Efficient base-free asymmetric one-pot synthesis of spiro[indoline-3,3′-pyrrolizin]-2-one derivatives catalyzed by chiral organocatalyst

Article abstract of DOI:10.1007/s11164-020-04303-8

A 1,3-dipolar cycloaddition reaction has been performed under organocatalytic conditions with high enantioselectivity by the utilization of bipyridine-based chiral quaternary ammonium bromide as an organocatalyst. Here, the reaction of 1,3-dipolar cycloaddition of azomethine ylide generated in situ from the decarboxylative condensation of α-amino acids and non-enolizable 1,2-diketones to the above dipolarophiles takes place.

Full text of DOI:10.1007/s11164-020-04303-8

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04303-8
Efcient base‑free asymmetric one‑pot synthesis of spiro[in
doline‑3,3′‑pyrrolizin]‑2‑one derivatives catalyzed by chiral
organocatalyst
Chinnadurai Chithiraikumar1 · Kottala Vijaya Ponmuthu1 ·
Muniyasamy Harikrishnan1 · Nelson Malini1 · Murugesan Sepperumal1 ·
Ayyanar Siva1
Received: 15 June 2020 / Accepted: 10 October 2020
© Springer Nature B.V. 2020
Abstract
A 1,3-dipolar cycloaddition reaction has been performed under organocatalytic con-
ditions with high enantioselectivity by the utilization of bipyridine-based chiral qua-
ternary ammonium bromide as an organocatalyst. Here, the reaction of 1,3-dipolar
cycloaddition of azomethine ylide generated in situ from the decarboxylative con-
densation of α-amino acids and non-enolizable 1,2-diketones to the above dipolaro-
philes takes place.
Keywords Organocatalyst · Indoline derivatives · Bipyridine · Cinchona alkaloid ·
Cycloaddition
Introduction
The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a
dipolarophile to form a fve-membered ring system. Mechanistic investigation and
synthetic applications were established in the 1960s, primarily through the work of
Rolf Huisgen [1, 2]. 1,3-Dipolar cycloaddition is an efcient method for the synthe-
sis of spiro pyrrolizidines with multiple stereogenic centers in a one-pot reaction [3,
4]. This reaction proceeded the HOMO of azomethine ylide directly interacted with
LUMO of the alkene [5]. Further, this reaction of azomethine ylide to dipolarophile
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04303-8) contains supplementary material, which is available to authorized users.
*
Ayyanar Siva
drasiva@gmail.com; siva.chem@mkuniversity.org
1
Supramolecular and Organometallic Chemistry Lab, Department of Inorganic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu 625 021, India
Vol.:(0123456789)
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C. Chithiraikumar et al.
with exocyclic double bond afords the spiro-heterocycles [6–10] like pyrrolizines,
pyrrolizidines, pyrazolidines, etc., and they have important biological activities [11].
Generally, 1,3-dipolar reactions are extremely useful in biological valuable prod-
uct synthesis, because they are stereospecifc, diastereoselective and regioselective
reaction. Previously reported procedures for the synthesis of spiro compounds have
some limitations, such as multi-step reactions, use of toxic solvents under refuxed
conditions and the formation of unwanted byproducts [12, 13]. In order to overcome
these problems, here, we report a simple modifed procedure for the synthesis of
spiro[indoline-3,3′-pyrrolizin]-2-one derivatives between the chalcone (dipolaro-
phile) and a dipole (azomethine ylide) from isatin and secondary amino acids like
L-proline provided an excellent yield of desired products. Chalcones itself have
enormous biological properties such as anti-infammatory, antimicrobial, antifun-
gal, antioxidant, cytotoxic, antitumor and anticancer activities [14–16]. Further,
the addition of chalcone moiety with the isatin molecule can enhance its biologi-
cal activities. Hence, most of the researchers concentrated on the synthesis of spiro
derivatives in the presence of metal catalysts [17–22] and chiral organocatalysts
[23–31] (Fig. 1).
To the best of our knowledge, there are few reports available for the asymmetric
dipolar cycloaddition reaction involving chiral organocatalyst. The synthesized new
Chiral phase transfer catalysts (CPTC) 4 (Fig. 2) was showing its excellent catalytic
reactivity in the asymmetric Michael addition of chalcones with diethylmalonate;
within two hours, these catalysts result in high chemical yield (up to 98%) and enan-
tiomeric excess (up to 99%) [32]. In connection with these, previous successes led
us to envision that CPTC 4 might be highly enantioselective catalyst for the asym-
metric one-pot 1,3-dipolar cycloaddition cascade sequence of chalcone, isatin and
proline. But, here this CPTC acts as an organocatalyst due to no need for biphasic
medium (aqueous/organic). Herein, we present our preliminary results on this sub-
ject; a wide range of spiro[indoline-3,3′-pyrrolizin]-2-one derivatives was obtained
in high yields (up to 99%) and excellent enantioselectivities (up to 96%).
Fig. 1 Previously reported chiral organo/organometallic catalysts for 1,3-dipolar cycloaddition reaction
1 3

Efcient base‑free asymmetric one‑pot synthesis of…
Fig. 2 Chiral organocatalyst for
one-pot reaction of 1,3-dipolar
cycloaddition
Results and discussion
Initially, we concentrated on the solvent optimization for the 1,3-dipolar cycload-
dition of azomethine ylide generated in situ from the decarboxylative conden-
sation of α-amino acids and non-enolizable 1,2-diketones to the above dipola-
rophiles. In this connection, we selected the reaction of chalcone 5a, isatin 6
and proline 7 that presumably afords 2′-benzoyl-1′-(p-tolyl)-1′,2′,5′,6′,7′,7a′-
hexahydrospiro [indoline-3,3′-pyrrolizin]-2-one 8a, as a model reaction, under
room temperature in various solvents (Table 1). From the data in Table 1, we
observed superior yield in less time in methanol when compared to other sol-
vent system for this cycloaddition reaction, wherein quantitative yield of 8a was
obtained (97%). Further, we carried out the cycloaddition reaction; without the
addition of organocatalyst 4, we got only less than 10% of product at 48 h.
Table 1 Screening the solvent for the one-pot synthesis of spiro[indoline-3,3′-pyrrolizin]-2-one deriva-
tives catalyzed by chiral organocatalyst.
Entry
Solvent
Time
Yield (%)a
1
2
3
4
5
6
Methanol
Ethanol
i- PrOH
1,4-Dioxane
Acetonitrile
Methanol
10 min
12 h
18 h
24 h
24 h
97
65
42b
56b
44b
<10c
48 h
aIsolated yield, byield after column chromatography, cwithout addition of organocatalyst
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C. Chithiraikumar et al.
Further, from Table 1 it is evident that methanol is the optimum solvent for fur-
ther investigation. After completion of the reaction as evident from the TLC, the
reaction mixture was poured into ice cold water and the resultant precipitate was
fltered and dried to obtain the product 8a. It is remarkable that the crude reaction
product was clean enough to be purifed just by crystallization, thereby eliminating
the need for column chromatography, which is the main source of waste.
A series of spiro[indoline-3,3′-pyrrolizin]-2-one derivatives have been synthe-
sized with the optimized reaction conditions in hand; the 1,3-dipolar cycloaddition
reaction of a wide range of chalcone 5(a–t) was investigated for the substrate scope.
As shown in Table 2, chalcone bearing both electron-donating and electron-with-
drawing substituents on phenyl group did not afect the reaction, and the correspond-
ing reactions proceeded smoothly to aford the desired products 8(a–t) with excel-
lent yield (up to 99%) as well as ee’s (or de’s) (up to 96%) in lesser reaction time.
The formation of single selective compound has also been evidenced from the crys-
tal data. In addition to that, the structure of compounds 8a and 8p was confrmed
by the ORTEP diagram for a single crystal structure (Fig. 3). Hence, we inveterated
all the products of isatin derivatives are similar structure remains irrespective of the
substituent present in the molecules.
Initially, Isatin and L-proline have ion pair interaction very closely with R4N+ of
the organocatalyst which leads to the formation of carboxylative cyclic ester (iv);
at the same time, decarboxylation may occur to form an azomethine ylide (v). The
formation of dipole is shown in Fig. 4. Then, the dipolarophile chalcone directly
interacts with the ylide in a concerted manner to give the cycloadduct product of
spirrolizidine (vi) and the catalyst (vii) removed from the reaction mixture.
Conclusion
In conclusion, we have developed an efcient and practical protocol to synthe-
size optically active spiro[indoline-3,3′-pyrrolizin]-2-one derivatives with many
stereogenic centers by chiral organocatalyzed enantioselective one-pot reac-
tion of 1,3-dipolar cycloaddition reaction. Based on this methodology, a series of
spiro[indoline-3,3′-pyrrolizin]-2-one were obtained in excellent yields (up to 99%)
with excellent ee’s (up to 96%) at room temperature.
Experimental section
Materials and methods
All the chemicals and reagents were used in this work as an analytical grade. p-Tolu-
aldehyde, veratraldehyde, 4-chlorobenzaldehyde, 2-chlorobenzaldehyde, 4-nitroben-
zaldehyde, 2,4-dichlorobenzaldehyde, 2,4-difurobenzaldehyde, 4-furobenzaldehyde,
acetophenone and 4-bromo acetophenone were purchased from Sigma-Aldrich. Ben-
zaldehyde, 2-methylbenzaldehyde, 4-methoxybenzaldehyde and 2-methoxybenzal-
dehyde were purchased from Alfa Aesar, and sodium hydroxide was obtained from
1 3

Efcient base‑free asymmetric one‑pot synthesis of…
Table 2 Substrate scope
Merck, and all the solvents were obtained from laboratory grade. The melting points
1
were measured in open capillary tubes and are uncorrected. The H and 13C NMR
spectra were recorded on a Bruker (Avance) 300 MHz NMR instrument using TMS
as an internal standard and CDCl3 as a solvent. Standard Bruker software was used
throughout. Chemical shifts are given in parts per million (δ-scale), and the coupling
1 3

C. Chithiraikumar et al.
Table 2 (continued)
The 1,3-dipolar cycloaddition reaction of various chalcone 5(a-t) (0.4 mmol), isatin 6 (0.4 mmol), proline 7 (0.4
mmol), and MCPTC 4 (1 mol%), with 5 ml of methanol at room temperature (30ºC). Isolated yield. Enantiopu-
rity was determined by HPLC analysis using a chiral column (Chiralcel OD-H) with hexane–IPA as the eluent.
constants are given in Hertz. Silica gel-G plates (Merck) were used for TLC analysis
with a mixture of n-hexane and ethyl acetate as an eluent. The HPLC was recorded
in SHIMADZU LC-6AD with a chiral column (Chiralcel OD-H), using HPLC grade
n-hexane and isopropanol as solvents. Optical rotations were measured on Rudolph
Research Analytical AUTOPOL-II (readability 0.01°) and AUTOPOL-IV (read-
ability 0.001°) automatic polarimeters.
General method for synthesis of chalcones 5(a–t) [34, 35]
Acetophenone or 4-bromo acetophenone (5 mmol) and aromatic aldehydes (5 mmol)
were dissolved in 5 mL of ethanol, and then 10% sodium hydroxide was added; the
mixture was stirred for about 5 min. After completion of the reaction, the mixture
was poured into ice; the precipitate was fltered and recrystallized with ethanol, to
get pure chalcone.
General method for one‑pot synthesis of spiro[indoline‑3,3′‑pyrrolizin]‑2‑one
derivatives (8a–t)
To the mixture of chalcone (0.4 mmol), isatin (0.4 mmol) and L-proline (0.4 mmol),
5 ml of methanol was dissolved, and 1 mol% of chiral organocatalysts 4 was added
1 3

Efcient base‑free asymmetric one‑pot synthesis of…
Fig. 3 ORTEP representation of the crystal structure of compound 8a and 8p [33]
and stirred at room temperature until the completion of reaction as indicated by
TLC. After completion of the reaction, the mixture was poured into ice; the precipi-
tate was fltered and recrystallized with ethanol, to get pure product without column
chromatography.
Spectral data for the synthesized spiro[indoline‑3,3′‑pyrrolizin]‑2‑one derivatives
(8)
2′‑Benzoyl‑1′‑(p‑tolyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑pyrrolizin]‑
2‑one (8a)
White solid (97% yield). m.p. 118–120 °C; 84% ee’s, determined by HPLC [Chiral-
cel OD-H, n-hexane/i-propanol=80/20, 1 ml/min, λ=254 nm, t (major)=4.38 min, t
(minor)=15.34 min]. [α] D25 =–31.4° (c=0.98, CHCl3); 1H NMR (300 MHz, CDCl3)
δH 8.06 (s, 1H), 7.43 (d, 2H, J=7.77 Hz), 7.40 (d, 2H, J=1.08 Hz), 7.33 (t, 1H,
J=4.15 Hz), 7.24 (d, 1H, J=18.78 Hz), 7.20–7.11 (m, 5H), 7.14 (t, 1H, J=19.17 Hz),
6.58 (d, 1H, J=7.71 Hz), 4.94 (d, 1H, J=11.46 Hz), 4.28–4.21 (m, 1H), 3.90 (t, 1H,
J=10.63 Hz), 2.75–2.00 (m, 2H), 2.31 (s, 3H), 2.10–2.00 (m, 2H), 1.95–1.71 (m,
2H). 13C NMR (75 MHz, CDCl3) δC 197.43, 181.80, 141.17, 137.47, 137.12, 136.91,
1 3

C. Chithiraikumar et al.
Fig. 4 Plausible mechanism for the formation of spirrolizidine from chalcone in the presence of chiral
organocatalyst
133.24, 129.76, 128.43, 128.35, 128.25, 127.87, 125.54, 122.62, 110.64, 74.25, 72.50,
64.81, 53.02, 48.67, 31.17, 27.71, 21.43; ESI Mass: m/z [M+H+]: 424.58.
2′‑(3‑Bromobenzoyl)‑1′‑(p‑tolyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑p
yrrolizin]‑2‑one (8b)
White solid (98% yield). m.p. 130–132 °C; 93% ee’s, determined by HPLC [Chiral-
cel OD-H, n-hexane/i-propanol=80/20, 1 ml/min, λ=254 nm, t (major)=5.55 min, t
(minor)=18.90 min]. [α]D25 =–42.3° (c=1.02, CHCl3); 1H NMR (300 MHz, CDCl3)
δH 7.83 (s, 1H), 7.39 (d, 2H, J=7.71 Hz), 7.33–7.23 (m, 6H), 7.13 (d, 2H, J=7.47 Hz),
7.02 (t, 1H, J=7.33 Hz), 6.59 (d, 1H, J=7.62 Hz), 4.86 (d, 1H, J=11.34 Hz),
4.25–4.18 (m, 1H), 3.851 (t, 1H, J=10.6 Hz), 2.67–2.59 (m, 2H), 2.297 (s, 3H),
2.05–1.87 (m, 2H), 1.75–1.70 (m, 2H). 13C NMR (75 MHz, CDCl3) δC 195.98, 181.03,
140.46, 136.58, 136.38, 135.70, 131.30, 129.43, 129.34, 127.99, 127.83, 127.43,
124.89, 122.26, 110.23, 73.64, 72.00, 64.30, 52.56, 48.20, 30.62, 27.20, 20.95; ESI
Mass: m/z [M+H+]: 503.16.
1 3

Efcient base‑free asymmetric one‑pot synthesis of…
2′‑Benzoyl‑1′‑(4‑methoxyphenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑
pyrrolizin]‑2‑one (8c)
White solid (96% yield). m.p. 154–156 °C; 92% ee’s, determined by HPLC
[Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/min, λ = 254 nm, t
(major) = 4.69 min, t (minor) = 16.38 min]. [α]D25 = – 50.07° (c = 1.05, CHCl3);
1H NMR (300 MHz, CDCl3) δH 7.90 (s, 1H), 7.44–7.37 (m, 4H), 7.31 (d,
1H, J = 7.35 Hz), 7.24 (d, 1H, J = 6.18 Hz), 7.17–7.13 (m, 3H), 7.03 (t, 1H,
J = 11.07 Hz), 6.84 (d, 2H, J = 8.67 Hz), 6.54 (d, 1H, J = 7.65 Hz), 4.87 (d,
1H, J = 11.49 Hz), 4.24–4.17 (m, 1H), 3.85 (t, 1H, J = 10.69 Hz), 3.75 (s, 3H),
2.71–2.56 (m, 2H), 2.05–1.69 (m, 4H). 13C NMR (75 MHz, CDCl3) δC 197.49,
181.68, 158.92, 141.11, 137.46, 133.25, 132.14, 129.76, 129.43, 128.44, 128.24,
127.88, 125.54, 122.61, 114.48, 110.57, 74.18, 72.39, 64.92, 55.61, 52.63, 48.66,
31.15, 27.69; ESI Mass: m/z [M + H+]: 440.56.
2′‑(3‑Bromobenzoyl)‑1′‑(4‑methoxyphenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro [ind
oline‑3,3′‑pyrrolizin]‑2‑one (8d)
White solid (97% yield). m.p. 210–212 °C; 94% ee’s, determined by HPLC
[Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/min, λ = 254 nm, t
(major) = 5.90 min, t (minor) = 9.67 min]. [α]D25 = – 60.4° (c = 1.57, CHCl3); H
1
NMR (300 MHz, CDCl3) δH 8.05 (s, 1H), 7.41 (d, 2H, J = 8.43 Hz), 7.33–7.23 (m,
4H), 7.14 (t, 2H, J = 7.65 Hz), 7.02 (t, 1H, J = 7.30 Hz), 6.85 (d, 2H, J = 7.26 Hz),
4.82 (d, 1H, J = 11.46 Hz), 4.24–4.16 (m, 1H), 3.84 (t, 1H, J = 10.30 Hz), 3.76
(s, 3H), 2.68–2.61 (m, 2H), 2.05–1.97 (m, 2H), 1.94–1.68 (m, 2H). 13C NMR
(75 MHz, CDCl3) δC 196.51, 181.59, 158.97, 141.03, 136.15, 131.88, 131.80,
129.92, 129.80, 129.40, 128.51, 127.88, 125.38, 122.72, 114.53, 110.77, 74.14,
72.37, 64.85, 55.62, 52.66, 48.69, 31.11, 27.70; ESI Mass: m/z [M + H+]: 519.23.
2′‑Benzoyl‑1′‑phenyl‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑pyrro
lizin]‑2‑one (8e)
White solid (99% yield). m.p. 104–106 °C; 93% ee’s, determined by HPLC
[Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/min, λ = 254 nm, t
(major) = 3.23 min, t (minor) = 11.01 min]. [α]D25 = – 66.7° (c = 2.73, CHCl3);
1H NMR (300 MHz, CDCl3) δH 8.05 (s, 1H), 7.51 (d, 2H, J = 7.44 Hz), 7.38 (d,
3H, J = 7.11 Hz), 7.29 (d, 3H, J = 7.68 Hz), 7.24 (d, 1H, J = 4.86 Hz), 7.21 (d,
1H, J = 7.41 Hz), 7.16 (d, 2H, J = 7.47 Hz), 7.10 (d, 1H, J = 7.8 Hz), 7.01 (t, 1H,
J = 6.96 Hz), 6.56 (d, 1H, J = 7.53 Hz), 4.93 (d, 1H, J = 11.46 Hz), 4.27–4.20 (m,
1H), 3.90 (t, 1H, J = 10.60 Hz), 2.77–2.57 (m, 2H), 2.08–1.71 (m, 4H). 13C NMR
(75 MHz, CDCl3) δC 196.86, 180.89, 140.44, 139.61, 136.87, 132.67, 129.21,
128.48, 127.92, 127.67, 127.35, 126.76, 124.92, 122.08, 109.91, 73.54, 71.93,
64.30, 52.75, 48.08, 30.57, 27.10; ESI Mass: m/z [M + H+]: 410.19.
1 3

C. Chithiraikumar et al.
2′‑(3‑Bromobenzoyl)‑1′‑phenyl‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑py
rrolizin]‑2‑one (8f)
White solid (99% yield). m.p. 110–112 °C; 89% ee’s, determined by HPLC [Chiral-
cel OD-H, n-hexane/i-propanol=80/20, 1 ml/min, λ=254 nm, t (major)=3.10 min, t
(minor)=9.24 min]. [α]D25 =–60.1° (c=1.82, CHCl3); H NMR (300 MHz, CDCl3)
1
δH 8.22 (s, 1H), 7.50 (d, 2H, J=7.20 Hz), 7.34–7.26 (m, 6H), 7.22 (d, 2H, J=8.31 Hz),
7.13 (d, 1H, J=7.59 Hz), 7.03 (t, 1H, J=7.24 Hz), 6.62 (d, 1H, J=7.59 Hz), 4.88
(d, 1H, J=11.46 Hz), 4.27–4.20 (m, 1H), 3.89 (t, 1H, J=10.63 Hz), 2.72–2.59 (m,
2H), 2.06–1.71 (m, 4H). 13C NMR (75 MHz, CDCl3) δC 196.51, 181.59, 158.97,
141.03, 136.15, 131.88, 131.80, 129.92, 129.80, 129.40, 128.51, 127.88, 125.38,
122.72, 114.53, 110.77, 74.14, 72.37, 64.85, 52.66, 48.69, 31.11, 27.70; ESI Mass: m/z
[M+H+]: 489.20.
2′‑Benzoyl‑1′‑(4‑fuorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑pyr
rolizin]‑2‑one (8g)
White solid (98% yield). m.p. 118–120 °C; 83% ee’s, determined by HPLC [Chiral-
cel OD-H, n-hexane/i-propanol=80/20, 1 ml/min, λ=254 nm, t (major)=4.29 min,
t (minor)=14.83 min]. [α]D25 =–27.3° (c=1.73, CHCl3); H NMR (300 MHz,
1
CDCl3) δH 8.04 (s, 1H), 7.50–7.46 (m, 3H), 7.38 (d, 2H, J=8.28 Hz), 7.33 (d, 1H,
J=7.26 Hz), 7.24 (d, 1H, J=7.41 Hz), 7.18 (d, 2H, J=19.77 Hz), 7.11 (d, 1H,
J=7.59 Hz), 7.04–6.97 (m, 3H), 4.86 (d, 1H, J=11.46 Hz), 4.25–4.17 (m, 1H), 3.89 (t,
1H, J=10.65 Hz), 2.73–2.58 (m, 2H), 2.08–1.69 (m, 4H). 13C NMR (75 MHz, CDCl3)
δC 197.41, 181.66, 141.16, 137.32, 135.88, 133.37, 130.00, 129.89, 128.50, 128.22,
127.81, 125.39, 122.68, 116.05, 115.77, 110.68, 74.14, 72.38, 64.99, 52.62, 48.65,
31.08, 27.67; ESI Mass: m/z [M+H+]: 428.23.
2′‑(3‑Bromobenzoyl)‑1′‑(4‑fuorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro [indolin
e‑3,3′‑pyrrolizin]‑2‑one (8h)
White solid (97% yield). m.p. 120–122 °C; 92% ee’s, determined by HPLC [Chiral-
cel OD-H, n-hexane/i-propanol=80/20, 1 ml/min, λ=254 nm, t (major)=8.19 min, t
(minor)=10.53 min]. [α]D25 =–60.0° (c=1.89, CHCl3); 1H NMR (300 MHz, CDCl3)
δH 8.44 (s, 1H), 7.46 (t, 2H, J=6.54 Hz), 7.32–7.21 (m, 5H), 7.13 (t, 2H, J=7.57 Hz),
7.00 (t, 3H, J=8.34 Hz), 6.62 (d, 1H, J=7.68 Hz), 4.80 (d, 1H, J=11.40 Hz),
4.23–4.16 (m, 1H), 3.87 (t, 1H, J=10.63 Hz), 2.68–2.61 (m, 2H), 2.04–1.94 (m, 2H),
1.91–1.65 (m, 2H). 13C NMR (75 MHz, CDCl3) δC 196.04, 181.32, 163.50, 160.26,
140.81, 135.61, 131.45, 129.65, 129.50, 129.39, 128.26, 127.42, 122.38, 115.46,
110.54, 73.74, 71.95, 64.49, 52.25, 48.29, 30.63, 27.25; ESI Mass: m/z [M+H+]:
507.09.
1 3

Efcient base‑free asymmetric one‑pot synthesis of…
2′‑Benzoyl‑1′‑(4‑chlorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑pyr
rolizin]‑2‑one (8i)
White solid (97% yield). m.p. 126–128 °C; 91% ee’s, determined by HPLC
[Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/min, λ = 254 nm, t
(major) = 3.61 min, t (minor) = 5.97 min]. [α]D25 = – 88.3° (c = 3.17, CHCl3); H
1
NMR (300 MHz, CDCl3) δH 7.91 (s, 1H), 7.45 (d, 2H, J = 8.40 Hz), 7.38 (d, 2H,
J = 7.20 Hz), 7.32 (d, 2H, J = 12.60 Hz), 7.26 (d, 1H, J = 2.10 Hz), 7.22 (d, 2H,
J = 7.50 Hz), 7.17 (d, 1H, J = 7.50 Hz), 7.13 (t, 1H, J = 7.80 Hz), 7.02 (d, 1H,
J = 7.80 Hz), 6.54 (d, 1H, J = 7.50 Hz), 4.86 (d, 1H, J = 11.40 Hz), 4.24–4.17 (m,
1H), 3.88 (t, 1H, J = 10.50 Hz), 2.73–2.59 (m, 2H), 2.05–1.97 (m, 2H), 1.92–1.66
(m, 2H). 13C NMR (75 MHz, CDCl3) δC 196.75, 180.91, 140.51, 138.15, 136.71,
132.80, 132.52, 129.29, 128.65, 127.93, 127.64, 127.23, 124.75, 122.12, 110.02,
73.47, 71.70, 64.37, 52.17, 48.04, 30.46, 27.05; ESI Mass: m/z [M+]: 444.18.
2′‑(3‑Bromobenzoyl)‑1′‑(4‑chlorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro [ind
oline‑3,3′‑pyrrolizin]‑2‑one (8j) White solid (99% yield). m.p. 108–110 °C; 87%
ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/
min, λ = 254 nm, t (major) = 2.92 min, t (minor) = 8.99 min]. [α]D25 = – 140.2°
1
(c = 1.35, CHCl3); H NMR (300 MHz, CDCl3) δH 7.66 (s, 1H), 7.44 (d, 2H,
J = 8.43 Hz), 7.32 (t, 4H, J = 6.66 Hz), 7.27 (d, 2H, J = 2.7 Hz), 7.24–7.19 (m,
1H), 7.01 (t, 1H, J = 7.12 Hz), 4.80 (d, 1H, J = 11.40 Hz), 4.23–4.16 (m, 1H), 3.85
(t, 1H, J = 10.63 Hz), 2.71–2.57 (m, 2H), 2.05–1.90 (m, 2H), 1.88–1.67 (m, 2H).
13C NMR (75 MHz, CDCl3) δC 196.13, 180.97, 147.94, 147.54, 141.03, 135.86,
131.91, 130.18, 129.70, 129.42, 128.77, 127.77, 125.01, 124.35, 122.87, 110.71,
73.74, 72.10, 65.23, 53.17, 48.50, 30.81, 27.49; ESI Mass: m/z [M + H+]: 523.11.
2′‑Benzoyl‑1′‑(4‑nitrophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3
′‑pyrrolizin]‑2‑one (8k) Pale orange solid (96% yield). m.p. 108–110 °C; 86%
ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/
min, λ = 254 nm, t (major) = 18.22 min, t (minor) = 20.57 min]. [α]D25 = – 120.1°
(c = 1.30, CHCl3); 1H NMR (300 MHz, CDCl3) δH 8.18 (d, 2H, J = 8.58 Hz), 8.09
(s, 1H), 7.69 (d, 2H, J = 8.61 Hz), 7.36 (d, 2H, J = 7.83 Hz), 7.26–7.12 (m, 4H),
7.00 (t, 1H, J = 7.17 Hz), 6.56 (d, 1H, J = 7.68 Hz), 4.90 (d, 1H, J = 11.34 Hz),
4.30–4.23 (m, 1H), 4.02 (t, 1H, J = 10.53 Hz), 2.76–2.58 (m, 2H), 2.06–1.94 (m,
2H), 1.91–1.69 (m, 2H). 13C NMR (75 MHz, CDCl3) δC 196.55, 180.58, 147.62,
146.91, 140.59, 136.57, 132.88, 129.44, 129.13, 128.87, 127.98, 127.62, 127.19,
124.59, 123.72, 122.18, 110.01, 73.25, 71.51, 64.63, 52.62, 47.92, 30.24, 26.89;
ESI Mass: m/z [M + H+]: 455.20.
2′‑(3‑Bromobenzoyl)‑1′‑(4‑nitrophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro [indoli
ne‑3,3′‑pyrrolizin]‑2‑one (8l) Pale orange solid (95% yield). m.p. 120–122 °C; 88%
ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/
min, λ = 254 nm, t (major) = 16.31 min, t (minor) = 22.44 min]. [α]D25 = – 73.5°
(c = 1.05, CHCl3); 1H NMR (300 MHz, CDCl3) δH 8.19 (d, 2H, J = 8.61 Hz), 7.95 (s,
1 3

C. Chithiraikumar et al.
1H), 7.69 (d, 2H, J = 8.55 Hz), 7.33 (d, 3H, J = 8.49 Hz), 7.25 (d, 3H, J = 8.94 Hz),
7.15 (d, 1H, J = 8.16 Hz), 7.14 (d, 1H, J = 7.53 Hz), 7.02 (t, 1H, J = 7.50 Hz), 4.84
(d, 1H, J = 11.31 Hz), 4.30–4.23 (m, 1H), 4.00 (t, 1H, J = 10.54 Hz), 2.75–2.59
(m, 2H), 2.07–1.90 (m, 2H), 1.77–1.66 (m, 2H). 13C NMR (75 MHz, CDCl3) δC
196.13, 180.97, 147.94, 147.54, 141.03, 135.86, 131.91, 130.18, 129.70, 129.42,
128.77, 127.77, 125.01, 124.35, 122.87, 110.71, 73.74, 72.10, 65.23, 53.17, 48.50,
30.81, 27.49; ESI Mass: m/z [M + H+]: 534.08.
2′‑Benzoyl‑1′‑(2,4‑difluorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline
‑3,3′‑pyrrolizin]‑2‑one (8m) White solid (98% yield). m.p. 125–127 °C; 72%
ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/
min, λ = 254 nm, t (major) = 3.49 min, t (minor) = 16.97 min]. [α]D25 = – 100.1°
1
(c = 1.29, CHCl3); H NMR (300 MHz, CDCl3) δH 7.66 (s, 1H), 7.54–7.46 (m,
2H), 7.41–7.33 (m, 4H), 7.24–7.12 (m, 3H), 7.10 (d, 1H, J = 7.14 Hz), 7.02 (t,
1H, J = 7.42 Hz), 6.88–6.77 (m, 2H), 6.53 (d, 1H, J = 7.56 Hz), 5.04 (d, 1H,
J = 11.34 Hz), 4.22–4.16 (m, 2H), 2.68–2.57 (m, 2H), 2.05–1.97 (m, 2H), 1.93–
1.74 (m, 2H). 13C NMR (75 MHz, CDCl3) δC 196.65, 180.95, 140.60, 136.68,
132.81, 129.62, 129.36, 127.92, 127.64, 127.10, 124.69, 122.19, 111.51, 111.23,
110.15, 104.00, 103.66, 73.42, 70.81, 62.58, 47.98, 45.53, 30.49, 27.07; ESI Mass:
m/z [M + H+]: 446.19.
2′‑(3‑Bromobenzoyl)‑1′‑(2,4‑difuorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydro spiro[
indoline‑3,3′‑pyrrolizin]‑2‑one (8n) White solid (99% yield). m.p. 135–137 °C;
75% ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20,
1 ml/min, λ = 254 nm, t (major) = 3.39 min, t (minor) = 12.42 min]. [α]D25 = – 51.7°
1
(c = 1.31, CHCl3); H NMR (300 MHz, CDCl3) δH 8.44 (s, 1H), 7.46 (t, 2H,
J = 6.54 Hz), 7.32–7.21 (m 5H), 7.13 (t, 2H, J = 7.57 Hz), 7.00 (t, 3H, J = 8.34 Hz),
6.62 (d, 1H, J = 7.68 Hz), 4.80 (d, 1H, J = 11.40 Hz), 4.23–4.16 (m, 1H), 3.87
(t, 1H, J = 10.59 Hz), 2.68–2.61 (m, 2H), 2.04–1.87 (m, 2H), 1.76–1.65 (m, 2H).
13C NMR (75 MHz, CDCl3) δC 196.04, 181.32, 163.50, 160.26, 140.81, 135.61,
131.45, 129.65, 129.50, 129.39, 128.26, 127.42, 122.38, 115.74, 115.46, 110.54,
73.74, 71.95, 64.49, 52.25, 48.29, 30.63, 27.25; ESI Mass: m/z [M+]: 524.09.
2′‑Benzoyl‑1′‑(2‑methoxyphenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indolin
e‑3,3′‑pyrrolizin]‑2‑one (8o) White solid (94% yield). m.p. 120–122 °C; 96%
ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/
min, λ = 254 nm, t (major) = 20.07 min, t (minor) = 28.28 min]. [α]D25 = – 73.5°
1
(c = 1.21, CHCl3); H NMR (300 MHz, CDCl3) δH 8.11 (s, 1H), 7.47–7.39 (m,
4H), 7.32 (t, 2H, J = 2.86 Hz), 7.16 (d, 2H, J = 7.14 Hz), 7.09–7.00 (m 2H), 6.93–
6.86 (m, 2H), 6.56 (d, 1H, J = 7.53 Hz), 5.33 (d, 1H, J = 10.50 Hz), 4.29 (t, 2H,
J = 10.14 Hz), 3.93 (s, 3H), 2.67–2.61 (m, 2H), 1.99–1.85 (m, 4H). 13C NMR
(75 MHz, CDCl3) δC 197.25, 181.25, 157.85, 140.62, 137.14, 132.52, 129.08,
128.63, 127.83, 127.65, 127.44, 127.31, 125.24, 122.02, 120.64, 110.97, 109.98,
73.70, 70.62, 61.62, 55.50, 48.01, 47.39, 30.81, 27.22; ESI Mass: m/z [M + H+]:
440.23.
1 3

Efcient base‑free asymmetric one‑pot synthesis of…
2′‑(3‑Bromobenzoyl)‑1′‑(2‑chlorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro [ind
oline‑3,3′‑pyrrolizin]‑2‑one (8p) White solid (95% yield). m.p. 226–228 °C; 94%
ee’s,determinedbyHPLC[ChiralcelOD-H,n-hexane/i-propanol = 80/20,1ml/min,
λ = 254 nm, t (major) = 3.08 min, t (minor) = 5.88 min]. [α]D25 = – 63.7° (c = 1.32,
1
CHCl3); H NMR (300 MHz, CDCl3) δH 8.61 (s, 1H), 7.62 (d, 1H, J = 7.74 Hz),
7.40 (d, 2H, J = 7.98 Hz), 7.31 (d, 4H, J = 8.85 Hz), 7.24 (d, 1H, J = 7.56 Hz),
7.18–7.11 (m, 2H), 7.05 (t, 1H, J = 7.48 Hz), 5.03 (d, 1H, J = 11.58 Hz), 4.62
(t, 1H, J = 10.71 Hz), 4.15–4.10 (m, 1H), 2.65 (d, 2H, J = 5.46 Hz), 1.97–1.88
(m, 4H).13C NMR (75 MHz, CDCl3) δC 196.18, 181.32 140.96, 137.39, 136.05,
135.23, 131.82, 130.44, 129.79, 128.53, 128.49, 128.35, 127.82, 127.66, 125.22,
123.02, 110.74, 74.04, 72.92, 64.22, 48.67, 48.45, 30.69, 27.62; ESI Mass: m/z
[M+]: 522.10.
2′‑(3‑Bromobenzoyl)‑1′‑(2,4‑dichlorophenyl)‑1′,2′,5′,6′,7′,7a’‑hexahydro spiro[
indoline‑3,3′‑pyrrolizin]‑2‑one (8q) White solid (97% yield). m.p. 125–127 °C;
76% ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20,
1 ml/min, λ = 254 nm, t (major) = 7.26 min, t (minor) = 15.35 min]. [α]D25 = – 63.7°
1
(c = 1.05, CHCl3); H NMR (300 MHz, CDCl3) δH 8.23 (s, 1H), 7.56 (d, 1H,
J = 8.55 Hz), 7.41 (d, 1H, J = 1.89 Hz), 7.32 (d, 3H, J = 8.55 Hz), 7.26 (d, 3H,
J = 7.74 Hz), 7.14 (t, 1H, J = 7.54 Hz), 7.03 (t, 1H, J = 7.51 Hz), 6.62 (d, 1H,
J = 7.65 Hz), 4.94 (d, 1H, J = 11.52 Hz), 4.55 (t, 1H, J = 10.65 Hz), 4.11–4.06
(m, 1H), 2.68–2.61 (m, 2H), 1.99–1.84 (m, 4H). 13C NMR (75 MHz, CDCl3) δC
195.72, 181.05, 140.75, 135.73, 135.51, 135.46, 133.00, 132.00, 131.47, 129.76,
129.37, 129.06, 128.29, 127.65, 127.33, 124.68, 122.65, 127.33, 124.68, 122.65,
110.51, 73.62, 72.35, 63.79, 48.28, 47.72, 30.19, 27.14; ESI Mass: m/z [M + H+]:
556.11.
2′‑(3‑Bromobenzoyl)‑1′‑(3,4‑dimethoxyphenyl)‑1′,2′,5′,6′,7′,7a’‑hexahy
dro spiro[indoline‑3,3′‑pyrrolizin]‑2‑one (8r) White solid (98% yield). m.p.
124–126 °C; 94% ee’s, determined by HPLC [Chiralcel OD-H, n-hexane/i-pro-
panol = 80/20, 1 ml/min, λ = 254 nm, t (major) = 20.07 min, t (minor) = 28.28 min].
[α]D25 = – 100.15° (c = 1.65, CHCl3); 1H NMR (300 MHz, CDCl3) δH 8.22 (s, 1H),
7.33–7.24 (m, 6H), 7.14 (t, 2H, J = 7.47 Hz), 7.04 (d, 2H, J = 9.00 Hz), 6.81 (d,
1H, J = 8.16 Hz), 6.62 (d, 1H, J = 7.53 Hz), 4.82 (d, 1H, J = 11.40 Hz), 4.28–4.20
(m, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 2.67–2.62 (m, 2H), 2.07–1.99 (m, 2H), 1.935–
1.676 (m, 2H). 13C NMR (75 MHz, CDCl3) δC 196.14, 181.26, 148.96, 147.98,
140.76, 135.73, 132.06, 131.42, 129.55, 129.43, 128.18, 127.47, 124.93, 122.31,
119.98, 111.36, 111.25, 110.48, 73.93, 71.91, 64.46, 55.94, 55.82, 52.66, 48.24,
30.88, 27.37; ESI Mass: m/z [M + H+]: 549.16.
2′‑Benzoyl‑1′‑(o‑tolyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑pyrrolizi
n]‑2‑one (8s) White solid (97% yield). m.p. 130–132 °C; 93% ee’s, determined
by HPLC [Chiralcel OD-H, n-hexane/i-propanol = 80/20, 1 ml/min, λ = 254 nm, t
(major) = 6.54 min, t (minor) = 8.22 min]. [α]D25 = – 120.1° (c = 1.29, CHCl3); H
1
NMR (300 MHz, CDCl3) δH 8.24 (s, 1H), 7.39 (d, 3H, J = 7.86 Hz), 7.32–7.23 (m,
1 3

C. Chithiraikumar et al.
5H), 7.12 (d, 3H, J = 7.62 Hz), 7.02 (t, 1H, J = 7.47 Hz), 6.61 (d, 1H, J = 7.62 Hz),
4.85 (d, 1H, J = 11.43 Hz), 4.25–4.17 (m, 1H), 3.85 (t, 1H, J = 10.65 Hz), 2.67–2.61
(m, 2H), 2.29 (s, 3H), 2.04–1.96 (m, 2H), 1.91–1.69 (m, 2H). 13C NMR (75 MHz,
CDCl3) δC 196.07, 181.39, 140.75, 136.66, 136.48, 135.76, 131.40, 129.44,
128.15, 127.93, 127.49, 125.00, 122.34, 110.47, 73.83, 72.09, 64.30, 52.68, 48.32,
30.72, 27.31, 21.06; ESI Mass: m/z [M + H+]: 424.21.
2′‑(3‑Bromobenzoyl)‑1′‑(o‑tolyl)‑1′,2′,5′,6′,7′,7a’‑hexahydrospiro[indoline‑3,3′‑p
yrrolizin]‑2‑one (8t) White solid (98% yield). m.p. 187–189 °C; 94% ee’s, determined
by HPLC [Chiralcel OD-H, n-hexane/i-propanol=80/20, 1 ml/min, λ=254 nm, t
(major)=7.67 min, t (minor)=10.69 min]. [α]D25 =–132.2° (c=1.43, CHCl3); H
1
NMR (300 MHz, CDCl3) δH 8.01 (s, 1H), 7.39 (t, 4H, J=7.15 Hz), 7.31 (d, 1H,
J=7.23 Hz), 7.25 (d, 2H, J=4.53 Hz), 7.18–7.09 (m, 3H), 7.02 (d, 1H, J=7.53 Hz),
6.55 (d, 1H, J=7.62 Hz), 4.91 (d, 1H, J=11.49 Hz), 4.25–4.18 (m, 1H), 3.87 (t,
1H, J=10.69 Hz), 2.69–2.60 (m, 2H), 2.29 (s, 3H), 2.05–1.97 (m, 2H), 1.91–1.75
(m, 2H). 13C NMR (75 MHz, CDCl3) δC 197.09, 181.49, 145.07, 140.87, 137.05,
136.73, 136.53, 132.89, 129.74, 129.39, 128.62, 128.54, 128.05, 127.98, 127.87,
127.46, 125.14, 122.22, 121.07, 110.33, 73.91, 72.13, 64.39, 52.63, 48.31, 30.78,
27.31, 21.58, 21.05; ESI Mass: m/z [M+]: 502.13.
Acknowledgements We acknowledge the fnancial support from the Council of Scientifc and Industrial
Research (CSIR), HRDG, File No. 01(2901)/17/EMR-II, New Delhi, and the Department of Science and
Technology, SERB, Extramural Major Research Project (Grant No. EMR/2015/000969), Department of
Science and Technology DST/TM/CERI/C130(G), New Delhi, India, and University Grants Commission,
New Delhi, India (Grant No. UGC No.41-215/2012 (SR). Further, we also acknowledge the DST-FIST,
DST-IRPHA, DST-PURSE and UGC-UPE for providing instrumental facilities.
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