Synthesis of spiropyrrolidines and spiropyrrolizidines by azomethine ylide cycloaddition of baylis-hillman adducts derived from N -methyl maleimide

Article abstract of DOI:10.1055/s-0030-1258810

The stereoselective synthesis of a series of novel spiropyrrolidines and spiropyrrolizidines has been accomplished through an intermolecular 1,3-dipolar cycloaddition of an azomethine ylides with dipolarophiles derived from the Baylis-Hillman reaction of -isatins with N-methyl maleimide.

Full text of DOI:10.1055/s-0030-1258810

LETTER
2751
Synthesis of Spiropyrrolidines and Spiropyrrolizidines by Azomethine Ylide
Cycloaddition of Baylis–Hillman Adducts Derived from N-Methyl Maleimide
S
ynthesis of Spiro
.pyrrolidines
K
a
nd Spiropyrrolizi
adines rthikeyan, N. Saranya, A. Kalaivani, P. T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 9 August 2010
In continuation of our research in the area of 1,3-dipolar
Abstract: The stereoselective synthesis of a series of novel spiro-
pyrrolidines and spiropyrrolizidines has been accomplished through
an intermolecular 1,3-dipolar cycloaddition of an azomethine ylides
with dipolarophiles derived from the Baylis–Hillman reaction of
isatins with N-methyl maleimide.
cycloadditions17 and Baylis–Hillman chemistry,18 we
herein report a simple and convenient route for the regio-
and stereoselective synthesis of spiropyrrolidine and
spiropyrrolizidine frameworks using the Baylis–Hillman
adducts derived from maleimides and isatins with sar-
cosine/proline-based dipoles generated via in situ imine
formation, decarboxylation, and intermolecular [3+2] cy-
cloaddition.
Key words: Baylis–Hillman reaction, azomethine ylide cycloaddi-
ton, spiropyrrolidines, spiropyrrolizidines
The Baylis–Hillman reaction, one of the most atom-eco-
nomical and important carbon–carbon bond-forming re-
actions,1,2 has made great progress recently in the areas of
shortening reaction time, extending the scope of the sub-
strates, asymmetric catalysis, and mechanistic studies.3–5
Isatin and a number of its derivatives posses a reactive
keto-carbonyl group that readily undergoes condensation
reactions under mild conditions.6 It was therefore specu-
lated that isatin would be a suitable electrophilic compo-
nent for the Baylis–Hillman reaction.7 The 1,3-dipolar
cycloaddition reaction is one of the efficient methods for
the construction of heterocyclic units in a highly regiose-
lective and stereoselective manner.8 In particular, the
chemistry of azomethine ylides has gained significance in
recent years as it serves as an expedient route for the con-
struction of nitrogen containing five-membered heterocy-
cles, which constitute the central skeleton of numerous
natural products.9,10
NH
NMe
O
MeO
O
N
N
H
HO
H
horsfiline
O
elacomine
O
N
O
H
H
N
H
O
N
H
H
O
N
O
N
H
MeO
Me
alstonisine
spirotryprostatin A
Figure 1
The 1,3-dipole (azomethine ylide) generated by the decar-
boxylative condensation of isatin and secondary amino
acid reacts with dipolarophiles to afford novel spiropyrro-
lidine or spiropyrrolizidine ring systems.11 The pyrroli-
dine moiety is one of the significant core structures among
the most extensively studied natural and unnatural hetero-
cyclic compounds with remarkable medicinal activities.12
In particular, pyrrolidine and its fused derivatives, such as
pyrrolizidines and indolizidines, have played a unique
role in the design and synthesis of novel biologically ac-
tive compounds. The spiropyrrolidine framework is an in-
tegral part of many natural products such as horsfiline,13a
elacomine,13b alstonisine,13c spirotryprostatin A13d
(Figure 1). In addition spiropyrrolidines have been shown
to posses anticancer, antimicrobial, antibiotic, and antineo-
plastic properties.14–16
Thus, we synthesized Baylis–Hillman adducts 3a by the
reaction of isatin 1a with N-methyl maleimide 2 in the
presence of 30 mol% DABCO at 80 °C under neat condi-
tions (Scheme 1). The reaction yielded Baylis–Hillman
adducts 3a in 79%. Further we have performed the reac-
tion in the presence of solvents like MeOH, THF, and
DMSO. The yield was very low. Even when the catalytic
amount of DABCO was increased up to 50 mol%, there
was no change in the yield.
The structure of the Baylis–Hillaman adduct 3a was con-
firmed through NMR and mass spectral analysis.19 In the
1H NMR spectrum of 3a, the NMe groups in pyrrolidine
and oxindole rings appeared as two singlets at d = 2.88
and 3.25 ppm, respectively. The proton singlet at d = 6.77
ppm was assigned to olefinic proton. The OH proton ap-
peared as a broad singlet at d = 4.73 ppm. In 13C NMR,
peaks at d = 168.9, 169.5, and 174.5 ppm were assigned to
amide carbonyl carbons. The mass spectrum revealed the
molecular ion peak [M + H]+ at m/z = 273.
SYNLETT 2010, No. 18, pp 2751–2754
x
x
.x
x
.2
0
1
0
Advanced online publication: 08.10.2010
DOI: 10.1055/s-0030-1258810; Art ID: G23610ST
© Georg Thieme Verlag Stuttgart · New York

2752
K. Karthikeyan et al.
LETTER
Me
Under the above conditions the reactions of various sub-
stituted isatins 1b–g with N-methyl maleimide 2 were ex-
amined and the corresponding Baylis–Hillman adducts
3b–g were obtained in moderate to good yields
(Scheme 1). The results are summarized in Table 1 (entry
1–7). The structure of compound 3f was further confirmed
by single crystal X-ray analysis.20
N
O
O
O
HO
O
+
MeNHCH2COOH
+
O
N
R1
4
N
R1
1a,h
1h R1 = H
MeOH, reflux
3a,c,d,g
Me
N
O
O
Me
N1
O
O
HO
N
R1
5
2
DABCO
R1
N
O
O
N
Me
+
O
3
neat, 80 °C
4
N
R1
O
N
R1
OH
O
O
O
N
1a–g
2
3a–g
5a–e
Scheme 1 Synthesis of Baylis–Hillman adducts 3a–g
Scheme 2 Synthesis of spiropyrrolidines 5a–e
Table 1 Synthesis of Baylis–Hillman Adducts 3a–g
Encouraged by this result, the reaction of Baylis–Hillman
adducts 3a,c,d,g, isatin 1a,h, and sarcosine 4 in methanol
at reflux temperature was carried out to synthesize spiro-
pyrrolidine 5b–e in 72–81% yields. The results are sum-
marized in Table 2. The structures were further confirmed
and stereochemistry was assigned by single crystal X-ray
studies of compound 5c.22
Entry Isatin (R1)
Product Time (h) Yield (%)a
1
2
3
4
5
6
7
Me
1a
1b
1c
1d
3a
3b
3c
3d
3e
3f
1.5
3.0
1.5
2.5
4.0
2.0
2.0
79
71
78
70
62
75
72
propargyl
Et
All
Table 2 Synthesis of Spiropyrrolidines 5a–e
ethyl metheonate 1e
Entry Dipolarophile 3 Isatin 1 Product 5 Time (h) Yield (%)a
Bu
Bn
1f
1
2
3
4
5
3a
3a
3d
3g
3c
1a
1h
1a
1h
1h
5a
5b
5c
5d
5e
2.0
3.0
2.5
3.0
2.5
81
76
80
72
78
1g
3g
a Isolated yield after column chromatography.
By using the above Baylis–Hillman adducts 3a–g, we
have synthesized spiropyrrolidines and spiropyrrolidi-
zines by azomethine ylide cycloaddition. We first selected
Baylis–Hillman adduct 3a as the starting material for
[3+2] cycloaddition with dipoles generated from sar-
cosine (4) and isatin 1a in methanol for two hours at reflux
temperature, which successfully provided the desired
spiropyrrolidine 5a in very good yield (81%, Scheme 2)
The compound 5a was characterized by NMR spectrosco-
py, mass spectrometry, and elemental analysis.21
In the 1H NMR spectrum of compound 5a, four singlets at
d = 1.99, 2.65, 3.21, and 3.24 ppm were assigned to NMe
protons of the two pyrrolidine and two oxindole rings, re-
spectively. The singlet at d = 3.92 ppm was attributed to
C3–H and two doublets at d = 3.62 (J = 11.5 Hz) and 4.32
(J = 11.5 Hz) were assigned to protons at C5 carbon. In
13C NMR spectrum, the peak at d = 74.3 ppm corresponds
to the spiro carbon and the amide carbonyl carbons reso-
nated at d = 174.0, 175.4, 177.1, and 177.6 ppm. The mass
spectrum revealed the molecular ion peak [M + H]+ at
m/z = 461.
a Isolated yield after column chromatography.
To probe further the generality of the reaction, we subject-
ed the Baylis–Hillman adducts 3a,c–f with the dipole gen-
erated from isatin and proline in methanol at reflux
temperature to synthesize spiropyrrolizidines 7a–e in 70–
86% (Scheme 3). The results are summarized in Table 3.
Table 3 Synthesis of Spiropyrrolizidines 7a–e
Entry Dipolarophile 3 Isatin 1 Product 7 Time (h) Yield (%)a
1
2
3
4
5
3a
3c
3d
3e
3f
1a
1a
1a
1a
1a
7a
7b
7c
7d
7e
1.0
2.5
2.5
1.5
2.0
86
75
70
74
81
a Isolated yield after column chromatography.
Synlett 2010, No. 18, 2751–2754 © Thieme Stuttgart · New York

LETTER
Synthesis of Spiropyrrolidines and Spiropyrrolizidines
2753
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Scheme 3 Synthesis of spiropyrrolizidines 7a–e
The structure of the spiropyrrolizidine derivatives 7a–e
were confirmed by spectral analyses.23 The 1H NMR spec-
trum of compound 7b, two singlets at d = 2.70 and 3.21
ppm were assigned to MMe protons of pyrrolidine and ox-
indole ring, respectively. The singlet at d = 4.15 ppm cor-
responds to C3–H and triplet at d = 4.76 (J = 6.9 Hz) ppm
was assigned to C5–H. In the 13C NMR spectrum, peak at
d = 75.3 ppm corresponds to the spiro carbon and the
amide carbonyl carbons resonated at d = 174.3, 175.0, and
177.2 ppm. The mass spectrum revealed the molecular ion
peak [M + H]+ at m/z = 501.
In summary, we have successfully developed a simple and
novel protocol for the synthesis of Baylis–Hillman ad-
ducts from isatins and N-methyl maleimide under neat
conditions. Further we have used Baylis–Hillman adducts
as a dipolarophiles to synthesize novel spiropyrrolidines
and spiropyrrolizidines in good yields.
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Acknowledgment
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The author, K. Karthikeyan thank the Council of Scientific and In-
dustrial Research, New Delhi, India for the research fellowship.
References and Notes
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K. Karthikeyan et al.
LETTER
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(21) Experimental Procedure for the Synthesis of
Spiropyrrolidines 5a–e
A mixture of isatin 1 (1 mmol), sarcosine (4, 1.5 mmol), and
Baylis–Hillman adducts 3 (1 mmol) was refluxed in MeOH
(10 mL). Completion of the reaction was evidenced by TLC
analysis. The solvent was removed under vacuo, and the
crude product was subjected to column chromatography
using EtOAc–PE (2:8) as an eluent to afford pure
spiropyrrolidines 5a–e.
3a¢-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl)-1,2¢,5¢-
trimethyl-3¢,3a¢-dihydro-2¢H-spiro{indoline-3,1¢-
pyrrolo[3,4-c]pyrrole}-2,4¢,6¢(5¢H,6a¢H)-trione (5a)
Colorless solid; mp 258–260 °C. IR: 3361, 2963, 1699,
1612, 1471, 1373, 1124 cm–1. 1H NMR (500 MHz, CDCl3):
d = 1.99 (s, 3 H), 2.65 (s, 3 H), 3.21 (s, 3 H), 3.24 (s, 3 H),
3.62 (d, 1 H, J = 11.5 Hz), 3.92 (s, 1 H), 4.32 (d, 1 H,
J = 11.5 Hz), 5.81 (br s, 1 H), 6.77 (d, 1 H, J = 7.7 Hz), 6.82
(d, 1 H, J = 7.7 Hz), 6.89–6.93 (m, 2 H), 7.08–7.10 (m, 2 H),
7.26 (t, 1 H, J = 6.9 Hz), 7.38 (t, 1 H, J = 7.6 Hz). 13C NMR
(125 MHz, CDCl3): d = 25.1, 26.2, 26.4, 34.6, 53.2, 55.0,
63.4, 72.3, 74.3, 108.8, 108.9, 121.8, 123.3, 123.4, 123.9,
126.4, 126.9, 130.4, 130.7, 143.9, 144.1, 174.0, 175.4,
177.1, 177.6. MS: m/z = 461 [M + H]+. Anal. Calcd for
C25H24N4O5 (460.17): C, 65.21; H, 5.25; N, 12.17. Found: C,
65.29; H, 5.23; N, 12.24.
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(22) Crystallographic data of compound 5c in this letter have
been deposited with the Cambridge Crystallographic Data
Centre as supplemental publication No. CCDC-787473.
Copies of the data can be obtained, free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033 or email:
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(19) Experimental Procedure for the Synthesis of Baylis–
Hillman Adducts 3a–g
(23) Experimental Procedure for the Synthesis of
Spiropyrrolizidines 7a–e
A mixture of isatin 1a–g (1.62 mmol), N-methyl maleimide
(2, 1.35 mmol), and DABCO (30 mol%) was stirred at 80 °C
under neat conditions. Completion of the reaction was
evidenced by TLC analysis. The residue was dissolved in
EtOAc (20 mL) and H2O washed (2 × 20 mL). The EtOAc
layer was dried over anhyd Na2SO4, and the solvent was
removed under reduced pressure to obtain a crude product,
which was purified by column chromatography with
EtOAc–PE (2:8) as an eluent to obtain Baylis–Hillman
adducts 3a–g.
A mixture of isatin 1 (1 mmol), L-proline (6, 1.5 mmol), and
Baylis–Hillman adducts 3 (1 mmol) was refluxed in MeOH
(10 mL). Completion of the reaction was evidenced by TLC
analysis. The solvent was removed under vacuo, and the
crude product was subjected to column chromatography
using EtOAc–PE (2:8) as an eluent to afford pure
spiropyrrolizidines 7a–e.
8b¢-(1-Ethyl-3-hydroxy-2-oxoindolin-3-yl)-1,2¢-
dimethyl-6¢,7¢,8¢,8a¢-tetrahydro-1¢H-spiro{indoline-3,4¢-
pyrrolo[3,4-a]pyrrolizine}-1¢,2,3¢(2¢H,3a¢H,8b¢H)-trione
(7b)
Baylis–Hillman Adduct 3a
Colorless solid; mp 148–150 °C. IR: 3368, 3115, 1722,
1610, 1488, 1380, 1162 cm–1. 1H NMR (500 MHz, CDCl3):
d = 2.88 (s, 3 H), 3.25 (s, 3 H), 4.73 (br s, 1 H), 6.77 (s, 1 H),
6.91 (d, 1 H, J = 7.7 Hz), 7.09 (t, 1 H, J = 7.7 Hz), 7.28 (d, 1
H, J = 6.9 Hz), 7.38 (t, 1 H, J = 7.6 Hz). 13C NMR (125
MHz, CDCl3): d = 23.8, 26.8, 74.6, 109.4, 123.8, 124.8,
127.5, 128.8, 131.2, 143.9, 147.4, 168.9, 169.5, 174.5. MS:
m/z = 273 [M + H]+. Anal. Calcd for C14H12N2O4 (272.08):
C, 61.76; H, 4.44; N, 10.29. Found: C, 61.84; H, 4.47; N,
10.16.
Brown solid; mp 230–232 °C. IR: 3342, 2935, 1705, 1610,
1468, 1371, 1089 cm–1. 1H NMR (500 MHz, CDCl3): d =
1.31 (t, 3 H, J = 6.9 Hz), 1.72–1.79 (m, 1 H), 1.87–1.91 (m,
3 H), 2.14–2.18 (m, 1 H), 2.31–2.36 (m, 1 H), 2.70 (s, 3 H),
3.21 (s, 3 H), 3.63–3.69 (m, 1 H), 3.80–3.86 (m, 1 H), 4.16
(s, 1 H), 4.76 (t, 1 H, J = 6.9 Hz), 5.66 (br s, 1 H), 6.78 (d, 1
H, J = 7.7 Hz), 6.86 (t, 2 H, J = 8.4 Hz), 6.93 (t, 1 H, J = 7.7
Hz), 7.06 (t, 1 H, J = 6.9 Hz), 7.17 (d, 1 H, J = 6.9 Hz), 7.26
(t, 1 H, J = 7.7 Hz), 7.35 (t, 1 H, J = 7.7 Hz). 13C NMR (125
MHz, CDCl3): d = 12.4, 24.6, 24.9, 25.8, 26.3, 35.0, 42.3,
58.5, 62.2, 65.0, 66.9, 75.0, 108.7, 108.8, 122.5, 122.9,
124.2, 124.3, 126.4, 127.6, 130.2, 130.5, 143.4, 143.7,
174.3, 175.0, 177.2. MS: m/z = 501 [M + H]+. Anal. Calcd
for C28H28N4O5 (500.21): C, 67.19; H, 5.64; N, 11.19.
Found: C, 67.42; H, 5.66; N, 11.40.
(20) Crystallographic data of compound 3fin this letter have been
deposited with the Cambridge Crystallographic Data Centre
as supplemental publication No. CCDC-787472. Copies of
the data can be obtained, free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
(1223)336033 or email: deposit@ccdc.cam.ac.uk].
Synlett 2010, No. 18, 2751–2754 © Thieme Stuttgart · New York

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