Aerobic Cu-catalyzed oxidative 1?:?2 coupling of benzynes with terminal alkynes

Article abstract of DOI:10.1039/d0cc03150j

Cu-Catalyzed oxidative 1?:?2 couplings of arynes with nucleophilic terminal alkynes under aerobic conditions are described herein. A mechanistic investigation revealed a plausible involvement of an aryl-Cu(iii)-generating pathway. By this method, ubiquitous arenediynes can be efficiently assembled in a single step under mild conditions. This journal is

Full text of DOI:10.1039/d0cc03150j

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Aerobic Cu-Catalyzed Oxidative 1:2 Coupling of Benzynes with
Terminal Alkynes
Received 00th January 20xx,
Accepted 00th January 20xx
Tianhao Lu, Yong Shen, Min Wang, Zibing Zhang, Shijun Li, and Chunsong Xie*
DOI: 10.1039/x0xx00000x
Described herein is the Cu-catalyzed oxidative 1:2 coupling of
arynes with nucleophilic terminal alkynes under aerobic
Nu
Nu
E
E
Nu-Cu(I)
conditions. Mechanistic investigation revealed
a plausible
Cu(I)
generation of aryl-Cu(III) pathway from arynes. By this method,
ubiquitous arenediynes can be efficiently assembled in a single
step under mild conditions.
Nu = alkynyl, CF3, B(pin), Br-, P(O)R2, CN, 2-(benz)oxazolyl etc.
E = H+, allyl halides, alkenyl epoxides, alkenyl aziridines, PhSO2SAr,
CO2, alkynyl bromide, acrylates, Bu3SnF, R2NOBz ect.
Scheme 1. Reaction Mode of Cu(I)-catalyzed Aryne Reactions.
Arynes are highly reactive and versatile synthetic
intermediates have found wide application in the synthesis of
many biologically active natural products1 and functional
materials2. Among various reaction modes of arynes,3-4
transition metals catalyzed reactions have attracted wide
attention and been widely used in assembly of many
important structures.5 Traditionally, transition metals proven
to be catalytically competent for arynes were mainly limited to
palladium6-7 and nickel8. The exploration on interaction of
arynes with other transition metals, especially those earth-
abundant and environmentally benign, is thereafer of much
significance and deserving investigation.
As a kind of cost-effective, environmental-friendly and
earth-abundant transition metal, copper has been widely used
in organic catalysis for years.9 In 2008, we reported for the first
time Cu(I) could catalyze aryne-terminal alkyne and terminal
alkyne-aryne-allylic chloride couplings.10 Since then, a series of
subsequent reports appeared, verifing Cu(I) was an efficient
catalyst for arynes.11 From the viewpoint of mechanism, these
reactions probably acted through one unified reaction mode,
namely the electrophilic capture of aryl-Cu(I) generated from
insertion of aryne into nucleophilic organo-Cu(I) species
between aryne and copper is of much importance and worthy
studying.
During our studies on Cu-catalyzed aryne reactions,10, 12 we
found performing the reaction of benzyne precursor 1a and
ethynylbenzene 2a using CuI as a catalyst under aerobic
conditions, an arenediyne 3aa could be afforded (Scheme 2).
This result was quite intriguing since compared to the above-
mentioned nucleophile-aryne-electrophile couplings, this was
a scarce example of Cu(I)-catalyzed intermolecular aryne
insertion into two molar of nucleophiles.13 Moreover, it was
noteworthy in this reaction, the above-mentioned protonation
of aryl-Cu(I), which had proven to be a yield-reducing side-
reaction always accompanied Cu(I)-catalyzed aryne reactions,
was completely inhibited under the aerobic condition.
Regarding that arenediynes were ubiquitous structures in
many biologically active substances14, functional materials15,
complex ligands16, and synthetic intermediates17, as well as the
significant mechanistic value of this transformation on both
aryne chemistry and copper catalysis, we decided to study this
reaction in detail and the results are summarized below.
(Scheme 1). Although has enabled
a variety of novel
Ph
CuI 10 mol%
CsF 2 equiv
transformations, this reaction mode still suffers from limited
substrate space and/or severe side reactions (eg. the
undesirable and always yield-reducing protonation of as-
formed strongly basic aryl-Cu(I) intermediates10,11g,i-l).
Thereafter, the development of novel reaction modes
OTf
Ph
Not formed!
Ph
Ph
+
Cs2CO3 3 equiv
MeCN, 80 oC, 12 h
in air
TMS
3aa
, 50%
1a
2a
Scheme 2. Initial experiment.
After establishing the optimal reaction conditions by a
detailed optimization (see SI, Table S1), we studied the
reaction scope and the results were summarized in Table 1.
First, we tested benzynes with different substitution and found
that besides 1a, benzynes with both symmetric (1b) and
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 311121, P. R. China. E-mail: chunsongxie@hznu.edu.cn
† Electronic Supplementary Information (ESI) available: The experimental details,
spectroscopic data (1H NMR, 13C NMR, and HRMS) for the products. See
DOI: 10.1039/x0xx00000x
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unsymmetric (1c-f) substitution could react smoothly with 2a, also well participate in the reaction with a slightlVyielwoAwrteiclre yOinelinlde
giving substituted arenediynes 3ba-3fa in moderate to good (38%) being delivered. Apart from theDseO,I: a10li.p10h3a9t/iDc0CteCr0m31i5n0aJl
yields. In general, electron-rich benzynes such as 1b, 1c and 1e alkynes such as 2n and 2o were also proven to be reliable
afforded higher yields than electron-poor benzynes (1d and 1f). reactants in the reaction, providing corresponding arenediynes
Steric hindrance showed little impact as both C3 (1e and 1f) 3an and 3ao in moderate yields. 1,7-Diyne 2p could likewise
and C4 (1c and 1d) substituted benzynes gave similar reaction react with 1a giving the 1,2-dialkynylbenzene 3ap in a 40%
yields.
yield. Ring-closing product formed by the insertion of benzyne
In addition, this reaction also showed wide applicability to a into the two terminal alkyne parts of 2p was not observed
variety of terminal alkynes. Besides aryl alkynes having even when the reaction was performed under a dilute
substitution on their para-position (2b-2d and 2f), those condition (c(1a) = 0.005 M).
bearing functionalities at their meta (2e, 2h and 2i) and ortho
To test the feasibility of benzyne insertion into two different
(2g) positions, could likewise efficiently participate in the terminal alkynes, we performed the three-component reaction
reaction, giving desired products 3ab-3ai in good to high yields. of 1a, 1-ethynyl-4-methoxybenzene 2b and 1-ethynyl-4-
Both sterical and eletronic properties of these functional fluorobenzene 2f under the standard condition, finding that
groups seemed having little influence on the reaction, the target product 3abf could be obtained in a 39% yield
indicating this reaction might be controlled by multiple factors. (Scheme 3).
Besides these, heteroaryl alkynes 2j, 1,3-Enyne 2k and 2-
methylbut-3-yn-2-yl benzoate 2l also proved to be good
OMe
MeO
reaction partners with 1a, furnishing arenediyne 3aj-3al in 94%,
79% and 58% yields respectively. Propiolates such as 2m could
2b
1.2 equiv
OTf
Standard condition
+
TMS
F
Table 1. Scope of the Reaction a
1a
1.0 equiv
2f
3abf
, 39%
3.0 equiv
F
R'
CuCl2 2H2O 10 mol%
Scheme 3. Insertion of benzyne into two different terminal alkynes.
OTf
CsF 2 equiv
R
+
R'
R
Cs2CO3 3 equiv
MeCN, 60 oC, 6 h
in air
TMS
2
1
3
R'
Apart from these, we also tested the reaction between
benzyne 1a and trimethyl(phenylethynyl)silane 2a’. We found
the reaction could successfully happen, giving the 1,2-
bis(phenylethynyl)benzene 3aa in a 42% yield in the absense
of Cs2CO3 (Scheme 4). As we know, alkynylsilanes are often the
intermediates for the preparation of many terminal alkynes.18
So the fact that this Cu-catalyzed 1:2 coupling of 1a and 2a’
could smoothly occur was quite intriguing since it offered a
straight way to arenediyne products from alkynylsilanes
without desilication.
Ph
Ph
Ph
Cl
Ph
Ph
Me
Ph
Ph
Me
Me
Me
Ph
Ph
Ph
3aa
3ba
3ca
3da
3ea
, 83%
, 74%
, 63%
, 66%
, 34%
Me
Et
OMe
F
Cl
Cl
Et
OMe
F
Me
Ph
3ac
3ad
, 58%
, 99%
3fi
3ab
, 63%
, 37%
CuCl2 2H2O 10 mol%
TMS
CsF 6.0 equiv
F
Ph
TMS
+
MeCN, 60 oC, 6 h
in air
wo Cs2CO3
OTf
Me
Me
F
F
2a'
1a
Ph
3aa
, 42%
Scheme4. Reaction of benzyne and alkynylsilane.
F
Based on this finding, we next conducted the reaction
between benzyne precursor 1a and 1,2-bis(2-
F
3ag
3ae
3ah
, 63%
, 56%
OBz
3af
, 61%
, 56%
((trimethylsilyl)ethynyl)phenyl)ethyne 4 under the Cs2CO3 free
condition (Scheme 5). To out delight, the intramolecular
bisalkynylation of benzyne efficiently took place, providing the
dehydrobenzo[12]annulene ([12]DBA] 5, which had proven to
be a core structure in the field of organic functional
materials,19 in a high yield (93%).
Cl
Cl
Me
N
Me
Me
Me
N
OBz
, 58%
3al
3ak
, 79%
3aj
, 94%
3ai
, 81%
CO2Et
n-Bu
OAc
OAc
CuCl2 2H2O 10 mol%
OTf
TMS
TMS
CsF 6.0 equiv
CO2Et
n-Bu
, 41%
+
MeCN, 60 oC, 6 h
in air
wo Cs2CO3
TMS
3am
, 38%
3an
, 62%
3ap
, 40%
3ao
5
4
1a
93% yield
a
Reaction conditions: 1 (0.5 mmol), 2 (2.0 mmol), CuCl2•2H2O (0.05 mmol), CsF
(1.0 mmol), Cs2CO3 (1.5 mmol), MeCN (2.5 mL), 60 C, 6 h. Isolated yields.
(0.24 mmol).
o
b
c
2
Scheme 5. Intramolecular bisalkynylation of benzyne.
2 | J. Name., 2012, 00, 1-3
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To probe the reaction mechanism, we conducted the biphenyl 4’ might be produced by the reaction ofVieewleAcrttircolepOhnililnice
DOI: 10.1039/D0CC03150J
reaction between 1a and 2a with the addition of a radical aryl-Cu(III) IV with nucleophilic aryl-Cu(I) III. So this result
trapping reagent TEMPO. It was found that little influence on indicated that aryl-Cu(I) III might be indeed generated and
the reaction was exerted with a slightly lower yield (61%) of verified the reasonability of the path A. After the generation of
3aa being dilivered (Scheme 6). Additionally, when performing aryl-Cu(III) IV, alkynyl-Cu(I) II might react with them giving the
this reaction in the presence of a radical scavenger BHT, the 1,2-dialkynylated arenes 3 and regenerating active Cu(I)
reaction could still happen in spite of that its yield decreased species. The active Cu(I) might subsequently react with
to 25%. These results implied a radical mechanism might be terminal alkynes 2 with the aid of bases, producing alkynyl-
unlikely for this Cu-catalyzed benzyne insertion reaction.
Cu(I) II to enter into next catalytic cycle.24
Ph
R
Cu(II)
I
Cu(II)
OTf
Standard condition
R
2
B
R
R
H
+
Ph
TMS
Cu(I)
with 6.0 equiv TEMPO: 61%
with 6.0 equiv BHT: 25%
R
Cu(I)
II
1a
2a
3aa
Ph
O2
path A
Cu(I)
III
path B
Scheme 6. Radical inhibition experiments.
2
B
R
Cu(I)
III'
Cu(III)
R
4'
Subsequently, we used electron paramagnetic resonance
(EPR) to analyze several systems relevant to the reaction
(Figure S1). From the results we found in both systems, with
and without benzyne precursors, the reactions were EPR-
active at the very beginning but turned EPR-silent after a few
minutes. These characteristics were quite similar to those
observed by Lei and his co-workers in their mechanistic
investigation on Cu-catalyzed aerobic homocoupling of
terminal alkynes,20 implying the mechanistic relevance of
these two reactions. Moreover, the disappearance of EPR
signal indicated that EPR-active Cu(II) species might not be the
resting-states of the active catalyst in the reaction.
During the past few years, Cu-catalyzed oxidative couplings
of two nucleophiles had received wide attention from both
academic and industrial community.21 Among these, much
work had been performed on the mechanistic explanation of
Cu-mediated oxidative homocouplings of two terminal
alkynes.22 In general, these reactions could be divided into two
categories: the aerobic Cu-catalyzed homocouplings (Glaser-
Hay type reactions), and the stoichiometric Cu salts promoted
homocouplings (Eglinton type reactions). Mechanistically, the
former were believed to proceed through O-bridged dinuclear
Cu(III) included mechemisms,22a whereas the latter pointed to
binuclear Cu(II) involved pathways.22b,c
R
3
R
2
II
or
Cu(III)
O2
IV
R
III
4'
Scheme 7. Possible catalytic cycle of the reaction.
Conclusions
In summary, we reported under areobic conditions, Cu could
catalyze oxidative 1:2 couling of arynes and nucleophilic
terminal alkynes, giving 1,2-dialkynylated arenes in a single
step. Studies on the reaction scope revealed the reaction could
tolerate a wide selection of functional groups. Mechanistic
analysis indicated generation of aryl-Cu(III) from arynes might
be involved. Due to aryl-Cu(III) has proven to be competent
electrophiles that can intermediate in many Cu-catalyzed
reactions,25 we believe this novel reaction mode can offer a
starting point for developing novel Cu-catalyzed
transformations of arynes. Currently, further researches on
detailed mechanism of this reaction, novel oxidative insertion
of arynes into nucleophiles, as well as Cu catalyzed novel
transformations of arynes, are vigorously undertaken in our
laboratory.
Based on these literature precedents and our observations
above, possible catalytic cycles could be outlined for our Cu
catalyzed aerobic 1:2 coupling of arynes and terminal alkynes
(Scheme 7). First, depending on the catalyst precursors
employed, alkynyl-Cu(I) II could be generated from terminal
alkynes 2 under the promotion of bases.23 Then, two pathways
(A and B) might be involved to give the aryl-Cu(III)
intermediates IV: the first was the production of aryl-Cu(I) III
by insertion of benzynes into the alkynyl-Cu(I) II and
subsequent in situ oxidation of the as-formed aryl-Cu(I) III by
oxygen in air to form the aryl-Cu(III) IV (path A); however,
another possibility was that alkynyl-Cu(I) II were oxidized first
by atmospheric oxygen to produce the alkynyl-Cu(III) III’
followed by insertion of arynes to provide the aryl-Cu(III) - IV
(path B). For these two possibilities, we inferred A was
preferred since we had successfully isolated a biphenyl
byproduct 4’ in one case (see SI for details). Obviously,
We thank the grant support from Natural Science
Foundation of China (21642011), Zhejiang Provincial Natural
Science Foundation of China (LY17B020007), Hangzhou City
Research Project (20191203B12), Pandeng Plan Foundation of
Hangzhou Normal University for Youth Scholars of Material,
Chemistry and Chemical Engineering, and PCSIRT (IRT 1231).
Conflicts of interest
There are no conflicts to declare.
Notes and references
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC03150J
R'
CuCl2 2H2O 10 mol%
in open air
OTf
R
+ 2 R'
X
R
CsF 2 equiv
TMS
Cs2CO3 Y equiv
MeCN, 60 oC, 6 h
X = H, Y = 3
X = Si, Y = 0
R'
21 examples
yields up to 99%
Cu(I)
Cu(III)
[O]
R'
R
via
R
R'
Aryl-Cu(III) may intermediate in Cu-catalyzed aerobic 1:2 coupling of arynes with
terminal alkynes, leading to one-step assembly of arenediynes.