C-N and C-O Bond Formation in Copper-Catalyzed/Mediated sp3C-H Activation: Mechanistic Studies from Experimental and Computational Aspects

Article abstract of DOI:10.1021/acs.joc.0c01038

Mechanistic studies on Cu-catalyzed/mediated sp3 C-H amidation and acetoxylation are investigated from experimental and computational aspects. The concerted metalation-deprotonation (CMD) mechanism rather than a radical-involved pathway is proved to occur in amidation and acetoxylation reactions, and this is the rare example of the CMD mechanism involved in the more challenging sp3 C-H activations. Theoretical calculations demonstrated that CMD is the rate-determining step either for methylic or benzylic positions in amidation and acetoxylation reactions, and intermolecular nucleophilic addition of acetate anions is more favorable than the ring opening of β-lactams and intramolecular acetoxylation. These mechanistic studies on the divergent and condition-dependent product formation are critical for developing Cu-promoted C-H functionalization via the CMD mechanism.

Full text of DOI:10.1021/acs.joc.0c01038

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Article
C-N and C-O Bonds Formation in Copper-Catalyzed/
Mediated sp3 C-H Activation: Mechanistic Studies
from Experimental and Computational Aspects
Yuhang Yang, Fei Cao, Linbin Yao, Tao Shi, Bencan Tang, Yoichiro Kuninobu, and Zhen Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01038 • Publication Date (Web): 17 Jul 2020
Downloaded from pubs.acs.org on July 17, 2020
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Page 1 of 14
The Journal of Organic Chemistry
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C-N and C-O Bonds Formation in Copper-Catalyzed/Mediated sp3 C-
H Activation: Mechanistic Studies from Experimental and
Computational Aspects
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Yuhang Yang,[a],‡ Fei Cao,[b],‡ Linbin Yao,[c],‡ Tao Shi,[a] Bencan Tang,*[c] Yoichiro Kuninobu,*[d] and
Zhen Wang*[a,b]
[a]School of Pharmacy, Lanzhou University, West Donggang Road No. 199, Lanzhou 730000, Gansu, China
[b]State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Gansu, China
[c]Department of Chemical and Environmental Engineering, Faculty of Science and Engineering, The University of
Nottingham Ningbo China, 199 Taikang East Road, Ningbo 315100, China
[d]Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-
8580, Japan
KEYWORDS amidation • acetoxylation • concerted metalation-deprotonation • C-H activation • density functional
calculations
ABSTRACT: Mechanistic studies on Cu-catalyzed/mediated sp3 C-H amidation and acetoxylation are investigated from
experimental and computational aspects. The concerted metalation-deprotonation (CMD) mechanism rather than a radical-
involved pathway is proved to occur in amidation and acetoxylation reactions, and this is the rare example of CMD
mechanism involved in the more challenging sp3 C-H activations. Theoretical calculations demonstrated that CMD is the rate
deter-mining step either for methylic or benzylic positions in amidation and acetoxylation reactions, and intermolecular
nucle-ophilic addition of acetate anions is more favorable than ring-opening of β-lactam and intramolecular acetoxylation.
These mechanistic researches on the divergent and condition-dependent product formation are critical for developing Cu-
promoted C−H functionalization via CMD mechanism.
Scheme 1. Examples of product switching reactions
INTRODUCTION
A product switching by changing reaction parameters,
(a) Cu-Catalyzed C(sp2)-H Alkoxylation and C-H/C-H Biaryl Homo-Coupling (Kanai's group)
such as solvents and anions, when using the same
transition metal catalyst and substrates in each reaction, is
an interesting phenomenon. Although such divergent
transformations are powerful tools to synthesize different
types of compounds, the exploration of such
transformations is still insufficient.1-4 As several recent
examples of product switching reactions, Cu-catalyzed
C(sp2)-H alkoxylation and C-H/C-H biaryl homo-coupling
without or with using a base (Scheme 1a),5 Cu-catalyzed
synthesis of 3-cyanoindoles and 9H-pyrimido[4,5-
b]indoles by changing the equivalents of aldehydes and
concentration of ammonia (Scheme 1b),6 and Brønsted
base-switched selective mono- and dithiolation of
benzamides under Cu catalysis (Scheme 1c)7 have been
reported. We reported Cu(OAc)2-catalyzed C(sp3)-
H/C(sp2)-H amidation8-9 and Cu(OAc)2-mediated C(sp3)-H
acetoxylation.10-11 The reactions can be switched by
changing the solvents and bases whereas the same copper
salt and substrates are used. These reactions are the rare
examples of solvent- and/or base-controlled product
switching reactions.
N
N
O
cat. CuCl, (tBuO)2
toluene
OH
HO
N
N
N
N
cat. CuCl, (tBuO)2
LiOtBu, toluene
N
OH
N
(b) Synthesis of 3-Cyanoindoles and 9H-Pyrimido[4,5-b]indoles (Zhang-Fan's group)
CN
cat. CuI, RCHO
R
X
N
NH3H2O, DMF
H
Br
R1
R
X
N
Br
Br
R
R
or
cat. CuI, RCHO
N
X
N
X
NH3H2O, DMF
N
N
H
H
(c) Brnsted Base-Switched Mono- and Dithiolation under Cu Catalysis (Wang's group)
O
O
SR
Ar
cat. Cu(OAc)2
AgO, DMF, NaF
N
O
N
H
O
N
O
N
cat. Cu(OAc)2
PIDA, DMSO, K2CO3
SR
Ar
Ar
H
N
O
N
H
RS
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In recently reported first-row transition-metal-catalyzed 1.1 Exclusion of the radical pathway on C-N formation
Page 2 of 14
1
C-H functionalization reactions, some C-H bonds cleavage
occur via a concerted metalation-deprotonation (CMD)
mechanism, in which metalation and intramolecular
deprotonation proceed simultaneously.1,12 One of the most
comprehensive mechanistic studies was reported by Stahl
in the Cu(II)-mediated C(sp2)-H methoxylation. In Stahl’s
mechanism, Cu(II) and Cu(III) species participate in the
C(sp2)-H activation and the subsequent reductive
elimination steps, respectively (Scheme 2a).1 The
mechanism is totally different from a radical involved
single-electron transfer (SET) mechanism reported by Yu’s
group for the explanation of the C(sp2)-H chlorination
(Scheme 2b).13-14 Notably, the recently reported
mechanistic studies mainly have focused on sp2 C-H
functionalizations, in-depth studies on more challenging
sp3 C-H functionalizations are still in infancy and worth
exploring.12 We herein report mechanistic studies on our
reported Cu(OAc)2-catalyzed C(sp3)-H/C(sp2)-H amidation
and Cu(OAc)2-mediated C(sp3)-H acetoxylation from
experimental and computational aspects.
At the beginning, we focused our concentration on
verifying the radical pathway mainly from the following
three aspects: (1) Electronic effects of substituents:
substrates bearing an electron-donating or -withdrawing
substituent on the benzene ring 1a-1d were tested under
the optimized C-H amidation conditions, and the overall
yields of amidated products were similar to each other.
(Table 1). These results indicated that amidation did not
proceed via the radical pathway because electron-deficient
aromatics should not be easily oxidized compared with
electron-rich ones.13-14 (2) Hammett plot of amidation:
the rates were faster for substrates with electron-
withdrawing groups on the aromatic rings, and the slope
calculated by a Hammett plot using σpara values was 0.70
(Figure 1, Tables S1 and S2, Figure S1). The positive
slope revealed that amidation did not proceeded via a
radical mechanism for electron-rich groups were more
beneficial to the reaction rates in radical-involved pathway
than electron-deficient ones.13-14 (3) Effect of the radical
inhibitor: 1-3 equivalents of the radical scavenger TEMPO,
did not influence the yields of amidated products, further
excluding the possibility of a radical pathway (Table 2).
2
3
4
5
6
7
8
9
10
11
12
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Scheme 2. Previously reported mechanism in Cu-
mediated C-H bond activation
Table 1. Electronic effects of substituents on C-H
amidation
a) CMD mechanism in Cu-mediated C-H methoxylation proposed by Stahl's group
Cu(OAc)2 (2.0 equiv)
Cs2CO3 (1.0 equiv)
O
pyridine (40 equiv)
O2 (1 atm)
O
O
X
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
O
N
N
O
N
+
MeOH, 50 oC, 24 h
H
N
N
H
N
N
DCE, 140 oC, 24 h
N
N
H
MeO
X
N
X
1a-1d
2a-2d
3a-3d
O
O
N
O
N
N
2
overall
yield(%)
N
N
N
CuII
O
CuII
CuII
OH
entry
substrate
X
3 (%)[a]
(%)[a]
OMe 53
H
O
O
O
O
1
2
3
4
1a
1b
1c
1d
36
37
44
47
89
94
91
95
O
O
O
H
Cl
F
57
47
48
2-
CH3OH, CO3
-
- 2 HCO3
O
O
O
CuII
[a] Yields were determined by 1H NMR.
N
CuIII
MeO
N
N
H
MeO
- CuI
N
- CuI
N
N
CuII
MeO
b) SET mechanism proposed by Yu's group
Et
Et
standard amidation
conditions
O
Q
O
X
N
N
Q
H
Q=8-quinolinyl
SET
SET
Et Et
N
CuI
N
N
CuII
Cl
N
X

+ 
Cl
H
1e-1h
2'e-2'h
Cl
Cl
H
Cl
Cl
[log(k/ko)]
Cl
RESULTS AND DISCUSSION
1. Mechanistic studies on C-N formation
Me
H
Considering that radical pathways and two-electron
transfer manifolds via organometallic C-Cu intermediates
are two kinds of mechanisms commonly proceeded in Cu-
promoted C-H activation,12,15-17 we postulated that the
mechanism of our proposed C-H amidation and
acetoxylation may be inseparable from the above two
types of mechanism.
[para
]
OMe
Figure 1. Hammett plot of 1e-1h
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Table 2. Effect of the radical inhibitor (TEMPO) Table S3 and Figure S2); (2) intermolecular competitive
C(sp3)-H amidation reaction of a mixture of non-
deuterated and deuterated substrates was studied in one
tube, and the KIE value was 2.6 (Scheme 3b, Table S4 and
Figure S3); (3) intramolecular competitive C(sp3)-H
amidation of substrate bearing one CH3 and one CD3
groups simultaneously was carried out, and the KIE value
was 2.7 (Scheme 3c, Table S5 and Figure S4). Taken the
above three experiments together, C(sp3)-H activation may
occur during the rate-determining step,29 and this is
consistent with the positive Hammett slope observed for
reactions in which C−H deprotonation contributes strongly
to the transition state,1 indicating the possibility of CMD
mechanism in amidation.
1
2
3
4
5
6
7
8
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
DCE, 140 oC, 24 h
Q
O
O
N
O
+
Q
N
N
Q
TEMPO, Q=8-quinolinyl
H
1b
2b
3b
TEMPO
(equiv)
2b
3b
overall
entry solvent
(%)[a]
58
(%)[a] yield(%)
9
1
2
3
4
DCE
DCE
DCE
DCE
0
32
31
25
28
90
89
85
91
10
11
12
13
14
15
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17
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19
20
21
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58
59
60
1.0
58
2.0
60
3.0
63
1.2.2 Reaction orders of amides and Cu(OAc)2 in C(sp3)-N
formation.
[a] Yields were determined by 1H NMR.
To further clarify the mechanism, we investigated
reaction orders of amides (Figure 2, Tables S6-7, Figures
S5-6) and Cu(OAc)2 (Figure 2, Tables S8-9, Figures S7-8)
in C(sp3)-N formation. The rates showed a first-order
dependence on concentrations of amides and Cu(OAc)2,
which indicated that Cu-catalyzed C-H activation was the
likely rate-determining step. This experiment provided
another evidence for CMD-involved C(sp3)-N formation.
1.2 Verification of the possibility of CMD pathway
Since the radical pathway in C-H amidation has been
denied by the above experiments, moreover, the
organometallic C−H activation pathways also typically
favor electron-rich substrates, albeit to a less extent than
radical reactions,1,18 thus we considered the CMD
mechanism may be more plausible, because CMD
supporting electron-deficient substrates has been
reported.1,19-28
1.2.1 Kinetic isotope effect in C(sp3)-N formation
A powerful technique especially suitable for studying
reaction mechanisms of C-H bond functionalization—
kinetic isotope effect (KIE), was measured to provide
information on whether C-H bond cleavage was included in
the rate determining step (RDS). The KIE values of C(sp3)-
H amidation were measured by the following three ways:
(1) C(sp3)-H amidation reactions of non-deuterated and
deuterated substrates were tested independently in
parallel tubes, and the KIE value was 2.4 (Scheme 3a,
Scheme 3. KIE experiments for C(sp3)-H amidation
Figure 2. Reaction orders of amides and Cu(OAc)2 in C(sp3)-
N formation.
KIE = 2.4
(a) Parallel reactions
Q
O
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
DCE, 140 oC, 24 h
O
N
1.2.3 Investigation of the importance of acetate and
carbonate anions in C(sp3)-N formation.
Q
Q
Ph
N
H
H2C
H3C CH3
Ph
Ph
CH3
1j
2j
Q=8-quinolinyl
According to the previous reports, acetate and carbonate
anions have been proved to be beneficial in the
organometallic C-H activation,1,7,22,30-33 thus we intended to
verify the CMD mechanism by elucidating the importance
of acetate and carbonate anions in C(sp3)-H amidation.
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
DCE, 140 oC, 24 h
Q
N
O
O
Ph
N
H
D2C
D3C CD3
CD3
1j-d6
2j-d5
KIE = 2.6
(b) Intermolecular competition
Q
O
To verify the importance of carbonate anions, several
silver salts with various anions were firstly screened in the
premise of using 20 mol% of Cu(OAc)2 as the catalyst.
However, all tested anions gave 2i in rather low yields
(Table 3, entries 1-6), demonstrating the importance of
carbonate anions in C-H amidation. Since the necessity of
carbonate anions in C-H amidation have been proved, then
carbonate anions contained Cu2(OH)2CO334 replacing
Cu(OAc)2 was employed to evaluate the significance of
acetate anions. As a result, 2i was not detected, albeit the
mixture contained carbonate anions (entry 7), which
implied there maybe another factor besides carbonate
anions infecting the amidation. In the case of using a
mixture of Cu2 (OH)2 CO3 and AgOAc, the reaction
N
H2C
Ph
Ph
CH3
2j
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
DCE, 140 oC, 24 h
O
O
Q
Ph
Q
Ph
+
N
N
+
H
H
H3C CH3
1j
D3C CD3
1j-d6
Q
N
O
D2C
1j 1j-d
: 6 = 1:1)
(
CD3
2j-d5
KIE = 2.7
(c) Intramolecular competition
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
DCE, 140 oC, 24 h
Q
O
Q
O
O
N
N
Q
Ph
+
N
H2C
D2C
H
H3C CD3
Ph
Ph
CD3
CH3
1j-d3
2j-d3
2j-d2
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Page 4 of 14
Table 3. Investigation of the importance of acetate and
carbonate anions.
competitive benzylic and methylic C(sp3)-H bonds
amidation (Vide infra).
1
2
3
4
5
Taken the above KIE values, first-order dependence on
concentrations of amides and Cu(OAc)2, importance of
acetate and carbonate anions and the tendency of
amidation at the more acidic benzylic site together, CMD
was proved to occur in C-N formation.
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
O
nC3H7
O
N
N
DCE, 140 oC, 24 h, 93%
N
H
nC3H7
N
1i
2i
6
7
8
9
Table 4. Regioselectivity between competitive benzylic
and methyl C(sp3)-H bonds in amidation
2i
entry
1
Ag salt
Ag3PO4
Cu
additive
-
(%)[a]
O
O
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
DCE, 140 oC, 24 h
Q=8-quinolinyl
Cu(OAc)2
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Q
O
X
+
N
N
Q
N
Q
H
2
AgOAc
AgO
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu2(OH)2(CO3)
Cu2(OH)2(CO3)
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
1
-
-
-
-
-
-
-
-
3
X
X
1k-1q
2k-2q
2'k-2'q
3
12
9
1k
1l
1m
H
1n
1o
Cl
1p
F
1q
substrate
4
Ag2O
OMe Me
Br
25
61
CF3
21
5
AgF
<1
<1
<1
6
2 (%) [a]
2’ (%)[a]
2/2’
25
38
52
25
64
26
62
30
61
6
AgF2
53
59
7
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
0.47
0.73 0.39 0.41 0.42 0.49 0.36
8
[a] Yields were determined by 1H NMR.
9
3
2. Mechanistic studies on C(sp3)-O formation and
exploration of its correlations with C(sp3)-N formation
[b]
10
11
12
13
K2CO3
15
21
31
31
[c]
K2CO3
2.1 Substrate scope investigation and reaction
conditions studies
[d]
K2CO3
2.1.1 Substrate scope in C-O formation
[e]
K2CO3
We
also
reported
copper-mediated
C(sp3)-H
acetoxylation (Table 5).10 Amides with a tertiary alkyl
group generated the corresponding mono- and di-
acetoxylated products 4r, 4i-4j, 4j-d5 and 5r, 5i-5j, 5j-d4
(entries 1−4). Notably, acetoxylation did not occur at the
acidic benzylic C(sp3)−H bonds in the case of substrate 1j
(entry 3). The results of substrates 1s−1v indicated that
acetoxylation occurred preferentially at the methyl groups,
and did not proceed at the terminal position of the ethyl
groups, methylene moieties (internal position), or benzylic
C(sp3)−H bonds (entries 5−8). The corresponding
acetoxylated product 4w was obtained in 68% yield for
substrate 1w bearing a methoxy group on the quinolyl
group (entry 9). The above examples showed the high
functional group tolerance of Cu-mediated C(sp3)-H
acetoxylation.
[a] Yields were determined by H NMR. [b] 0.5 equiv of
K2CO3. [c] 1.0 equiv of K2CO3. [d] 2.0 equiv of K2CO3. [e] 3.0
equiv of K2CO3.
proceeded whereas the yield of 2i was 6% (entry 8),
implying acetate anions may be beneficial to amidation. In
addition, acetate anions contained AgOAc and Cu(OAc)2
only gave 3% of the product (entry 9), but the yield could
be improved by using K2CO3 as an additive and increasing
the amount of K2CO3 (entries 10-13).
Judging from the above results, only Cu(OAc)2 in concert
with Ag2CO3 could generate the amidated product 2i in the
highest yield, identifying the significance of carbonate and
acetate anions in amidation, and the species is similar to
that of the reported C-H transformations via CMD
mechanism.1
2.1.2 The amount of copper in C-N and C-O formation
1.2.4 Competitive benzylic and methylic C(sp3)-H bonds
cleavage
It is worth noting that β-hetero substituted substrate 1x
proceeded well in acetoxylation, but a tragic situation was
observed in amidation in which the amidated product was
not formed in detectable yield. In addition, the α-hetero
substituted substrate 1y gave a similarly frustrating result
in amidation (Scheme 4). As for the different behaviors of
substrate 1x in amidation and acetoxylation, we
hypothesized that the β-heteroatom as a Lewis base could
coordinate with Cu atom deactivating Cu and further
hindering the catalytic cycle of amidation, but the addition
of stoichiometric quantities of Cu is adequate to prevent
acetoxylation from being affected by the heteroatom.
With the desire to find more evidence(s) to support the
CMD mechanism, the regioselectivity of C(sp3)-H
amidation between competitive benzylic and methylic
C(sp3)-H bonds was investigated. When various substrates
with both benzyl and methyl groups located at the
competitive β-positions of amides were subjected to the
standard conditions, all substrates with an electron-
donating or withdrawing group on the para-position of the
aromatic ring gave both methylic and benzylic C(sp3)-H
bond amidated products 2 and 2ʹ (Table 4). Judging from
the facts that C(sp3)-H amidation was apt to occur at a
more acidic benzylic site rather than a less hindered
methyl group, C-H bond activation may involve in the key
step. Subsequently, we conducted DFT calculation of
substrates 1k-1q to explain the regioselectivity between
In order to probe the coordination of heteroatoms, we
examined acetoxylation and amidation of 1i in the
presence of acetoxylated amide 4i (Scheme 5). As a result,
18% of substrate 1i was transformed to a mixture of
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Table 5. Investigation of Substrate Scope.[a]
Scheme 5. Verification of the coordination of acetoxy
group to Cu atom in C-N and C-O formation.
1
2
3
4
5
6
7
8
R3
O
O
Cu(OAc)2 (1.0 equiv)
AgOAc (5.0 equiv)
O
O
Q
nC3H7
Q
nC3H7
nC3H7
R1
R2
N
N
+
Q
N
H
H
N
NaOAc (1.0 equiv)
NMP, 145 °C, 24 h
OAc
H
H
R3
N
OAc
4i
OAc
5i
Cu(OAc)2 (1.0 equiv)
AgOAc (5.0 equiv)
O
4
+
1i
Conversion yield: 18% (With the addition of 1.0 equiv of 4i)
OAc
R1
R2
N
NaOAc (1.0 equiv)
NMP, 145 °C, 24 h
R3
4i
Conversion yield: 78% (Without the addition of
)
H
O
N
1
R1
Cu(OAc)2 (20 mol%)
O
O
N
Q
Ag2CO3 (3.0 equiv)
DCE, 140 oC, 24 h
nC3H7
Q
nC3H7
H
N
OAc
N
9
N
5
OAc
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1i
Yield: 24% (With the addition of 1.0 equiv of
4i
2i
yield
4i
)
yield
entry
4
5
(%)[b
Yield: 93% (Without the addition of
)
(%)[b]
]
mono- and di- acetoxylated products, and the conversion
yield was much lower than that of the reaction without the
addition of 4i (78% conversion yield). In amidation, the
yield of 2i sharply diminished to 24% in the existence of 4i,
compared to the 93% yield observed in the absence of 4i.
O
O
R1
R1
Q
Q
N
H
N
H
OAc
OAc
OAc
1
2
3
R1 = Me
R1 = nC3H7
R1 = (CH2)2Ph
4r 39
4i 55
5r 38
5i 23
5j 21
These results indicated that the stronger coordination
ability of oxygen in acetoxy group of 4i to the Cu center in
a tridentate fashion than a bidentate starting substrate,
could deactivate the catalytic activity of Cu salt,35 resulting
in the low yields of amidation and acetoxylation. This also
reminds us that in normal situation the newly formed di-
acetoxylated product is very likely to coordinate with Cu in
a tetradentate manner, which is like the tridentate manner
of mono-acetoxylated product, just because the
coordination of product to catalyst is masked by the
addition of stoichiometric quantities copper in
acetoxylation. While in amidation, in the premise of
without other heteroatom existed in the substrates, the
weak coordination ability of previously formed amidated
products would not affect the subsequent amidation, thus
catalytic amount of Cu is adequate to amidation.
4j 55
O
O
Ph
Q
N
H
4j-d5
51
5j-d4
18
Ph
Q
Q
N
H
4
D2CD2C OAc
OAc
CD3
OAc
D2C
O
R1
N
H
OAc
5
6
R1 = (CH2)2Ph
R1 = CH2Ph
4s 78
4t 86
O
Ph
Q
N
H
7
8
9
4u 87
4v 79
4w 68
OAc
CF3
2.1.3 Comparison of the reactivity differences between C-H
amidation and acetoxylation
O
Since catalytic amount of copper has been proved to be
adequate in amidation conditions, could the amidation
occur in the stoichiometric quantities copper contained
acetoxylation conditions? In addition, we wonder know if
there is any correlation between C-H amidation and
acetoxylation. Therefore, substrate 1i was then subjected
to the conditions of C-H amidation and C-H acetoxylation
(Table 6). In the case of using 1,2-dichloroethane as the
solvent, the amidated product 2i was obtained in 93%
with no detection of the acetoxylated products 4i when
using 3 equiv AgCO3 and 20 mol% Cu(OAc)2, while only 3%
of the acetoxylated product 4i was formed with no
company of 2i in the combination of 5 equiv AgOAc and 1
equiv Cu(OAc)2. In the case of employing NMP as the
solvent, the mono- and di- acetoxylated products were
obtained in a combined yield of 78% in the presence of 5
equiv AgOAc and 1 equiv Cu(OAc)2, in which the amidated
product 2i was not formed. On the other hand, 8.3% of the
amidated product 2i was provided in the presence of 3
equiv AgCO3 and 20 mol% Cu(OAc)2, similarly, with no
formation of the mono- and di- acetoxylated products.
These results elaborated that a combination of Ag2CO3 and
DCE was beneficial in giving the amidated products,
whereas a cooperation of AgOAc and NMP was better for
Q
N
H
OAc
MeO
O
N
Bn
H
N
OAc
[a] The data are cited from ref 10. [b] Isolated yields.
Scheme 4. Investigation of the inhibition effect of α/β-
heteroatom on acetoxylation and amidation.
O
O
Cu(OAc)2 (1.0 equiv)
AgOAc (5.0 equiv)
O
Q
Q
N
OBn
N
OBn
OAc
+
Q
N
H
OBn
OBn
H
H
NaOAc (1.0 equiv)
NMP, 145 °C, 24 h
OAc
4x 54%
OAc
1x
1x
5x 22%
Cu(OAc)2 (20 mol%)
Ag2CO3 (3.0 equiv)
O
O
Q
or
NR
Q
DCE, 140 oC, 24 h
N
N
H
OBn
H
1y
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Table 6. Comparison of the reactivity differences amidated product to render the acetoxylated products. To
1
2
3
4
5
6
7
8
between C-H amidation and acetoxylation.
provide evidence for the above proposal, experiment and
calculation were respectively conducted to verify the
possibility of ring-opening of four-membered amidated
products and the intermolecular addition of acetate anions
to the CMD intermediate. In addition, the regioselectivity
in acetoxylation was also clarified via calculation (Vide
infra).
O
N
Q
CH3
Cu(OAc)2 (20 mol%), [Ag]
Solvent (1.0 M), 140 oC, 24 h
or
Q
CH3
CH3
2i
HN
or
Cu(OAc)2 (1.0 equiv), [Ag]
NaOAc (1.0 equiv)
Solvent, 145 °C, 24 h
Q=8-quinolinyl
OAc
CH3
OAc
OAc
O
Q
Q
1i
+
HN
HN
2.3 Exploration of the possibility of forming C-O bonds
via cleavage of C-N bonds.
O
O
9
4i
5i
In order to explore if the β-lactam ring could open under
the standard acetoxylation conditions to form the
acetoxylated product, amidated product 2i was directly
subjected to the standard conditions of C-H acetoxylation
(Equation (1)), nevertheless, the desired acetoxylated
product 4i was not detected at all. This result denied the
formation of acetoxylated product involving ring-opening
of the amidated product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Oxidant
Solvent
Ag2CO3 (3 equiv)[a]
AgOAc (5 equiv)[b]
DCE
2i = 93%[c]
2i = 8.3%[c]
4i = 3%[c]
4i : 5i = 55 % : 23%[c]
NMP
[a] 20mol% of Cu(OAc)2 was used. [b] 1 equiv of Cu(OAc)2
was used. [c] Yields were determined by 1H NMR.
Cu(OAc)2 (1.0 equiv)
O
nC3H7
AgOAc (5.0 equiv)
O
N
Equation (1)
N
rendering the acetoxylated products. In other words,
amidation could not occur in the acetoxylation condition
and acetoxylation would not happen in the amidation
conditions.
H
N
nC3H7
NaOAc (1.0 equiv)
NMP, 145 °C, 24 h
N
OAc
2i
4i
3. Computational analysis on CMD process and the
subsequent C-N/C-O bonds formation
2.2 Regioselectivity between a more acidic benzylic
and a less hindered methylic C(sp3)-H bonds in C-O
formation
DFT calculation was conducted in Gaussian 0936 to find
more evidences for the CMD process the subsequent C-
N/C-O bonds formation. Cu(II) species Int0 was considered
as the zero point in these energy profiles, as some similar
structures of Int0 has been reported.12
Another kind of special substrates were then
investigated to reveal the regioselectivity between
competitive benzylic and methylic C(sp3)-H bonds in C-H
acetoxylation. The yields of the acetoxylated products
enhanced with an increase in the electron-withdrawing
ability of the functional group, indicating the acetoxylation
reaction may not proceed via a SET mechanism and further
supporting the CMD pathways in acetoxylation. In addition,
whether the electron-donating or -withdrawing groups at
the para-position of the aromatic ring, absolutely
selectivity toward the less hindered β-methyl site over a
more acidic β-benzylic site was observed, suggesting that
the steric effect rather than electronic effect determined
the distribution of final products. Unexpectedly, the
selectivity in acetoxylation was in sharp contrast to the C-
H amidation (Table 7).
Started from Int0, oxidation of which with AgOAc to
provide Int1 was downhill and uphill by 0.6 kcal/mol in
DCE and NMP, respectively (Figure 3). In this mechanism,
formation of Int2 involved a deprotonation of the C(sp3)-H
by the acetate ligand with concomitant Cu−C bond
formation, analogous to the organometallic intermediates
reported for CuII or PdII -promoted C−H activation
reactions.1,22,33 The activation free energy for this step was
25.1 kcal/mol in DCE or 25.4 kcal/mol in NMP, which was
similar to that of deprotonation of the arene C-H bond by
the carbonate ligand on a Cu(II) species, where 25.9
kcal/mol was reported,1 but was different with the energy
barrier of 21.2 kcal/mol in the CMD process of C–H/N–H
annulation of electron-deficient acrylamides with arynes
reported by Zhang28 and the energy barrier of 17.7
kcal/mol in the CMD process of amination of phenol
derivatives with diarylamines demonstrated by Hirano and
Miura as these are more acidic protons.37
This prompted us to propose an interaction mode, which
is different from the intramolecular interaction in
amidation, intermolecular nucleophilic addition of acetate
anions to the CMD intermediate or the four-membered
Table 7. Regioselectivity between competitive benzylic
and methylic C(sp3)-H bonds in C-H acetoxylation.
On the other hand, in many well-documented metal-
promoted C–H functionalization reactions, stoichiometric
Ag(I)-salts were often added to act as oxidants or to play
additional roles in C–H activation,38-41 so it is plausible to
propose that AgOAc may also participate in the CMD
process of this reaction. Indeed, our calculation suggested
that a Ag involved CMD process was also energetically
possible, for a Ag-contained complex Int1Ag with a lower
Gibbs free energy of 9.5 kcal/mol in NMP and 11.0
kcal/mol in DCE, relative to Int0, was obtained when
oxidation of Int0 with AgOAc, suggesting that this
intermediate was stabilized by Ag coordination. The Gibbs
O
O
O
OAc
Cu(OAc)2 (1.0 equiv)
AgOAc (5.0 equiv)
Q
Q
Q
N
N
+
N
H
H
NaOAc (1.0 equiv)
NMP, 145 °C, 24 h
H
X
X
X
OAc
1k-1q
4k-4q
4'k-4'q
substrate
1k
1l
1m
H
1n
1o
Cl
1p
1q
CF3
83
<1
OMe
67
Me
71
<1
Br
62
<1
F
4 (%) [a]
4’ (%)[a]
74
<1
78
<1
81
<1
<1
[a] Yields were determined by 1H NMR.
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1
2
3
4
O
N
O
N
2.73
1.94
O
1.91 Cu
2
O
.
2
2.23
1.36
O
1.32 H3
5
1TS1,2
6
7
24.5[26.0]
(19.1)
8
9
N
AcO Cu
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
G25.1
[25.4] kcal/mol
OAc
O
N
Int1
-0.6[0.6]
(-6.4)
Cu
O
N
O
O
Int0
0.0 [0.0]
(0.0)
Ag(s)
AgOAc
1.00 O
H
O
N2.57
1.66
O
O
O
N
N
Cu
N
Cu
1.96
1.88
O
AcO
1Int2
Int3
-32.1 [-30.4]
(-37.6)
-31.8 [-30.5]
(-38.2)
HOAc
Figure 3. Computed free energy profile for CMD process. The relative free energies calculated in the gas phase with (U)B3LYP/6-
31G(d)-SDD(Cu) are given in kcal/mol and presented in brackets. The relative free energies in DCE given in kcal/mol are calculated
by PCM(DCE)-(U)B3LYP-d3(BJ)/6-311++G(d,p)-SDD (Cu) // (U)B3LYP/6-31G(d)-SDD(Cu). The relative free energies in NMP
given in kcal/mol are calculated by PCM(DCE)-B3LYP- d3(BJ) //6-311++G(d,p)-SDD (Cu) // B3LYP/6-31G(d)-SDD(Cu), which are
quoted in square brackets. Bond distance in Å. Molecular graphics for transition state structures were produced by CYLview.
O
N
2.13
N
Cu
2.28
AcO
OAc
O
N
Cu
N
AcO
AcO
2.04
2.47
TS5,6
[-13.6]
(-43.9)
H
OAc
1.34
1.16
AcO
N
N
Cu
O
AcO
Int5
[-17.1]
(-44.8)
N
TS6b,7b
[-25.1]
(-54.9)
OAc
G=16.9
kcal/mol
N
Cu
O
Int7b
[-30.7]
(-65.5)
AcO
AcO
Int6b
[-24.4]
(-56.3)
OAc
AcO
Int7a
[-38.4]
(-44.6)
Int3
Int6
[-30.4]
(-72.3)
[-30.5]
(-38.2)
O
O
AcO
N
Cu
AcO
N
N
O
H
Cu
N
Cu
AcO
N
N
O
H
AcO
O
Figure 4. Computed free energy profile for acetoxylation. The relative free energies calculated in the gas phase with (U)B3LYP/6-
31G(d)-SDD(Cu) are given in kcal/mol and presented in brackets. The relative free energies in DCE given in kcal/mol are calculated
by PCM(DCE)-(U)B3LYP- d3(BJ)//6-311++G(d,p)-SDD (Cu) // B3LYP/6-31G(d)-SDD(Cu). The relative free energies in NMP given
in kcal/mol are calculated by PCM(DCE)-B3LYP- d3(BJ) //6-311++G(d,p)-SDD (Cu) // B3LYP/6-31G(d)-SDD(Cu), which are
quoted in square brackets. Bond distance in Å. Molecular graphics for transition state structures were produced by CYLview.
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free activation energy of CMD process via TS1,2Ag was 25.2 determining step. The energy barriers of the CMD step of
1
2
3
4
5
6
7
8
kcal/mol relative to Int1Ag (as evaluated in DCE or NMP),
which was approximately equal to the energy barriers
without the assistance of Ag (Figure S9), indicating that
Ag had negligible influence on the CMD, and further
reminding us that Ag was likely to play more important
roles in oxidizing Cu(II) to Cu(III) to participate in the
CMD or/and Cu(I) to Cu(II) to recycle Cu.
methylic and benzylic sites in amidation were similar to
each other, as in the case that energy barriers of the
subsequent C-N formation step of methylic and benzylic
sites in amidation had slight difference, which could
explain the phenomenon why both methylic and benzylic
C-H bonds could be amidated. In the case of acetoxylation,
there was negligible difference on the energy barriers of
the CMD step of methylic and benzylic sites, but the energy
barriers of the C-O formation step of benzylic sites were
6.3-6.8 kcal/mol higher than that of the methylic sites, we
speculated this may be due to the fact that the high
polarity of NMP and high concentration of ligand (acetate
anions) made the surroundings of benzylic copper
intermediate more crowed. Therefore, the lower energy
barriers of the less hindered methylic sites could
contribute to the absolute regioselectivities on methylic
sites in acetoxylation.
After releasing AcOH from Int2 (Figure 3) or AcOH and
Ag from Int2Ag (Figure S9), Int3 was formed. Acetoxylation
of Int3 may proceed via several possible pathways (Figure
S10). Among them, intermolecular nucleophilic addition of
acetate anions to metalacyclic intermediate Int3 to give
rise to acetoxylated products Int6 was the most
energetically favored (Figures S10). In addition, the
energy barrier for intermolecular nucleophilic addition
was 16.9 kcal/mol (in NMP, Figures 4 and S10), which
was 6.7 kcal/mol (in NMP) lower than the amidation
process (ΔG⧧ = 23.6 kcal/mol in NMP, Figures 5),42 and
this outcome was in accordance with the phenomenon that
acetoxylated product 4 could not be formed via ring-
opening of amidated product (Equation (1)) since it must
firstly conquer higher energy barrier than direct
intermolecular acetoxylation. Subsequently, cleavage of
Cu-N bond in Int6 via TS6b,7b and releasing acetate anions
gave Int7a with a lower Gibbs free energy of 7.9 kcal/mol
(in NMP) compared to Int3 (Figure 4).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 8. Computed free energy activation barriers for
methyl and benzylic amidation.[a]
∆G‡
benzyli
c
CMD
Subst
rate
∆G‡
methyl
∆G‡
(2)
∆G‡
C-N
(2’)
∆∆
CMD
CMD
C-N
G‡
1k
1l
27.6
28.0
27.6
25.3
27.1
26.9
22.2
20.0
21.2
18.2
18.7
19.8
2.3
0.9
0.7
1m
1n
1o
1p
1q
28.1
27.7
27.3
27.8
27.8
27.3
27.3
28.0
22.4
22.5
22.4
22.5
19.8
20.0
19.6
20.7
0.3
0.4
0.0
-0.2
1.98
O
N
Cu
N
2.29
AcO
TS3,4
-8.1[-6.9]
(-12.6)
TS3,4
[a] The relative free energies in DCE given in kcal/mol are
calculated by PCM(DCE)-(U)B3LYP-d3(BJ)/6-311++G(d,p)-
SDD (Cu) // (U)B3LYP/6-31G(d)-SDD(Cu).
N
G=[23.6] kcal/mol
N
Cu
AcO
O
Table 9. Computed free energy activation barriers for
methyl and benzylic acetoxylation.[a]
O
N
Cu
N
AcO
Int4
-36.4[-35.4]
(-40.4)
Int3
-31.8 [-30.5]
(-38.2)
∆G‡
Benzyl
ic
CMD
Subst ∆G‡
∆G‡
(4)
∆G‡
C-
O (4’)
∆∆G‡ ∆∆G
CMD
C-O
‡
rate
Methyl
CMD
C-O
Figure 5. Computed free energy profile for amidation step. The
relative free energies calculated in the gas phase with
(U)B3LYP/6-31G(d)-SDD(Cu) are given in kcal/mol and
presented in brackets. The relative free energies in DCE given
in kcal/mol are calculated by PCM(DCE)-(U)B3LYP-
d3(BJ)//6-311++G(d,p)-SDD (Cu) // B3LYP/6-31G(d)-
SDD(Cu). The relative free energies in NMP given in kcal/mol
are calculated by PCM(DCE)-B3LYP-d3/6-311++G(d,p)-SDD
(Cu) // B3LYP/6-31G(d)-SDD(Cu), which are quoted in square
brackets. Bond distance in Å. Molecular graphics for transition
state structures were produced by CYLview.
1k
1l
[27.8]
[28.2]
[27.8]
[28.4]
[27.9]
[27.5]
[28.0]
[25.4]
[27.2]
[27.1]
[28.0]
[27.5]
[27.4]
[28.2]
[12.2] [19.0] 2.4
[12.4] [18.7] 1.0
[12.4] [19.0] 0.7
[12.3] [19.0] 0.4
[12.6] [18.9] 0.4
[12.4] [18.9] 0.1
-6.8
-6.3
-6.6
-6.7
-6.3
-6.5
-6.6
1m
1n
1o
1p
1q
[12.4]
[19.0] -0.2
[a] The relative free energies in NMP given in kcal mol-1 are
calculated by PCM(NMP)-B3LYP- d3(BJ) //6-311++G(d,p)-
SDD (Cu) // B3LYP/6-31G(d)-SDD(Cu), which are quoted in
square brackets.
Afterwards, we calculated the energy barriers of CMD
and the subsequent C-N or C-O bonds formation in
methylic or benzylic sites of substrates 1k-1q to make
clear the regioselectivity changes in amidation and
acetoxylation (Tables 8-9, Figures S11-14, Tables S13-
23). The results revealed that whether in amidation or
acetoxylation, and whether in methylic or benzylic sites,
CMD step with or without the assistance of Ag was the rate
3. Proposed mechanism
3.1 Proposed mechanism for C-N formation
Based on the reported literatures12 and the evidence
above, we speculated the mechanism of C(sp3)-H
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amidation and acetoxylation. The mechanism depicted in addition of acetate anions to form Int6, and this pathway
1
2
3
4
5
6
7
8
Scheme 6 is for the formation of β-lactams: (1)
coordination of substrate 1 to CuII species with the
elimination of acetic acid generates intermediate Int0; (2)
was proved to be energetically the most favored one and
thus the most likely pathway for the C-H acetoxylation in
NMP; (5) dissociation of Cu species to liberate the
acetoxylated product 4, which is a stronger ligand than the
starting material 1 thus leading to the necessity of
stoichiometric copper salt. Notably, Ag-assisted CMD
process was also proved to be energetically feasible in
both C-N and C-O formation reactions.
43
oxidation of the copper intermediate Int0 with Ag2CO3
and ligand exchange to give intermediate I via leaving Ag
and AgOAc free, the driving force for this step is that
carbonate is dianion ligand; (3) formation of metalacyclic
intermediate II was proceeded via a CMD pathway (C(sp3)-
H bond activation),44 which was supported by the
necessity of acetate and carbonate anions, first order
dependence on concentrations of Cu(OAc)2 and substrate,
the large KIE value and positive Hammett slope; (4)
subsequent C-N reductive elimination of Cu(III) contained
II proceeds rendering Cu(I) contained III; and (5) oxidation
of III with Ag(I) to give amidated product 2.43 However, the
disproportionation of Cu(II) to form Cu(III) species could
not be ruled out for mechanisms including Cu(II)
disproportionation were also proposed in some C-H bond
transformations.12
9
CONCLUSION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we conducted experimental and
computational experiments to elucidate the detailed
mechanisms of our reported Cu-catalyzed intramolecular
sp3/sp2 C-H amidation and Cu-mediated sp3 C-H
acetoxylation. It was identified that the Cu(II)-catalyzed or
mediated C-H activation occurred via a CMD mechanism,
and this is the rare example of CMD involving in the more
challenging sp3 C-H activation. The theoretical calculations
revealed that whether in amidation or acetoxylation, and
whether in methylic or benzylic sites, CMD step with or
without the assistance of Ag was the rate determining step,
and intermolecular nucleophilic addition of acetate anions
was energetically more favorable over ring-opening of β-
Scheme 6. Proposed mechanism for C(sp3)-H
amidation
O
O
N
H
R
lactams
or
intramolecular
acetoxylation.
These
N
N
N
mechanistic researches of the divergent and condition-
dependent product formation are critical for developing
Cu-promoted C−H functionalization via CMD mechanism.
N
(R=H or Ar)
1
R
2
R
Cu
O
N
O
CuII(OAc)2
(1)
O
AcOH
Int0
Ag(s)
EXPERIMENTAL SECTION
Ag2CO3
(5)
Ag(I)
(2)
General information
Ag(s) AgOAc
All reactions were carried out in a dry solvent under
argon atmosphere unless otherwise noted. [Cu(OAc)2]
(purity: 99.99%) was purchased from Aldrich Co. Solvents
and silver salts were purchased from Wako Pure Chemical
Industries, solvents were dried and degassed before use.
Heating mantle was used as the heat source for all
reactions requiring heating. NMR Spectra were recorded
N
Cu
O
N
(3)
N
N
R
N
R
O
O
Cu
O
Cu
O
N
O
O
O
(4)
HOAc
OH
III
O
R
O
OH
II
I
3.2 Proposed mechanism for C-O formation
1
The following mechanism is for the formation of
acetoxylated product (Scheme 7): (1) coordination of
substrate 1 to CuII species with elimination of acetic acid
generates the identical intermediate with the amidation
process; (2) oxidation of CuII with Ag salt to afford CuIII
species Int1; (3) formation of metalacyclic intermediate
Int3 via CMD pathway; (4) intermolecular nucleophilic
on JEOL ECX500 (500 MHz for H NMR and 126 MHz for
13C NMR) and JEOL ECS400 (400 MHz for 1H NMR and 101
MHz for 13C NMR) spectrometer. Proton chemical shifts are
reported relative to a residual solvent peak (CDCl3 at 7.26
ppm or TMS at 0 ppm). Carbon chemical shifts are
reported relative to a residual solvent peak (CDCl3 at 77.26
ppm). The following abbreviations were used to designate
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, m = multiplet, br = broad. IR spectra were
recorded on a JASCO FT/IR-410. High-resolution mass
spectra (HRMS) were measured on a JEOL JMS-T100LC
AccuTOF spectrometer (for HRMS).
Scheme 7. Proposed mechanism for C(sp3)-H
acetoxylation.
O
N
H
R
N
O
R
N
Cu
O
N
N
R
The spectra of amides 1b,8 1i,10 1j-1q,8 1j-d6,8 1r-1x10
O
(R=H or Ar)
1
H
N
CuII(OAc)2
O
and compounds 2b,8 2j-2q,8 2j-d5,8 2'k-2'q,8 3b,8 4i-4x,10
4j-d5,10 5i-5j,10 5r,10 5x10 have been reported in our
previous study. Compounds 1c-1d,45 1f,46 1g,47 1h46 and
2’f-2’h46 were known compounds.
OAc
"Cu"
4
Int0
(1)
AcOH
Ag(I)
Ag(s)
(5)
(2)
Statement for the kinetic data
O
O
R
N
In our experience, the yields of amidation or
acetoxylation reactions were low when the reactions were
stirred for 24 h at temperature that was below the optimal
one, while the yields would be satisfactory only if the
(4)
HOAc
(3)
N
N
N
Cu
R
AcO
CMD
N
Cu
AcO Cu
OAc
Int1
N
OAc
OAc
R
O
Int6
Int3
OAc
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Na2SO4 and concentrated in vacuo. After that, the residue
reaction temperatures were up to the optimal conditions,
indicating an induction period may be existed before the
steady stage. On the other hand, the kinetic data in the
supporting information, in which all of the runs exhibit
non-zero y-intercepts, would be regarded as another
evidence to support the existence of induction period. We
speculated the reasons of the above-mentioned
phenomenon may be considered as follows: in both
amidation and acetoxylation reactions, the C-H activation
step has been proposed as the rate determining step (RDS).
That is, energy provided must be adequate to conquer the
energy barriers of this key step to promote the advance of
these two reactions. In the process of temperature rising, in
which the temperatures of reaction systems were below the
optimal one, it seems to be difficult to provide sufficient
energy to conquer the barriers of RDS, thus maybe
blocking the progress of reactions and ultimately resulting
in the appearance of an induction period. On the other
hand, Cu(III) was proposed to participate in the CMD step,
thus the oxidation of Cu(II) to Cu(III) should happen before
the CMD step. In conclusion, the processes of catalyst
activation by ligand, oxidation of Cu(II) to Cu(III), and
temperatures rise would take some time and result in the
low reaction rates at the initial stage, therefore leading to
the appearance of induction period.
was directly analyzed by 1H NMR using 1,1,2,2-
tetrachloroethane as the internal standard to determine
the yields of products or was subjected to column
chromatography on silica gel (hexane/ethyl acetate = 3:1)
to give the desired products.
1
2
3
4
5
6
7
8
Procedure for a gram-scale acetoxylation reaction for
synthesizing 4v.
A reaction tube was covered with aluminum foil, and a
mixture of amide 1v (1.32 g, 4.93 mmol), Cu(OAc)2 (984.3
mg, 4.93 mmol), AgOAc (4.1 g, 24.7 mmol), NaOAc (404.3
mg, 4.93 mmol), and N-methyl-2-pyrrolidone (49.3 mL)
was stirred at 145 °C for 24 h under argon atmosphere.
The reaction mixture was cooled to room temperature,
filtrated through Celite, and the residue was washed with
ethyl acetate (200 mL). Then, water (100 mL) was added
to the filtrate, and the mixture was extracted with ethyl
acetate (3 x 150 mL). The organic phase was dried over
Na2SO4 and was concentrated in vacuo. The crude mixture
was subjected to column chromatography on silica gel
(hexane/ethyl acetate = 3:1) to give the desired product 4v
(1.13 g, 70% yield).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Characterization
data
for
compounds
2-(4-
Methoxyphenyl)-2-methyl-N-(quinolin-
8yl)propenamide (1a):
Eluent: hexane/ethyl acetate = 10:1, 52.0 mg, 95% yield,
General synthetic procedure for compounds 2a-2d,
2'e-2'h, 2i-2q, 2'k-2'q, 2j-d2, 2j-d3, 2j-d5 and 3a-3d
1
pale yellow oil. H NMR (CDCl3, 500 MHz) δ 1.76 (s, 6H),
3.82 (s, 3H), 6.95 – 6.92 (m, 2H), 7.36 (dd, J = 8.2, 4.2 Hz,
1H), 7.48 – 7.43 (m, 3H), 7.51 (t, J = 8.0 Hz, 1H), 8.08 (dd, J
= 8.2, 1.5 Hz, 1H), 8.62 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (dd, J =
7.5, 0.9 Hz, 1H), 9.88 (s, 1H); 13C{1H} NMR (CDCl3, 126 MHz)
δ 27.4, 47.9, 55.6, 114.3, 116.2, 121.4, 121.7, 127.6, 127.7,
128.1, 135.0, 136.3, 137.2, 138.9, 148.4, 158.8, 176.4; IR
(KBr, ν / cm-1) 3437, 2972, 2936, 2835, 1671, 1578, 1524,
1486, 1423, 1386, 1299, 1252, 1184, 1147, 1102, 1056,
1034, 908, 826, 792, 754, 732, 669; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C20H20N2O2Na 343.1417; Found
343.1411.
A screw cap vial was charged with substrate 1 (0.10
mmol), Cu(OAc)2 (3.63 mg, 20.0 μmol), Ag2CO3 (82.7 mg,
0.30 mmol), and solvent (1.0 mL) under Ar atmosphere.
The vial was sealed and stirred vigorously at 140 ˚C for 24
h. Then the reaction mixture was cooled to room
temperature, filtered through a pad of Celite and
concentrated in vacuo. The residue was directly analyzed
1
by H NMR using 1,1,2,2-tetrachloroethane as the internal
standard to determine the yields of products or purified by
column chromatography on silica gel (hexane/ethyl
acetate = 8:1) to give the desired products.
2-Ethyl-2-(4-methoxybenzyl)-N-(quinolin-8-
yl)butanamide (1e):
Procedure for a gram-scale amidation reaction for
synthesizing 2j.
Eluent: hexane/ethyl acetate = 10:1, 35.5 mg, 59%, pale
1
A screw cap vial was charged with substrate 1j (1.40 g,
4.40 mmol), Cu(OAc)2 (175.8 mg, 0.88 mmol), Ag2CO3 (3.64
g, 13.2 mmol), and solvent (44.0 mL) under Ar atmosphere.
The vial was sealed and stirred vigorously at 140 ˚C for 24
h. Then the reaction mixture was cooled to room
temperature, filtered through a pad of Celite and
concentrated in vacuo. The residue was directly purified
by column chromatography on silica gel (hexane/ethyl
acetate = 8:1) to give 2j (1.0 g, 73% yield) as a yellow oil.
yellow oil. H NMR (CDCl3, 500 MHz) δ 1.01 (t, J = 7.4 Hz,
6H), 1.76 – 1.66 (m, 2H), 1.91 – 1.82 (m, 2H), 3.00 (s, 2H),
3.67 (s, 3H), 6.68 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H),
7.42 (dd, J = 8.2, 4.2 Hz, 1H), 7.50 – 7.47 (m, 1H), 7.54 (t, J =
7.8 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.75 – 8.73 (m, 1H),
8.84 (d, J = 7.6 Hz, 1H), 10.11 (brs, 1H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 8.8, 26.6, 40.0, 52.7, 55.3, 113.7, 116.5,
121.4, 121.70, 127.71, 128.2, 130.1, 131.2, 134.8, 136.4,
139.1, 148.4, 158.3, 175.4; IR (KBr, ν / cm-1) 3444, 3054,
2969, 2936, 2837, 2788, 1653, 1528, 1514, 1488, 1457,
1423, 1385, 1325, 1265, 1179, 826, 793, 740, 705, 669;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H26N2O2Na
385.1886; Found 385.1880.
General synthetic procedure for compounds 4i-4q, 4j-
d5, 4r-4x, 5i-5j, 5r, 5x and 5j-d4
A mixture of substrate 1 (0.10 mmol), Cu(OAc)2 (18.2 mg,
0.10 mmol), NaOAc (8.20 mg, 0.10 mmol), AgOAc (83.5 mg,
0.50 mmol), and N-methyl-2-pyrrolidone (1.0 mL) was
stirred in a tube reaction covered with aluminum foil at
145 °C for 24 h under argon atmosphere. Then the reaction
mixture was cooled to room temperature, and water (10
mL) was added. The mixture was extracted with ethyl
acetate (3 × 15 mL), and the organic phase was dried over
3-(4-Methoxyphenyl)-3-methyl-1-(quinolin-8-
yl)azetidin-2-one (2a):
Eluent: hexane/ethyl acetate = 8:1, 16.9 mg, 53% yield,
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.80 (s, 3H), 3.80
(s, 3H), 4.65 (d, J = 7.3 Hz, 1H), 4.78 (d, J = 7.2 Hz, 1H), 6.95
– 6.89 (m, 2H), 7.37 (dd, J = 8.2, 4.1 Hz, 1H), 7.53 – 7.46 (m,
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The Journal of Organic Chemistry
4H), 8.10 (dd, J = 8.2, 1.7 Hz, 1H), 8.55 (dd, J = 6.4, 2.7 Hz, Eluent: hexane/ethyl acetate = 8:1, 14.7 mg, 48% yield,
1H), 8.80 (dd, J = 4.1, 1.8 Hz, 1H); 13C{1H} NMR (CDCl3, 126
MHz) δ 23.8, 55.5, 58.7, 61.3, 114.3, 119.8, 121.4, 123.2,
127.0, 127.4, 129.2, 133.6, 135.2, 136.1, 140.6, 148.7, 158.8,
171.7; IR (KBr, ν / cm-1) 3445, 3007, 2963, 2930, 2906,
2864, 2834, 1739, 1645, 1612, 1571, 1514, 1505, 1473,
1426, 1402, 1349, 1296, 1249, 1206, 1182, 1153, 1101,
1032, 957, 900, 826, 812, 790, 759, 736, 700, 668; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C20H18N2O2Na 341.1260;
Found 341.1259.
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.80 (s, 3H), 4.67
(d, J = 7.3 Hz, 1H), 4.80 (d, J = 7.3 Hz, 1H), 7.09 – 7.03 (m,
2H), 7.38 (dd, J = 8.2, 4.1 Hz, 1H), 7.55 – 7.48 (m, 4H), 8.11
(dd, J = 8.4, 1.6 Hz, 1H), 8.54 (dd, J = 7.0, 1.9 Hz, 1H), 8.80
(dd, J = 4.0, 1.7 Hz, 1H); 13C{1H} NMR (CDCl3, 126 MHz) δ
24.0, 58.8, 61.2, 115.7 (d, J = 21.4 Hz), 119.9, 121.5, 123.4,
127.0, 128.0 (d, J = 7.56 Hz), 129.2, 135.1, 136.2, 137.3 (d, J
= 3.5 Hz), 140.6, 148.8, 162.1 (d, J = 247 Hz), 171.2; IR (KBr,
ν / cm-1) 3468, 3066, 3008, 2966, 2922, 2866, 1741, 1652,
1609, 1596, 1571, 1506, 1474, 1426, 1403, 1350, 1302,
1263, 1226, 1154, 1093, 1034, 1015, 957, 903, 825, 804,
789, 758, 736; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C19H15FN2ONa 329.1061; Found 329.1063.
1
2
3
4
5
6
7
8
9
5-Methoxy-3,3-dimethyl-1-(quinolin-8-yl)indolin-2-
one (3a):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Eluent: hexane/ethyl acetate = 8:1, 11.5 mg, 36% yield,
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.55 (s, 3H), 1.63
(s, 3H), 3.65 (s, 3H), 5.96 (d, J = 2.2 Hz, 1H), 6.59 (dd, J = 8.1,
2.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 8.3, 4.1 Hz,
1H), 7.67 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.94 (d,
J = 8.3 Hz, 1H), 8.23 – 8.20 (m, 1H), 8.85 – 8.82 (m, 1H);
13C{1H} NMR (CDCl3, 126 MHz) δ 24.9, 25.7, 44.4, 55.7, 97.7,
106.8, 122.1, 123.1, 126.6, 128.0, 129.4, 129.9, 130.1, 132.8,
136.3, 144.6, 145.5, 151.2, 159.8, 182.6; IR (KBr, ν / cm-1)
3436, 3054, 2969, 2937, 2835, 1718, 1627, 1541, 1505,
1473, 1456, 1393, 1375, 1362, 1204, 1168, 1130, 1095,
1029, 991, 939, 884, 827, 793, 749, 681; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C20H18N2O2Na 341.1260; Found
341.1259.
5-Fluoro-3,3-dimethyl-1-(quinolin-8-yl)indolin-2-one
(3d):
Eluent: hexane/ethyl acetate = 8:1, 14.4 mg, 47% yield,
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.56 (s, 3H), 1.63
(s, 3H), 6.09 (dd, J = 9.1, 2.4 Hz, 1H), 6.78 – 6.72 (m, 1H),
7.23 (dd, J = 8.2, 5.4 Hz, 1H), 7.44 (dd, J = 8.2, 4.2 Hz, 1H),
7.70 – 7.66 (m, 1H), 7.77 (dd, J = 7.3, 1.4 Hz, 1H), 7.96 (dd, J
= 8.2, 1.4 Hz, 1H), 8.23 (dd, J = 8.3, 1.7 Hz, 1H), 8.83 (dd, J =
4.1, 1.7 Hz, 1H); 13C{1H} NMR (CDCl3, 126 MHz) δ 24.8, 25.5,
44.6, 98.6 (d, J = 27.72 Hz), 108.8 (d, J = 22.68 Hz), 122.2,
123.4 (d, J = 8.82 Hz), 126.6, 129.6, 129.9, 130.0, 131.1 (d, J
= 2.52 Hz), 132.4, 136.4, 144.4, 145.7 (d, J = 12.6 Hz), 151.3,
162.8 (d, J = 243.18 Hz), 182.2; IR (KBr, ν / cm-1) 3427,
3044, 2979, 2946, 2827, 2768, 1721, 1646, 1542, 1523,
1499, 1472, 1393, 1376, 1362, 1324, 1274, 1196, 1166,
1110, 1092, 830, 792, 729, 696, 669; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C19H15FN2ONa 329.1061; Found
329.1055.
3-(4-Chlorophenyl)-3-methyl-1-(quinolin-8-
yl)azetidin-2-one (2c):
Eluent: hexane/ethyl acetate = 8:1, 15.1 mg, 47% yield,
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.80 (s, 3H), 4.67
(d, J = 7.3 Hz, 1H), 4.79 (d, J = 7.3 Hz, 1H), 7.40 – 7.32 (m,
3H), 7.55 – 7.45 (m, 4H), 8.13 – 8.07 (m, 1H), 8.55 – 8.50
(m, 1H), 8.80 (dd, J = 4.0, 2.3 Hz, 1H); 13C{1H} NMR (CDCl3,
126 MHz) δ 23.9, 58.9, 61.0, 119.9, 121.5, 123.4, 127.0,
127.8, 129.0, 129.2, 133.2, 135.0, 136.2, 140.0, 140.6, 148.8,
170.9; IR (KBr, ν / cm-1) 3472, 3048, 2967, 2936, 2878,
2836, 1742, 1611, 1596, 1570, 1504, 1473, 1426, 1400,
1366, 1349, 1311, 1297, 1252, 1204, 1180, 1155, 1129,
1099, 1060, 1033, 1013, 953, 909, 850, 826, 789, 757, 733,
667, 637; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C19H15ClN2ONa 345.0765; Found 345.0764.
3,3-Diethyl-4-(4-methoxyphenyl)-1-(quinolin-8-
yl)azetidin-2-one (2'e):
Eluent: hexane/ethyl acetate = 8:1, Colorless oil. 1H NMR
(CDCl3, 500 MHz) δ 0.82 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.4
Hz, 3H), 1.33 – 1.25 (m, 1H), 1.61 – 1.52 (m, 1H), 2.12 –
1.99 (m, 2H), 3.69 (s, 3H), 6.08 (s, 1H), 6.72 (d, J = 8.5 Hz,
2H), 7.15 (d, J = 8.5 Hz, 2H), 7.23 (dd, J = 8.3, 4.1 Hz, 1H),
7.57 – 7.50 (m, 2H), 7.99 (d, J = 8.1 Hz, 1H), 8.35 – 8.33 (m,
1H), 8.65 (d, J = 4.0 Hz, 1H); 13C{1H} NMR (CDCl3, 126 MHz)
δ 8.5, 9.2, 22.6, 25.5, 55.3, 63.7, 69.0, 113.7, 121.3, 122.4,
124.3, 126.7, 128.1, 129.2, 130.7, 133.3, 135.8, 141.5, 148.9,
158.8, 173.2; IR (KBr, ν / cm-1) 3444, 2966, 2935, 2838,
2786, 1739, 1647, 1541, 1514, 1504, 1472, 1424, 1398,
1365, 1338, 1248, 1176, 1129, 1099, 1034, 827, 790, 756,
5-Chloro-3,3-dimethyl-1-(quinolin-8-yl)indolin-2-one
(3c):
Eluent: hexane/ethyl acetate = 8:1, 14.2 mg, 44% yield,
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.56 (s, 3H), 1.63
(s, 3H), 6.35 (d, J = 1.8 Hz, 1H), 7.04 (dd, J = 7.9, 2.0 Hz, 1H),
7.22 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 8.3, 4.1 Hz, 1H), 7.70 –
7.66 (m, 1H), 7.76 (dd, J = 7.3, 1.4 Hz, 1H), 7.96 (dd, J = 8.2,
1.2 Hz, 1H), 8.23 (dd, J = 8.3, 1.6 Hz, 1H), 8.82 (dd, J = 4.1,
1.6 Hz, 1H); 13C{1H} NMR (CDCl3, 126 MHz) δ 24.6, 25.4,
44.6, 110.5, 122.2, 122.6, 123.5, 126.6, 129.7, 129.9, 130.1,
132.3, 133.3, 134.2, 136.4, 144.4, 145.5, 151.3, 181.9; IR
(KBr, ν / cm-1) 3435, 3054, 2929, 1725, 1646, 1541, 1498,
1489, 1471, 1457, 1426, 1392, 1373, 1360, 1265, 1204,
1152, 1122, 1080, 939, 911, 884, 824, 809, 792, 755, 710,
668; HRMS (ESI-TOF) m/z: [M
C23H24N2O2Na 383.1730; Found 383.1734.
+
Na]+ Calcd for
3-Methyl-3-propyl-1-(quinolin-8-yl)azetidin-2-one (2i):
Eluent: hexane/ethyl acetate = 8:1, 19.6 mg, 93% yield,
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 0.97 (t, J = 7.3 Hz,
3H), 1.48 – 1.39 (m, 4H), 1.64 – 1.52 (m, 1H), 1.75 – 1.70
(m, 2H), 4.24 (d, J = 7.3 Hz, 1H), 4.40 (d, J = 7.3 Hz, 1H),
7.36 (dd, J = 8.3, 4.1 Hz, 1H), 7.51 – 7.45 (m, 2H), 8.08 (dd, J
= 8.3, 1.7 Hz, 1H), 8.49 (dd, J = 6.0, 3.0 Hz, 1H), 8.79 (dd, J =
4.1, 1.7 Hz, 1H); 13C{1H} NMR (CDCl3, 126 MHz) δ 14.7,
18.4, 19.8, 37.4, 55.6, 58.8, 119.6, 121.4, 122.9, 126.9,
129.1, 135.3, 136.1, 140.5, 148.6, 173.7; IR (KBr, ν / cm-1)
3458, 2959, 2929, 2904, 2871, 2845, 1743, 1637, 1612,
1595, 1570, 1527, 1504, 1474, 1426, 1401, 1365, 1348,
693; HRMS (ESI-TOF) m/z: [M
+
Na]+ Calcd for
C19H15ClN2ONa [M + Na]+ 345.0765; Found 345.0770.
3-(4-Fluorophenyl)-3-methyl-1-(quinolin-8-
yl)azetidin-2-one (2d):
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[7]
Jiang, Y.; Feng, Y.-Y.; Zou, J.-X.; Lei, S.; Hu, X.-L.; Yin, G.-F.;
1200, 1188, 1151, 1133, 1107, 1060, 1030, 971, 905, 826,
814, 790, 758, 641; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C16H18N2ONa 277.1311; Found 277.1306.
Tan, W.; Wang, Z. Brønsted Base-Switched Selective Mono- and
Di-thiolation of Benzamides via Copper Catalysis. J. Org. Chem.
2019, 84, 10490-10500.
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[8]
Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. Copper-
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, compound characterization data
and spectra, details of calculation (PDF)
This material is available free of charge via the Internet at
http://pubs.acs.org.
Catalyzed Intramolecular C(sp3)-H and C(sp2)-H Amidation by
Oxidative Cyclization. Angew. Chem. Int. Ed. 2014, 53, 3496-3499.
[9]
similar reaction, please see: Wu, X.; Zhao, Y.; Zhang, G.; Ge, H.
Copper-Catalyzed Site-Selective Intramolecular Amidation of
Unactivated C(sp3)-H Bonds. Angew. Chem. Int. Ed. 2014, 53,
Slightly after our publication, Ge’s group reported a
3706-3710.
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[10] Wang, Z.; Kuninobu, Y.; Kanai, M. Copper-Mediated
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4790-4793.
[11] Almost at the same time, Ge’s group reported a similar
reaction, please see: Wu, X.; Zhao, Y.; Ge, H. Copper-Promoted
Site-Selective Acyloxylation of Unactivated C(sp3)-H Bonds. Chem.
Asian J. 2014, 9, 2736-2739.
[12] Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.;
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[13] Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. Cu(II)-
Catalyzed Functionalizations of Aryl C-H Bonds Using O2 as an
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[15] Evano, G.; Blanchard, N. Copper-Mediated Cross-Coupling
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[16] Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
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[17] Alexakis, A.; Krause, N.; Woodward, S. Copper-Catalyzed
Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany, 2014.
[18] A comparison of the electronic effects of ″electrophilic″
C−H activation by Pd II and other more-classical electrophiles,
please see: Stock, L. M.; Tse, K-t.; Vorvick, L. J.; Walstrum. S. A.
Palladium(II) acetate catalyzed aromatic substitution reaction. J.
Org. Chem. 1981, 46, 1757−1759.
[19] A. D. Ryabov, I. K. Sakodinskaya, A. K. Yatsimirsky,
Kinetics and mechanism of ortho-palladation of ring-substituted
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2629−2638.
[20] Karig, G.; Moon, M. T.; Thasana, N.; Gallagher, T. C−H
Activation and Palladium Migration within Biaryls under Heck
Reaction Conditions. Org. Lett. 2002, 4, 3115−3118.
[21] Davies, D. L.; Donald, S. M. A.; Macgregor, S. A.
Computational Study of the Mechanism of Cyclometalation by
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[22] García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. Proton Abstraction Mechanism for the
Palladium-Catalyzed Intramolecular Arylation. J. Am. Chem. Soc.
2006, 128, 1066−1067.
[23] Gorelsky, S. I.; Lapointe, D.; Fagnou, K. Analysis of the
Concerted Metalation-Deprotonation Mechanism in Palladium-
Catalyzed Direct Arylation Across a Broad Range of Aromatic
Substrates. J. Am. Chem. Soc. 2008, 130, 10848−10849.
[24] Balcells, D.; Clot, E.; Eisenstein, O. C—H Bond Activation
in Transition Metal Species from a Computational Perspective.
Chem. Rev. 2010, 110, 749−823.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bencan.tang@nottingham.edu.cn
*E-mail: kuninobu@mol.f.u-tokyo.ac.jp
*E-mail: zhenw@lzu.edu.cn
Author Contributions
‡ Y. Y., F. C. and L. Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by Grant-in-Aid for Scientific
Research (B) from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan, and the Recruitment
Program of Global Experts (1000 Talents Plan) and the
Fundamental Research Funds for the Central Universities
(lzujbky-2019-ct08). The authors (BT & LB) acknowledge the
financial support from Ministry of Science and Technology of
the People’s Republic of China under funding figure National
Key R&D Program of Intergovernmental Kay Projects (Grant
No. 2018YFE0101700), the National Natural Science
Foundation of China (21502101), the Natural Science
Foundation of Ningbo (2017A610070), the International
Doctoral Innovation Centre, Ningbo Education Bureau, Ningbo
Science and Technology Bureau, and the University of
Nottingham for the use of High Performance Computing
Facility.
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O
CMD
O
R2
N
1
2
N
R2
R1
N
G  kcal/mol
Cu
H
R1
R
N
R=OAc/CO3
3
R=OAc
R=CO3
4
5
6
7
8
9
ring-opening
pathways
G   NMP
intermolecular
addition of OAc-
G  16.9 (NMP)
VS.
kcal/mol
kcal/mol
favored
O
unfavored
R2
O
N
R2
R1
N
N
H
N
OAc
OAc
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