Copper-catalyzed alkene arylation with diaryliodonium salts

Article abstract of DOI:10.1021/ja3039807

Alkenes and arenes represent two classes of feedstock compounds whose union has fundamental importance to synthetic organic chemistry. We report a new approach to alkene arylation using diaryliodonium salts and Cu catalysis. Using a range of simple alkenes, we have shown that the product outcomes differ significantly from those commonly obtained by the Heck reaction. We have used these insights to develop a number of new tandem and cascade reactions that transform readily available alkenes into complex arylated products that may have broad applications in chemical synthesis.

Full text of DOI:10.1021/ja3039807

Communication
pubs.acs.org/JACS
Copper-Catalyzed Alkene Arylation with Diaryliodonium Salts
Robert J. Phipps, Lindsay McMurray, Stefanie Ritter, Hung A. Duong, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
S
* Supporting Information
ABSTRACT: Alkenes and arenes represent two classes of
feedstock compounds whose union has fundamental
importance to synthetic organic chemistry. We report a
new approach to alkene arylation using diaryliodonium
salts and Cu catalysis. Using a range of simple alkenes, we
have shown that the product outcomes differ significantly
from those commonly obtained by the Heck reaction. We
have used these insights to develop a number of new
tandem and cascade reactions that transform readily
available alkenes into complex arylated products that
may have broad applications in chemical synthesis.
hemical reactions that link alkenes and arenes are central
to both industrial and academic research, as the products
C
of their union provide a foundation upon which natural
products, medicines, polymers, and fine chemicals can be
synthesized. The development of novel reactions that exploit
the vast array of alkene feedstocks therefore represents a
continuing challenge to chemical synthesis.1 While alkenes
activated with functional groups tend to be predisposed toward
bond-forming reactions, simple unfunctionalized alkenes are
often less reactive as either nucleophiles or electrophiles. Many
of these reactivity limitations have been overcome by using
transition-metal (TM) catalysts, as evidenced by the Heck
reaction, which takes advantage of the affinity of Pd(II)−aryl
intermediates for the π system of alkenes.2 While Cu-catalyzed
processes have frequently paralleled Pd-catalyzed cross-
couplings,3a−d Cu-catalyzed Heck-type coupling reactions are
less common.3e−i
We have recently developed a new Cu-catalyzed arylation
strategy that is often complementary to Pd-catalyzed methods.4
On the basis of an original working hypothesis that Cu(III)−
aryl intermediates5 would be isoelectronic with the correspond-
ing Pd(II) species, a series of Cu-catalyzed site-selective direct
arylations can be used to form biaryl compounds from a range
of simple arenes and diaryliodonium salts (eq 1).6,7 While the
precise mechanism remains unclear, this combination of a Cu
catalyst and a diaryliodonium salt appears to behave as an
activated aromatic electrophile, paralleling the Friedel−Crafts-
type reactivity operational in more established electrophilic
aromatic substitutions. We therefore investigated the arylation
of alkenes based on this mechanistic postulate on the premise
that such a catalytic process (eq 2) would potentially open up a
wide and mechanistically distinct range of new C−C bond-
forming reactions (eqs 2 and 3).8,9 Furthermore, such a
transformation would complement the recent reports of Cu-
catalyzed alkene trifluoromethylation using hypervalent iodine
reagents,10 reinforcing the potential efficacy of the reaction
platform. Herein we describe the realization of this ideal
through an operationally simple Cu-catalyzed process for the
union of alkenes and arenes. This new Cu-catalyzed arylation
may proceed by a reaction pathway displaying carbocation-like
character, allowing the development of a number of novel
tandem and cascade reactions that could expedite the synthesis
of complex molecules.
To test our Cu-catalyzed alkene arylation, we treated 1-
decene (1a) with diphenyliodonium triflate, 2,6-di-tert-
butylpyridine (DTBP) as the base, and 10 mol % Cu(OTf)2
in dichloroethane (DCE) at 70 °C, the standard conditions
adopted in our previous studies.4 We were pleased to find that
Received: April 25, 2012
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja3039807 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
alkene arylation proceeded to give a mixture of 3a and 4a in
reasonable yield (Table 1). Intriguingly, the nonconjugated
Table 2. Scope of the Alkene Arylation
Table 1. Optimization of Cu-Catalyzed Alkene Arylation
a
1
Yields and ratios were determined by H NMR analysis using 1,3,5-
b
trimethoxybenzene as an internal standard. Yield of isolated product
after chromatography. 3a (E:Z = 5.5:1), 4a (E:Z = 3.0:1).
c
major product 3a contrasts with the outcome of a typical Heck
reaction, which would produce a styrene. Encouraged by this
initial result, we assessed the effect of varying the Cu catalyst,
diaryliodonium salt, and solvent as well as the standard reaction
parameters. The most pertinent observations during the
optimization study were that (a) Cu(I) and Cu(II) salts
catalyzed the reaction, (b) diphenyliodonium triflate was the
superior coupling partner,7 and (c) reaction was observed in
the absence of the Cu catalyst only at 110 °C (entry 10). The
optimal conditions gave alkene arylation in 72% yield as a 3.5:1
mixture of nonconjugated:styrene products (entry 9).10
On the basis of our catalyst screening (Table 1), we routinely
assessed a number of Cu salts in our alkene scope study. While
we did not identify any consistent trends between the Cu salt
and the yield, some catalysts clearly worked better for some
substrates than others. Along with arylation of linear terminal
olefins (Table 2, entry 1), the arylation of cyclohexene
proceeded smoothly, delivering a 4:1 ratio of styrene 4b to
allylic product 3b (entry 2). This contrasts sharply with the
typical outcome of Heck reactions on this substrate. Since Heck
reactions on indenes11a and dihydronaphthalenes11b commonly
afford mixtures of arylalkenes, we were pleased to find that our
arylation process gave single isomers for these substrates
(entries 3−5). Styrenes were arylated smoothly to give (E)-
stilbene products (entries 6 and 7), and an allyl pivalate gave a
single arylated regioisomer, 4h, with no evidence of allylic
substitution (entry 8). Enol ethers underwent exclusive
arylation at the β-position (entry 9),11c whereas the
corresponding Heck reaction frequently delivers the α-aryl
product.11d Pleasingly, 1,1-disubstituted alkenes and a hetero-
cyclic variant delivered products with a high selectivity for the
isomer with the endocyclic double bond (entries 10 and 11).11e
Vinylcyclohexene produced a mixture of three double-bond
regioisomers, with the major isomer being the homoallylic
arene product 5l (entry 12). Heck reactions on substrates
similar to those in entries 10−12 produce the styrenyl isomers
exclusively.11f,g A trisubstituted alkene underwent arylation to
give 3m, although the yield was low, presumably because steric
effects hindered the reaction. While less reactive alkenes such as
trans-2-octene gave a complex mixture of arylation and
isomerization products, placement of a trimethylsilyl group at
a
b
A 9% yield of a diarylated isomer was obtained. An 8% yield of a
c
diarylated isomer was obtained. 5l:3l:4l ratio.
the terminal C atom gave only a single isomer, 3n, with an
alkenyl- and aryl-substituted stereogenic center (entry 14).
We selected a number of alkenes (from entries 1, 7, and 9) to
test the catalyst-free reaction. With the exception of the highly
reactive 4-methylstyrene (1g), none of these alkenes underwent
any reaction in the absence of catalyst at 70 °C. In contrast to
1a, which underwent catalyst-free arylation only at 110 °C, 1g
produced a 73% NMR yield of 4g and dihydropyran 1i a 10%
NMR yield of 4i at 90 °C in the absence of a Cu catalyst. While
we rigorously excluded Cu from all of our control reactions, we
cannot rule out the possibility that trace Cu (<10 ppm) that
may have been present in the reagents or solvent could catalyze
the reaction at higher temperatures.12
Our previous studies of meta arylation of pivanilides and α-
aryl carbonyl compounds revealed a crucial reliance on the
presence of a specifically located, remote carbonyl group to
direct the selectivity.4b,d We observed a similar effect in our
alkene arylation, whereby substituted, nonsymmetrical cyclo-
hexenes undergo arylation exclusively at the remote alkene
B
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Journal of the American Chemical Society
Communication
carbon atom (Scheme 1). We propose that the carbonyl motif
Scheme 2. Mechanistic Probes and New Tandem Reactions
controls the selectivity by a neighboring-group effect that could
Scheme 1. Carbonyl-Directed Alkene Arylation
stabilize a developing positive charge or direct a reactive Cu
species to the specific position.13a
Having demonstrated the new phenylation process on a
range of alkenes, we were delighted to find that diaryliodonium
salts with aryl groups displaying electron-rich, electron-
deficient, halogen, and heterocyclic functionality also worked
well (Table 3).6
comb’s “radical clock” cyclopropane motif provided further
mechanistic insight.15 We established that arylation was
accompanied by cyclopropyl ring fragmentation of the bond
between C1 and C2 to afford enol ether 8 (Scheme 2b). This
outcome suggests the intermediacy of a methoxy-stabilized
carbocation, in line with Newcomb’s model, and is based on the
assumption that fragmentation of a cyclopropyl radical would
be faster than oxidation of the radical to a carbocation.13b
While the precise reaction mechanism is not yet known,
these studies provide a compelling model upon which to design
new reactions founded on a putative carbocation intermediate.
In particular, we reasoned that the strain-release-driven
reactivity inherent within 2r and 2s could be applied to other
readily available alkenes. We were pleased to find that
cyclobutyl-derived tertiary allylic alcohols 2t and 2u afforded
the corresponding benzylated cyclopentanones 9t and 9u,
presumably via a mechanism involving tandem arylation and
semipinacol ring-expanding rearrangement (Scheme 2c).13c
Similarly, norbornenol (2v) was transformed into disubstituted
cyclopentenal 10, where the structural change upon arylation
followed a Grob-type fragmentation pathway (Scheme 2d).13d
We were able to effect our arylation−semipinacol rearrange-
ment on estrol derivative 11; the expansion of the D-ring to
give 12 (Scheme 3a) represents an interesting change in the
structural complexity of this steroid derivative.
Table 3. Scope of Aryl Transfer in the Alkene Arylation
a
b
Scheme 3. Arylation of Complex Molecular Scaffolds
1.1 equiv of mesitylaryliodonium triflate and DTBP were used. Yield
1
determined by H NMR spectroscopy.
Interestingly, many of the arylation reactions give products
that could be formed through a mechanism involving the
Friedel−Crafts-type reaction of an alkene with an aromatic
electrophile, whereby the selectivity in the arylation step would
be determined by the location of the resulting partial positive
charge in the most stabilized position.8 This hypothesis was
further supported when we tested our Cu-catalyzed arylation
on β-pinene (2r); here, we isolated 7, a phenylated derivative of
limonene, as a 1:1 mixture of elimination products (Scheme
2a). This product can be rationalized by arylation followed by
either a carbocation- or a radical-mediated structural rearrange-
ment of the bicyclo[3.1.1]heptane framework,14 but a further
experiment using terminal alkene 2s substituted with New-
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Journal of the American Chemical Society
Communication
Tetrahedron Lett. 2005, 46, 4941. Cu-mediated Meerwein arylation:
(i) Rondestvedt, C. S., Jr. Org. React. 1976, 24, 225.
Finally, by exploiting the presence of two reactive alkenes
and a strained cyclobutane ring in the terpene β-caryophyllene
(2w), we were able to engineer a cascade reaction that formed
13, a phenylated analogue of the complex molecule clovene
(Scheme 3b). We believe that this cascade reaction begins with
arylation of the strained trisubstituted (E)-alkene to give I. This
carbocation-like intermediate is intercepted through attack of
the exomethylene group, generating a new carbocation adjacent
to a cyclobutane (II) that subsequently fragments to form the
clovene derivative after elimination from III. This remarkable
process represents a novel transformation that mimics Barton’s
acid-mediated structural reorganization while introducing a new
functional group embedded within the framework of the
complex architecture.16
In summary, we have developed a new approach to alkene
arylation using diaryliodonium salts and Cu catalysis. We have
surveyed a range of simple alkenes and shown that the product
outcomes differ significantly from those commonly obtained by
the Heck reaction. Preliminary studies have shown that a
carbocation-type mechanism may be involved in these
reactions. We have used this hypothesis to design a number
of new tandem and cascade reactions that transform readily
available alkenes into complex molecules that may have broad
synthetic appeal.
(4) For previous work by us using Cu catalysts and diaryliodonium
salts, see: Indoles: (a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J.
Am. Chem. Soc. 2008, 130, 8172. Anilides: (b) Phipps, R. J.; Gaunt,
M. J. Science 2009, 323, 1593. Electron-rich arenes: (c) Ciana, C.-L.;
Phipps, R. J.; Brandt, J. R.; Meyer, F. M.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2010, 50, 457. α-Aryl carbonyls: (d) Duong, H. A.; Gilligan,
R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J. Angew. Chem., Int. Ed.
2010, 50, 463. Enantioselective arylation of enol silanes: (e) Bigot,
A.; Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778.
Related work: (f) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc.
2011, 133, 4260. (g) Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 13782.
(5) For reports of the oxidation of Cu(I) salts with diaryliodonium
salts, see: (a) Lockhart, T. P. J. Am. Chem. Soc. 1983, 105, 1940.
(b) Beringer, F. M.; Geering, E. J.; Kuntz, I.; Mausner, M. J. Phys.
Chem. 1956, 60, 141. For reports of Cu(III) intermediates in Chan−
Lam coupling, see: (c) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am.
Chem. Soc. 2009, 131, 5044. For the isolation of a Cu(III)−aryl
complex, see: (d) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl,
S. S.; Ribas, X. Chem. Sci. 2010, 1, 326.
For a review, see:
(e) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.
(6) For a recent review of diaryliodonium salts, see: Merritt, E. A.;
Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.
(7) For a review of the use of diaryliodonium salts with TM catalysts,
see: Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(8) For mechanistic studies related to alkene Friedel−Crafts
acylation, see: (a) Beak, P.; Berger, K. R. J. Am. Chem. Soc. 1980,
102, 3848. For the reaction of perfluorolalkyliodonium salts with
alkenes, see: (b) Umeoto, T.; Kuriu, Y.; Nakayama, S.-I. Tetrahedron
Lett. 1982, 23, 1169.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(9) For related Heck-type alkene arylations, see: (a) Werner, E. W.;
Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 9692. (b) Werner, E. W.;
Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 13981. (c) Delcamp, J. H.;
White, M. C. J. Am. Chem. Soc. 2006, 128, 15076.
AUTHOR INFORMATION
Corresponding Author
mjg32@cam.ac.uk.
■
(10) For Cu-catalyzed alkene trifluoromethylation by hypervalent
iodine compounds, see: (a) Parsons, A. T.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2011, 50, 9120. (b) Wang, X.; Ye, Y.; Zhang, S.; Feng,
J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410.
(11) For the Heck reactions, see: Indene: (a) Nifant’ev, I. E.;
Sitnikov, A. A.; Andriukhova, N. V.; Laishevtsev, I. P.; Luzikov, Y. N.
Tetrahedron Lett. 2002, 43, 3213. Dihydronapthalene: (b) Maeda, K.;
Farrington, E. J.; Galardon, E.; John, B. D.; Brown, J. M. Adv. Synth.
Catal. 2002, 344, 104. (c) Datta, G. P.; von Schenck, H.; Hallberg, A.;
Larhed, M. J. Org. Chem. 2006, 71, 3896. (d) Loiseleur, O.; Hayashi,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Phillip and Patricia Brown for the Next
Generation Fellowship (M.J.G.); EPSRC and ERC (M.J.G),
BBSRC (R.J.P.), the Marie Curie Foundation (H.A.D.), and the
Deutsche Forschungsgemeinschaft (S.R.) for fellowships; and
AstraZeneca (L.M.) for a studentship. We acknowledge the
EPSRC Mass Spectrometry Service (University of Swansea).
M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338.
Cyclic
exomethylenes: (e) Larock, R. C.; Gong, W. H.; Baker, B. E.
Tetrahedron Lett. 1989, 30, 2603. (f) Furman, B.; Dziedzic, M.
Tetrahedron Lett. 2003, 44, 8249. Vinylcyclohexene: (g) Yao, Q.;
Kinney, E. P.; Yang, Z. J. Org. Chem. 2003, 68, 7528.
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