A microwave assisted intramolecular-furan-Diels-Alder approach to 4-substituted indoles

Article abstract of DOI:10.1039/b816989f

The key steps of a versatile new protocol for the convergent synthesis of 3,4-disubstituted indoles are the addition of an α-lithiated alkylaminofuran to a carbonyl compound, a microwave-accelerated intramolecular Diels-Alder cycloaddition and an in situ

Full text of DOI:10.1039/b816989f

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A microwave assisted intramolecular-furan-Diels–Alder approach to
4-substituted indolesw
Filip Petronijevic, Cody Timmons,z Anthony Cuzzupey and Peter Wipf*
Received (in Cambridge, UK) 29th September 2008, Accepted 30th October 2008
First published as an Advance Article on the web 11th November 2008
DOI: 10.1039/b816989f
The key steps of a versatile new protocol for the convergent
synthesis of 3,4-disubstituted indoles are the addition of
an a-lithiated alkylaminofuran to a carbonyl compound, a
microwave-accelerated intramolecular Diels–Alder cyclo-
addition and an in situ double aromatization reaction.
The indole moiety is a ubiquitous structural motif that is
found in a wide array of naturally occurring alkaloids and
designed therapeutic agents. Interestingly, a relatively uniform
fraction of B4% of all pharmaceuticals, high-throughput
screening samples, as well as natural products, contain
an aromatic or partially saturated indole core (Fig. 1).1
Accordingly, the search for efficient protocols for the synthesis
of substituted indoles has remained an important research
topic for over a century.2 As part of a program aimed at
the synthesis of Ergot alkaloids,3,4 we have investigated
suitable methodologies for the late-stage introduction of a
4-substituted indole ring system. Padwa and co-workers have
Fig.
1
Representative synthetic and natural products with
4-substituted indole scaffolds (outlined in bold).1
developed an intramolecular Diels–Alder furan cycloaddition
reaction that provides substituted indolines from N-homo-
allylic 2-aminofurans.5,6 We envisioned that the addition of an
a-lithiated alkylaminofuran, 1, to an a,b-unsaturated carbonyl
compound, 2, followed by the in situ cycloaddition and
dehydrative aromatization of 6, would allow an extension of
this methodology to the direct preparation of 4-substituted
indoles, 7 (Scheme 1).
The preparation of lithium reagent 1 was accomplished by
transmetalation of stannane 10 (Scheme 2), which was readily
obtained from known iodide 87 and Boc-protected 2-amino-
furan 98 in the presence of sodium hydride. We next explored
conditions for the addition of 10 to a,b-unsaturated carbonyl
compounds. Transmetalation with n-butyllithium in THF
occurred only sluggishly at ꢀ100 1C, and decomposition was
found to be the major pathway at 0 1C. However, at ꢀ78 1C,
transmetalation was complete within 15 min, and upon treat-
ment with an excess of cinnamaldehyde, the expected addition
product, 11, was obtained in 66% yield.
Scheme 1 Proposed indole synthesis.
Department of Chemistry, University of Pittsburgh, Pittsburgh,
Pennsylvania, 15260, USA. E-mail: pwipf@pitt.edu;
Fax: +1 412-624-0787; Tel: +1 412-624-8606
w Electronic supplementary information (ESI) available: Experimental
procedures and full characterization of all the final products.
See DOI: 10.1039/b816989f
z Current address: Department of Chemistry and Physics, South-
western Oklahoma State University, Weatherford, Oklahoma,
73096, USA.
y Current address: Cytopia Research PTY Ltd., Richmond, 3121,
Australia
Scheme 2 The preparation of furanyl stannane 10, and a typical
transmetalation and aldehyde addition reaction.
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104 | Chem. Commun., 2009, 104–106

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Table 1 Scope of the microwave-accelerated intramolecular Diels–Alder indole formation cascade reaction
Entry
1
Time/min
20
Yield (%)
79
Substrate
Product
2
3
20
20
76
83
4
5
20
20
69
77
6
7
20
20
81
71
8
9
20
25
61 (7 : 4)
69
10
30
48
11
12
30
30
36
84
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After establishing a viable route to homoallylic furanyl
amines, we turned our attention to the intramolecular
Diels–Alder cascade indole formation process. Initially,
alcohol 11 was heated in toluene at reflux. After 48 h, gradual
decomposition of the starting material was observed. In con-
trast, when 11 was heated in o-dichlorobenzene under micro-
wave irradiation for 30 min at 170 1C, complete consumption
of the starting material was observed, and 4-phenylindole (12)
was isolated in 72% yield, presumably according to the
mechanism shown in Scheme 1. Indeed, this process proceeded
concomitantly with thermal Boc deprotection.9 In an effort to
shorten the reaction time, temperatures were varied, and
optimal conditions were found to involve microwave heating
of furan derivatives for 20 min at 180 1C. Under these
conditions, 12 was obtained in 79% yield from 11 (Table 1,
entry 1). The success of the microwave conditions vs. standard
heating is likely to be a consequence of the much faster heating
process and the higher temperatures in the pressurized reac-
tion vial, which can easily be accomplished with current
microwave reactors.
annulated indole 35 in 84% yield. Tricycle 35 is representative
of the core heterocycle of many Ergot alkaloids.
In conclusion, we have developed a new method for the
convergent and rapid preparation of 4-monosubstituted and
3,4-disubstituted indoles featuring the microwave-assisted
Diels–Alder cyclization of furans. The cascade process is quite
tolerant of functional groups and associated substitution
patterns. This strategy is a convenient alternative to the
common transition metal-mediated coupling processes for
the synthesis of these heterocycles.
This work has been supported by the NIH/NIGMS CMLD
program (GM067082), and, in part, by Merck Research
Laboratories.
Notes and references
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4 For our previous studies on indoline and isoindolinone synthesis
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This annulation strategy is quite tolerant of functional
groups. Initially, we varied the 4-aryl substituents from simple
electron-rich (entries 2 and 4) to electron-deficient arenes
(entry 3), observing a slight increase in yield to 83% in
the case of the 4-fluoro aryl substituent. Para- and meta-
substituted arenes with ester-functionalized side chains
behaved analogously to the methyl group (entries 5 and 6).
The use of a tosyl-protected indole ring in substrate 23
provided the corresponding 3,40-bisindole 24 (entry 7).
When symmetric bisfuran 25 was subjected to the
Diels–Alder cascade process, diannulated products 26 and 27
were obtained exclusively in a 7 : 4 ratio, with no mono-
cyclization being observed (entry 8). Interestingly, in this case,
the major product still contained a single Boc protecting
group. The formation of a monoprotected derivative of an
otherwise symmetrical bisindole could potentially be advanta-
geous for selective functionalizations and desymmetrizations.
Alternatively, re-subjecting this compound to thermal reaction
conditions (microwave irradiation at 180 1C, 20 min) cleanly
removed the residual Boc functionality to afford fully
deprotected species 27 in 89% yield after chromatographic
purification.
The introduction of alkenyl and alkyl groups in position 4
of the newly formed indole ring was also possible (entries
9–12). Propenyl derivative 29 was isolated in 69% yield in a
7 : 1 ratio of E : Z isomers, while the efficiency of the process
was slightly reduced for cyclopropyl compound 31 (48% yield)
and isopropyl indole 33 (36% yield). In spite of the lower
yield observed for 31, the successful use of a cyclopropane-
substituted compound in this reaction sequence is noteworthy.
We were also interested in expanding the scope of this
reaction to 3,4-disubstituted indoles, derived analogously from
additions of lithium reagent 1 to a,b-unsaturated ketones.
Specifically, tert-alcohol 34 was obtained by the treatment of
1 with 5 equiv. of 2-cyclohexene-1-one. The exposure of 34 to
the standard microwave conditions provided cyclohexane-
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This journal is The Royal Society of Chemistry 2009
106 | Chem. Commun., 2009, 104–106