.50 (m, 1H), 3.42 (d, J =
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15.8 Hz, 1H), 3.21 (dd, J = 16.6, 9.1 Hz, 1H), 2.49 (d, J = 15.9 Hz, 1H), 2.33 (s, 3H), 1.98–1.83
(m, 2H), 1.66 (ddd, J = 12.5, 7.2, 1.6 Hz, 1H), 0.73–0.62 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 183.1, 155.0, 144.2, 138.3, 130.0, 128.3, 125.5, 123.4, 123.3, 120.1, 119.8, 119.4, 112.6,
111.6, 61.3, 55.5, 47.5, 35.8, 26.8, 23.3, 16.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C21H19N3Na 336.1471; found 336.1474.
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1-(4-(2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinolin]-8'-yl)phe
nyl)ethan-1-one (3m). White solid; 36.1 mg, 89% yield, dr 5:1; mp 258–261 °C; column
chromatography eluent, petroleum ether/EtOAc = 10:1; 1H NMR (500 MHz, CDCl3) δ 8.04 (t, J =
7.0 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.07 (d, J
= 7.6 Hz, 1H), 6.98–6.90 (m, 2H), 6.82 (s, 1H), 6.61 (d, J = 7.4 Hz, 1H), 4.04–3.96 (m, 1H),
3.65–3.58 (m, 1H), 3.47 (d, J = 15.5 Hz, 1H), 3.31 (dd, J = 16.5, 8.7 Hz, 1H), 2.65 (s, 3H), 2.51 (d,
J = 15.6 Hz, 1H), 2.34 (s, 3H), 1.94–1.87 (m, 1H), 1.87–1.79 (m, 1H), 1.70–1.64 (m, 1H),
0.72–0.64 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 197.8, 183.9, 155.0, 146.5, 144.4, 139.8,
138.9, 135.7, 130.1, 128.9 (2C), 128.0, 127.2 (2C), 125.2, 123.9, 119.8, 118.4, 114.9, 108.7, 61.4,
56.4, 47.5, 35.5, 26.8, 26.7, 23.3, 16.3; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C28H26N2NaO
429.1937; found 429.1944.
2-methyl-6a',6b',7',8',9',10',10a',11'-octahydro-5'H-spiro[indole-3,6'-isoindolo[2,1-a]quinoli
ne] (3n). Yellow solid; 30.8 mg, 90% yield, dr 3.8:1; mp 148–150 °C; column chromatography
eluent, petroleum ether/EtOAc = 10:1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.7 Hz, 1H),
7.28–7.13 (m, 2H), 6.93 (d, J = 7.3 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.66–6.54 (m, 2H), 6.46 (d, J
= 7.4 Hz, 1H), 4.13 (d, J = 9.3 Hz, 1H), 3.44 (d, J = 15.3 Hz, 1H), 3.33–3.21 (m, 2H), 2.40–2.30
(m, 4H), 1.95–1.89 (m, 1H), 1.71–1.15 (m, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 184.8, 154.9,
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144.5, 139.2, 129.4, 128.1, 127.7, 125.1, 123.7, 119.9, 117.5, 115.5, 109.9, 61.1, 56.1, 53.7, 39.5,
36.9, 36.5, 28.6, 25.7, 24.9, 22.0, 16.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H27N2
343.2169; found 343.2170.
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2'-methyl-6a,7,8,9,10,11-hexahydro-5H-spiro[azepino[1,2-a]quinoline-6,3'-indole]
(3o).
Colorless oil; 25.0 mg, 79% yield, dr 4:1; column chromatography eluent, petroleum ether/EtOAc
= 15:1; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.7 Hz, 1H), 7.28 (td, J = 7.7, 1.8 Hz, 1H), 7.16
(td, J = 7.5, 1.5 Hz, 1H), 7.09–6.91 (m, 3H), 6.75 (d, J = 8.5 Hz, 1H), 6.65 (t, J = 7.2 Hz, 1H),
3.62 (ddd, J = 15.2, 5.7, 3.4 Hz, 1H), 3.48 (dd, J = 8.7, 4.9 Hz, 1H), 3.32 (ddd, J = 15.0, 9.5, 2.9
Hz, 1H), 3.06 (d, J = 16.3 Hz, 1H), 2.79 (d, J = 16.3 Hz, 1H), 2.21 (s, 3H), 1.94–1.83 (m, 1H),
1.65–1.32 (m, 7H); 13C{1H} NMR (125 MHz, CDCl3) δ 185.7, 154.9, 146.0, 140.6, 129.6, 128.0,
127.8, 124.8, 124.6, 119.8, 118.6, 116.6, 111.9, 61.7, 58.7, 50.7, 33.7, 30.4, 29.1, 27.8, 26.2, 17.6;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H25N2 317.2012; found 317.2015.
1',2-dimethyl-1',4'-dihydro-2'H-spiro[indole-3,3'-quinoline] (3p). White solid; 12.8 mg, 49%
yield; mp 94–96 °C; column chromatography eluent, petroleum ether/EtOAc = 5:1; 1H NMR (500
MHz, CDCl3) δ 7.56 (d, J = 7.7 Hz, 1H), 7.31 (td, J = 7.6, 1.1 Hz, 1H), 7.22 (td, J = 7.8, 0.5 Hz,
1H), 7.06 (t, J = 7.5 Hz, 1H), 7.00‒6.94 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.70 (t, J = 7.3 Hz, 1H),
3.46 (d, J = 11.4 Hz, 1H), 3.13 (d, J = 16.0 Hz, 1H), 3.04 (dd, J = 11.4, 1.7 Hz, 1H), 2.96 (s, 3H),
2.71 (d, J = 16.0 Hz, 1H), 2.26 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 184.6, 154.0, 145.3,
142.2, 129.6, 128.1, 127.9, 125.3, 123.0, 119.9, 118.9, 117.0, 110.8, 55.4, 54.5, 39.0, 33.9, 17.1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H19N2 263.1543; found 263.1544.
5-methoxy-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline]
(3q). Brown oil; 28.6 mg, 90% yield, dr 3.3:1; column chromatography eluent, petroleum
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ether/EtOAc = 6:1; 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 7.6 Hz,
1H), 6.96 (d, J = 7.3 Hz, 1H), 6.77 (dd, J = 8.4, 2.5 Hz, 1H), 6.63 (t, J = 7.5 Hz, 1H), 6.57 (d, J =
8.1 Hz, 1H), 6.11 (d, J = 2.4 Hz, 1H), 3.92 (dd, J = 9.9, 5.9 Hz, 1H), 3.56–3.48 (m, 4H), 3.40 (d, J
= 15.5 Hz, 1H), 3.21 (dd, J = 16.5, 8.8 Hz, 1H), 2.43 (d, J = 15.4 Hz, 1H), 2.28 (s, 3H), 1.98–1.79
(m, 2H), 1.67–1.60 (m, 1H), 0.73–0.63 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 182.0, 157.5,
148.6, 144.0, 140.5, 129.7, 128.2, 119.7, 117.6, 115.9, 112.4, 110.6, 110.1, 61.4, 56.5, 55.3, 47.5,
35.8, 26.8, 23.4, 16.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H23N2O 319.1805; found
319.1809.
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5-fluoro-2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3r).
Yellow solid; 28.2 mg, 92% yield, dr 4:1; mp 140–142 °C; column chromatography eluent,
petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.51–7.39 (m, 1H), 7.23 (t, J = 7.7
Hz, 1H), 6.99–6.91 (m, 2H), 6.65 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.26 (dd, J = 8.6,
2.6 Hz, 1H), 3.91 (dd, J = 10.5, 5.5 Hz, 1H), 3.55–3.48 (m, 1H), 3.42 (d, J = 15.6 Hz, 1H), 3.26
(dd, J = 16.5, 8.9 Hz, 1H), 2.44 (d, J = 15.5 Hz, 1H), 2.30 (s, 3H), 2.00–1.80 (m, 2H), 1.64 (ddd, J
= 12.7, 7.5, 1.9 Hz, 1H), 0.69–0.59 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 184.0 (d, J = 3.5
Hz), 160.9 (d, J = 241.9 Hz), 151.0 (d, J = 2.0 Hz), 143.7, 140.9 (d, J = 9.3 Hz), 129.6, 128.4,
120.1 (d, J = 9.0 Hz), 117.4, 116.2, 114.4 (d, J = 23.6 Hz), 111.7 (d, J = 25.1 Hz), 110.4, 61.2, 57.1
(d, J = 2.1 Hz), 47.3, 35.6, 26.8, 23.2, 16.3; 19F NMR (470 MHz, CDCl3) δ –117.1; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C20H20FN2 307.1605; found 307.1609.
1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3s). Faint yellow oil;
20.3 mg, 74% yield, dr 1:1; column chromatography eluent, petroleum ether/EtOAc = 5:1; 1H
NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.93 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.7 Hz,
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1H), 7.38 (td, J = 7.6, 1.0 Hz, 1H), 7.31–7.27 (m, 2H), 7.23–7.16 (m, 3H), 7.03 (d, J = 7.3 Hz, 1H),
6.98 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.66–6.61 (m, 2H), 6.61–6.54 (m, 3H), 4.13 (dd,
J = 9.7, 5.8 Hz, 1H), 3.96 (dd, J = 10.0, 5.9 Hz, 1H), 3.58 (d, J = 15.5 Hz, 1H), 3.51–3.43 (m, 3H),
3.31 (dd, J = 16.5, 8.8 Hz, 1H), 3.21 (dd, J = 16.3, 8.9 Hz, 1H), 2.59 (d, J = 16.2 Hz, 1H), 2.41 (d,
J = 15.5 Hz, 1H), 1.92–1.74 (m, 4H), 1.73–1.67 (m, 1H), 1.50 (ddd, J = 12.7, 7.5, 2.0 Hz, 1H),
1.00–0.91 (m, 1H), 0.70–0.61 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 176.9, 175.4, 156.1,
155.6, 144.1, 143.9, 141.0, 138.6, 129.6, 128.7, 128.3, 128.2, 128.1, 128.0, 126.6, 126.3, 124.0,
121.6, 121.4, 121.1, 119.8, 117.4, 116.0, 115.9, 111.0, 110.2, 62.8, 60.0, 57.0, 56.9, 47.4, 47.3,
35.8, 34.0, 27.6, 27.0, 23.4, 23.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2 275.1543;
found 275.1541.
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5-methoxy-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3t). White
solid; 20.4 mg, 67% yield, dr 1.1:1; mp 132‒134 °C; column chromatography eluent, petroleum
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ether/EtOAc = 5:1; H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 7.80 (s, 1H), 7.56 (d, J = 8.5 Hz,
1H), 7.52 (d, J = 8.5 Hz, 1H), 7.22–7.16 (m, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 7.3 Hz,
1H), 6.89 (dd, J = 8.5, 2.5 Hz, 1H), 6.80 (dd, J = 8.5, 2.6 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H),
6.66–6.61 (m, 2H), 6.59–6.54 (m, 2H), 6.12 (d, J = 2.5 Hz, 1H), 4.13 (dd, J = 9.8, 5.8 Hz, 1H),
3.91 (dd, J = 10.0, 5.9 Hz, 1H), 3.85 (s, 3H), 3.59–3.54 (m, 4H), 3.52–3.45 (m, 2H), 3.40 (d, J =
16.1 Hz, 1H), 3.30 (dd, J = 16.5, 8.8 Hz, 1H), 3.20 (dd, J = 16.4, 9.0 Hz, 1H), 2.61 (d, J = 16.1 Hz,
1H), 2.42 (d, J = 15.5 Hz, 1H), 1.96–1.77 (m, 4H), 1.73 (ddd, J = 12.6, 7.2, 1.6 Hz, 1H), 1.54 (ddd,
J = 12.7, 7.5, 2.0 Hz, 1H), 1.03–0.94 (m, 1H), 0.75–0.67 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 174.7, 173.2, 159.0, 158.3, 149.7, 149.3, 144.0, 143.8, 142.7, 140.2, 129.7, 128.7, 128.2,
127.9, 121.6, 121.2, 119.7, 117.1, 115.9, 115.8, 112.5, 112.5, 110.9, 110.6, 110.1, 108.3, 62.8, 60.2,
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56.9, 56.8, 55.7, 55.3, 47.4 (2C), 36.0, 34.1, 27.6, 27.0, 23.4, 23.2; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C20H21N2O 305.1648; found 305.1651.
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solid; 21.6 mg, 75% yield, dr 1.5:1; mp 138–140 °C; column chromatography eluent, petroleum
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7.20–7.15 (m, 2H), 7.03 (d, J = 7.3 Hz, 1H), 6.99 (s, 1H), 6.64 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.1
Hz, 1H), 3.94 (dd, J = 10.0, 5.9 Hz, 1H), 3.50–3.45 (m, 1H), 3.43 (d, J = 16.1 Hz, 1H), 3.31 (dd, J
= 16.4, 8.9 Hz, 1H), 2.59 (d, J = 16.2 Hz, 1H), 2.42 (s, 3H), 1.93–1.77 (m, 2H), 1.53 (ddd, J =
12.6, 7.5, 2.1 Hz, 1H), 1.02–0.93 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ174.4, 153.5, 143.8,
141.1, 136.5, 128.8, 128.7, 127.9, 122.3, 120.8, 119.8, 115.7, 110.9, 62.7, 56.7, 47.4, 35.9, 27.6,
23.2, 21.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H21N2 289.1699; found 289.1696.
7-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3v). Colorless
oil; 18.7 mg, 65% yield, dr 1:1; column chromatography eluent, petroleum ether/EtOAc = 10:1; 1H
NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.90 (s, 1H), 7.21–7.15 (m, 4H), 7.09 (d, J = 7.6 Hz, 1H),
7.03–6.98 (m, 2H), 6.93 (d, J = 7.3 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.66–6.60 (m, 2H),
6.59–6.54 (m, 2H), 6.38 (d, J = 7.4 Hz, 1H), 4.12 (dd, J = 9.7, 5.8 Hz, 1H), 3.92 (dd, J = 9.9, 5.9
Hz, 1H), 3.56 (d, J = 15.5 Hz, 1H), 3.47 (ddd, J = 17.5, 8.7, 2.6 Hz, 2H), 3.41 (d, J = 16.2 Hz, 1H),
3.30 (dd, J = 16.5, 8.7 Hz, 1H), 3.20 (dd, J = 16.4, 8.9 Hz, 1H), 2.66–2.53 (m, 7H), 2.39 (d, J =
15.6 Hz, 1H), 1.93–1.74 (m, 4H), 1.73–1.67 (m, 1H), 1.50 (ddd, J = 12.7, 7.6, 2.1 Hz, 1H),
1.00–0.91 (m, 1H), 0.75–0.61 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.7, 174.1, 154.4,
154.0, 144.0, 143.8, 140.8, 138.4, 130.9, 130.5, 129.6, 129.5, 129.4, 128.7, 128.0, 127.9, 126.5,
126.2, 121.3, 119.8, 118.9, 117.4, 115.8, 115.7, 110.9, 110.1, 62.7, 60.0, 57.0, 56.8, 47.3, 47.2,
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35.9, 34.0, 27.6, 27.0, 23.4, 23.2, 16.8 (2C); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H21N2
289.1699; found 289.1702.
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solid; 23.9 mg, 82% yield, dr 1.2:1; mp 156–158 °C; column chromatography eluent, petroleum
ether/EtOAc = 20:1; 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.57 (dd, J = 8.5, 4.7 Hz, 1H),
7.24–7.17 (m, 1H), 7.01–6.95 (m, 2H), 6.65 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.29 (dd,
J = 8.4, 2.6 Hz, 1H), 4.12 (dd, J = 9.8, 5.8 Hz, 1H), 3.59 (d, J = 15.6 Hz, 1H), 3.49 (dd, J = 12.1,
5.4 Hz, 1H), 3.25 (dd, J = 16.4, 8.9 Hz, 1H), 2.43 (d, J = 15.6 Hz, 1H), 1.95–1.79 (m, 2H),
1.76–1.70 (m, 1H), 0.72–0.63 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 176.6 (J = 3.8 Hz),
161.5 (J = 243.5 Hz), 152.0 (J = 2.3 Hz), 143.7, 140.6 (J = 9.4 Hz), 129.6, 128.4, 121.6 (J = 9.0
Hz), 116.8, 116.2, 114.7 (J = 23.9 Hz), 111.7 (J = 25.0 Hz), 110.4, 59.9, 57.4 (J = 2.3 Hz), 47.1,
33.8, 27.0, 23.3; 19F NMR (470 MHz, CDCl3) δ –115.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C19H18FN2 293.1449; found 293.1449.
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5-chloro-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3x). White
solid; 21.8 mg, 71% yield, dr 1.1:1; mp 149‒152 °C; column chromatography eluent, petroleum
ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H,), 7.92 (s, 1H), 7.58 (d, J = 8.2 Hz,
1H), 7.55 (d, J = 8.2 Hz, 1H), 7.37 (dd, J = 8.2, 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 2.1 Hz, 1H), 7.23 (t,
J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.97 (d,
J = 7.4 Hz, 1H), 6.69–6.64 (m, 2H), 6.60 (d, J = 4.6 Hz, 1H), 6.59 (d, J = 4.6 Hz, 1H), 6.54 (d, J =
2.1 Hz, 1H), 4.11 (dd, J = 9.8, 5.8 Hz, 1H), 3.94 (dd, J = 10.0, 5.9 Hz, 1H), 3.59 (d, J = 15.6 Hz,
1H), 3.51–3.45 (m, 2H), 3.43 (d, J = 16.1 Hz, 1H), 3.32 (dd, J = 15.5, 7.9 Hz, 1H), 3.27 (dd, J =
15.5, 7.9 Hz, 1H), 2.62 (d, J = 16.1 Hz, 1H), 2.43 (d, J = 15.6 Hz, 1H), 1.98–1.78 (m, 4H),
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1.76–1.72 (m, 1H), 1.56 (ddd, J = 12.7, 7.6, 2.2 Hz, 1H), 1.01–0.93 (m, 1H), 0.72–0.63 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 177.1, 175.8, 154.5, 154.1, 143.7, 143.6, 142.8, 140.4, 132.5,
132.2, 129.5, 128.7, 128.4, 128.4, 128.3, 128.1, 124.3, 122.2, 122.1, 121.8, 119.3, 116.8, 116.3,
116.0, 111.0, 110.5, 62.6, 59.8, 57.5, 57.5, 47.3, 47.0, 35.7, 33.7, 27.6, 26.9, 23.2, 23.2; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H18ClN2 309.1153; found 309.1153.
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6-chloro-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3y). Colorless
oil; 20.3 mg, 66% yield; dr 1.2:1; column chromatography eluent, petroleum ether/EtOAc = 10:1;
1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.23–7.17 (m, 1H), 6.97 (dd,
J = 8.1, 1.9 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.64 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H),
6.47 (d, J = 8.0 Hz, 1H), 4.11 (dd, J = 9.7, 5.9 Hz, 1H), 3.57 (d, J = 15.5 Hz, 1H), 3.51–3.45 (m,
1H), 3.20 (dd, J = 16.4, 8.8 Hz, 1H), 2.39 (d, J = 15.5 Hz, 1H), 1.94–1.77 (m, 2H), 1.74–1.68 (m,
1H), 0.70–0.60 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 178.4, 157.1, 143.8, 136.9, 133.7,
129.5, 128.3, 126.2, 124.5, 121.5, 117.0, 116.1, 110.3, 59.9, 56.9, 47.1, 33.9, 26.9, 23.3; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H18ClN2 309.1153; found 309.1157.
4-bromo-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3z). White
solid; 23.9 mg, 68% yield, dr >20:1; mp 182‒184 °C; column chromatography eluent, petroleum
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ether/EtOAc = 20:1; H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.60 (dd, J = 7.6, 0.7 Hz, 1H),
7.40 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H),
6.67 (td, J = 7.4, 0.8 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 4.59 (dd, J = 10.0, 6.0 Hz, 1H), 4.19 (d, J
= 16.2 Hz, 1H), 3.52–3.43 (m, 1H), 3.35 (dd, J = 16.9, 8.1 Hz, 1H), 2.54 (d, J = 16.2 Hz, 1H),
1.98–1.90 (m, 2H), 1.70–1.65 (m, 1H), 1.03–0.93 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
176.7, 157.8, 143.7, 138.3, 130.5, 129.9, 128.8, 127.9, 120.6, 119.1, 117.5, 116.0, 111.1, 60.2,
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58.6, 47.1, 31.6, 27.4, 23.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18BrN2 353.0648;
found 353.0647.
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5-bromo-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (3za). White
solid; 26.4 mg, 75% yield, dr 1.4:1; mp 148–150 °C; column chromatography eluent, petroleum
ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ7.91 (s, 1H), 7.53–7.48 (m, 1H), 7.32 (d, J = 0.8
Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.74–6.63 (m, 2H), 6.61–6.57 (m, 1H),
3.93 (dd, J = 9.9, 5.9 Hz, 1H), 3.50–3.45 (m, 1H), 3.42 (d, J = 16.1 Hz, 1H), 3.31 (dd, J = 15.6,
7.9 Hz, 1H), 2.61 (d, J = 16.1 Hz, 1H), 1.94–1.81 (m, 2H), 1.60–1.53 (m, 1H), 1.00–0.92 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 175.7, 154.6, 143.6, 143.2, 131.4, 128.7, 128.1, 125.0, 122.7,
120.5, 119.3, 116.0, 111.0, 62.6, 57.5, 47.3, 35.7, 27.6, 23.2; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C19H18BrN2 353.0648; found 353.0648.
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2-(1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolin-4-yl)-1',2',3',3a'-tetrahydro-5'H-spiro[indol
e-3,4'-pyrrolo[1,2-a]quinoline] (4a). Yellow solid; 29.4 mg, 66% yield, dr 2:1; mp 188–191 °C;
column chromatography eluent, petroleum ether/EtOAc = 20:1; 1H NMR (500 MHz, CDCl3) δ
7.61 (d, J = 7.5 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H),
7.05 (d, J = 7.2 Hz, 1H), 7.01–6.91 (m, 2H), 6.66–6.56 (m, 3H), 6.55–6.44 (m, 2H), 4.02 (dd, J =
9.1, 5.7 Hz, 1H), 3.96 (td, J = 10.2, 4.8 Hz, 1H), 3.59–3.44 (m, 3H), 3.34–3.20 (m, 3H), 2.95 (dd,
J = 15.6, 3.7 Hz, 1H), 2.60–2.49 (m, 1H), 2.40 (d, J = 15.2 Hz, 1H), 2.17–2.07 (m, 2H), 2.04–1.94
(m, 1H), 1.91–1.71 (m, 3H), 1.51–1.35 (m, 1H), 0.79–0.63 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 189.1, 155.1, 143.9, 143.8, 138.6, 129.5, 128.4, 128.1, 127.9, 127.7, 125.4, 123.9, 120.5,
120.1, 117.4, 115.8, 114.8, 110.2, 110.1, 62.4, 60.3, 56.7, 47.6, 47.1, 37.8, 36.1, 34.6, 32.0, 27.9,
23.8, 23.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C31H32N3 446.2591; found 446.2595.
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6'-fluoro-2-(6-fluoro-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolin-4-yl)-1',2',3',3a'-tetrahyd
ro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (4b). White solid; 28.4 mg, 59% yield, dr 3:1;
mp 264–264 °C; column chromatography eluent, petroleum ether/EtOAc = 20:1; 1H NMR (500
MHz, CDCl3) δ 7.61 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.18–7.10 (m, 1H), 7.10–7.02
(m, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 6.46–6.31 (m, 3H), 6.27 (t, J = 8.0 Hz,
1H), 4.02–3.85 (m, 2H), 3.53–3.45 (m, 2H), 3.40–3.12 (m, 4H), 2.93 (dd, J = 16.1, 12.1 Hz, 1H),
2.66 (d, J = 15.8 Hz, 1H), 2.54–2.42 (m, 1H), 2.19 (dt, J = 11.4, 5.6 Hz, 1H), 2.15–2.08 (m, 1H),
2.05–1.71 (m, 4H), 1.55–1.44 (m, 1H), 0.82–0.64 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
188.5, 161.8 (d, J = 240.1 Hz), 161.8 (d, J = 239.3 Hz), 155.0, 145.3 (d, J = 7.9 Hz), 145.2 (d, J =
7.8 Hz), 138.5, 128.5 (d, J = 10.6 Hz), 128.2, 128.0 (d, J = 10.8 Hz), 125.7, 123.6, 120.2, 107.5 (d,
J = 20.3 Hz), 106.0 (d, J = 2.0 Hz), 105.8 (d, J = 2.0 Hz), 104.6 (d, J = 20.0 Hz), 102.6 (d, J =
22.5 Hz), 101.6 (d, J = 22.5 Hz), 61.8, 59.8, 56.1, 47.9, 47.4, 37.2, 31.9, 28.3 (d, J = 4.3 Hz), 27.8,
27.1 (d, J = 4.5 Hz), 23.7, 23.3; 19F NMR (470 MHz, CDCl3) δ –117.7, –118.0; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C31H30F2N3 482.2402; found 482.2404.
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7'-bromo-2-(7-bromo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolin-4-yl)-1',2',3',3a'-tetrahyd
ro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (4c). White solid; 37.8 mg, 63% yield, dr 2:1;
mp 224–226 °C; column chromatography eluent, petroleum ether/EtOAc = 20:1; 1H NMR (500
MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz, 1H), 7.33–7.25 (m, 2H), 7.18 (d, J = 8.5 Hz, 1H), 7.11 (d, J =
10.7 Hz, 1H), 7.06 (s, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.48 (t, J = 7.6 Hz, 1H), 6.42 (d, J = 8.6 Hz,
1H), 6.32 (d, J = 8.6 Hz, 1H), 3.98–3.84 (m, 2H), 3.51–3.36 (m, 3H), 3.27–3.14 (m, 3H), 2.86 (dd,
J = 15.7, 2.9 Hz, 1H), 2.48–2.38 (m, 1H), 2.33 (d, J = 15.4 Hz, 1H), 2.14–1.76 (m, 6H), 1.46–1.36
(m, 1H), 0.78–0.69 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 188.0, 154.9, 142.8, 142.8,
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138.2, 131.8, 130.8, 130.8, 130.2, 128.2, 125.7, 123.7, 122.4, 120.3, 119.3, 111.7, 111.5, 107.4,
106.4, 62.4, 60.2, 56.3, 47.7, 47.2, 37.4, 35.7, 34.2, 31.9, 27.8, 23.7, 23.3; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C31H30Br2N3 602.0801; found 602.0793.
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2-(1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolin-4-yl)-5-methoxy-1',2',3',3a'-tetrahydro-5'H-
spiro[indole-3,4'-pyrrolo[1,2-a]quinoline] (4d). White solid; 27.1 mg, 57% yield, dr 2:1; mp
226–228 °C; column chromatography eluent, petroleum ether/EtOAc = 20:1; 1H NMR (500 MHz,
CDCl3) δ 7.49 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.04 (d, J =
7.4 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.79 (dt, J = 8.4, 2.4 Hz, 1H), 6.64–6.54 (m, 3H), 6.48 (t, J
= 7.7 Hz, 1H), 6.06 (d, J = 2.3 Hz, 1H), 4.00 (dd, J = 9.3, 5.6 Hz, 1H), 3.93 (td, J = 10.2, 4.7 Hz,
1H), 3.56–3.43 (m, 6H), 3.33–3.19 (m, 3H), 2.93 (dd, J = 15.7, 3.6 Hz, 1H), 2.55–2.46 (m, 1H),
2.39 (d, J = 15.2 Hz, 1H), 2.17–1.78 (m, 6H), 1.50–1.41 (m, 1H), 0.83–0.76 (m, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 186.8, 157.7, 148.9, 143.9, 143.8, 140.1, 129.6, 128.4, 128.2, 127.7,
120.6, 120.2, 117.1, 115.8, 114.8, 112.5, 110.5, 110.0 (2C), 62.4, 60.4, 56.7, 55.3, 47.7, 47.1, 37.7,
36.1, 34.8, 32.0, 27.9, 23.8, 23.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C32H34N3O 476.2696;
found 476.2691.
5-fluoro-2-(1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolin-4-yl)-1',2',3',3a'-tetrahydro-5'H-spi
ro[indole-3,4'-pyrrolo[1,2-a]quinoline] (4e). White solid; 25.0 mg, 54% yield, dr 2:1; mp
254–256 °C; column chromatography eluent, petroleum ether/EtOAc = 20:1; 1H NMR (500 MHz,
CDCl3) δ 7.59–7.41 (m, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.2 Hz,
1H), 7.00–6.92 (m, 2H), 6.64 (t, J = 7.3 Hz, 1H), 6.61–6.54 (m, 2H), 6.48 (t, J = 7.7 Hz, 1H), 6.22
(dd, J = 8.6, 2.4 Hz, 1H), 3.98 (dd, J = 9.2, 5.7 Hz, 1H), 3.92 (td, J = 10.2, 4.8 Hz, 1H), 3.57–3.43
(m, 3H), 3.33–3.18 (m, 3H), 2.93 (dd, J = 15.6, 3.7 Hz, 1H), 2.56–2.47 (m, 1H), 2.38 (d, J = 15.3
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Hz, 1H), 2.16–2.07 (m, 2H), 2.04–1.74 (m, 4H), 1.50–1.41 (m, 1H), 0.75 (dt, J = 12.1, 9.1 Hz,
1H); 13C{1H} NMR (125 MHz, CDCl3) δ 189.0 (d, J = 3.5 Hz), 161.0 (d, J = 242.4 Hz), 151.1 (d,
J = 2.0 Hz), 143.8, 143.5, 140.5 (d, J = 9.3 Hz), 129.5, 128.4, 128.4, 127.8, 120.5 (d, J = 8.9 Hz),
120.4, 116.8, 116.1, 114.9, 114.5 (d, J = 23.8 Hz), 111.7 (d, J = 25.0 Hz), 110.3, 110.1, 62.4, 60.1,
57.3 (d, J = 2.1 Hz), 47.4, 47.1, 37.8, 36.1, 34.5, 32.0, 27.9, 23.8, 23.3; 19F NMR (470 MHz,
CDCl3) δ ‒116.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C31H31FN3 464.2497; found
464.2501.
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11-methoxy-1,2,3,9,9a,14b-hexahydrobenzo[6,7]pyrrolo[1',2':1,2]azepino[3,4-b]indole
(5).
White solid; 18.3 mg, 60% yield; mp 194–196 °C; column chromatography eluent, petroleum
ether/EtOAc = 10:1; 1H NMR (500 MHz, CDCl3) δ 7.49 (s, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.21 (t,
J = 7.6 Hz, 1H), 7.18–7.07 (m, 3H), 6.97 (t, J = 7.3 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 4.27 (d, J =
15.0 Hz, 1H), 3.93 (t, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.75 (d, J = 15.0 Hz, 1H), 3.39 (dd, J = 17.4,
8.6 Hz, 1H), 3.30 (t, J = 7.2 Hz, 1H), 2.48–2.35 (m, 1H), 2.16–1.93 (m, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 154.0, 148.0, 137.3, 136.8, 130.6, 128.6, 127.7, 126.9, 122.9, 118.3, 111.1, 111.0,
108.6, 100.3, 61.7, 56.0, 50.9, 32.4, 29.0, 21.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H21N2O 305.1648; found 305.1647.
2-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[indole-3,4'-pyrrolo[1,2-a]quinoline]-1',1',3a',5'-d4
([D]-3a). White solid; 25.4 mg, 87% yield, dr 3.3:1; mp 237–239 °C; column chromatography
eluent, petroleum ether/EtOAc = 5:1; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz, 1H),
7.30–7.20 (m, 2H), 6.97 (d, J = 7.4 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 6.58
(d, J = 8.1 Hz, 1H), 6.53 (d, J = 7.0 Hz, 1H), 3.40 (s, 0.5H), 2.41 (s, 0.5H), 2.31 (s, 3H), 1.85 (td, J
= 11.9, 7.2 Hz, 1H), 1.76 (ddd, J = 12.4, 7.8, 1.6 Hz, 1H), 1.61 (ddd, J = 12.2, 7.2, 1.8 Hz, 1H),
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