[Cp*IrCl2]2-catalyzed indirect functionalization of alcohols: Novel strategies for the synthesis of substituted indoles

Article abstract of DOI:10.1021/ol071274v

We report novel iridium(III)-catalyzed reactions that afford substituted indoles via the indirect functionalization of alcohols via C-3 selective alkylation of indoles with alcohols and a one-pot cascade strategy from amino- or nitro-phenyl ethyl alcohols, which incorporates oxidative cyclization and C-3 alkylation.

Full text of DOI:10.1021/ol071274v

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3299-3302
[Cp*IrCl2]2-Catalyzed Indirect
Functionalization of Alcohols: Novel
Strategies for the Synthesis of
Substituted Indoles
Simon Whitney,† Ronald Grigg,*,† Andrew Derrick,‡ and Ann Keep§
Molecular, InnoVation, DiVersity and Automated Synthesis (MIDAS) Centre,
Department of Chemistry, UniVersity of Leeds, Leeds LS2 9JT, United Kingdom
r.grigg@leeds.ac.uk
Received May 30, 2007
ABSTRACT
We report novel iridium(III)-catalyzed reactions that afford substituted indoles via the indirect functionalization of alcohols via C-3 selective
alkylation of indoles with alcohols and a one-pot cascade strategy from amino- or nitro-phenyl ethyl alcohols, which incorporates oxidative
cyclization and C-3 alkylation.
The indole ring is a privileged structure found in many
structurally diverse natural products and pharmaceutical
agents,1 and new methods for indole synthesis and function-
alization continue to attract attention.2,3
Increasing demand for environmentally benign processes
has focused attention on transition metal catalyzed processes.
We have a long-standing interest in direct catalytic alkylation
with alcohols, which offers an attractive green chemistry
solution due to its high atom efficiency.4 Recent work in
this area includes R-alkylation of ketones with alcohols,5
indirect Wittig reactions with alcohols,6 and several publica-
tions utilizing [Cp*IrCl2]2 in reactions of this type,7a including
the direct â-alkylation of secondary alcohols with primary
alcohols.7b
Previously we have shown the high activity of transition
metal catalysts and in particular [Cp*IrCl2]2 in the monoalkyl-
ation of arylacetonitriles8 and barbituric acid9 with alcohols.
As part of our ongoing interest in this area, we report two
related [Cp*IrCl2]2-catalyzed cascade reactions that afford
substituted indoles.
(4) (a) Bibby, C. E.; Grigg, R.; Price, R. J. Chem. Soc., Dalton Trans.
1977, 872. (b) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S. Tetrrahedron
Lett. 1979, 20, 1067. (c) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.;
Tongpenyai, N. J. Chem. Soc., Chem. Commun. 1981, 611. (d) Grigg, R.;
Mitchell, T. R. B.; Sutthivaiyakit, S. Tetrahedron 1981, 37, 4313.
(5) Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.; Ishii,
Y. J. Am. Chem. Soc. 2004, 126, 72.
† University of Leeds.
‡ Pfizer Ltd., Chemical Research and Development, Ramsgate Road,
Sandwich, Kent CT13 9NJ, U.K.
§ Johnson Matthey, Orchard Road, Royston, Hertfordshire SG8 5HE,
U.K.
(6) Edwards, M. G.; Williams, J. M. J. Angew. Chem., Int. Ed. 2002,
41, 4740.
(1) Feniuk, W.; Humphrey, P. P. A. Drug DeV. Res. 1992, 26, 235.
(2) For reviews on the synthesis of indoles, see: (a) Humphrey, G. R.;
Kuethe, J. T. Chem. ReV. 2006, 106, 2875. (b) Gilchrist, T. L. J. Chem.
Soc., Perkin Trans. 1 2001, 2491. (c) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045. (d) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988,
25, 1. (e) Kuethe, J. T. Chimia 2006, 50, 543.
(7) (a) Fujita, K.; Yamaguchi, R. Synlett. 2005, 560. (b) Fujita, K.; Asai,
C.; Yamaguchi, T.; Hanasaka, F.; Yamaguchi, R. Org. Lett. 2005, 7, 4017.
(8) (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N.
Tetrahedron Lett. 1981, 22, 4107. (b) Lofberg, C.; Grigg, R.; Whittaker,
M.; Keep, A.; Derrick, A. J. Org. Chem. 2006, 71, 8023.
(9) Lofberg, C.; Grigg, R.; Keep, A.; Derrick, A.; Sridharan, V.; Kilner,
C. Chem. Commun. 2006, 5000.
(3) Robinson, B. The Fischer Indole Synthesis; Wiley-Interscience: New
York, 1982.
10.1021/ol071274v CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/21/2007

First we investigated the [Cp*IrCl2]2-catalyzed alkylation
of indole with alcohols under essentially solvent-free condi-
tions using a slight excess of alcohol to achieve a stirrable
mixture (Table 1). Indole was readily alkylated with aromatic,
Table 2. Alkylation of Substituted Indoles with Benzyl
Alcohol Using [IrCp*Cl2]2 and KOHa
Table 1. Alkylation of Indole with a Variety of Alcohols
Using [IrCp*Cl2]2 and KOHa
a Reactions were carried out in a sealed tube at 110 °C for 24 h with the
indole (1.0 mmol), benzyl alcohol (3.0 mmol), [Cp*IrCl2]2 (2.5 mol %),
and KOH (0.2 mmol). b Isolated yield. c Ratio of desired:bis-indolylmethane
byproduct was 6:1. d Reaction time was 48 h. e No product was observed
after 72 h.
has been reported,11 and it was therefore of interest to
investigate a [Cp*IrCl2]2-catalyzed/oxidative cyclization/
Scheme 1. Proposed Mechanism for the [Cp*IrCl2]2-Catalyzed
a Reactions were carried out in a sealed tube at 110 °C for 24 h with
indole (1.0 mmol), alcohol (3.0 mmol), [Cp*IrCl2]2 (2.5 mol %), and KOH
(0.2 mmol). Bis-indolylmethane byproducts 11-20% (Scheme 2) were
observed by 1H NMR. b Isolated yield. c Reaction time 48 h. d Reaction time
48 h, ratio of product : bis-indolylmethane byproduct was 3.5:1.
Alkylation of Indole with Alcohols
heteroaromatic, and aliphatic alcohols to give a variety of
3-substituted indoles in moderate to high yield. To the best
of our knowledge this is the first reported hydrogen transfer
mediated alkylation of indoles with alcohols using a transition
metal catalyst.
Next we investigated the alkylation of substituted indoles
(Table 2). Introduction of electron-donating and electron-
withdrawing groups was tolerated as was substitution in the
2-position. However N-methyl indole failed to undergo
alkylation (Table 2, entry 6), implicating the indole anion
in the alkylation (Scheme 1).
Scheme 1 is supported by the formation of minor bis-
indolylmethane byproducts arising from Michael addition of
indole to the intermediate A (Scheme 2).10
alkylation cascade of 2-aminophenyl ethyl alcohol and benzyl
alcohol (Table 3).
Initial trials using 5 molar equiv of benzyl alcohol to aid
solubility gave a mixture of N- and 3-benzyl indole due to
similar rates of intramolecular cyclization and intermolecular
N-alkylation. However at higher base concentration the
The use of transition metal catalysts for the oxidative
cyclization of 2-aminophenyl ethyl alcohols to give indoles
(11) (a) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2004, 4,
2691. (b) Aoyagi, Y.; Mizusaki, T.; Ohta, A. Tetrahedron Lett. 1996, 37,
9203. (c) Tsuji, Y.; Kotachi, S.; Huh, K.; Watanabe, Y. J. Org. Chem. 1990,
55, 580. (d) Tsuji, Y.; Huh, K.; Yokoyama, Y.; Watanabe, Y. J. Chem.
Soc., Chem. Commun. 1986, 1575.
(10) Gibbs, T. J. K.; Tomkinson, N. C. O. Org. Biomol. Chem. 2005, 3,
4043.
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Org. Lett., Vol. 9, No. 17, 2007

Scheme 2. Proposed Mechanism for the Formation of Minor
Table 4. One-Pot Synthesis of Substituted Indoles from
2-Aminophenyl Ethyl Alcohol and Primary Alcoholsa
Bis-indolylmethane Byproducts
reaction was highly selective for 3-benzylindole, which was
isolated in 78% yield (Table 3, entry 5).
Table 3. Oxidative Cyclization/Alkylation of 2-Aminophenyl
Ethyl Alcohol with Benzyl Alcohol Using [Cp*IrCl2]2 and
Varying Amounts of KOHa
entry
KOH (mmol)
conversionb (%)
ratiob B:C
1
2
3
4
5
0.1
0.2
0.5
1.0
2.0
60
>95
>95
>95
>95
50:50
50:50
33:67
13:87
1:99 (78%)c
a Reactions were carried out in a sealed tube at 110 °C for 24 h with
amino alcohol (1.0 mmol), benzyl alcohol (5.0 mmol), [Cp*IrCl2]2 (2.5
mol %), and KOH. b Estimated from 1H NMR. c Isolated yield of 3-ben-
zylindole (C).
a Reactions were carried out in a sealed tube at 110 °C for 24 h with
amino alcohol (1.0 mmol), alcohol (5.0 mmol), [Cp*IrCl2]2 (2.5 mol %),
and KOH (2.0 mmol). b Isolated yield. c Reaction time 48 h.
The synthesis of C-3 substituted indoles from 2-amino-
phenyl ethyl alcohol and a variety of alcohols was investi-
gated using the optimized conditions (Table 4). Moderate
to high yields were achieved for aromatic, heteroaromatic,
and aliphatic alcohols. The high yielding synthesis of N,N-
dimethyltryptamine (Table 4, entry 7) is of particular interest
as analogues of this compound form a class of commercially
important anti-migraine drugs.2a
demonstrates the ability to incorporate further steps into the
already complex catalytic cascade, which is dependent on
the relative rates of the individual steps in the sequence. In
this reaction [Cp*IrCl2]2 is performing multiple oxidation
and reduction steps. In Tables 4 and 5 and Scheme 4 little,
Next we investigated the effect of substitution on the
amino alcohol (Table 5). Good yields of disubstituted indoles
were achieved with substitution tolerated on the aromatic
ring (Table 5, entries 1 and 2) and also on the ethanol side
chain to give 2-methyl-3-benzyl indole in 71% yield (Table
5, entry 3).
Table 5. One-Pot Synthesis of 3-Benzylindoles from Amino
Alcohols and Benzyl Alcohola
The overall catalytic sequence consists of two interlocking
[Cp*IrCl2]2-catalyzed cycles (Scheme 3). The first cycle is
the oxidative cyclization of the amino alcohol to generate
the indole component.11a The second is the C-3 alkylation
of the in situ formed indole as described in Scheme 1.
Fujita et al. reported the use of [Cp*IrCl2]2 in the reduction
of 2-nitrophenyl ethyl alcohol in the presence of propan-2-
ol as a sacrificial hydrogen donor to give indole.11a In order
to incorporate the reduction of the nitro group into our
chemistry, we explored the reaction of 2-nitrophenyl ethyl
alcohol and benzyl alcohol (Scheme 4).
Using 10 molar equiv of benzyl alcohol, we obtained
3-benzylindole in 49% yield. This result is significant as it
a Reaction conditions as for Table 3. b Isolated yield
Org. Lett., Vol. 9, No. 17, 2007
3301

Scheme 3. Proposed Mechanism for the One-Pot, Tandem Oxidative Cyclization/Alkylation of 2-Aminophenyl Ethyl Alcohol and
Primary Alcohols To Afford Substituted Indoles
if any, bis-indolylmethane byproducts were evident, high-
lighting indole concentration as the key factor in the
generation of these species.
In conclusion, two novel [Cp*IrCl2]2-catalyzed methods
for the synthesis of substituted indoles have been developed,
utilizing the indirect functionalization of alcohols. These
allow one-pot access to a wide range of key building blocks.
Work continues on the development and application of this
methodology.
Acknowledgment. This work was a collaboration be-
tween the MIDAS Centre, Pfizer Chemical Research and
Development, and Johnson Matthey.
Scheme 4. One-Pot Synthesis of 3-Benzylindole from
2-Nitrophenyl Ethyl Alcohol and Benzyl Alcohol
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL071274V
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Org. Lett., Vol. 9, No. 17, 2007