Electron transfer photoredox catalysis: Intramolecular radical addition to indoles and pyrroles

Article abstract of DOI:10.1021/ol902703k

(Figure presented) The utilization of the photoredox catalyst, trls(2,2-blpyrldyl)ruthenium dichloride, and a household light bulb to effect radical cyclizations onto indoles and pyrroles at room temperature is reported. A reactive free radical intermediate is generated via the reduction of an activated C-Br bond by the single electron reductant, Ru(I), generated in a visible light induced photocatalytic cycle. This system represents an expansion of the application of photoredox catalysis in conventional free radical processes.

Full text of DOI:10.1021/ol902703k

ORGANIC
LETTERS
2010
Vol. 12, No. 2
368-371
Electron Transfer Photoredox Catalysis:
Intramolecular Radical Addition to
Indoles and Pyrroles
Joseph W. Tucker, Jagan M. R. Narayanam, Scott W. Krabbe, and Corey
R. J. Stephenson*
Department of Chemistry, Boston UniVersity, Boston, Massachusetts 02215
crjsteph@bu.edu
Received November 23, 2009
ABSTRACT
The utilization of the photoredox catalyst, tris(2,2′-bipyridyl)ruthenium dichloride, and a household light bulb to effect radical cyclizations onto
indoles and pyrroles at room temperature is reported. A reactive free radical intermediate is generated via the reduction of an activated C-Br
bond by the single electron reductant, Ru(I), generated in a visible light induced photocatalytic cycle. This system represents an expansion
of the application of photoredox catalysis in conventional free radical processes.
Concerted efforts over the past 40 years have established
single-electron transfer (SET) and the formation of radicals
as reliable processes to form new carbon-carbon bonds.1-3
Despite this prominence, there are still relatively few methods
for the generation of radicals under benign conditions. For
example, the stalwarts for radical formation have long been
the highly toxic and persistent environmental pollutants,
trialkyltin hydrides.4 Furthermore, these radical initiation
systems often lack the necessary chemoselectivity and
functional group tolerance for use with highly functionalized
substrates.5 In light of these issues, and cognizant of the
broad chemical community’s interest in the development of
more environmentally benign chemical transformations,6 we
have been exploring the application of photoredox catalysis
as a new means of accessing free radical chemistry (Scheme
1).7,8 We have recently demonstrated the ability of the visible
light activated photoredox catalyst, tris(2,2′-bipyridyl)ruthe-
nium(II) chloride,9 to efficiently and chemoselectively act
as a single electron reductant and afford the reductive de-
(5) For examples of functional group reactivity using other radical
initiation systems, see: (a) Ferris, J. P.; Antonucci, F. R. J. Am. Chem. Soc.
1972, 94, 8091. (b) Molander, G. A. Org. React. 1994, 46, 211. (c)
Bebbington, D.; Bentley, J.; Nilsson, P. A.; Parsons, A. F. Tetrahedron
Lett. 2000, 41, 8941. (d) Bowman, W. R.; Bridge, C. F.; Brookes, P.
Tetrahedron Lett. 2000, 41, 8989.
(1) Balzani, V. Electron Transfer in Chemistry; Wiley-VCH: Weinheim,
2001; Vol. 1
.
(2) For recent reviews of photoelectron transfer chemistry in organic
synthesis, see: (a) Hoffmann, N. J. Photochem. Photobiol. C, Photochem.
ReV. 2008, 9, 43. (b) Cossy, J.; Belotti, D. Tetrahedron 2006, 62, 6459
.
(6) For reviews on sustainable chemistry, see: (a) Albini, A.; Fagnoni,
M. Green Chem. 2004, 6, 1. (b) Jenck, J. F.; Agterberg, F.; Droescher,
M. J. Green Chem. 2004, 6, 544.
(3) For reviews on radical chemistry, see: (a) Curran, D. P. Synthesis
1988, 6, 417. (b) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96,
177
.
(7) Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am.
(4) For selected recent examples of tin-free radical reactions see: (a)
Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood,
J. L. J. Am. Chem. Soc. 2005, 127, 12513. (b) Hayashi, N.; Shibata, I.;
Baba, A. Org. Lett. 2005, 7, 3093. (c) Gong, H.; Andrews, R. S.; Zuccarello,
J. S.; Lee, S. J.; Gagne´, M. R. Org. Lett. 2009, 11, 879.
Chem. Soc. 2009, 131, 8756.
(8) For the use of dihydroacridines as a hydrogen atom source for the
reduction of R-haloacetophenones using Ru-mediated photoredox catalysis,
see: Fukuzumi, S.; Mochizuki, S.; Tanaka, T. J. Phys. Chem. 1990, 94,
722
.
10.1021/ol902703k  2010 American Chemical Society
Published on Web 12/16/2009

visible light irradiation yielded 52% of the desired
cyclization product, 2. The major byproduct, present to
varying degrees in all subsequent cyclization reactions,
is the corresponding reduced compound, 3, obtained here
in 40% yield (Scheme 2). In the absence of any of the
Scheme 1. Generation of Radicals Using Photoredox Catalysis
Scheme 2. Initial Cyclization Result
halogenation of compounds with activated carbon-halogen
bonds via a reactive alkyl radical.10,11
The functionalization of indoles and pyrroles, thanks to
their abundance in biologically and medicinally active
compounds, has received much attention to date.12 We were
inspired to investigate the utility of Ru-photoredox chem-
istry in the area of heterocycle functionalization by recent
developments in Mn(III)-based malonyl radical cyclization
reactions.13,14 In particular, Kerr and co-workers have
recently demonstrated the utility of the oxidative generation
of malonyl radicals with Mn(OAc)3 for the intramolecular
functionalization of indoles, indolines, and pyrroles.15 In this
letter we report the application of photoredox catalysis to
the intramolecular functionalization of substituted indoles and
pyrroles.
i
reaction components, Ru(bpy)3Cl2, light, and/or Pr2NEt,
no reaction was observed.
Optimization of the reaction conditions involved the
screening of amine bases to act as a sacrificial electron donor
to reductively quench the photoinduced excited Ru(II)*
species. To minimize the formation of the reductively
dehalogenated product, bases that do not serve as good
hydrogen atom donors were sought. Amines such as Ph3N,
Et3N, DABCO, Me3N, and (HOCH2CH2)3N were all screened.
Although DABCO, Me3N, and (HOCH2CH2)3N all proved
to be effective hydrogen donors, they were poorly selective
and provided product mixtures favoring 3. Triethylamine
provided the best balance of efficient reactivity and selectivity
for the cyclization reaction over the competitive dehaloge-
nation process. Of note, the most selective reaction involved
the use of triphenylamine as an electron source resulting only
in formation of the desired cyclization product, although even
after prolonged reaction time (>48 h) only 60% conversion
(34% isolated yield) was observed.
Upon initial investigations of reaction conditions, we
i
were encouraged to find that treatment of 1 with Pr2NEt
(2 equiv) and Ru(bpy)3Cl2 (2.5 mol %) in DMF under
(9) For excellent reviews on the photochemistry and photophysics of
2+
Ru(bpy)3 and related complexes, see: (a) Kalyanasundaram, K. Coord.
Chem. ReV. 1982, 46, 159. (b) Juris, A.; Balzani, V.; Barigelletti, F.;
Campagna, S.; Belser, P.; von Zelewsky, A. Coord. Chem. ReV. 1988, 84,
85.
(10) For recent examples of photoredox catalysis, see: (a) Nicewicz,
We next applied the optimized reaction conditions, con-
sisting of the cyclization substrate in combination with
Ru(bpy)3Cl2 (1.0 mol %) and Et3N (2 equiv) in DMF under
irradiation by a 14 W household light bulb, to a series of
substituted indoles (Table 1). Both six- and five-membered
fused rings are possible, although five-membered rings are
more difficult to form and generally require a substituent at
C-3 to stabilize the tertiary radical resulting from cyclization.
The chemoselectivity of this photoredox system for the
reduction of activated C-Br bonds over aryl C-Br bonds
is demonstrated by entry 5. In addition, functional groups
including esters, amides, and cyano groups are all well
tolerated. Electron-rich indoles provided the desired cycliza-
tion product, and even electron-deficient indoles were modest
substrates for this reaction, providing the corresponding
cyclization product in 40% yield (entry 9).16 The reaction
also works well for the preparation of linear tricyclic systems
resulting from an endo cyclization of the malonyl radical
(entry 10).
D. A.; MacMillan, D. W. C. Science 2008, 322, 77. (b) Ischay, M. A.;
Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12886.
(c) Koike, T.; Akita, M. Chem. Lett. 2009, 38, 166. (d) Borak, J. B.; Falvey,
D. E. J. Org. Chem. 2009, 74, 3894. (e) Du, J.; Yoon, T. P. J. Am. Chem.
Soc. 2009, 131, 14604. (f) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2009, 131, 10875
.
(11) For reviews on the photoactivation of metal complexes, see: (a)
Salomon, R. G. Tetrahedron 1983, 39, 485. (b) Kutal, C. Coord. Chem.
ReV. 1985, 65, 191. (c) Hennig, H. Coord. Chem. ReV. 1999, 182, 101. (d)
Hoffmann, N. Chem. ReV. 2008, 108, 1052
.
(12) For selected recent examples of the functionalization of indoles
and pyrroles, see: (a) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature
2007, 446, 404. (b) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (c)
Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo,
M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857. (d) Tanaka, M.;
Ubukata, M.; Matsuo, T.; Yasue, K.; Matsumoto, K.; Kajimoto, Y.; Ogo,
T.; Inaba, T. Org. Lett. 2007, 9, 3331. (e) Antos, J. M.; McFarland, J. M.;
Iavarone, A. T.; Francis, M. B. J. Am. Chem. Soc. 2009, 131, 6301.
(13) For an excellent review on Mn(III) chemistry, see: Snider, B. B.
Chem. ReV. 1996, 96, 339
.
(14) For selected examples of radical initiated methods of indole/pyrrole
functionalization, see: (a) Baciocchi, E.; Muragli, E. J. Org. Chem. 1993,
58, 7610. (b) Byers, J. H.; DeWitt, A.; Nasveschuk, C. G.; Swigor, J. E.
Tetrahedron Lett. 2004, 35, 6587. (c) Guadarrama-Morales, O.; Me´ndez,
F.; Mirana, L. D. Tetrahedron Lett. 2007, 48, 4515. (d) Lindsay, K. B.;
Ferrando, F.; Christensen, K. L.; Overgaard, J.; Roca, T.; Benasar, M.;
Skrydstrup, T. J. Org. Chem. 2007, 72, 4181
(15) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561. Magolan, J.;
Carson, C. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437.
.
(16) The reduced compound is also observed in the crude 1H NMR,
present as an approximately 1:1 mixture with the cyclized product.
Org. Lett., Vol. 12, No. 2, 2010
369

pyrrole substrates wherein the pyrrole substrates generally
performed better than indoles.17 Again, good functional group
tolerance was observed for the cyclization reaction onto
pyrrole subunits. Furthermore, substitution at the C-2 and
C-3 positions is well tolerated. Both electron-rich and -poor
pyrroles fared well in the cyclization reaction; however,
3-phenylpyrrole, while providing the cyclization in an
efficient yield of 82%, afforded an equal mixture of two
regioisomeric cyclization products (entry 15). The R-bro-
mooxazolidinone was also an excellent substrate, affording
the cyclized product in 89% yield (entry 16). In general, the
cyclization reactions proceed more quickly for the more
electron-rich pyrroles, resulting in the formation of less of
the corresponding reduction products.
Table 1. Photoredox-Catalyzed Intramolecular Radical
Functionalization of Indoles and Pyrroles*
To further expand upon this methodology, we wanted to
examine the possibilty of cascade radical cyclizations using
photoredox-mediated reactions (Scheme 3). Treatment of 418
Scheme 3. Cascade Radical Cyclization
under the cyclization reaction conditions resulted in the
formation of the double cyclization product 5 as a single
diastereoisomer in 79% yield.19
Given the observed reactivity, we propose the mechanism
outlined in Scheme 4 to account for the formation of the
observed cyclization product. Visible light irradiation gener-
ates the metal-to-ligand charge-transfer (MLCT) excited
ruthenium(II)* species which is reductively quenched by
Et3N to generate the electron-rich ruthenium(I) complex and
the triethylammonium radical cation. The reduced ruthenium
species then acts as the single electron transfer agent and
affords selective reduction of the activated carbon-bromine
bond, generating the electron-deficient alkyl radical 6 and
regenerating the catalyst, Ru(bpy)32+. The desired tricyclic
product is produced via an initial intramolecular cyclization
of the electron-rich aromatic species with the electrophilic
(17) For a discussion on the kinetic nucleophilicity of pyrroles, see:
Nigst, T. A.; Westermaier, M.; Ofial, A. R.; Mayr, H. Eur. J. Org. Chem.
2008, 2369. For a comparison of the rates of formylation of pyrroles and
indoles, see: Cipiciani, A.; Clementi, S.; Linda, P.; Marino, G.; Savelli, G.
J. Chem. Soc., Perkin Trans. 2 1977, 1284.
* Reaction conditions: cyclization substrate (1.0 equiv), Et3N (2.0 equiv),
Ru(bpy)3Cl2 (1.0 mol %), visible light, DMF, rt, 12 h. a Isolated yield after
purification by chromatography on SiO2. b Combined yield of regioisomers
(1:1).
(18) See the Supporting Information for the preparation of 4.
(19) The relative configuration of the product was determined by X-ray
crystallographic analysis. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre (CCDC 748503) via www.
ccdc.cam.ac.uk/data_request/cif.
We next broadened the scope of the radical functional-
ization of heteroaromatic compounds to a series of substituted
370
Org. Lett., Vol. 12, No. 2, 2010

In conclusion, we report an efficient and operationally
simple functionalization reaction of indoles and pyrroles via
a single electron transfer process initiated by visible light
irradiation. This methodology represents a potential means
for accessing a variety of medicinally and biologically active
natural products and provides an additional example of the
utility of photoredox catalysis in the context of radical
chemistry. Further studies into the application to the total
synthesis of complex molecules as well as expanding upon
the scope of photoredox catalysis in the realm of organic
chemistry will further demonstrate its utility as a new avenue
for free radical-mediated reactions.
Scheme 4. Proposed Mechanism
Acknowledgment. We thank Boston University and the
Department of Chemistry for financial support. Acknowledg-
ment is also made to the donors of the American Chemical
Society Petroleum Research Fund (48479-G1) for partial
support of this research. J.M.R.N. thanks the Swiss National
Science Foundation for a postdoctoral fellowship. We thank
the NSF-REU summer research program (CHE-0649114) for
support of SWK. NMR (CHE-0619339) and MS (CHE-
0443618) facilities at BU are supported by the NSF. The
authors thank Professor John Porco (Boston University) and
Professor Peter Wipf (University of Pittsburgh) for insightful
comments.
radical to afford 7. The resultant benzylic radical is then
oxidized, possibly by the excited state Ru(II)* species20 or
by bromomalonate 1, to afford intermediate 8a or 8b,
respectively. Elimination affords the aromatized product 2
along with triethylammonium hydrobromide.
Supporting Information Available: Experimental pro-
1
cedures, H and 13C NMR spectra for all new compounds,
(20) MacMillan and coworkers have previously postulated the oxdiation
of R-aminylradicals by the Ru(II) excited state (see refs 10a and 10f). For
a discussion on electron recycling in catalysis, see: Buckel, W. Angew.
Chem., Int. Ed. 2009, 48, 6779. Oxidation via the action of adventitious
oxygen or trialkylammonium radical cations cannot be ruled out at this
time.
and crystallographic data for 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL902703K
Org. Lett., Vol. 12, No. 2, 2010
371