Copper-catalyzed 1,1-Arylalkylation of terminal alkynes with diazo esters and organoboronic acids

Article abstract of DOI:10.1039/c9cc07461a

A novel copper-catalyzed 1,1-Arylalkylation of terminal alkynes with diazo esters and organoboronic acids is described. With this methodology, (E)-β-Aryl-β,γ-unsaturated esters can be easily constructed in good to excellent yields directly from readily available and inexpensive traditional coupling reagents.

Full text of DOI:10.1039/c9cc07461a

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Copper-catalyzed 1,1-arylalkylation of terminal
alkynes with diazo esters and organoboronic
acids†
Cite this: Chem. Commun., 2019,
55, 13446
Received 23rd September 2019,
Accepted 17th October 2019
ab
Yunhe Lv,
*
Weiya Pu,a Xueru Liu,a Jinye Suna and Mengxing Cuia
DOI: 10.1039/c9cc07461a
rsc.li/chemcomm
A novel copper-catalyzed 1,1-arylalkylation of terminal alkynes with Cu(I)-catalyzed cross-couplings of terminal alkynes,8 and they have
diazo esters and organoboronic acids is described. With this metho- been used in 1,1-difunctionalizations of alkynes (Scheme 1a).7g,i
dology, (E)-b-aryl-b,c-unsaturated esters can be easily constructed in Recently, we realized a regio- and stereoselective copper-catalyzed
good to excellent yields directly from readily available and inexpensive three-component 1,1-arylalkylation of alkynes with a-chloro-
traditional coupling reagents.
acetamides and organoboronic acids with a cleavable bidentate
8-aminoquinoline auxiliary (Scheme 1b).9 An allene is also gener-
b,g-Unsaturated esters are important structural motifs in natural ated as an intermediate in this transformation. Although it under-
products,1 and they are also useful intermediates in organic goes highly selective syn-carbocupration and protonolysis to afford
synthesis.2 The methods generally used to synthesize these key the product, to the best of our knowledge, copper-catalyzed regio-
compounds include carbonylation reactions with allylic substrates,3 selective hydroarylations of allenes with arylboronic acids have
cross-couplings of potassium alkenyltrifluoroborates or alkenyl-9-BBN not been explored.10 Therefore, we envisioned that an allene,
with 2-chloroacetate esters,4 or decarboxylative alkylcarboxylation of generated in situ from a terminal alkyne and a diazo compound
a,b-unsaturated acids.5 Despite these significant achievements, the in the presence of a copper catalyst, could undergo hydroaryla-
difunctionalization of alkynes for the synthesis of b,g-unsaturated tion to realize the 1,1-arylalkylation of a terminal alkyne given
esters has not yet been reported. Therefore, the development of new, suitable conditions for the above two processes. Herein, as part
versatile and reliable methods is still of great importance.
of our ongoing interest in the 1,1-difunctionalization of alkynes,
Difunctionalizations of alkynes have received significant we report a novel, copper-catalyzed 1,1-arylalkylation of terminal
interest for the synthesis of multisubstituted olefins in organic alkynes with diazo esters and organoboronic acids for the
synthesis.6 In this context, classical methods for the difunctio- synthesis of (E)-b-aryl-b,g-unsaturated esters (Scheme 1c).
nalization of alkynes almost exclusively involve the addition of
Inspired by our previous research on copper-catalyzed 1,1-
two functional groups to the two carbons of the alkyne, namely, arylalkylations of alkynes, we commenced our study by testing
1,2-difunctionalizations (vicinal). Compared to classical difunctio-
nalization reactions, 1,1-difunctionalizations of alkynes are under-
explored. In the past few decades, Iwasawa, Takai, Zhu, Chirik,
Sawamura, Yin, Wang and Jiang have independently reported
1,1-dicarbofunctionalizations, 1,1-aminoacylations, 1,1-diborations
and 1,1-carbosulfonylations of terminal alkynes.7 Among which,
strategies through allenes provided a new perspective for the
1,1-difunctionalization of alkynes. Diazo compounds are becoming
very popular as synthons for the preparation of allenes through
a College of Chemistry and Chemical Engineering, Anyang Normal University,
Anyang, 455000, P. R. China. E-mail: luyh086@nenu.edu.cn,
lvyunhe0217@163.com
b Jilin Provincial Key Laboratory of Organic Functional Molecular Design &
Synthesis, Northeast Normal University, Changchun 130024, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1943644. For ESI
Scheme 1 Strategies for the 1,1-difunctionalization of alkynes through
allenes.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc07461a
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Table 2 The scope of alkynes in the 1,1-arylalkylationa
the coupling of ethynylbenzene (1a) with ethyl 2-diazoacetate
(2a) and p-tolylboronic acid (3a) in the presence of a catalytic
amount of CuI (10 mol%), 1,10-phenanthroline (10 mol%) and
Cs2CO3 (2.0 equiv.) in dioxane at 100 1C. To our delight, the
desired 1,1-arylalkylation product 4a was smoothly obtained in
40% yield along with 14% of ethyl 4-phenylbut-3-ynoate (4a0)
and trace ethyl 4-phenylbuta-2,3-dienoate (4a00) (Table 1, entry 1).
To improve the utility of this 1,1-arylalkylation reaction, various
conditions were then optimized. The choice of base has a
significant effect on these transformations, and K3PO4 afforded
the best results (Table 1, entries 2–5). Bipy was also an effective
ligand for this transformation (Table 1, entry 6), and other
ligands, such as PPh3 and DPPE, were examined but did not lead
to any significant improvement (Table 1, entries 7 and 8). Further
investigations of different solvents (e.g., CH3CN, EtOAc, acetone
and DMSO) revealed that dioxane gave the best reaction outcome
(Table 1, entries 9–12). In addition, other catalysts, such as CuCl
and CuBr, were not as effective as CuI (Table 1, entries 13 and 14).
Finally, control reactions demonstrated that the catalyst, ligand
and base were essential for the reaction (Table 1, entries 15–17).
With the optimal reaction conditions in hand, we examined
the substrate scope of this methodology employing a series of
alkynes, and the results are presented in Table 2. In general,
ethynylbenzenes 1b–1n bearing different substituents were viable
substrates and smoothly reacted with ethyl 2-diazoacetate (2a) and
a
Reactions were carried out with 1 (0.36 mmol), 2a (0.3 mmol), 3a
(0.90 mmol), CuI (10 mol%), Phen (10 mol%) and K3PO4 (0.6 mmol) in
dioxane (1.0 mL) under a N2 atmosphere at 100 1C for 1.5 h. Yield of the
isolated product.
Table 1 Optimization of the reaction conditionsa
p-tolylboronic acid (3a) to give 1,1-arylalkylation products 4b–4n in
moderate to good yields. Sterically bulky groups on the substrates
did not have an obvious effect on the reaction, and the para-,
meta-, and ortho-fluoro and chloro ethynylbenzenes afforded
the corresponding products 4h, 4i, and 4k–4n in similar yields.
N-Propargyl amides, such as tert-butyl prop-2-yn-1-ylcarbamate
(1o), also provided the desired product (4o) in 90% yield. Alkyl
propargyl ethers 1p–1r underwent the 1,1-arylalkylation reaction
to give the corresponding products 4p–4r in good yields. Impor-
tantly, an aliphatic alkyne (ethynylcyclopropane, 1s) was a suitable
substrate and gave 4s in 90% yield. Meanwhile, pent-1-yne and
hex-1-yne proceeded smoothly to afford 4t and 4u in 55% and
56% yields, respectively. However, methyl propiolate and propio-
lamide were not effective for this 1,1-arylalkylation reaction.
Notably, a broad range of synthetically crucial functional groups,
such as F, Cl, Br, OH, oxirane and cyclopropyl, were well tolerated
in the transformation and remained intact.
We then evaluated the scope of arylboronic acids, and the
results are summarized in Table 3. Arylboronic acids bearing
alkyl, vinyl, Cl, and Br substituents at the para position of the
aromatic ring all worked well with 1a and 2a producing desired
products 5b–5h in moderate to good yields. Electron-donating
and electron-withdrawing groups, including alkyl (3i), alkoxyl
(3j), formyl (3k), and halide (3l–3n) moieties, were tolerated.
Disubstituted arylboronic acids were found to be compatible
with this coupling and produced 5o–5r. In addition, 2-diazo-N-
phenylacetamide (2b) and ethyl 2-diazo-2-phenylacetate (2c)
provided desired products 5s and 5t in 34% and 42% yields,
Yieldb (%)
Entry Metal Ligand Base
Solvent
4a
4a0
4a00
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Phen
Phen
Phen
Phen
Phen
Bipy
PPh3
Dppe
Phen
Phen
Phen
Phen
Phen
Phen
Cs2CO3 Dioxane 40
14
26
Trace
10
K2CO3
K3PO4
Et3N
Dioxane 32
Dioxane 85
Trace Trace
Dioxane Trace Trace Trace
Dioxane
Dioxane 83 Trace Trace
DBU
0
0
0
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
None
Dioxane Trace o5
o5
o5
0
0
0
Dioxane o5
o5
20
12
21
0
9
CH3CN
EtOAc
40
48
10
11
12
13
14
15
16
17
Acetone 28
DMSO
0
0
Dioxane 36
Trace Trace
Trace Trace
0
Dioxane o5
None Phen
CuI
CuI
Dioxane
0
0
0
o5
None
Phen
Dioxane o5
10
Dioxane Trace o5
a
Reactions were carried out with 1a (0.36 mmol), 2a (0.3 mmol), 3a
(0.9 mmol), metal (10 mol%), ligand (10 mol%) and base (2.0 equiv.) in
1.0 mL of solvent under a N2 atmosphere at 100 1C for 1.5 h unless
b
otherwise noted. Yield of the isolated product.
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Table 3 The scope of organoboronic acids and diazo compounds in the
1,1-arylalkylationa
Scheme 2 Transformation of a product and synthetic applications of this
reaction.
scavengers, such as 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO,
2.0 equiv.) and 2,6-di-tertbutyl-4-methylphenol (BHT, 2.0 equiv.),
were added to reactions conducted under the standard conditions,
and product 4a was isolated in 72% and 71% yields, respectively
(Scheme 3c). This result excludes the involvement of a radical
process in this reaction.
On the basis of the previous studies and the abovementioned
experiments, a possible mechanism was proposed (Scheme 4).
Initially, the copper-catalyzed cross coupling of 1a with 2a
generated intermediate 4a0 though an alkynyl migratory inser-
tion of Cu(I) carbene A,13 and 4a0 then undergoes facile rearran-
gement to afford intermediate 4a00. Then, the arylcopper species
readily generated via transmetalation of 3a, via regeneration of
the Cu(I) species in the presence of Phen,14 reacted with 4a00 to
form intermediates B and B0. The carbonyl-substituted double
bond selectively coordinates to the arylcopper species on the side
opposite the phenyl group to avoid steric interactions. Inter-
mediate B then undergoes syn-carbocupration to afford inter-
mediate C, which gives the product and regenerates the Cu(I)
catalyst through protonolysis.
a
Reactions were carried out with 1a (0.36 mmol), 2a (0.3 mmol), 3
(0.90 mmol), CuI (10 mol%), Phen (10 mol%) and K3PO4 (0.6 mmol) in
dioxane (2.0 mL) under a N2 atmosphere at 100 1C for 1.5 h. Yield of the
isolated product.
respectively. However, the reaction of diethyl 2-diazomalonate
(2d) did not give the desired product.
Further transformations of the 1,1-arylalkylation products were
surveyed to illustrate the value of this method (Scheme 2). Treat-
ment of 4a with NaOH in EtOH afforded (E)-4-phenyl-3-(p-tolyl)-
but-3-enoic acid (6) in 89% yield (Scheme 2a). The absolute
configuration of product 6 (CCDC 1943644†), as determined by
X-ray diffraction, further confirmed the regioselectivity of dicar-
bofunctionalization of the alkyne. Under concentrated H2SO4, 4a
and 4c could be transformed into 3-aryl-1-naphthols (Scheme 2b),
which are important motifs in pharmaceuticals and photoelectric
materials.11 This novel transformation was also applied to the
late-stage modification of biologically relevant compounds con-
taining alkyne groups. Citronellol-derived alkyne 8 smoothly
underwent the developed 1,1-arylalkylation to afford desired
products 9 in 76% yield (Scheme 2c).
In conclusion, a novel, copper-catalyzed 1,1-arylalkylation of
terminal alkynes with diazo esters and organoboronic acids has
Control experiments were performed to elucidate the
mechanism of the reaction (Scheme 3). In the absence of 3a
and K3PO4, the reaction of 1a and 2a generated a mixture of
cross-coupling products 4a0 and 4a00 in nearly a 5 : 1 ratio, albeit
in 42% yield.12 Subsequently, compounds 4a0 and 4a00 could be
reacted with 3a to give product 4a in 45% and 73% yields,
respectively (Scheme 3a and b). Therefore, compounds 4a0 and
4a00 are likely intermediates in this reaction. In addition, radical
Scheme 3 Control experiments.
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Scheme 4 Plausible mechanistic pathway.
been described. This transformation is a powerful approach for the
construction of (E)-b-aryl-b,g-unsaturated esters. Further mechanistic
investigations and explorations of the gem-difunctionalization of
other types of alkynes are currently underway in our laboratory.
We gratefully acknowledge the National Natural Science
Foundation of China (21801008), the Science & Technology
Foundation of Henan Province (162300410208), the Foundation
of Henan Educational Committee (18A150001), the Henan Key
Laboratory of New Optoelectronic Functional Materials and the
Jilin Provincial Key Laboratory of Organic Functional Molecular
Design & Synthesis (130028911) for their financial support.
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Conflicts of interest
The authors declare no conflicts of interest.
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