Visible light-mediated intermolecular C-H functionalization of electron-rich heterocycles with malonates

Article abstract of DOI:10.1021/ol101146f

The photoredox-mediated direct intermolecular C-H functionalization of substituted indoles, pyrroles, and furans with diethyl bromomalonate is described, utilizing the visible light-induced reductive quenching pathway of Ru(bpy)₃Cl₂.

Full text of DOI:10.1021/ol101146f

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3104-3107
Visible Light-Mediated Intermolecular
C-H Functionalization of Electron-Rich
Heterocycles with Malonates
Laura Furst, Bryan S. Matsuura, Jagan M. R. Narayanam, Joseph W. Tucker, and
Corey R. J. Stephenson*
Department of Chemistry, Boston UniVersity, Boston, Massachusetts 02215
crjsteph@bu.edu
Received May 18, 2010
ABSTRACT
The photoredox-mediated direct intermolecular C-H functionalization of substituted indoles, pyrroles, and furans with diethyl bromomalonate
is described, utilizing the visible light-induced reductive quenching pathway of Ru(bpy)3Cl2. An analysis of reductive quenchers and mechanistic
considerations has led to an optimized protocol for the heteroaromatic alkylations, providing products in good yields and regioselectivities,
as well as successfully eliminating previously observed competitive side reactions. This methodology is highlighted by its neutral conditions,
activity at ambient temperatures, low catalyst loading, functional group tolerance, and chemoselectivity.
The direct R-arylation of carbonyl compounds constitutes
an important class of reactions for the synthesis of medici-
nally and biologically relevant molecules. Metal-mediated
processes have catapulted progress in this field in terms of
efficiency, ease of operation, and functional group tolerance.1
For example, Kawatsura and Hartwig demonstrated a Pd(0)-
mediated intermolecular coupling of substituted aryl halides
with malonates, providing high yields of R-arylated products
(Figure 1).2,3 However, an efficient and general method for
direct, intermolecular enolate arylations with electron-rich
Figure 1. Photocatalytic approach to aromatic malonation.
(1) For an excellent review, see: Johansson, C. C. C.; Colacot, T. J.
Angew. Chem., Int. Ed. 2010, 49, 676.
(2) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473
.
heteroaromatic compounds remains comparatively lim-
ited.4-6 The ubiquity of heterocycle-containing compounds
in biologically interesting molecules necessitates further
development in this area. We have proposed to accomplish
(3) For selected recent examples, see: (a) Yip, S. F.; Cheung, H. Y.;
Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469. (b) Hama, T.; Hartwig,
J. F. Org. Lett. 2008, 10, 1545. (c) Dai, X.; Strotman, N. A.; Fu, G. C.
J. Am. Chem. Soc. 2008, 130, 3302
.
(4) For selected examples of the functionalization of indoles and pyrroles,
see: (a) Tsai, A.-I.; Lin, C.-H.; Chuang, C.-P. Heterocycles 2005, 65, 2381.
(b) 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. (c)
Antos, J. M.; McFarland, J. M.; Iavarone, A. T.; Francis, M. B. J. Am.
Chem. Soc. 2009, 131, 6301. (d) Chan, W.-W.; Yeung, S.-H.; Zhou, Z.;
(5) A photoinduced radical substitution of unfunctionalized indoles and
pyrroles has previously been described using a 450 W Hanovia lamp using
either (Bu3Sn)2 or Na2S2O3 as the initiator in combination with excess of
arene (5-15 equiv). See: Byers, J. H.; Campbell, J. E.; Knapp, F. H.;
Chan, A. S. C.; Yu, W. Y. Org. Lett. 2010, 12, 604
.
Thissell, J. G. Tetrahedron Lett. 1999, 40, 2677.
10.1021/ol101146f  2010 American Chemical Society
Published on Web 06/02/2010

this goal with the use of visible light photoredox catalysis,7
an emerging technology in the area of single-electron-transfer
(SET) processes.8
Trialkylamines are particularly effective reductive quench-
ers in the photoredox catalytic cycle due to their low
oxidation potentials. However, we have observed several
undesired side reactions during our previous investigations
into the intramolecular malonation of indoles and pyrroles
which are compounded in the intermolecular coupling (Figure
2).9 Specifically, the use of trialkylamines can result in
mediates (iminium ions and enamines) formed as a conse-
quence of this reduction. The enamine undergoes competitive
alkylation giving 15-30% yield of the undesired acetalde-
hyde derivatives. Aromatic amines, in contrast, typically have
higher oxidation potentials than trialkylamines but are not
capable hydrogen atom donors, thereby relieving some major
problems facing successful implementation of intermolecular
radical coupling using photoredox catalysis. However, the
amine must be chosen carefully such that nonproductive
charge recombination does not interfere with the desired
radical formation. Herein we report the successful realization
of this proposal: coupling of an unactivated heteroaromatic
compound and commercially available bromomalonate in the
presence of photoredox catalyst Ru(bpy)3Cl2, visible light,
and a suitable tertiary amine electron donor.
Our initial screening focused upon the arylation of 2 with
1. Using Et3N as the electron donor, 3 was obtained in only
25% yield after 24 h even when a large excess of 1 or 2 was
employed (eq 1).10 An excess of indole was required with
these conditions in order to compete with the undesired
reductive dehalogenation. However, the yield remained
disappointingly low. Optimization of the reductive quencher
led to the discovery of commercially available 4-methoxy-
N,N-diphenylaniline (p-CH3OC6H4NPh2, 4) as a competent
electron donor, which cannot act as a hydrogen atom source.
The replacement of Et3N with 4 (2 equiv)11 provided 82%
yield of 3 (Table 1, entry 1). Furthermore, the catalyst loading
(1 mol %) and stoichiometry of the reagents (1 equiv 1, 2
equiv 2) are improved by using 4 as the electron donor.
Similar to the results reported by MacMillan,8a the tuning
of the light source using blue LEDs (1W, λmax ) 435 nm)12
was found to accelerate the reaction and complete conversion
was achieved after only 12 h.13 In the absence of
Ru(bpy)3Cl2, light, or 4, no conversion to 3 was observed.
Figure 2
chemistry.
. Challenges facing intermolecular photoredox radical
competitive hydrogen atom abstraction by the malonyl radical
to form the reduced malonate. Indeed, our initial attempts
to couple simple indoles with bromomalonate in the presence
of Et3N as an electron donor led to poor isolated yield of
the coupling product due to preferential reductive dehalo-
genation (vide infra). Further complicating the desired
intermolecular coupling is the formation of reactive inter-
A series of heteroaromatic compounds were then screened
as suitable coupling partners for diethyl bromomalonate using
the optimized reaction conditions (Table 1). The reaction
generally worked well for substituted indoles, including
5-bromo-7-azaindole, although the yield was moderate (49%,
(6) For selected examples of radical addition to indoles and pyrroles,
see: (a) Baciocchi, E.; Muraglia, E. J. Org. Chem. 1993, 58, 7610. (b) Byers,
J. H.; DeWitt, A.; Nasveschuk, C. G.; Swigor, J. E. Tetrahedron Lett. 2004,
45, 6587. (c) Guadarrama-Morales, O.; Me´ndez, F.; Miranda, L. D.
Tetrahedron Lett. 2007, 48, 4515. (d) Lindsay, K. B.; Ferrando, F.;
Christensen, K. L.; Overgaard, J.; Roca, T.; Bennasar, M.; Skrydstrup, T.
J. Org. Chem. 2007, 72, 4181.
(7) For a review on visible light photoredox catalysis and its applications
in organic chemistry, see: Narayanam, J. M. R.; Stephenson, C. R. J. Chem.
Soc. ReV. 2010, 39, DOI:10.1039/b913880n.
(10) The regioselectivity observed in this reaction (C2 vs. C3) is
consistent with a radical process. For a recent example, see: Reyes-Gutie´rrez,
P. E.; Torres-Ochoa, R. O.; Mart´ınez, R.; Miranda, L. D. Org. Biomol.
Chem. 2009, 7, 1388.
(8) For recent examples, see: (a) Nicewicz, 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) Narayanam, J. M. R.; Tucker, J. W.; Stephenson,
C. R. J. J. Am. Chem. Soc. 2009, 131, 8756. (e) Nagib, D. A.; Scott, M. E.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875. (f) Du, J.; Yoon,
T. P. J. Am. Chem. Soc. 2009, 131, 14604. (g) Condie, A. G.; Gonza´lez-
Go´mez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464. (h)
Tucker, J. W.; Nguyen, J. D.; Narayanam, J. M. R.; Krabbe, S. W.;
Stephenson, C. R. J. Chem. Commun. 2010, 46, DOI: 10.1039/c0cc00981d.
(9) Tucker, J. W.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson,
C. R. J. Org. Lett. 2010, 12, 368.
(11) Using 1 equiv of 4 also provided the desired product in comparable
yield at the expense of reaction time; however, the use of sub-stoichiometric
quantites of 4 did not result in complete conversion. At this time, we believe
the excess base is helpful in sequestering HBr. Unreacted 4 could be
recovered upon purification on SiO2.
(12) The blue LEDs have a maximum emission at 435 nm ((15 nm
at half-maximum intensity). See the Supporting Information for further
details.
(13) Using a 14 W fluorescent light bulb, the reaction was complete in
5 days.
Org. Lett., Vol. 12, No. 13, 2010
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Table 1. Visible Light-Mediated Intramolecular Radical C-H Functionalization of Indoles and Pyrroles
a Isolated yield after purification by chromatography on SiO2. b 2.0 mmol scale. c The reaction was performed in water, and the product was isolated as
its methyl ester (yield based upon recovered SM). d 5 equiv of furan was used.
3106
Org. Lett., Vol. 12, No. 13, 2010

entry 9).14 The functional group tolerance of this reaction is
highlighted by the use of unprotected indoles or pyrroles;
sensitive functional groups such as alkyl and aryl halides;
and acid-labile carbamates, peptides, ketones, and esters.
Importantly, these reactions also proceed well on a prepara-
tive scale providing the coupled product in comparable yield
(entry 6). To further demonstrate the utility of this transfor-
mation, furans and pyrroles were also tested and found to
work well under the conditions (entries 12-14). Moving
from DMF to water, N-Boc-tryptophan was also a viable
substrate for this reaction, providing the coupled product in
40% yield, despite the solubility issues of both bromoma-
lonate and 4.
alkylated product were observed, and 5 was recovered. We
hypothesized that competitive charge recombination was
thwarting the reduction of 5 by Ru(bpy)31+. To test this
hypothesis, we prepared electron-rich amine 6. Upon treat-
ment of 1 with 5 using 6 as the electron donor, a complex
mixture of products resulting from coupling of 5 with the
amine 6 was observed (eq 2). Although the use of 6 as the
reductive quencher did not afford the desired indole alky-
lation product, we were pleased to discover that our
hypothesis was correct. Indeed, the charge recombination
pathway was suppressed, reinvigorating the pathway leading
to reduction of 5 by Ru(bpy)31+, followed by alkylation of
the electron-rich triarylamine. At this stage, further optimiza-
tion of the electron donor, possibly in concert with the
photocatalyst, is required to successfully engage less reactive
halides such as 5 with the electron-rich arenes in a controlled
fashion.
A plausible mechanism based upon these results is shown
2+
in Scheme 1. First, Ru(bpy)3 is excited by visible light
Scheme 1. Proposed Mechanism
In conclusion, we have developed an efficient method for
the direct intermolecular C-H functionalization of indoles,
pyrroles, and furans with malonates using visible light
photoredox catalysis. This enables rapid access to complex
moieties and motifs commonly seen in biologically active
natural products. Importantly, the successful functionalization
of dipeptide substrates and initial success with reactions
conducted in an aqueous environment bode well for future
application of this mild reaction in the area of protein
modification and bioconjugation chemistries. Efforts are
currently underway to achieve these goals and to expand the
scope of the coupling reaction by the modification of
photocatalyst and electron donor.
providing Ru(bpy)32+*, which is then reductively quenched
by 4 to produce Ru(bpy)3 and the ammonium radical
1+
cation. Luminescence quenching experiments indicate that
4 is the only reaction component which quenches the excited
state.12 The Ru1+ species in turn performs a single-electron
reduction of the activated C-Br bond, regenerating Ru(b-
2+
py)3 and forming a carbon-centered radical. Coupling of
this electron-deficient radical at C2 of the electron-rich arene
affords a stabilized radical (benzylic or allylic). Oxidation
of the benzylic radical followed by rearomatization provides
the observed product.15
When a less reactive alkyl bromide such as methyl
R-bromophenylacetate (5) was treated with 1 under our
optimized conditions, no detectable traces of an indole
Acknowledgment. Boston University and the Department
of Chemistry are gratefully acknowledged for financial
support. L.F. thanks the Novartis Institutes for BioMedical
Research for a graduate fellowship. NMR (CHE-0619339)
and MS (CHE-0443618) facilities at BU are supported by
the NSF.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Functionalization of azaindoles is generally more challenging than
indoles. For a review, see: Popowycz, F.; Routier, S.; Joseph, B.; Me´rour,
J.-Y. Tetrahedron 2007, 63, 1031.
(15) The excited-state Ru(II)* or radical-chain transfer to the benzylic
bromide may be responsible for the benzylic oxidation; however, adventi-
tious oxygen or triarylammonium radical cation cannot be ruled out at this
time.
OL101146F
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