Regio- And stereoselective synthesis of spiropyrrolidine-oxindole and bis-spiropyrrolizidine-oxindole grafted macrocycles through [3 + 2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1039/c9ra10463a

A convenient and efficient method for the regioselective macrocyclization of triazole bridged spiropyrrolidine-oxindole, and bis-spiropyrrolizidine-oxindole derivatives was accomplished through intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides. The chalcone isatin precursors 9a-i required for the click reaction were obtained from the reaction of N-alkylazidoisatin 4 and propargyloxy chalcone 8a-i which in turn were obtained by the aldol condensation of propargyloxy salicylaldehyde 6 and substituted methyl ketones 7a-i. The regio- and stereochemical outcome of the cycloadducts were assigned based on 2D NMR and confirmed by single crystal XRD analysis. High efficiency, mild reaction conditions, high regio- and stereoselectivity, atom economy and operational simplicity are the exemplary advantages of the employed macrocyclization procedure.

Full text of DOI:10.1039/c9ra10463a

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Regio- and stereoselective synthesis of
spiropyrrolidine-oxindole and bis-
Cite this: RSC Adv., 2020, 10, 10263
spiropyrrolizidine-oxindole grafted macrocycles
through [3 + 2] cycloaddition of azomethine ylides†
*
Perumal Prabhakaran and Perumal Rajakumar
A
convenient and efficient method for the regioselective macrocyclization of triazole bridged
spiropyrrolidine-oxindole, and bis-spiropyrrolizidine-oxindole derivatives was accomplished through intra
and self-intermolecular [3 + 2] cycloaddition of azomethine ylides. The chalcone isatin precursors 9a–i
required for the click reaction were obtained from the reaction of N-alkylazidoisatin 4 and propargyloxy
chalcone 8a–i which in turn were obtained by the aldol condensation of propargyloxy salicylaldehyde 6
and substituted methyl ketones 7a–i. The regio- and stereochemical outcome of the cycloadducts were
assigned based on 2D NMR and confirmed by single crystal XRD analysis. High efficiency, mild reaction
conditions, high regio- and stereoselectivity, atom economy and operational simplicity are the
exemplary advantages of the employed macrocyclization procedure.
Received 12th December 2019
Accepted 21st February 2020
DOI: 10.1039/c9ra10463a
rsc.li/rsc-advances
coordination bonds in organometallics19,20 functioning as
sensors for the recognition of selective ions in host gest
chemistry21 make macrocyclic molecules an important class of
Introduction
Macrocyclic molecules have received signicant attention
because of varied ring size and chemical constitution
commonly found in natural products and pharmaceutical
molecules, and such molecules have potential application in
chemistry, biology, nanotechnology and medical elds.1,2
Further, heteroatom-containing macrocyclic molecules have
privileged structural units that are essential in the area of drug
discovery.3 The druglike “rule of ve” properties are not obeyed
by the macromolecules and the improved binding properties,
unique stereochemical and structural feature and conforma-
tional exibility make macrocycle molecules function as
important biological targets.4,5 Moreover, proteins with various
functional groups in preorganized three-dimensional constel-
lation can increase the catalytic efficiency in enzyme active sites
and molecular recognition in protein binding sites. Therefore,
there is acute necessity for the development of synthetic
macrocyclic scaffolds that can be used for the preorganized
constellation of functional groups for catalytic and molecular
recognition applications.6 Hence, macrocyclic compounds of
the following type such as calixarenes,7,8 cyclodextrin,9,10
cucurbiturils,11 resorcinarenes,12,13 conjugated aromatic
systems,14 and Schiff base macrocycles,15–17 are important from
the synthetic view point. Noncovalent self-assembly18 of
supramolecules.
Spiro compounds comprise two rings fused at a central spiro
atom, and possess a unique three dimensional architecture.
Synthetic chemists have been fascinated by spirocycles for more
than hundred years and the rst spiran was synthesized by
Baeyer in 1900.22 Spirocyclic oxindoles occupy a privileged
position in organic and diversity-oriented synthesis,23 and
attract a wide range of natural and synthetic products and
display a variety of bioactivities and present in pharmaceutically
active compounds24,25 In particular multifunctional polycyclic
spiropyrrolidine-oxindole and spiropyrrolizidine-oxindole are
the privileged heterocyclic skeleton which contain spiro ster-
eocenter at the C3 position of the oxindole frequently encoun-
tered in natural alkaloids and in important structural moieties
exhibiting versatile bioactivities,26 such as antibacterial, anti-
cancer, antimicrobial, antimycobacterial, antitumor, anti-
fungal, acetylcholinesterase (AChE) inhibitory properties and
cholinesterase inhibitory activity.27–29 The spirooxindoles unit
occurs in several natural products, such as (ꢀ)-horsline,
coerulescene, elacomine, spirotryprostatin A, peteropodine,
rhynchophylline, and also in spirooxindole alkaloids (Fig. 1).
Spiro pyrrolidine-3,3-oxindole alkaloids also shows anticancer
activity and inhibition of p53-MDM2 protein–protein interac-
tion with rapid regression of tumor cells.30 Thus, the anticancer
effect of spirooxindole natural products allow more signicant
non-natural analogues design. Presently, MI-77301 (SAR405838)
is yet another promising anticancer drug under clinical trials.31
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai-600 025, Tamil Nadu, India. E-mail: perumalrajakumar@gmail.com
† Electronic supplementary information (ESI) available. CCDC 1938425. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ra10463a
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Fig. 1 Representative examples of naturally occurring bioactive spiropyrrolidine-oxindole alkaloids.
1,3-Dipolar cycloaddition32 of azomethine ylide is a powerful can be prepared by the O-propargylation of salicylaldehyde with
method for the synthesis of biologically signicant ve- propargyl bromide followed by the aldol condensation using
membered
heterocyclic
compounds.
Electron-decient suitable methyl aryl ketone (Scheme 1).
Hence we began the synthesis of the desired azido
alkenes are employed as dipolarophiles in the presence of
either transition metals or organo catalysts to achieve highly compound 4 from isatin (1). Reaction of isatin (1) with one
functionalized and stereochemically enriched pyrroldine, pyr- equivalent of 1,2-dibromoethane in the presence of K2CO3 in
rolizidine and spirocyclic oxindole molecules.33 The simplicity, DMF at room temperature gave the N-alkylbromo ketone 3 in
atomic economy, mild reaction conditions and extension of the 58% yield along with the bisalkylated tetraketone 2 in 24%
scope of substrates make such cycloaddition as the current yield. The monobromoketone 3 was smoothly converted to the
direction in combinatorial chemistry. Driven thorough litera- desired azide 4 in 93% by NaN3 in DMF at room temperature
ture survey, we are encouraged to construct hybrid macrocyclic (Scheme 2). The structure of the N-alkylazidoketone 4 was
1
systems. However, the extensive applications of 1,3-dipolar conrmed from H and 13C NMR spectra. Synthesis of O-prop-
cycloaddition for the synthesis of such macrocycles still argylated chalcone fragments 8a–i was achieved from salicy-
remains a challenge.34 To the best of our knowledge there is no laldehyde (5) by adopting a reported procedure35 (Scheme 2).
report in the literature on a one pot self-intermolecular [3 + 2] Reaction of salicylaldehyde (5) with 1.2 equiv. of propargyl
cycloaddition to give bis-spiropyrrolizidine-oxindole graed bromide in the presence of potassium carbonate in DMF at
macrocyles.
room temperature gave propargyloxy salicylaldehyde 6 in 92%
We disclose a novel method for the synthesis and electro- yield, which on further aldol condensation with 1.2 equiv. of
chemical property and biological activity35 of 1,2,3-triazole each of the various substituted aromatic and heteroaromatic
bridged pyrrolidine graed macrocycles with high regio- and methyl ketones viz., 4-bromoacetophenone 7a, 4-chlor-
stereoselectivity via [3 + 2] cycloaddition approach. We wish to oacetophenone 7b, 3,4-dimethoxyacetophenone 7c, 4-methox-
report herein the synthesis of novel spiropyrrolidine oxindole yacetophenone
7d,
4-methylacetophenone
7e,
2-
graed macrocyles 12a–i (Fig. 2) and bis-spiropyrrolizidine methoxyacetophenone 7f, 4-nitroacetophenone 7g, acetophe-
oxindole graed macrocycles 16a–i (Fig. 3) through intra and none 7h and 2-acetylthiophene 7i in the presence of 20%
self-intermolecular [3 + 2] cycloaddition of azomethine ylides aqueous NaOH solution in EtOH gave the substituted chalcone
(AMY) generated in situ by the decarboxylative condensation of derivatives 8a–i in 75–85% yields.
cyclic ketones and secondary amino acids.
In convergent approach, the 1,3-dipolar cycloaddition of
propargyloxychalcone derivatives 8a–i with 1.0 equiv. of N-
alkylazidoketone 4 under click reaction conditions using
CuSO4$5H2O and sodium ascorbate in THF : H2O as solvent
gave the 1,4-triazole bridged chalcone isatin 9a–i in 80–90%
yields (Scheme 2). The structure of the 1,4-triazole bridged
chalcone isatin 9a–i was characterized from spectroscopic
methods. In the 1H NMR spectrum of 9a the triazole –CH–
proton resonated at d 7.75 as a singlet. The geometry of the
olenic double bond showed the E conguration as evidenced
Results and discussion
The synthetic plan for achieving the spiropyrrolidine-oxindole
graed macrocycles 12a–i is shown in Scheme 1. The macro-
cyclic spiropyrrolidine-oxindole 12a–i can be obtained by the
intramolecular (3 + 2) cycloaddition of chalcone isatins 9a–i
with the azomethine ylide generated from the corresponding
amino acids. The chalcone isatins 9a–i can be derived from the
click reaction of the propargyloxy chalcone 8a–i with the azido
fragment derived from isatin. The propargyloxy chalcone 8a–i
1
from H NMR spectrum. The olenic protons of the chalcone
isatin 9a appeared as a doublet at 7.99 with a coupling constant
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Fig. 2 Molecular structure of spiropyrrolidine-oxindole grafted macrocyles 12a–i.
of 15.9 Hz which conrms the E conguration of the double substituted chalcone isatin 9b–i. Regio- and stereoselective [3
bond. In the 13C NMR spectrum of 9a, the carbonyl carbons + 2] cycloaddition of azomethine ylide from sarcosine (10) with
exhibited peaks at 182.2 and 189.7 ppm.
the substituted chalcone isatin 9b–i gave the cycloadducts
To optimize the conditions for 1,3-dipolar cycloaddition, 12b–i in 65–75% yields (Scheme 3). The intramolecular dipo-
the cycloaddition of the chalcone isatin 9a and sarcosine was larophile O-alkyl enone regioselectively reacts with the azo-
chosen as the model reaction (Table 1). The reaction mixture methine ylide (dipole) in toluene under reuxing conditions
with equimolar amounts of chacone isatin 9a and sarcosine for 6 h in Dean–Stark apparatus to give the regio- and stereo-
(10) was tested under various reaction conditions. The effects selective macrocyclic adducts 12a–i in 65–75% yields.
of solvent and temperature on the 1,3-dipolar cycloaddition
The structure and the regiochemistry of the spi-
was evaluated and from the optimization study the best results ropyrrolidine oxindole graed macrocyles 12a–i was unam-
were obtained by reuxing the reaction mixture in toluene for biguously established from spectroscopic data. In the 1H NMR
6 h in Dean–Stark apparatus to give the regio- and stereo- spectrum, the cycloadduct 12a displayed the N-methyl protons
selective cycloadduct 12a in 74% yields. Having established of the pyrrolidine ring as a singlet at d 2.14 and the two dia-
suitable reaction conditions (Table 1, entry 4), we tried to stereotopic N-methylene protons of the pyrrolidine moiety
extend the scope of the reaction, using a series of various resonated as triplets at d 3.38 and d 3.92 (J ¼ 8.1, J ¼ 9.6 Hz).
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Fig. 3 Molecular structure of bis-spiropyrrolizidine-oxindole grafted macrocyles 16a–i.
The two O-methylene protons appeared as two doublets at of d 3.57–3.61. The pyrrolidine Hb proton adjacent to the
d 5.09 and 5.37 (J ¼ 10.2 Hz, J ¼ 10.5 Hz). The benzylic proton carbonyl group appeared as a doublet at d 5.21 (J ¼ 6.9 Hz),
Hb of the pyrrolidine ring appeared as a multiplet in the region which clearly proved the regiochemistry of the cycloaddition.
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Scheme 1 Synthetic plan for spiropyrrolidine-oxindole grafted macrocycles 12a–i.
Scheme 2 Synthesis of 1,2,3-triazole bridged chalcone isatin 9a–i. Reagent and conditions: (i) 1,2-dibromoethane, K2CO3, DMF, rt, 2 h, 2 (24%), 3
(58%); (ii) NaN3, DMF, rt, 8 h, 4 (93%); (iii) propargyl bromide, K2CO3, DMF, rt, 12 h, 6 (92%); (iv) methyl ketones 7a–i, NaOH, EtOH, rt, 6 h 8a–i (75–
85%). (v) N-Alkylazidoketone 4, CuSO4$5H2O, sodium ascorbate, THF : water (1 : 1), rt, 9a–i (80–90%).
Further, the triazolyl –CH– proton appeared at d 8.12 as
Table 1 Optimizing the reaction conditions for the synthesis of
cycloadduct 12a
a singlet.
In the 13C NMR spectrum, the cycloadduct 12a showed the N-
methyl, N-methylene and carbonyl carbons at d 34.5, 60.1 and
199.3 ppm respectively. In DEPT-135 13C NMR spectrum, the
cycloadduct 12a exhibited the four peaks in the negative region
at d 39.5, 48.7, 60.1 and 62.3 ppm which conrm the presence of
four methylene carbons in 12a. Moreover, 1H–1H COSY and
1H–13C COSY experiments were carried out to conrm the
structure of regio- and stereoselective isomer 12a (ESI†). The
macrocyclic compound 12a showed a peak at m/z 584.1271 (M +
Entry
Solvent
Temperature (ꢁC)
Time (h)
Isolated yield (%)
1
2
3
4
Benzene
MeOH
CH3CN
Toluene
Reux
Reux
Reux
Reux
6
6
6
6
Trace
34
58
74
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Scheme 3 Synthesis of spiropyrrolidine-oxindole grafted macrocycles 12a–i. Reagent and conditions: (i) sarcosine 10, toluene, N2 atm, Dean–
Stark water separator, 6 h, 12a (74%), 12b (75%), 12c (68%), 12d (70%), 12e (68%), 12f (65%), 12g (72%), 12h (70%), 12i (65%).
Fig. 4 Regioselectivity due to SOI in the transitions state that leads to the cycloadduct 12a–i.
H)+ in HRMS (TOF MS ES+ 3.35 ꢂ 107). Similarly, the structure which could undergo self-intermolecular [3 + 2] cycloaddition.
of the pyrrolidine graed macrocycles 12b–i was conrmed The azomethine ylides 15a–i underwent smooth self-
from the spectral and analytical data.
intermolecular 1,3-dipolar cycloaddition to give the bis-
The electron withdrawing or electron donating substituents spiropyrrolizidine oxindole graed macrocyles 16a–i in 55–
on the phenyl ring of the dipolarophiles tolerated the reaction 65% yields (Scheme 4).
conditions, leading to the spirooxindolo pyrrolidine macro-
Optimization of the reaction condition for the formation
cycles in good yields. The regioselectivity of the macro- of the cycloadduct 16a was then focused. Variation with
cyclization can be demonstrated by the intramolecular respect to solvent, temperature and reaction time for the
secondary orbital interaction (SOI)36 between the orbital of the formation of 16a was carried out and the resulting yield of
dipolarophile carbonyl group and dipole azomethine ylide, as 16a is show in Table 2. The best optimized yield of 64% is
shown in Fig. 4. Formation of the observed regioisomer 12a–i show in entry 4.
through path A is favorable because of the SOI, which is not
The structure and regioselective of self-intermolecular
possible in the transitions state 110 which could have given the cycloadducts 16a–i were established from spectroscopic data.
regioisomer 13a–i (path B). The relative stereochemistry at the The 1H NMR spectrum of the cycloadduct 16b displayed
positions of spiro center of the macrocycles was observed as a multiplet at d 1.68–2.69 for the pyrrolizidine ring methylene
highly stereocontroled cycloaddition and the favorable SOI protons. The O–CH2– protons appeared as a ABq at d 5.24, 5.49 (J
results in the formation of the regioisomer 12a–i only.
¼ 11.7 Hz). A doublet at d 5.60 (J ¼ 11.7 Hz) was observed for the
As a logical extension of the methodology, synthesis of bis- benzoyl protons. The benzylic proton of the pyrrolidine ring
spiropyrrolizidine-oxindole graed macrocycles 16a–i was appeared as a multiplet in the region of d 4.47–4.58, which
then focused. Reaction of the triazole bridged chalcone isatin clearly showed the stereo- and regiochemistry of the self-
9a–i with L-proline (14) generated the 1,3-dipolar intermediate intermolecular cycloaddition of azomethine ylides. A neat
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Scheme 4 Synthesis of bis-spiropyrrolizidine-oxindole grafted macrocycles 16a–i. Reagents and conditions: (i) proline (14), toluene, N2 atm,
Dean–Stark water separator, 6 h, 16a (64%), 16b (65%), 16c (58%), 16d (60%), 16e (56%), 16f (55%), 16g (62%), 16h (60%), 16i (56%).
Table 2 Optimizing the reaction conditions for the synthesis of
cycloadduct 16a
with triazole as spacer unit via regioselective click reaction,
intra and self-intermolecular 1,3-dipolar cycloaddition of
azomethine ylide derived from sarcosine and proline under
thermal decarboxylative condensation by relatively simple
procedure. The [3 + 2] cycloaddition methodology was found
to be highly regioselective and the structure of the regio- and
stereo isomer was determined from 2D NMR and conrmed
by XRD studies.
Entry
Solvent
Temperature (ꢁC)
Time (h)
Isolated yield (%)
1
2
3
4
Benzene
MeOH
CH3CN
Toluene
Reux
Reux
Reux
Reux
6
6
6
6
Trace
18
32
64
Experimental
General considerations
singlet appeared at d 9.85 corresponding to triazole –CH–
proton which proved the presence of a triazole unit. The
stereochemistry of the cycloadduct 16b was also deduced on the
basis of 2D 1H–1H COSY and 1H–13C COSY (ESI†) experiments.
In DEPT-135 13C NMR spectrum, the methylene carbons
exhibited six peaks in the negative region at d 28.4, 32.6, 40.0,
46.6, 47.4 and 64.2 ppm which conrms the presence of six
methylene carbons in the macrocycle 16b. Furthermore, the
presence of molecular ion peak at m/z 1131.3840 (M + 1) in
HRMS, also conrmed the structure of the cycloadduct 16b. The
carbonyl carbon exhibited a peak at 196.6 ppm in the 13C NMR
spectrum. The remaining carbons resonated at the
corresponding ppm values (ESI†). Finally, the structure of the
macrocyclic compound 16b was again established from the
single crystal XRD analysis (Fig. 5) However, the structure of the
bis-spiropyrrolizidine-oxindole graed macrocycles 16a and
16c–i was conrmed from the spectral and analytical data.
In conclusion, for the rst time we have developed an
efficient protocol for the macrocyclizations of spi-
ropyrrolidine oxindole and bis-spiropyrrolizidine oxindole
All reagents and solvents were of analytical grade and used
without further purication as obtained from commercial
suppliers. Ethanol, N,N-dimethylformamide (DMF), tetrahy-
drofuran (THF), and toluene were retrieved from a solvent
purication system. Routine monitoring of the reaction was
done by thin-layer chromatography (TLC) using hexane/ethyl
acetate mixtures as eluent. Column chromatography was
carried out on Silica gel (100–200 meshes) by using increasing
polarity. All melting points are uncorrected. 1H NMR, 13C NMR
and DEPT 135 spectra were recorded in CDCl3 using TMS as an
internal standard on 300 MHz Bruker instrument. 2D NMR
spectra were recorded at 500 MHz spectrometer on Bruker
instrument. Chemical shis are reported in ppm relative to
deuterated solvent peaks as internal standards (dH ¼ CDCl3
7.26 ppm, and DMSO-d6 2.50 ppm; dC ¼ CDCl3 77.16 ppm, and
DMSO-d6 39.5 ppm). Coupling constants (J) are quoted in Hertz
(Hz). The HRMS spectra were recorded on Xevo G2s Qtof (ESI)
instruments.
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Fig. 5 ORTEP diagram of bis-spiropyrrolizidine-oxindole grafted macrocycle 16b.
Synthesis of 1,2,3-triazole bridged chalcone isatin 9a–i
Chalcone isatin 9d. Yield 85%, orange solid. Mp: 158–160 ꢁC.
1H NMR (300 MHz, CDCl3): d 3.82 (s, 3H); 4.17 (t, J ¼ 5.4 Hz, 2H);
4.72 (t, J ¼ 5.4 Hz, 2H); 5.13 (s, 2H); 6.47 (d, J ¼ 8.1 Hz, 1H); 6.88–
7.00 (m, 5H); 7.27–7.34 (m, 3H); 7.39 (t, J ¼ 7.2 Hz, 1H); 7.55–
7.60 (m, 2H); 7.90–7.98 (m, 3H). 13C NMR (75 MHz, CDCl3):
d 40.6, 47.8, 55.4, 62.1, 109.5, 112.7, 113.7, 117.3, 121.4, 122.5,
123.9, 124.2, 124.5, 125.3, 129.1, 130.7, 131.0, 131.6, 131.6,
138.5, 138.9, 143.9, 150.0, 157.2, 158.5, 163.3, 182.6, 188.9.
Chalcone isatin 9e. Yield 82%. Orange-yellow solid. Mp: 182–
184 C. H NMR (300 MHz, CDCl3): d 2.38 (s, 3H); 4.19 (t, J ¼
5.4 Hz, 2H); 4.73 (t, J ¼ 5.4 Hz, 2H); 5.16 (s, 2H); 6.47 (d, J ¼
7.8 Hz, 1H); 6.91–7.02 (m, 3H). 7.24 (d, J ¼ 7.8 Hz, 2H); 7.28–7.32
(m, 2H); 7.42 (d, J ¼ 7.5 Hz, 1H); 7.55–7.61 (m, 2H); 7.84 (d, J ¼
8.1 Hz, 2H); 7.94 (s, 1H); 7.99 (d, J ¼ 15.6 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d 21.6, 40.6, 47.9, 62.2, 109.4, 112.7, 117.3,
121.4, 122.6, 124.0, 124.1, 124.5, 125.4, 128.6, 129.0, 129.3,
131.7, 135.6, 138.5, 139.4, 143.6, 150.0, 157.3, 158.6, 182.5,
189.9.
(i) General procedure. To solution of propargyloxy chalcones
8a–i (1 eq.) and N-alkylazidoketones 4 (1 eq.) in a mixture of THF
(20 mL), and H2O (20 mL), was added CuSO4$5H2O (0.5 eq.) and
sodium ascorbate (0.5 eq.). The resulting solution was then
stirred for 12 h at room temperature. The solvent was evapo-
rated under vacuum and the residue was dissolved in chloro-
form (150 mL) and washed with water (50 mL) and brine (50 mL)
dried over Na2SO4 and concentrated. The crude product was
puried by column chromatography using hexane : EtOAc
(3 : 2) as eluent to give the chalcone isatin 9a–i.
1
ꢁ
Chalcone isatin 9a. Yield 86%, orange-yellow solid. Mp: 174–
176 ꢁC. 1H NMR (300 MHz, CDCl3): d 4.23 (t, J ¼ 6.0 Hz, 2H); 4.73
(t, J ¼ 6.0 Hz, 2H); 5.20 (s, 2H); 6.55 (d, J ¼ 7.8 Hz, 1H); 6.97–7.05
(m, 3H); 7.31–7.41 (m, 2H); 7.47–7.51 (m, 1H); 7.56–7.61 (m, 4H);
7.75 (s, 1H); 7.83 (d, J ¼ 8.1 Hz, 2H); 7.99 (d, J ¼ 15.9 Hz, 1H). 13
C
NMR (75 MHz, CDCl3): d 40.6, 47.8, 62.4, 109.4, 113.0, 117.5,
121.6, 122.6, 123.9, 124.0, 124.3, 125.5, 127.6, 129.4, 130.1, 131.8,
131.9137.1, 138.4, 140.5, 144.1, 149.9, 157.5, 158.5, 182.2, 189.7.
Chalcone isatin 9b. Yield 88%. Yellow solid. Mp: 162–164 ꢁC.
1H NMR (300 MHz, CDCl3): d 4.24 (t, J ¼ 5.7 Hz, 2H); 4.72 (t, J ¼
5.7 Hz, 2H); 5.2 (s, 2H); 6.53 (d, J ¼ 8.1 Hz, 1H); 7.00–7.05 (m,
3H); 7.26–7.41 (m, 2H); 7.43–7.54 (m, 3H); 7.60–7.63 (m, 2H);
Chalcone isatin 9f. Yield 85%, orange-yellow solid. Mp: 128–
1
ꢁ
130 C. H NMR (300 MHz, CDCl3): d 3.86, (s, 3H); 4.23 (t, J ¼
6.0 Hz, 2H); 4.69 (t, J ¼ 6.0 Hz, 2H); 5.20 (s, 2H); 6.56 (d, J ¼
8.1 Hz, 1H); 6.97–7.04 (m, 5H); 7.29–7.33 (m, 1H); 7.36–7.43 (m,
2H); 7.45–7.48 (m, 1H); 7.53 (d, J ¼ 7.5 Hz, 1H); 7.56–7.59 (m,
2H); 7.63 (s, 1H). 7.89 (d, J ¼ 15.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d 40.6, 47.8, 55.8, 62.7, 109.4, 111.9, 113.1, 117.5, 120.7,
121.6, 123.7, 124.1, 124.8, 125.5, 127.7, 128.4, 129.7, 130.3,
131.5, 132.6, 138.1, 138.5, 149.9, 157.2, 158.5, 186.4, 193.1.
Chalcone isatin 9g. Yield 80%. Orange-yellow solid. Mp: 180–
7.80 (s, 1H); 7.91 (d, J ¼ 9.9 Hz, 2H); 8.01 (d, J ¼ 15.6 Hz, 1H). 13
C
NMR (75 MHz, CDCl3): d 40.6, 47.9, 62.2, 109.4, 112.8, 117.4,
121.5, 122.4, 124.1, 124.2, 125.6, 128.8, 129.3, 129.6, 129.9,
131.9, 136.6, 138.6, 139.1, 140.5, 144.1, 149.9, 157.4, 158.5,
182.3, 189.4.
1
ꢁ
182 C. H NMR (300, MHz, CDCl3): d 4.26 (t, J ¼ 4.7 Hz, 2H);
4.75 (t, J ¼ 6.0 Hz, 2H); 5.22 (s, 2H); 6.60 (d, J ¼ 8.1 Hz, 1H); 7.00–
7.06 (m, 3H); 7.36–7.43 (m, 2H); 7.51 (d, J ¼ 7.2 Hz, 1H); 7.60–
7.63 (m, 2H); 7.78 (s, 1H); 8.03 (d, J ¼ 15.6 Hz, 1H); 8.11–8.14 (m,
2H); 8.31 (d, J ¼ 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 40.5,
47.7, 62.0, 109.5, 112.7, 117.9, 121.6, 122.4, 124.1, 124.2, 123.7,
125.6, 129.6, 130.1, 132.4, 138.6, 142.1, 143.9, 149.9, 150.1,
157.6, 158.5, 182.2, 189.4.
Chalcone isatin 9c. Yield 82%, orange-yellow solid. Mp: 198–
1
ꢁ
200 C. H NMR (300 MHz, CDCl3): d 3.95 (s, 3H); 3.96 (s, 3H);
4.23 (t, J ¼ 6 Hz, 2H); 4.73 (t, J ¼ 6 Hz, 2H); 5.22 (s, 2H); 6.50 (d, J
¼ 7.8 Hz, 1H); 6.92 (d, J ¼ 8.4 Hz, 1H); 6.99–7.05 (m, 3H); 7.31–
7.40 (m, 2H); 7.49 (d, J ¼ 7.2 Hz, 1H); 7.57–7.65 (m, 4H); 7.80 (s,
1H); 8.01 (d, J ¼ 15.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 40.6,
47.9, 56.09, 56.1, 62.4, 109.3, 110.1, 110.9, 112.9, 117.4, 121.5,
122.5, 123.1, 124.6, 125.6, 128.9, 131.6, 138.5, 139.0, 149.2,
149.9, 153.2, 157.2, 158.5, 182.3, 188.9.
Chalcone isatin 9h. Yield 84%. Orange-yellow solid. Mp: 82–
84 ꢁC. 1H NMR (300 MHz, CDCl3): d 4.21 (t, J ¼ 6.0 Hz, 2H); 4.72
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(t, J ¼ 6.0 Hz, 2H); 5.18 (s, 2H); 6.49 (d, J ¼ 7.8 Hz, 1H); 6.94–7.04 125.5, 126.2, 126.6, 126.8, 128.3, 129.2, 129.3, 133.0, 136.2,
(m, 3H); 7.31–7.37 (m, 2H); 7.40–7.48 (m, 4H); 7.52–7.56 (m, 138.7, 142.9, 144.3, 156.9, 178.2, 199.1 DEPT135: 34.5, 39.5,
1H); 7.61–7.63 (m, 1H); 7.86 (s, 1H); 7.93–7.95 (m, 2H); 8.02 (d, J 44.8, 48.7, 52.1, 60.1, 62.3, 107.0, 112.6, 121.1, 122.8, 126.6,
¼ 15.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 40.6, 47.92, 62.3, 126.8, 128.3, 129.2, 129.3, 133.0 ppm. HRMS (TOF MS ES+ 3.36
109.4, 112.8, 117.4, 121.5, 122.7, 124.1, 124.2, 124.3, 125.5, ꢂ 107) m/z calcd for C30H26ClN5O5 + H2 [M + 2]+ 541.1881 found
128.1, 128.5, 128.6, 129.1, 131.8, 132.7, 138.3, 138.5, 139.8, 541.1859.
144.1, 150.0, 157.3, 158.6, 182.4, 190.7.
Spiropyrrolidine-oxindole graed macrocycle 12c. 68%; white
1
Chalcone isatin 9i. Yield 80%, yellow solid. Mp: 110–112 C. solid; mp; 218–220 ꢁC. H NMR (300 MHz, CDCl3): d 2.15 (s, 3H);
1H NMR (300 MHz, CDCl3): d 4.24 (t, J ¼ 6.0 Hz, 2H); 4.71 (t, J ¼ 3.36 (t, J ¼ 8.1 Hz, 1H); 3.55–3.59 (m, 1H); 3.78 (s, 3H); 3.87 (s,
6.0 Hz, 2H); 5.23 (s, 2H); 6.55 (d, J ¼ 8.1 Hz, 1H); 6.98–7.06 (m, 3H); 3.90–3.96 (m, 1H); 4.41–4.52 (m, 3H); 4.88–4.92 (m, 1H);
2H); 7.14–7.17 (m, 1H); 7.34–7.49 (m, 3H); 7.49–7.53 (m, 2H); 5.12 (d, J ¼ 10.5 Hz, 1H); 5.31 (d, J ¼ 6.9 Hz, 1H); 5.43 (d, J ¼
7.60–7.65 (m, 2H); 7.72 (s, 1H); 7.82 (d, J ¼ 3.6 Hz, 1H); 8.05 (J ¼ 10.5 Hz, 1H); 6.57 (d, J ¼ 8.1 Hz, 1H); 6.67–6.76 (m, 2H); 6.82–
15.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 31.6, 40.6, 47.9, 60.4, 6.91 (m, 2H); 6.96–6.98 (m, 2H); 7.01–7.07 (m, 2H); 7.21–7.27
62.3, 69.7, 69.9, 70.1, 72.7, 80.7, 109.5, 112.8, 117.4, 121.5, 124.0, (m, 2H); 8.08 (s, 1H). 13C NMR (75 MHz, CDCl3): d 34.6, 39.9,
124.1, 124.3, 124.5, 125.6, 128.8, 131.3, 135.8, 138.6, 144.2, 45.5, 49.0, 52.6, 55.9, 56.0, 60.0, 62.3, 73.9, 106.7, 109.3, 110.3,
ꢁ
150.0, 157.2, 158.6, 182.4, 193.5.
112.5, 121.1, 122.2, 122.6, 125.9, 126.3, 126.5, 127.2, 128.3,
129.0, 131.9, 133.1, 142.9, 148.6, 152.7, 157.0, 178.3, 199.4.
DEPT135: d 34.6, 39.9, 45.5, 49.0, 52.6, 55.9, 56.0, 60.0, 62.3,
106.7, 109.3, 110.3, 112.5, 121.1, 122.2, 122.6, 126.5, 127.2,
128.3, 129.1, 133.1. HRMS (TOF MS ES+ 9.65 ꢂ 108) m/z calcd for
Synthesis of 1,2,3-triazole bridged spiropyrrolidine-oxindole
graed macrocycles 12a–i/bis-spiropyrrolizidne-oxindole
graed macrocycles 16a–i
C
32H31N5O5 + H+ [M + H]+ 566.2403 found 566.2404.
(ii) General procedure. A solution of the chalcone isatins 9a–i
Spiropyrrolidine-oxindole graed macrocycle 12d. Yield: 70%;
(1 mmol) and sarcosine (10)/proline (14) (2.5 mmol) was white solid; mp; 232–234 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.14
reuxed in dry toluene under N2 atmosphere for 12 h at 120 ꢁC (s, 3H); 3.36 (t, J ¼ 8.1 Hz, 1H); 3.58 (t, J ¼ 6.3 Hz, 1H); 3.77 (s,
using Dean–Stark apparatus. Aer the completion of reaction as 3H); 3.89–3.96 (m, 1H); 4.43–4.41 (m, 1H); 4.52–4.61 (m, 2H);
indicated by TLC, toluene was evaporated under reduced pres- 4.87–4.92 (m, 1H); 5.12 (d, J ¼ 10.2 Hz, 1H); 5.27 (d, J ¼ 6.9 Hz,
sure. The crude product was washed with water and extracted 1H); 5.41 (d, J ¼ 10.2 Hz, 1H); 6.57 (d, J ¼ 7.8 Hz, 1H); 6.72 (d, J ¼
with dichloromethane (4 ꢂ 20 mL). The combined organic layer 8.7 Hz, 2H); 6.81 (t, J ¼ 8.1 Hz, 1H); 6.86–6.91 (m, 1H); 6.97–7.04
was dried (MgSO4) and ltered, concentrated in vacuum. The (m, 3H); 7.21–7.27 (m, 4H); 8.09 (s, 1H). 13C NMR (75 MHz,
crude product was puried by column chromatography using CDCl3): d 34.6, 39.8, 45.3, 48.9, 52.2, 55.4, 60.0, 62.3, 73.9, 106.7,
hexane/ethyl acetate (1 : 1) as eluent to give the 112.5, 113.7, 121.1, 122.7, 125.8, 126.4, 126.5, 127.1, 128.2,
spiropyrrolidine-oxindole graed macrocycles 12a–i and bis- 129.0, 130.1, 131.4, 133.1, 142.9, 144.4, 157.1, 157.0, 162.8,
spiropyrrolizidine-oxindole graed macrocylcles 16a–i.
178.3, 198.7. DEPT135: d 34.6, 39.8, 45.3, 49.0, 52.2, 55.4, 60.0,
Spiropyrrolidine-oxindole graed macrocycle 12a. Yield 74%. 62.3, 106.7, 112.5, 113.7, 121.1, 126.5, 127.1, 128.3, 129.1, 130.1,
White solid. Mp 206–208 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.14 133.1. HRMS (TOF MS ES+ 2.50 ꢂ 108) m/z calcd for C31H29N5O4
(s, 3H); 3.38 (t, J ¼ 8.1 Hz, 1H); 3.56–3.60 (m, 1H); 3.92 (t, J ¼ 9.1 + H+ [M + H]+ 536.2298 found 536.2377.
Hz, 1H); 4.44–4.52 (m, 1H); 4.56–4.72 (m, 2H); 4.81–4.88 (m,
Spiropyrrolidine-oxindole graed macrocycle 12e. Yield: 68%.
1H); 5.09 (d, J ¼ 10.2 Hz, 1H); 5.21 (d, J ¼ 6.9 Hz, 1H); 5.37 (d, J ¼ White solid; mp 184–186 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.14
10.5 Hz, 1H); 6.58 (d, J ¼ 7.8 Hz, 1H); 6.77 (t, J ¼ 7.2 Hz, 1H); (s, 3H); 2.26 (s, 3H); 3.34 (t, J ¼ 7.8 Hz, 1H); 3.51–3.61 (m, 1H);
6.86–6.93 (m, 2H); 6.99 (t, J ¼ 8.7 Hz, 1H); 7.03–707 (m, 3H); 3.90–3.96 (m, 1H); 4.41–4.52 (m, 3H); 4.91 (d, J ¼ 10.2 Hz, 1H);
7.20–7.27 (m, 2H); 7.39 (d, J ¼ 8.4 Hz, 2H); 8.12 (s, 1H). 13C NMR 5.09 (d, J ¼ 10.5 Hz, 1H); 5.34 (d, J ¼ 6.9 Hz, 1H); 5.48 (d, J ¼
(70 MHz, CDCl3): d 34.5, 39.5, 44.8, 48.7, 52.1, 60.1, 62.3, 73.8, 10.5 Hz, 1H); 6.56 (d, J ¼ 8.1 Hz, 1H); 6.81–6.90 (m, 2H); 6.98–
107.0, 112.6, 121.1, 122.8, 125.5, 126.2, 126.6, 126.8, 127.5, 7.12 (m, 5H); 7.10 (d, J ¼ 8.1 Hz, 2H); 7.22–7.26 (m, 3H); 7.99 (s,
128.3, 129.2, 129.4, 131.3, 133.0, 136.6, 142.9, 144.3, 156.9, 1H). 13C NMR (75 MHz, CDCl3): 21.5, 34.55, 40.1, 45.7, 49.2,
178.2, 199.3. DEPT135: 34.5, 39.5, 44.8, 48.7, 52.1, 60.1, 62.3, 52.8, 59.9, 62.4, 73.8, 106.7, 112.5, 121.1, 122.7, 125.9, 126.2,
107.0, 112.6, 121.1, 122.8, 126.6, 126.8, 128.3, 129.3, 129.4, 126.4, 127.3, 127.7, 128.3, 128.7, 129.0, 133.1, 136.1, 142.9,
131.3, 133.0. HRMS (TOF MS ES+ 3.35 ꢂ 107) m/z calcd for 143.0, 144.5, 157.1, 178.2, 210.4. DEPT135: d 21.5, 34.6, 40.1,
C
30H26BrN5O5 + H+ [M + H]+ 584.1297 found 584.1271.
45.7, 49.2, 52.8, 59.9, 62.4, 106.7, 112.5, 121.1, 122.3, 126.4,
Spiropyrrolidine-oxindole graed macrocycle 12b. Yield: 75%; 127.3, 128.4, 128.7, 129.0, 133.2. HRMS (TOF MS ES+ 9.22 ꢂ 108)
white solid; mp; 146–148 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.14 m/z calcd for C31H29N5O3 + H2 [M + 2]+ 521.2427 found
(S, 3H); 3.38 (t, J ¼ 7.8 Hz, 1H); 3.57–3.61 (m, 1H); 3.92 (t, J ¼ 521.2437.
7.5 Hz, 1H); 4.45–4.53 (m, 1H); 4.57–4.72 (m, 2H); 4.81–4.91 (m,
Spiropyrrolidine-oxindole graed macrocycle 12f. Yield: 65%;
1H); 5.10, (d, J ¼ 10.5 Hz, 1H); 5.22 (d, J ¼ 6.6 Hz, 1H); 5.38 (d, J white solid; mp; 196–198 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.11
¼ 10.5 Hz, 1H); 6.58 (d, J ¼ 7.8 Hz, 1H); 6.77 (t, J ¼ 7.5 Hz, 1H); (s, 3H); 3.14 (s, 3H); 3.38–3.52 (m, 1H); 3.52–3.61 (m, 1H); 3.75–
6.87–6.93 (m, 2H); 6.96–7.04 (m, 2H); 7.13 (d, J ¼ 8.4 Hz, 2H); 3.88 (m, 1H); 4.01–4.11 (m, 1H); 4.20–4.29 (m, 1H); 4.76–4.80
7.21–7.26 (m, 4H); 8.13 (s, 1H). 13C NMR (75 MHz,CDCl3): d 34.5, (m, 1H); 4.89 (d, J ¼ 10.5, Hz, 1H); 5.45–5.53 (m, 3H); 6.57–6.63
39.5, 44.8, 48.7, 52.1, 60.1, 62.3, 73.8, 107.0, 112.6, 121.1, 122.8, (m, 2H); 6.69 (d, J ¼ 8.4 Hz, 1H); 6.78 (s, 1H); 6.89–6.94 (m, 1H);
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7.02 (d, J ¼ 7.8 Hz, 1H); 7.14–7.19 (m, 2H); 7.21–7.24 (m, 3H); 7.47 (d, J ¼ 6.9 Hz, 2H); 9.85 (s, 2H). 13C NMR (75 MHz, CDCl3):
7.24–7.28 (m, 1H); 7.31–7.33 (m, 2H). 13C NMR (75 MHz, CDCl3): d 28.4, 32.6, 40.0, 46.6, 47.4, 53.3, 61.6, 64.3, 67.8, 74.1, 108.6,
d 34.3, 40.8, 47.8, 50.0, 56.4, 58.9, 59.3, 63.3, 73.3, 106.4, 112.0, 112.5, 121.7, 122.8, 124.9, 125.4, 126.3, 127.3, 127.6, 128.8,
112.7, 121.1, 121.2, 123.1, 126.0, 126.4, 126.5, 126.8, 127.1, 129.3, 129.9, 131.1, 133.5, 136.4, 141.9, 145.2, 156.8, 179.2,
128.3, 128.4, 129.1, 131.2, 133.2, 134.1, 143.8, 144.7, 156.2, 196.8. DEPT135: d 28.4, 32.6, 40.0, 46.6, 47.4, 53.3, 61.6, 64.2,
158.4, 178.0, 205.2. DEPT135: d 34.3, 40.8, 47.7, 50.0, 56.4, 58.9, 67.8, 108.7, 112.5, 121.7, 122.9, 125.4, 127.3, 128.8, 129.3, 129.9,
59.3, 63.3, 106.4, 112.0, 112.7, 121.1, 121.2, 123.1, 126.0, 126.3, 131.1, 133.5. HRMS (TOF MS ES+ 2.29 ꢂ 108) m/z calcd for
128.3, 128.4, 129.1, 131.2, 133.2.
C
64H56Br2N10O6 + H+ [M + H]+ 1219.2829 found 1219.2828.
Spiropyrrolidine-oxindole graed macrocycle 12g. Yield: 72%;
Bis-spiropyrrolizidine-oxindole graed macrocycle 16b. Yield:
1
1
white solid; mp; 228–230 ꢁC. H NMR (300 MHz, CDCl3): d 2.14 65%; white solid; mp; 236–238 C. H NMR (300 MHz, CDCl3):
(s, 3H); 3.41 (t, J ¼ 8.1 Hz, 1H); 3.58–3.62 (m, 1H); 3.88–3.95 (m, d 1.68–1.78 (m, 4H); 1.90–2.0 (m, 4H); 2.43–2.5 (m, 2H); 2.67–
1H); 4.52–4.55 (m, 1H); 4.75–4.83 (m, 3H); 5.12 (d, J ¼ 10.5 Hz, 2.69 (m, 2H); 3.79–3.85 (m, 2H); 3.87–3.97 (m, 4H); 4.35–4.44
1H); 5.19 (d, J ¼ 6.6 Hz, 1H); 5.35 (d, J ¼ 10.5 Hz, 1H); 6.57 (d, J ¼ (m, 2H); 4.47–4.58 (m, 2H); 4.62–4.67 (m, 2H); 5.24, 5.49 (AB q, J
7.8 Hz, 1H); 6.74 (t, J ¼ 7.5 Hz, 1H); 6.85–6.87 (m, 1H); 6.91–6.97 ¼ 11.7 Hz, 4H); 5.60 (d, J ¼ 11.7 Hz, 2H); 6.58 (d, J ¼ 7.8 Hz, 2H);
(m, 3H); 7.01–7.26 (m, 2H); 7.35 (d, J ¼ 8.4 Hz, 2H); 8.10 (d, J ¼ 6.94–7.01 (m, 4H); 7.05–7.09 (m, 8H); 7.14 (t, J ¼ 7.8 Hz, 2H);
8.4 Hz, 2H); 8.22 (s, 1H). 13C NMR (75 MHz, CDCl3): d 34.4, 39.2, 7.26–7.30 (m, 4H); 7.31–7.35 (m, 2H); 7.47 (d, J ¼ 7.5 Hz, 2H);
44.3, 48.3, 52.1, 60.2, 62.3, 73.8, 107.2, 112.7, 121.2, 122.9, 123.2, 9.85 (s, 2H). 13C NMR (75 MHz, CDCl3): d 28.4, 31.6, 32.6, 40.0,
125.2, 125.9, 126.7, 126.8, 128.4, 129.2, 129.5, 133.0, 142.9, 46.6, 47.4, 53.3, 61.7, 64.3, 67.8, 74.1, 108.6, 112.5, 121.7, 122.8,
144.3, 149.6, 157.0, 178.1, 198.7 ppm. DEPT135: d 34.4, 39.2, 125.0, 125.4, 126.3, 127.3, 128.1, 128.8, 129.2, 129.9, 133.5,
44.3, 48.3, 52.1, 60.2, 62.3, 107.2, 112.7, 121.14, 122.8, 135.9, 138.9, 141.9, 145.2, 156.8, 179.3, 196.6. DEPT135: d 28.4,
123.2.126.7, 126.8, 128.4, 129.2, 129.5, 133.0. HRMS (TOF MS 31.6, 32.6, 40.0, 46.6, 47.4, 53.3, 61.7, 64.3, 67.8, 108.6, 112.5,
ES+ 4.14 ꢂ 107) m/z calcd for C30H26N6O5 + H2 [M + 2]+ 552.2122 121.7, 122.9, 125.4, 127.3, 128.2, 128.8, 129.2, 129.9, 133.5.
ꢁ
found 552.2100.
HRMS (TOF MS ES+ 4.22 ꢂ 108) m/z calcd for C64H56Cl2N10O6 +
Spiropyrrolidine-oxindole graed macrocycle 12h. Yield: 73%; H+ [M + H]+ 1131.3838 found 1131.3840.
white solid; mp; 216–218 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.14
Bis-spiropyrrolizidine-oxindole graed macrocycle 16c. Yield:
1
ꢁ
(s, 3H); 3.34 (t, J ¼ 8.1 Hz, 1H); 3.52–3.56 (m, 1H); 3.90–3.96 (m, 58%; white solid; mp; 270–272 C. H NMR (300 MHz, CDCl3):
1H); 4.39–4.50 (m, 3H); 4.87–4.91 (m, 1H); 5.09, (d, J ¼ 10.5 Hz, d 1.61–1.75 (m, 4H); 1.79–1.90 (m, 4H); 2.50 (t, J ¼ 6.3 Hz, 4H);
1H); 5.38 (d; J ¼ 7.2 Hz, 1H); 5.43 (d, J ¼ 10.5 Hz, 1H); 6.54 (d, J ¼ 3.54 (s, 6H); 3.74 (s, 6H); 3.79–3.83 (m, 4H); 4.17–4.27 (m, 2H);
7.8 Hz, 1H); 6.82–6.91 (m, 2H); 6.98–7.05 (m, 3H); 7.15 (d, J ¼ 4.33–4.44 (m, 4H); 4.46–4.52 (m, 2H); 5.21, 5.35 (AB q, J ¼ 12 Hz,
7.2 Hz, 2H); 7.20–7.26 (m, 4H); 7.29–7.34 (m, 1H); 7.94 (s, 1H). 4H); 5.67 (d, J ¼ 11.7 Hz, 2H); 6.58 (d, J ¼ 7.2 Hz, 2H); 6.71–6.72
13C NMR (70 MHz, CDCl3): d 34.5, 40.1, 45.6, 49.2, 53.2, 59.9, (m, 2H); 6.80 (d, J ¼ 7.8 Hz, 2H); 6.86–6.89 (m, 2H); 6.93 (d, J ¼
62.4, 73.8, 106.7, 112.6, 121.6, 122.8, 125.9, 126.2, 126.4, 127.2, 7.5 Hz, 4H); 7.09 (t, J ¼ 7.5 Hz, 2H); 7.19–7.24 (m, 4H); 7.33 (d, J
127.5, 128.0, 128.4, 129.1, 132.1, 133.1, 138.9, 143.0, 144.5, ¼ 7.2 Hz, 2H); 7.40–7.43 (m, 2H); 9.65 (s, 2H). 13C NMR (75 MHz,
157.1, 178.2, 200.9. DEPT135: d 34.5, 40.1, 45.6, 49.2, 53.2, 59.8, CDCl3): d 27.6, 31.6, 39.2, 45.6, 48.1, 54.5, 55.5, 56.1, 60.1, 63.8,
62.4, 106.7, 112.5, 121.1, 122.8, 126.4, 127.2, 127.4, 128.0, 128.4, 67.5, 74.2, 108.3, 109.8, 110.4, 111.8, 121.7, 121.9, 122.8, 124.7,
129.1, 132.2, 133.2. HRMS (TOF MS ES+ 3.97 ꢂ 107) m/z calcd for 125.3, 126.0, 127.6, 128.7, 129.7, 130.5, 133.8, 141.5, 144.8,
C
30H27N5O3 + H2 [M + 2]+ 507.2270 found 507.2260.
148.4, 153.1, 156.7, 179.4, 195.7. DEPT135: 27.6, 31.6, 39.2, 45.6,
Spiropyrrolidine-oxindole graed macrocycle 12i. Yield: 70%; 48.2, 54.4, 55.5, 56.1, 60.2, 63.8, 67.5, 108.3, 109.7, 110.4, 111.8,
white solid; mp; 238–240 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.14 121.7, 121.9, 122.8, 124.7, 127.6, 128.7, 129.7, 133.8. HRMS (TOF
(s, 3H); 3.33 (t, J ¼ 8.1 Hz, 1H); 3.58–3.71 (m, 1H); 3.92–3.98 (m, MS ES+ 5.86 ꢂ 107) m/z calcd for C68H66N10O10 + H+ [M + H]+
1H); 4.45–4.51 (m, 1H); 4.56–4.62 (m, 1H); 4.85–4.95 (m, 1H); 1183.5041 found 1183.5045.
4.99 (d, J ¼ 6.6 Hz, 1H); 5.11 (d, J ¼ 10.5 Hz, 1H); 5.40 (d, J ¼
Bis-spiropyrrolizidine-oxindole graed macrocycle 16d. Yield:
1
ꢁ
10.5 Hz, 1H); 6.61 (d, J ¼ 7.5 Hz, 1H); 6.81 (t, J ¼ 7.5 Hz, 1H); 60%. White solid; mp 250–252 C. H NMR (300 MHz, CDCl3):
6.86–6.89 (m, 1H); 6.92–6.98 (m, 1H); 7.00–7.21 (m, 2H); 7.21– d 1.73–1.83 (m, 4H); 1.86–1.98 (m, 4H); 2.59 (t, J ¼ 6.3 Hz, 4H);
7.26 (m, 4H); 7.40 (d, J ¼ 4.8 Hz, 1H) 8.23 (s, 1H). 13C NMR (75 3.73 (s, 6H); 3.74–3.76 (m, 2H); 3.86 (t, J ¼ 8.1 Hz, 2H); 4.39–4.48
MHz,CDCl3): d 34.6, 40.1, 44.9, 49.0, 54.7, 62.2, 73.9, 106.8, (m, 4H); 4.54–4.60 (m, 4H); 5.33, 5.42 (ABq J ¼ 11.7 Hz, 4H); 5.75
112.5, 121.1, 122.8, 126.8, 127.1, 127.9, 128.4, 129.4, 132.3, (d, J ¼ 12 Hz, 2H); 6.67 (d, J ¼ 8.7 Hz, 4H); 6.89 (d, J ¼ 7.5 Hz,
133.0, 133.1, 142.6, 144.8, 157.0, 178.2, 199.3. DEPT 135: d 34.6, 2H); 6.98–7.02 (m, 4H); 7.17–7.23 (m, 6H); 7.28–7.35 (m, 4H);
44.9, 49.0, 54.7, 59.7, 62.2, 106.8, 112.5, 121.1, 121.5, 122.8, 7.41 (d, J ¼ 7.5 Hz, 2H); 7.49–7.52 (m, 2H); 9.73 (s, 2H). 13C NMR
126.8, 127.1, 127.9, 128.4, 129.2, 132.3, 133.1, 133.3.
(75 MHz, CDCl3): 27.7, 29.7, 31.6, 39.4, 45.6, 48.2, 54.3, 55.4,
Bis-spiropyrrolizidine-oxindole graed macrocycle 16a. Yield: 60.4, 63.7, 67.6, 74.3, 108.4, 111.7, 113.1, 121.7, 122.8, 124.6,
1
ꢁ
64%; white solid; mp; 220–222 C. H NMR (300 MHz, CDCl3): 125.3, 126.0, 127.5, 128.6, 129.8, 130.1, 130.4, 133.8, 141.4,
d 1.63–1.77 (m, 4H); 1.79–1.94 (m, 4H); 2.43–2.65 (m, 4H); 3.77– 145.0, 156.6, 163.4, 179.2, 195.7. DEPT135: d 27.7, 29.7, 31.6,
3.83 (m, 2H); 3.86–3.97 (m, 4H); 4.38–4.40 (m, 2H); 4.41–4.53 39.4, 45.6, 48.2, 54.3, 55.4, 60.4, 63.7, 67.6, 108.4, 111.7, 113.1,
(m, 2H); 4.59–4.67 (m, 2H); 5.24, 5.49 (ABq, J ¼ 11.7 Hz, 4H); 5.60 121.7, 122.8, 124.6, 127.5, 128.6, 129.8, 130.1, 133.8. HRMS (TOF
(d; J ¼ 11.7 Hz, 2H); 6.79 (d, J ¼ 7.5 Hz, 2H); 6.95–7.02 (m, 8H); MS ES+ 1.24 ꢂ 109) m/z calcd for C66H62N10O8 + H+ [M + H]+
7.14 (t, J ¼ 7.5 Hz, 2H); 7.23–7.25 (m, 8H); 7.32–7.35 (m, 2H); 1123.4830 found 1123.4847.
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Bis-spiropyrrolizidine-oxindole graed macrocycle 16e. Yield
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48.2, 54.1, 60.9, 63.7, 67.7, 74.1, 108.5, 111.8, 121.7, 122.9, 124.7,
125.1, 125.9, 127.3, 127.7, 127.8, 127.9, 128.7, 129.9, 132.6,
133.8, 137.7, 141.5, 144.9, 156.6, 178.9, 197.9. DEPT135: d 27.6,
31.5, 39.4, 45.6, 48.2, 54.1, 60.9, 63.7, 67.7, 108.5, 111.8, 121.7,
122.9, 124.6, 127.3, 127.7, 127.8, 127.9, 128.7, 129.9, 132.6,
133.8. HRMS (TOF MS ES+ 4.89 ꢂ 107) m/z calcd for C29H27N5O5
+ H+ [M + H ]+ 1063.4619 found 1063.4640.
Bis-spiropyrrolizidine-oxindole graed macrocycle 16i. Yield:
56%; white solid; mp; 202–204 ꢁC. 1H NMR (300 MHz, CDCl3):
d 1.67–1.83 (m, 4H); 1.81–2.04 (m, 4H); 2.61 (t, J ¼ 6 Hz, 4H);
3.84–3.93 (m, 4H); 4.49–4.65 (m, 8H); 5.27, 5.39 (AB q, J ¼
11.7 Hz, 4H); 5.62 (d, J ¼ 12 Hz, 2H); 6.84 (t, J ¼ 7.8 Hz, 2H); 6.97
(t, J ¼ 7.5 Hz, 6H); 7.18 (t, J ¼ 7.5 Hz, 2H); 7.25–7.36 (m, 8H);
7.40–7.45 (m, 4H); 9.70 (s, 2H). 13C NMR (75 MHz, CDCl3):
d 27.8, 31.7, 39.8, 45.8, 48.1, 54.3, 61.9, 63.9, 67.7, 74.8, 108.6,
111.9, 121.8, 123.1, 124.7, 125.3, 125.8, 127.0, 127.7, 128.8,
130.0, 131.5, 133.9, 134.2, 141.5, 144.6, 145.1, 156.8, 179.5,
188.7. DEPT135: d 27.8, 31.7, 39.8, 45.8, 48.1, 54.3, 61.9, 63.9,
67.7, 108.6, 111.9, 121.8, 123.1, 124.7, 127.0, 127.8, 128.8, 130.0,
131.5, 133.8, 134.2.
1
ꢁ
56%. White Solid. Mp 238–240 C. H NMR (300 MHz, CDCl3):
d 1.69–1.75 (m, 4H); 1.92–1.94 (m, 4H); 2.22 (s, 6H); 2.49 (t, J ¼
3 Hz, 2H); 2.62 (t, J ¼ 2.4 Hz, 2H); 3.72–3.80 (m, 2H); 3.90–3.97
(m, 4H); 4.26–4.33 (m, 2H); 4.52–4.57 (m, 4H); 5.25, 5.49 (ABq, J
¼ 11.7 Hz, 4H); 5.67 (d, J ¼ 11.4 Hz, 2H); 6.76 (d, J ¼ 7.8 Hz, 2H);
6.90–6.97 (m, 4H); 6.99–7.02 (m, 4H); 7.01–7.10 (m, 4H); 7.13–
7.16 (m, 2H); 7.25–7.30 (m, 4H); 7.34–7.36 (m, 2H); 7.49 (d, J ¼
7.2 Hz, 2H); 9.87 (s, 2H). 13C NMR (70 MHz, CDCl3): d 21.5, 28.1,
32.4, 40.2, 46.4, 47.6, 53.6, 61.3, 64.1, 67.7, 74.1, 108.5, 112.3,
121.7, 122.7, 125.2, 125.3, 126.5, 127.3, 127.8, 128.6, 128.7,
129.7, 133.7, 135.2, 141.9, 143.4, 152.3, 156.8, 179.4, 197.3.
DEPT135: 21.5, 28.1, 32.4, 40.2, 46.4, 47.6, 53.6, 61.3, 64.1, 67.7,
108.5, 112.3, 121.7, 122.7, 125.3, 127.3, 127.8, 128.5, 128.6,
128.7, 129.7, 133.7. HRMS (TOF MS ES+ 1.21 ꢂ 109) m/z calcd for
C
66H62N10O6 + H+ [M + H]+ 1091.4932 found 1091.4944.
Bis-spiropyrrolizidine-oxindole graed macrocycle 16f. Yield:
55%; white solid; mp; 228–230 ꢁC. 1H NMR (300 MHz, CDCl3):
d 1.58–1.75 (m, 4H); 1.71–1.94 (m, 4H); 2.32–2.40 (m, 2H); 2.50–
2.55 (m, 2H); 3.33 (s, 6H); 3.44–3.53 (m, 2H); 3.78–3.89 (m, 4H);
4.21–4.28 (m, 2H); 4.41–4.51 (m, 4H); 5.27, 5.47 (ABq, J ¼
12.0 Hz, 4H); 5.93 (d, J ¼ 11.7 Hz, 2H); 6.14 (d, J ¼ 6.6 Hz, 2H);
6.52–6.57 (m, 4H); 6.84 (d, J ¼ 7.8 Hz, 2H); 6.96 (t, J ¼ 7.2 Hz,
2H); 7.02 (d, J ¼ 8.4 Hz, 2H); 7.12–7.16 (m, 4H); 7.28 (d, J ¼
9.3 Hz, 2H); 7.35 (d, J ¼ 7.8 Hz, 4H); 7.49 (d, J ¼ 7.2 Hz, 2H); 9.81
(s, 2H). 13C NMR (75 MHz, CDCl3): d 28.1, 32.5, 40.1, 46.7, 47.2,
53.0, 55.3, 64.0, 64.2, 67.8, 73.6, 108.5, 110.8, 112.0, 119.8, 121.5,
122.6, 125.7, 127.0, 127.2, 128.5, 128.9, 129.1, 129.7, 132.2,
133.7, 142.7, 145.1, 156.8, 157.5, 178.8, 199.6 ppm. DEPT135:
d 28.1, 32.4, 40.1, 46.7, 47.2, 53.0, 55.3, 64.0, 64.2, 67.8, 108.4,
110.8, 112.0, 119.8, 121.5, 122.6, 125.7, 127.2, 128.5, 128.9,
129.7, 132.2, 133.7.
Conflicts of interest
The authors have no conicts of interest.
Acknowledgements
The authors thank DST-FIST for providing NMR and HRMS
facility to the Department of Organic Chemistry, University of
Madras, Chennai, India, and the authors also thank SAIF, IIT
Madras for single crystal XRD analysis. PP thanks Council of
Scientic and Industrial Research (CSIR) New Delhi, India for
SRF (grant number: 09/115(0775)/2014 EMR-I).
Bis-spiropyrrolizidine-oxindole graed macrocycle 16g. Yield:
62%; white solid; mp; 196–198 ꢁC. 1H NMR (300 MHz, CDCl3):
d 1.69–1.81 (m, 4H); 1.94–2.01 (m, 4H); 2.45–2.53 (m, 2H); 2.65–
2.72 (m, 2H); 3.64–3.77 (m, 4H); 3.92–3.97 (m, 2H); 4.39–4.55
(m, 4H); 4.61–4.71 (m, 2H); 5.22, 5.50 (ABq, J ¼ 12 Hz, 4H); 5.63
(d, J ¼ 11.7 Hz, 2H); 6.76 (d, J ¼ 7.8 Hz, 2H); 6.95–7.02 (m, 4H);
7.16 (t, J ¼ 7.5 Hz, 2H); 7.25–7.31 (m, 8H); 7.33–7.35 (m, 2H);
7.46–7.49 (m, 2H); 7.94 (d, J ¼ 8.7 Hz, 4H); 9.81 (s, 2H). 13C NMR
(75 MHz, CDCl3): d 28.4, 29.7, 32.8, 39.8, 46.7, 47.3, 53.2, 62.2,
64.4, 67.8, 73.9, 108.7, 112.6, 121.8, 122.9, 123.1, 124.8, 125.5,
126.0, 127.3, 128.8, 129.0, 130.2, 133.5, 141.8, 142.2, 145.1,
149.8, 156.8, 179.1, 196.5. DEPT135: d 28.4, 29.7, 32.8, 39.8, 46.7,
47.3, 53.2, 62.3, 64.4, 67.8, 108.7, 112.6, 121.8, 122.9, 123.1,
125.5, 127.3, 128.8, 129.1, 130.2, 133.5. HRMS (TOF MS ES+ 9.19
ꢂ 108) m/z calcd for C64H56N12O10 + H+ [M + H ]+ 1153.4320
found 1153.4332.
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