A facile synthesis of novel polycyclic spiropyrrolidine oxindoles incorporating the 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1080/00397911.2020.1799011

This study describes the synthesis of novel polycyclic spiropyrrolidine oxindoles through the 1,3-dipolar cycloaddition of azomethine ylides generated in situ with 3-(arylmethylene)-indolin-2-ones. Effect of substituents of azomethine ylides and various d

Full text of DOI:10.1080/00397911.2020.1799011

Synthetic Communications
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ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A facile synthesis of novel polycyclic
spiropyrrolidine oxindoles incorporating the 1,3-
dipolar cycloaddition of azomethine ylides
Krisztina E. Treuerne Balázs , Márk Molnár , Zoltán Madarász & Miklós
Nyerges
To cite this article: Krisztina E. Treuerne Balázs , Márk Molnár , Zoltán Madarász &
Miklós Nyerges (2020): A facile synthesis of novel polycyclic spiropyrrolidine oxindoles
incorporating the 1,3-dipolar cycloaddition of azomethine ylides, Synthetic Communications, DOI:
10.1080/00397911.2020.1799011
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https://doi.org/10.1080/00397911.2020.1799011
A facile synthesis of novel polycyclic spiropyrrolidine
oxindoles incorporating the 1,3-dipolar cycloaddition of
azomethine ylides
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Krisztina E. Treuerne Balazs , Mark Molnar, Zoltan Madarasz, and Miklos Nyerges
Department of Early Process Development, Servier Research Institute of Medicinal Chemistry,
Budapest, Hungary
ABSTRACT
ARTICLE HISTORY
Received 4 May 2020
This study describes the synthesis of novel polycyclic spiropyrrolidine
oxindoles through the 1,3-dipolar cycloaddition of azomethine ylides
generated in situ with 3-(arylmethylene)-indolin-2-ones. Effect of sub-
stituents of azomethine ylides and various dipolarophiles on reactiv-
ity, as well as on the products regio- and stereoselectivity was
investigated.
KEYWORDS
Azomethine ylide;
13-dipolar cycloaddition;
oxindole; regioselectivity;
spiro-heterocycle;
stereoselectivity
GRAPHICAL ABSTRACT
Introduction
Azomethine ylides are used widely as reactive intermediates in inter- and intramolecular
[3 þ 2] cycloadditions,[1] and are also known to engage in 1,5- and 1,7-electrocycliza-
tions.[2] Reports on the ability of these dipolar species to participate in non-pericyclic
reactions are rare but some very interesting transformations exist.[3]
The [3 þ 2] cycloaddition between azomethine ylides and electron-deficient alkenes
constitutes an efficient route to highly substituted pyrrolidines in inter- or intramolecu-
lar fashion leading to natural products, drug candidates or other synthetically useful
derivatives.[4] The spiro[pyrrolidin-3,3,0-oxindole] unit constitutes a core structural
ꢀ
CONTACT Miklos Nyerges
miklos.nyerges@servier.com
Servier Research Institute of Medicinal Chemistry, 7,
ꢀ
Zahony Street, 1031 Budapest, Hungary.
New address: K. E. Treuerne Balazs, 1 The University of Sydney, Faculty of Medicine and Health, School of Pharmacy,
A15 Science road, 2006 Camperdown, New South Wales, Australia.
ꢀ
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
K. E. T. BALÁZS ET AL.
Mitraphylline
Spirotryprostatin A
Alstonisine
Rhynchophyline
Figure 1. Representative bioactive natural alkaloids with a spiro-oxindole scaffold.
element prevalent in a large family of alkaloid natural products exhibiting important
bioactivity profiles and interesting structural properties (Fig. 1).
Beside many synthetic approaches using 2-oxoindolin-3-ylidene derivatives as 2p
components in 1,3-dipolar cycloadditions of azomethine ylides for the synthesis of these
heterocycles are described and used in total synthesis.[5]
The 1,3-dipolar cycloadditions of azomethine ylides derived from dihydroisoqinoli-
nium salts by deprotonation has been well described. These reactive dipoles can be pro-
duced in situ by base-mediated dehydrohalogenation, then reacted with a wide range of
dipolarophiles, for example, maleimides, maleates, nitro-styrenes etc.[6] We have investi-
gated the use of these isoquinolinium salts for the tandem in situ generation of azome-
thine ylides and base-sensitive dipolarophiles[7] and later described the first examples of
the 1,7-electrocyclization of ester-stabilized a,b:c,d-unsaturated azomethine ylides, which
were generated by the deprotonation of the corresponding isoquinolinium salts.[8]
Interestingly, the reaction of the readily available, and synthetically versatile, 3-(aryl-
methylene)indolin-2-ones with azomethine ylides has been rarely described.[9] In this
study, these somewhat neglected dipolarophiles were reacted with various dihydroisoqi-
nolinium azomethine ylides, resulting in the formation of 20-oxo-spiro[3,5,6,10b-tetrahy-
dro-pyrrol[2,1-a]isoquinoline-indoline] heterocycles with diverse substitution patterns.
The scope and limitations of this reaction have been studied in detail.
Results and discussion
The 2-oxoindolin-3-ylidene derivatives 3 were synthesized from the corresponding com-
mercially available oxindoles 1 and aryl-aldehydes 2 under microwave conditions in a
very convenient manner (Scheme 1). The products were formed in a 20-minute reaction
in ethanol in the presence of catalytic amount of piperidine and afterwards isolated by a
simple filtration and used in the next step without any further purification.[10]

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3
i
1
2
3
3d
Scheme 1. Reagents and conditions: i. EtOH, MW, 140 ꢂC, 20 min.
4
5
6
3
Scheme 2. Reagents and conditions: i. Et3N, EtOH, r.t.
These dipolarophiles 3 were first reacted with ethyl 2-(3,4-dihydroisoquinolin-2-ium-2-
yl)acetate bromide 4 in ethanol at room temperature in the presence of triethylamine
(Scheme 2). The main products (5a–f) were formed in most cases as a white precipitate
from the reaction mixture, which was separated by simple filtration to give a single regio-
and stereoisomer. We have also examined the mother liquors and, using preparative HPLC,
we were able to isolate and characterize some regioisomeric products (6a–e) formed.
These heterocycles are even less well documented. In a 1,3-dipolar cycloaddition of
azomethine ylide they should be the main product only when the aromatic ring is
replaced with a much more electron-withdrawing moiety, such as a nitro substituent, as
we have observed earlier.[6] In one case, instead of the expected regioisomer 6f a minor
stereoisomer 7 was isolated and identified. The products obtained and the yields are
summarized in Table 1.
The structures of the cycloadducts 5 and 6 were elucidated by NMR spectroscopy
1
1
1
1
using H, 13C, H–1H COSY, H–13C HSQC and H–13C HMQC techniques. The rela-
1
1
tive stereochemistry was established mostly by Hf Hg n.O.e studies. For example in
the case of 5a, the irradiation of H-3 (d, 5.20) caused enhancement of H-2 (d, 3.96,
5%), while there was no n.O.e. effect observed between H-3 and H-10b. The irradiation
of the singlet for H-10b at 4.91) gave only a large n.O.e. enhancement to the indol-4
proton (d, 5.75). In general, for 5, the strongly shielded aromatic H-40 protons, are the
consequence of the anisotropy of the amide carbonyl group resulting in a chemical shift
around 5.5 ꢁ 5.8 ppm, to further confirm the proposed structures.

4
K. E. T. BALÁZS ET AL.
Table 1. Results of 1,3-dipolar cycloaddition reaction describes on Scheme 2.
Entry
1
Dipolarophile
Ar
Major isomer (5) (isolated yield)
5a (75%)
Minor isomer (6) (isolated yield)
6a (1.7%)P
3a
2
3
4
3b
3c
3d
5b (50%)
5c (57%)
5d (38%)
6b (1.2%)P
6c (1.4%)P
Detected but not isolated
5
6
3e
3f
5e (46%)
5f (38%)
6e (1.0%)P
7 (0.4%)
Ppurified and isolated after preparative HPLC
i
8a
3
9
10
Scheme 3. Reagents and conditions: i. Et3N, EtOH, r.t.
In the next set of experiments the quaternary salt 8 formed in the reaction of 3,4-
dimethoxydihydroisoquinoline and a-bromoacetophenone were reacted with the same
set of dipolarophiles (Scheme 3). The main products 9 again precipitated from the reac-
tion mixture (with one exception, entry 5), while the minor regioisomeric products 10
were isolated from the mother liquor. Not surprisingly, the same stereoisomers were
formed as in the previous cases; however, in most cases, significantly lower isolated
yields were observed.
The in situ generation of azomethine ylides from benzyl-6,7-dimethoxy-3,4-dihydroi-
soquinolin-2-ium hydrobromide (11a) was attempted in a similar manner in the pres-
ence of dipolarophile 3. The dipole formed from this quaternary salt after the

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5
11
12
3
13
Scheme 4. Reagents and conditions: i. Et3N, EtOH, r.t.
4 R = OEt
8b R =
i.
15
14
3
Scheme 5. Reagents and conditions: i. Et3N, EtOH, r.t.
dehydrohalogenation would be expected to react with various dipolarophiles, but in
these cases, only traces of the expected products (12 or 13) were formed (Scheme 4). In
one case, the product was detected by HPLC-MS, while in another (12b) an analytical
sample was isolated by preparative HPLC and characterized. In order to increase the
reactivity of the azomethine ylide formed, we synthesized the corresponding quaternary
salt 11b from p-fluorobenzyl bromide, hoping that the presence of an electron-with-
drawing group would have the benefit on the reactivity of the dipole. It was reacted
with three dipolarophiles, however only the most electron-deficient p-nitro-derivative 3a
gave the expected products of the 1,3-dipolar cycloaddition, as a regioisomeric mixture
of 12c and 13c.
Finally, the effect of substituents on the oxindole ring in various positions was investi-
gated. For this purpose, some new dipolarophiles (3f, 3g, 3h) were synthesized using our
standard method. From this set of reactions only the major isomers were isolated, we found
the additional substituent did not affect the reactivity of the dipolarophile; however, not
unexpectedly, the presence of the chlorine substituent at the position 4 on the oxindole 3h
has a direct effect on the stereochemical outcome of the cycloaddition reaction. Instead of
the normally observed syn-endo isomers 14 in these two cases (Entries 2 and 6) the syn-exo
isomers 15 were formed as the major products (endo and exo being referenced to the nitro-
phenyl group on the alkene). This change clearly indicated by the changes in the chemical

6
K. E. T. BALÁZS ET AL.
Table 2. Comparison of chemical shifts in products 14 and 15.
Entry
Cycloadduct
H-2
H-3
H-10
H-10b
1
2
3
4
5
6
14a
15a
14b
14c
14d
15b
4.01 d, (6 Hz)
4.94 s
3.97 d, (6 Hz)
4.25 d, (6 Hz)
4.30 d, (6 Hz)
5.19 d, (11 Hz)
5.16 d, (6 Hz)
4.94 s
5.17 d, (6 Hz)
6.10 d, (6 Hz)
6.09 d, (11 Hz)
5.64 d, (11 Hz)
5.43 s
5.59 s
5.40 s
5.43 s
5.47 s
5.65 s
4.69 s
5.46 s
4.90 s
4.93 s
4.92 s
5.64 s
shifts in the 1H-NMR spectra; H-2, H-10 and H-10b protons all had a significant downfield
shift, while the coupling constants of H-2 and H-3 changed (Table 2). The relative stereo-
1
chemistry was further confirmed by 1Hf Hg n.O.e studies.
In conclusion, we have developed a facile synthesis of novel polycyclic spiropyrroli-
dine oxindoles through the 1,3-dipolar cycloaddition of azomethine ylides generated in
situ with 3-(arylmethylene)indolin-2-ones. Most of those reactions were regio- and
stereoselective, the main products were isolated by simple filtration in high purity.
Experimental
General remarks
The starting materials were purchased from commercial sources. IR spectra were
1
recorded with a Bruker Tensor 27 FT-IR spectrophotometer. H, 13C NMR spectra were
recorded in DMSO-d6 using TMS as an internal reference with a Bruker Avance III
spectrometer operating at 500 and 125 MHz, respectively (1H-, DEPTQ-, HSQC-,
HMBC-, NMR). High-resolution MS spectra were measured on an Agilent 6230 TOF
LC/MS spectrometer.
General procedure for the synthesis of 3,4-dihydroisoquinolinium bromides
The 6,7-dimethoxy-3,4-dihydroisoquinoline (1.91 g, 10.0 mmol) was dissolved in dry
diethyl ether (30 ml) and ethyl bromoacetate, benzyl bromide or the corresponding
a-bromoacetophenone (15 mmol) was added. The reaction mixture was stirred over-
night at room temperature under an argon atmosphere. The yellow precipitate was fil-
tered off, washed with diethyl ether and dried in vacuo to give the products as a
yellow powder.[6,11]
General procedure for the synthesis of dipolarophiles
The appropriate oxindole (1 mmol) and aldehyde (1 mmol) were dissolved in ethanol
(3 mL) and piperidine (0.05 mL) was added. The mixture was heated in an Anton-Paar
microwave reactor for 20 minutes at 140 ꢂC. After cooling, the precipitate formed was
filtered off, recrystallized from hot ethanol, and dried in vacuo. All used compound has
been reported earlier in the literature.[10]
General procedure for the 1,3-dipolar cycloadditions
The corresponding 3,4-dihydroisoquinolinium bromide (1.1 mmol) was suspended
in ethanol (10 mL) and the appropriate dipolarophile (1 mmol) was added. After

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7
Table 3. Results of 1,3-dipolar cycloaddition reaction describes on Scheme 3.
Entry
1
Dipolarophile
Ar
Major isomer (9) (isolated yield)
9a (25%)
Minor isomer (10) (isolated yield)
10a (0.8%)P
3a
]
]
2
3
3b
3c
9b (25%)
9c (35%)
10b (1.2%)P
Detected but not isolated
]
]
]
4
5
6
3d
3e
3f
9d (26%)
9e (14.9%)P
9f (20.4%)
10d (1.8%)P
10e (10.9%)P
10f (0.9%)P
Ppurified and isolated after preparative HPLC
5 minutes stirring triethylamine (1.1 g, 1.5 mL, 1.1 mmol) was added and the reaction
mixture was stirred at room temperature for 24 hours. White precipitate formed was
filtered off, yielding the main isomer, while the minor isomer was obtained from the
filtrate after preparative HPLC purification. All compounds obtained (Table 1 and
Tables 3–5) were analyzed after drying for 24 hours in vacuum at room temperature.
Ethyl 8,9-dimethoxy-2-(4-nitrophenyl)-20-oxo-spiro[3,5,6,10b-tetrahydro-2H-pyr-
rolo[2,1-a]isoquinoline-1,30-indoline]-3-carboxylate (5a): 0.41 g (76%), white solid,
1
mp. 170–2 ꢂC; H NMR (DMSO-d6, 500 MHz): d 10.21 (s, 1H, NH), 8.21 (d, J ¼ 9 Hz,
2H, Ar-30 and 50H), 7.73 (d, J ¼ 9 Hz, 2H, Ar-20 and 6’H), 7.11 (t, J ¼ 7.5 Hz, 1H, Ind-
60H), 6.71 (d, J ¼ 7.5 Hz, 1H, Ind-7’H), 6.69 (s, 1H, H-7), 6.66 (t, J ¼ 7.5 Hz, 1H, Ind-
50H), 5.75 (d, J ¼ 7.5 Hz, 1H, Ind-40H), 5.34 (s, 1H, H-10), 5.20 (d, J ¼ 6 Hz, 1H, H-3),
4.91 (s, 1H, H-10b), 3.96 (d, J ¼ 6 Hz, 1H, H-2), 3.88 and 3.79 (m þ m, 2H, OCH2CH3),
3.68 (s, 3H, OCH3-8), 3.25 (m, 1H, CH2-5), 3.03 (s, 3H, OCH3-9), 2.99 (m, 2H, CH2-5
and 6), 2.37 (m, 1H, CH2-6), 0.72 (t, J ¼ 7.0 Hz, 3H, OCH2CH3). 13C NMR (DMSO-d6,
125 MHz): d 178.4 (q), 171.6 (q), 147.5 (q), 147.1 (q), 146.6 (q), 146.4 (q), 143.3 (q),
131.8 (2 ꢃ CH), 130.2 (q), 129.0 (CH), 127.4 (q), 125.2 (q), 125.1 (CH), 123.6 (2 ꢃ
CH), 121.7 (CH), 112.0 (CH), 109.7 (CH), 107.7 (CH), 68.1 (CH), 67.5 (CH), 62.9 (q),
60.2 (CH2), 55.7 (CH3), 54.7 (CH3), 52.4 (CH), 46.3 (CH2), 25.4 (CH2), 14.1 (CH3). IR
(KBr, cmꢁ1): 3242, 2913, 1712, 1344, 1516. HRMS (M þ H): calcd for C30H29N3O7:
544.2083; found: 544.2090.
Ethyl 8,9-dimethoxy-1-(4-nitrophenyl)-20-oxo-spiro[3,5,6,10b-tetrahydro-1H-pyr-
rolo[2,1-a]isoquinoline-2,30-indoline]-3-carboxylate (6a): 9.2 mg (1.7%) colorless
1
amorf solid; H NMR (500 MHz, DMSO-d6): d 10.42 (s, 1H, NH), 7.95 (d, J ¼ 9 Hz, 2H,
Ar-30 and 5’H), 7.66 (d, J ¼ 7.5 Hz, 1H, Ind-40H), 7.25 (d, J ¼ 9 Hz, 2H, Ar-20 and 60H),

8
K. E. T. BALÁZS ET AL.
Table 4 Results of 1,3-dipolar cycloaddition reaction describes on Scheme 4.
Entry
11
Dipolaro-phile
Ar
Major isomer (12) (isolated yield)
12a (traces)
Minor isomer (13) (isolated yield)
1
R ¼ H
3a
–
2
3
R ¼ H
R ¼ F
3d
3a
12b (11%)P
12c (24%)P
Detected but not isolated
13c (17%)P
4
5
R ¼ F
R ¼ F
3e
3f
Traces
Traces
–
–
Ppurified and isolated after preparative HPLC.
7.66 (t, J ¼ 7.5 Hz, 1H, Ind-60H), 7.00 (t, J ¼ 7.5 Hz, 1H, Ind-50H), 6.81 (s, 1H, H-7),
6.61 (d, J ¼ 7.5 Hz, 1H, Ind-70H), 5.87 (s, 1H, H-10), 5.25 (d, J ¼ 10 Hz, 1H, H-10b),
4.34 (s, 1H, H-3), 3.42 (d, J ¼ 10 Hz, 1H, H-1), 3.75 and 3.61 (m þ m, 2H, OCH2CH3),
3.71 (s, 3H, OCH3-8), 3.21 (m, 1H, CH2-5), 3.16 (s, 3H, OCH3-9), 3.02 (m, 1H, CH2-5),
2.93 (m, 1H, CH2-6), 2.50 (m, 1H, CH2-6), 0.61 (t, J ¼ 7.0 Hz, 3H, OCH2CH3). 13C
NMR (125 MHz, DMSO-d6): d 176.4 (q), 169.5 (q), 147.6 (q), 147.2 (q), 147.1 (q), 143.7
(q), 142.7 (q), 130.7 (2 ꢃ CH), 129.4 (q), 129.3 (CH), 128.3 (q), 126.8 (CH), 126.3 (q),
123.2 (2 ꢃ CH), 121.7 (CH), 112.6 (CH), 109.8 (CH), 109.6 (CH), 69.3 (CH), 62.6
(CH), 62.5 (CH), 61.0 (q), 60.2 (CH2), 55.9 (CH3), 55.4 (CH3), 46.6 (CH2), 23.8 (CH2),
13.7 (CH3). IR (KBr, cmꢁ1): 1740, 1708, 1516, 1346, 1211, 1103, 1028. HRMS (M þ H):
calcd for C30H29N3O7: 544.2083; found 544.2081.
3-Benzoyl-8,9-dimethoxy-2-(4-nitrophenyl)spiro[3,5,6,10b-tetrahydro-2H-pyr-
rolo[2,1-a]isoquinoline-1,30-indoline]-20-one (9a): 0.14 g (25%), white solid, mp.
1
188–190 ꢂC; H NMR (500 MHz, DMSO-d6): d 10.28 (s, 1H, NH), 8.05 (d, J ¼ 9.0 Hz,
2H, Ar-30 and 50H), 7.68 (d, J ¼ 8.0 Hz, 2H, Bz-20 and 60H), 7.52 (t, J ¼ 8.0 Hz, 1H, Bz-
40H), 7.51 (d, J ¼ 9.0 Hz, 2H, Ar-20 and 60H), 7.39 (t, J ¼ 8.0 Hz, 2H, Bz-30 and 50H),
7.10 (t, J ¼ 7.5 Hz, 1H, Ind-60H), 6.72 (d, J ¼ 7.5 Hz, 1H, Ind-70H), 6.71 (s, 1H, H-7),
6.64 (t, J ¼ 7.5 Hz, 1H, Ind-50H), 6.19 (d, J ¼ 6.0 Hz, 1H, H-3), 5.75 (t, J ¼ 7.5 Hz, 1H,
Ind-40H), 5.37 (s, 1H, H-10), 4.95 (s, 1H, H-10b), 4.24 (d, J ¼ 6.0 Hz, 1H, H-2), 3.69 (s,
3H, OCH3), 3.05 (s, 3H, OCH3), 3.16 (m, 1H, CH2-5), 3.05 (m, 2H, CH2-5 and ꢁ6),
2.39 (m, 1H, CH2-6). 13C NMR (125 MHz, DMSO-d6): d 198.8 (q), 178.6 (q), 147.9 (q),
147.7 (q), 146.9 (q), 142.9 (q), 139.9 (q), 135.6 (q), 133.4 (q), 132.1 (2 ꢃ CH), 129.1 (2
ꢃ CH), 129.3 (q), 129.0 (CH), 127.8 (2 ꢃ CH), 126.1 (q), 125.1 (CH), 123.4 (2 ꢃ CH),
121.7 (CH), 112.0 (CH), 109.7 (CH), 107.8 (CH), 72.3 (CH), 61.7 (q), 53.3 (CH), 46.3
(CH2), 25.7 (CH2). IR (KBr, cmꢁ1): 1698, 1515, 1345, 1234, 1136, 1008. HRMS Calcd
for C34H29N3O6 (M þ H): 576.2134; found: 576.2136.

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SYNTHETIC COMMUNICATIONSV
9
Table 5. Results of 1,3-dipolar cycloaddition reaction describes on Scheme 5.
Entry
R
Dipolaro-phile
R1
R2
R3
Product
Yield
42%
1
3g
H
Br
H
14a
2
3h
Cl
H
H
H
15a
33%
3
3f
H
F
14b
44%
4
5
6
EtO-
EtO-
EtO-
3f
3g
3h
H
H
Cl
H
Br
H
F
H
H
14c
14d
15b
70%
78%
62%
3-Benzoyl-8,9-dimethoxy-1-(4-nitrophenyl)spiro[3,5,6,10b-tetrahydro-1H-pyr-
rolo[2,1-a]isoquinoline-2,30-indoline]-20-one (10a): 4.6 mg (0.8%), colorless amorphous
1
solid; H NMR (500 MHz, DMSO-d6): d 9.91 (s, 1H, NH), 7.91 (d, J ¼ 9.0 Hz, 2H, Ar-30
and 50 H), 7.61 (t, J ¼ 7.5 Hz, 1H, Ind-40 H), 7.47 (t, J ¼ 8.0 Hz, 1H, Bz-40 H), 7.37 (d,
J ¼ 8.0 Hz, 2H, Bz-20 and 60 H), 7.27 (t, J ¼ 8.0 Hz, 2H, Bz-30 and 50 H), 7.24 (d,
J ¼ 9.0 Hz, 2H, Ar-20 and 60 H), 7.02 (t, J ¼ 7.5 Hz, 1H, Ind-60 H), 6.97 (t, J ¼ 7.5 Hz,
1H, Ind-50 H), 6.85 (s, 1H, H-7), 6.30 (d, J ¼ 7.5 Hz, 1H, Ind-70 H), 5.99 (s, 1H, H-10),
5.37 (s, 1H, H-10b), 5.31 (d, J¼10.5 Hz, 1H, H-3), 3,75 (s, 3H, OCH3), 3.69 (d,
J¼10.5 Hz, 1H, H-1), 3.23 (s, 3H, OCH3), 3.17 (m, 2H, CH2-5), 3.08 (m, 1H, CH2-6),
2.62 (m, 1H, CH2-6). 13C NMR (125 MHz, DMSO-d6): d 198.3 (q), 178.0 (q), 147.7 (q),
147.4 (q), 147.0 (q), 143.4 (q), 142.1 (q), 133.0 (CH), 132.0 (q), 130.8 (2 ꢃ CH), 129.3
(q), 129.0 (CH), 128.3 (2 ꢃ CH), 128.0 (2 ꢃ CH), 127.9 (q), 127.7 (CH), 126.0 (q),
123.0 (2 ꢃ CH), 121.6 (CH), 113.3 (CH), 110.6 (CH), 109.6 (CH), 73.5 (CH), 63.5 (q),
63.2 (CH), 62.7 (CH), 53.3 (CH), 47.1 (CH2), 24.9 (CH2). IR (KBr, cmꢁ1): 2924, 1673,
1618, 1519, 1347. HRMS Calcd for C34H29N3O6 (M þ H): 576.2134; found: 576.2134.
40-Chloro-8,9-dimethoxy-3-(4-methoxybenzoyl)-2-(4-nitrophenyl)spiro[3,5,6,10b-
tetrahydro-2H-pyrrolo[2,1-a]isoquinoline-1,30-indoline]-20-one (15a): 0.21 g (33%),
1
white solid, mp. 182–184 ꢂC; H NMR (500 MHz, DMSO-d6): d 10.32 (s, 1H, NH), 8.23
(d, J ¼ 8.5 Hz, 2H, Ar3-20 and 60H), 8.01 (d, J ¼ 9 Hz, 2H, Ar2-30 and 50H), 7.30 (d,
J ¼ 9 Hz, 2H, Ar2-20 and 60H), 5.30 (t, J ¼ 7.5 Hz, 1H, Ind-60H), 7.23 (d, J ¼ 7.5 Hz, 1H,
Ind-50H), 7.09 (d, J ¼ 8.5 Hz, 2H, Ar3-30 and 50H), 6.73 (s, 1H, H-7), 6.63 (d, J ¼ 7.5 Hz,
1H, Ind-70H), 5.65 (s, 1H, H-10), 5.64 (d, J ¼ 11 Hz, 1H, H-3), 5.64 (s, 1H, H-10b), 5.19
(d, J ¼ 11 Hz, 1H, H-2), 3.85 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.17 (s, 3H, OCH3),
3.19 (m, 1H, CH2-5), 3.02 (m, 1H, CH2-6), 2.94 (m, 1H, CH2-5), 2.50 (m, 1H, CH2-6).
13C NMR (125 MHz, DMSO-d6): d 198.7 (q), 175.1 (q), 164.0 (q), 147.6 (q), 147.4 (q),
147.1 (q), 145.1 (q), 142.3 (q), 131.7 (CH), 131.6 (2 ꢃ CH), 130.1 (2 ꢃ CH), 129.8
(q),129.7 (q), 129.2 (q), 125.7 (q), 123.95 (q), 123.9 (2 ꢃ CH), 123.85 (CH), 114.7 (2 ꢃ
CH), 112.2 (CH), 109.1 (CH), 107.8 (CH), 69.4 (CH), 66.9 (q), 63.1 (CH), 56.1 (CH3),
55.8 (CH3), 54.9 (CH3), 50.5 (CH), 46.4 (CH2), 26.6 (CH2). IR (KBr, cmꢁ1): 2936, 1714,
1346, 1517. HRMS Calcd for C35H30ClN3O7 (M þ H): 640.1849; found: 640.1845.
1
Full experimental detail, H NMR and HRMS spectra. This material can be found via
the “Supplementary Content” section of this article’s webpage.

10
K. E. T. BALÁZS ET AL.
Acknowledgments
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The authors acknowledge Barbara Balazs and Tamas Gati for spectral measurements.
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