Copper-Mediated Synthesis of Aryl α-Keto Amides from Epoxide Derivatives

Article abstract of DOI:10.1055/s-0040-1707990

A novel Cu ^II -mediated synthesis of aryl α-keto amides from epoxide derivatives is reported. This transformation was conducted by using O ₂ as a green oxidant that meets the requirements of sustainable chemistry.

Full text of DOI:10.1055/s-0040-1707990

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
F. Liu et al.
Letter
Synlett
Copper-Mediated Synthesis of Aryl -Keto Amides from Epoxide
Derivatives
Fenghua Liu ◊a
Yunjian Cui ◊a
O
O
R2
O
Cu(OAc)2
R2
N
+
R2
H
N
R2
R1
R1
Yi Dongb
0
0
0
0-0
0
0
1-
7
8
4
4-7
2
0
6
O2, 120 °C
O
Heng Xu*b
0
0
0
0-0
0
0
2-1
7
2
0-
5
2
8
6
R1 = EDG (Me, tBu)
EWG (halo, CF3, NO2)
2 = alkyl
13 examples
up to 75% yield
a School of Pharmacy, Jiamusi University, Jiamusi 154007, P. R. of China
b Beijing Key Laboratory of Active Substances Discovery and Druggability
Evaluation, Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100050, P. R. of China
xuheng@imm.ac.cn
R
◊ These authors contributed equally.
Received: 18.02.2020
Accepted after revision: 20.02.2020
Published online: 03.03.2020
such as methyl ketones, -hydroxy ketones, alkynes, or
alkenes, have been reported (Figure 2).5 Although these
methods are effective and economical, the development of
new methods not only enriches the range of syntheses of
aryl -keto amides and their derivatives but, more impor-
tantly, could also play an important role in diverse synthe-
ses of -keto amide derivatives in medicinal chemistry.
DOI: 10.1055/s-0040-1707990; Art ID: st-2019-u0677-l
Abstract A novel CuII-mediated synthesis of aryl -keto amides from
epoxide derivatives is reported. This transformation was conducted by
using O2 as a green oxidant that meets the requirements of sustainable
chemistry.
OH
Key words copper catalysis, keto amides, epoxides, green chemistry
O
R
OH
R
O
R
Aryl -keto amides are a class of compounds with high
medicinal value that exhibit various significant pharmaco-
logical effects, including as RAR agonism,1 orexin receptor
agonism,2 and epoxide hydrolase inhibition3 (Figure 1).4
O
H
O
R
O
N
R
Cl
O
R
α-keto amides
O
R
R
O
O
R
H
N
(This work)
N
CH3
CH3
X
R
O
O
F3C
O
Figure 2 Synthetic methods for aryl -keto amides
Oxerin receptor agonist
Epoxide hydrolase inhibitor
O
H
N
O
H
N
CF3
To our knowledge, the synthesis of aryl -keto amides
from epoxide derivatives has yet to be reported. Here, we
report that aryl epoxides6 were effectively transformed into
aryl -keto amides by using formamides7 as aminating re-
agents under copper-mediated conditions.8
Our copper-mediated synthesis of -keto amides was
initially investigated by testing the reaction of 2-phenyl-
oxirane (1a) with 5.0 equivalents of N,N-dimethylform-
amide (2a; DMF) in the presence of 2.0 equivalents of
Cu(OAc)2 under an oxygen atmosphere at 120 °C (Table 1).
When the reaction was conducted in 1,4-dioxane, a trace
amount of the desired product was detected by liquid
O
O
F
CO2H
MeO
Cl
Cytokine inhibitor
RARγ agonist
Figure 1 Selected biologically active molecules containing aryl -keto
amide groups
Owing to the potential medicinal applications of aryl -
keto amides, methods for the synthesis of these compounds
have recently received much attention and a number of ef-
fective transformations from various starting materials,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. Liu et al.
Letter
Synlett
chromatography–mass spectrometry (Table 1, entry 1). Nei-
ther DCE nor toluene as solvent afforded the desired prod-
uct (entries 2 and 3). When the reaction was conducted un-
der neat conditions with 25 equivalents of DMF as a re-
agent, the desired -keto amide 3a was obtained in 71%
yield (entry 4). Screening of various Cu salts showed that
only Cu(OAc)2 was effective, with other tested Cu salts
(CuCl2, CuBr2, CuSO4, CuCl, CuBr, and CuI) failing to give the
desired product (entries 5–11). Further investigation
showed that decreasing the amount of Cu(OAc)2 to 20 mol%,
decreasing the temperature to 100 °C, or conducting the re-
action under an air atmosphere resulted in a sharp decrease
in the yield of the desired product (entries 12–14). When
the reaction was conducted without Cu(OAc)2, none of the
desired -keto amide 3a was obtained (entry 15).
thermore, this CuII-mediated method was also efficient in
the case of the polysubstituted epoxide 3l (entry 11). In ad-
dition to N,N-dimethylformamide, N,N-diethylformamide
(2b) gave the corresponding -keto amides 3m in 50% yield
(entry 12). However, the reaction failed in the case of 2-
benzyloxirane (1p; entry 13).
Table 2 Synthesis of -Keto Amide Derivativesa
O
R2
N
O
O
Cu(OAc)2
R2
R1
R2
R1
+
H
N
R2
O2, 120 °C
O
1
2
3
Entry
1
R1
2
R2
3
Yield(%)
of 3
Table 1 Optimization of the Reaction Conditionsa
1
2
1b
1c
1d
1e
1f
4-MeC6H4
2a
Me
3b
65
62
61
62
68
62
45
72
50
74
51
50
0
4-t-BuC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4-F3CC6H4
4-O2NC6H4
2-MeC6H4
2-ClC6H4
3-MeC6H4
2,5-Me2C6H3
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3c
3d
3e
3f
O
O
O
3
Cu salt
N
+
H
N
4
solvent, O2, 120 °C
O
5
1a
2a
3a
6
1g
1h
1i
3g
3h
3i
Entry
Cu salt
2a (equiv)
Solvent
Yield (%)
7
1
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
5
5
1,4-dioxane
trace
0
8
toluene
9
1j
3j
3
5
DCE
–
0
10
11
12
13
1k
1l
3k
3l
4
25
25
25
25
25
25
25
25
25
25
25
25
75
0
5
–
1a
1p
3m
3n
6
CuBr2
–
0
Bn
Me
a Reaction conditions: 1 (1.0 mmol), 2 (25 mmol), Cu(OAc)2 (2.0 mmol),
O2, 120 °C. Isolated yields are given.
7
Cu(acac)2
CuSO4
–
0
8
–
0
9
CuCl
–
0
Several control experiments were conducted to explore
the mechanism of our copper-mediated synthesis of the
aryl -keto amide 3a (Scheme 1). Replacement of Cu(OAc)2
with Bu4NOAc or CuCl2 and Bu4NOAc gave none of the de-
sired product, whereas CuCl2 and NaOAc gave a 15% yield of
3a, suggesting that Cu(OAc)2 is necessary for this reaction
(Scheme 1, eq. 1 and 2). Because aryl epoxides can be con-
verted into aryl methyl ketones and aryl acetaldehydes un-
der Lewis acid catalysis,9 we subjected compounds 1m and
1n to the optimized conditions, and we obtained the de-
sired product 3a in 45% yield from ketone 1m and in 25%
yield from aldehyde 1n. When the reaction of 1-phenyl-
ethan-1-ol was conducted under the optimized conditions,
only a small amount of the desired product (<5% yield) was
obtained (Scheme 1, eq. 3–5). These results suggested that
ketone 1m and aldehyde 1n might be intermediates in this
reaction, whereas 1-phenylethan-1-ol (1o) is not. When
epoxide 1a was treated with N,N-dimethylacetamide (2c),
the -keto amide 3a was obtained in 32% yield, suggesting
that C–N bond cleavage of 2c had occurred (Scheme 1, eq.
6).
10
11
12b
13c
14d
15
CuBr
–
0
CuI
–
0
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
–
29
56
55
0
–
–
–
a Reaction conditions: 1a (1.0 mmol), 2a (5 or 25 mmol), Cu salt (2.0 mmol),
solvent, O2, 120 °C. Isolated yields are given.
b 20 mol% Cu(OAc)2.
c Under air.
d 100 °C.
With the optimal conditions in hand, we examined the
substrate scope of this reaction for a series of aryl epoxides
(Table 2). Para-substituted aryl epoxides performed well in
the synthesis of -keto amides 3b–h, regardless of whether
an electron-rich or an electron-deficient substituent was
present (Table 2, entries 1–7). Notably, ortho- and meta-
substituted substrates also gave the corresponding -keto-
amides 3i–k in moderate to good yields (entries 8–10). Fur-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
F. Liu et al.
Letter
Synlett
Funding Information
O
O
O
O
nBu4NOAc
N
N
(1)
(2)
+
+
H
H
N
N
We gratefully acknowledge the financial support from the CAMS In-
novation Fund for Medical Sciences (2017-I2M-3-011) and the Non-
profit Central Research Institute Fund of Chinese Academy of Medical
O2, 120 °C
O
O
0% yield
1a
2a
3a
Sciences (2018PT35003, 2019-RC-HL-008).
C
h
i
n
ese
A
c
a
d
e
m
y
of
M
e
d
i
c
a
lS
c
i
e
n
c
es(2
0
1
7-I
2
M-3-0
1
1)C
h
i
n
ese
A
c
a
d
e
m
y
of
M
e
d
i
c
a
lS
c
i
e
n
c
es(2
0
1
8
P
T
3
5
0
0
3)C
h
i
n
ese
A
c
a
d
e
m
y
of
M
e
d
i
c
a
lS
c
i
e
n
c
es(2
0
1
8
P
T
3
5
0
0
3)
O
CuCl2
MOAc
O
O2, 120 °C
Supporting Information
1a
2a
M = nBu4N, 0% yield
M = Na, 15% yield
3a
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707990.
O
O
O
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
ngInformati
o
n
Cu(OAc)2
N
(3)
+
H
N
O2, 120 °C
O
References and Notes
45% yield
1m
2a
3a
O
O
(1) Álvarez, S.; Álcarez, R.; Khanwalkar, H.; Germain, P.; Lemaire,
G.; Rodríguez-Barrios, F.; Gronemeyer, H.; de Lera, Á. R. Bioorg.
Med. Chem. 2009, 17, 4345.
(2) Knust, H.; Nettekoven, M.; Pinard, E.; Roche, O.; Rogers-Evans,
M. WO 2009016087, 2009.
Cu(OAc)2
N
N
CHO
(4)
(5)
+
H
N
O2, 120 °C
O
O
1n
2a
3a
25% yield
OH
O
O
(3) Patel, D. V.; Gless, R. D. Jr.; Webb Hsu, H. K.; Anandan, S. K.;
Aavula, B. R. WO 2008073623, 2008.
Cu(OAc)2
+
H
N
O2, 120 °C
(4) (a) Lu, R.-J.; Tucker, J. A.; Pickens, J.; Ma, Y.-A.; Zinevitch, T.;
Kirichenko, O.; Konoplev, V.; Kuznetsova, S.; Sviridov, S.;
Brahmachary, E.; Khasanov, A.; Mikel, C.; Yang, Y.; Liu, C.; Wang,
J.; Freel, S.; Fisher, S.; Sullivan, A.; Zhou, J.; Stanfield-Oakley, S.;
Baker, B.; Sailstad, J.; Greenberg, M.; Bolognesi, D.; Bray, B.;
Koszalka, B.; Jeffs, P.; Jeffries, C.; Chucholowski, A.; Sexton, C. J.
Med. Chem. 2009, 52, 4481. (b) Martina, M. R.; Tenori, E.;
Bizzarri, M.; Menichetti, S.; Caminati, G.; Procacci, P. J. Med.
Chem. 2013, 56, 1041. (c) Wedler, H. B.; Palazzo, T. A.;
Pemberton, R. P.; Hamann, C. S.; Kurth, M. J.; Tantillo, D. J.
Bioorg. Med. Chem. Lett. 2015, 25, 4153.
(5) For selected reviews, see: (a) De Risi, C.; Pollini, G. P.; Zanirato,
V. Chem. Rev. 2016, 116, 3241. (b) Kumar, D.; Vemula, S. R.;
Cook, G. R. ACS Catal. 2016, 6, 4920.
(6) For recent reviews, see: (a) Liang, Y.; Wei, J.; Qiu, X.; Jiao, N.
Chem. Rev. 2018, 118, 4912. (b) Peng, J.-B.; Wu, F.-P.; Wu, X.-F.
Chem. Rev. 2019, 119, 2090.
1o
2a
<5% yield
3a
O
O
O
Cu(OAc)2
N
(6)
+
N
O2, 120 °C
O
32% yield
1a
2c
3a
Scheme 1 Mechanistic studies
Based on the above experiments, a preliminary mecha-
nism for the copper-mediated synthesis of -keto amides
from epoxides was proposed in which the aryl epoxide 1a
undergoes a 1,2-hydride shift in the presence of Cu(OAc)2,
acting as a Lewis acid, to give the ketone intermediate 1m
or the aldehyde intermediate 1n.9 Methyl ketone 1m might
undergo enamine formation and oxidation to afford the -
keto amide, as previously proposed,8b,h whereas aldehyde
intermediate 1n might also undergo a similar process to af-
ford the desired -keto amide. This speculation has not
been well confirmed at the current stage, and further stud-
ies will be needed to elucidate the mechanism more clearly.
In summary, a copper-mediated method has been de-
veloped for the synthesis of aryl -keto amides from epox-
ides.10 This method is attractive owing to its broad sub-
strate scope and potential applications. Importantly, this is
the first report of the synthesis aryl -keto amides from ep-
oxides, thereby providing a new strategy for the prepara-
tion of -keto amide derivatives. Owing to the medicinal
value of -keto amides, this method is expected to play a
potential role in -keto amide drug synthesis and discovery.
Further investigations to determine the precise mechanism
and to expand the substrate scope are underway in our lab-
oratory.
(7) (a) Zhao, Q.; Miao, T.; Zhang, X.; Zhou, W.; Wang, L. Org. Biomol.
Chem. 2013, 11, 1867. (b) Li, D.; Wang, M.; Liu, J.; Zhao, Q.;
Wang, L. Chem. Commun. 2013, 49, 3640. (c) Bannwart, L.; Abele,
S.; Tortoioli, S. Synthesis 2016, 48, 2069.
(8) (a) Liu, J.; Zhang, R.; Wang, S.; Sun, W.; Xia, C. Org. Lett. 2009, 11,
1321. (b) Du, F.-T.; Ji, J.-X. Chem. Sci. 2012, 3, 460. (c) Zhang, C.;
Zong, X.; Zhang, L.; Jiao, N. Org. Lett. 2012, 14, 3280. (d) Zhang,
J.; Wei, Y.; Lin, S.; Liang, F.; Liu, P. Org. Biomol. Chem. 2012, 10,
9237. (e) Zhang, J.; Liu, Y.; Chiba, S.; Loh, T.-P. Chem. Commun.
2013, 49, 11439. (f) Wang, H.; Guo, L.-N.; Duan, X.-H. Org.
Biomol. Chem. 2013, 11, 4573. (g) Liu, C.; Yang, Z.; Guo, S.; Zeng,
Y.; Zhu, N.; Li, X.; Fang, Z.; Guo, K. Org. Biomol. Chem. 2016, 14,
8570. (h) Nekkanti, S.; Veeramani, K.; Kumar, N. P.;
Shankaraiah, N. Green Chem. 2016, 18, 3439. (i) Zhang, X.; Yang,
H.; Huo, Y.; Li, J.; Ma, J.; Ma, J. Dalton Trans. 2016, 45, 8972.
(j) Liu, F.; Zhang, K.; Liu, Y.; Chen, S.; Chen, Y.; Zhang, D.; Lin, C.;
Wang, B. RSC Adv. 2017, 7, 7158. (k) Liu, C.; Yang, Z.; Zeng, Y.;
Fang, Z.; Guo, K. Org. Chem. Front. 2017, 4, 2375.
(9) (a) Miyashita, A.; Shimada, T.; Sugawara, A.; Nohira, H. Chem.
Lett. 1986, 15, 1323. (b) Ertürk, E.; Göllü, M.; Demir, A. S. Tetra-
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

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F. Liu et al.
Letter
Synlett
(10) -Keto Amides 3a–l; General Procedure
1H NMR (400 MHz, CDCl3):  = 8.12–7.84 (m, 2 H), 7.72–7.57
(m, 1 H), 7.57–7.41 (m, 2 H), 3.08 (s, 3 H), 2.93 (s, 3 H). 13C NMR
(101 MHz, CDCl3):  = 191.9, 167.2, 134.9, 133.2, 129.8, 129.1,
37.2, 34.1.
N,N-Dimethyl-2-oxo-2-(4-tolyl)acetamide (3b)
Colorless oil; yield: 124 mg (65%); Rf = 0.5 (EtOAc–PE, 1:3). 1H
NMR (400 MHz, CDCl3):  = 7.79 (d, J = 8.2 Hz, 2 H), 7.26 (d, J =
7.9 Hz, 2 H), 3.06 (s, 3 H), 2.90 (s, 3 H), 2.39 (s, 3 H). 13C NMR
(101 MHz, CDCl3):  = 191.7, 167.4, 146.1, 130.8, 130.0, 129.9,
37.2, 34.1, 22.0.
A mixture of the appropriate epoxide 1 (1.0 mmol) and
Cu(OAc)2 (2.0 mmol) in DMF (2.0 mL) was stirred overnight at
120 °C under O2, then cooled to r.t. and diluted with EtOAc. H2O
was added, and the mixture was extracted with EtOAc. The
organic layer was washed with brine, dried (Na2SO4), and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel).
N,N-Dimethyl-2-oxo-2-phenylacetamide (3a)
Colorless oil; yield: 133 mg (75%), Rf = 0.5 (EtOAc–PE, 1:3).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D