Facile three-component synthesis of spirooxindolepyrrololine ring systems via 1,3-dipolar cycloaddition with 1,4-naphthoquinone

Article abstract of DOI:10.1080/00397911.2010.517413

1,3-Dipolar cycloadditions involving 1,4-naphthoquinone and an azomethine ylide generated from α-amino acids and isatins have been used in this reaction to afford the pyrrolidine-2-spiro-3′-oxindole 4 or 5 with moderate to excellent yields.

Full text of DOI:10.1080/00397911.2010.517413

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Facile Three-Component Synthesis of
Spirooxindolepyrrololine Ring Systems
via 1,3-Dipolar Cycloaddition with 1,4-
Naphthoquinone
Hua Chen a , Shun-Yi Wang a , Xiao-Ping Xu a & Shun-Jun Ji a
a Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Material Sciences, Suzhou
(Soochow) University, Suzhou, China
Version of record first published: 26 Jul 2011.
To cite this article: Hua Chen, Shun-Yi Wang, Xiao-Ping Xu & Shun-Jun Ji (2011): Facile Three-
Component Synthesis of Spirooxindolepyrrololine Ring Systems via 1,3-Dipolar Cycloaddition with 1,4-
Naphthoquinone, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:22, 3280-3288
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Synthetic Communications1, 41: 3280–3288, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517413
FACILE THREE-COMPONENT SYNTHESIS OF
SPIROOXINDOLEPYRROLOLINE RING SYSTEMS VIA
1,3-DIPOLAR CYCLOADDITION WITH
1,4-NAPHTHOQUINONE
Hua Chen, Shun-Yi Wang, Xiao-Ping Xu, and Shun-Jun Ji
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Material Sciences, Suzhou (Soochow)
University, Suzhou, China
GRAPHICAL ABSTRACT
Abstract 1,3-Dipolar cycloadditions involving 1,4-naphthoquinone and an azomethine ylide
generated from a-amino acids and isatins have been used in this reaction to afford the
pyrrolidine-2-spiro-30-oxindole 4 or 5 with moderate to excellent yields.
Keywords a-Amino acids; 1,3-dipolar cycloaddition; isatin; 1,4-naphthoquinone
INTRODUCTION
The 1,3-dipolar cycloaddition reactions have attracted continuous attention as
an efficient method for the preparation of heterocycles and natural products. Beyond
the ability of the 1,3-dipolar cycloaddition reaction to produce heterocycles, its
importance extends to two other areas of organic synthesis. First, the heteroatom-
containing cycloadducts may be transformed into a variety of other functionalized
organic molecules, whether cyclic or acyclic. Second, many 1,3-dipolar
Received September 1, 2009.
Address correspondence to Shun-Jun Ji, Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Material Sciences, Suzhou (Soochow) University, Renai
Road, Suzhou Industrial Park, Suzhou 215123, China. E-mail: chemjsj@suda.edu.cn
3280

1,3-DIPOLAR CYCLOADDITION
3281
cycloadditions have the ability to generate rings (and the functionality derived from
transformations of such rings) containing several contiguous stereocenters in one
synthetic operation.[1] The pyrrolidino-2-spiro-30-oxindole ring system can be found
in several pharmacologically active alkaloids. Various strategies have been used to
obtain these spiro compounds, such as oxidative rearrangement of b-carbolines
and 1,3-dipolar cycloadditions.[2] Larger dipolarophiles, such as chalcones and phe-
nyacetylene, have been used successfully in the three-component reaction of isatin, a-
amino acids, and dipolarophiles.[3–6] In 2001, Azizian et al.[7] published a study of
some reactions of proline (2a), isatin (1a), and N-arylmaleimide in refluxing ethanol,
which are the conditions that yielded the pyrrolidine-2-spiro-30-oxindole derivatives.
Recently, Bergman et al.[8] performed 1,3-dipolar cycloadditions involving different
dipolarophiles such as N-benzylmaleimide and an azomethine ylide prepared from
the decarboxylative condensation between N-substituted a-amino acids and isatin
under reflux at 90 ꢀC in a mixture of methanol and water. This type reaction can also
be performed under microwave conditions.[7] However, few of the reactions of
1,4-naphthoquinone as dipolarophiles have been reported in this type of reaction.[9]
First, our studies were set in motion by exposing isatin to proline and 1,4-
naphthoquinone, via anti-azomethine ylides, which attack the dipolarophiles 3 in
methanol at 40–50 ꢀC under ultrasounic radiation. The reaction flask was located
in the water bath of the ultrasonic cleaner, and the temperature of the reaction
system was controlled by adding H2O. A facile reaction leading to the exclusive
formation of 3-spiro[pyrrolidino-oxindoles] derivative 4a occurred (Scheme 1).
The product 4a was characterized by spectroscopic analysis. Final proof for
the structure assigned for 4a was derived from single-crystal x-ray analysis (Fig. 1).
Compound 4a also could be obtained in 89% yield under reflux conditions using
a mixture of methanol and water as solvent (Table 1, entry 1). It was noted that
no desired product was formed when the reaction was carried out at room tem-
perature. Other amino acids such as L-tryptophan, L-isoleucine, L-penylalanine,
and L-tryptophan (2b–2d) also could be used for this three-component
reaction; the desired products 4b–4d were obtained in good yields with high regio-
and stereoselectivities (Table 1, entries 2–4). It was interesting that different types
of product 5 were obtained in 78% yield when L-valine was used this reaction
(Table 1, entry 5).
Scheme 1. The 1,3-dipolar of isatin, amino acids, and 1,4-naphthoquinone.

3282
H. CHEN ET AL.
Figure 1. The x-ray crystal structure of 4a.
Table 1. Three-component reaction between isatin 1a with different a-amino acids and 3a
Entry
1
Amino acids
Products
Time (h)
Yield (%)b
1.5
1.5c
98
89
L-Proline
2a
2b
2c
4a
4b
4c
2
3
L-Isoleucine
5
80
81
L-Penylalanine
0.3
4
5
L-Tryptophan
2d
2e
4d
5
1
88
78
L-Valine
5
aAll reactions were carried out in methanol under sonic waves.
bIsolated yields.
cThe reaction was carried out in methanol under reflux conditions.

1,3-DIPOLAR CYCLOADDITION
3283
Table 2. The reaction of isatin 1a–g with L-proline and 3a
Entry
Isatin
Products
Time (h)
Yield (%)b
1
1a
1b
4a
4e
2
1
98
72
2
3
1c
4f
1.5
0.4
85
76
4
1d
4g
5
1e
4h
1
81
6
7
1f
4i
0.3
0.5
70
90
1g
4j
aAll reactions were performed in methanol under sonic waves.
bChemical yields are given for the isolated product.

3284
H. CHEN ET AL.
Scheme 2. The plausible mechanism.
Finally, we also performed a similar three-component reaction of substituted
isatins with L-proline and 3, giving the desired products. The results are listed in
Table 2. N-Benzylisatin 1 g with 2a and 3 afforded 4j in 90% yield under sonic
conditions (Table 2, entry 7).
We proposed the mechanism of the reaction of 1,4-naphthoquinone, a-amino
acids, and isatins as shown in Scheme 2. At first, the intermediate anti-ylide I was
formed by mixing a-amino acid and isatin under ultrasonic or reflux conditions.
Followed the regio- and stereoselective cycloaddition of I with 1,4-naphthoquinone,
cycloaddition product II was formed. In most cases, the initial addition product II
tautomerized to the hydronaphthquinone III, which subsequently underwent rapid
oxidation under air conditions, resulting in the formation of the desired product 4
(Scheme 2).
In conclusion, a series of 3-spiro[pyrrolidino-oxindoles] derivatives can be
obtained via 1,3-dipolar cycloadditions of isatins, a-amino acids, and 1,4-naphtho-
quinone. We have unraveled some interesting reactivity profiles of the 1,4-naphtho-
quinone, thus achieving novel three-component reactions that offer a simple and
efficient route to the synthesis of highly functionalized 1,4-naphthoquinone and pyr-
rolidinyl derivatives. It is interesting to note that a wide range of biologically active
molecules contain naphthoquinone and pyrrolidinyl moieties. It is anticipated that
the work presented in this article will arouse much interest in the area of 1,3-dipolar
cycloaddition of 1,4-naphthoquinone.
EXPERIMENTAL
Melting points were recorded on an Electrothermal digital melting-point
1
apparatus and are uncorrected. H NMR (400-MHz) spectra were recorded on a
Varian Mercury spectrometer in CDCl3. Infrared (IR) spectra were obtained on a
Nicolet Fourier transform (FT)–IR 500 spectrophotometer using KBr pellets. High-
resolution mass spectra were obtained using a gas chromatography time-of-flight
(GCT-TOF) mass spectrometry instrument.

1,3-DIPOLAR CYCLOADDITION
3285
General Procedure for Synthesis of 4
A mixture of isatin 1a (0.147 g, 1 mmol), L-proline 2a (0.115 g, 1 mmol), and
1,4-naphthoquinone 3 (0.158 g, 1 mmol) was irradiated in the presence of ultrasound
in methanol (6 mL) at about 40 ꢀC until the disappearance of the starting 3 (moni-
tored by thin-layer chromatography, TLC). After standing 1 h, the reaction mixture
was washed by cool water (2 ꢁ 25 mL) and cool ethanol (2 ꢁ 0.5 mL). The crude
mixture was recrystallized from hot methanol to afford the pure product 4a
(0.349 g, yield: 98%).
Selected Data
Compound 4a. Orange-yellow needles; mp 221–223 ꢀC; IR (KBr): n 726, 762,
1
1030, 1121, 1470, 1590, 1612, 1666, 1738, 2889, 2967, 3169 (NH) cmꢂ1; H NMR
(400 MHz, CDCl3): d 1.72–1.78 (m, 1H, CH), 2.02–2.04 (m, 2H, CH2), 2.47–2.50
(m, 1H, CH), 2.79–2.83 (m, 2H, CH2), 5.07 (t, 1H, CH, J ¼ 7.6 Hz), 6.94–7.03
(m, 3H), 7.33 (t, 1H, J ¼ 7.6 Hz), 7.66–7.75 (m, 2H), 7.82 (br, s, 1H, NH), 7.90
(d, 1H, J ¼ 8.4 Hz), 8.12 (d, 1H, J ¼ 6.8 Hz). HRMS found: m=z 356.1169(Mþ);
calcd. for C22H16N2O3: M, 356.1161.
Crystallographic data for the structural analysis have been deposited with the
Cambridge Crystallographic Data Centre, CCDC No. 252479, for compound 4a.
Copies of this information may be obtained free of charge from the director, CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK (e-mail: linstead@ccdc.cam.ac.uk or
deposit@ccdc.cam.ac.uk; fax: þ44 1223 336033). Structural parameters for 4a
MeOH are as follows: data collection: Rigaku Mercury CCD area detector; radi-
3
˚
ation: MoK, wavelength: k ¼ 0.71070 A; crystal size: 0.50 ꢁ 0.35 ꢁ 0.12 mm ;
C23H20N2O4 ꢃ C3H4O, Mr ¼ 388.41, monoclinic, space group p 21=c, a ¼ 13.684(3),
˚
b ¼ 8.0715(15), c ¼ 17.223(3) ꢂA3, a ¼ 90.00, b ¼ 99.624(4), c ¼ 90.00, V ¼ 1875.5(6)
3
.
˚
A , Z ¼ 4, Dcalc ¼ 1.376 g cm
.
Compound 4b. Pink needles; mp 210–212 ꢀC (dec); IR (KBr): n 7710, 760,
1336, 1470, 1618, 1660, 1732, 2867, 2956, 3165, 3269 (NH) cmꢂ1 1H NMR
;
(400 MHz, CDCl3): d1.02 (d, 3H, CH3, J ¼ 6.4 Hz), 1.06 (d, 3H, CH3, J ¼ 6.4 Hz),
1.57–1.62 (m, 1H, CH), 1.91–1.92 (m, 1H, CH), 2.19 (dd, 1H, J1 ¼ 7.2 Hz,
J2 ¼ 6.8 Hz), 2.52 (br, s, 1H, NH), 4.99 (d, 1H, J ¼ 9.2 Hz), 6.96 (d, 1H, J ¼ 7.6 Hz),
7.05(t, 1H, J ¼ 7.6 Hz), 7.17 (d, 1H, J ¼ 7.6 Hz), 7.30 (d, 1H, J ¼ 7.6 Hz), 7.66–7.75
(m, 2H), 7.90 (d, 1H, J ¼ 7.6 Hz), 7.98 (br, s, 1H, NH), 8.10 (d, 1H, J ¼ 6.8 Hz).
HRMS found: m=z 372.1466 (Mþ); calcd. for C23H20N2O3: M, 372.1474.
Compound 4c. Pink needles; mp 200–203 ꢀC (dec); IR (KBr): n 696, 740,
1
1264, 1470, 1621, 1687, 1705, 2868, 2960, 3067, 3180, 3290 (NH) cmꢂ1; H NMR
(400 MHz, CDCl3): d 2.35 (br, s, 1H, NH), 2.98–3.04 (m, 1H, CH), 4.03 (d, 1H,
J ¼ 8.4 Hz), 4.41–4.46 (m, 1H, CH), 5.07 (dd, 1H, CH, J1 ¼ 7.2 Hz, J2 ¼ 8.0 Hz),
6.35 (d, 1H, J ¼ 7.6 Hz), 6.61 (t, 1H, J ¼ 7.6 Hz), 6.74 (d, 1H, J ¼ 7.6 Hz), 7.08 (dd,
1H, J1 ¼ 8.4 Hz, J2 ¼ 7.6 Hz), 7.19 (dd, 1H, J1 ¼ 6.8 Hz, J2 ¼ 7.6 Hz), 7.28 (d, 2H,
J ¼ 6.8 Hz), 7.34 (d, 2H, J ¼ 6.8 Hz), 7.43 (br, s, 1H, NH), 7.68–7.74 (m, 2H), 7.81
(t, 1H, J ¼ 7.6 Hz), 8.14 (d, 1H, J ¼ 6.8 Hz). HRMS found: m-1=z 405.1209 (Mþ);
calcd. for C26H18N2O3: M, 406.1317.

3286
H. CHEN ET AL.
Compound 4d. Pink needles; mp 185–187 ꢀC (dec); IR (KBr): n 710, 740,
1
1180, 1471, 1619, 1665, 1738, 2909, 3283, 3407 (NH) cmꢂ1; H NMR (400 MHz,
CDCl3): d 2.25 (br, s, 1H, NH), 3.38–3.50 (m, 1H, CH), 3.72–3.77 (m, 1H, CH),
5.29-5.32 (m, 1H, CH), 6.34 (d, 1H, J ¼ 7.2 Hz), 6.80 (dd, 1H, J1 ¼ 8.0 Hz,
J2 ¼ 7.2 Hz), 6.85 (d, 2H, J ¼ 8.0 Hz), 7.03–7.07(m, 2H), 7.16–7.21 (m, 2H), 7.28
(d, 2H, J ¼ 6.8 Hz), 7.37 (d, 2H, J ¼ 8.0 Hz), 7.62–7.65 (m, 2H), 7.69 (t, 1H,
J ¼ 7.6 Hz), 7.76 (t, 1H, J ¼ 7.2 Hz), 8.10 (br, s, 1H, NH), 8.19 (d, 1H, J ¼ 6.4 Hz).
HRMS found: m-1=m 444.1303 (Mþ); calcd. for C28H19N3O3: M, 445.1426.
Compound 4e. Pink needles; mp 253–255 ꢀC; IR (KBr): n 681, 724, 1083,
1
1450, 1606, 1661, 1724, 2880, 2964, 3213 (NH) cmꢂ1; H NMR (400 MHz, CDCl3):
d 1.61–1.678 (m, 1H, CH), 1.92–1.96 (m, 2H, CH2), 2.39–2.42 (m, 1H, CH),
2.65–2.76 (m, 2H, CH2), 4.98 (dd, 1H, CH, J1 ¼ 8.4 Hz, J2 ¼ 7.6 Hz), 6.74 (d, 1H,
J ¼ 8.4 Hz), 7.08 (d, 2H, J ¼ 8.4 Hz), 7.61–7.70 (m, 3H), 7.90 (d, 1H, J ¼ 7.6 Hz),
8.12 (d, 1H, J ¼ 6.8 Hz). HRMS found: m=z 434.0038 (Mþ); calcd. for
C22H15N2O3 79Br: M, 434.0089.
Compound 4f. Pink needles; mp 220–221 ꢀC; IR (KBr): n 688, 761, 1084,
1
1132, 1494, 1609, 1665, 1712, 2863, 2970 cmꢂ1; H NMR (400 MHz, CDCl3): d
1.64–1.73 (m, 1H, CH), 1.90–1.94 (m, 2H, CH2), 2.39–2.42 (m, 1H, CH), 2.71 (t,
2H, CH2, J ¼ 6.8 Hz), 3.24 (s, 3H, CH3), 5.00 (dd, 1H, CH, J1 ¼ 8.4 Hz,
J2 ¼ 7.2 Hz), 6.88–6.97 (m, 3H), 7.32 (dd, 1H, J1 ¼ 8.0 Hz, J2 ¼ 7.6 Hz), 7.57–7.67
(m, 2H), 7.78 (d, 1H, J ¼ 7.6 Hz), 8.12 (d, 1H, J ¼ 7.2 Hz). HRMS found: m=z
370. 1333 (Mþ); calcd. for C23H18N2O3: M, 370.1317.
Compound 4g. Pink needles; mp 193–195 ꢀC (dec); IR (KBr): n 758, 1176,
1
1356, 1466, 1609, 1667, 1723, 2873, 2970 cmꢂ1; H NMR (400 MHz, CDCl3): d
1.71–1.80 (m, 1H, CH), 1.98–2.02 (m, 2H, CH2), 2.46–2.50 (m, 1H, CH), 2.79 (t,
2H, J ¼ 6.8 Hz), 4.35–4.52 (m, 2H, CH2), 5.08 (dd, 1H, CH, J1 ¼ 8.4 Hz,
J2 ¼ 7.6 Hz), 5.28–5.46 (m, 2H), 5.89–5.97 (m, 1H, CH), 6.94–7.06 (m, 3H), 7.35
(dd, 1H, J1 ¼ 7.6 Hz, J2 ¼ 8.0 Hz), 7.65–7.74 (m, 2H), 7.88 (d, 1H, J ¼ 7.6 Hz), 8.11
(d, 1H, J ¼ 7.6 Hz). HRMS found: m=z 396.1491 (Mþ); calcd. for C25H20N2O3: M,
396.14741.
Compound 4h. Pink needles; mp 179–181 ꢀC; IR (KBr): n 754, 1137, 1335,
1
1357, 1466, 1609, 1666, 1728, 2868, 2933, 2951 cmꢂ1; H NMR (400 MHz, CDCl3):
d 0.92 (dd, 3H, CH3, J1 ¼ 6.8 Hz, J2 ¼ 6.4 Hz), 1.41 (s, 4H, 2CH2), 1.72–1.80 (m, 3H,
CH, CH2), 1.96–2.04 (m, 2H, CH2), 2.44–2.51 (m, 1H, CH), 2.78 (dd, 2H, CH2,
J1 ¼ 5.6 Hz, J2 ¼ 6.8 Hz), 3.72–3.82 (m, 2H, CH2), 5.05–5.09 (m, 1H, CH),
6.95–7.02 (m, 3H), 7.37 (dd, 1H, J1 ¼ 6.8 Hz, J2 ¼ 7.6 Hz), 7.64–7.74 (m, 2H), 7.87
(d, 1H, J ¼ 7.6 Hz), 8.11 (d, 1H, J ¼ 6.4 Hz). HRMS found: m=z 426.1934 (Mþ);
calcd. for C27H26N2O3: M, 426.1943.
Compound 4i. Pink needles; mp 182–184 ꢀC (dec); IR (KBr): n 756, 1167,
1
1353, 1467, 1607, 1668, 1722, 2878, 1924, 2955 cmꢂ1; H NMR (400 MHz, CDCl3):
d 1.72–1.79 (m, 1H, CH), 2.02–2.03 (m, 2H, CH2), 2.38 (t, 2H, CH2, J ¼ 6.8 Hz),
2.47–2.49 (m, 1H, CH), 2.78–2.80(m, 2H, CH2), 3.52–3.64 (m, 2H, CH2),
3.85–4.05 (m, 2H, CH2), 5.06 (dd, 1H, CH, J1 ¼ 7.6 Hz, J2 ¼ 8.0 Hz), 6.96 (d, 1H,
J ¼ 6.4 Hz), 7.03 (dd, 1H, J1 ¼ 8.0 Hz, J2 ¼ 7.6 Hz), 7.11 (d, 1H, J ¼ 7.6 Hz), 7.40

1,3-DIPOLAR CYCLOADDITION
3287
(dd, 1H, J1 ¼ 6.8 Hz, J2 ¼ 7.6 Hz), 7.65–7.74 (m, 2H), 7.86 (d, 1H, J ¼ 6.8 Hz), 8.11
(d, 1H, J ¼ 7.6 Hz). HRMS found: m=z 476.0742 (Mþ); calcd. for C25H21N2O3
79Br: M, 476.0736.
Compound 4j. Pink needles; mp 178–180 ꢀC (dec); IR (KBr): n 694, 759,
1
1175, 1346, 1466, 1609, 1664, 1729, 2863, 2965, 3062 cmꢂ1; H NMR (400 MHz,
CDCl3): d 1.72–1.80 (m, 1H, CH), 1.99–2.04 (m, 2H, CH2), 2.46–2.49 (m, 1H,
CH), 2.76–2.80 (m, 2H, CH2), 4.92–5.11 (m, 3H), 6.76 (d, 1H, J ¼ 7.6 Hz),
6.96–7.02 (m, 2H), 7.26–7.44 (m, 6H), 7.66–7.74 (m, 2H), 7.91 (d, 1H, J ¼ 7.6 Hz),
8.12 (d, 1H, J ¼ 7.2 Hz). HRMS found: m=z 446.1613 (Mþ); calcd. for
C29H22N2O3: M, 446.1630.
Compound 5. Pink needles; mp 180–182 ꢀC; IR (KBr): n 751, 1292, 1472,
1
1585, 1623, 1681, 1711, 2870, 2960, 3224, 3296 (NH) cmꢂ1; H NMR (400 MHz,
CDCl3): d 1.07 (d, 3H, CH3, J ¼ 6.4 Hz), 1.20 (d, 3H, CH3, J ¼ 6.0 Hz), 2.35 (br, s,
1H, NH), 2.70–2.79 (m, 1H, CH), 3.55–3.59 (m, 1H, CH), 3.65–3.68 (m, 1H, CH),
4.10 (d, 1H, J ¼ 7.6 Hz), 6.27 (d, 1H, J ¼ 7.6 Hz), 6.52 (dd, 1H, J1 ¼ 8.0 Hz,
J2 ¼ 7.2 Hz), 6.75 (d, 1H, J ¼ 8.0 Hz), 7.04 (ddt, 1H, J1 ¼ 8.0 Hz, J2 ¼ 7.6 Hz),
7.62–7.76 (m, 3H), 7.80 (dd, 1H, J1 ¼ 7.2 Hz, J2 ¼ 5.6 Hz), 8.10 (d, 1H, J ¼ 8.0 Hz).
HRMS found: m=z 360.1481 (Mþ); calcd. for C26H20N2O3: M, 360.1474.
ACKNOWLEDGMENTS
This work was supported in part by the Natural Science Foundation of Jiangsu
Province (No. BK2006048), the Nature Science Key Basic Research of Jiangsu Prov-
ince for Higher Education (No. 06KJA15007), and the National Natural Science
Foundation of China (Nos. 20472062 and 20672079).
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