Photocatalytic synthesis of dihydrobenzofurans by oxidative [3+2] cycloaddition of phenols

Article abstract of DOI:10.1002/anie.201406393

We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible-light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations.

Full text of DOI:10.1002/anie.201406393

Angewandte
Chemie
DOI: 10.1002/anie.201406393
Photocatalysis
Photocatalytic Synthesis of Dihydrobenzofurans by Oxidative [3+2]
Cycloaddition of Phenols**
Travis R. Blum, Ye Zhu, Sarah A. Nordeen, and Tehshik P. Yoon*
Abstract: We report a protocol for oxidative [3+2] cyclo-
additions of phenols and alkenes applicable to the modular
synthesis of a large family of dihydrobenzofuran natural
products. Visible-light-activated transition metal photocatalysis
enables the use of ammonium persulfate as an easily handled,
benign terminal oxidant. The broad range of organic substrates
that are readily oxidized by photoredox catalysis suggests that
this strategy may be applicable to a variety of useful oxidative
transformations.
feature a 2,3-dihydrobenzofuran core (Figure 1),[8] the bio-
genic origin of which presumably involves an oxidative [3+2]
phenol–alkene cycloaddition. Several synthetic approaches to
this transformation have been reported,[9] but they often
suffer from low yields, limited scope, or a need for specialized
equipment.[10,11] The most practical methods for this reaction
reported to date exploit hypervalent iodine(III) reagents,[12]
which generate iodoarenes as stoichiometric byproducts. We
report herein an alternate photocatalytic protocol for the
[3+2] phenol–olefin cycloaddition that enables the use of
ammonium persulfate as an inexpensive terminal oxidant
with a benign bisulfate salt as the stoichiometric byproduct.[13]
Our initial investigations (Table 1) focused on the photo-
catalytic reaction of p-methoxyphenol (3) with methylisoeu-
T
he choice of the terminal oxidant is an important consid-
eration in the design of oxidative reactions.[1] Many of the
most commonly used oxidants in organic synthesis produce
stoichiometric amounts of byproducts that can be practically
or environmentally problematic. Our laboratory has a long-
standing interest in the propensity of photoexcited Ru*-
2+
genol (4). A screen of oxidants in the presence of Ru(bpy)3
(1) revealed that inorganic and organic hydroperoxides were
ineffective (entries 1–4), whereas the desired cycloadduct is
formed slowly upon irradiation in the presence of Oxone
(entry 5). This observation led us to examine other persul-
fates, and K2S2O8 proved to be a more effective terminal
oxidant (entry 6). Peroxydisulfates have long been known as
oxidative quenchers of photoexcited ruthenium polypyridyl
complexes,[14] but their use as terminal oxidants for synthetic
photocatalytic reactions has been limited.[15] A brief screen of
2+
(bpy)3 to undergo redox reactions with a diverse range of
quenchers,[2] a feature that has been increasingly exploited in
the design of synthetic reactions.[3] We wondered if photo-
redox catalysis might offer a general strategy to employ
benign, kinetically inert oxidants in oxidative transforma-
tions. Recent interest in photoredox catalysis has largely been
focused on redox-neutral and net reductive reactions; the
examples of net oxidative transformations published to date
have generally utilized either stoichiometric halocarbon
oxidants,[4] which are not ideal from an environmental
standpoint, or molecular oxygen,[5] which is a triplet quencher
of many photoexcited molecules[6] that can negatively impact
the overall efficiency of photocatalytic reactions. Thus, there
exists a need for a more practical, general approach to the
design of oxidative photoredox reactions.
We became interested in studying phenol oxidation as
a starting point to explore this challenge. Phenols participate
in a rich variety of oxidatively induced transformations,[7]
which can produce a number of complex structures commonly
found in bioactive molecules. For example, many neolignans,
resveratrol oligomers, and peptide-derived natural products
[*] T. R. Blum, Dr. Y. Zhu, S. A. Nordeen, Prof. T. P. Yoon
Department of Chemistry, University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
E-mail: tyoon@chem.wisc.edu
Homepage: http://yoon.chem.wisc.edu
[**] This research was conducted using funds from the NIH
(GM095666), the Sloan Foundation, the Beckman Foundation, and
the Research Corporation. The NMR facilities at UW-Madison are
funded by the NSF (CHE-9208463, CHE-9629688) and the NIH
(RR08389-01, RR13866-01). T.R.B. acknowledges support from an
NIH Chemical Biology Interface training grant (5 T32 GM850520).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406393.
Figure 1. Bioactive dihydrobenzofuran-containing natural products and
an oxidative [3+2] cycloaddition strategy for their synthesis.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Optimization of conditions for oxidative [3+2] cycloaddition.
Entry[a]
Catalyst
Oxidant
Yield [%][b]
1
2
3
4
5
6
7
8
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpz)3(PF6)2
Ru(bpz)3(PF6)2
Ru(bpz)3(PF6)2
Ru(bpz)3(PF6)2
none
H2O2 (30% aq)
H2O2·urea
tBuOOH
m-CPBA
Oxone
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
0
0
0
0
7
20
75
23
78
0
9
10[c]
11
0
[a] All reactions were irradiated for 24 h using 0.10 mmol phenol,
0.13 mmol styrene, 0.20 mmol oxidant, and 0.005 mmol catalyst, unless
otherwise noted. [b] Yields determined by 1H NMR spectroscopy using
trimethylsilyl benzene as an internal standard. [c] Reaction performed in
the dark.
photocatalysts revealed that the more strongly oxidizing
2+
Ru(bpz)3 (2) chromophore gave higher rates than Ru-
(bpy)32+, affording a good yield of the cycloadduct after 24 h.
We also examined other peroxydisulfate salts and found that
(NH4)2S2O8 led to optimal yields. Finally, control studies
indicated that this reaction requires both catalyst and light
(entries 10–11), validating the photocatalytic nature of this
process.
A broad range of coupling partners participate readily in
this oxidative [3+2] cycloaddition (Figure 2). The reaction
requires electron-rich phenols bearing alkoxy substituents at
the 2- or 4-position, consistent with the need to stabilize the
putative phenoxonium intermediate. Within this constraint,
however, the scope proved to be quite broad. Benzyl (7) and
allyl (8) ethers were tolerated easily without any trace of
oxidative degradation, as were unprotected alcohols (9).
Other substituents are also tolerated, including aryl substitu-
ents (11), bulky alkyl groups (12), and halides (14). Unsym-
metrical 3-substituted phenols undergo clean, highly regiose-
lective [3+2] cycloadditions (15 and 16), suggesting that the
reaction is susceptible to steric control. Nevertheless, 3,5-
disubstituted phenols do not exhibit a significantly lower
reactivity (17), and condensed polycyclic phenols are also
excellent substrates for this reaction (18). We also examined
Figure 2. Scope studies for the oxidative [3+2] cycloaddition. All
reactions conducted with 0.40 mmol phenol, 0.52 mmol alkene,
0.80 mmol (NH4)2S2O8, and 0.02 mmol 2·(PF6)2, unless otherwise
noted. Yields represent the averaged yields of the isolated products of
two reproducible experiments. [a] Reactions conducted with 0.80 mmol
alkene.
the scope of this reaction with respect to the styrene
component. In line with the highly electrophilic nature of
the phenoxonium intermediate, electron-rich styrenes bear-
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
ing para or ortho alkoxy groups were the most reactive
cycloaddition partners (19–21). However, styrenes lacking
these activating groups still reacted smoothly (22–24). As with
the phenol component, a variety of potentially sensitive
functional groups could be present on the alkene substrate,
including halides (25), sulfonamides (26), and acetals (27).
The reaction was also tolerant of steric bulk at the a and b
positions of the styrene (28–30).
Several experiments were conducted to probe the mech-
anism of this reaction (Scheme 1). Although both coupling
partners are electron-rich, we designed this reaction as an
Scheme 2. Proposed mechanism for the oxidative [3+2] cycloaddition
2+
of phenols using Ru(bpz)3
.
sponding radical cation, which can be further oxidized to
generate a resonance-stabilized phenoxonium cation that is
trapped by an electron-rich olefin to afford the observed
dihydrobenzofuran.[12a]
Many bioactive natural products feature dihydrobenzo-
furan scaffolds, and the broad scope of the oxidative [3+2]
cycloaddition makes it readily applicable to the efficient
modular assembly of compounds in this class (Scheme 3). For
instance, the dihydrobenzofuran 35, isolated along with
several similar benzofuranoid neolignans from Piper
aequale,[19] presumably arises from an oxidative [3+2]
phenol cycloaddition. This putative biosynthesis can be
replicated using photocatalytic [3+2] cycloaddition of 33,
which is available in two high-yielding steps from 4-methox-
yphenol, with TBS-protected 4-propenylphenol 34. Subse-
quent deprotection of the silyl group affords the natural
Scheme 1. Evidence for initial phenol oxidation.
entry into the versatile reactivity of oxidized phenol com-
pounds. In accord with this hypothesis, reactions conducted
with readily oxidized phenols such as 3 (Eox =+ 1.05 V vs.
SCE)[10b] proceed even in the presence of alkenes that possess
oxidation potentials outside of the working range for the
photocatalyst ([Ru]3+/2+, + 1.98 V; styrene 31, + 2.05 V).[16]
However, readily oxidized alkenes, such as anethole (4,
+ 1.10 V),[17] do not generate product in the presence of a less
electron-rich phenol (32, Eox =+ 1.30 V).[18] This suggests that
phenol oxidation, rather than alkene oxidation, is the key step
that initiates the cycloaddition.
Additionally, we observe an induction period of several
hours (see the Supporting Information, Figure S1), during
which an orange precipitate forms in the reaction mixture.
Upon filtration, the supernatant is not catalytically active
(Figure S2). The precipitate, however, can be used to catalyze
the [3+2] cycloaddition, and we observed no induction period
in this experiment (Figure S3). One reasonable interpretation
of these data is that the active photocatalyst is an insoluble
Ru(bpz)32+ persulfate complex that forms through a slow salt
metathesis process. Consistent with this interpretation,
authentic Ru(bpz)3(S2O8), precipitated from a combination
of Ru(bpz)3(PF6)2 with (Bu4N)2(S2O8) in the dark, proved to
be a competent catalyst, and we also observed no induction
period in this experiment (Figure S4).
Based upon these observations, we have proposed the
mechanistic model outlined in Scheme 2. A slow salt meta-
thesis results in the precipitation of Ru(bpz)3(S2O8). Photo-
excitation of this salt followed by oxidative quenching then
generates the active oxidant, Ru(bpz)33+, along with a sulfate
radical anion. The oxidation of phenol generates the corre-
Scheme 3. Modular synthesis of neolignan natural products.
TBS=tert-butyldimethylsilyl; TBAF=tetrabutylammonium fluoride;
PMP=p-methoxyphenyl.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[6] Q. G. Mulazzani, H. Sun, M. Z. Hoffman, W. E. Ford, M. A. J.
Rodgers, J. Phys. Chem. 1994, 98, 1145 – 1150.
[7] a) S. Quideau, L. Pouysꢀgu, D. Deffieux, Curr. Org. Chem. 2004,
8, 113 – 148; b) S. Yamamura, S. Nishiyama, Synlett 2002, 533 –
543.
[8] a) E. D. Coy, L. E. Cuca, M. Sefkow, Bioorg. Med. Chem. Lett.
2009, 19, 6922 – 6925; b) E. D. Coy Barrera, L. E. C. Suarez,
Chem. Pharm. Bull. 2009, 57, 639 – 642; c) T. Shen, X.-N. Wang,
H.-X. Lou, Nat. Prod. Rep. 2009, 26, 916 – 935; d) H. Zhang, S.
Qiu, P. Tamez, G. T. Tan, Z. Aydogmus, N. V. Hung, N. M.
Cuong, C. Angerhofer, D. D. Soejarto, J. M. Pezzuto, H. H. S.
Fong, Pharm. Biol. 2002, 40, 221 – 224; e) M. Lachia, C. J.
Moody, Nat. Prod. Rep. 2008, 25, 227 – 253.
[9] For recent reviews of dihydrobenzofuran syntheses, see: a) F.
Bertolini, M. Pineschi, Org. Prep. Proced. Int. 2009, 41, 385 – 418;
b) T. D. Sheppard, J. Chem. Res. 2011, 35, 377 – 385; c) M.
Sefkow, Synthesis 2003, 2595 – 2625.
[10] For examples using preparative electrochemistry, see: a) Y.
Shizuri, K. Nakamura, S. Yamamura, J. Chem. Soc. Chem.
Commun. 1985, 530 – 531; b) B. D. Gates, P. Dalidowicz, A.
Tebben, S. Wang, J. S. Swenton, J. Org. Chem. 1992, 57, 2135 –
2143; c) M. L. Kerns, S. M. Conroy, J. S. Swenton, Tetrahedron
Lett. 1994, 35, 7529 – 7532; d) K. Chiba, M. Fukuda, S. Kim, Y.
Kitano, M. Tada, J. Org. Chem. 1999, 64, 7654 – 7656; e) H. R.
El-Seedi, S. Yamamura, S. Nishiyama, Tetrahedron 2002, 43,
3301 – 3304.
product in 81% yield over these two steps. Similarly, the
antiprotozoal neolignan 37, isolated from K. ixina,[20] is
available in three steps from cycloadduct 7. Selective hydro-
genolysis of the primary benzyl ether followed by treatment
with triflic anhydride affords aryl triflate 36 in 93% yield over
two steps. Suzuki coupling with trans-propenyl boronic acid
produces 37 in 95% yield. Together, these syntheses demon-
strate the applicability of this photocatalytic method to access
this large family of bioactive benzofuranoid natural products.
In conclusion, we have developed a robust photocatalytic
method for the oxidative [3+2] cycloaddition of phenols and
electron-rich styrenes. Transition metal photoredox catalysis
enables the use of ammonium persulfate as a terminal
oxidant, which results in the formation of an innocuous and
easily separated inorganic byproduct. Given the diverse range
of organic substrates that participate readily in electron
transfer processes with photogenerated ruthenium poly-
pyridyl oxidants, this strategy should be widely applicable to
the design of other photocatalytically enabled oxidative
transformations. This broad objective is a continuing goal of
research in our laboratory.
Received: June 19, 2014
Published online: && &&, &&&&
[11] Oxidative [3+2] cycloadditions using Mn(OAc)3: B. B. Snider, L.
Han, C. Xie, J. Org. Chem. 1997, 62, 6978 – 6984.
[12] Oxidative [3+2] cycloadditions using hypervalent iodide: a) S.
Wang, B. D. Gates, J. S. Swenton, J. Org. Chem. 1991, 56, 1979 –
1981; b) D. Bꢀrard, A. Jean, S. Canesi, Tetrahedron Lett. 2007,
48, 8238 – 8241; c) D. Bꢀrard, M. Giroux, L. Racicot, C. Sabot, S.
Canesi, Tetrahedron 2008, 64, 7537 – 7544; d) D. Bꢀrard, L.
Racicot, C. Sabot, S. Canesi, Synlett 2008, 1076 – 1080; e) A. L.
Mohr, V. M. Lombardo, T. M. Arisco, G. W. Morrow, Synth.
Commun. 2009, 39, 3845 – 3855.
[13] A very recent report describes the oxidative dimerization of
resveratrol oligomers using a mesoporous carbon nitride photo-
catalyst: T. Song, B. Zhou, G.-W. Peng, Q.-B. Zhang, L.-Z. Wu,
Q. Liu, Y. Wang, Chem. Eur. J. 2014, 20, 678 – 682.
[14] For leading references, see: a) F. Bolletta, A. Juris, M. Maestri,
D. Sandrini, Inorg. Chim. Acta 1980, 44, L175 – L176; b) H. S.
White, W. G. Becker, A. J. Bard, J. Phys. Chem. 1984, 88, 1840 –
1846.
[15] a) C. Dai, F. Meschini, J. M. R. Narayanam, C. R. J. Stephenson,
J. Org. Chem. 2012, 77, 4425 – 4431; b) D. A. Fancy, C. Denison,
K. Kim, Y. Xie, T. Holdeman, F. Amini, T. Kodadek, Chem. Biol.
2000, 7, 697 – 708; c) U. Nickel, Y.-H. Chen, S. Schneider, M. I.
Silva, H. D. Burrows, S. J. Formosinho, J. Phys. Chem. 1994, 98,
2883 – 2888; d) T. Minisci, A. Citterio, C. Giordano, Acc. Chem.
Res. 1983, 16, 27 – 32.
Keywords: cycloaddition · heterocycles · phenols ·
photocatalysis · photooxidation
.
[1] a) L. V. Desai, H. A. Malik, M. S. Sanford, Org. Lett. 2006, 8,
1141 – 1144; b) A. N. Campbell, S. S. Stahl, Acc. Chem. Res. 2012,
45, 851 – 863.
[2] K. Kalyanasundaram, Coord. Chem. Rev. 1982, 46, 159 – 244.
[3] a) K. Zeitler, Angew. Chem. Int. Ed. 2009, 48, 9785 – 9789;
Angew. Chem. 2009, 121, 9969 – 9974; b) T. P. Yoon, M. A.
Ischay, J. Du, Nat. Chem. 2010, 2, 527 – 532; c) J. M. R. Naraya-
nam, C. R. J. Stephenson, Chem. Soc. Rev. 2011, 40, 102 – 113;
d) J. Xuan, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828 –
6838; Angew. Chem. 2012, 124, 6934 – 6944; e) C. K. Prier, D. A.
Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322 – 5363.
[4] a) G. Bergonzini, C. S. Schindler, C.-J. Wallentin, E. N. Jacobsen,
C. R. J. Stephenson, Chem. Sci. 2014, 5, 112 – 116; b) M. D.
Konieczynska, C. Dai, C. R. J. Stephenson, Org. Biomol. Chem.
2012, 10, 4509 – 4511; c) D. B. Freeman, L. Furst, A. G. Condie,
C. R. J. Stephenson, Org. Lett. 2012, 14, 94 – 97; d) Y. Zhao, Z.
Li, C. Yang, R. Lin, W. Xia, Beilstein J. Org. Chem. 2014, 10,
622 – 627.
[5] a) Y. Su, L. Zhang, N. Jiao, Org. Lett. 2011, 13, 2168 – 2171; b) Y.-
Q. Zou, J.-R. Chen, X.-P. Liu, J.-Q. Lu, R. L. Davis, K. A.
Jorgensen, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51, 784 – 788;
Angew. Chem. 2012, 124, 808 – 812; c) Y. Cheng, J. Yang, Y. Qu,
P. Li, Org. Lett. 2012, 14, 98 – 101; d) S. Cai, X. Zhao, X. Wang, Q.
Liu, Z. Li, D. Z. Wang, Angew. Chem. Int. Ed. 2012, 51, 8050 –
8053; Angew. Chem. 2012, 124, 8174 – 8177; e) M. Rueping, C.
Vila, R. M. Koenigs, K. Poscharny, D. C. Fabry, Chem. Commun.
2011, 47, 2360 – 2362; f) D. P. Hari, B. Kçnig, Org. Lett. 2011, 13,
3852 – 3855; g) Y.-Q. Zou, L.-Q. Lu, L. Fu, N.-J. Chang, J. Rong,
J.-R. Chen, W.-J. Xiao, Angew. Chem. Int. Ed. 2011, 50, 7171 –
7175; Angew. Chem. 2011, 123, 7309 – 7313.
[16] a) D. P. Rillema, G. Allen, T. J. Meyer, D. Conrad, Inorg. Chem.
1983, 22, 1617 – 1622; b) N. P. Schepp, L. J. Johnston, J. Am.
Chem. Soc. 1996, 118, 2872 – 2881.
[17] W. Yueh, N. L. Bauld, J. Phys. Org. Chem. 1996, 9, 529 – 538.
[18] D. A. Pratt, R. P. Pesavento, W. A. van der Donk, Org. Lett.
2005, 7, 2735 – 2738.
[19] A. Maxwell, D. Dabideen, W. F. Reynolds, S. McLean, Phyto-
chemistry 1999, 50, 499 – 504.
[20] H. Achenbach, W. Utz, A. Usubillaga, H. A. Rodriguez,
Phytochemistry 1991, 30, 3753 – 3757.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Photocatalysis
T. R. Blum, Y. Zhu, S. A. Nordeen,
T. P. Yoon*
&&&& — &&&&
Photocatalytic Synthesis of
Dihydrobenzofurans by Oxidative [3+2]
Cycloaddition of Phenols
In a good light: The versatile photoredox
properties of RuII chromophores offer
a strategy to couple powerful oxidative
transformations to benign inorganic per-
oxysulfate oxidants. In this example, the
photocatalytic [3+2] cycloaddition of
phenols and electron-rich styrenes for the
synthesis of diverse dihydrobenzofurans
is presented.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!