Copper-catalyzed carboarylation of alkynes via vinyl cations

Article abstract of DOI:10.1021/ja405972h

Copper-catalyzed arylation of electron rich alkynes reveals stabilized trisubstituted vinyl cation equivalents that react with pendant arene nucleophiles to form all carbon tetrasubstituted alkenes. The new process streamlines the synthesis of important medicinally relevant molecules.

Full text of DOI:10.1021/ja405972h

Communication
pubs.acs.org/JACS
Copper-Catalyzed Carboarylation of Alkynes via Vinyl Cations
Andrew J. Walkinshaw, Wenshu Xu, Marcos G. Suero, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, United Kingdom, CB2 1EW
S
* Supporting Information
ABSTRACT: Copper-catalyzed arylation of electron rich
alkynes reveals stabilized trisubstituted vinyl cation
equivalents that react with pendant arene nucleophiles to
form all carbon tetrasubstituted alkenes. The new process
streamlines the synthesis of important medicinally relevant
molecules.
he hydroarylation of alkynes is an important synthetic
process as it provides general access to substituted styrene
T
derivatives, molecules that display significant utility as building
blocks for chemical synthesis, medicines, and functionalized
materials. In the simplest case, an alkyne is protonated by a
strong acid and the resulting vinyl cation intermediate is
intercepted by an arene nucleophile.1 Many transition metal
salts are also capable of catalyzing hydroarylation, and this
continues to inspire the development of new general catalytic
methods for the preparation of highly substituted styrenes.2
Most metal-catalyzed hydroarylation processes involve carbon−
carbon triple bond activation by the π-Lewis acidity of the
metal salt. This promotes an anti-addition of the nucleophilic
aryl group to the π-complex followed by protonation of the
resulting vinyl-metal bond. Despite its broad use, the
hydroarylation of alkynes is limited to the formation of
mono-, di-, or trisubstituted alkenes. The development of
catalytic methods that lead to the carboarylation of
disubstituted alkynes remains a challenge to synthetic chemists,
and while the overall transformation can be achieved in a
stepwise fashion,3 catalytic processes to form all-carbon
tetrasubstituted alkenes are still rare.4
Inspired by the simplicity of acid mediated hydroarylation,
we questioned whether a related process could be initiated
through the reaction of a carbon electrophile with an alkyne
(eqs 1,2).5 On the basis of recent reports from our laboratory,6
we proposed that a catalytically generated aromatic electrophile
equivalent (eq 3), formed via activation of a diaryliodonium
triflate with a Cu(I) salt,7 would react with an electron rich
carbon−carbon triple bond to form a putative stabilized
trisubstituted vinyl cation-type intermediate.8
This reactive species could then be intercepted by a latent
aromatic nucleophile via a Friedel−Crafts-type process to form
the all-carbon tetrasubstituted substituted alkene. Here we
report the development of a copper-catalyzed intramolecular
carboarylation process that forms cyclic tetrasubstituted
alkenes. The new process is operationally simple, works with
a range of alkynes and diaryliodonium salts, and can
accommodate a variety of electronically distinct arenes as the
nucleophilic component of the reaction. This alkyne carboar-
ylation can also be used to streamline the synthesis of
important anticancer therapeutics and has great potential for
the synthesis of complex alkenes.
Our initial studies were guided by an observation made
during our work on the copper-catalyzed carbotriflation of
alkynes using diaryliodonium salts.6b Reactions on alkynes
Received: June 14, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja405972h | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
bearing one alkyl group and one phenyl group resulted in an E-
selective reaction, whereas alkynes with two alkyl groups
displayed Z-selectivity under the same conditions. We reasoned
that the E-selectivity observed in the phenyl-substituted system
could arise from the intermediacy of the vinyl cation; aromatic
substituents appended directly to the carbenium atom are
known to stabilize vinyl cations (eq 5).
Table 2. Scope of Electrophilic Component
The feasibility of the carboarylation hypothesis was first
examined using alkyne 1a, an alkyne displaying an electron rich
aryl group that should stabilize the vinyl cation species formed
in the proposed mechanistic pathway. A survey of reaction
parameters is shown in Table 1 and revealed that optimal
Table 1. Selected Optimization of Carboarylation
lower yield was obtained for the transfer of a 4-methoxyphenyl
group (3g), and no reaction was observed for the transfer of
ortho-substituted aryl groups, most likely due to the low
reactivity of salt 2h. However, we were pleased to find that this
process was amenable to the use of vinyl(aryl)iodonium
salts,10c with styrenyl and functionalized vinyl groups trans-
ferred in good yields (3i−j).
DTBP,
equiv
temp, yield 3a,
a
entry
catalyst
solvent
2a, equiv
°C
%
The electronic requirements for the substituent on the
carbon−carbon triple bond were more rigid, and we observed
that it is essential to have a group capable of adequately
stabilizing a cation intermediate (Table 3).11 In addition to the
1
2
3
4
Cu(OTf)2
CuCl
DCE
DCE
DCE
DCE
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
70
70
70
70
0
50
42
51
CuTC
CuI +
AgOTf
5
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
dioxane
C6H5Cl
toluene
Me2CO
DCE
1.0
1.0
70
70
18
58
62
13
94
95
93
0
Table 3. Scope of Alkyne Substituent and Linking Unit
6
1.0
1.0
7
1.0
1.0
70
8
1.0
1.0
70
b
d
9
2 × 1.0
2.0
2 × 1.0
2.0
70
10
11
12
13
14
DCE
50
c
CuCl
DCE
2.0
2.0
50
none
none
none
DCE
2.0
2.0
50
DCE
2.0
2.0
90
0
DCE
2.0
2.0
110
0
a
Reactions performed with 0.1 mmol of 1a and yield of 3a are
1
presented as an average of two runs determined by H NMR with
Ph3CH as the internal standard. Portionwise addition of 2.0 equiv of
2a and DTBP. 2.5 mol % CuCl. Yield of isolated product.
b
c
d
conditions could be achieved by treating 1a with 2.5 mol %
CuCl as the catalyst and 2.0 equiv of diaryliodonium triflate
(2a) and 2,6-di-tert-butyl pyridine (DTBP)9a with 1,2-dichloro-
ethane as the solvent at 50 °C.9b No reaction was observed in
the absence of the copper salt, even at higher temperatures.
With an optimized set of reaction conditions in hand we next
turned our attention to assessing the scope of the alkyne
carboarylation. We first explored the electrophilic aryl coupling
partner by testing a variety of unsymmetrical aryl(mesityl)-
iodonium triflates (Table 2).10a,b We found that aryl groups
displaying halogen substituents and electronic withdrawing
groups could be transferred giving excellent yields of the
desired dihydronaphthalene products (3b−f). Surprisingly, a
anisyl group, a simple phenyl group was sufficiently reactive,
providing a good yield of the corresponding product 3k after 48
h. We were pleased to find that a styrenyl substituent on the
alkyne also worked well, further reflecting the similarities with
established vinyl carbocation stability (3l).8 While alkynes with
alkyl substituents undergo the aryltriflation reaction, a substrate
with a cyclopropyl substituent (a group that is capable of
stabilizing an adjacent positive charge) led to an intractable
mixture of products. Heteroatom functional groups directly
B
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Journal of the American Chemical Society
Communication
appended to the alkyne also worked well and provided a route
in more complex dihydronaphthalene derived systems (3n,o).
We next investigated substrates displaying a selection of
linkers between the alkyne and the arene nucleophile (Table 3).
In addition to the ethylene linkage, oxygen and nitrogen
substituents could also be incorporated to provide the
substituted chromene and dihydroquinoline ring systems
(4a,b). Complex mixtures were observed when we tried to
form the corresponding indene derivative 4c. However, we
were delighted to find that a seven-membered ring could be
formed in good yield, further extending the efficacy of this
process (4d).
Scheme 1. Applications of the Carboarylation
The final aspect of our scope studies focused on the arene
used to intercept the proposed vinyl cation intermediate (Table
4). We found that the arene nucleophile could accommodate
Scheme 2. Intermolecular Carboarylation
Table 4. Scope of Arene Nucleophile
unsaturated systems using a simple multicomponent ap-
proach.6b,c
In summary, we have developed a Cu-catalyzed alkyne
carboarylation process that generates highly functionalized all
carbon tetrasubstituted alkenes as part of a dihydronaphthalene
framework. We believe the process exploits a catalytically
generated aromatic electrophile that reacts with an alkyne to
form a trisubstituted vinyl cation intermediate, which is
intercepted by a tethered arene nucleophile. The carboarylation
proceeds under mild conditions, produces the products in high
yields, and can be used to streamline the synthesis of complex
molecules. Current studies are focused on the synthesis of
naphthoquinone and chromenone derived natural products15
and on exploiting the vinyl cation reactivity that underpins this
novel transformation.
substituents at the ortho or para positions with respect to the
alkyne containing appendage and in all cases gave rise to
excellent yields of the products; meta substituents led to
isomeric mixtures of products (3u). Electron donating, electron
withdrawing, and naphthalene groups, heterocycles, and a wide
range of useful functionality could be introduced as the
nucleophilic component of the carboarylation.12
To demonstrate the utility of this new copper-catalyzed
carboarylation we showed that the dihydronaphalene products
can be oxidized to the polyaromatic naphthalenes 5.13 We also
developed a short route toward the anticancer agent nafoxidine
(Scheme 1).14 Subjecting the alkyne 6 to the standard reaction
conditions produced a 73% yield of the desired dihydro-
naphthalene (not shown) on gram scale. Treatment with
pyrrolidine at 100 °C in ethanol provided nafoxidine 7 in
excellent yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
mjg32@cam.ac.uk
Notes
The authors declare no competing financial interest.
Finally, we showed that external nucleophiles can be
accommodated as part of the carboarylation process (Scheme
2). Our preliminary experiments revealed that a three
component carboarylation reaction between alkyne 8, diphe-
nyliodonium triflate (2a), and anisole (9) as the nucleophilic
component is also possible, forming the all carbon tetrasub-
stituted alkene 10 in 67% yield. This is a promising result that
opens potential new strategies for the synthesis of complex
ACKNOWLEDGMENTS
■
We are grateful to the EPSRC and Syngenta for the Industrial
Case Award (A.J.W.), Marie Curie Foundation (M.G.S.), the
ERC, and EPSRC for fellowships (M.J.G.). We acknowledge
Dr. Nick Mulholland (Syngenta) for useful discussions. Mass
spectrometry data were acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
C
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Journal of the American Chemical Society
Communication
(12) A competition experiment between a substrate containing a
phenyl ring and one displaying an electron deficient aromatic ring
(CF3) showed a 1:1 mixture of products (3a:3s), suggesting that the
rate determining step is prior to the Friedel−Crafts stage of the
reaction pathway.
(13) Itami, K. Pure Appl. Chem. 2012, 84, 907.
(14) (a) Lednicer, D.; Lyster, S. C.; Duncan, G. W. J. Med. Chem.
1967, 10, 78.
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D
dx.doi.org/10.1021/ja405972h | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX