Synthesis of novel dispiro-oxindoles via 1,3-dipolar cycloaddition reactions of azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2012.02.097

The 1,3-dipolar cycloaddition of 1-allyl-5-haloisatin derivatives as dipolarophiles with the azomethine ylides generated in situ from N-allylisatin and l-proline to furnish novel dispiro-oxindoles has been investigated. The structures and relative stereoc

Full text of DOI:10.1016/j.tetlet.2012.02.097

Tetrahedron Letters 53 (2012) 2328–2331
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Tetrahedron Letters
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Synthesis of novel dispiro-oxindoles via 1,3-dipolar cycloaddition reactions
of azomethine ylides
Khalil Al Mamari a, Hamid Ennajih a,b, Hafid Zouihri c, Rachid Bouhfid b, Seik Weng Ng d,e
,
El Mokhtar Essassi a,b,
⇑
a Laboratoire de Chimie Organique Hétérocyclique, URAC 21, Pôle de Compétences Pharmacochimie, Université Mohammed V-Agdal, Faculté des Sciences, Av. Ibn Battouta,
BP 1014 Rabat, Morocco
b MAScIR (Moroccan Foundation for Advanced Science, Innovation, and Research), Institute of Nanomaterials and Nanotechnology (INANOTECH), ENSET, Av. de l’Armée Royale,
Madinat El Irfane 10100 Rabat, Morocco
c Laboratoires de Diffraction des Rayons X,CNRST, Rabat, Morocco
d Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
e Chemistry Department, King Abdulaziz University, PO Box 80203 Jeddah, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,3-dipolar cycloaddition of 1-allyl-5-haloisatin derivatives as dipolarophiles with the azomethine
Received 17 January 2012
Revised 9 February 2012
Accepted 23 February 2012
Available online 3 March 2012
ylides generated in situ from N-allylisatin and L-proline to furnish novel dispiro-oxindoles has been inves-
tigated. The structures and relative stereochemistry of both types of cycloadducts were confirmed by sin-
gle crystal X-ray diffraction, 1H and 13C NMR spectroscopy and mass spectrometry.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Isatin
L-proline
Azomethine ylide
1,3-Dipolar cycloaddition
X-ray diffraction
Multicomponent 1,3-dipolar cycloaddition reactions are very
useful processes for the construction of five-membered heterocy-
clic ring systems.1–3 These multicomponent strategies offer signif-
icant advantages allowing the construction of complex molecular
architectures from readily available starting materials in a single
synthetic operation without the need for the isolation of interme-
diates. The chemistry of azomethine ylides has gained significance
in recent years for the construction of nitrogen-containing five-
membered heterocycles, which are the central ring systems of
numerous natural products.4 Among various nitrogen-containing
heterocycles, functionalized pyrrolidine and pyrrolizidine alkaloids
constitute classes of compounds with interesting biological activ-
ity.5,6 Spiro compounds represent an important class of naturally
occurring substances characterized by highly pronounced biologi-
cal properties.7–14
constructing pyrrolidine rings with high selectivity.16 The exten-
sive use of isatin as a precursor for 1,3-dipolar cycloadditions
stems from the fact that a wide variety of azomethine ylides con-
taining primary and secondary amines can be generated from this
precursor and are trapped with suitable dipolarophiles.17
The spirooxindole unit is a privileged heterocyclic motif that
forms the core of a large family of alkaloids and natural products
with strong bioactivity profiles and interesting structural proper-
ties.18–20
In previous work we showed that alkyl-isatin derivatives re-
acted as dipolarophiles with diphenylnitrilimines and aryl oxides
to afford new cycloadducts containing pyrazole, pyrazoline, isoxaz-
ole, isoxazoline, dioxazoline, oxadiazoline, oxindole, and indole
rings.21,22 In continuation of our investigations in this field, we
studied the 1,3-dipolar cycloaddition of azomethine ylides with
1-alkyl-isatin derivatives with the aim to synthesize new pyrroli-
dine-based heterocycles for biological screening.
Five-membered nitrogen heterocycles, especially highly substi-
tuted pyrrolidines, feature widely in pharmaceuticals, natural alka-
loids, organocatalysts, and are also useful building blocks in
organic synthesis.15 1,3-Dipolar cycloaddition of azomethine ylides
to electron deficient alkenes provides an efficient approach for
Thus, two mol equivalents of 1-allylisatins 2a–c were refluxed
in ethanol, in the presence of one mole of
alent of 1-allylisatin reacts with one equivalent of
L
-proline 3.23 One equiv-
L
-proline to yield
azomethine ylide which would be expected to react with the
second mole of 1-allylisatin to give spiro compounds 6a–c via
intermolecular 1,3-dipolar cycloaddition. However, in all cases,
⇑
Corresponding author. Tel./fax: +212 37 77 54 40.
E-mail address: emessassi@yahoo.fr (E.M. Essassi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.097

K. Al Mamari et al. / Tetrahedron Letters 53 (2012) 2328–2331
2329
we isolated only one compound in good yield which, from 1H, 13C
NMR and mass spectrometry data, allowed us to propose the struc-
tures 4a–c and 5a–c. A crystallographic study confirmed the struc-
tures 4a–c (Scheme 1, Fig. 1).
HRMS (ESI) analysis of compound 4b gave a molecular ion
(MH+) at m/z 548.1730 (calcd 548.1746), assigned to the molecular
ion C30H30Cl2N4O2, indicating that two molecules of 1-allyl-5-
chloroisatin 2b and two L-proline moieties were involved in the
reaction. The FTIR absorption bands indicated the existence of a
carbonyl of the amide group. The 1H NMR spectrum of 5b demon-
strated signals at d 1.57, 1.92, 2.43, and 3.58 assignable to 12 meth-
ylene protons and two methine protons respectively, of the
pyrrolidine rings, and a doublet of doublets at d 4.07 and two mul-
tiplets at d 5.00 and 5.61 assignable to the NCH2, @CH2 and @CH
protons, respectively, of the allylic groups. The spiro carbons ap-
peared at d 99.7 in the 13C NMR spectrum while the carbonyl
groups occurred at d 173.4.24
As noted from the centric nature of the space group, the com-
pound has no chiral carbons.25
As an extension of this work, we also studied the condensation
of 1-benzyl-5-haloisatins 2d–f with L-proline under the same con-
Figure 1. Thermal ellipsoid plot of 4b at the 50% probability level; hydrogen atoms
are drawn as spheres of arbitrary radii.
ditions. In all cases, compounds 4d–f were isolated in good yields
(Scheme 2).
These results can be explained by the following mechanism
(Scheme 3). The condensation of L-proline with 1-alkyl-5-haloisat-
self-condensation relating to A + A or B + B leading to the forma-
tion of compounds 5a–f, the second consists of the reaction of
forms A+B giving the dispiro-oxindoles 4a–f.
in derivatives gives an iminium carboxylate intermediate 7 which
cyclizes into oxazolidin-5-one intermediate 8. This undergoes
thermal decarboxylation leading to the azomethine ylide. This
dipole is present in two mesomeric forms A and B, which undergo
dimerisation. Two pathways are possible: the first one involves
In summary, we have described an efficient synthesis of new
dispiro-heterocyclic derivatives containing oxindole, pyrrolidine,
and piperazine rings from commercially accessible isatin and
L-proline. The synthesized products are potentially biologically
active molecules, having the core structure of similar biologically
O
X
X
N
N
X
O
N
1a-cH
N
N
O
O
4a
4b
4c
X = H : 76%
X = Cl : 83%
X = Br : 83%
K2CO3 / DMF
TBAB / allyl bromide
N
X
O
CO2H
NH
O
X
N
EtOH / Δ
O
N
N
O
X
N
5a-c
6a-c
X
2a X = H : 82%
2b X = Cl : 88%
2c X = Br : 89%
3
O
O
N
N
X
O
N
Scheme 1. Condensation of 2a–c with
L
-proline.

2330
K. Al Mamari et al. / Tetrahedron Letters 53 (2012) 2328–2331
X
N
O
CO2H
NH
X
N
X
Ethanol/ Δ
O
+
N
N
N
O
O
3
4d X = H : 75%
4e X = Cl : 80%
4f X = Br : 76%
2d-f
Scheme 2. Synthesis of compounds 4d–f.
O
O
N
CO2H
NH
N
CO 2
O
X
X
X
O
O
O
N
+
N
N
R
R
R
7
8
X
N
N
O
A + A or
X
X
N
- CO2
R
B + B
N
O
O
N
N
R
N
R
N
O
R
A
B
5a-f
X
X
N
N
X
N
N
X
X
O
O
N
R
N
N
R
N
O
O
R
R
B
4a-f
A
Scheme 3. Proposed mechanism for the formation of dispiro-oxindoles 4a–f.
8. Howe, R. K.; Shelton, B. R. J. Org. Chem. 1990, 55, 4603.
important molecules including spiro[pyrrolidine-oxindole]
alkaloids.
9. Dc Amici, M.; De Michelli, C.; Sani, V. M. Tetrahedron 1975, 1990, 46.
10. Cohen, V. L.; Kleinmann, E. E. PCT. Int. Appl. W.O. 24,398, 1995; Chem. Abstr.
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11. (a) Caroll, W. A.; Grieco, P. A. J. Am. Chem. Soc. 1993, 115, 1164; (b) Early, W. G.;
Oh, T.; Overman, L. E. Tetrahedron Lett. 1988, 29, 3785; (c) Ban, Y.; Taga, N.;
Oishi, T. Chem. Pharm. Bull. 1976, 24, 736; (d) Ban, Y.; Seto, M.; Oishi, T. Chem.
Pharm. Bull. 1975, 23, 2605.
12. Ban, Y.; Taga, N.; Oishi, T. Tetrahedron Lett. 1974, 2, 187; Van Tamle, E. E.;
Yardley, J. P.; Miyano, M.; Hinshaw, W. B., Jr. J. Am. Chem. Soc. 1969, 26,
7333.
Acknowledgments
The authors thank the University Mohammed V-Agdal, the Ye-
men Government, and the University of Malaya (UM.C/625/1/HIR/
033/10) for supporting this study.
13. Kobayashi, J.; Tsuda, M.; Agemi, K.; Shigemori, H.; Ishibashi, M.; Sasaki, T.;
Mikami, Y. Tetrahedron 1991, 47, 6617.
References and notes
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2. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984;
Vols. 1 and 2,.
3. Grigg, R.; Sridharan, V. In Advances in Cycloaddition; Curran, D. P., Ed.; Jai:
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K. Al Mamari et al. / Tetrahedron Letters 53 (2012) 2328–2331
2331
23. Synthesis of dispiro-oxindoles: A mixture of isatin (0.147 g, 1 mmol),
L
-proline
CH2), 1.57 (m, 4H, CH2); 13C NMR (75 MHz, DMSO-d6) d 21.0 (CH2), 27.5 (CH2),
41.5 (NCH2), 47.4 (NCH2), 58.9 (CH), 99.7 (Cspiro), 108.9 (@CH), 117.7 (@CH2),
122.0, 126.0, 129.6 (CHAr), 129.6, 132.3, 143.3 (Cq), 173.4 (C@O). HRMS (ESI) m/
z Calcd for C30H30Cl2N4O2 [MH]+, 548.1746; Found, 548.1730.
(0.115 g, 1 mmol) in EtOH (20 mL) was stirred at reflux for 1–2 h. After
completion of the reaction, as indicated by TLC, H2O (40 mL) was added, and
the precipitated solid was separated by filtration to afford the corresponding
product. The product structure was determined by FTIR, 1H and 13C NMR
spectroscopy, mass spectrometry, and single crystal X-ray diffraction for 4b.
The pure cycloadduct was obtained by recrystallization from EtOH.
25. Crystals of C30H30Cl2N2O4 belong to the P21/c space group [a = 11.0081(1),
b = 12.5807(2), c = 19.8594(3) Å, b = 93.297(1)°; V = 2745.77(7) Å3]. The 11712
room-temperature diffraction data were measured on
diffractometer using Mo-K radiation up to a 2hmax of 34.60°, and the crystal
structure was refined to a final R-index of 0.0505 for 7938 I P 2 reflections.
a Bruker DUO
24. 1,100-Diallyl-10,20,30,80,90,100,10a0,10b0-octahydrodispiro[(5-chloro-indole)-3,50-
dipyrrolo[1,2-a:20,10-c]pyrazine-60,300-(5-chloro-indole)]-2,200(1H,100H)-dione,
a
r
mp = 209–211 °C, FTIR
m
max: 1612, 1481, 1357, 740 cmꢀ1,1H NMR (300 MHz,
The crystallographic information file has been deposited with the Cambridge
Data Centre, CCDC 862933.
DMSO-d6) d 7.17–6.53 (m, 6H, HAr), 5.61 (m, 2H, @CH), 5.00 (m, 4H, @CH2), 4.07
(dd, 4H, NCH2, J = 6.2, 1.4 Hz), 3.58 (m, 2H, CH), 2.43 (m, 4H, CH2), 1.92 (m, 4H,