Stereoselective synthesis of oxazino[4,3-a]indoles employing the oxa-Pictet-Spengler reaction of indoles bearing N-tethered vinylogous carbonate

Article abstract of DOI:10.1039/c0cc05558a

A one-pot, sequential 2,3-bis-functionalization of indoles bearing N-tethered vinylogous carbonates employing an intramolecular oxa-Pictet-Spengler reaction followed by electrophilic substitution is developed for the stereoselective synthesis of oxazino[4,3-a]indoles.

Full text of DOI:10.1039/c0cc05558a

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COMMUNICATION
Stereoselective synthesis of oxazino[4,3-a]indoles employing the
oxa-Pictet–Spengler reaction of indoles bearing N-tethered
vinylogous carbonatew
Santosh J. Gharpure* and A. M. Sathiyanarayanan
Received 14th December 2010, Accepted 18th January 2011
DOI: 10.1039/c0cc05558a
A one-pot, sequential 2,3-bis-functionalization of indoles bearing
N-tethered vinylogous carbonates employing an intramolecular
oxa-Pictet–Spengler reaction followed by electrophilic substitu-
tion is developed for the stereoselective synthesis of oxazino[4,3-a]-
indoles.
Scheme
1
Oxa-Pictet–Spengler cyclization for the synthesis of
oxazinoindoles.
The indole nucleus is ubiquitous in nature and is an integral
part of various alkaloid families and several pharmacologically
attractive synthetic targets.1 N-fused indoles have attracted
considerable attention due to the varied biological activity
Vinylogous carbonates have been extensively used in the
synthesis of cyclic ethers under radical conditions.10 Recently,
it has been demonstrated that they can act as Michael acceptors
under anionic conditions.11 It has also been shown that viny-
logous carbonates can function similar to enol ethers and can
act as a source of oxo-carbenium in the Prins type cyclization
reaction.12 However, these reports not withstanding, their
utility under Lewis acidic conditions is still not well explored.
In a program directed at using vinylogous carbonates in the
synthesis of cyclic ethers,13 particularly under non-radical
conditions,14 we envisaged that the oxazinoindole derivative 1
can be readily assembled via an intramolecular oxa-Pictet–
Spengler reaction on the indole derivative 2 bearing an
N-tethered vinylogous carbonate moiety (Scheme 1). The requisite
indole derivative 2 in turn could be readily prepared from the
substituted indoles and appropriate epoxides (see ESIw).
To test the hypothesis, the vinylogous carbonate 2a was
subjected to the oxa-Pictet–Spengler reaction with various
Lewis and Bronsted acids as catalysts. The results are summarized
in Table 1. Lewis acids like BF3ÁOEt2, BiBr3, TiCl4, SnCl4 and
FeCl3 gave the oxazinoindole 1a in poor to moderate yields
albeit with excellent diastereoselectivity (Table 1, entries 1–5).
Interestingly, when TMSOTf was used as the Lewis acid, the
oxazinoindole 1a was obtained in excellent yield and
diastereoselectivity (Table 1, entry 6). On the other hand,
Bronsted acids like TFA gave only a moderate yield due to
partial decomposition (Table 1, entry 7). Milder Bronsted acid
like (Æ)-binolphosphoric acid was found to be ineffective and
only starting material was recovered even after prolonged
reaction time (Table 1, entry 8). The cis stereochemistry of
the oxazinoindole 1a was ascertained by NOE experiments
and by the single crystal X-ray diffraction studies (see, ESIw).
Table 2 outlines the scope of this oxa-Pictet–Spengler reaction
of indole to vinylogous carbonates for the stereoselective synthesis
of the oxazinoindoles 1. The reaction was found to work well
associated with them. Mitomycin
C and cryptaustoline
possessing an N-fused indole unit have been associated with
antitumour2 and tubulin polymerization inhibitory activities.3
Pyrazino[1,2-a]indoles are reported to be 5-HT2c receptor
agonists,4 whereas oxazino[4,3-a]indole systems have been
studied for their antidepressant and antitumor properties.5
Given the biological significance of N-fused indoles, various
methods have been reported for the synthesis of N-fused indole
derivatives over the last several years. Recently, pyrazinoindoles
have drawn significant attention from synthetic chemists.6
However, methods for the synthesis of oxazinoindoles are
scarcely available in the literature. Very recently, Chen and
Xiao et al. reported synthesis of oxazino[4,3-a]indoles by
cascade addition–cyclization reactions of (1H-indol-2-yl)methanols
and vinyl sulfonium salts.7 Though useful, this elegant method
was largely limited to an unsubstituted or monosubstituted
oxazine core and the stereoselective synthesis of the oxazine
core was not discussed. Herein, we now describe a new
approach for the stereoselective synthesis of oxazinoindoles
employing an intramolecular oxa-Pictet–Spengler reaction of
an indole moiety with N-tethered vinylogous carbonate.8
The intramolecularity of the reaction ensures preferential
electrophilic substitution of indole at a less nucleophilic C2
position. We further demonstrate that one-pot, electrophilic,
bis-functionalization of indoles at C2 followed by the C3 position
can also be achieved by sequencing the reaction judiciously.9
Department of Chemistry, Indian Institute of Technology Madras,
Chennai–600036, Tamil Nadu, India. E-mail: sjgharpure@iitm.ac.in;
Fax: +91 44 2257 4202; Tel: +91 44 2257 4228
w Electronic supplementary information (ESI) available: Synthetic
procedures and characterization data for all the new compounds.
CCDC 801688–801689. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc05558a
c
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Chem. Commun., 2011, 47, 3625–3627 3625

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Table 1 Optimization of the oxa-Pictet–Spengler cyclization for the
synthesis of oxazinoindole 1a using indole 2a (R1 = R2 = H, R3 = Me)
Entry
Catalyst
Equiv.
Temp./1C
Time/h
Yielda,b (%)
1
2
3
4
5
6
7
8
BF3ÁOEt2
BiBr3
TiCl4
SnCl4
FeCl3
1.1
1.1
1.1
1.1
1.1
1.1
2.0
1.1
0–rt
rt
0-rt
0-rt
rt
0–rt
rt
rt
1.5
1.5
1.5
3.5
0.5
0.5
1.2
24
30
54
42
56
53
91
42
0
Scheme 2 One-pot, tandem oxa-Pictet–Spengler cyclization Friedel–
Crafts acylation for the synthesis of oxazinoindoles.
TMSOTf
CF3CO2H
(Æ)-BPAc
Inability of the 3-acetyl substituted indole derivative to
undergo cyclization prompted a rethink of the strategy. It was
envisaged that an acetyl group can be introduced at the C3
position of the indole in a tandem fashion via a Lewis acid
mediated Friedel–Crafts acylation reaction post facto i.e. after
the oxa-Pictet–Spengler cyclization of the indole moiety to
vinylogous carbonate is effected at the C2 position to generate
oxazinoindole. To test the hypothesis, the vinylogous carbonate
2a was reacted with TMSOTf to generate the oxazinoindole 1a
(TLC control) which was acylated in situ in a tandem fashion by
introducing Ac2O to the reaction mixture. Gratifyingly, the
reaction indeed furnished the acylated oxazinoindole derivative
1m in excellent overall yield and diastereoselectivity (Scheme 2).
A careful survey of the literature revealed that there are very
few reports available for the sequential electrophilic substitution
of C2 and C3 positions of indoles, particularly cases where C2 is
functionalized prior to the C3 position.1 Hence, we decided to
expand the scope of this tandem oxa-Pictet–Spengler electro-
philic substitution reaction by trapping the C3 position of the
indole moiety with various electrophiles leading to the synth-
esis of the substituted oxazinoindoles (Scheme 3).
a
b
Isolated yield. In all the cases, dr was determined on the crude
reaction mixtures by 1H NMR and was found to be Z 19 : 1.
c
(Æ)-Binolphosphoric acid.
Table 2 Scope of the oxa-Pictet–Spengler cyclization for the synthesis
of oxazinoindoles
Entry R1
R2 R3
Product Yielda,b (%) drc
1
2
3
4
5
6
7
8
H
H
H
H
Ph 2b 1b
CH2OBn 2c 1c
85
60
56
32
92
72
54
64
85
75
74
0
Z 19 : 1
Z 19 : 1
Z 19 : 1
Z 19 : 1
Z 19 : 1
Z 19 : 1
Z 19 : 1
Z 19 : 1
10 : 1
H
H
–(CH2)4–
–(CH2)3–
2d 1d
2e 1e
2f 1f
2g 1g
2h 1h
2i 1i
2j 1j
2k 1k
2l 1l
2m 1m
5-OMe
5-OMe
5-Br
5-Br
3-Me
3-Me
3-Ph
3-Ac
H
H
H
H
H
H
H
H
Me
Ph
Me
Ph
Me
Ph
Ph
Me
9
Various anhydrides and acid chlorides like propionic anhy-
dride (3), ethyl chlorooxoacetate (4), trifluoroacetic anhydride
(5) were added to the reaction mixture after complete conver-
sion of vinylogous carbonate 2a to furnish the requisite
3-substituted oxazinoindoles 1n–p in good yields and excellent
diastereoselectivity (Scheme 3). Not only acyl equivalents but
also Michael acceptors like methyl vinyl ketone (6) and methyl
acrylate (7) were found to be useful electrophiles in this
tandem oxa-Pictet–Spengler-electrophilic substitution reaction
10
11
12
7 : 1
5 : 1
—
a
b
Isolated yield. In all the cases, reaction was conducted for 0.5–1.5 h
c
(TLC control). In all the cases, dr was determined on the crude
1
reaction mixtures by H NMR.
with alkyl and aryl substitutions leading to the formation of the
product oxazinoindoles 1b–c in good to excellent yields and
diastereoselectivities (Table 2, entries 1 and 2). When an
additional ring, either a six-membered or a five-membered, was
present, reaction gave only a moderate yield of the corresponding
oxazinoindoles 1d–e, albeit with excellent diastereoselectivity
(Table 2, entries 3 and 4). Substitution on the phenyl ring of
the indole moiety did not have any detrimental effect on this
reaction (Table 2, entries 5–8). Interestingly, in the cases where an
alkyl or aryl substitution was present at the C3 position of indole,
the products were formed in good yields but only with moderate
diastereoselectivity (Table 2, entries 9–11). This could be
attributed to the steric interaction similar to 1,3-allylic strain.
Presence of an electron withdrawing acetyl group at the C3
position of indole, however, deactivated the indole moiety and
the desired product could not be obtained (Table 2, entry 12).
Prolonging the reaction time only led to decomposition of the
starting material. Formation of the cis isomer as the major product
in all the cases is consistent with the preference of the substituent
R3 and the incipient bulkier substituent (CH2CO2Et) to occupy the
pseudo-equatorial as opposed to pseudo-axial orientation in the
transition state in order to avoid 1,3-diaxial interaction.
Scheme 3 Scope of the one-pot, tandem oxa-Pictet–Spengler cyclization
electrophilic substitution for the synthesis of oxazinoindoles.
c
3626 Chem. Commun., 2011, 47, 3625–3627
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leading to disubstituted oxazinoindoles via a one pot, tandem
oxa-Pictet–Spengler-electrophilic substitution reaction. Further,
the oxazinoindole derivatives were efficiently elaborated into the
oxa-spirooxindole derivatives using oxidative cyclization reaction.
We thank DST and CSIR, New Delhi for financial support.
We thank Mr Ramkumar of the X-ray facility of the Department
of Chemistry, IIT Madras for collecting the crystallographic data
and SAIF, IIT Madras for NMR data. We are grateful to CSIR,
New Delhi for the award of research fellowship to AMS.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3625–3627 3627