Oxyarylation and aminoarylation of styrenes using photoredox catalysis

Article abstract of DOI:10.1021/ol401940c

A three-component coupling of styrenes is reported, using photoredox catalysis to achieve simultaneous arylation and C-O or C-N bond formation across the styrene double bond.

Full text of DOI:10.1021/ol401940c

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4398–4401
Oxyarylation and Aminoarylation of
Styrenes Using Photoredox Catalysis
Gabriele Fumagalli,† Scott Boyd,‡ and Michael F. Greaney*,†
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL,
U.K., and AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
Michael.Greaney@manchester.ac.uk
Received July 10, 2013
ABSTRACT
A three-component coupling of styrenes is reported, using photoredox catalysis to achieve simultaneous arylation and CꢀO or CꢀN bond
formation across the styrene double bond.
Photoredox catalysis (PRC) is receiving renewed atten-
tion as a powerful method for organic synthesis under mild
conditions, with impressively broad application across
diverse reaction types.1,2 Using readily available visible
light sources, transition metal complexes or organic dyes
are photoactivated to mediate electron transfer to organic
substrates. The resulting radical cation and anion inter-
mediates offer lower energy pathways for bond formation,
enabling both the discovery of new reactions and the
enhancement of classical transformations via improved
reaction conditions. Application of PRC to [2 þ 2] and
[4 þ 2] photocycloadditions, for example, removes the
need for specialized glassware and powerful UV light
sources.3 Excitation of the photoredox catalyst is highly
selective, with colorless organic substrates generally being
inert to photoexcitation by visible light. As a result,
deleterious radical side reactions can be avoided, widening
the substrate scope and improving yields.
Photoredox-catalyzed arylation, in particular, has cre-
ated new approaches to the controlled incorporation of
aryl and heteroaryl moieties.4,5 Proceeding through aryl
radicals, as opposed to the aryl organometallics typical of
modern arylation reactions, photoredox-catalyzed aryla-
tion opens up different and complementary reaction mani-
folds. Importantly, the PRC approach enables highly
reactive aryl radicals to be harnessed in intermolecular
couplings, a difficult transformation to achieve using con-
ventional radical-generating methods.
† University of Manchester.
‡ AstraZeneca.
(1) Reviews: (a) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem.
2012, 77, 1617. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem.
Soc. Rev. 2011, 40, 102. (c) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48,
9785. (d) Yoon, T. P.; Ischay, M. A.; Du, J. N. Nat. Chem 2010, 2, 527.
(2) Selected recent examples: (a) Nagib, D. A.; MacMillan, D. W. C.
Nature 2011, 480, 224. (b) Nguyen, J. D.; Tucker, J. W.; Konieczynska,
M. D.; Stephenson, C. R. J. J. Am. Chem. Soc. 2011, 133, 4160. (c) Zou,
Y. Q.; Chen, J. R.; Liu, X. P.; Lu, L. Q.; Davis, R. L.; Jorgensen, K. A.;
Xiao, W. J. Angew. Chem., Int. Ed. 2012, 51, 784. (d) Tucker, J. W.;
Zhang, Y.; Jamison, T. F.; Stephenson, C. R. J. Angew. Chem., Int. Ed.
2012, 51, 4144. (e) Cai, S. Y.; Zhao, X. Y.; Wang, X. B.; Liu, Q. S.; Li,
Z. G.; Wang, D. Z. G. Angew. Chem., Int. Ed. 2012, 51, 8050. (f) Yasu,
Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2012, 51, 9567. (g) Lu,
Z.; Yoon, T. P. Angew. Chem., Int. Ed. 2012, 51, 10329. (h) Kim, H.; Lee,
C. Angew. Chem., Int. Ed. 2012, 51, 12303. (i) Miyake, Y.; Nakajima, K.;
Nishibayashi, Y. J. Am. Chem. Soc. 2012, 134, 3338. (k) DiRocco, D. A.;
Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094. (l) Wallentin, C. J.;
Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc.
2012, 134, 8875. (m) Ye, Y. D.; Sanford, M. S. J. Am. Chem. Soc. 2012,
134, 9034. (n) Grandjean, J. M. M.; Nicewicz, D. A. Angew. Chem., Int.
Ed. 2013, 52, 3967. (o) Zhu, S. Q.; Das, A.; Bui, L.; Zhou, H. J.; Curran,
D. P.; Rueping, M. J. Am. Chem. Soc. 2013, 135, 1823. (p) Mizuta, S.;
Engle, K. M.; Verhoog, S.; Galicia-Lopez, O.; O’Duill, M.; Medebielle,
M.; Wheelhouse, K.; Rassias, G.; Thompson, A. L.; Gouverneur, V.
Org. Lett. 2013, 15, 1250. (q) Yasu, Y.; Koike, T.; Akita, M. Org. Lett.
2013, 15, 2136.
We envisaged that the mild conditions typical of PRC
could enable the arylative functionalization of styrenes, 1
(Scheme 1). Styrenes are fundamental building blocks in
(3) (a) Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 14604. (b)
Lin, S. S.; Ischay, M. A.; Fry, C. G.; Yoon, T. P. J. Am. Chem. Soc. 2011,
133, 19350. (c) Lu, Z.; Yoon, T. P. Angew. Chem., Int. Ed. 2012, 51,
10329.
(4) Seminal work on PRC arylation: (a) Cano-Yelo, H.; Deronzier,
A. J. Chem. Soc., Faraday Trans. 1 1984, 80, 3011. (b) Cano-Yelo, H.;
Deronzier, A. J. Chem. Soc., Perkin Trans. 2 1984, 1093. (c) Cano-Yelo,
H.; Deronzier, A. Tetrahedron Lett. 1984, 25, 5517. (d) Hamada, T.;
Ishida, H.; Usui, S.; Watanabe, Y.; Tsumura, K.; Ohkubo, K. Chem.
Commun. 1993, 909.
r
10.1021/ol401940c
Published on Web 08/08/2013
2013 American Chemical Society

organic and materials chemistry, whose functionalization
is hindered by facile polymerization under acidic, basic, or
UV photochemical conditions. If PRC could be used to
generate aryl radicals from a suitable precursor (2), at
ambient temperature under neutral conditions, it might be
possible to capture the styrene double bond to give 4,
avoiding the undesired polymerization pathway. Oxida-
tion of 4 to close the PRC cycle would then generate a
benzylic cation for a second CꢀX bondforming stepwith a
nucleophile. The resultant three-component coupling
would create diverse, doubly functionalized phenylethyl
scaffolds that would see broad application in synthesis.
then required to cleave the TEMP group and produce the
hydroxyarylated products.
We began by screening photoredox catalysts for the
reaction of styrene (1 equiv) with diphenyliodonium tetra-
fluoroborate (2 equiv) in degassed methanol, using a 30 W
domestic light bulb (Table 1). While organic dye PRCs
(<5%) and Ru(bpy)3Cl2 (12%) were largely ineffective
(see Supporting Information), we were encouraged to
observe that Ir(ppy)3 did effect methoxyarylation, albeit
in a modest 27% yield (entry 1). A significant increase in
yield was obtained using the iodonium salt as the limiting
reagent, with a 5-fold excess of the cheaper and easily
accessible styrene reagent affording 3a in 51% yield (entry 2).
Raising the temperature did not lead to significant improve-
ments, with similar yields recorded at 40 °C, 60 °C, and room
temperature (entries 4 and 5).
Scheme 1. Proposed Three-Component Coupling of Styrenes
Table 1. Reaction Optimization
temp
additive
yield
(%)a
entry
(°C)
(20 mol %)
Three-component coupling reactions of styrenes and
arenes are rare.6 Lloyd-Jones and co-workers described a
gold-catalyzed methoxarylation of styrenes with aryl silanes
in the presence of an iodine(III) oxidant.7 They observed
that oxyarylation systems using Selectfluor,8,9 previously
successful with alkenes, failed with styrenes, reflecting the
difficulties in capturing these reactive substrates in simul-
taneous CꢀC and CꢀX bond coupling.10 Multistep hy-
droxyarylation was achieved by Studer and co-workers
using a diazonium salt with a stoichiometric amount of
TEMPO/Na.11 Subsequent zinc mediated reduction was
1b
2c
3d
4
rt
ꢀ
27
51
32
55
45
50
70
69
0
rt
ꢀ
rt
ꢀ
40
60
40
rt
ꢀ
5
ꢀ
6e
7
ꢀ
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
8f
rt
9g
10h
11i
rt
rt
<5
0
100
a Isolated yields. b Reaction conditions: styrene (1 equiv), Ph2IBF4,
2a (2 equiv), Ir(ppy)3 (5 mol %), methanol (0.17 M), rt for 18 h. c 5 equiv
of 1a and 1 equiv of 2a used (entries 2ꢀ11). d 1 M concentration.
e Distilled styrene. f Ir(ppy)3 (1 mol %). g Irradiated with no Ir(ppy)3.
h Ir(ppy)3 (1 mol %) but no irradiation. i No irradiation and no Ir(ppy)3.
(5) Recent examples: (a) McNally, A.; Prier, C. K.; MacMillan,
D. W. C. Science 2011, 334, 1114. (b) Kalyani, D.; McMurtrey, K. B.;
Neufeldt, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 18566. (c)
€
Hari, D. P.; Schroll, P.; Konig, B. J. Am. Chem. Soc. 2012, 134, 2958. (d)
€
Hering, T.; Hari, D. P.; Konig, B. J. Org. Chem. 2012, 77, 10347. (e)
Neufeldt, S. R.; Sanford, M. S. Adv. Synth. Catal. 2012, 354, 3517. (f)
Nguyen, J. D.;D’Amato, E. M.;Narayanam, J. M. R.;Stephenson, C. R. J.
Nat. Chem. 2012, 4, 854. (g) Wang, Z. Q.; Hu, M.; Huang, X. C.; Gong,
L. B.; Xie, Y. X.; Li, J. H. J. Org. Chem. 2012, 77, 8705. (h) Zhu, S. Q.;
Rueping, M. Chem. Commun. 2012, 48, 11960. (i) Pirnot, M. T.; Rankic,
D. A.; Martin, D. B. C.; MacMillan, D. W. C. Science 2013, 339, 1593. (j)
Sahoo, B.; Hopkinson, M. N.; Glorius, F. J. Am. Chem. Soc. 2013, 135,
5505. (k) Deng, G. B.; Wang, Z. Q.; Xia, J. D.; Qian, P. C.; Song, R. J.; Hu,
M.; Gong, L. B.; Li, J. H. Angew. Chem., Int. Ed. 2013, 52, 1535.
(6) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.; Sigman, M. S.
J. Am. Chem. Soc. 2010, 132, 7870. (b) Satterfield, A. D.; Kubota, A.;
Sanford, M. S. Org. Lett. 2011, 13, 1076. (c) Kalyani, D.; Satterfield,
A. D.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 8419.
(7) Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Chem.;Eur. J.
2012, 18, 2931.
(8) Ball, L. T.; Green, M.; Lloyd-Jones, G. C.; Russell, C. A. Org.
Lett. 2010, 12, 4724.
(9) Melhado, A. D.; Brenzovich, W. E.; Lackner, A. D.; Toste, F. D.
J. Am. Chem. Soc. 2010, 132, 8885.
(10) For related studies on alkene oxyarylation and aminoarylation,
see: (a) Schultz, D. M.; Wolfe, J. P. Synthesis 2012, 351. (b) Hopkins,
B. A.; Wolfe, J. P. Angew. Chem., Int. Ed. 2012, 51, 9886.
(11) Hartmann, M.; Li, Y.; Studer, A. J. Am. Chem. Soc. 2012, 134,
16516.
Reactant concentration was important with respect to
maintaining the catalyst and reactants in solution, since at
1 M or above the solutions became cloudy and yields
dropped (entry 3). Interestingly, the presence of an inhi-
bitor (4-tert-butylcatechol) in commercial samples of styr-
ene did not lead to appreciable differences in reaction yield
(entry 6). Finally, to enhance the reaction yield we surveyed
a variety of additives and found Zn(OAc)2 (20 mol %)
to be effective, affording 3a in 70% yield (entry 7). Im-
portantly, this level of efficiency was maintained with the
Ir(ppy)3 loading reduced to 1 mol % (entry 8). Control
reactions without a catalyst or light gave no conversion at
both rt and 100 °C, indicating that PRC was essential to the
methoxyarylation transformation (entries 9ꢀ11).
With optimized conditions established for the three-
component methoxyarylation, we surveyed a range of
styrenes to explore the substrate scope in this component.
Org. Lett., Vol. 15, No. 17, 2013
4399

Substitution at the aromatic ring was generally well toler-
ated across a range of functional groups, both electron
donating and withdrawing, with alkyl, trifluoroalkyl, ha-
logen, amide, and ester groups all undergoing successful
phenylmethoxyarylation (3aꢀ3n, Scheme 2). Pleasingly,
the reaction was also successful for substituted styrenes.
Methyl cinnamate gave a 48% yield of 3o as a single
diastereoisomer, and both R- and β-methyl styrenes were
productive, the former giving an excellent 83% yield of the
tertiary benzylic compound 3q. Unsuccessful substrates that
were screened included simple alkenes such as cyclohexene,
vinyl pyridines, and m-nitro-substituted styrene, all of which
gave no conversion under the reaction conditions.
Table 2. Aryl Component Substrate Scopea
entry
Ar
compound
yielda
1b
m-MeC6H4 (2b)
m-,p-(Me)2C6H3 (2c)
o-FC6H4 (2d)
5a
5b
5c
5d
5e
5f
45%
56%
70%
61%
59%
50%
58%
68%
71%
65%
56%
81%
25%
27%
71%
45%
2b
3b
4b
m-FC6H4 (2e)
5b
p-FC6H4 (2f)
6b
p-ClC6H4 (2g)
7b
o-BrC6H4 (2h)
5g
5h
5i
8b
m-IC6H4 (2i)
Scheme 2. Styrene Substrate Scope for Methoxyarylationa
9b
m-,p-(Cl)2C6H3 (2j)
o-F,p-BrC6H3 (2k)
m-(CF3)C6H4 (2l)
p-(MeO2C)C6H4 (2m)
p-(NHAc)C6H4 (2n)
p-MeOC6H4 (2o)
p-(EtO2C)C6H4 (2p)
p-(NO2)C6H4 (2q)
10b
11b
12b
13b
14b
15c
16c
5j
5k
5l
5m
5n
5o
5p
a Isolated yields. b X = IþAr. c X = N2
.
þ
Scheme 3. Alkoxy- and Aminoarylation
a Isolated yields. b Yield is the average of three experiments.
Investigation into the scope of the iodonium species
revealed a similarly robust range of functionality (Table 2).
Tetrafluoroborates were found to be more effective than the
analogous triflate salts,12 and screening was conducted on
this basis. Alkyl, halogen, trifluoromethyl, and ester groups
were all well-tolerated (entries 1ꢀ12), with a variety of
substitution patterns being effective in the reaction. Notably,
iodo-substitution on the iodonium salt (2i) is tolerated under
the photoredox conditions (entry 8), indicating the comple-
mentarity of the overall approach with traditional transition
metal and radical arylation techniques.
Substitution of electron-donating groups in the para-
positionofthediaryliodonium salt, however, did notprove
rewarding, with p-NHAc and p-MeO returning low yields
of methoxyarylated products (entries 13 and 14). We also
evaluated diazonium salts in the reaction, as alternative
aryl radical precursors, and were pleased to observe suc-
cessful methoxyarylation of 1a for p-(EtO2C)C6H4N2BF4
(entry 15) and p-(NO2)-C6H4N2BF4 (entry 16). The com-
plementarity of iodonium and diazonium salts in synthesis
has been remarked upon13 and adds flexibility to the
(13) Bonin, H.; Fouquet, E.; Felpin, F. X. Adv. Synth. Catal. 2011,
353, 3063.
(14) Attempted synthesis of bis-4-nitrophenyliodonium tetrafluoro-
borate according to the Olofsson procedure (Bielawski, M.; Aili, D.;
Olofsson, B. J. Org. Chem. 2008, 73, 4602) was not successful.
(12) For Cu-catalyzed alkene and alkyne carbofunctionalization
using diaryliodonium triflates, see: (a) Phipps, R. J.; McMurray, L.;
Ritter, S.; Duong, H. A.; Gaunt, M. J. J. Am. Chem. Soc. 2012, 134,
10773. (b) Suero, M. G.; Bayle, E. D.; Collins, B. S. L.; Gaunt, M. J.
J. Am. Chem. Soc. 2013, 135, 5332.
4400
Org. Lett., Vol. 15, No. 17, 2013

discover the successful formation of the CꢀN bond using
both MeCN and PhCN as solvents in the reaction, acces-
sing the biologically active phenylethylamide scaffolds 10
and 11, albeit in moderate yields.
Scheme 4. Proposed Reaction Mechanism
A proposed mechanism is outlined in Scheme 4 and
involves initial reduction of the iodonium salt 2a with
photoexcited Ir(III)*. The resultant aryl radical is trapped
with styrene, present in excess, forming benzylic radical 4
which can be oxidized by Ir(IV) to the cation 13. Trapping
with the appropriate nucleophile then affords the three-
component coupled products 3. The generation of aryl
radicals from iodonium salts is known,15 and their inter-
mediacy was further supported by the observations of
TEMPO (2.5 equiv) completely inhibiting the methoxy-
phenylation of styrene, and degassing of the reaction
solvent being necessary for successful reaction. We further
trialed PhI(OAc)2 and PhI as aryl sources under the reaction
conditions and observed no conversion in either case.
In summary, we have developed a novel three-component,
photoredox-catalyzed coupling of styrenes with aryl groups
and heteroatom nucleophiles such as alcohols, water, or
nitriles. The mild conditions of the reaction allow the reactive
styrene moiety to undergo smooth conversion to useful
products at ambient temperature, with no polymerization
observed under the reaction conditions. The coupling
can be extended to diazonium reagents, furthering the
range of aryl functionality that may be incorporated into
the reaction.
current approach in terms of widening the aryl substrate
scope. The p-NO2 phenyliodonium tetrafluoroborate salt,
for example, could not be readily synthesized in our hands
using literature procedures.14
We then examined the third component in the reaction,
as variation at this position would substantially enhance
the scope of the three-component coupling. We could use
alternative alcohols in the reaction to afford the ethers 6, 7,
and 8, with these reactions being conducted in the absence
of Zn(OAc)2 (Scheme 3). Most importantly, we found that
water was effective as a nucleophile when used as a
cosolvent with THF. The tertiary alcohol 9 was formed
in a good 70% yield from R-methylstyrene, with the
OH-group available for diverse further functionalizations.
Finally, we explored the scope of Ritter-type reactions
to access aminoarylation chemistry. We were pleased to
Acknowledgment. We thank the University of Manche-
ster, AstraZeneca, and the EPSRC for funding (Studentship
to G.F., Leadership Fellowship to M.F.G.).
Supporting Information Available. Optimization tables
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Lalevee, J.; Blanchard, N.; Tehfe, M. A.; Peter, M.; Morlet-
Savary, F.; Fouassier, J. P. Macromol. Rapid Commun. 2011, 32, 917.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4401