Copper-catalyzed regioselective reaction of internal alkynes and diaryliodonium salts

Article abstract of DOI:10.1021/ol4003543

The copper-catalyzed highly regioselective reaction of internal alkynes with diaryliodonium salts was achieved for the first time. α-Arylketones were obtained in moderate to good yields from arylpropargylic alcohols or aryl alkyl alkynes under mild condit

Full text of DOI:10.1021/ol4003543

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2096–2099
Copper-Catalyzed Regioselective
Reaction of Internal Alkynes and
Diaryliodonium Salts
Ze-Feng Xu, Chen-Xin Cai, and Jin-Tao Liu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Science, Shanghai 200032, China
jtliu@sioc.ac.cn
Received February 6, 2013
ABSTRACT
The copper-catalyzed highly regioselective reaction of internal alkynes with diaryliodonium salts was achieved for the first time. R-Arylketones
were obtained in moderate to good yields from arylpropargylic alcohols or aryl alkyl alkynes under mild conditions. It was found that the two kinds
of substrates underwent two different arylationÀoxygenation pathways under different reaction conditions based on deuterated experiments,
controlling experiments, and spectroscopic analysis of reaction intermediates.
Carbonyl compounds, especially R-aryl carbonyl
compounds, are of particular importance in organic and
pharmaceutical chemistry, and Markovnikov hydration of
alkynes is an ideal method for their synthesis. Mercury(II)
salts combined with acids, such as HgO/H2SO4 and
HgO/BF3, although of potential toxicity, are reliable
catalytic systems for this transformation and are widely
used.1 Alternative transition metallic catalysts have been
sought in recent years, such as Pt, Fe, Pd, Ir, Ag, SnÀW,
and Co.2 Recently, it has been found that gold complexes
can efficiently catalyze the transformation of alkynes to
ketones (Scheme 1A).3 Among some recent significant
studies, Zhang’s group made a major contribution to the
gold-catalyzed transformations of propargylic esters to
eneketons, and a AuI/III catalysis cycle was established to
synthesize R-arylketones utilizing boronic acids as the
coupling partners and selectfluor as an oxidant to transfer
(3) (a) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew.
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Soc. 2011, 133, 13782. (e) Bigot, A.; Williamson, A. E.; Gaunt, M. J.
J. Am. Chem. Soc. 2011, 133, 13778. (f) Allen, A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2011, 133, 4260. (g) Duong, H. A.; Gilligan, R. E.;
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r
10.1021/ol4003543
Published on Web 04/15/2013
2013 American Chemical Society

Table 1. Optimization of Reaction Conditions
Scheme 1
yield (%)a
base
temp
t
entry
[Cu]
CuI
solvent
(equiv)
(°C) (h) 4a
6a
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
À
60
60
60
24
À
À
2
CuI
À
Li2CO3 (2.0)
Li2CO3 (2.0)
24 21
À
3
24
24
24
À
4
À
4
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuCN
Na2CO3 (2.0) 60
À
5
K2CO3 (2.0)
Li2CO3 (1.8)
Li2CO3 (1.8)
Li2CO3 (1.8)
Li2CO3 (1.8)
Li2CO3 (1.8)
Li2CO3 (1.8)
Li2CO3 (1.8)
Li2CO3 (1.8)
60
60
70
80
70
70
70
70
70
70
70
À
À
6
24 28
24 32
À
AuI to AuIII, which was able to undergo a transmetalation
reaction and the following reductive elimination reaction
to produce the products and regenerate the AuI catalyst
(Scheme 1B).4
7
À
8
24
72
3
6
50
50
57
61
52
À
9
10
11
12
13
14
15
24 <2
24 <2
24 <2
24 18
Recently, the direct copper-catalyzed arylation of var-
ious compounds with iodonium salts has been extensively
studied.5 Iodonium salts are indeed extremely appealing as
they are air- and moisture-stable and can be easily pre-
pared in one step from commercially available materials.6
Gaunt’s research group has demonstrated that, in the
presence of copper and diaryliodonium salts, a CuIII-aryl
intermediate formed, and as bearing a d8-configuration, it
was a highly electrophilic metal species.5c The selective Cu-
catalyzed arylation of indoles,5j aromatic compounds,5gÀi
and alkenes5c was also reported with the combination of
copper salt and hyperiodonium by his group. MacMillan
et al. described an elegant Cu-catalyzed enantioselective
R-arylation5d,f of carbonyl groups.
Inspired by these significant works, we envisioned that
the CuIII-aryl intermediate, as highly electrophilic metal
species, may also coordinate with the CÀC triple bond as
in the AuI species. Then the nucleophilic attack on the
activated triple bond would result in the formation of
a new CuIII species, which undergoes reductive elimina-
tion to give the coupling product. Accordingly, we de-
signed the following transformations: propargyl alcohol
1a coordinated first with the CuIII-aryl species, then the
intramolecular nucleophilic attack by oxygen produced
intermediate 2, reductive elimination of 2 gave the 2H-
oxete derivative 3,7 and the final product, R,β-unsaturated
ketone 4, was formed through the pericyclic reaction of 3
(Scheme 1C).
Cu(OTf)2 DCE
CuCl
CuI
DCM Li2CO3 (1.8)
DCM Li2CO3 (1.8)
24
24
18
À
3
51
87
87
46
16b CuI
17c CuI
DCM Li2CO3 (1.8) 70
DCM Li2CO3 (1.8) 70
6
24 12
a Determined by 1H NMR with MesH as an internal standard.
b 1.1 equiv of Ph2IOTf was utlized. c 1.0 equiv of H2O was added.
regioselective synthesis of arylketones from propargylic
alcohols. Furthermore, a similar transformation of aryl
alkyl alkynes was also achieved without a base.
At the outset of the study, 3-phenylprop-2-yn-1-ol (1a)
and diphenyliodonium triflate (5a) were chosen as model
substrates to establish the optimized reaction conditions
(Table 1). The reaction was first examined in 1,2-dichlor-
oethane (DCE) at 60 °C using 20 mol % CuI as a catalyst,
but no desired product was formed and 1a decomposed
(Table 1, entry 1). When 2.0 equiv of Li2CO3 was added, 4a
was formed in 21% yield (entry 2). The copper catalyst was
necessary for the reaction, and 1a remained unchanged in
the absence of CuI (entry 3). Further screening of bases
and their equivalents (entries 4À7) showed that a better
result was obtained when the reaction was carried out at
70 °C using 1.8 equiv of Li2CO3 (entry 7), but the yield was
still very low. When a higher temperature (80 °C, 24 h) or a
prolonged reaction time (70 °C, 72 h) was utilized, the
hydrated product (6a) was formed in moderate yields
(entries 8 and 9). Using other Cu sources gave almost the
same results (entries 10À12) or a low yield of 4a (entry 13).
Using dichloromethane (DCM) instead of DCE as solvent
did not improve the yield of 6a in the case of CuCl
(entry 14). To our delight, when the reaction was carried
out in DCM using CuI as a catalyst, an 87% yield of 6a
was achieved (entry 15). It was also found that a shorter
reaction time was required when a slight excess of 5a was
used (entry 16). Residual H2O in starting materials was
Herein we describe the successful execution of the above
design via a CuI/III catalytic cycle, which provides a highly
(6) For recent reviews, see: (a) Merritt, E. A.; Olofsson, B. Angew.
Chem., Int. Ed. 2009, 48, 9052. (b) Deprez, N. R.; Sanford, M. S. Inorg.
Chem. 2007, 46, 1924. For synthesis of diaryliodonium salts, see also:
(c) Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602.
(d) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349,
2610. (e) Kitamura, T.; Matsuyuki, J.; Nagata, K.; Furuki, R.; Taniguchi,
H. Synthesis 1992, 945.
(7) (a) Martino, P. C.; Shevlin, P. B. J. Am. Chem. Soc. 1980, 102,
5430. (b) Friedrich, L. E.; Lam, P. Y.-S. J. Org. Chem. 1981, 46, 306.
Org. Lett., Vol. 15, No. 9, 2013
2097

To further enlarge the scope of the reaction, several
propargyl alcohols were next investigated. In the case
t
of Ar3 = Ph, R = Bu, the unhydrated product 4k was
Scheme 2. Scope of the Substrates
obtained in 48% yield, and when R = iPr or 4-Cl-C6H4,
complex mixtures were obtained and could not be sepa-
rated by flash column chromatography or even pre-
parative TLC. For alcohols with two alkyl substituents
at the R-carbon, ene-ynes were formed as major products
(Supporting Information (SI)).
The regioselectivity of the above reaction was excellent,
and no methyl ketones were observed. Both electron-
donating and -withdrawing groups on the aromatic ring
in diaryliodonium salts were tolerated. This made it pos-
sible to further functionalize these products, demonstrat-
ing the potential of this protocol.
Regarding the mechanism for the formation of 6, two
possible pathways might be involved (Scheme 3). In path a,
a CuIII-aryl species and the 2H-oxete 3 were formed as
the crucial intermediates as we assumed in our design
(Scheme 1C). Under the reaction conditions, the desired
product 4 was hydrated to give 6 as the final product. In
path b, after the coordination of the CuIII-aryl species with
the substrate, water or TfOÀ rather than the hydroxyl
group might attack the activated triple bond, followed by
reductiveelimination, hydrolysis, and tautomerism, to give
the product 6.
Careful study showed that 4 was always formed prior to
6 at the beginning of the reaction by 1H NMR, and 4 could
be easily converted to 6 under the reaction conditions,
whereas the reverse transformation did not occur. Further-
more, when 1-phenyl-1-propyne (8a) was used to react
with 5a under the same conditions, only 2% of the desired
product 9a was obtained (eq 1, also entry 1 in Table S1
(SI)). Therefore it is reasonable to infer that the reaction
took place through path a.
enough for the transformation, and the addition of water
resulted in a lower yield (entry 17). Finally, the optimized
reaction conditions were established as indicated in entry 16.
The scope of this reaction was then promptly investi-
gated. The results are shown in Scheme 2. In general,
symmetrical diaryliodonium salts (Ar1 = Ar2) were
successfully employed, and both electron abundant and
deficient aryls were found to be suitable for this reaction,
affording the corresponding R-arylketones in good yields
(Scheme 2, upper section, 6aÀd). Unsymmetrical diary-
liodonium salts containing a usual aryl group and a more
steric aryl unit (Ar1 = Mes) that would transfer ineffi-
ciently in the Cu-catalyzed process5j,8 were also studied.
Diaryliodonium salts containing anelectron abundant aryl
gavethe desiredproducts ingood yields (Scheme 2, bottom
section, 6a, 6eÀf). A slightly lower yields were obtained
with electron-deficient ones (Scheme 2, bottom section,
6bÀd, 6gÀh). The reaction was also successfully applied to
the diaryliodonium salt containing a heteroaromatic ring
(6j). However, R,β-unsaturated ketones were obtained as
the major products in the case of the diaryliodonium salt
with a m-NO2 substituted group (4i).
It was interesting to find that the R-arylketone 9a with
the main byproduct propiophenone 10 was formed regio-
selectively when the reaction of 8a with 5a was carried out
in the absence of base under conditions similar to those
for eq 1 (entry 2, Table S1 (SI)). To improve the yield of 9a,
the reaction conditions were further investigated. As
shown in Table S1 (SI), the best result was obtained when
the reaction was carried out in DCM at 80 °C in the
presence of 1.0 equiv of water using Cu(OAc)2 as the
catalyst under an oxygen atmosphere entry 18, Table S1
(SI), also the equation in Scheme 4.
Scheme 3. Proposed Mechanism for the Formation of 6
Under the optimized reaction conditions, the substrate
scope of the reaction was screened next. The results were
summarized in Scheme 4. Both symmetrical and unsym-
metrical diaryliodonium salts could react with 8a to give
the corresponding R-arylketones in moderate to good
yields. Usually, a shorter reaction time was required
with unsymmetrical diaryliodonium salts containing an
electron-abundant aryl (9bÀc). Other alkynes such as
1-(p-ethylphenyl)-1-propyne, 1-(p-fluorophenyl)-1-propyne,
(8) (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am.
Chem. Soc. 2006, 128, 4972. (b) Deprez, N. R.; Sanford, M. S. Inorg.
Chem. 2007, 46, 1924.
2098
Org. Lett., Vol. 15, No. 9, 2013

Scheme 4. Reaction of 8 with 5a
Scheme 5. Proposed Mechanism for the Reaction of 8a with 5
electrophilic metalation between the electron-abundant
olefin 14 and the electrophilic CuIII-aryl intermediate
would produce the intermediate 15. After reductive elim-
ination and hydrolysis, the product 9 could be afforded
along with the regeneration of a proton and the active
CuI species. The byproduct 10 may be formed through the
hydrolysis of intermediate 14.
b
a Isolated yields. 1.0 equiv of diaryliodonium salts were used.
c Ar1 = Ar2. d Ar1 = Mes.
In summary, we have developed a new approach to the
synthesis of R-arylketones by the Cu-catalyzed reaction of
alkynes and diaryliodonium salts. The features of this
protocol are as follows: (1) it is the first example of the
Cu-catalyzed transformation of the CÀC triple bonds to
ketones, to our knowledge; (2) the reaction takes place
under mild conditions with excellent regioselectivity; (3)
unlike AuI/III catalyzed reactions in whichan outer oxidant
and a large excess of arylation reagent are needed, the
iodonium salt acts as both an oxidant and arylation reagent
inthis reaction, and only 1.1À1.5 equiv of the iodonium salt
is required; and (4) the reaction tolerates many functional
groups, making it possible to further functionalize the
products and synthesize more complicated compounds.
These features demonstrate the potential of this protocol,
and we believe that it will find many applications in organic
synthesis.
and 1-phenyl-1-butyne were also examined. The correspond-
ing products were obtained (9kÀm), but the yields were
lower.
According to several mechanism studies (SI), a plaus-
ible CuI/III cycle was proposed for the above reaction
(Scheme 5). The active species CuI would be initially
formed through the disproportionation of CuII.9,10 Oxida-
tive addition of 5a to the CuI species gave a strongly
electrophilic CuIII-aryl species, which could coordinate
with 8a. The resulting CuIII complex then would undergo
either an insertion reaction to the CÀC triple bond or
attack by nucleophiles to generate 11. Reductive elimina-
tion of 11 may regenerate the active CuI species and the
intermediates 12, which would produce the final product 9
after hydrolysis and tautomerism accompanied with the
generation of a proton. Meanwhile, another pathway may
alsooccurinacidicconditionsalongwiththeaccumulation
of a proton. In the presence of a proton, 8a may undergo
an addition reaction to give intermediate 14, which could
also be formed through the protonation of 11. Then an
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 21172243) is
gratefully acknowledged.
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Supporting Information Available. Experimental details
and spectroscopic data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
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