Cu-Catalyzed aerobic oxidative cleavage of C(sp3)–C(sp3) bond: Synthesis of α-ketoamides

Article abstract of DOI:10.1016/j.tetlet.2020.152555

A novel synthesis of α-ketoamides from Cu-catalyzed aerobic oxidative C(sp3)–C(sp3) bond cleavage of hydrocinnamaldehydes has been developed. Readily available and environmentally benign oxygen is used as the oxidant. This reaction avoids the use of noble metal catalysts or specialized oxidants, and chemoselectively yields α-ketoamide. Moreover, based on various control experiments, a reasonable mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2020.152555

Journal Pre-proofs
Cu-Catalyzed aerobic oxidative cleavage of C(sp3)–C(sp3) bond: synthesis of
α-ketoamides
Jingming Zhang, Chengkou Liu, Man Yang, Zheng Fang, Kai Guo
PII:
S0040-4039(20)31048-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152555
TETL 152555
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 June 2020
21 August 2020
9 October 2020
Please cite this article as: Zhang, J., Liu, C., Yang, M., Fang, Z., Guo, K., Cu-Catalyzed aerobic oxidative
cleavage of C(sp3)–C(sp3) bond: synthesis of α-ketoamides, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.152555
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Tetrahedron Letters
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Cu-Catalyzed aerobic oxidative cleavage of C(sp3)–C(sp3) bond: synthesis of α-
ketoamides
Jingming Zhang,‡a Chengkou Liu,‡a Man Yang,a Zheng Fang,a* and Kai Guoa,b*
aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University,30 Puzhu South Road, Nanjing, 211816, China
bState Key Laboratory of Materials-Oriented Chemical Engineering, 30 Puzhu Rd S., Nanjing, 211816, China
‡These authors contributed equally.
*Corresponding authors. E-mail addresses: fzcpu@163.com (Z. Fang), guok@njtech.edu.cn (K. Guo).
ABSTRACT
A novel synthesis of α-ketoamides from Cu-catalyzed aerobic oxidative C(sp3)–C(sp3) bond cleavage of hydrocinnamaldehydes has been developed.
Readily available and environmentally benign oxygen is used as the oxidant. This reaction avoids the use of noble metal catalysts or specialized
oxidants, and chemoselectively yields α-ketoamide. Moreover, based on various control experiments, a reasonable mechanism is proposed.
Keywords:Copper catalyst, Oxidative cleavage, Hydrocinnamaldehyde, α-Ketoamide, Oxygen
Hydrocinnamaldehydes are important synthetic building blocks for pharmaceuticals and fine chemicals, such as the synthesis of an
intermediate for the treatment of HIV as HIV protease inhibitors.1 Selective carbon
–
carbon bond cleavage attracted considerable
attention in recent years2 for its potential significance in academic research3 and industrial applications.4 However, the extreme
thermodynamic stability of the C C bond makes it difficult, especially the unstrained carbon
carbon bond.5
–
–
Nowadays molecular oxygen has been widespreadly used in chemical synthesis for its abundant, green, sustainable virtues.
Nevertheless, the selective cleavage of C–C bond with O2 as the oxidant has been a problem until the development of some creative
catalyst system.6 Historically, several pioneering discoveries on the functionalization of carbonyl compounds which used O2 as the
oxidant and were transformed into aldehydes,7a acids,7b amides,7c ketones7d and esters7e were reported via selective C–C(CO) bond
cleavage in conjunction with transition metal catalyst such as Cu,8 Mn,9 Ru,10 Fe,11 Pd12 and so on (Scheme 1a). Recently, Xia and his
co-workers reported a Ru(Ⅱ)-catalyzed cleavage of aldehydes under air atmosphere for the synthesis of ketones (Scheme 1b).13
Moreover, the fragments from the cleavage of aldehydes were used in Huang’s work for the coupling of alkynes to produce ynones
under aerobic conditions (Scheme 1c).14 Later, the contribution from Hu’s work on the transformation of aldehydes to ketones without
singlet oxygen showed the efficiency of C–C bond cleavage under metal-free condition (Scheme 1d).15 However, noble metal or costly
oxidant limited their application. Despite great achievements having been made in the cleavage of aldehydes, the development of
efficient and environmentally friendly method under mild condition is still desirable. Herein,
Cu, Mn, Ru, Fe, Pd
O
O
(Y = H, OH, NHR, R, OR)
a)
R2
Y
O2
R1
R2
O
-
N
H
R1
R2
N
R1
R2
O2
b)
O
R1
R2
[Ru], air, visible light
O
O
O
[Au]
pyrrolidine/ O2
O
R2
I
c)
R1
R1
H
R2
Ar
PhNO
DCM, rt or 50 o
O
O
H
d)
e)
R1
C
R1
Ar
H
OH
O
This work:
Ar
O
Cu(OAc)2
O2 / DMF, 80 o
N
Ar
C
N
O
H
O
Scheme 1 C–C(CO) bond oxidative cleavage reactions.

2
Tetrahedron Letters
we described a Cu-catalyzed aerobic oxidative cleavage of C(sp3)–C(sp3) bond of hydrocinnamaldehydes to α-ketoamides under mild
and practical conditions (Scheme 1e). Based on the isolated intermediates, this method was experimentally found to involve two
C(sp3)–C(sp3) bonds cleavage and C–N bond formation process.
We first evaluated our reaction conditions with hydrocinnamaldehyde and morpholine under an oxygen atmosphere (Table 1).
Initially, the catalytic activity of several metal compounds was investigated (Table 1, entries 1-8). Obviously, a series of experiments
revealed that copper catalysts exhibited higher efficiency compared with other metal catalysts such as CoCl2, NiBr2 and FeCl3. Among
the copper catalysts examined, CuSCN and Cu(OAc)2 showed the highest reactivity with up to 85% isolated yield of 3aa which
revealed a preference for the C–C bond cleavage. Conversely, this reaction produced more coupling product when CuBr or CuBr2 was
involved, with 18% isolated yields of 4aa product for the best yield.
Table 1 The cleavage of C–C(alkyl) bond of hydrocinnamaldehydea.
O
O
O
N
O
Catalyst, Solvent
O2, 80 oC, 6h
N
N
O
O
N
H
O
O
1a
3aa
2a
4aa
Yield (%)
Entry Catalyst
Base
Solvent
3aa
4aa
1
2
CuSCN
CuBr
DMAP
DMAP
toluene
toluene
85
71
6
16
3
4
5
6
7
8
9
CuBr2
DMAP
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
H2O
69
91
54
23
15
18
Cu(OAc)2 DMAP
0
CoCl2
FeCl3
NiBr2
DMAP
DMAP
DMAP
9
5
0
Pd(OAc)2 DMAP
Cu(OAc)2 K2CO3
trace
72
trace
0
10 Cu(OAc)2 NaOAc
11 Cu(OAc)2 NaOEt
79
0
trace
0
trace
81
12 Cu(OAc)2
13 Cu(OAc)2
14 Cu(OAc)2
15 Cu(OAc)2
16 Cu(OAc)2
17 Cu(OAc)2
18 Cu(OAc)2
19b Cu(OAc)2
_
_
_
_
_
_
_
_
trace
80
trace
0
PhCN
1,4-Dioxane
DMSO
DMF
23
0
78
0
87
0
AcOH
trace
56
trace
0
DMF
aReaction conditions: 1a (1 mmol), 2a (3 mmol), catalyst (0.2 mmol), base (2 mmol), solvent (2 mL), 80℃, O2 (O2 balloon), 6 h, isolated yield. bUnder air.
Considering the efficiency and selectivity of this conversion, Cu(OAc)2 was chosen as the catalyst for further optimized condition to
construct α-ketoamides 3aa. To our delight, the yield of determine product was not decreased apparently without the addition of base
(Table 1, entries 9-12). 80℃ was the best choice for this transformation (see Table S2) and DMF was found to be a better solvent
compared with DMSO, AcOH, dioxane, H2O and PhCN (Table 1, entries 12-18). Moreover, further screening of catalyst and amine
showed that 0.2 equiv. of catalyst and 2 equiv. of amine gave a desirable yield (see Table S3). As expected, a reduced yield was
obtained when oxygen was replaced with air (56%). Finally, the optimal reaction conditions were 1a (1 mmol), 1b (2 mmol), Cu(OAc)2
(0.2 mmol), in DMF (2 ml) at 80℃ under O2 balloon for 6 h based on the reaction parameters above.

With the determination of the optimized reaction conditions, we examined a wide range of amines with hydrocinnamaldehyde
produced corresponding α-ketoamides to explore the substrate scope of this reaction (Table 2). Firstly, the cyclic amines were
investigated. Encouragingly, these amines (2a-2f) were successfully transformed into the corresponding products in 69~89% isolated
yields (3aa-3af). Then, we explored the other secondary amine and primary amine including aliphatic amine, aniline, benzylamine. As
expected, the aliphatic secondary amine could also be transformed into the desired product (3ag, 3ah), while the primary amine was
failed to give the desired product (3ak). And no major product was detected when this reaction was applied to the aniline, benzylamine
or pyrrole (3i, 3j, 3l). All the results above have clearly demonstrated that the secondary amine is essential for the success synthesis of
α-ketoamide, and its structure may be a reasonable evidence for the mechanism of this reaction.
Table 2 Substrate scope for the cleavage of hydrocinnamaldehyde with variation of amines.
O
R1
N
Cu(OAc)2
R1 R2
R2
N
H
2 , DMF, 80 oC, 6 h
O
O
O
1a
2a~2l
3aa~3al
O
O
N
O
O
O
N
N
N
N
N
O
O
O
O
3ad, 79% yield
3ac, 84% yield
3aa, 85% yield
3ab, 89% yield
O
O
N
O
O
O
O
N
N
N
O
O
O
O
3ae, 69% yield
3ag, 47% yield
3ah, 36% yield
O
3af, 74% yield
O
H
O
H
O
H
N
N
Ph
N
N
O
O
O
O
CN
3al, 0% yield
3ak, 0% yield
3ai, 0% yield
3aj, 0% yield
Reaction conditions: 1a (1 mmol), 2a-2j (2 mmol), Cu(OAc)2 (0.2 mmol), DMF (2 mL), were heated under O2 (O2 balloon) at 80oC for 6 h, isolated yield.
To broaden the scope of this transformation, a variety of hydrocinnamaldehydes were applied under the standard conditions (Table
3). When the hydrocinnamaldehydes extended to some structure having electron donating groups on the aryl ring, this reaction afforded
up to 74% yields of target product wherever the substituents at the para-, meta- or ortho-positions (3ba-3fa). To our delight, the yields
of α-ketoamide increased when the substituents were halo groups (bromo, chloro, and fluoro) or electron-withdrawing groups (3ga-
3ma, 81%~89%). It implies that the electron-withdrawing substituents are helpful for the efficiency of the oxidation reaction.
Moreover, it is noteworthy that this reaction survived well when the phenyl groups were replaced by other heterocycles (3na-3pa,
69%~75%). Correspondingly, we examined the other secondary amines using hydrocinnamaldehyde with different substituents, and
they were readily converted into the corresponding α-ketoamides in good yields (3cb-3ob, 78%~84%).
Table 3 Substrate scope for the cleavage of hydrocinnamaldehydes.
O
Cu(OAc)2
N
O
O2, DMF, 80 oC, 6h
N
R
O
H
1
2a or 2b
3
O
O
O
O
O
O
O
O
N
N
N
N
O
O
O
O
3ca, 82% yield
3da, 80% yield
3ea, 74% yield
3ba, 83% yield
O
N
O
O
O
O
N
O
O
N
O
O
N
O
O
O
O
O
H3CO
Cl
F
Cl
Br
3fa, 79% yield
3ga, 83% yield
3ha, 85% yield
3ia, 84% yield
O
N
O
O
N
NO2
O
O
O
O
N
N
O
O
O
O
O2N
O
Cl
NO2
3ka, 86% yield
3la, 85% yield
3ja, 81% yield
3ma, 89% yield
O
N
O
N
O
N
O
N
O
O
O
O
N
S
O
3na, 72% yield
3oa, 75% yield
3pa, 69% yield
3cb, 80% yield
O
N
O
N
O
N
O
S
O
O
Cl
3hb, 82% yield
3lb, 84% yield
3ob, 78% yield
NO2
Reaction conditions: 1 (1 mmol), 2a-2b (2 mmol), Cu(OAc)2 (0.2 mmol), DMF (2 mL), were heated under O2 (O2 balloon) at 80oC for 6 h. Isolated yield.

4
Tetrahedron Letters
In order to elucidate this transformation mechanism, several control experiments were carried out (Scheme 2). Firstly, we
performed the standard reaction condition under N2 balloon, and no desired product was obtained, which indicated that molecular
oxygen was necessary in the process of the C-C(CO) bond cleavage (Scheme 2a). Then, we noticed that this transformation was
difficult to react without the copper salt (Scheme 2b). To gain more information, we tested some analogous substrates in standard
conditions such as phenylbutyraldehyde, cinnamyl aldehyde, hydrocinnamyl alcohol, hydrocinnamic acid (Scheme 2c-2f). The desired
product of 3aa was generated in excellent yield (88%) when cinnamyl aldehyde was used (Scheme 2d). And, phenylbutyraldehyde or
hydrocinnamyl alcohol was transformed into 3aa with 43% or 34% isolated yield (Scheme 2c, 2e). While there were no 3aa or 4aa
detected using hydrocinnamic acid as the starting material (Scheme 2f). The results above revealed that carbonyl was indispensable in
the process of aerobic oxidative cleavage. Interestingly, the byproduct of A1 and A2 was generated when the 2a was added 6 hours later
(Scheme 2g). The generation of A1 might involve the formation of benzyl radical, further aerobic oxidation to a four-membered
intermediate and cleavage of C-C and O-O bonds. A2 was obtained via Aldol reaction in the presence of weak base of 2a.16 However,
no A1 or A2 was detected under the standard conditions, which indicated that a faster process existed in the presence of 1a and 2a.
On the basis of the control experiments and literature overview, a possible mechanism for the aerobic oxidative cleavage of
hydrocinnamaldehydes was proposed (Scheme 3). Initially, imine intermediate 1a-1 was generated from the reaction of aldehyde 1a and
secondary amine 2a, which could be converted into enamine 1a-1’ via intramolecular hydrogen shift. Addition reaction of O2 to double
bonds led to the formation of four-membered intermediate 1a-2 with the help of copper salt,17 which gave the oxidation intermediate 1a-
3 by the cleavage of O-O and C-N bonds.18 Furthermore, 1a-6 was obtained by the same process above. Activation of carbonyl by
Cu(II) led to the generation of addition product 1a-8. Further oxidation gave intermediate 1a-9, which underwent a 1, 2-Wagner-
Meerwein-type rearrangement of a benzoyl group to electrophilic carbon resulting in the intermediate 1a-10.19 Finally, the desired
product 3aa was produced by liberation of carbon monoxide.
Scheme 2 Control experiments.
Cu(OAc)2, DMF
O
2a
2a
2a
2a
3aa
NO
4aa
NO
a)
b)
c)
d)
e)
N2, 80oC, 6 h
DMF
O
3aa
16%
4aa
NO
O2, 80oC, 24 h
O
"standard condition"
"standard condition"
"standard condition"
3aa
43%
4aa
NO
O
3aa
88%
4aa
6%
OH
2a
3aa
34%
4aa
NO
O
"standard condition"
2a
3aa
NO
4aa
NO
f)
OH
O
Cu(OAc)2, DMF
O2, 80oC, 6 h
2a
O
1a
3aa
4aa
g)
trace
trace
A1, 42%
A2, 36%
Scheme 3 Proposed mechanism.
2a
O
N
N
O
O
1a
1a-1
1a-1'
O
2a
O2, [Cu]
O
N
H
O
H
O
1a-2
O
2a
1a-3
O
H
O
N
O
O
O
O
N
N
O
O
1a-4
1a-4'
1a-5
O
N
O
O
2a
O2
O
O
O
O
OH
CuII(OAc)2
O
O
CuII(OAc)2
1a-6
1a-7
1a-8
CO +Cu(II)
O
Cu(II)
O
O
O
O
N
O
N
N
O
CuII(OAc)2
O
3aa
O
O
O
1a-9
1a-10

In summary, a simple and efficient strategy for the synthesis of primary α-ketoamides was developed from hydrocinnamaldehydes
using Cu-Catalyzed aerobic oxidative cleavage. The exclusivity of this strategy lies in the use of hydrocinnamaldehydes as a single
substrate, which directly converts into primary α-ketoamides via muti-oxidation using O2 as oxidation. The advantages of this
methodology include high-efficiency transformation, straightforward operation, mild reacting condition and little contamination to the
environment. Further synthetic application of this cleavage method is currently in progress in our laboratory.
Acknowledgments
The research was supported by the National Key Research and Development Program of China (2016YFB0301501), the National
Science Foundation of China (Grant No. 21776130 & 21878145), the Jiangsu Synergetic Innovation Center for Advanced Bio-
Manufacture (No. X1821 and X1802) and Postgraduate Research & Practice Innovation Program of Jiangsu Province.
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20. General procedure for the synthesis of 3 (3aa as an example):
Hydrocinnamaldehyde 1a (134 mg, 1 mmol) and morpholine 2a (174 mg, 2 mmol) were dissolved in DMF (2 mL). Then, Cu(OAc)2 (36mg, 0.2mmol) was
added to the reaction mixture. The reaction mixture was degassed 3 times by O2 and stirred under O2 balloon in a preheated oil batch at 80℃ for 6h. After
cooling down to room temperature, the reaction mixture was diluted with H2O (30 mL) and extracted by ethyl acetate (30 mL) or dichloromethane (30 mL).
The separated organic layers were dried over by anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was
chromatographed on silica gel using hexane/ethyl acetate or dichloromethane/methanol to afford the desired product 3aa (85% yield).
Conflict of interest statement
The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or
associative interest that represents a conflict of interest in connection with the work submitted.

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A Cu-catalyzed aerobic oxidative cleavage method is developed.
It involves two C(sp3)–C(sp3) bonds cleavage and C–N bond formation process.
This reaction features simple starting materials and a broad substrate scope.
Based on various control experiments, a reasonable mechanism is proposed.
Conflict of interest statement

6
Tetrahedron Letters
The authors declared that they have no conflicts of interest to this work. We declare that
we do not have any commercial or associative interest that represents a conflict of interest in
connection with the work submitted.