Expedient synthesis of N-fused indoles through an intramolecular [3+2]-cycloaddition approach

Article abstract of DOI:10.1055/s-0029-1219551

A variety of N-fused indolo pyrrolo-pyrroles and pyrrolo-pyrrolizidines were synthesized by intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylide generated from N-alkenylindole carbaldehyde which were prepared by the N-alkylation of indole 2-aldehyde with Baylis-Hillman bromides. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219551

952
LETTER
Expedient Synthesis of N-Fused Indoles through an Intramolecular
[3+2]-Cycloaddition Approach
Synthesis of
N
u
-Fused Indo
b
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Fax +91(44)22352494; E-mail: ragharaghunathan@yahoo.com
Received 18 November 2009
Despite the importance of N-fused indole derivatives, the
synthesis of this class of compounds has not yet been fully
developed: alkyl-chain elongation and ring closure on an
existing indole platform have been reported by many re-
search groups (e.g., by intermolecular alkylation,7a radical
cyclization,7b,c and other methods7d–f). Transannulation
reactions8 also afford N-fused indoles.
Abstract: A variety of N-fused indolo pyrrolo-pyrroles and pyrro-
lo-pyrrolizidines were synthesized by intramolecular 1,3-dipolar
cycloaddition reaction of azomethine ylide generated from N-alke-
nylindole carbaldehyde which were prepared by the N-alkylation of
indole 2-aldehyde with Baylis–Hillman bromides.
Key words: N-fused indoles, indolo pyrrolo-pyrroles, pyrrolo-
pyrrolizidines 1,3-dipolar cycloaddition, azomethine ylides,
Baylis–Hillman adducts
Although many methods are available for the synthesis of
N-fused indoles, many of them requires vigorous reaction
conditions and use of expensive catalyst, which also re-
sults in poor yields of the products.9 In recent years many
transition-metal-catalyzed reactions have been reported.10
However, the ring-closure strategy still posed many prob-
lems and most importantly, a multistep synthesis of the
substrate is required regardless of the synthetic strategy
selected.
Many natural and synthetic biologically active com-
pounds containing the indole skeleton are being used for
therapeutic purposes.1 N-Fused indoles, for example, mi-
tomycin C2 and cryptaustoline3 possess the N-fused in-
dole structure (Figure 1), exhibit antitumor4 and tubulin
polymerization inhibitory5 activities. Pyrazino[1,2-a]in-
doles behave as 5-HT2c receptor agonists6 and are used for
the treatment of hyperglycemia and other diseases.
Intramolecular [3+2] cycloaddition of azomethine ylides
has been used widely to construct complex cyclic systems
from relatively simple precursors. This mode of cycload-
dition simultaneously constructs two carbon–carbon
bonds and forms complex ring systems with regio- and
stereocontrol.11–14
In continuation of our ongoing research program,15 herein
we describe an expedient synthesis of N-fused indoles by
means of direct, intramolecular 1,3-dipolar cycloaddition
of azomethine ylide from N-alkenylindole-2-carbalde-
hyde. Our strategy consists of N-alkylation of 3-methylin-
dole with Baylis–Hillman bromides16 and Vilsmeier–
Haack formylation followed by intramolecular cycloaddi-
tion to afford N-fused indole derivatives.
OMe
OH
O
NH
N
Me
MeO
MeO
N+
OMe
I–
H2N
O
OCONH2
mitomycin C
cryptaustoline
R1
NH
R2
N
pyrazino[1,2-a]indole
Thus we have prepared the substrates 1a–g by treating 3-
methylindole with Baylis–Hillman adducts followed by
Figure 1 Biologically active N-fused indoles
Me
N
CHO
O
H
N
toluene
reflux
N
+
N
Me
OH
MeOOC
MeO
O
R
3a–g (65–88%)
1a–g
2
R = H, 4-Cl, 3-NO2, 4-Br, 4-Me, 4-OMe, 2-Cl
Scheme 1 [3+2] Cycloaddition between precursor and sarcosine
SYNLETT 2010, No. 6, pp 0952–0954
x
x.
x
x.
2
0
1
0
Advanced online publication: 26.02.2010
DOI: 10.1055/s-0029-1219551; Art ID: G39210ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of N-Fused Indoles
953
Table 1 Synthesis of N-Fused Indole Derivatives 3 (continued)
formylation using Vilsmeier–Haack reaction (Scheme 1).
The substrates thus prepared (1a–g) were treated with 1.5
equivalents of sarcosine in toluene and heated to reflux
until the completion of the starting material as evidenced
by TLC. The reaction completed in 7 h to afford N-fused
indole derivatives 3a–g in good yield (Table 1 entry 1).
The conversion rate improved dramatically when the nitro
substituent in the benzene ring was used, giving 3c in 88%
yield (Table 1 entry 3).
Entry Precursor Products
Time
(h)a
Yield
(%)b
Me
N
N
6
1f
6.5
65
MeOOC
Table 1 Synthesis of N-Fused Indole Derivatives 3
OMe
Entry Precursor Products
Time
(h)a
Yield
(%)b
3f
Me
N
Me
N
N
7
1g
7
75
N
Cl
MeOOC
1
1a
7
78
MeOOC
3g
3a
a Reaction time of the cycloaddition step.
b Yield obtained after column chromatography.
Me
N
N
The structure and the regiochemistry of the cycloadducts
were confirmed by spectral analysis.17 The IR spectrum of
3a showed a sharp peak at 1740 cm–1 for the ester carbo-
nyl. The 1H NMR spectrum of 3a showed a singlet at d =
1.843 ppm corresponding to NCH3 protons. The methyl
protons attached to indole unit showed a sharp singlet at d
= 2.60 ppm. The two NCH2 protons appeared as multip-
lets in the range of d = 3.25–3.38 and 3.71–3.81 ppm. The
CH2 protons attached to indole skeleton showed a sharp
singlet at d = 2.60 ppm. The proton attached to the ester
carbonyl carbon appeared as a multiplet at d = 4.07–4.18
ppm. A singlet at d = 4.81 ppm was observed for the NCH
proton. The off-resonance proton-decoupled 13C spectrum
of 3a exhibited peaks at d = 21.04, 39.66, and 67.95 ppm
due to the CCH3, NCH3, and OCH3 bonds. The ester car-
bonyl resonated at d = 174.93 ppm. Finally, the structure
of 3a was confirmed by mass spectrometry, which
showed a peak at m/z = 346.85 [M+].
2
1b
6
80
MeOOC
Cl
3b
Me
N
N
3
1c
5
88
MeOOC
O2N
3c
Me
N
N
When secondary amino acids such as proline (n = 1) and
pipecolinic acid (n = 2) were employed, the correspond-
ing linearly fused pentacyclic pyrrolizidines and indoli-
zidines were accessed (Scheme 2).
4
1d
5
85
MeOOC
Br
In summary, we have developed a new route to biological-
ly and pharmacologically important N-fused indole deriv-
atives. For the first time the efficient construction of the
structurally novel indole derivatives has been synthesized
via a highly stereoselective intramolecular [3+2]-cycload-
dition reaction of azomethine ylides generated from
functionalized N-alkyl-3-methylindole-2-carbaldehydes.
Further studies are in progress to expand the reaction
scope and to use ferrocene-substituted N-alkenylindole
aldehydes for the synthesis of other novel heterocyclic
systems, and will be reported in due course.
3d
Me
N
N
5
1e
8
70
MeOOC
Me
3e
Synlett 2010, No. 6, 952–954 © Thieme Stuttgart · New York

954
S. Kathiravan, R. Raghunathan
LETTER
N
CHO
toluene
reflux
n
+
N
N
n
COOH
N
H
MeOOC
MeO
n = 1 or 2
R
O
4a–g n = 1 (72–89%)
5a–g n = 2 (69–85%)
1a–g
R = H, 4-Cl, 3-NO2, 4-Br, 4-Me, 4-OMe, 2-Cl
Scheme 2 [3+2] Cycloaddition between precursor and cyclic amino acid
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Int. Ed. 2003, 42, 3042; Angew. Chem. 2003, 115, 3151.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
S.K. thanks the Council of Scientific and Industrial Research
(CSIR) for the award of Senior Research Fellowship (SRF). S.K.
and R.R. thank DST-FIST New Delhi for NMR facility.
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A solution of 1a (1 mmol) and sarcosine 2 (1.5 mmol) in
toluene (10 mL) was stirred and heated at reflux for 6 h.
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crude product was purified by short column chromatography
on silica gel (hexane–EtOAc, 5:95) to provide the product in
78% yield as viscous colorless oil. 1H NMR (300 MHz,
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3.38 (m, 1 H), 3.71–3.81 (m, 1 H), 3.74 (s, 3 H), 4.07–4.15
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Synlett 2010, No. 6, 952–954 © Thieme Stuttgart · New York