Copper-catalyzed aerobic oxidative coupling of terminal alkynes with α-carbonyl aldehydes: An expedient approach toward ynediones

Article abstract of DOI:10.1016/j.tetlet.2019.07.005

An efficient and mild one-pot approach for copper-catalyzed aerobic oxidative coupling of α-carbonyl aldehydes with terminal alkynes toward ynediones has been developed. Moreover, a variety of ynediones were constructed under the optimized reaction condit

Full text of DOI:10.1016/j.tetlet.2019.07.005

Accepted Manuscript
Copper-catalyzed aerobic oxidative coupling of terminal alkynes with α-car-
bonyl aldehydes: An expedient approach toward ynediones
Bochao Zhou, Shiyu Guo, Zheng Fang, Zhao Yang, Kai Guo
PII:
S0040-4039(19)30651-3
https://doi.org/10.1016/j.tetlet.2019.07.005
TETL 50914
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
21 May 2019
1 July 2019
4 July 2019
Please citethis articleas: Zhou, B., Guo, S., Fang, Z., Yang, Z., Guo, K., Copper-catalyzed aerobic oxidative coupling
of terminal alkynes with α-carbonyl aldehydes: An expedient approach toward ynediones, Tetrahedron Letters
(2019), doi: https://doi.org/10.1016/j.tetlet.2019.07.005
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Copper-catalyzed aerobic oxidative coupling
of terminal alkynes with α-carbonyl
aldehydes: An expedient approach toward
ynediones
Leave this area blank for abstract info.
Bochao Zhou[a], Shiyu Guo[a], Zheng Fang[a], Zhao Yang[b], and Kai Guo*[a][c]
College of Biotechnology and Pharmaceutical Engineering Nanjing Tech University, 30 Puzhu Rd S., Nanjing,
211816, China College of Engineering China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210003,
China
O
O
R'
Cu(OAc)2
80oC, O2
O
Ph
H2O
+
R'
H
Ph
H
O
R'= Allkyl, Aryl

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper-catalyzed aerobic oxidative coupling of terminal alkynes with α-carbonyl
aldehydes: An expedient approach toward ynediones
Bochao Zhou a, Shiyu Guo a, Zheng Fang a, Zhao Yang b and Kai Guo* a c
aCollege of Biotechnology and Pharmaceutical Engineering Nanjing Tech University, 30 Puzhu Rd S., Nanjing, 211816, China College of Engineering China
Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210003, China
b College of Engineering China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210003, China
c State Key Laboratory of Materials-Oriented Chemical Engineering, 30 Puzhu Rd S., Nanjing, 211816, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and mild one-pot approach for copper-catalyzed aerobic
oxidative coupling of α-carbonyl aldehydes with terminal alkynes toward
ynediones has been developed. Moreover, a variety of ynediones were
constructed under the optimized reaction conditions, and a plausible
mechanism was presented based on a series of control experiments.
Available online
Keywords:
Copper-catalyzed
Aerobic oxidative coupling
Terminal alkynes
1,2-diketone
2019 Elsevier Ltd. All rights reserved.
Ynediones
1. Introduction
establish a simple and effective method to prepare ynediones
under low-cost reaction system. Herein, we presented an
Heteroaryl 1,2-diketone, a class of versatile and powerful
structure units in organic synthesis, are an ideal choice to prepare
heterocyclic compounds with pharmacological properties
including hydantoins, imidazoles, oxadiazoles and thiopheno-
diones.[1] Ynediones contain a continuous two-carbonyl and are
more densely functionalized electrophiles, which could be easily
converted to a series of specific heterocycles.[2][3] Despite their
excellent organic potential, ynediones have remained rarely
explored because of a lack of ready and practical preparation.[4]
Therefore, a directly expedient and efficient access to this class
of compounds would be much meaningful.
expedient and efficient method for copper-catalyzed aerobic
oxidative coupling of α-carbonyl aldehydes with terminal alkynes
toward ynediones, which has a low-cost reaction system and high
conversion (Scheme 1, Eq. 4).
2. Results and discussion
Initially, the reaction of phenylglyoxal monohydrate 1a with
phenylacetylene 2a was chosen as the model reaction to identify
optimal reaction conditions through screening a range of reaction
factors. All reactions were conducted under an O2 environment
and the results were showed in Table 1. The model reaction was
carried out in the presence of various copper catalysts in 4 mL
Toluene at 90 ℃ for 4h (Table 1, entry 1-4). Among these copper
catalysts, Cu(OAc)2 performed the best catalytic effect, affording
the target product 3aa in 34% yield (Table1, entry 1). With the
view of further improving its catalytic capacity, additives were
screened (Table 1, entry 5-7). To our delight, acetic acid was
added to inhibit Glaser coupling of 2a and the yield of 3aa
increased to 64% (Table 1. entry 6). Then, the reaction
temperature was also screened (Table 1, entry 8-11). When the
reaction temperature was decreased to 80 ℃, 85% yield of 3aa
was obtained (Table 1, entry 9). However, when the reaction
temperature was too high, yield of 3aa decreased probably owing
In the past few years, reports about the synthesis of ynediones
were extremely rare. To our knowledge, the most of the reported
strategies for synthesis of ynediones employed Castro-Stephens
coupling with glyoxylyl chlorides and terminal alkynes (Scheme
1, Eq. 1). [5][6] Müller’s group developed a method through in situ
glyoxylation of electron-rich heteroaromatic nucleophiles and α-
keto carboxylic acids with oxalyl chloride (Scheme 1, Eq. 2). In
addition, Zhang and co-workers established a copper-catalyzed
oxidative coupling approach toward ynediones from α-hydroxy
[7]
ketone and terminal alkyne (Scheme 1, Eq. 3). Nevertheless,
the advances mentioned before suffered from some drawbacks:
(1) starting materials were not easily available and reaction cost
was expensive, which might limit their application; (2)
conversion of target products was not very high owing to Glaser
coupling of terminal alkynes. [8] Therefore, it is highly eager to

2
Tetrahedron Letters
Table 1. Screening of optimal conditionsa
Zhang's work
O
O
R'
Catalyst, Additive
Solvent, Temp.
O
O
R
O
CuI, Et3N
+
Cl
H2O
(1)
+
R'
R
O
O
O
1a
2a
3a
R= Allkyl, Aryl
R'= -OiPr, -OEt, -NEt2
Yieldb
(%)
Müller's
Entry
1
Cat.
Add.[d]
-
Sol.
Temp.
90 ℃
90 ℃
90 ℃
90 ℃
90 ℃
90 ℃
90 ℃
50 ℃
80 ℃
110 ℃
120 ℃
80 ℃
80 ℃
80 ℃
80 ℃
work
O
O
Ar'
Ar'
Toluen
Ar
(COCl)2
(COCl)2
Electron-rich
heteroaryl
Cl
Cu(OAc)2
CuTC
34
16
0
Ar
Ar
Ar
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
Toluen
e
DMSO
DMF
1,4-
Dioxan
e
H2O
Toluen
e
CuI, Et3N
O
O
O
(2)
2
O
O
O
Ar
Cl
OH
Ar
Ar
CuI, Et3N
3
CuBr
-
-
O
O
4
CuI
0
Zhang's work
O
R'
Pyridine
AcOH
O
CuTC, O2
5
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Trace
64
0
R'
OH
+
Ar
(3)
Ar
O
R'= Allkyl, Aryl
6
AcOH
Pyridine
AcOH
AcOH
AcOH
AcOH
TFA
This work
7
O
O
R'
Cu(OAc)2
80oC, O2
O
8
0
Ph
H2O
+
R'
H
Ph
O
(4)
H
R'= Allkyl, Aryl
9
85
51
43
Trace
41
0
Scheme 1. Copper-catalyzed aerobic oxidative coupling of α-
carbonyl aldehydes with terminal alkynes to ynediones.
10
11
12
13
14
15
to decomposition of 1a under high temperature atmosphere.
Subsequently, the reaction proceeded in other different acid, and
results showed that acetic acid is the ideal additive (Table 1,
entry 12- 15). And, a series of solvents were examined, such as
DMSO, DMF, H2O and 1, 4-Dioxane, which presented that
Toluene is the best solvent in this reaction (Table 1, entry 16-19).
Next, different concentrations of 2a were also tested for the
reason that atomic economy is one of the significant contents of
green chemistry. Gratifyingly, only 1 equiv. of 2a was added to
this reaction affording the highest yield 92% of 3aa (Table 1,
entry 20), the optimized reaction conditions were finally
determined: 0.2 mmol phenylglyoxal monohydrate 1a, 0.2 mmol
phenylacetylene 2a, 10 mol% Cu(OAc)2 and 20 mol% AcOH
dissolved in 4 mL Toluene and stirred at 80 ℃ for 4h in a sealed
tube under an O2 environment.
TfOH
2-picolinic
acid
2-TCA
54
16
17
Cu(OAc)2
Cu(OAc)2
AcOH
AcOH
0
0
80 ℃
80 ℃
18
Cu(OAc)2
AcOH
0
80 ℃
19
Cu(OAc)2
Cu(OAc)2
AcOH
AcOH
0
80 ℃
80 ℃
20c
92
With the optimized conditions identified, both α-carbonyl
aldehydes and terminal alkynes were explored (Table 2). It
should be mentioned that when 1a was scaled up to 10 mmol
(1.34 g), the yield of 3aa remained excellent (Supporting
information). As is shown in Table 2, α-carbonyl aldehydes both
with electron-donating and electron-withdrawing groups could
react smoothly to afford the corresponding ynediones in
moderate to excellent yields (3ba-3ea). Notably, electron-
donating groups were more reactive than electron-withdrawing
groups. Furthermore, the inactive halogen substituted substrates
including Cl and Br could also produce good yields (3fa and
3ga).
a
Reaction conditions: 1a (0.2 mmol), 2a (4 equiv.), catalyst (10
mol%) and additive (20 mol%) dissolved in solvent (4 mL) and
stirred at 80 ℃ for 4 h in a sealed tube equipped with an O2 balloon,
unless otherwise noted; b Isolated yields; c 1 equiv. of 2a was added; d
TFA= trifluoroacetic acid; TfOH= rifluoromethanesulfonic acid; 2-
TCA= 2-thiophenezoic acid.
converted to the desired products in 91% and 86% yield,
respectively (3ak and 3al). Terminal alkyl acetylenes bearing
hydroxyl protection groups including TBS and TBDPS were
compatible in this transformation to provide the desired products,
which presented great application potential in organic synthesis
(3am and 3an). Alkyl acetylenes containing heterocycle
employing ester as a linkage afforded target products as well
(3ao and 3ap).
After the tolerance of α-carbonyl aldehydes was demonstrated,
various functionalized terminal alkynes also performed well.
Actually, not only aryl acetylenes but also alkyl acetylenes show
good reactivity in this transformation. Aryl acetylenes with
electron-donating groups gave excellent yields, such as methyl,
methoxyl and ethyl (3ab-3ae). Halogen substituted substrates
could also afford a moderate yield (3af-3ah). Long-chain alkyl-
substituted alkynes containing 1-hexyne and 1-octyne could be
subjected to the reaction (3ai and 3aj). Cycloalkane-substituted
alkynes, such as cyclopropyl and cyclohexyl acetylenes, could be
Then, we carried out some control experiments in order to
explore the mechanism of this transformation (Scheme 3). No
target product 3aa was formed when the reaction was preceded in
the absence of Cu(OAc)2 (Scheme 3. Eq.1). The reaction also
proceeded and provided the desired product in 43% yield under
the modified conditions without AcOH (Scheme 3. Eq.2). These

3
experiments show that Cu(OAc)2 is essential for the reaction and
AcOH is as an additive to inhibit side reaction and improve the
yield. Moreover, we investigated the role of O2 in the reaction
system (Scheme 3. Eq.3). The results indicate that O2 is the
significant oxidant in the reaction.
Scheme 2. Control experiments.
oxidation and reduction to produce target product 3aa with
elimination of Cu(l), which undergoes O2–assisted regeneration
to Cu(ll) that re-enters the reaction system.
On the basis of results above and previous literature reports,[9]
a plausible reaction mechanism for copper-catalyzed aerobic
oxidative coupling of α-carbonyl aldehydes with terminal alkynes
was described in Scheme 3. Initially, there is an equilibrium
between 1a and its monohydrate 1a’ in the system. Then,
phenylacetylene 2a reacts with Cu(OAc)2 to provide alkynyl
copper A, which attacks 1a resulting in the formation of the
intermediate B. Eventually, the intermediate B undergoes self-
3. Conclusion
In conclusion, we established a protocol for copper-catalyzed
aerobic oxidative coupling of α-carbonyl aldehydes with terminal
alkynes toward ynediones under mild conditions. These
transformations afforded various ynediones in high yields with a
broad substrate scope under an easy reaction system, and a
Table 2. Substrates scopea
2a
Ph
OAc
O
Ph
Cu
(ll)
Cu(OAc)2
O2
O
R'
O
O
Cu(OAc)2, AcOH
Ph
H2O
Ph
O
H2O
A
H
2O
+
R'
AcOH
R
R
Toluene,80o
O2
C
1a
O
3
1
2
AcOH
Cu(OAc)
O
O
Ph
O
O
O
O
OH
O
Ph
Ph
H
O
O
O
O
OH
1a'
H
3C
O
2N
H
3CO
OAc
Cu(II)
Ph
O
3da 67%
O
3ca 90%
3aa 92%
61%b
3ba 94%
B
3aa
CH3
O
O
O
O
Scheme 3. Plausible reaction mechanism.
Cl
O
O
O
3fa 85%
O
3ga 74%
F
3C
Br
3ab 93%
3ea 72%
plausible mechanism was presented based on some control
experiments. Further investigations of their applications are
underway in our laboratory.
CH3
OCH3
F
O
O
O
O
O
O
O
O
References and notes
3af 42%
3ac 94%
3ad 91%
3ae 82%
Cl
Br
1.
(a) Wu, J. C.; Song, R. J.; Wang, Z. Q.; Huang, X. C.; Xie, Y. X.;
Li, J. H. Angew. Chem. Int. Ed. 2012, 51, 3453-3457 ; (b) Tang, R.
Y.; Guo, X. K.; Xiang, J. N.; Li, J. H. J. Org. Chem. 2013, 78,
11163-11171; (c) Gers, C. F.; Nordmann, J.; Kumru, C.; Frank,
W.; Muller, T. J. J. J. Org. Chem. 2014, 79, 3296-3310.; (d)
Mupparapu, N.; Battini, N.; Battula, S.; Khan, S.; Vishwakarma, R.
A.; Ahmed, Q. N. Chem. Eur. J. 2015, 21, 2954-2960; (e) Yang, J.
M.; Cai, Z. J.; Wang, Q. D.; Fang, D.; Ji, S. J. Tetrahedron 2015,
71, 7010-7015; (f) Zhang, Z.; Dai, Z.; Jiang, X. As. J. Org. Chem.
2015, 4, 1370-1374; (g) Wu, C. L.; Zhao, F.; Shu, S. J.; Wang, J.;
Liu, H. RSC Adv. 2015, 5, 90396-90399; (h) Yan, J. W.; He, G. J.;
Yan, F. L.; Zhang, J. X.; Zhang, G. S. Rsc Adv. 2016, 6, 44029-
44033.
(a) Boersch, C.; Merkul, E.; Mueller, T. J. J. Angew. Chem. Int.
Edi. 2011, 50, 10448-10452; (b) Merkul, E.; Dohe, J.; Gers, C.;
Rominger, F.; Muller, T. J. J. Angew. Chem. Int Ed 2011, 50,
2966-2969; (c) Gers, C. F.; Nordmann, J.; Kumru, C.; Frank, W.;
Mueller, T. J. J. J.Org. Chem. 2014, 79, 3296-3310.
(a) Liu, Y.; Liu, M.; Guo, S.; Tu, H.; Zhou, Y.; Gao, H. Org. Lett.
2006, 8, 3445-3448; (b) Mukherjee, A. K.; Margaretha, P.; Agosta,
W. C. J. Org. Chem. 1996, 61, 3388; (c) Mukherjee, A. K.; Agosta,
W. C. J. Chem. Soc. Chem. Commun.,1994, 1821.
(a) Kashiwabara, T.; Tanaka, M. J. Org. Chem. 2009, 74, 3958-
3961; (b) Katritzky, A. R.; Wang, Z. Q.; Lang, H. Y.; Feng, D. M.
J. Org. Chem. 1997, 62, 4125-4130; (c) Cariou, M.; Simonet, J.
Chem. Soc. Chem. Comm. 1990, 445-446; (d) Ahmad, S.; Iqbal, J.
J. Chem. Soc. Chem. Comm. 1987, 692-693; (e) Leyendecker, J.;
Niewçhner, U.; Steglich, W. Tetrahedron Lett.,1983, 24, 2375 –
2378.
Stephens, R. D.; Castro, C. E. J. Org. Chem.,1963, 28, 3313.
Guo, M. J.; Li, D.; Zhang, Z. G. J. Org. Chem. 2003, 68, 10172-
10174.
O
O
O
O
CH3
CH3
3
5
O
O
O
O
3ai 86%
3aj 89%
3ah 55%
3ag 54%
O
OTBS
O
O
O
OTBDPS
O
O
O
O
3an 79%
3al 86%
3am 84%
3ak 91%
S
S
O
O
O
O
2.
3ao 91%
3ap 88%
a
Reaction conditions: 1 (0.2 mmol), 2 (4 equiv.), Cu(OAc)2 (10
mol%) and AcOH (20 mol%) dissolved in solvent (4 mL) and stirred
at 80 ℃ for 4 h in a sealed tube equipped with an O2 balloon；b 10
mmol of 1a.
3.
4.
O
O
Optimized conditions
O
(a)
H2O
+
without Cu(OAc)2
0%
O
3aa
2a
1a
O
O
O
5.
6.
O
Optimized conditions
(b)
(c)
H2O
+
43%
without AcOH
O
O
1a
2a
3aa
3aa
7.
8.
Zhang, Z.; Jiang, X. Org. Lett. 2014, 16, 4400-4403.
(a) Glaser; Dtsch, C. Ber. Chem. Ges.,1869, 2, 422; (b) Eglinton,
G.; Galbraith, A. R.; J. Chem. Soc.,1959, 889; (c) Hay, A. S. J.
Org. Chem.,1962, 27, 3320; (d) Bohlmann, F.; Schönowsky, H.;
Inhoffen, E. G.; Grau Chem. Ber., 1964, 97, 794.
(a) S. Lam, P. Y.; Vincent, G.;. Bonne, D; Clark, C. G.
Tetrahedron Lett., 2003, 44, 4927; (b) Lam, P. Y. S.; Deudon, S.;
O
Optimized conditions
O
H2O
+
Air
N2
O2
1a
2a
9.
trace
34%
92%

4
Tetrahedron Letters
Averill, K. M.; Li, R. H.; He, M. Y.; DeShong, P.; Clark, C. G. J.
submitted along with the manuscript and graphic files to the
appropriate editorial office.
Am. Chem. Soc. 2000, 122, 7600-7601; (c) Shang, M.; Sun, S.-Z.;
Dai, H.-X.; Yu, J.-Q. Org. Lett. 2014, 16, 5666-5669; (d) Battini,
N.; Battula, S.; Ahmed, Q. N. Eur. J. Org. Chem. 2016, 658-662.
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Highlights:

Copper-catalyzed
aerobic
oxidative
coupling of terminal alkynes with α -
carbonyl aldehydes was developed.
Twenty two examples of ynediones were
synthesized in moderate to excellent yields.
A plausible mechanism was presented based
on a series of control experiments.
A gram scale-up reaction proceeded in good
yield.


