Visible light photocatalysis of intramolecular radical cation Diels-Alder cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2012.04.021

Intramolecular radical cation Diels-Alder reactions can be conducted under photocatalytic conditions using visible light irradiation. The photocatalyst system involves the use of a Ru(bpy)32+ chromophore and methyl viologen as a co-oxidant. These reaction

Full text of DOI:10.1016/j.tetlet.2012.04.021

Tetrahedron Letters 53 (2012) 3073–3076
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Tetrahedron Letters
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Visible light photocatalysis of intramolecular radical cation Diels–Alder
cycloadditions
⇑
Shishi Lin, Christian E. Padilla, Michael A. Ischay, Tehshik P. Yoon
Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular radical cation Diels–Alder reactions can be conducted under photocatalytic conditions
2þ
Received 25 March 2012
Accepted 4 April 2012
Available online 14 April 2012
using visible light irradiation. The photocatalyst system involves the use of a RuðbpyÞ3 chromophore
and methyl viologen as a co-oxidant. These reactions enable the cycloaddition of substrates whose ther-
mal Diels–Alder cycloadditions are electronically mismatched and thus require forcing conditions. Nev-
ertheless, the radical cation cycloadditions can be conducted on gram scale using ambient sunlight as the
only source of irradiation.
Keywords:
Diels–Alder cycloaddition
Intramolecular
Photocatalysis
Ó 2012 Elsevier Ltd. All rights reserved.
Diels–Alder cycloadditions have long been recognized as impor-
tant chemical transformations for the synthesis of structurally
complex organic molecules. Intramolecular Diels–Alder (IMDA)
reactions, in particular, can provide extraordinarily efficient routes
to construct complex polycyclic ring systems from significantly
less complex polyene precursors. These reactions are powerful be-
cause they result in the formation of two new carbon–carbon
bonds and multiple stereocenters, often with excellent diastereo-
control. As a result, IMDA reactions have been the subject of
numerous studies that have been extensively reviewed in the
literature.1
The rates of Diels–Alder cycloadditions are fastest when the
reaction partners are electronically well matched; typically, rea-
sonable reaction times are observed when electron-deficient
dienophiles react with electron-rich dienes. Diels–Alder cycloaddi-
tions can be dramatically accelerated by Lewis or Bronsted acid
catalysis,2 but the presence of a Lewis basic activating group on
the dienophile is required for successful implementation of this
strategy. An alternative but underutilized approach is the radical
cation Diels–Alder cycloaddition, in which one-electron oxidation
of an electron-rich dienophile generates an intrinsically electron-
deficient alkene radical cation that can undergo rapid [4+2] cyclo-
addition with an electron-rich diene partner.3 The requisite radical
cations have been generated by both chemical4 and photoinduced5
one-electron oxidation.
Scheme 1. Thermal cycloaddition of electronically mismatched Diels–Alder sub-
strate 1.
transition metal complexes that enable the use of visible light
instead of conventional high-energy UV sources.7,8 Recently, we
described a highly efficient method for photocatalysis of intermo-
lecular radical cation Diels–Alder cycloadditions of electron-rich
alkenes.26þb This system features low loadings of a strongly oxidizing
RuðbpzÞ3 photocatalyst9 and the ability to use any number of
convenient sources of visible light including ambient sunlight.
Given that the pioneering studies of radical cation Diels–Alder cyc-
loadditions by Bauld and others demonstrated that radical cation
Diels–Alder reactions are efficient in both inter- and intramolecu-
lar contexts,10 we wondered if we could demonstrate that radical
cation mediated intramolecular Diels–Alder reactions could also
be achieved by visible light photocatalysis.
For the past several years, our group has been investigating the
chemistry of radical cations generated by visible light photocatal-
ysis.6 These reactions exploit the reactivity of photoactive
⇑
Corresponding author.
E-mail address: tyoon@chem.wisc.edu (T.P. Yoon).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.021

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S. Lin et al. / Tetrahedron Letters 53 (2012) 3073–3076
To test this idea, we synthesized and probed the Diels–Alder
reactivity of model substrate 1 (Scheme 1). As expected, the ther-
mal Diels–Alder cycloaddition of 1 required high temperatures
and long reaction times; after 24 h at 130 °C, we were able to
isolate 80% yield of Diels–Alder cycloadduct 2 as a 3:1 mixture of
diastereomers favoring the exo diastereomer. The forcing condi-
tions required to drive this reaction to completion are consistent
with the electronically mismatched nature of Diels–Alder cycload-
ditions between an electron-rich diene and an electron-rich dieno-
phile. On the other hand, Bauld has shown that the radical cation
generated by oxidation of 1 with triarylaminium radical salts
undergoes rapid, high-yielding Diels–Alder cycloaddition at 0 °C.11
We were surprised, therefore, to observe that the conditions we
had optimized for visible light photocatalysis of intermolecular
Diels–Alder reactions6b failed to translate to the intramolecular
context (Scheme 2). Irradiation of 1 with a 23 W compact fluores-
cent light bulb in the presence of 0.5 mol % Ru(bpz)3(BArF)2
(3ꢀ(BArF)2) resulted in complete consumption of the substrate in
2 h, but the expected Diels–Alder cycloadduct was formed in only
35% combined yield (3:1 endo:exo). The remainder of the material
was a complex mixture of unidentified products that could not be
separated by flash chromatography. Speculating that the poor yield
2þ
was attributable to the strongly oxidizing conditions of RuðbpzÞ3
-
photocatalyzed reactions, we also attempted the intramolecular
Diels–Alder reaction of 4 under conditions we had initially re-
ported for [2+2] cycloadditions of tethered bis(styrenes).6a We
had previously found that these conditions were less successful
for intermolecular radical cation Diels–Alder reactions; however,
Scheme 2. Comparison of photocatalyst systems for radical cation IMDA.
irradiation of
4 in the presence of 5 mol % Ru(bpy)3(PF6)2
Table 1
Scope studies on intramolecular photocatalytic radical cation Diels–Alder cycloadditionsa
Entry
Substrate
Product
Time (h)
1.5
Yieldb (endo:exo)
1
89% (8:1)
2
3
5
8
74% (3:1)
65% (5:1)
4
–
24
0%
5
6
24
18
23% (>10:1)
75% (2:1)

S. Lin et al. / Tetrahedron Letters 53 (2012) 3073–3076
3075
Table 1 (continued)
Entry
Substrate
Product
Time (h)
24
Yieldb (endo:exo)
7
8
58% (>10:1)
40% (7:1)
16
7
9
72% (2:1)
10
11
4
2
90% (>10:1)
–
0%
12
20
55%
a
Reactions conducted by irradiating a solution of 1 equiv of substrate, 0.05 equiv of 4ꢀ(PF6)2, 0.15 equiv of 5ꢀ(PF6)2, and 2 wt. equiv of MgSO4 in degassed MeNO2 in front of
a 23 W household compact fluorescent light bulb. See Supplementary data for details.
b
Isolated yields. Diastereomer ratios determined by 1H NMR analysis of the unpurified reaction mixture.
(4ꢀ(PF6)2) and 15 mol % methyl viologen (5ꢀ(PF6)2) provided the
desired intramolecular cycloadduct in 89% yield and good endo dia-
stereoselectivity after just 1.5 h.
Table 1 outlines the experiments conducted to probe the scope
of the intramolecular radical cation Diels–Alder reaction under
these conditions. A variety of substrates bearing three-carbon teth-
ers transformed smoothly into the desired cycloadducts (entries 1–
3). Reactions of substrates with four-carbon tethers, on the other
hand, did not give appreciable amounts of product (entry 4). The
styrene moiety also tolerated significant substitution. Although
the aryl group required an electron-donating group to facilitate
the generation of the corresponding radical cation, this group could
be at either the ortho or para position (entries 1 and 5), and addi-
tional electron-donating and withdrawing groups were both toler-
ated at other positions of the ring (entries 6 and 7). Other electron-
rich olefins such as 2-vinylfurans12 also successfully initiated the
reaction (entry 8). The diene moiety also tolerated substitution at
various positions (entry 9), including at an internal position that
results in the formation of a quaternary carbon stereocenter at
the ring junction (entry 10). The monosubstituted diene substrate,
however, gave a complex mixture of products from which the
Diels–Alder product could not be isolated (entry 11). Finally, disub-
stitution of the diene terminus with geminal methyl groups re-
sulted in the formation of the [2+2] cycloadduct rather than the
desired Diels–Alder cycloadduct (entry 12), underscoring the fact
that both [2+2] and [4+2] pericyclic reactivities are accessible using
radical cation methods.
Scheme 3. Large-scale photoreaction in ambient sunlight.
the scalability of the photocatalytic intramolecular Diels–Alder,
we conducted the cycloaddition of 1 on gram scale. As an addi-
tional challenge to the system, we conducted the reaction in a lab-
oratory window using ambient sunlight as the source of irradiation
instead of the standard 23 W compact fluorescent light bulb used
in small-scale reactions. Nevertheless, the reaction proceeded to
completion in 3 h, and cycloadduct 2 could be isolated in 80% yield
and 8:1 endo:exo selectivity (Scheme 3).
In conclusion, visible light photocatalysis offers a useful and
operationally simple method to construct polycyclic Diels–Alder
products under conditions that are significantly milder than those
required to promote the corresponding electronically mismatched
thermal cycloadditions. Notably, cycloadditions of the styrenyl
substrates examined in this study are not amenable to acceleration
by conventional Lewis or Brønsted acid catalysis. Photocatalytic
radical cation Diels–Alder cycloadditions are thus a useful comple-
mentary approach to the catalysis of this important class of
reactions.
Reactions using transition metal photocatalysts can be extre-
mely efficient and easily scalable. Indeed, as a demonstration of

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S. Lin et al. / Tetrahedron Letters 53 (2012) 3073–3076
4. (a) Bauld, N. L.; Bellville, D. J.; Pabon, R.; Chelsky, R.; Green, G. J. Am. Chem. Soc.
Acknowledgments
1983, 105, 2378–2382; (b) Bellville, D. J.; Bauld, N. L.; Pabon, R.; Gardner, S. A. J.
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Chem. Soc. 1981, 103, 718–720; (e) Yueh, W.; Bauld, N. L. J. Phys. Org. Chem.
1996, 9, 529–538.
The substrate for Table 1, entry 12, was prepared by Valerie J.
Winton. This research was conducted using funds from the NIH
(GM095666) and the Sloan Foundation. The NMR facilities at
UW–Madison are funded by the NSF (CHE-9208463, CHE-
9629688) and the NIH (RR08389-01, RR13866-01).
5. (a) Maroulis, A. J.; Arnold, D. R. .J. Chem. Soc., Chem. Commun. 1979, 351–352;
(b) Jones, C. R.; Allman, B. J.; Mooring, A.; Spahic, B. J. Am. Chem. Soc. 1983, 105,
652–654; (c) Pabon, R. A.; Bellville, D. J.; Bauld, N. L. J. Am. Chem. Soc. 1983, 105,
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
021.
7. For recent reports of transition metal-photosensitized cycloaddition reactions
from other groups, see: (a) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.;
Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171–7175; (b) Maity, S.;
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Angew. Chem., Int. Ed. 2009, 48, 9785–9789; (b) Yoon, T. P.; Ischay, M. A.; Du, J.
Nat. Chem. 2010, 2, 527–532; (c) Narayanam, J. M. R.; Stephenson, C. R. J. Chem.
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