Indole functionalization via photoredox gold catalysis

Article abstract of DOI:10.1021/acs.orglett.5b01260

The use of photoredox catalyst [Au₂(dppm)₂]Cl₂ to initiate free-radical cyclizations onto indoles is reported. Excitation of the dimeric Au(I) photocatalyst for the reduction of unactivated bromoalkanes and bromoarenes is used for the generation of carbon-centered radicals. Previous to this work, reduction processes leading to indole functionalization utilizing photoredox catalysts were limited to activated benzylic or α-carbonyl-positioned bromoalkanes. This method offers a mild and safe alternative to organostannanes and pyrophoric initiators for access to high energy radicals that were previously inaccessible through catalytic or stoichiometric means.

Full text of DOI:10.1021/acs.orglett.5b01260

Letter
pubs.acs.org/OrgLett
Indole Functionalization via Photoredox Gold Catalysis
Sherif J. Kaldas, Alexandre Cannillo, Terry McCallum, and Louis Barriault*
Centre for Catalysis, Research and Innovation, Department of Chemistry and Biomolecular Science, University of Ottawa, 10 Marie
Curie, Ottawa K1N 6N5, Canada
S
* Supporting Information
ABSTRACT: The use of photoredox catalyst [Au2(dppm)2]-
Cl2 to initiate free-radical cyclizations onto indoles is reported.
Excitation of the dimeric Au(I) photocatalyst for the reduction
of unactivated bromoalkanes and bromoarenes is used for the
generation of carbon-centered radicals. Previous to this work,
reduction processes leading to indole functionalization utilizing photoredox catalysts were limited to activated benzylic or α-
carbonyl-positioned bromoalkanes. This method offers a mild and safe alternative to organostannanes and pyrophoric initiators
for access to high energy radicals that were previously inaccessible through catalytic or stoichiometric means.
adical chemistry has grown significantly in recent years,
although its roots extend more than a century. Many
photoredox process 2 → 3, which are common motifs in
natural products and biologically active molecules (Scheme 1).
R
advances have been made in understanding the reactivity of
carbon-centered radicals and its application in synthesis.1
Current methods to generate carbon-centered radicals from
unactivated organohalides generally use potentially hazardous/
toxic radical initiators (AIBN, peroxides, Et3B/O2) and
hydrogen atom donors (organostannane).2 With much interest
being placed on sustainable chemistry, recent literature has
shown movement toward the use of photoredox catalysis,
which offers safe, efficient, and waste-minimizing methods to
generate organic radicals.3
Scheme 1. Photoredox Transformation
Inspired by biocomplexes that perform photosynthesis in
nature, chemists have developed a variety of photoredox
complexes for research in energy storage, water splitting, and
photovoltaic devices.4 Among these, polypyridine Ru(II)5 and
Ir(III) complexes such as [Ru(bpy)3Cl2], [Ir(ppy)2(dtbbpy)]-
PF6, and fac-Ir(ppy)3 possess high-energy, long-lived, and
highly emissive excited states that are useful in organic
synthesis. While these catalysts can generate carbon-centered
radical intermediates via the reduction of carbon−halogen
bonds, they suffer from low reduction potentials, limiting
radical intermediates to those derived from activated carbon−
halogen bonds. These include bromomalonates,6 polyhalo-
methanes,7 electron-deficient benzyl halides,8 and iodoalkane9
and iodoarenes. With these limitations in mind, it is important
to develop new photoredox catalysts that offer the ability to
reduce unactivated carbon−halogen bonds with higher
reduction potentials, thus giving access to a wide range of
organic free radicals.
In 2013, we reported the reductive scission of unactivated
bromoalkanes/arene bonds using a catalytic amount of
photoluminescent dimeric gold complex, [Au2(dppm)2]Cl2
(1).10 UVA irradiation of 1 generates a long-lived excited
state, which can either undergo an oxidative or reductive
quench cycle.11,12 On the basis of these results, we were
interested in the applicability of [Au2(dppm)2]Cl2 (1) as a
catalyst for the functionalization of indoles through a
In general, oxidative radical additions to indoles and pyrroles
require the use of stoichiometric oxidants13 such as Mn-
14,15
(OAc)3
or activated carbon−halogen bonds using [Ru-
(bpy)3Cl2] as photocatalyst.16 We hypothesized that the C−Br
reduction of 2 via an oxidative quenching cycle should produce
the corresponding primary alkyl radical 4, which upon
cyclization would give the benzylic radical intermediate 5.
Received: April 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01260
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Concomitant oxidation of intermediate 5 and reduction of the
[Au−Au]3+ complex should provide the desired indole 3 and
the dimeric gold photocatalyst (1) turnover.
Table 2. Scope of the Reaction
To verify the hypothesis depicted in Scheme 1, bromoalkane
2a was irradiated (UVA LED, 365 nm) in the presence of
[Au2(dppm)2]Cl2 (2.5 mol %) and DIPEA (5 equiv) in MeCN
to produce an inseparable mixture of indole 3a (42%), indoline
9a (20%), and dehalogenated product 10a (7%), along with
some starting material (20%) (Table 1, entry 1). While amine
a
Table 1. Optimization of the Reaction Conditions
product (%)
entry
base
time (h)
2a
20
3a
9a
10a
b
1
2
DIPEA
1
1
42
10
20
10
7
b
TMEDA
60
97
9
12
b
3
DABCO
1
b
4
PMP
1
54
41
78
98
20
7
c
5
Na2CO3
Na2CO3
Na2CO3
1
51
15
c
6
6
c
7
12
12
12
12
8
>98
>98
>98
c
c
,
,
d
e
9
Na2CO3
Na2CO3
10
a
b
c
1H NMR yield with mesitylene as internal standard. 5 equiv.
2
d
e
equiv. No catalyst. No light.
bases act as sacrificial electron donors, one could envisage the
diminution of the reduced side products 9a and 10a by using
poor hydrogen donor amine bases. Irradiation in the presence
of TMEDA, DABCO, or 1,2,2,6,6-pentamethylpiperidine
(PMP) did not lead to any noticeable improvement (Table 1,
entries 2−4). However, the replacement of the amine base by
sodium carbonate led to the formation of 3a in 41% yield
(Table 1, entry 5). Although the reaction was not complete, no
traces of reduced product 9a and/or 10a were observed in the
crude reaction mixture. Finally, a complete conversion was
reached after 12 h of irradiation (Table 1, entries 6 and 7).
Indole 3a was obtained as the sole product in 98% yield (Table
1, entry 7). Standard control experiments showed that in the
absence of gold photocatalyst, UVA irradiation, or base a
complete recovery of the starting material was obtained (Table
1, entries 8−10).
With these optimized conditions in hand, we proceeded to
examine the scope of the photoredox cyclization by using
substituted N-alkylindole substrates (Table 2). Gold(I)-
catalyzed photoredox cyclization of primary and secondary
bromoalkanes 2b and 2c provided the desired indoles 3b and
3c in 88% and 98% yields respectively (Table 2, entries 1 and
2). The nature of the substitution on the indole ring has no
detrimental effect on the photoredox transformation. The
substrates having electron-withdrawing groups such as 4-cyano-
and 5-chloroindoles 2d and 2e were easily converted to the
corresponding cyclized products 3d and 3e in 90% and 95%
yields, respectively (Table 2, entries 3 and 4). 5-Methoxyindole
2f was converted to the tricyclic product 3f in 98% yield (Table
2, entry 5). Although the addition of a primary radical at C2 is
expected to be particularly favorable, apprehensions were raised
regarding the photoredox cyclization of indoles 2g−i. Assuming
a
[Au2(dppm)2][Cl]2 (2.5 mol %) and Na2CO3 (5 equiv) in MeCN,
b
c
UVA (365 nm), rt, 12 h. Isolated yields and c = 0.2 M. The yield in
parentheses corresponds the dehalogenated products 10l and 10m.
that the conversion of 5 to 3 does not proceed through a radical
disproportionation, the concomitant oxidation/reduction mani-
B
DOI: 10.1021/acs.orglett.5b01260
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Organic Letters
Letter
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S
* Supporting Information
1
Experimental procedures and H and 13C NMR spectra for all
new compounds. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01260.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lbarriau@uottawa.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(12) Xie, J.; Zhang, T.; Mehrkens, N.; Rudolph, M.; Hashmi, A. S. K.
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■
We thank the Natural Sciences and Engineering Research
Council (for Accelerator, Discovery and CREATE grants to
L.B.) and the University of Ottawa (for a University Research
Chair to L.B.) for support of this research. Acknowledgement is
also made to the donors of the American Chemical Society
Petroleum Research Fund for support of this research. T.M.
and S.J.K. thank NSERC (CREATE on medicinal chemistry
and biopharmaceutical development). A.C. thanks the Uni-
versity of Ottawa for a Vision 2020 postdoctoral scholarship.
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DOI: 10.1021/acs.orglett.5b01260
Org. Lett. XXXX, XXX, XXX−XXX