Copper-catalyzed electrophilic carbofunctionalization of alkynes to highly functionalized tetrasubstituted alkenes

Article abstract of DOI:10.1021/ja401840j

Copper catalysts enable the electrophilic carbofunctionalization of alkynes with vinyl- and diaryliodonium triflates. The new process forms highly substituted alkenyl triflates from a range of alkynes via a pathway that is opposite to classical carbometalation. The alkenyl triflate products can be elaborated through cross-coupling reactions to generate synthetically useful tetrasubstituted alkenes

Full text of DOI:10.1021/ja401840j

Communication
pubs.acs.org/JACS
Copper-Catalyzed Electrophilic Carbofunctionalization of Alkynes to
Highly Functionalized Tetrasubstituted Alkenes
Marcos G. Suero, Elliott D. Bayle, Beatrice S. L. Collins, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
S
* Supporting Information
The formation of tetrasubstituted alkenes by these catalytic
ABSTRACT: Copper catalysts enable the electrophilic
carbofunctionalization of alkynes with vinyl- and diary-
liodonium triflates. The new process forms highly
substituted alkenyl triflates from a range of alkynes via a
pathway that is opposite to classical carbometalation. The
alkenyl triflate products can be elaborated through cross-
coupling reactions to generate synthetically useful
tetrasubstituted alkenes
methods is difficult due to steric hindrance around the
unsaturated core and is restricted to specific examples.2 Despite
this, their useful properties mean they find many important
applications as medicines, biological probes, functional
materials, and building blocks for synthesis. The most reliable
method to form tetrasubstituted alkenes is alkyne carbometa-
lation (eq 1),3 although there is still a paucity of general
catalytic methods available.4 Surprisingly, methods based on
intermolecular carbopalladation have not become a mainstay
for tetrasubstituted alkene synthesis, despite notable recent
advances.5
he invention of processes that use transition metals to
T
exploit the inherent reactivity of carbon−carbon triple
bonds has captured the imagination of chemists.1 These
reactions have become cornerstone methodologies for the
synthesis of many important chemical products in both
academic and industrial laboratories. Arguably, the most
prevalent class of alkyne reactions are π-insertion processes to
the triple bond, forming alkenes. It is, however, surprising that
the majority of these processes stem from a small number of
related activation pathways. A metal catalyst binds to the π-
orbitals of the alkyne and transfers a group via an external
nucleophilic attack (nucleometalation) or via the metal
(hydrometalation).1a The resulting nucleophilic vinyl-metal
species can undergo a range of further reactions to form
substituted alkenes (eq 1).
Given the inherent reactivity within the carbon−carbon triple
bond, we were surprised that little consideration has been
afforded to a “polarity-reversed” alkyne carbofunctionalization
strategy to form tetrasubstituted alkenes (eq 2). The catalyzed
union of a carbon electrophile with an alkyne would preclude
the use of reactive organometallics and, more importantly,
generate a highly substituted electrophilic vinyl intermediate
whose reactivity would contrast to the vinyl-nucleophile species
formed in classical carbometalation. The scarcity of such
catalytic processes is striking considering that the addition of
acids and halogen-derived reagents to alkynes is well
documented via electrophilic pathways.6
Here we report the development of a Cu-catalyzed
electrophilic carbofunctionalization of alkynes with vinyl- and
diaryliodonium triflates (eq 3). The new process forms highly
functionalized tetrasubstituted alkenyl triflates, is operationally
simple, and works with a range of alkynes and electrophile
coupling partners. The alkenyl triflate products can be further
elaborated through well-established cross-coupling reactions to
generate synthetically useful tetrasubstituted alkenes, difficult to
make by other methods.
We reasoned diaryl- and vinyl(aryl)iodonium salts could
function as suitable carbon electrophiles,7 acknowledging two
important features relating to their reactivity. First, Beringer et
al.8 had shown that treatment of diphenyliodonium chloride
with Cu(I) salts forms chlorobenzene; we9 (and subsequently
others)10 have demonstrated that the combination of diary-
liodonium salts and copper catalysts produces aromatic
electrophile equivalents which react with π-rich nucleophiles.
We believe the mechanism involves a high oxidation state
Cu(III)-aryl intermediate, where both the aryl group and the
counteranion have been assembled on the Cu(III) center.11 As
part of our polarity reversal hypothesis, this intermediate could
Received: February 20, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja401840j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
engage the alkyne (int-I), facilitating the insertion of the aryl-
Cu(III) species to the carbon−carbon triple bond (int-II, eq 4).
4−8), and when the reaction was conducted using 10 mol %
copper(I) chloride in dioxane at 50 °C, 81% yield of the highly
functionalized and synthetically useful 3a was obtained
selectively as the Z-isomer (>20:1 Z:E, entry 8).13−17
The scope of this new electrophillic carbofunctionalization
process was first explored by varying the substituents on the
alkyne. We found that a selection of symmetrical dialkyl and
diaryl alkynes worked well in the process and delivered the
alkene products in excellent yield and selectivity for the Z-
isomer (Table 2A, 3a−c). We also found that the reaction can
a b
,
Table 2. Vinyl Triflation of Symmetrical Alkynes
Taken together with Berenger’s observation,9 the resulting
Cu(III) species, which displays a vinyl group and the
counteranion from the diaryliodonium salt, could undergo
reductive elimination, producing the alkene product bearing a
versatile functional group 3.12
Initially, we selected styryl(o-tolyl)iodonium salts displaying
different halide counteranions with which to test our hypothesis
(Table 1). After screening a range of conditions for the reaction
between 3-hexyne 1a and styryl(o-tolyl)iodonium salts 2 (X =
Cl, I), with CuCl as catalyst and dichloromethane as solvent, we
were disappointed to find that none of these reactions
produced the desired tetrasubstituted alkene, and instead we
observed the formation of the corresponding styryl chloride
(entry 1), or no reaction (entry 2). Speculating that a more
electron-withdrawing counteranion might afford a more
reactive Cu(III)-styryl intermediate, we were pleased to find
that changing the counteranion to triflate (2c) had a dramatic
effect on the outcome, and the desired tetrasubstituted vinyl
triflate 3a was formed as a 6:1 ratio of Z:E isomers (entry 3).
This result is particularly notable as the vinyl triflate product
may result from a rare example of the reductive elimination of a
triflate group from a metal center.12 Following this break-
through, an optimization screen revealed that the nature of the
solvent also had an important influence on the reaction (entries
a
Reactions performed with 2.0 mmol of 1, 0.5 mmol of 2; yields are of
b
c
isolated product. Ratio of isomers determined by 19F NMR. 12 g
scale with 1 mol % CuCl.
a
Table 1. Selected Optimization Results
b
c
entry
catalyst
X
solvent
CH2Cl2
temp, °C
yield 3a, %
ratio Z:E
1
CuCl
CuCI
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
Cl
50
−
−
−
−
6:1
2
l
CH2Cl2
CH2Cl2
dichloroethane
PhMe
50
3
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
50
66
61
50
67
71
4
50
7:1
5
50
13:1
16:1
16:1
>20:1
>20:1
>20:1
−
6
EtOAc
50
7
Et2O
50
d
8
dioxane
dioxane
dioxane
dioxane
dioxane
50
81
9
50
65
46
−
10
11
12
CuTC
none
none
50
50
90, 110
−
−
a
b
Reactions performed with 0.4 mmol of 1a, 0.1 mmol of 2. 1H NMR yields, calculated using trimethyl 1,3,5-benzenetricarboxylate as internal
c
d
standard. Determined by 19F NMR. Yield of isolated product.
B
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Journal of the American Chemical Society
Communication
be performed on multigram scale and with lower catalyst
loading, without compromising the outcome of the reaction
(3b). A range of substituted vinyliodonium triflates can be
successfully applied in this reaction, maintaining good yields
and excellent selectivities (Table 2B, 3d−h). Furthermore, the
corresponding arylative reaction using diphenyliodonium
triflate also works well, producing 72% yield of a fully
substituted styryl triflate, 3i (8:1, Z:E), further enhancing the
potential synthetic utility of this process.
A significant selectivity challenge is presented by carbon−
carbon triple bonds with two different substituents; however,
this Cu-catalyzed process can still distinguish between both
steric and electronically differentiated alkynes (Table 3A). For
that, while arylpropynes gave predominantly Z-isomers in the
vinylation reactions, the corresponding arylation processes
resulted in the selective formation of the E-isomers. While this
represents a useful extension to the reaction, we cannot yet
explain this unusual result (3o,p).
We next investigated the reaction of terminal alkynes as a
means of extending our reaction to the formation of
trisubstituted dienyl triflates. The combination of terminal
alkynes with Cu(I) catalysts presents a potential problem in the
way of oxidative dimerization reactions. Furthermore, Kang et
al. reported a Cu-catalyzed Sonogashira-type coupling of
alkynes and diaryliodonium salts in the presence of base.18
However, when we tested the reaction of terminal alkynes
under our standard conditions, we were delighted to observe
the formation of the desired trisubstituted dienyltriflates,
predominantly as the Z-isomer and in favor of the
Markovnikov-type regioisomer (Table 3B). We did not observe
the alkyne homodimerization or the Sonogashira product. A
range of simple terminal alkynes worked well in this reaction
(3q−w), and even the feedstock alkyne, acetylene, can be
transformed with excellent selectivity to the corresponding
dienyl triflate (3u). This example underlines the efficacy of this
new process in converting inexpensive starting materials into
versatile building blocks. The ratios for 3l,m,o−r,t,v,w are
expressions of the major product (shown) to the sum of all
other isomers, which comprises the E-isomer of the major
product and a regiosiomer.16,19
a
Table 3. Scope of Alkyne Carbofunctionalization
Finally, we demonstrated the utility of the alkenyl triflate
products by further transformation into synthetically versatile
tetrasubstituted alkenes. A series of Pd-catalyzed cross-coupling
methods diversify the vinyl triflates to a range of useful
products in high yields without the loss of isomeric purity
(Scheme 1, 4a−f).16,20 The alkenyl triflates can also be
hydrolyzed to form α-aryl ketones (5), chemo- and stereo-
selectively dihydroxylated (6), and hydrogenated (7).
Scheme 1. Reactions of Tetrasubstituted Vinyl Triflates
a
Ratio of isomers determined by 19F NMR; yields are of isolated
products; ratios shown are of major isomer to the sum of all other
b
isomers, unless otherwise stated; rr = regioselectivity ratio. In
c
d
e
f
dioxane. In CH2Cl2. In dichloroethane. In toluene. In cyclopentyl
g
1
methyl ether. Yield of major product based on H NMR using 1,2-
dimethoxyethane as standard.
example, substrates displaying isopropyl and methyl groups
result in 3j, where the vinyl group is added to the more
sterically hindered position with a regioselectivity ratio (rr) of
3:1, exclusively as the Z-isomer. Interestingly, this regioselec-
tivity is opposite to that observed in conventional alkyne
carbometalation.3 We also observed a 1.4:1 rr in the reaction of
2-pentyne (Et vs Me, 3k). A simple ethylene unit can be
transferred in the reaction of arylpropynes (3l); enynes react
selectively to form conjugated trienes, molecules that may have
interesting applications in the synthesis of functionalized
materials (3m).
We see excellent regio- and stereoselectivity in the arylation
process of propargylic amides, providing highly functionalized
vinyl triflates in good yield (3n). We were surprised to find
C
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Journal of the American Chemical Society
Communication
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In summary, we have developed a Cu-catalyzed synthesis of
highly functionalized tri- and tetrasubstituted alkenyl triflates
from alkynes and vinyl(aryl)- and diaryliodonium salts. We
believe that this method operates through an electrophilic
carbofunctionalization pathway involving a high oxidation state
Cu(III) species. Notable features of this process are the Z-
selectivity, an apparent reductive elimination of a triflate group
to form an electrophilic vinyl product, and compatibility with
both disubstituted and terminal alkynes. Well-established
catalytic reactions transform the products into synthetically
useful tetrasubstituted alkenes. This Cu-catalyzed alkyne
activation pathway employs a reactivity principle that is
opposite to classical carbometalation and could provide a
series of strategic bond-forming processes that will have broad
appeal in synthesis.
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(13) We cannot rule out a pathway proceeding via Lewis acid
activation of the iodonium salt6b,c,14 or through vinyl carbocation-like
intermediates.15 However, we observed no product formation in the
presence of Brønsted acids, Lewis acids, or other transition metal
catalysts.16 We also observed that the Z:E ratios remained constant
throughout the reactions to form 3a and 3o, suggesting the geometric
ratios are not the result of isomerization.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. 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.
ACKNOWLEDGMENTS
■
We are grateful to the Marie Curie Foundation (M.G.S.),
Cancer Research UK (E.D.B.), University of Cambridge
(B.S.L.C.), the ERC and EPSRC for Fellowships (M.J.G.),
and the EPSRC Mass Spectrometry Service, University of
Swansea.
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