Synthesis of 2-oxo-acetamidines via copper-catalyzed oxidative cross-coupling of Α-amino ketone compounds with amines

Article abstract of DOI:10.1016/j.catcom.2019.105766

A general and efficient method for the synthesis of 2-oxo-acetamidines via copper-catalyzed oxidative cross-coupling of amines with α-amino ketone compounds was achieved. In this reaction, the C ? N bond of α-amino ketone is broken and new C ? N and C[dbnd]N bonds are constructed in one single transformation. This reaction system has a broad substrate scope and provides a facile pathway for the synthesis of 2-oxo-acetamidines.

Full text of DOI:10.1016/j.catcom.2019.105766

Accepted Manuscript
Synthesis of 2-oxo-acetamidines via copper-catalyzed oxidative
cross-coupling of α-amino ketone compounds with amines
Pengjie Wang, Yi Xiong, Yiqun Qin, Jiajia Zhang, Niannian Yi,
Jiannan Xiang, Wei Deng
PII:
DOI:
Article Number:
Reference:
S1566-7367(19)30228-6
https://doi.org/10.1016/j.catcom.2019.105766
105766
CATCOM 105766
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
12 June 2019
28 July 2019
30 July 2019
Please cite this article as: P. Wang, Y. Xiong, Y. Qin, et al., Synthesis of 2-oxo-
acetamidines via copper-catalyzed oxidative cross-coupling of α-amino ketone compounds
with amines, Catalysis Communications, https://doi.org/10.1016/j.catcom.2019.105766
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ACCEPTED MANUSCRIPT
Synthesis of 2-oxo-acetamidines via copper-catalyzed oxidative cross-
coupling of α-amino ketone compounds with amines
Pengjie Wanga, Yi Xionga,b, Yiqun Qina, Jiajia Zhanga, Niannian Yib, Jiannan
Xianga, Wei Denga,*
aState Key Laboratory of Chemo/Biosensing andChemometrics,Collegeof Chemistry andChemical Engineering, HunanUniversity, Changsha,410082, P.
R. China
bSchool of Chemistry andChemical Engineering, Hunan Instituteof Engineering, Xiangtan, 411104,P. R. China.
A R T I C L E I N F O
Keywords:
cross-coupling
α-amino ketone
2-oxo-acetamidine
1. Introduction

ACCEPTED MANUSCRIPT
A B S T R A C T
A general and efficient method for the synthesis of 2-oxo-acetamidines via copper-catalyzed oxidative cross-coupling of amines with α-amino ketone
compounds was achieved. In this reaction, the C−N bond of α-amino ketone is broken and new C−N and C=N bonds are constructed in one single
transformation.This reactionsystemhas a broadsubstratescopeandprovides a facile pathwayfor the synthesis of 2-oxo-acetamidines.
As an important means of constructing carbon carbon bonds and carbon heteroatom bonds, the oxidative cross -
coupling reaction through the functionalization of C-H bonds makes it possible to directly synthesize complex compounds
from simple raw materials, and plays an irreplaceable role in organic synthesis, medicinal chemistry and synthesis of
natural products.[1-5] The α-amino carbonyl structure subunits exists widely in natural products, biomolecules,
constituting the core structures of a large variety of medicines.[6-11] It’s also treated as a kind of important intermediate in
organic synthesis because of activity of its carbonyl and amino groups, [12-16] some significant progress has been achieved
in past decades for the functionalization of α-C-H of α-amino carbonyl compounds when different nucleophiles are
employed to form C-S, C-P, C-N, C-O bonds. [17-19] For examples: Huang’s group described an easy and efficient
methods to synthetize 2-oxo -aceta-midines in good yields, however, it was shown that only secondary amines can be
applied in this system.[20] Lately, our group reported a copper-catalyzed system which constructs C-N bond and C=N
bond between the α-amino ketones and anilines to synthetize 2-oxo-acetamidines in excellent yields. However, long
reaction time is required. [21]
Acetamidine and its substituted products have important applications in natural products, medicinal chemistry and
functional materials. They are also important organic synthesis intermediates. [22-26] The synthesis of 2-oxo-acetamidines
has been a longstanding hot topic due to their high activity of carbonyl groups.
*Corresponding author
Email-address:weideng@hnu.edu.cn
ORCID(s): 0000-0002-5972-560X(W. Deng)
[27-28] However, most traditional methods for the synthesis of 2-oxo-acetamidines require long times, harsh conditions, low
selectivity, but yield totally unsatisfactory. Therefore, it is necessary to develop a new catalytic method for the synthesis of 2-
oxo-acetamidines.
For continuing interest in this area, we decided to explore a valuable catalytic system and to explore the possibility of the
C-N bond formation at the methylene in α-amino ketones. After series of trials, a catalytic system for the reaction between
primary amines and α-amino ketones leading to 2-oxo-acetamidines was found, which was Cu(OAc)2·H2O combined with DCP
(bis(1-methyl-1-phenylethyl) peroxide) under a nitrogen atmosphere. Herein we report that the oxidative cross -coupling of α-
amino carbonyl compounds with primary amines can be accomplished to afford 2-oxo-acetamidines in moderate to good yields
using Cu(OAc)2·H2O/DCP system, in which the carbon nitrogen double bond and carbon nitrogen single bond can be
successfully constructed at the same time.
2. Result and discussion
We began our investigation by using 4-methyl-N-(2-oxo-2-phenylethyl)benzenesulfonamide (1a) and aniline (2a) as
the raw materials (Table 1). At first, we explored the reactivity of this reaction under the conditions of Cu(OAc)2·H2O (10
mol%) TBHP (tert-Butyl hydroperoxide) (1 equiv.), DCE (1,2-dichloroethane) (2 mL) under N2 atmosphere at 80o C for 24
h. Fortunately, we obtained the expected product 3a with an isolated yield of 35% (entry 1).Then, We proceeded to screen
metal salt catalyst,such as Pd(OAc)2, Co(OAc)2, AgOAc, and other
Page 1 of 5

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Scheme 1
different types of copper catalysts, and results found that Cu(OAc)2·H2O was still the optimal catalyst (entries 2-8). Base also
has an impact on the reaction, so we chose three bases ( NaOH, NaOAc and Et3N) as the representatives (entries 9-11). When
NaOAc (1 equiv.) was added to the reaction, the yield of product 3a increased to 38%. Screening
of different oxidants (such as TBHP, K2S2O8, DCP and DTBP (bis(tert-butyl) peroxide)) showed that DCP was the best, up to
50% yield was obtained (entries 12-14). Moreover, when EtOAc was used as the solvent instead of DCE, the yield of 3a was
increased to 60% from 50%, but results of DMF and MeCN were not ideal (entries 15-17). When the reaction was carried out
under air atmosphere, the yield was slightly reduced to 56%
(entry 18). Increasing or lowering the temperature could not
increase the yield, so 80oC was also the best choice (entries 19
and 20). When 3 equivalent of DCP was used as the oxidant,
the yield increased to 83%, and the reaction time could be
shortened to 1 h from 24 h. As a result, it was meaningless to
Entry
1
2
Catalyst
Cu(OAc)2·H2O
Pd(OAc)2
Oxidant
TBHPc
TBHP
Solvent
DCE
DCE
Base
Yieldb (%)
35
24
further increase the amount of DCP (entries 21-23). In summary, the optimal reaction conditions are 1a (0.3 mmol), 2a (1.2
mmol, 4 equiv.), Cu(OAc)2·H2O (10 mol%), DCP(0.9 mmol, 3 equiv.), EtOAc 2mL under a nitrogen atmosphere for 1h to
afford the desired product within 85% yield.
Page 2 of 3
Table 1
Optimization of the reaction conditionsa

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3
4
5
6
7
Co(OAc)2·H2O
AgOAc
Cu(acac)2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
K2S2O8
DCP
DTBP
DCP
DCP
DCP
DCP
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
32
6
27
12
11
18
31
38
36
9
50
36
60
33
47
56
41
59
83
82
85
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Cu2O
Cu2(OH)2(NO3)2
Cu2(OH)2CO3
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Table 2
8
9
Variation of carbonyl groupsa,b
NaOH
NaOAc
Et3N
10
11
12
13
14
15
16
17
18d
19e
20f
21
22
23i
DCE
DCE
DCE
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
EtOAc
DMF
MeCN
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DCP
DCP
DCPg
DCPh
DCPg
a
Reaction conditions: 1a (0.3mmol), 2a (1.2mmol), [cat] 10mol%, [O] 1equiv. base
1equiv. and solvent (2mL) under a nitrogen atmosphere at 80 oC for 24 h unless
otherwise noted.
b
Isolated yield.
c
70% in aqueous.
d
under an airatmosphere.
at 60 oC .
e
at 90 oC .
f
g
[O] 3equiv.
[O] 4equiv.
for 1h.
h
a
.
Reaction conditions: 1 (0.3mmol), 2a (1.2mmol), Cu(OAc)2 H2O (10mol%), DCP (0.9
i
mmol) and NaOAc(0.3mmol) in EtOAc (2mL) under a nitrogen atmosphere at 80 oC for 1h
b
Isolated yield.
Based on the optimal reaction conditions, we began to explore the effect of substituents on this oxidative cross -coupling
reaction (Table 2). At first, we designed different substrates 1 to react with aniline by changing the group R1 attached to the
carbonyl group. Different substrates with -Me, -Br and -OMe groups on the aromatic ring were all well-tolerated, and the
corresponding products were obtained in moderate to good yields. And election-withdrawing groups were superior to election-
donating groups. In addition, positions of substituents on benzene rings also show different influence to the reaction. The y ield
of para-methyl group is 63% and ortho-methyl group is 77%.
Table
3
Variation of sulfamido groupsa,b
a
.
Reaction conditions: 1 (0.3mmol), 2a (1.2mmol), Cu(OAc)2 H2O (10mol%), DCP (0.9 mmol) and NaOAc (0.3mmol) in EtOAc(2mL) under a nitrogen atmosphere at 80 oC for 1h
Isolated yield
b
Page 2 of 3
Next we tested the effect of the different sulfonamide groups by changing group R2, including 2-tolyl, 4-methoxyphenyl,
4-bromophenyl, 4-trifluoromethylphenyl and ethyl (Table 3). When these substrates were chosen to react with aniline, the

ACCEPTED MANUSCRIPT
yields of product 3a were between 60-93%. In addition, we found that electron withdrawing groups (such as -Br, -CF3) on the
aromatic ring were superior to electron donating groups (such as -Me, -OMe).
Table 4
Variation of anilinesa,b
a
.
Reaction conditions: 1a (0.3mmol), 2 (1.2mmol), Cu(OAc)2 H2O (10mol%), DCP (0.9 mmol) and NaOAc (0.3mmol) in EtOAc(2mL) under a nitrogen atmosphere at 80 oC for 1h unless
otherwise noted.
b
Isolated yield
c
.
Reaction conditions: 1a (0.3mmol), 2a (0.6mmol), 2 (0.6mmol) Cu(OAc)2 H2O (10mol%), DCP (0.9 mmol) and NaOAc(0.3mmol) in EtOAc (2mL) under a nitrogen atmosphere at 80 oC for
1h
d
40% methylamine in aqueous
Finally, we chose different amine compounds to explore their reactivity. Aromatic amines, including 4-tolyl, 2-tolyl, 4-
methoxyphenyl, 4-fluorophenyl, and 4-chlorophenyl, were all well-tolerated (Table 4), and electron withdrawing groups (-F, -
Cl) on the aromatic ring were superior to electron donating groups (-Me, -OMe). Unfortunately, when pyridin-2-amine was
used as the substrate, the reaction could not happen. Moreover, we chose two types of amines as reaction substrates to find out
their reactivity with α-amino ketones 1a. When aniline and methylamine reactions with α-amino ketones 1a ,the desired product
with different R3 and R4 was obtained in 27% yield. However, when combination of aniline and morpholine was used, the
desired product was obtained in a yield of 11%.
Page 3 of 5
Scheme 2
control experiment

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To study the mechanism of this reaction, we designed the following control experiments (Scheme 2). When the reaction
was carried out without copper catalyst, the target product cannot be detected (reaction 1). Similarly, when the reaction was
carried out in the absence of DCP, no target product was formed (reaction 3). The results of these two experiments showed that
copper catalyst and DCP were both necessary for the reaction. However, when reaction carried out in the absense of base, targ et
product was provided with a yield in 77% (reaction 2). Then, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to the
reaction under the standard conditions and the desired product was obtained in 81% yield, which showed that the reaction was
not a radical process (reaction 4). Moreover, 2-oxo-2-phenylacetaldehyde was detected by GC-MS when the reaction was
carried out in the absence of aniline (reaction 5). We then designed the reaction of aniline and 2-oxo-2-phenylacetaldehyde, and
the desired product was obtained in 79% yield (reaction 6). The results of reaction 5 and 6 led us to believe that the aldehyde 4
was an intermediate of the reaction.
Based on experimental results, a plausible mechanism for this reaction is proposed in Scheme 3. At first, α-amino ketone
1a coordinated with copper catalyst and base to form an active intermediate 5 and hydrogen atoms on amino and
Page 2 of 3
methylene were activated in the meanwhile and then oxidized to intermediate 6 in the presence of DCP.[29-32] Then, the
intermediate 6 was hydrolyzed by H2O to afford the intermediate 4, which then reacted with aniline to form imine 7.[33-34]
Finally, the activated copper complex 8 formed when imine 7 coordinated with copper catalyst. The desired product 3a was
obtained when 8 was attacked by aniline.
Scheme 3
plausible mechanism

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3. Conclusion
In summary, we have developed a general methods for synthesis 2-oxo-acetamidines via α-amino carbonyl compounds and
amines. This novel protocol has some attractive features: Firstly, a variety of substrates scope can be adapted in the system with
a moderate to excellent yield; then, stable starting materials are used in this system; finally, a short reaction time is required.
Importantly, this new protocal provides another process to synthetise the 2-oxo-acetamidines and makes the α-amino carbonyl
compounds more valuable with some unique chemical activity.
4. Experimental
A nitrogen-dried round-bottomed flask was charged with 1a (86.7mg, 0.3 mmol), aniline 2a (111.6 mg, 1.2mmol),
Cu(OAc)2·H2O (6 mg, 0.03 mmol), DCP (81 mg, 0.3 mmol) in ethyl acetate (2 mL) under nitrogen atmosphere. The reaction
mixture was stirred at 80o C for 1h. The reaction mixture was washed with saturated NaCl aqueous when reaction finished. The
aqueous phase was reextracted with ethyl acetate (3×10mL). The organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl
acetate=8:1, V/V) to afford 3a as a yellow solid in yield of 85%.
Page 4 of 5
Acknowledgement
We are grateful for financial support from the National Natural Science Foundation of China (Nos. 21502049), Hunan
Provincial Natural Science Foundation of China (Nos. 2018JJ2032).
Appendix A. Supplementary data
Appendix sections are coded under \appendix.
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Graphical Abstract
Synthesis of 2-oxo-acetamidines via copper-catalyzed oxidative cross-coupling of α-amino ketone
compounds with amines
Pengjie Wanga, Yi Xionga,b, Yiqun Qinga, Jiajia Zhanga, Niannian Yib,*, Jiannan Xianga, Wei Denga,*
Highlights

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Synthesis of 2-oxo-acetamidines via copper-catalyzed oxidative cross-coupling of α-amino ketone
compounds with amines
Pengjie Wanga, Yi Xionga,b, Yiqun Qinga, Jiajia Zhanga, Niannian Yib,*, Jiannan Xianga, Wei Denga,*
•
•
High total yield up to 99%
Short time required
•
Stable raw material and broad scope
Page 5 of 5