Novel one pot regioselective multicomponent synthesis of highly functionlaized spiro pyrrolidines through 1,3-dipolar cycloaddition approach

Article abstract of DOI:10.1080/00397911.2011.621098

One-pot multicomponent synthesis of novel highly functionalized spiro pyrrolidine oxindoles has been accomplished in good yields through 1,3-dipolar cycloaddition reaction of azomethine ylide derived from sarcosine and oxindole with various benzimdazole s

Full text of DOI:10.1080/00397911.2011.621098

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Novel One Pot Regioselective
Multicomponent Synthesis of Highly
Functionlaized Spiro Pyrrolidines
Through 1,3-Dipolar Cycloaddition
Approach
Subban Kathiravan a & Raghavachary Raghunathan a
a Department of Organic Chemistry, University of Madras, Guindy
Campus, Chennai, India
Accepted author version posted online: 27 Feb 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Subban Kathiravan & Raghavachary Raghunathan (2013): Novel One Pot
Regioselective Multicomponent Synthesis of Highly Functionlaized Spiro Pyrrolidines Through 1,3-
Dipolar Cycloaddition Approach, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:7, 1041-1054
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Synthetic Communications1, 43: 1041–1054, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.621098
NOVEL ONE POT REGIOSELECTIVE
MULTICOMPONENT SYNTHESIS OF HIGHLY
FUNCTIONLAIZED SPIRO PYRROLIDINES THROUGH
1,3-DIPOLAR CYCLOADDITION APPROACH
Subban Kathiravan and Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai, India
GRAPHICAL ABSTRACT
Abstract One-pot multicomponent synthesis of novel highly functionalized spiro pyrrolidine
oxindoles has been accomplished in good yields through 1,3-dipolar cycloaddition reaction
of azomethine ylide derived from sarcosine and oxindole with various benzimdazole substi-
tuted Baylis–Hillman derivatives. The regiochemical and stereochemical outcome of the
multicomponent cycloaddition reaction is ascertained by spectroscopic studies, and one of
the products was characterized through x-ray crystallographic analysis.
Keywords Baylis–Hillman; benzimidazole; cycloaddition; imidazole; spirooxindoles
INTRODUCTION
Multicomponent reactions (MCRs) have attracted much attention because of
their convergence, ease of execution, and good yields of products.[1] Over the past dec-
ade, greater efforts have been made to develop new MCRs, which has led to tremen-
dous advances in generating libraries of molecules for the discovery of biologically
active lead compounds and also for the optimization of potent drug candidates.[2]
Oxindole derivatives have drawn considerable attention because of their abun-
dance in numerous natural products as well as their extensive applications in biology
and pharmacology.[3] A great number of compounds that carry oxindole moieties are
reported to possess significant antibacterial, antiprotozoal, anti-inflammatory, and
antitumor properties,[4] and they have been widely employed as potential synthons
for the synthesis of alkaloids and clinical pharmaceuticals (Fig. 1).[5] In particular,
Received May 20, 2011.
Address correspondence to Raghavachary Raghunathan, Department of Organic Chemistry,
University of Madras, Guindy Campus, Chennai 600 025, India. E-mail: ragharaghunathan@yahoo.com
1041

1042
S. KATHIRAVAN AND R. RAGHUNATHAN
Figure 1. Some typical oxindole derivatives.
compounds containing the spirooxindole ring systems have been reported to behave
as aldose reductase, poliovirus, and rhinovirus 3C-proteinase inhibitors,[6] so great
efforts have been devoted to the expeditious synthesis of these structural frameworks.
The Baylis–Hillman reaction is well known as one of the powerful carbon–
carbon bond-forming methods in organic synthesis.[7] The adducts of the reactions,
3-hydroxy-2-methylidene-alkanoates (derived from acrylate esters), have been uti-
lized as important precursors for stereoselective synthesis of different multifunctional
molecules.[8] Among these transformations, the employment of corresponding
Baylis–Hillman halides was quite limited except for their use in the synthesis of a-
methyledene-c-butryolactone, a-alkyledene-b-lactam, and flavanoids.[9]
Intermolecular [3 þ 2] cycloaddition of azomethine ylides with various dipolar-
ophiles have been used in an efficient and convenient protocol for the construction of
highly substituted five-membered pyrrolidine units that possess significant biological
Figure 2. ORTEP diagram of 17. (Figure is provided in color online.)

SYNTHESIS OF SPIRO PYRROLIDINES
1043
activities.[10–12] However, to the best of our knowledge, there is no report available
for the synthesis of highly biologically active spiropyrrolidines having an imidazole
and benzimidazole moiety attached to the pyrrolidine ring.
Imidazole, benzimidazole moiety, is usually found in numerous natural products
and biologically active pharmaceuticals.[13] For example, a number of N-substituted
imidazole derivatives, such as miconazole, ketoconazole, genaconazole, and bifonazole,
have become well-established drugs for the treatment of many mycotic infections.[14]
In continuation of our studies in the area of cycloaddition reactions,[15] and with
a view to synthesize a rare class of novel imidazole-grafted spiroheterocyclic deriva-
tives, we herein report for the first time reaction of N-substituted imidazole derivatives
by multicomponent 1,3-dipolar cycloaddition reaction for the synthesis of hitherto
unknown imidazole-containing spirooxindalopyrrolidines.
The N-substituted imidazole-containing spirooxindalo pyrrolidine derivatives
were prepared by treating Baylis–Hillman bromide 2 with imidazole 1 in the presence
of triethyl amine to give the corresponding N-substituted imidazoles 5 a–e in excel-
lent yields [formed in situ], which when reacted with azomethine ylide generated by
the decarboxylative condensation of oxindole 3 with secondary amino acid sarcosine
4 in refluxing methanol gave novel 3-spiropyrrolidine oxindoles (7–11) (Scheme 1,
Table 1) in good yields. The synthesis proceeded through a straightforward route
and gave the anticipated products both regioselectively and stereoselectively in mod-
erate to good yields.
The formation of the cycloadducts was confirmed by spectral and elemental
analysis. The infrared(IR) spectrum of 10 exhibited peaks at 1727.5 and 1619.3 cmꢀ1
due to ester carbonyl and oxindole carbonyl groups. In the 1H NMR spectrum of 10
the –NCH3 protons of the pyrrolidine ring exhibited a singlet at d 2.13. The ester
methyl group appeared as a singlet at d 3.36. The –NCH2 protons of the pyrrolidine
ring appeared as doublet of doublet at d 3.36 and 3.80. The pyrrolidine ring proton
attached to aryl unit appeared as a triplet at d 4.67. The imidazole protons exhibited
a multiplets at d 5.99–6.6.80. The aromatic protons exhibited multiplets in the range
Scheme 1. Synthesis of functionalized spirooxindolo pyrrolidines.

1044

1045

1046
S. KATHIRAVAN AND R. RAGHUNATHAN
Table 2. Conditions for regioselective cycloaddtion reaction for the synthesis of 7
Temperature
(ꢁC)a
Time
(h)
Yield
(%)b
Entry
Solvent
1
2
3
4
5
6
THF
H2O
Dioxane
70
100
80
12
10
12
11
10
8
20
5
29
35
52
88
CH3CN
Methanol–dioxane
Methanol
70
85
70
aGradually raised when the reaction was conducted.
bIsolated yield after column chromatography.
d 7.01–7.52. The –NH proton of the oxindole ring appeared as a singlet at d 9.99. The
off-resonance decoupled 13C NMR spectra of 8 exhibited peaks for the –NCH3 and –
OCH3 at d 21.1 and 58.3 ppm. The spiro carbon exhibited a peak at d 77.83. The oxin-
dole carbonyl and ester carbonyl resonated at d 176.6 and 172.6 ppm. These observed
chemical shift values confirmed the proposed structure of 10. The formation of the pro-
duct was also confirmed by mass spectral and elemental analysis. The mass spectrum of
10 showed a peak at m=z 430.12 (Mþ). The reactions were found to be highly regiose-
lective, leading to the formation of only one product 10, and the formation of other
possible regioisomer was not observed.
With the optimal conditions in hand, we investigated the generality of the reac-
tion with various substitutents in the substrates (Table 1). In the multicomponent
1,3-dipolar cycloaddition, a wide range of substrates were tolerated, and the yields
were good in all cases (Table 1).
We have tried the reaction with various solvents at different temperatures
(Table 2), and it was observed that methanol was the best suited solvent to give good
yield of the products at an optimum temperature of 80 ꢁC.
Scheme 2. Synthesis of functionalized spirooxindolo pyrrolidines.

1047

1048

SYNTHESIS OF SPIRO PYRROLIDINES
1049
In the next step, synthesis of N-substituted benzimidazole containing spiro oxi-
ndalo pyrrolidines 14–18 was accomplished in good yield (70–86%) by the reaction of
benzimidazole-derived dipolarophiles 13a–e with oxindole 3 and sarcosine 4 in reflux-
ing methanol. The formation of the cycloadducts was evidenced by the spectral and
elemental analysis and also by x-ray crystallographic analysis.[16] (Scheme 2, Table 3).
CONCLUSION
In conclusion, we have synthesized successfully a series of hitherto unknown
novel imidazole- and benzimidazole-attached spirooxindalo pyrrolidines by employing
multicomponent 1,3-dipolar-cycloaddition reactions of azomethine ylides. These spiro
heterocycles could serve as novel and potential candidates for biological screening.
EXPERIMENTAL
All melting points are uncorrected. Infrared (IR) spectra were recorded on a
Shimadzu Fouier transform FT–(IR) 8300 instrument. Mass spectra were recorded
1
on a Jeol DX 303 HF spectrometer with Maspec System (msw=9629). H and 13C
NMR were recorded in CDCl3 using tetramethylsilane (TMS) as internal standard
on a Bruker spectrometer at 300 and 75 MHz, respectively. Elemental analyses were
carried out on a Perkin-Elmer 2400 B instrument.
General Procedure for Synthesis of Cycloadducts
A mixture of imidazole 1 (2.5 equiv) and Baylis–Hillman bromide 2 (1 equiv) was
first stirred for 10min in the presence of triethyl amine (1.1 equiv) as base to
form (E)-methyl-2-[(1H-imidazol-1-yl)methyl]-3-phenylacrylate 5a–g (formed in situ),
followed by the addition of oxindole 3 (1 equiv), and amino acid 4 (1 equiv) and the
stirring was continued in refluxing methanol until the completion of reaction as
evidenced by thin-layer chromatography (TLC) analysis. The solvent was removed
under reduced pressure, and the crude product was subjected to column chromato-
graphy using chloroform–methanol (99:1) as eluent. The product was then recrystal-
lized from methanol.
1N-Methyl-3-((1H-imidazol-1-yl)methyl)-1-methyl-4-phenyl-2-
oxindolepyrrolidine-3-carboxylate 7
1
Colorless solid, yield 88%, mp: 34 ꢁC, H NMR (300 MHz, CDCl3): d 1.95 (s,
3H), 1.95 (s, 3H), 2.03 (s, 2H), 3.29 (s, 2H), 3.39 (t, J ¼ 9.6 Hz, 1H), 3.74 (t, J ¼ 8.5 Hz,
Hz, 1H), 4.61–4.72 (m, 1H), 6.55 (s, 1H), 6.76–6.81 (m, 1H), 6.90–6.95 (m, 1H),
7.07–7.47 (m, 5H), 7.47 (d, J ¼ 6.3 Hz, 2H), 8.21 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 34.1, 46.4, 46.9, 51.2, 57.1, 63.4, 66.5, 76.2, 109.5, 119.4, 121.4, 124.6, 124.8, 125.8,
126.9, 127.9, 128.9, 129.1, 136.6, 140.8, 171.3, 175.6; m=z 416.26 [Mþ]. Anal. calc. for
C24H24N4O3: C, 69.23; H, 5.76; N, 13.46. Found: C, 69.35; H, 5.69; N, 13.56%.

1050
S. KATHIRAVAN AND R. RAGHUNATHAN
1N-Methyl-3-((1H-imidazol-1-yl)methyl)-1-methyl-4-(4-
chlorophenyl)-2-oxindolepyrrolidine-3-carboxylate 8
1
Colorless solid, yield 86%, mp: 36 ꢁC; H NMR (300 MHz, CDCl3): d 2.09 (s,
3H), 3.24 (s, 3H), 3.48 (t, J ¼ 9.4 Hz, 1H), 3.59 (t, J ¼ 8.1 Hz, 1H), 4.48 (d, J ¼ 14.7 Hz,
Hz, 1H), 4.62 (t, J ¼ 7.6 Hz, 1H), 4.75 (d, J ¼ 14.7 Hz, 1H), 5.99 (s, 1H); 6.42 (s, 1H);
6.56 (s, 1H), 6.88 (d, J ¼ 7.6 Hz, 1H), 6.99–7.55 (m, 7H), 10.60 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 34.7, 45.8, 46.0, 51.4, 58.6, 64.1, 76.1, 109.8, 119.1, 121.2,
125.0, 125.6, 127.2, 128.0, 129.2, 131.0, 132.4, 137.1, 137.7, 141.8, 171.5, 175.6; m=z
450.12 [Mþ]. Anal. calc. for C24H23N4O3Cl: C, 64.01; H, 5.11; N, 12.44. Found: C,
64.15; H, 5.05; N, 12.59%.
1N-Methyl-3-((1H-imidazol-1-yl)methyl)-1-methyl-4-(4-
bromophenyl)-2-oxindolepyrrolidine-3-carboxylate 9
1
Colorless solid, yield 78%, mp: 34 ꢁC; H NMR (300 MHz, CDCl3): d 2.12 (s,
3H), 3.40 (s, 3H), 3.50 (t, J ¼ 9.1 Hz, 1H), 3.72 (t, J ¼ 8.4 Hz, 1H), 4.30 (d, J ¼ 14.7 Hz,
Hz, 1H), 4.60 (s, 1H), 4.63 (d, J ¼ 5.7 Hz, 1H), 6.61 (s, 1H), 6.76–6.80 (m, 1H),
7.01–7.06 (m, 1H), 7.20–7.26 (m, 4H), 7.44–7.46 (m, 4H), 8.58 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 35.1, 47.3, 47.8, 52.3, 58.6, 64.6, 76.6, 110.1, 119.8, 121.7,
122.5, 125.7, 126.2, 127.7, 129.8, 130.2, 131.7, 131.8, 137.1, 138.9, 141.4, 172.8,
176.1. Mass spectrum m=z: 495.2 (Mþ); CHN anal calc. for C24H23N4O3Br: C,
58.18; H, 4.64; N, 11.31%. Found: C, 58.12; H, 4.61; N, 11.37%.
1N-Methyl-3-((1H-imidazol-1-yl)methyl)-1-methyl-4-(4-
methylphenyl)-2-oxindolepyrrolidine-3-carboxylate 10
1
Colorless solid, yield 85%, mp: 35 ꢁC; H NMR (300 MHz, CDCl3): d 2.13 (s,
3H), 2.36 (s, 3H), 3.36 (s, 3H), 3.46 (s, J ¼ 9.5 Hz, 1H), 3.84 (t, J ¼ 8.5 Hz, 1H),
4.36 (d, J ¼ 14.7 Hz, 1H), 4.70 (t, J ¼ 16.5 Hz, 1H), 4.81 (d, J ¼ 14.7 Hz, 1H), 6.56
(s, 1H); 6.66 (s, 1H), 6.80 (d, J ¼ 7.5 Hz, 1H), 7.01–7.04 (m, 1H), 7.16–7.27 (m,
4H), 7.49 (d, J ¼ 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 21.1, 35.2, 46.6, 48.0,
52.0, 58.3, 64.69, 77.83, 110.1, 120.1, 122.2, 125.8, 126.3, 127.4, 129.5, 129.6, 130.1,
134.7, 137.5, 139.3, 141.9, 172.6, 176.6; Mass spectrum m=z: 430.12 (Mþ). CHN anal.
calc. for C25H26N4O3: C, 69.76; H, 6.04; N, 13.02%; Found: C, 69.72; H, 5.99; N,
13.10%.
1N-Methyl-3-((1H-imidazol-1-yl)methyl)-1-methyl-4-(4-
methoxyphenyl)-2-oxindolepyrrolidine-3-carboxylate 11
1
Colorless solid, yield 73%, mp: 32 ꢁC; H NMR (300 MHz, CDCl3): d 2.05 (s,
3H), 2.27 (s, 3H), 3.27 (s, 3H), 3.74 (t, J ¼ 8.5 Hz, 1H), 4.27 (d, J ¼ 14.7 Hz, 1H),
4.62 (t, J ¼ 8.2 Hz, 1H), 4.74 (d, J ¼ 15.0 Hz, 1H), 5.91 (s, 1H), 6.52 (d, J ¼ 18.6 Hz,
1H), 6.72 (d, J ¼ 18.6 Hz, 1H), 6.93 (t, J ¼ 7.5 Hz, 1H), 7.08–7.44 (m, 8H), 10.15 (s,
1H); 13C NMR (75 MHz, CDCl3): d 21.0, 35.2, 46.6, 47.9, 51.9, 58.4, 64.8, 77.5,
109.9, 120.0, 122.4, 125.9, 126.4, 127.6, 129.5, 129.6, 130.1, 134.7, 137.6, 139.3,

SYNTHESIS OF SPIRO PYRROLIDINES
1051
141.5, 172.5, 176.3 ppm; Mass spectrum m=z: 446.23 (Mþ). CHN anal. calc. for
C25H26N4O4: C, 67.26; H, 5.82; N, 12.55%. Found: C, 67.21; H, 5.78; N, 12.60%.
1N-Methyl-3-((1H-benzo[d]imidazol-1-yl)methyl)-1-methyl-4-phenyl-
2-oxindolepyrrolidine-3-carboxylate 14
1
Colorless liquid, yield 83%; H NMR (300 MHz, CDCl3): d 2.19 (s, 3H), 2.66
(s, 3H), 3.50 (t, J ¼ 10.0 Hz, 1H), 3.87 (t, J ¼ 8.4 Hz, 1H), 4.51 (d, J ¼ 15.3 Hz, 1H),
4.95 (t, J ¼ 8.6 Hz, 1H), 5.66 (d, J ¼ 15.3 Hz, 1H), 6.69–7.78 (m, 14H), 9.87 (s, 1H);
13C NMR (75 MHz, CDCl3): d 36.4, 41.0, 48.6, 52.3, 66.7, 109.7, 120.2, 122.1, 122.8,
126.5, 128.3, 129.0, 129.1, 129.8, 134.0, 142.8, 143.0, 143.5, 144.8, 166.8 ppm; Mass
spectrum m=z: 466.62 (Mþ). CHN anal calc. for C28H26N4O3: C, 72.10; H, 5.57; N,
12.01%. Found: C, 72.05; H, 5.51; N, 12.13%.
1N-Methyl-3-((1H-benzo[d]imidazol-1-yl)methyl)-1-methyl-
4-(4-chlorophenyl)-2-oxindolepyrrolidine-3-carboxylate 15
1
Colorless liquid, yield 78%; H NMR (300 MHz, CDCl3): d 2.18 (s, 3H), 2.83
(s, 3H), 3.51 (t, J ¼ 9.9 Hz, 1H), 3.74–3.80 (m, 1H), 4.45 (d, J ¼ 15.0 Hz, 1H),
4.82–4.87 (m, 1H), 5.36 (d, J ¼ 15.0 Hz, 1H), 6.68–7.62 (m, 13H), 9.23 (s, 1H); 13C
NMR (75 MHz, CDCl3): 35.4, 43.2, 47.8, 51.9, 58.0, 64.5, 110.0, 119.3, 121.9,
121.9, 122.4, 122.5, 125.82, 126.17, 128.81, 129.8, 131.5, 133.6, 136.1, 141.2, 142.0,
143.4, 171.8, 176.2; m=z: 500.09 (Mþ). CHN anal. calcd. for C28H25N4O3Cl: C,
67.20; H, 5.00; N, 10.00%. Found: C, 67.32; H, 5.10; N, 10.11%.
1N-Methyl-3-((1H-benzo[d]imidazol-1-yl)methyl)-1-methyl-
4-(2-chlorophenyl)-2-oxindolepyrrolidine-3-carboxylate 16
Colorless liquid, yield 80%; 1H NMR (300 MHz, CDCl3): d 2.17 (s, 3H), 3.54 (t,
J ¼ 9.8 Hz, 1H), 3.75–3.92 (m, 1H), 4.43 (d, J ¼ 6.9 Hz, 1H), 4.54–4.4.61 (m, 1H), 5.13
(d, J ¼ 6.9 Hz, 1H), 6.62–7.81 (m, 13H), 9.23 (s, 1H); 13C NMR (75 MHz, CDCl3): d
35.4, 43.2, 47.8, 51.9, 58.0, 64.5, 110.0, 119.3, 121.9, 121.9, 122.4, 122.5, 125.82,
126.17, 128.81, 129.8, 131.5, 133.6, 136.1, 141.2, 142.0, 143.4, 171.8, 176.2 ppm. Mass
spectrum m=z; 500.26 (Mþ). CHN anal. calc. for C28H25N4O3Cl: C, 67.20; H, 5.00; N,
10.00%. Found: C, 67.12; H, 4.93; N, 10.15%.
1N-Methyl-3-((1H-benzo[d]imidazol-1-yl)methyl)-1-methyl-
4-(4-methylphenyl)-2-oxindolepyrrolidine-3-carboxylate 17
Colorless liquid, yield 82%; 1H NMR (300 MHz, CDCl3): d 2.17, (s, 1H), 2.35 (s,
3H), 2.68 (s, 3H), 3.47 (t, J ¼ 8.1 Hz, 1H), 3.85 (d, J ¼ 7.6 Hz, 1H), 4.51 (d, J ¼ 15.3 Hz,
1H), 4.906 (t, J ¼ 11.7 Hz, 1H), 5.63 (d, J ¼ 15.3 Hz, 1H), 6.78–7.65 (m, 12H), 9.42 (s,
1H); 13C NMR (75 MHz, CDCl3): 21.0, 35.6, 42.2, 48.0, 51.5, 57.8, 64.7, 110.2, 119.1,
121.7, 122.4, 122.7, 123.5, 125.5, 125.9, 126.2, 127.5, 128.3, 129.6, 129.7, 130.5, 134.4,
137.8, 141.3, 143.9, 171.3, 176.8; m=z: 480.51(Mþ). CHN anal. calcd. for C29H28N4O3:
C, 72.50; H, 5.83; N, 11.66%. Found: C, 72.63; H, 5.79; N, 11.60%.

1052
S. KATHIRAVAN AND R. RAGHUNATHAN
1N-Methyl-3-((1H-benzo[d]imidazol-1-yl)methyl)-1-methyl-
4-(4-methoxyphenyl)-2-oxindolepyrrolidine-3-carboxylate 18
Colorless liquid, yield 79%, 1H NMR (300 MHz, CDCl3): d 2.17 (s, 3H), 2.34 (s,
3H), 2.67 (s, 3H), 3.47 (t, J ¼ 10.2 Hz, 1H), 3.83–3.89 (m, 1H), 4.53 (d, J ¼ 15.3 Hz,
1H), 4.89–4.94 (m, 1H), 5.66 (d, J ¼ 15.3 Hz, 1H), 6.79–7.65 (m, 12H), 9.97 (s, 1H);
13C NMR (75 MHz, CDCl3): 21.9, 35.4, 42.6, 48.5, 51.8, 57.6, 64.7, 78.2, 110.9,
111.4, 120.7.1, 121.2, 122.8, 122.0, 125.1, 129.3, 132.1, 134.0, 134.4, 137.6, 141.1,
141.7, 143.6, 171.2, 176.9 ppm; Mass spectrum m=z: 496.18 (Mþ). CHN anal. calc.
for C29H28N4O4: C, 70.16; H, 5.64; N, 11.29%. Found: C, 70.11; H, 5.59; N, 11.36%.
ACKNOWLEDGMENTS
S. K. thanks the Council of Scientific and Industrial Research for the award of
a senior research fellowship. S. K. and R. R. thank the Department of Science and
Technology–Funding for Infrastructure in Science and Technology, New Delhi, for
the NMR facility.
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