A two step route to indoles from haloarenes - A versatile variation on the Fischer indole synthesis

Article abstract of DOI:10.1039/c0cc04306k

In a new variation on the Fischer indole synthesis, readily available haloarenes are converted into a wide range of indoles in just two steps by halogen-magnesium exchange, quenching with di-tert-butyl azodicarboxylate, followed by reaction with ketones u

Full text of DOI:10.1039/c0cc04306k

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A two step route to indoles from haloarenes—a versatile variation on the
Fischer indole synthesisw
Martyn Inman and Christopher J. Moody*
Received 8th October 2010, Accepted 1st November 2010
DOI: 10.1039/c0cc04306k
In a new variation on the Fischer indole synthesis, readily
available haloarenes are converted into a wide range of indoles
in just two steps by halogen-magnesium exchange, quenching
with di-tert-butyl azodicarboxylate, followed by reaction with
ketones under acidic conditions.
Owing to the potent and wide-ranging biological activity of
indoles, and the complex and unusual architectures found
among their naturally occurring derivatives, this important
ring system continues to hold a fascination for chemists
worldwide.1–4 As a result, useful methodologies for the
synthesis of this venerable, but nonetheless ever relevant,
heterocycle continue to be developed. Unfortunately, even
modern methods, often transition-metal catalysed, frequently
start from ortho-substituted anilines,5–7 thereby greatly
restricting the availability of starting materials. A more
general approach would start from a mono-functionalised
arene followed by cyclisation with C–C bond formation to
an unactivated C–H bond, and a few notable advances
towards this goal have been reported recently. Thus Glorius
and colleagues described the palladium(II)-catalysed oxidative
Scheme 1 The Fischer indole synthesis.
cyclisation of N-aryl enamines derived from anilines and
1,3-dicarbonyl compounds,8 with related copper, iron and
iodine(III) mediated oxidative cyclisations being subsequently
reported,9–11 whilst the Fagnou group conceived a comple-
mentary approach involving rhodium catalysed coupling of
acetanilides with alkynes.12
In planning a straightforward route to aryl hydrazines,16
and hence indoles, we were attracted by the use of di-tert-butyl
azodicarboxylate as a source of the hydrazine unit, since the
resulting Boc-protecting groups would undergo concomitant
cleavage under the Brønsted or Lewis acidic conditions of the
Fischer cyclisation. Although azodicarboxylates have found
use as electrophiles in reactions with electron rich aromatic
rings,17,18 organolithiums and Grignard reagents,19,20
organozincs,21 or boronic acids under copper22,23 or palladium
catalysis,24 we elected to use the under utilised Grignard based
procedure because of the advantages of functional group
compatibility using modern methods of halogen-magnesium
exchange.25 Thus aryl iodides or bromides 1 underwent
halogen-magnesium exchange upon treatment with isopropyl-
magnesium chloride in THF,25 or phenylmagnesium chloride
in the case of nitro containing aromatics,26 followed by
reaction with di-tert-butyl azodicarboxylate to give the
However, some of the historically most important indole
syntheses also fall into this reaction category, and also involve
cyclisation with C–C bond formation to an unactivated C–H
bond. Pre-eminent amongst these is the most famous of all
indole syntheses, the Fischer reaction,13,14 that involves
functionalisation of an unactivated aromatic C–H position
by way of a [3,3]-sigmatropic shift (Scheme 1). Although
maybe unfashionable, this celebrated reaction satisfies the
requirements of a modern indole synthesis in its convenience
and simplicity—coupling a mono-functionalised arene with a
readily available aldehyde or ketone, the only disadvantage
being the lack of availability of aryl hydrazines. Mindful of
this limitation, and inspired by the mechanistic elegance
of the reaction, we now present a new variation on the
Fischer reaction that starts from much more readily available
haloarenes and delivers a wide range of indoles in just two
steps.15
di-Boc-protected aryl hydrazines
2
in 71–98% yield
(Scheme 2, Table 1). As expected, aryl bromides underwent
slower halogen-magnesium exchange than the iodides,27
allowing for selective magnesiation of 2-bromoiodobenzene
(entry 1), and the reaction is tolerant of a wide range of
functional groups including fluoride, chloride, tosyloxy, nitro
and carboxylate ester.
School of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: c.j.moody@nottingham.ac.uk;
Fax: +44 115 951 3564
w Electronic supplementary information (ESI) available: Full
experimental details and characterisation data for all compounds.
See DOI: 10.1039/c0cc04306k
Reaction of hydrazines 2 with an array of ketones under
acidic conditions resulted in cleavage of the protecting
groups, hydrazone formation and Fischer indolisation in a
single pot to give a range of indoles 3 in excellent yield
c
788 Chem. Commun., 2011, 47, 788–790
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Scheme 2
Table 1 Two-step conversion of haloarenes 1 into indoles 3 via aryl hydrazides 2
Entry ArX
2
Yield (%) R2
R3
Conditionsa Indole
3
Yield (%)
1
2a 72
CO2H Me
A
3ab 70
2
2b 93
CO2H Me
A
A
3bb 66
3
4
5
2c 87
2c 76
2d 71
(CH2)4
3c
—
3d
90
—
89
—
—
—
B
—
(CH2)4
6
7
2e 74
CO2H Me
C
A
3e
3f
83
76
2f 81
Me
Me
Me
8
2g 76
4-MeOC6H4
A
3g
68
9
2h 98
Ph
—
Me
—
A
3h
92
—
10
2h 66
—
—
—
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 788–790 789

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Table 1 (continued )
Entry ArX
2
Yield (%) R2
R3
Conditionsa Indole
3
Yield (%)
11
12
13
2i
80c
Me
Me
C
3i
96
2i
CO2H Me
C
3j
100
2i
2i
CO2Et Me
B
C
3k
3l
97
75
14
(CH2)5
a
b
c
Conditions: A, aq. HCl (35%), EtOH; B, TFA; C, aq. HCl (35%), AcOH. Esterification occurs during reaction. Phenylmagnesium chloride
used in metalation step.
(Scheme 2, Table 1). A variety of acidic conditions were
investigated (Table 1), but the most generally applicable were
the use of concentrated hydrochloric acid in ethanol at 70 1C,
although in some cases the use of acetic acid as solvent, or the
use of neat TFA was found to be superior (Table 1). Indoles
bearing a broad range of substituents were readily obtained by
this method, the meta-chloro-substituted hydrazide 2f giving,
as expected,28 only the 6-chloroindole 3f. Likewise, the
hydrazone derived from hydrazide 2g gave a single indole
product 3g.
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The advantages of this new variation of the classical Fischer
indole synthesis, incorporating the previously little used reaction
of Grignard reagents with azodicarboxylate electrophiles as a
key step, lie in its simplicity and versatility. Haloarenes are
appealing and readily available starting materials, and obviate
the need to prepare aryl hydrazines from anilines by the oft
problematic diazotisation–reduction sequence, simultaneously
avoiding undesirable anilines such as naphthylamines. These
features combine to make this an attractive and highly
practical alternative modern protocol for the synthesis of the
fundamentally important indole ring system.
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We thank the University of Nottingham and QGenta
Inc. for support. C. J. M. is a scientific cofounder of, and
stockholder in, QGenta Inc.
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Notes and references
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c
790 Chem. Commun., 2011, 47, 788–790
This journal is The Royal Society of Chemistry 2011