Synthesis of novel functionalized 3-spiropyrrolizidine and 3-spiropyrrolidine oxindoles from Baylis-Hillman adducts of iatin and heteroaldehydes with azomethine ylides via [3+2]-cycloaddition

Article abstract of DOI:10.1021/ol701533d

A novel regioselective synthesis of a number of functionalized 3-spiropyrrolizidine and 3-spiropyrrolidine oxindoles from Baylis-Hillman adducts of satin and heteroaldehydes via [3+2] cycloaddition of azomethine ylides in excellent yields has been reported.

Full text of DOI:10.1021/ol701533d

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4095-4098
Synthesis of Novel Functionalized
3-Spiropyrrolizidine and
3-Spiropyrrolidine Oxindoles from
Baylis
Heteroaldehydes with Azomethine Ylides
via [3 2]-Cycloaddition
−Hillman Adducts of Isatin and
+
Ponnusamy Shanmugam,* Baby Viswambharan, and Suchithra Madhavan
Chemical Sciences and Technology DiVision, National Institute for Interdisciplinary
Science and Technology (NIST), TriVandrum-695 019, Kerala, India
shanmu196@rediffmail.com
Received July 2, 2007
ABSTRACT
A novel regioselective synthesis of a number of functionalized 3-spiropyrrolizidine and 3-spiropyrrolidine oxindoles from Baylis
−Hillman adducts
of isatin and heteroaldehydes via [3 2] cycloaddition of azomethine ylides in excellent yields has been reported.
+
Oxindoles derivatized at C3 as spirocarbo- and heterocyclics,
spirolactones, and spirocyclic ethers are elegant targets in
organic synthesis due to their significant biological activities
(Figure 1).1 These derivatives have been served as potential
synthons for the synthesis of alkaloids, drug intermediates,
and clinical pharmaceuticals.1 Hence, a number of synthetic
routes have been developed for the expedition of these
structural frameworks.2,3 Azomethine ylides are a class of
powerful reagents to utilize in the [1,3]-dipolar cycloaddition
reactions which generally afford a range of pharmacologi-
cally important heterocyclic compounds.4 The synthetic
versatility of isatin and its derivatives has led to the extensive
use of this compound in synthetic organic chemistry.5 Among
various carbon-carbon bond-forming reactions, the Baylis-
Hillman reaction is an important reaction giving rise to
densely functionalized molecules and is considered to be
atom economic.6 The synthesis of title compounds exploiting
Baylis-Hillman adducts of isatin and heteroaldehydes via
cycloaddition reaction is unknown. Thus, as part of our
research in the area of novel synthetic applications of
Baylis-Hillman adducts,7 particularly with isatin-derived
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10.1021/ol701533d CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/18/2007

Scheme 1. Retrosynthetic Approach for Spiropyrrolizidine and
Spiropyrrolidine Oxindole Synthesis
Figure 1. Spirooxindole alkaloid natural products.
Baylis-Hilman adducts,8 we explored the [3+2]-cycload-
dition reaction of Baylis-Hillman adducts of isatin and
heteroaldehydes with azomethine ylides. The reaction af-
forded novel 3-spiropyrrolizidine and 3-spiropyrrolidine
oxindoles. The preliminary results of the study are the content
of this letter.
pyrrolizidine derivatives of oxindols A could be synthesized
from the [3+2]-cycloaddition reaction of the Baylis-Hillman
adduct of isatin C and dipole B. Similarly, the spiropyrro-
lidine derivatives D could be synthesized from the dipole E
and Baylis-Hillman adduct C. The dipoles B and E could
be generated in situ from isatin and proline or sarcosine by
thermal decarboxylation reaction.
In a prototype experiment, the reaction of the Baylis-
Hillman adduct of N-methylisatin 1 with in situ generated
azomethine ylide B (isatin, proline, and eco-friendly mont-
morillonite K10 clay) in methanol was refluxed for 0.5 h to
afford the corresponding spiropyrrolizidine oxindole deriva-
tive 8 in 88% yield (Table 1, entry 1). The 1H NMR spectrum
of the compound 8 showed a singlet at δ 8.37 and a broad
singlet at δ 5.3 due to the hydrogens attached to nitrogen
and oxygen at the spiroxindole moiety. Two doublets
centered at δ 3.51 and δ 3.26 with a coupling constant J )
14.1 Hz showed the mutually coupled geminal protons at
the 2′-carbon of the pyrrolizidine ring.
To check the effect of solvent and catalyst requirements,
the reactions in 1,4-dioxane, toluene, and methanol as
solvents and with and without montmorillonite K10 clay
catalyst were tested. The combination of methanol as a
solvent and 100% w/w montmorillonite K10 clay as the
catalyst gave better yields and was found as the optimum
conditions. Reactions in 1,4-dioxane also provided the same
yields as that of methanol, whereas in toluene, poor yields
of the products (∼20%) were observed. The adduct of
N-benzylisatin 2 with dipole B under optimized conditions
The synthetic strategy for the construction of the title
compounds is shown in Scheme 1. Accordingly, the spiro-
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Org. Lett., Vol. 9, No. 21, 2007

Table 1. Synthesis of Bis[3-spiro-3′-pyrrolizidine]oxindoles
from the Baylis-Hillman Adduct of Isatin
Table 2. Synthesis of Bis[3-spiro-3′-pyrrolidine]oxindoles from
the Baylis-Hillman Adduct of Isatin
entry
R1
R2
Z
yield %
1
2
3
4
5
6
7
methyl
benzyl
allyl
methyl
propargyl
methyl
methyl
H
H
H
H
H
Me
H
CO2Me
CO2Me
CO2Me
SO2Ph
CO2Me
CN
88
85
90
75
89
91a
60b
yield %
entry
R1
R2
R3
Z
P1
P2
1
2
3
4
5
6
7
H
H
H
H
H
Br
NO2
methyl
benzyl
allyl
propargyl
methyl
H
Me
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CN
70
65
40
40
65
70
60
-
-
35
36
-
COMe
a
b
Mixture of inseparable regioisomers determined by 1H NMR. An
eliminated product was observed as determined by NMR and mass
spectroscopic data.
H
Me
Me
H
CO2Me
CO2Me
-
-
methyl
afforded pyrrolizidine oxindole derivative 9 in 85% yield
(Table 1, entry 2). Similarly, other Baylis-Hillman adducts
3-7 having different substituents at the heterocyclic nitrogen
and at activated alkenes underwent [3+2]-cycloaddition
smoothly with dipole B and afforded the corresponding
spiropyrrolizidine oxindoles 10-14 in excellent yields. All
the compounds were thoroughly characterized by spectro-
free hydoxyl proton and N-H protons in the products was
confirmed by D2O exchange experiments. The results are
summarized in Table 2.
1
scopic methods (IR, H, 13C NMR and FAB-mass spectra).
Table 3. Synthesis of 3-Spiropyrrolizidine Oxindoles from the
Hetero Baylis-Hillman Adduct
The results are summarized in Table 1.
It was noticed that the bis[3-spiro-3′-pyrrolizidine]oxindole
14 is unstable in solution at room temperature and underwent
elimination to give spiropyrrolizidine oxindole 15. However,
the compound was found stable when it was stored as
crystalline solid. The observation was evidenced from its
proton NMR and mass spectral data. The transformation is
shown in Scheme 2.
entry
X
R1
R2
yield %
1
2
3
4
O
O
O
S
H
Br
H
H
H
H
CH3
H
80
60
35
25
Scheme 2. Elimination of N-Methylisatin from 14
Having excellent preliminary results, we then turned our
attention to examine the reaction of Baylis-Hillman adducts
Table 4. Synthesis of 3-Spiropyrrolidine Oxindoles from the
Hetero Baylis-Hillman Adduct
Subsequent to the preliminary study, we extended the study
to [3+2]-cycloaddition reaction of Baylis-Hillman adducts
1-5, 16, and 17 with azomethine ylide E derived from
sarcosine under optimized reaction conditions to afford
spiropyrrolidine oxindole derivatives 18-26 in excellent
yield. Interestingly, in addition to the major pyrrolidine
oxindoles, other regioisomers 21 and 23 were isolated from
the reaction of azomethine ylide E with N-allyl and N-
propargyl isatin derivatives of Balyis-Hillman adducts
(Table 2, entries 3 and 4), respectively. The presence of a
entry
X
R1
R2
yield %
1
2
3
4
O
O
O
S
H
Br
H
H
H
H
CH3
H
68
50
30
22
Org. Lett., Vol. 9, No. 21, 2007
4097

27-30 derived from heteroaromatic aldehydes and azo-
methine ylides B and E. These reactions under optimized
reaction conditions furnished novel spiropyrrolizidine oxin-
doles 31-34 and spiropyrrolidine oxindole derivatives 35-
38 with 3′-heterocyclic (furan/thiophene) substituents, re-
spectively, in moderate to good yields. The results are
collected in Tables 3 and 4.
To our surprise, extension of the methodology to the
reaction of the Baylis-Hillman adduct of pyridine-3-
aldehyde with azomethine ylides B or E remined unaffected,
and the reaction is shown in Scheme 3.
3-spiropyrrolidine oxindoles starting from Baylis-Hillman
adducts of isatin and heteroaldehydes with azomethine ylides
via [3+2]-cycloaddition. Further studies using these products
for total synthesis of indole alkaloids are underway in this
laboratory.
Acknowledgment. We thank Prof. Dr. T. K. Chan-
drashekar, Director-NIST, for providing infrastructure facili-
ties. Financial support from the DST (New Delhi) vide
sanction No. SR/S1/OC-38/2005 is acknowledged. Construc-
tive suggestions from the reviewers of this manuscript are
acknowledged. B.V. thanks CSIR (New Delhi) for the award
of a Senior Research Fellowship. Thanks are due to Mrs.
Viji and Mrs. Soumini Mathew for providing mass and NMR
spectra.
Scheme 3. Reaction of the Baylis-Hillman Adduct of
Pyridine-3-aldehyde and Azomethine Ylides B and E
Supporting Information Available: Synthetic procedures
and spectroscopic characterization of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed a synthetic route for
the construction of functionalized 3-spiropyrrolizidine and
OL701533D
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Org. Lett., Vol. 9, No. 21, 2007