B2pin2-mediated copper-catalyzed oxidation of alkynes into 1,2-diketones using molecular oxygen

Article abstract of DOI:10.1016/j.tetlet.2019.02.023

An intriguing aerobic oxidation of alkynes through copper catalysis is described, in which bis(pinacolato)diboron (B₂pin₂) played a dominant intermediary role in the formation 1,2-diketones. This novel protocol, which can be performed at room temperature, is versatile for various substituted alkynes, including diarylalkynes and arylalkylalkynes. The mechanism of this reaction was preliminarily investigated by control experiments.

Full text of DOI:10.1016/j.tetlet.2019.02.023

Accepted Manuscript
B pin -mediated copper-catalyzed oxidation of alkynes into 1,2-diketones using
2
2
molecular oxygen
Yadong Zhai, Zhenni Su, Hao Jiang, Jing Rong, Xianfan Qiu, Chuanzhou Tao
PII:
S0040-4039(19)30144-3
https://doi.org/10.1016/j.tetlet.2019.02.023
TETL 50617
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 December 2018
31 January 2019
10 February 2019
Please cite this article as: Zhai, Y., Su, Z., Jiang, H., Rong, J., Qiu, X., Tao, C., B pin -mediated copper-catalyzed
2
2
oxidation of alkynes into 1,2-diketones using molecular oxygen, Tetrahedron Letters (2019), doi: https://doi.org/
1
0.1016/j.tetlet.2019.02.023
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B pin -mediated copper-catalyzed oxidation
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2
2
of alkynes into 1,2-diketones using molecular
oxygen
Yadong Zhai , Zhenni Su , Hao Jiang , Jing Rong , Xianfan Qiu , Chuanzhou Tao *
a
a
a
a
a
a,b

1
Tetrahedron Letters
B pin -mediated copper-catalyzed oxidation of alkynes into 1,2-diketones using
2
2
molecular oxygen
a
a
a
a
a
a,b
Yadong Zhai , Zhenni Su , Hao Jiang , Jing Rong , Xianfan Qiu , and Chuanzhou Tao 
a
School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, P. R. of China
Marine Resources Development Institute of Jiangsu, Lianyungang 222005, P. R. of China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
An intriguing aerobic oxidation of alkynes through copper catalysis is described, in which
bis(pinacolato)diboron (B pin ) played a dominant intermediary role in the formation 1,2-
2 2
Received in revised form
Accepted
Available online
diketones. This novel protocol, which can be performed at room temperature, is versatile for
various substituted alkynes, including diarylalkynes and arylalkylalkynes. The mechanism of
this reaction was preliminarily investigated by control experiments.
Keywords:
B
2
pin
2
-mediated
2009 Elsevier Ltd. All rights reserved.
Copper-catalyzed
Aerobic oxidation
Alkyne
1
,2-Diketone
—
——

Corresponding author. Tel.: +86-518-85895401; fax: +86-518-85895401; e-mail: taocz@hhit.edu.cn

2
Tetrahedron
1
,2-Diketones are very important structural moieties in
(entry 11). We tried to reduce the amount of the lithium tert-
butoxide, however, the yield of benzil (2a) was decreased (entry
13).
numerous biologically interesting compounds [1] and are broadly
utilized for construction of complex structures in organic
synthesis [2]. An efficient access to 1,2-diketones is oxidation of
alkynes through the combined use of transition-metal and
stoichiometric oxidants such as PhI(OAc) [3], NaIO [4], oxone
Table 1. Development of copper-catalyzed B
synthesis of 1,2-diketones.
2
pin
2
-mediated aerobic oxidative
[a]
2
4
2
-
[
5], [S O ] [6], peroxide [7] and sulfoxide [8]. Compared with
2 8
these oxidants, molecular oxygen is a more appealing oxidant,
because of its abundance, low cost, and benign by-products
(
usually H O). For this reason, considerable efforts have been
2
[b]
Entry Change from optimal conditions Yield /%
devoted in recent years to develop transition-metal-catalyzed
aerobic oxidation reactions [9]. Referred to aerobic oxidation of
alkynes into 1,2-diketones, catalysis has been developed with Pd
1
2
3
4
5
6
7
8
9
No change
PPh
XPhos
XantPhos
BINAP
IPrCuCl
CuCl
79
76
70
21
51
22
67
65
68
45
77
75
67
3
[
10]. The reactions represented major advances, but usually were
o
carried out at 60–85 C. Very recently, photocatalysis were used
for aerobic oxidation of internal alkynes into 1,2-diketones at
room temperature [11]. Photoredox catalysts (PC) and light
irradiation were critical for this transformation and a mechanism
of single electron transfer was usually proposed (Scheme 1).
As part of our ongoing efforts to develop aerobic oxidation
Cu(OTf)
DMF
2
1
0
1,4-Dioxane
1
1
1
1
2
3
DMF/1,4-dioxane = 1/1
DMF/1,4-dioxane = 1/2
1.0 eq. of LiOBu
[
12], herein, we demonstrate an efficient strategy to convert
alkynes into the corresponding 1,2-diketones (Scheme 1). With
bis(pinacolato)diboron (B pin ) as mediator, copper as catalyst,
t
[
a]
2
2
Reaction conditions: dibenzenyl 1a 0.2 mmol, copper salts 10 mol%,
t
the oxidation reaction occurred effectively under O atmosphere
Ligand 25 mol%, or IPrCuCl 10 mol%, LiOBu 0.24 mmol, B
O 0.2 mmol, solvent 1.5 mL, room temperature, time 48 h.
2 2
pin 0.3 mmol,
2
H
2
at room temperature. This novel approach is versatile for various
substituted alkynes to yield the important frameworks of 1,2-
diketones. Additionally, this protocol expands the toolbox for
synthesis of 1,2-diketones through aerobic oxidation of alkynes
at room temperature.
[
b]
The yields are isolated yields with flash chromatography.
Using the optimized conditions, we next explored the scope
and generality of this aerobic oxidative process (Table 2). The
reaction was proven to be effective for 1,2-diarylacetylene
carrying electron-withdrawing and electron-donating groups, and
moderate to good isolated yields of 1,2-diketones were obtained
(32–79%, 2a–2g, 2p–2r). It was shown that electron-
withdrawing substrates, which could be harder to oxidize, gave
lower yields (see products 2d–2f and 2r) than the electron-
donating ones (see products 2b, 2c, 2p and 2q). The substrates
carrying an ortho-substituent on the phenyl group were also
found to readily participate in the reaction and moderate yields
were obtained (56–64%, 2h, 2i). Moreover, for 1-naphthyl and 2-
naphthyl acetylenes, the corresponding 1,2-diketones were
produced in 71% and 70% yields (2j, 2k). Surprisingly, the
catalysis was tolerant of heteroaryl group, and 1,2-
diarylacetylene containing furyl, thienyl and quinolinyl reacted
smoothly to afford the corresponding 1,2-diketones in good
yields (68–73%, 2l, 2m, 2o). Nevertheless, 1,2-diarylacetylene
having a pyridinyl group gave low yield. To our great satisfaction,
Scheme 1. Oxidation of internal alkynes into 1,2-diketones using molecular
oxygen as the sole oxidant.
We commenced our investigation with 1,2-diphenylethyne
(1a) as the model substrate to perform aerobic oxidative
1
-alkyl-2-arylacetylene could be converted into 1,2-diketones
synthesis of 1,2-diketones (2a). With B pin as mediator we
2
2
under the standard conditions, and excellent yields were obtained.
For instance, the oxidation yield of 1-phenyl-1-propyne (1s) was
as high as 82% and 1-phenyl-1-dodecyne (1t) could give an
isolated yield of 66%.
developed a protocol for aerobic oxidation of interminal alkynes,
shown in Table 1. The best results are obtained using Cu(OAc)2
as catalyst, Cy-JohnPhos as ligand, and the reactions were
performed in a co-solvent of DMF and 1,4-dioxane (Table 1,
entry 1). During our efforts to optimize the reaction conditions,
we made several observations summarized in Table 1. Even the
phosphine ligands gave good yields in the aerobic oxidative
synthesis of 1,2-diketones, monodentate phosphine (entries 1–3)
seemed better than bidentate phosphine ligands and produced
high yields (entries 4,5). Copper catalysts, supported by carbene
ligand (IPr), performed worse than phosphine as ligand (entry 6).
Cuprous and cupric salts both gave high yields in the aerobic
oxidation of interminal alkynes to 1,2-diketones (entries 7,8).
2 2
Table 2 The scope and generality of B pin -mediated copper-catalyzed
[a],[b]
Using Cu(OAc) /Cy-JohnPhos as catalyst at room temperature,
2
aerobic oxidative synthesis of 1,2-diketones.
the solvents were evaluated (entries 9–12). It was found that
slight decreasement in the yields, when single solvent of DMF or
1
,4-dioxane was used, or changing the ratio of the co-solvent of
DMF and 1,4-dioxane. For example, moderate yields were
obtained in DMF (entry 9) and the 1:1 of DMF:1,4-dioxane

3
Scheme 3. Gram-scale aerobic oxidative synthesis1,2-diketone
To shed light on the possible mechanism, we conducted the
control experiments (Scheme 4). Since the literatures have
reported copper-catalyzed borylation of alkynes could give the
intermediate alkenylborates [13], we performed the experiments
with
(Z)-2-(1,2-diphenylvinyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (5) as starting substrate. Removing copper
catalysts or bases from the standard conditions, we did not obtain
the oxidation product (2a) (Scheme 4, eq 1, 2). Then, we carried
out the reaction under nitrogen atmosphere, no expected product
was observed, and the starting material was recycled (Scheme 3,
eq 3). However, after flushing the reaction mixture with O , the
2
designed product (2a) was formed in 57% yield.
Scheme 4. Control experiments on the aerobic oxidation mechanism.
On the basis of the above results, a postulated mechanism for
this transformation was depicted in Scheme 5. By analogy to
precedent mechanistic investigations for copper-catalyzed
borylation of alkynes [13], the metathesis reaction between
t
t
[
a]
Reaction conditions: 1,2-disubstituent-acetylene (1) 0.2 mmol, Cu(OAc)
2
10
O 0.2
mmol, DMF : 1,4-dioxane = 0.6 mL : 0.9 mL, room temperature, time 48 h.
LCuX and LiOBu would initially afford LCuOBu (I), which
t
mol%, Cy-JohnPhos 25 mol%, B
2
pin
2
0.3 mmol, LiOBu 0.24 mmol, H
2
upon reaction with B pin could generate the borylcopper
2
2
complex LCu−Bpin (II). Subsequent insertion of alkyne (1) into
the LCu−Bpin in a syn fashion would give β-borylalkenylcopper
[b]
The yields are isolated yields with flash chromatography.
complex (III). Protonation of the alkenylcopper spieces with H O
To further demonstrate the synthetic utility and compatibility
of this process, sequential aerobic oxidation/cyclization reactions
were performed with benzil (1a) and amines as starting materials.
2
to yield alkenylborates which was oxidized with O
to produce
2
the 1,2-diketones (2), and regenerate the active catalyst (I).
2
,3-Diphenylquinoxaline (3, 77%) and 2,4,5-triphenylimidazole
(4, 68%) were both successfully produced in one-pot manner,
which are important compounds in organic and medicinal
chemistry (Scheme 2).
2 2
Scheme 5. The postulated mechanism for the B pin -mediated copper-
catalyzed aerobic oxidation of alkynes.
In summary, we have developed an aerobic oxidative
synthesis of 1,2-diketones from alkynes. With
bis(pinacolato)diboron (B pin ) as mediator, copper as catalyst,
2 2
Scheme 2. Synthetic utilities of the B pin -mediated copper-catalyzed aerobic
oxidation of alkyne
2
2
To showcase the scalability of this process, a gram-scale
reaction was performed with 1,2-diphenylethyne (1a).
Gratifyingly, 1,2-diphenylethyne underwent efficient oxidation
on gram-scale (10 mmol/1.78 g) resulting in an 73% isolated
yield of the benzil (2a, 1.53g) without modification of the
optimized conditions (Scheme 3).
the conversion of diarylalkynes or arylalkylalkynes into
corresponding 1,2-diketones were realized using molecular
oxygen. This new protocol combines bis(pinacolato)diboron and
copper in a single reaction system and shows great substrate
tolerance providing efficient access to a variety of 1,2-diketones
in a highly concise fashion. Additionally, The mechanism of this
reaction was preliminarily investigated by control experiments.
Given the fact that 1,2-diketones play an important role in
organic synthesis and bioactive molecule, we anticipate this

4
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1
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(
We are grateful to the National Natural Science Foundation of
China (21402062), the Six Talent Peaks Project of Jiangsu
Province (2016-YY-004), and the Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions, Haiyan Project of Lianyungang (2018-QD-004), 521
Project of Lianyungang and Postgraduate Research & Practice
Innovation Program of Jiangsu Province (KYCX17_2076,
KYCX18_2600).
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5
Highlights


B pin as mediator, copper as catalyst.
2
2
Molecular oxygen as the sole oxidant at room
temperature.


Versatile for various substituted alkynes,
including diarylalkynes and arylalkylalkynes.
Preliminary mechanism experiments indicated
alkenyl borates are the key intermediates.