Palladium-Catalyzed Multistep Tandem Carbonylation/N-Dealkylation/Carbonylation Reaction: Access to Isatoic Anhydrides

Article abstract of DOI:10.1021/acs.joc.9b02771

A novel and efficient synthesis of isatoic anhydride derivatives was developed via palladium-catalyzed multistep tandem carbonylation/N-dealkylation/carbonylation reaction with alkyl as the leaving group and tertiary anilines as nitrogen nucleophiles. This approach features good functional group compatibility and readily available starting materials. Furthermore, it provided a convenient approach for the synthesis of biologically and medicinally useful evodiamine.

Full text of DOI:10.1021/acs.joc.9b02771

Subscriber access provided by BIU Pharmacie | Faculté de Pharmacie, Université Paris V
Note
Palladium-Catalyzed Multi-step Tandem Carbonylation/N-
dealkylation/Carbonylation Reaction: Access to Isatoic Anhydrides
Shoucai Wang, Xuan Li, Jiawang Zang, Meichen Liu, Siyu Zhang, Guangbin Jiang, and Fanghua Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02771 • Publication Date (Web): 30 Dec 2019
Downloaded from pubs.acs.org on December 31, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Palladium-Catalyzed Multi-step Tandem
Carbonylation/N-dealkylation/Carbonylation
Reaction: Access to Isatoic Anhydrides
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
Shoucai Wang, Xuan Li, Jiawang Zang, Meichen Liu, Siyu Zhang,
Guangbin Jiang,* Fanghua Ji*
Guangxi Key Laboratory of Electrochemical and Magnetochemical Function Materials, College of
Chemistry and Bioengineering, Guilin University of Technology, 12 Jiangan Road, Guilin
541004, China.
E-mail: fanghuaji@glut.edu.cn
R2
R2
N
O
O
N
CO
[Pd],
/O2
....
R1
CH3
...
R1
N
O
[O], solvent, T o
C
....
H
...
O
N
N
H
Multi-step tandem reaction system for isatoic anhydrides
Novel and efficient strategy for the synthesis of Evodiamine
Readily available substrates and good functional tolerance
Evodiamine
, 70%
Abstract: A novel and efficient synthesis of isatoic anhydride derivatives was
developed via palladium-catalyzed multi-step tandem
carbonylation/N-dealkylation/carbonylation reaction with alkyl as leaving group and
tertiary anilines as nitrogen nucleophiles. This approach features good functional
group compatibility and readily available starting materials. Furthermore, it provided
a convenient approach for the synthesis of biologically and medicinally useful
Evodiamine.
Carbonylation, the incorporation of CO into an organic molecule, is now widely
recognized as an attractive strategy in organic synthesis, which meets the
requirements of “atom economy” and “green chemistry”.1 In recent decades, much
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 30
1
2
3
4
5
6
7
8
9
progress has been made in C-H carbonylation.2 In this area, palladium-catalyzed
oxidation carbonylation reactions using CO as simplest C-1 unit have proven to be
one of the most important methods for the synthesis of many carbonyl-containing
compounds. On the other hand, C-N bond activation has attracted more attention and
become a hot research topic in organic synthesis, in which most efforts were focused
on the amination transformation.3 Tertiary anilines are valuable commodity chemicals
and useful core structures for agrochemicals, pharmaceutical ingredients, and
functional materials.4 As a typical example, tertiary anilines have also been utilized in
C-N bond cleavage transformations.5 However, most C-N bond activation of tertiary
anilines has focused on the cross-coupling of the Csp2-N bond with organometallic
reagents.6 Therefore, the development of a simple, efficient, and atom-economical
methods to access diverse functionalized tertiary anilines remains highly desirable.
Isatoic anhydride is an important scaffold found in many natural products and
valuable pharmaceuticals with various biological activities.7 Consequently,
considerable efforts have been made to develop efficient methods for the synthesis of
isatoic anhydride derivatives. However, present methods for the synthesis of isatoic
anhydrides involve cyclization of anthranilic acid by highly toxic chloroformate or
triphosgene.8 Based on our continuous interest in trasition-metal-catalyzed oxidative
carbonylation and C-N bond activition,9 we designed a reasonable approach to
synthesize isatoic anhydrides utilizing palladium-catalyzed multi-step tandem
carbonylation/N-dealkylation/carbonylation reaction with alkyl as leaving group and
tertiary anilines as nitrogen nucleophiles (Scheme 1).
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
ACS Paragon Plus Environment

Page 3 of 30
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 1. Strategies towards Syntheses of Isatoic Anhydrides.
6
7
8
9
R2
N
R2
N
R2
N
O
R3
CO
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
R1
R1
R3
OH
R1
CO
O
H
O
O
We began our investigation by utilizing N, N-dimethylaniline(1a) as a model
substrate in the presence of 1 atm CO/O2, using PdCl2 as catalyst and Cu(OAc)2 as
oxidant in a mixed solvent of toluene and DMF (10:1) at 100 oC, which afforded 2a in
only 27% (Table 1, entry 1). Gratifyingly, the experiment results showed that the
yield increased obviously when PdCl2(CH3CN)2 was used as a catalyst (Table 1, entry
4). Furthermore, O2 was vital to the reaction, the corresponding yield was decreased
to 17% without the use of O2 (Table 1, entry 7). By switching different oxidants, we
found that other common oxidants such as CuO, BQ, K2S2O8, Ag2CO3 and CuCl2
turned out to be unfavorable in the system (Table 1, entries 8-12). No product was
detected without the addition of Cu(OAc)2 (Table 1, entry 13). It is worth noting that
other solvents including toluene, DMF, DMSO, CH3CN and dioxane are less effective
in the system (Table 1, entries 14-18). Furthermore, the ratio variation of the mixed
solvent also led to lower yields (Table 1, entries 19 and 20). Decreasing and
increasing the reaction temperature slowed the reaction, affording 45% and 55%
yields of 2a (Table 1, entries 21 and 22).
Table 1. Optimization of the Reaction Conditions a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 30
1
2
3
4
5
6
7
8
Me
N
Me
N
O
PdCl2(CH3CN)2 (10 mol%)
Me
O
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
o
CO
/O2 (1:1), 100 C
O
2a
1a
9
entry
1
[Pd]
oxidant
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuO
solvent
yieldb (%)
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
PdCl2
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe
27
0
2
Pd(OAc)2
3
PdCl2(PPh3)2
49
80
Trace
Trace
17
0
4
PdCl2(CH3CN)2
PdBr2
5
6
7c
PdI2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
8
9
BQ
0
10
11
12
13
14
15
16
17
18
19
20
21d
22e
23f
K2S2O8
0
Ag2CO3
CuCl2
0
Trace
0
----
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
0
DMF
10
0
DMSO
CH3CN
0
dioxane
0
PhMe/DMF (5:1)
PhMe/DMF (1:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
PhMe/DMF (10:1)
37
21
45
55
12
aReaction conditions: unless otherwise noted, all reactions were performed with 1a (0.2 mmol),
o
b
c
[Pd] (10 mol %), oxidant (1 equiv), CO/O2 (1:1) 1 atm, 100 C, 24 h. Isolated yield. Reactions
were carried out without O2. dThe reaction temperature is 90 oC. eThe reaction temperature is 110
oC. fThe loading of Cu(OAc)2 is 10 mol %.
With the optimized conditions in hand, the carbonylation of a variety of N,
N-dialkylanilines were tested (Table 2). N, N-dimethylanilines substituted with
electron-donating (methyl, methoxy and tert-butyl) groups in different positions all
ACS Paragon Plus Environment

Page 5 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
gave the corresponding substituted isatoic anhydrides in good yields (2b-2g). N,
N-dimethylanilines bearing halogens and electron-withdrawing substituents reacted
satisfactorily to give the corresponding products in moderate yields (2h-2o).
Interestingly, when N-ethyl-N-methylaniline was used as substrate, two types of
products 2p and 2a were obtained in 46% and 21% yields respectively, indicating that
the less sterically hindered alkyl group is much more facile for cleavage.10 The isatoic
anhydride 2q from the carbonylation of N, N-dimethylnaphthalen-2-amine 1q was
observed as the only product in 66% yield. Moreover, the carbonylation of
1-methyl-1,2,3,4-tetrahydroquinoline 1r and 1,6-dimethyl-1,2,3,4-tetrahydroquinoline
1s proceeded smoothly to give the tricyclic isatoic anhydrides 2r and 2s in 68% and
74% yields respectively. To our surprise, N, N-dimethylnaphthalen-1-amine afforded
the corresponding isatoic anhydride 2t in 45% yield, in which
1-methylbenzo[cd]indol-2(1H)-one 3t was detected as a byproduct.11
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
2.
Palladium-Catalyzed
Multi-step
Tandem
Carbonylation/N-dealkylation/Carbonylation Reaction of N, N-dimethyl
Anilinesa
R2
R2
N
O
PdCl2(CH3CN)2 (10 mol%)
N
R1
Me
R1
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
O
/O2 (1:1), 100 oC
CO
O
2
1
Me
Me
Me Me
N
Me
N
N
O
N
O
O
Me
O
O
O
O
O
Me
O
, 80%
O
, 82%
O
O
2b
2a
2d
, 79%
2c
, 80%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 30
1
2
3
4
5
Me
N
OMe Me
Me
F
Me
N
O
N
O
O
N
O
6
7
8
9
O
O
O
O
MeO
t-Bu
O
, 75%
O
2f
O
O
2e
, 70%
2h
, 57%
2g
, 75%
Me
Me
N
Me
N
Me
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
N
O
O
O
F3C
N
O
O
O
X
O
O
O
NC
F3C
O
O
O
2i
2j
2k
, X = F, 55%
, X = Cl, 71%
, X = Br, 69%
2l
2m
, 62%
, 60%
2n
, 70%
Me
N
N
O
Et/Me
Me
O
N
O
N
O
O
O
R3
O
O
O
O
MeO2C
Me
O
3
O
2r
, R = H, 68%
3
2q
, 66%
2p/2a
2s
2o
67%(2.2:1)
, R = Me, 74%
, 68%
Me
N
O
Me
Me
N
O
N
PdCl2(CH3CN)2 (10 mol%)
+
O
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
/O2 (1:1), 100 oC
O
, 45%
CO
3t
1t
, 18%
2t
Gram Scale Reaction
Me
N
O
PdCl2(CH3CN)2 (10 mol%)
N
O
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
/O2 (1:1), 100 oC
CO
O
2a
1a
, 4 mmol, 45%
, 9 mmol
aReaction conditions: 1 (0.2 mmol), PdCl2(CH3CN)2 (10 mol %), Cu(OAc)2 (0.2 mmol),
PhMe/DMF (10: 1) (2.5 mL), CO/O2 (1:1) 1 atm, 100 oC, 24 h. Yields referred to isolated yields.
Furthermore, this protocol could also be applied to N, N-dialkylanilines with
different N-alkyl substituents (Scheme 2). When N, N-diethylaniline and N,
N-diisopropylaniline were employed as a substrates, the reaction also took place
smoothly to furnish the desired isatoic anhydrides 2p and 2u in 55% and 37% yields
(Scheme 2, Eq. 1 and Eq. 2). The reaction of N, N-dibenzylaniline afforded the
desired product 2v in 41% yield as well as 38% yield of benzaldehyde, which
indicated that the benzyl group was converted into benzaldehyde by C-N bond
cleavage in our reaction system (Scheme 2, Eq. 3).12
ACS Paragon Plus Environment

Page 7 of 30
The Journal of Organic Chemistry
1
2
3
4
5
Scheme
2.
Palladium-Catalyzed
Multi-step
Tandem
6
7
Carbonylation/N-dealkylation/Carbonylation Reaction of N, N-dialkyl Anilinesa
8
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
N
O
PdCl2(CH3CN)2 (10 mol%)
N
N
O
(1)
(2)
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
/O2 (1:1), 100 oC
CO
O
2p
, 55%
N
O
O
O
PdCl2(CH3CN)2 (10 mol%)
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
/O2 (1:1), 100 oC
CO
2u
, 37%
Ph
Ph
O
CHO
N
Ph
N
O
O
PdCl2(CH3CN)2 (10 mol%)
(3)
+
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
/O2 (1:1), 100 oC
CO
2v
, 41%
38%
aReaction conditions: N, N-dialkylanilines (0.2 mmol), PdCl2(CH3CN)2 (10 mol %), Cu(OAc)2
o
(0.2 mmol), toluene/DMF (10: 1) (2.5 mL), CO/O2 (1:1) 1 atm, 100 C, 24 h. Yields referred to
isolated yields.
Scheme 3. Subsequent Decarboxylative Transformations
H
N
HCl (15%), 100 oC
A
B
(
(
)
)
OH
99%
O
Me
N
H
N
O
K2CO3, EtOH
100 oC, 89%
OEt
NH2
O
O
2a
O
H
N
NH3 H2O, CH3CN
rt, 97%
C
(
)
O
To demonstrate the utility of this protocol, isatoic anhydride 2a was easily
transformed into N-methylanthranilic acid A, ethyl 2-(methylamino)benzoate B
and 2-(methylamino)benzamide C (Scheme 3). Through our protocol, we could
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 30
1
2
3
4
5
6
7
achieve these products in high yields starting from isatoic anhydride 2a via a
series of decarboxylative transformations.
8
9
In order to highlight the synthetic application of the carbonylation product
isatoic anhydrides, we successfully converted our product 2a to the clinically
useful Evodiamine with 70% overall yield (Scheme 4).13 Compared with
previously reported procedures for the synthesis of Evodiamine, our synthetic
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
protocol is much more facile and convenient.14
O
N
O
NH
N
TsOH (30 mol%)
HC(OEt)3 (1.5 equiv.)
PhMe, 120 oC
H
NH2
O
HN
N
N
N
H
O
2a
CH3CN, rt
O
NH
4a
Evodiamine
, 70%
, 95%
Scheme 4. Synthesis of Evodiamine
To gain some preliminary understanding of the reaction mechanism, control
experiments were carried out. Firstly, no desired product was detected by utilizing
N-methylaniline as the substrate under the standard conditions, which indicated
that this transformation is different from Guan’s research for the synthesis of
isotoic anhydrides starting from N-methylaniline (Scheme 5, Eq. 1).15 Furthermore,
when 1a was used to react with MeOH (5 eq.) using 1.2 eq. of PdCl2(CH3CN),
corresponding oxidative C-H alkyloxycarbonylation product 5a was detected,
indicating that the N, N-dimethylamino group could be directly used as the
directing group (Scheme 5, Eq. 2). Under the standard conditions,
2-(dimethylamino)benzoic acid 6a underwent carbonylation reaction smoothly to
afford 2a in 75% yield, indicating that 6a was the intermediate in the catalytic
system (Scheme 5, Eq. 3). Additionally, no product was detected starting from 6a
ACS Paragon Plus Environment

Page 9 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
without the use of CO, which implied that the carbonyl source is not from the
methyl group of DMF (Scheme 5, Eq. 4). To our delight, no reaction occured
starting from 1-methylindoline-2,3-dione 7a, a possible precursor of 2a, indicating
that 7a was not the intermediate in this catalytic system (Scheme 5, Eq. 5).
Scheme 5. Preliminary Mechanistic Studies
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
N
O
NH
PdCl2(CH3CN)2 (10 mol%)
O
(1)
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
o
O
CO
/O2 (1:1), 100 C
0.2 mmol
2a
,n.d
N
PdCl2(CH3CN)2 (1.2 equiv.)
N
OMe
(2)
(3)
CO
PhMe/DMF (10:1),
100 oC
, MeOH (5 equiv.)
O
5a
, 45%
1a
6a
, 0.2 mmol
N
N
O
PdCl2(CH3CN)2 (10 mol%)
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
O
o
COOH
CO
/O2 (1:1), 100 C
O
2a
, 0.2 mmol
, 75%
N
O
PdCl2(CH3CN)2 (10 mol%)
N
(4)
(5)
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
O2 (1:1), 100 oC
O
COOH
O
2a
6a
, 0.2 mmol
CO
without
,n.d
N
O
PdCl2(CH3CN)2 (10 mol%)
N
O
Cu(OAc)2 (1 equiv.), PhMe/DMF (10:1)
O2 (1:1), 100 oC
O
O
O
2a
CO
without
7a
, 0.2 mmol
,n.d
Huang et al. proposed that C-N bond activation was promoted by copper and
oxygen. The above experimental results induced us to propose a mechanism for this
novel
palladium-catalyzed
multi-step
tandem
carbonylation/N-dealkylation/carbonylation reaction (Scheme 6).15-16 Taking N,
N-dimethylaniline 1a as an example, the electrophilic palladation of 1a afforded the
intermediate II, followed by CO insertion and reductive elimination produced
intermediate 6a. Then, 6a underwent C-N bond cleavage in the presence of copper
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 30
1
2
3
4
5
6
7
8
9
salts and O2, giving the intermediate IV, which further underwent transmetalation
with palladium catalyst and sencondary CO insertion to form the intermediate VI. The
subsequent nucleophilic reaction and reductive elimination afforded the annulation
product 2a and released Pd(0) species, which was oxidized by copper salts and
oxygen to regenerate Pd(II).
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
Scheme 6. Proposed mechanism
N
Pd OH
CO
II
1a
+ CO
Ac2O
N
Pd(OAc)2
Pd OH
I
O
III
Cu(OAc)2, O2
Pd(0)
N
O
N
O
Cu
CuII, O2
6a
OH
OH
IV
Pd(OAc)2
Cu(OAc)2, O2
Pd(0)
N
O
PdOAc
OH
2a
V
O
N
Pd
O
O
N
CO
COPdOAc
OH
VII
VI
O
In conclusion, we have developed a novel palladium-catalyzed multi-step tandem
carbonylation/N-dealkylation/carbonylation reaction of tertiary aniline to form isotoic
anhydrides. Moderate to good yields were obtained and a variety of functional groups
were tolerated. This transformation provides an effective and straightforward method
ACS Paragon Plus Environment

Page 11 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
towards the synthesis of biologically and medicinally useful Evodiamine from
commercial and simple substrate N, N-dimethylaniline. Preliminary mechanism
studies revealed that the N, N-dimethylamino group could be directly used as the
directing group. A detailed mechanistic investigation and further application in
C-N bond cleavage transformations are currently underway in our laboratory.
EXPERIMENTAL SECTION
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
General Information. All purchased reagents and solvents were used without further
purification unless otherwise noted. Melting points were measured with a melting
point instrument and were uncorrected. 1H and 13C NMR spectra were recorded using
a Bruker DRX-400 or Bruker DRX-600 spectrometer using CDCl3 or DMSO-d6 as
solvent. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm,
respectively. TLC was performed by using commercially prepared 100-400 mesh
silica gel plates and visualization was effected at 254 nm.
General Procedure for the Synthesis of N-methyl isatoic anhydrides.15 The
mixture of 1 (0.2 mmol, 1.0 equiv), Cu(OAc)2 (0.2 mmol ， 1.0 equiv) and
PdCl2(CH3CN)2 (0.02 mmol, 0.1 equiv) was stirred in PhMe/DMF(10:1) (2.5
o
mL/mmol) in an oil bath at 100 C, in a 20 mL tube with a balloon CO/O2 (1:1).
When the reaction was completed (detected by TLC), the mixture was cooled to room
temperature. The reaction was quenched with H2O (10 mL) and extracted with EtOAc
(3×10 mL) or CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
anhydrous Na2SO4 and then evaporated in vacuo. The residue was purified by column
chromatography on silica gel to afford the corresponding isatoic anhydrides 2 with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 30
1
2
3
4
5
6
7
CH2Cl2 /ethyl acetate as the eluent (the synthesis of other compound 2 was previously
reported).15
8
9
Experimental
Procedure
for
Evodiamine.
(a)
(2a)
The
(1.0
mixture
mmol)
of
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
1-Methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
and
2-(1H-indol-3-yl)ethan-1-amine (1.0 mmol) were stirred in CH3CN in an oil bath at
room temperature for 8 h. The desired products 4a were obtained in 95% yield; (b)
The mixture of 4a (1.0 mmol), TsOH (0.3 mmlol) and triethoxy methane (1.5 mmol)
o
were stirred and refluxed in toluene in an oil bath at 120 C. The desired products
Evodiamine were obtained in 74% yield after purified by column chromatography on
silica gel with mixture of petroleum ether and ethyl acetate.
Experimental Procedure for Gram Scale Reaction
The mixture of 1a (1089.0 mg, 9.0 mmol, 1.0 equiv), Cu(OAc)2 (1620.0 mg, 9.0
mmol， 1.0 equiv) and PdCl2(CH3CN)2 (232.2 mg, 0.9 mmol, 0.1 equiv) was stirred
o
in PhMe/DMF(10:1) (25 mL/mmol) in an oil bath at 100 C, in a 100 mL
round-bottom flask with a balloon CO/O2 (1:1). When the reaction was completed
(detected by TLC), the mixture was cooled to room temperature. The reaction was
quenched with H2O (50 mL) and extracted with EtOAc (3×50 mL) or CH2Cl2 (3 × 50
mL). The combined organic layers were dried over anhydrous Na2SO4 and then
evaporated in vacuo. The residue was purified by column chromatography on silica
gel to afford the corresponding isatoic anhydrides 2a (716.6 mg, 45%) with CH2Cl2
/ethyl acetate as the eluent.
1-Methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2a)
ACS Paragon Plus Environment

Page 13 of 30
The Journal of Organic Chemistry
1
2
3
4
5
1
Yield 28.3 mg (80%, white solid); mp 176-178 °C. H NMR (400 MHz, CDCl3) δ
6
7
7.97 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.62 (t, J =
8
9
13
7.4 Hz, 1H), 2.93 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 174.0, 152.7, 135.7,
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
132.6, 114.6, 110.9, 108.6, 29.6. HRMS Calcd (ESI-TOF) m/z for C9H7NNaO3
[M+Na]+, 200.0318; Found 200.0326.
1,6-Dimethyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2b)
1
Yield 31.3 mg (82%, white solid); mp 166-169 °C. H NMR (400 MHz, CDCl3) δ
7.92 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H), 2.42 (s,
13
3H); C{1H} NMR (100 MHz, CDCl3) δ 158.6, 148.0, 139.9, 138.4, 134.2, 130.3,
113.9, 111.4, 31.8, 20.4. HRMS Calcd (ESI-TOF) m/z for C10H9NNaO3 [M+Na]+,
214.0475; Found 214.0482.
1,7-Dimethyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2c)
1
Yield 30.6 mg (80%, brown solid); mp 162-164 °C. H NMR (600 MHz, CDCl3) δ
7.89 (d, J = 8.1 Hz, 1H), 6.51 (s, 1H), 6.48 (d, J = 8.1 Hz, 1H), 2.95 (s, 3H), 2.37 (s,
13
3H); C{1H} NMR (150 MHz, CDCl3) δ 174.1, 174.1, 152.7, 146.7, 132.6, 116.1,
111.1, 106.3, 29.6, 22.3. HRMS Calcd (ESI-TOF) m/z for C10H9NNaO3 [M+Na]+,
214.0475; Found 214.0480.
1,8-Dimethyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2d)
Yield 30.2 mg (79%, brown solid); mp 187-188 °C. 1H NMR (400 MHz, DMSO-d6) δ
7.84 (dd, J = 7.7, 1.7 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 3.56
(s, 3H), 2.57 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.0, 149.6, 143.0,
141.4, 127.8, 126.7, 124.6, 114.5, 38.5, 22.2. HRMS Calcd (ESI-TOF) m/z for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 30
1
2
3
4
5
C10H9NNaO3 [M+Na]+, 214.0475; Found 214.0480.
6
7
6-Methoxy-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2e)
8
9
Yield 31.1 mg (75%, brown solid); mp 238-239 °C. 1H NMR (400 MHz, DMSO-d6) δ
7.43 (m, 3H), 3.84 (s, 3H), 3.45 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
159.4, 155.7, 148.1, 136.8, 125.5, 117.1, 112.7, 111.3, 56.3, 32.2. HRMS Calcd
(ESI-TOF) m/z for C10H10NO4 [M+H]+, 208.0604; Found 208.0606.
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
8-Methoxy-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2f)
Yield 28.9 mg (70%, white solid); mp 162-164 °C. 1H NMR (400 MHz, DMSO-d6) δ
7.59 (dd, J = 7.8, 1.4 Hz, 1H), 7.53 (dd, J = 8.2, 1.5 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H),
3.89 (s, 3H), 3.63 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.6, 149.1, 148.6,
132.9, 125.3, 121.5, 121.4, 114.7, 57.5, 37.4. HRMS Calcd (ESI-TOF) m/z for
C10H10NO4 [M+H]+, 208.0604; Found 208.0606.
6-(tert-Butyl)-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2g)
1
Yield 34.9 mg (75%, white solid); mp 165-166 °C. H NMR (400 MHz, CDCl3) δ
8.14 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 3.58 (s, 3H), 1.36 (s,
13
9H); C{1H} NMR (100 MHz, CDCl3) δ 158.9, 148.1, 147.6, 139.8, 135.0, 127.0,
113.7, 111.2, 34.6, 31.8, 31.1. HRMS Calcd (ESI-TOF) m/z for C13H16NO3 [M+H]+,
234.1125; Found 234.1127.
8-Fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2h)
1
Yield 22. mg (57%, white solid); mp 205-206 °C. H NMR (600 MHz, DMSO-d6) δ
7.49 (dd, J = 9.8, 3.2 Hz, 1H), 7.29 (ddd, J = 9.2, 8.0, 3.2 Hz, 1H), 6.68 (dd, J = 9.2,
4.5 Hz, 1H), 2.82 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 169.6, 152.5 (d, J =
ACS Paragon Plus Environment

Page 15 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
228.0 Hz), 149.2, 130.1, 122.3 (d, J = 22.5 Hz), 112.6 (d, J = 6.0 Hz), 116.9 (d, J =
22.5 Hz), 110.6, 30.0. HRMS Calcd (ESI-TOF) m/z for C9H6FNO3Na [M+Na]+,
218.0224; Found 218.0226.
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
6-Fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2i)
Yield 21.5 mg (55%, yellow solid); mp 137-138 °C. 1H NMR (400 MHz, DMSO-d6)
δ 7.74 (t, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.7, 4.0 Hz, 1H), 3.47 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 158.6 (d, J = 3.0 Hz), 158.1 (d, J = 158.0 Hz), 147.9, 139.4
(d, J = 1.0 Hz), 125.0 (d, J = 23.0 Hz), 117.8 (d, J = 8.0 Hz), 115.0 (d, J = 25.0 Hz),
113.3 (d, J = 9.0 Hz), 32.4. HRMS Calcd (ESI-TOF) m/z for C9H6FNO3Na [M+Na]+,
218.0224; Found 218.0225.
6-Chloro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2j)
Yield 29.9 mg (71%, white solid); mp 118-119 °C. 1H NMR (500 MHz, DMSO-d6) δ
7.94 (d, J = 2.5 Hz, 1H), 7.89 (dd, J = 9.0, 2.6 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 3.46
(s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 158.5, 147.9, 141.6, 137.1, 128.4,
128.1, 117.6, 113.7, 32.4. HRMS Calcd (ESI-TOF) m/z for C9H6ClNNaO3 [M+Na]+,
233.9928, Found: 233.9936.
6-Bromo-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2k)
Yield 35.1 mg (69%, white solid); mp 202-203 °C. 1H NMR (500 MHz, DMSO-d6) δ
8.05 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 8.9, 2.4 Hz, 1H), 7.41 (d, J = 8.9 Hz, 1H), 3.45
(s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 158.4, 147.9, 141.9, 139.9, 131.3,
117.8, 115.6, 114.1, 32.4. HRMS Calcd (ESI-TOF) m/z for C9H6BrNNaO3 [M+Na]+,
277.9423; Found 277.9424.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 30
1
2
3
4
5
1-Methyl-6-(trifluoromethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2l)
6
7
Yield 29.4 mg (60%, brown solid); mp 188-189 °C. 1H NMR (400 MHz, DMSO-d6) δ
8
9
13
8.43-8.05 (m, 2H), 7.65 (d, J = 8.8 Hz, 1H), 3.52 (s, 3H); C{1H} NMR (100 MHz,
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
DMSO-d6) δ 158.6, 147.9, 145.5, 133.7 (q, J = 3.0 Hz), 126.6 (q, J = 4.0 Hz), 124.3
(q, J = 33.0 Hz), 124.0 (d, J = 270.0 Hz), 116.7, 112.8, 32.5. HRMS Calcd (ESI-TOF)
m/z for C10H7F3NO3 [M+H]+, 246.0373; Found 246.0373.
1-Methyl-7-(trifluoromethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2m)
Yield 30.4 mg (62%, white solid); mp 136-137 °C. 1H NMR (400 MHz, DMSO-d6) δ
8.20 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 3.53 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 158.7, 147.9, 143.3, 136.5 (q, J = 32.0 Hz), 131.1,
123.7 (q, J = 272.0 Hz), 120.1 (q, J = 3.0 Hz), 115.6, 112.5 (q, J = 4.0 Hz), 32.5.
HRMS Calcd (ESI-TOF) m/z for C10H7F3NO3 [M+H]+, 246.0373; Found 246.0373.
1-Methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile (2n)
Yield 28.3 mg (70%, white solid); mp 235-236 °C. 1H NMR (400 MHz, DMSO-d6) δ
8.43 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 3.50 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 158.1, 147.8, 145.7, 140.2, 134.2, 118.0, 116.7, 113.2,
106.4, 32.6. HRMS Calcd (ESI-TOF) m/z for C10H7N2O3 [M+H]+, 203.0451; Found
203.0453.
Methyl 1-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylate
(2o)
Yield 31.9 mg (68%, yellow solid); mp 163-164 °C. 1H NMR (400 MHz, DMSO-d6)
δ δ 8.40 (d, J = 1.8 Hz, 1H), 8.28 (dd, J = 8.7, 2.2 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H),
ACS Paragon Plus Environment

Page 17 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3.89 (s, 3H), 3.50 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.1, 158.8, 147.9,
145.9, 137.4, 130.7, 124.9, 116.0, 115.9, 112.3, 52.9, 32.5. HRMS Calcd (ESI-TOF)
m/z for C11H10NO5 [M+H]+, 236.0553; Found 236.0557.
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
1-Ethyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2p)
Yield 17.6 mg (46%, white solid); mp 123-125 °C. 1H NMR (400 MHz, DMSO-d6) δ
7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.77 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.42 (d, J = 8.5 Hz,
1H), 7.25 (t, J = 7.5 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 159.5, 147.8, 141.6, 137.7, 130.1, 124.0,
115.1, 112.3, 40.00, 12.4. HRMS Calcd (ESI-TOF) m/z for C10H9NO3Na [M+Na]+,
214.0475; Found 214.0478.
1-Methyl-2H-naphtho[2,3-d][1,3]oxazine-2,4(1H)-dione (2q)
Yield 29.9 mg (66%, brown solid); mp 222-224 °C. 1H NMR (400 MHz, DMSO-d6) δ
8.74 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.70 (t, J
= 7.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 3.54 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 159.5, 148.0, 137.6, 137.4, 132.4, 130.8, 129.9, 128.9, 127.9, 126.4,
112.3, 111.3, 32.4. HRMS Calcd (ESI-TOF) m/z for C13H10NO3 [M+H]+, 228.0655;
Found 228.0658.
6,7-Dihydro-1H,3H,5H-[1,3]oxazino[5,4,3-ij]quinoline-1,3-dione (2r)
Yield 27.6 mg (68%, white solid); mp 184-186 °C. 1H NMR (400 MHz, DMSO-d6) δ
7.82 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 7.4, 1.4 Hz, 1H), 7.22 (td, J = 7.7, 1.5 Hz, 1H),
3.88 (td, J = 5.6, 1.4 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.18-1.82 (hept, J = 4.3 Hz,
2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.6, 147.6, 139.0, 137.0, 127.7, 125.9,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 30
1
2
3
4
5
6
123.6, 111.5, 44.2, 26.3, 20.1. HRMS Calcd (ESI-TOF) m/z for C11H10NO3 [M+H]+,
204.0655; Found 204.0658.
7
8
9
9-Methyl-6,7-dihydro-1H,3H,5H-[1,3]oxazino[5,4,3-ij]quinoline-1,3-dione (2s)
Yield 32.1 mg (74%, white solid); mp 220-221 °C. 1H NMR (400 MHz, DMSO-d6) δ
7.62 (s, 1H), 7.45 (s, 1H), 4.07-3.60 (m, 2H), 2.81 (t, J = 6.2 Hz, 2H), 2.31 (s, 3H),
1.97 (p, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.6, 147.6, 137.9,
136.9, 133.0, 127.2, 125.9, 111.2, 44.1, 26.2, 20.4, 20.2. HRMS Calcd (ESI-TOF) m/z
for C12H12NO3 [M+H]+, 218.0812; Found 218.0820.
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
1-Methyl-2H-naphtho[1,2-d][1,3]oxazine-2,4(1H)-dione (2t)
1
Yield 20.4 mg (45%, brown solid); mp 69-70 °C. H NMR (400 MHz, DMSO-d6) δ
8.45 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.85 (q, J = 8.5 Hz, 2H), 7.77 (t, J =
7.0 Hz, 1H), 7.67 (t, J = 7.1 Hz, 1H), 3.77 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 159.9, 150.2, 143.9, 138.6, 130.2, 129.4, 127.0, 126.6, 125.5, 123.0,
122.9, 110.4, 41.5. HRMS Calcd (ESI-TOF) m/z for C13H10NO3 [M+H]+, 228.0655;
Found 228.0659.
1-Methylbenzo[cd]indol-2(1H)-one (3t)
1
Yield 13.1 mg (18%, white solid); mp 77-79 °C. H NMR (600 MHz, CDCl3) δ 8.02
(d, J = 7.0 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.67 (dd, J = 8.1, 6.9 Hz, 1H), 7.50 (d, J
= 8.4 Hz, 1H), 7.44 (dd, J = 8.4, 7.0 Hz, 1H), 6.86 (d, J = 6.9 Hz, 1H), 3.42 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 168.30, 140.17, 130.78, 129.07, 128.72, 128.57,
126.87, 125.20, 124.28, 120.39, 104.75, 26.40. HRMS Calcd (ESI-TOF) m/z for
C12H10NO [M+H]+, 184.0757; Found 184.0759.
ACS Paragon Plus Environment

Page 19 of 30
The Journal of Organic Chemistry
1
2
3
4
5
1-Isopropyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2u)
6
7
1
Yield 15.2 mg (37%, white solid); mp 115-116 °C. H NMR (600 MHz, CDCl3) δ
8
9
8.12 (dd, J = 7.8, 1.7 Hz, 1H), 7.73 (ddd, J = 8.8, 7.3, 1.7 Hz, 1H), 7.32 (d, J = 8.6 Hz,
1H), 7.29 – 7.21 (m, 1H), 4.77 (d, J = 8.3 Hz, 1H), 1.59 (d, J = 6.9 Hz, 6H); 13C{1H}
NMR (150 MHz, CDCl3) δ 159.06, 146.34, 141.87, 137.09, 131.10, 123.84, 114.32,
112.39, 50.09, 19.34. HRMS Calcd (ESI-TOF) m/z for C11H11NO3Na [M+Na]+,
228.0631; Found 228.0637.
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
1-Benzyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (2v)
Yield 20.7 mg (41%, white solid); mp 136-138 °C. 1H NMR (400 MHz, DMSO-d6) δ
8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.83-7.61 (m, 1H), 7.43 (d, J = 7.4 Hz, 2H), 7.39-7.21
13
(m, 5H), 5.30 (s, 2H); C{1H} NMR (100 MHz, DMSO-d6) δ 159.3, 148.8, 141.8,
137.5, 135.8, 130.0, 129.1, 127.9, 127.1, 124.2, 115.6, 112.5, 48.1. HRMS Calcd
(ESI-TOF) m/z for C15H12NO3 [M+H]+, 254.0812; Found 254.0819.
2-(Methylamino)benzoic acid (A)
1
Yield 29.9 mg (99%, brown solid); mp 170-172 °C. H NMR (400 MHz, CDCl3) δ
7.77 (s, 1H), 7.39-7.33 (m, 2H), 6.69 (d, J = 8.0 Hz, 1H), 6.60-6.56 (m, 1H), 2.87 (s,
13
3H); C{1H} NMR (100 MHz, CDCl3) δ 172.2, 151.2, 133.6, 128.2, 114.4, 113.0,
111.4, 29.7.
Ethyl 2-(methylamino)benzoate (B)
1
Yield 31.8 mg (89%, white solid); mp 38-39 °C. H NMR (400 MHz, CDCl3) δ 7.83
(d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.54- 6.45 (m, 2H), 4.20 (q, J = 7.0 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 30
1
2
3
4
5
6
2H), 1.26 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168. 7, 151.9,
134.5, 131.5, 114.4, 110.8, 110.4, 60.2, 14.4.
7
8
9
2-(Methylamino)benzamide (C)
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
1
Yield 29.1 mg (97%, white solid); mp 161-162 °C. H NMR (400 MHz, CDCl3) δ
8.00 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 6.71, 6.69-6.62 (m, 2H), 2.94 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 173.9, 152.5, 135.7, 132.6, 114.7, 111.1, 108.8,
29.7.
N-(2-(1H-indol-3-yl)ethyl)-2-(methylamino)benzamide (4a)
1
Yield 55.7 mg (95%, yellow solid); mp 207-209 °C. H NMR (400 MHz, CDCl3) δ
8.19 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.8 Hz,
1H), 7.18 (t, J = 7.4 Hz, 1H), 7.12-7.08 (m, 2H), 6.95 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H),
6.48 (t, J = 7.6 Hz, 1H), 6.13 (s, 1H), 3.70 (q, J = 6.4 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H),
2.81 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 169.9, 150.5, 136.5, 132.8, 127.3,
13
127.2, 122.2, 122.2, 119.5, 118.8, 115.5, 114.6, 113.0, 111.4, 111.2,40.0, 30.0, 254.
HRMS Calcd (ESI-TOF) m/z for C18H20N3O [M+H]+, 294.1601; Found 294.1600.
Evodiamine
Yield 42.2 mg (70%, yellow solid); mp 277-278 °C. 1H NMR (400 MHz, DMSO-d6)
δ 11.05 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.48-7.47 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H ),
7.13-6.95 (m, 4H), 6.12 (s, 1H), 4.66- 4.62 (m, 1H), 3.23-3.17 (m, 1H), 2.94-2.78 (m,
5H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 164.7, 149.3, 137.0, 133.9, 131.1, 128.5,
126.5, 122.3, 120.8, 119.8, 119.4, 118.7, 118.0, 112.1, 112.0, 70.2, 41.3, 36.9, 20.0.
HRMS Calcd (ESI-TOF) m/z for C19H18N3O [M+H]+, 304.1444; Found 304.1444.
ACS Paragon Plus Environment

Page 21 of 30
The Journal of Organic Chemistry
1
2
3
4
5
Supporting Information
6
7
8
9
1H and 13C NMR spectra of all synthesized compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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
Acknowledgements
This work was financially supported by Guangxi Natural Science Fundation
(2017GXNSFBA198224, 2018GXNSFAA281203 and 2018GXNSFBA050024),
Guangxi Science and Technology Base and Special Fund for Talents (AD19110110)
and Key Laboratory of Electrochemical and Magnetochemical Function Materials.
References
1. (a) Gabriele, B.; Mancuso, R.; Salerno, G. Oxidative Carbonylation as a Powerful
Tool for the Direct Synthesis of Carbonylated Heterocycles. Eur. J. Org. Chem.
2012, 6825-6839. (b) Wu, X.-F.; Neumann, H.; Beller, M. Palladium-Catalyzed
Oxidative Carbonylation Reactions. ChemsSucChem. 2013, 6, 229-241. (c) Gadge,
S. T.; Bhanage, B. M. Recent Developments in Palladium Catalysed
Carbonylation Reactions. RSC Adv. 2014, 4, 10367-10389. (d) Wu, L.; Fang, X.;
Liu, Q.; Jackstell, R.; Beller, M.; Wu, X.-F. Palladium-Catalyzed Carbonylative
Transformation of C(sp3)−X Bonds. ACS Catal. 2014, 4, 2977-2989. (e) Wu, X.-F.
Palladium-Catalyzed Carbonylative Transformation of Aryl Chlorides and Aryl
Tosylates. RSC Adv. 2016, 6, 83831-83837. (f) Shen, C.; Wu, X.-F.
Palladium-Catalyzed Carbonylative Multicomponent Reactions. Chem. Eur. J.
2017, 23, 2973-2987. (g) Li, Y.; Hu, Y.; Wu, X.-F. Non-noble Metal-Catalysed
Carbonylative Transformations. Chem. Soc. Rev. 2018, 47, 172-194. (h) Peng,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 30
1
2
3
4
5
6
7
8
9
J.-B.; Geng, H.-Q.; Wu, X.-F. The Chemistry of CO: Carbonylation. Chem. 2019,
5, 526-552. (i) Mancuso, R.; Della Ca’, N.; Veltri, L.; Ziccarelli, I.; Gabriele, B.
PdI2-Based Catalysis for Carbonylation Reactions: A Personal Account. Catalysts
2019, 9, 610-610. (j) Peng, J.-B.; Wu, F.-P.; Wu, X.-F. First-Row
Transition-Metal-Catalyzed Carbonylative Transformations of Carbon
Electrophiles. Chem. Rev. 2019, 119, 2090-2127.
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
2. (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Catalytic Functionalization of Arenes and
Alkanes via C-H Bond Activation. Acc. Chem. Res. 2001, 34, 633-639. (b) Le, Z.;
Ying, J.; Wu, X.-F. More than a CO Source: Palladium-Catalyzed Carbonylative
Synthesis of Butenolides from Propargyl Alcohols and TFBen. Org. Chem. Front.
2019, 6, 3158-3161. (c) Liu, J.; Yang, J.; Baumann, W.; Jackstell, R.; Beller, M.
Stereoselective Synthesis of Highly Substituted Conjugated Dienes via
Pd-Catalyzed Carbonylation of 1,3-Diynes. Angew. Chem. Int. Ed. 2019, 58, 1-6.
(d) Tanaka, K.; Ewing, W. R.; Yu, J.-Q. Hemilabile Benzyl Ether Enables
γ-C(sp3)-H Carbonylation and Olefination of Alcohols. J. Am. Chem. Soc. 2019,
141, 15494-15497. (e) Veltri, L.; Giofrè, S. V.; Devo, P.; Romeo, R.; Dobbs, A. P.;
Gabriele,
B.
A
Palladium
Iodide-Catalyzed
Approach to
Oxidative
Aminocarbonylation-Heterocyclization
Functionalized
Benzimidazoimidazoles. J. Org. Chem. 2018, 83, 1680-1685. (f) Verbitskiy, E. V.;
Rusinov, G. L.; Chupakhin, O. N.; Charushin, V. N. Recent Advances in Direct
C-H Functionalization of Pyrimidines. Synthesis 2018, 50, 193-210. (g) Mancuso,
R.; Maner, A.; Ziccarelli, I.; Pomelli, C.; Chiappe, C.; Della Ca’, N.; Veltri, L.;
ACS Paragon Plus Environment

Page 23 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Gabriele, B. Auto-Tandem Catalysis in Ionic Liquids: Synthesis of
2-Oxazolidinones by Palladium-Catalyzed Oxidative Carbonylation of
Propargylic Amines in EmimEtSO4. Molecules 2016, 21, 897-903. (h) Veltri, L.;
Grasso, G.; Rizzi, R.; Mancuso, R.; Gabriele, B. Palladium-Catalyzed
Carbonylative Multicomponent Synthesis of Functionalized Benzimidazothiazoles.
Asian J. Org. Chem. 2016, 5, 560-567. (i) Veltri. L.; Mancuso, R.; Altomare, A.;
Gabriele, B. Divergent Multicomponent Tandem Palladium-Catalyzed
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
Aminocarbonylation-Cyclization
Approaches
to
Functionalized
Imidazothiazinones and Imidazothiazoles. ChemCatChem. 2015, 7, 2206-2213.
3. (a) Liu, Y.; Tse, C.-W.; Lam, K.-Y.; Chang, X.-Y.; Guan, X.; Chao, M.-Y.;
Huang, J.-S.; Che, C.-M. Intramolecular Nitrene Insertion into Saturated
C-H-Bond-Mediated C-N Bond Cleavage of a Coordinated NHC Ligand. Chem.
Eur. J. 2019, 25, 10828-10833. (b) Li, C.-L.; Jiang, X.; Lu, L.-Q.; Xiao, W.-J.;
Wu, X.-F. Cobalt(II)-Catalyzed Alkoxycarbonylation of Aliphatic Amines via C−
N Bond Activation. Org. Lett. 2019, 21, 6919-6923. (c) Kadam, A. A.; Metz, T. L.;
Qian, Y.; Stanley, L. M. Ni-Catalyzed Three-Component Alkene Carboacylation
Initiated by Amide C-N Bond Activation. ACS Catal. 2019, 9, 5651-5656. (d)
Wang, D.; Leng, X.; Ye, S.; Deng, L. Substrate Redox Non-innocence Inducing
Stepwise Oxidative Addition Reaction: Nitrosoarene C-N Bond Cleavage on
Low-Coordinate Cobalt(0) Species. J. Am. Chem. Soc. 2019, 141, 7731-7735. (e)
Skhiri, A.; Chatani, N. Nickel-Catalyzed Reaction of Benzamides with Bicylic
Alkenes: Cleavage of C-H and C-N Bonds. Org. Lett. 2019, 21, 1774-1778. (f)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 30
1
2
3
4
5
6
7
8
9
Jiang, X.; Zhang, M.-M.; Xiong, W.; Lu, L.-Q.; Xiao, W.-J. Deaminative
(Carbonylative) Alkyl-Heck-type Reactions Enabled by Photocatalytic C-N Bond
Activation. Angew. Chem. Int. Ed. 2019, 58, 2402-2406. (g) Wang, C.; Zhang, L.;
Chen, C.; Han, J.; Yao, Y.; Zhao, Y. Oxalyl Amide Assisted Palladium-Catalyzed
Synthesis of Pyrrolidones via Carbonylation of γ-C(sp3)–H Bonds of Aliphatic
Amine Substrates. Chem. Sci. 2015, 6, 4610-4614. (h) Zhang, L.; Wang, C.; Han,
J.; Huang, Z.-B.; Zhao, Y. Palladium-Catalyzed Carbonylation of
β-Arylethylamide Directed by Oxalyl Amide in the Presence of Carbon Monoxide.
J. Org. Chem. 2016, 81, 5256-5262.
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
4. (a) Li, Z.; Li, C.-J. CuBr-Catalyzed Efficient Alkynylation of sp3 C-H Bonds
Adjacent to a Nitrogen Atom. J. Am. Chem. Soc. 2004, 126, 11810-11811. (b)
Murahashi, S.-I.; Nakae, T.; Terai, T.; Terai, H.; Komiya, N.
Ruthenium-Catalyzed Oxidative Cyanation of Tertiary Amines with Molecular
Oxygen or Hydrogen Peroxide and Sodium Cyanide: sp3 C-H Bond Activation
and Carbon-Carbon Bond Formation. J. Am. Chem. Soc. 2008, 130, 11005-11012.
(c) Kawade, R. K.; Huple, D. B.; Lin, R.-J.; Liu, R.-S. Cu-Catalyzed Oxidative
Povarov Reactions between N-alkyl N-methylanilines and Saturated Oxa- and
Thiacycles. Chem. Commun. 2015, 51, 6625-6628. (d) Tan, Y.; Yuan, W.; Gong,
L.; Meggers, E. Aerobic Asymmetric Dehydrogenative Cross‐Coupling between
Two Csp3-H Groups Catalyzed by a Chiral‐at‐Metal Rhodium Complex. Angew.
Chem. Int. Ed. 2015, 54, 13045-13048. (e) Hering, T.; Mühldorf, B.; Wolf, R.;
König, B. Halogenase‐Inspired Oxidative Chlorination Using Flavin
ACS Paragon Plus Environment

Page 25 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Photocatalysis. Angew. Chem. Int. Ed. 2016, 55, 5342-5345. (f) Kennedy, N.; Liu,
P.; Cohen, T. Fundamental Difference in Reductive Lithiations with Preformed
Radical Anions versus Catalytic Aromatic Electron‐Transfer Agents: N,
N‐Dimethylaniline as an Advantageous Catalyst. Angew. Chem. Int. Ed. 2016, 55,
383-386.
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
5. (a) Zhao, X.; Liu, D.; Guo, H.; Liu, Y.; Zhang, W. C-N Bond Cleavage of Allylic
Amines via Hydrogen Bond Activation with Alcohol Solvents in Pd-Catalyzed
Allylic Alkylation of Carbonyl Compounds. J. Am. Chem. Soc. 2011, 133,
19354-19357. (b) Allah, T. N.; Savourey, S.; Berthet, J.-C.; Nicolas, E.; Cantat, T.
Carbonylation of C-N Bonds in Tertiary Amines Catalyzed by Low-Valent Iron
Catalysts. Angew. Chem. Int. Ed. 2019, 58, 10884-10887. (c) Jing, H.; Ge, H.; Li,
C.; Jin, Y.; Wang, Z.; Du, C.; Fu, X.; Fang, H. C-H and C-N Bond Activation of
Tertiary Amines by Cationic Germanium(IV) Corrole. Organometallics 2019, 38,
2412-2416. (d) Zhou, P.-X.; Shi, S.; Wang, J.; Zhang, Y.; Li, C.; Ge, C.
Palladium/Copper-Catalyzed Decarbonylative Heteroarylation of Amides via C-N
Bond Activation. Org. Chem. Front. 2019, 6, 1942-1947. (e) Nagae, H.; Hirai, T.;
Kato, D.; Soma, S.; Akebi, S.; Mashima, K. Dinuclear Manganese Alkoxide
Complexes as Catalysts for C-N Bond Cleavage of Simple Tertiary N,
N-Dialkylamides to Give Esters. Chem. Sci. 2019, 10, 2860-2868. (f) Zhang, Y.;
Yu, B.; Gao, B.; Zhang, T.; Huang, H. Triple-Bond Insertion Triggers Highly
Regioselective 1,4-Aminomethylamination of 1,3-Enynes with Aminals Enabled
by Pd-Catalyzed C-N Bond Activation. Org. Lett. 2019, 21, 535-539. (g) Chen, C.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 30
1
2
3
4
5
6
7
8
9
Liu, W.; Liu, B.; Tan, H. Acylation of Arylamines with Triethylamine Derivatives
in Combination with tert‐Butyl Hydroperoxide. Asian J. Org. Chem. 2019, 8,
470-474.
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
6. (a) Shearer, J.; Zhang, C. X.; Hatcher, L. Q.; Karlin, K. D. Distinguishing
Rate-Limiting Electron versus H-Atom Transfers in Cu2(O2)-Mediated Oxidative
N-Dealkylations:ꢀ Application of Inter-versus Intramolecular Kinetic Isotope
Effects. J. Am. Chem. Soc. 2003, 125, 12670-12671. (b) Ueno, S.; Chatani, N.;
Kakiuchi, F. Ruthenium-Catalyzed Carbon-Carbon Bond Formation via the
Cleavage of an Unreactive Aryl Carbon-Nitrogen Bond in Aniline Derivatives
with Organoboronates. J. Am. Chem. Soc. 2007, 129, 6098-6099. (c) Xie, L.-G.;
Wang, Z.-X. Nickel‐Catalyzed Cross‐Coupling of Aryltrimethylammonium
Iodides with Organozinc Reagents. Angew. Chem. Int. Ed. 2011, 50, 4901-4904.
(d) Yao, B.; Wang, Q.; Zhu, J. Palladium‐Catalyzed Coupling of
ortho‐Alkynylanilines with Terminal Alkynes Under Aerobic Conditions:
Efficient Synthesis of 2,3‐Disubstituted 3‐Alkynylindoles. Angew. Chem. Int. Ed.
2012, 51, 12311-12315. (e) Yao, B.; Wang, Q.; Zhu, J. Palladium(II)‐Catalyzed
Intramolecular Diamination of Alkynes under Aerobic Oxidative Conditions:
Catalytic Turnover of an Iodide Ion. Angew. Chem. Int. Ed. 2012, 51, 5170-5174.
(f) Yao, B.; Wang, Q.; Zhu, J. Palladium(II)‐Catalyzed Cyclizative
Cross‐Coupling of ortho‐Alkynylanilines with ortho‐Alkynylbenzamides under
Aerobic Conditions. Angew. Chem. Int. Ed. 2013, 52, 12992-12996. (g) Xia, X.-F.;
Zhang, L.-L.; Song, X.-R.; Niu, Y.-N.; Liu, X.-Y.; Liang, Y.-M.
ACS Paragon Plus Environment

Page 27 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Palladium-Copper-Cocatalyzed Intramolecular Oxidative Coupling: An Efficient
and Atom-economical Strategy for the Synthesis of 3-acylindoles. Chem.
Commun. 2013, 49, 1410-1412. (h) Sheng, J.; Li, S.; Wu, J. Synthesis of
3-((trifluoromethyl)thio)indoles via a Reaction of 2-alkynylaniline with
Trifluoromethanesulfanylamide. Chem. Commun. 2014, 50, 578-580.
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
7. (a) Coppola, G. M.; Hardtmann, G. E.; Pfister, O. R. Chemistry of
2H-3,1-benzoxazine-2,4-(1H)-dione (Isatoic anhydride). 2. Reactions with
Thiopseudoureas and Carbanions. J. Org. Chem. 1976, 41, 825-831. (b) Beutner,
G. L.; Kuethe, J. T.; Yasuda, N. A Practical Method for Preparation of
4-Hydroxyquinolinone Esters. J. Org. Chem. 2007, 72, 7058-7061. (c) Lu, W.;
Chen, J.; Liu, M.; Ding, J.; Gao, W.; Wu, H. Palladium-Catalyzed
Decarboxylative Coupling of Isatoic Anhydrides with Arylboronic Acids. Org.
Lett. 2011, 13, 6114-6117. (d) D’Souza, A. M.; Spiccia, N.; Basutto, J.; Jokisz, P.;
Wong, L. S.-M.; Meyer, A. G.; Holmes, A. B.; White, J. M.; Ryan, J. H.
1,3-Dipolar Cycloaddition-Decarboxylation Reactions of an Azomethine Ylide
with Isatoic Anhydrides: Formation of Novel Benzodiazepinones. Org. Lett. 2011,
13, 486-489.
8. Brouillette, Y.; Martinez, J.; Lisowski, V. Chemistry of Ring‐Fused
Oxazine‐2,4‐diones. Eur. J. Org. Chem. 2009, 3487-3503.
9. (a) Ji, F.; Li, X.; Wu, W.; Jiang, H. Palladium-Catalyzed Oxidative Carbonylation
for the Synthesis of Polycyclic Aromatic Hydrocarbons (PAHs). J. Org. Chem.
2014, 79, 11246-11253. (b) Ji, F.; Li, X.; Guo, W.; Wu, W.; Jiang, H.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 30
1
2
3
4
5
6
7
8
9
Palladium-Catalyzed Oxidative O-H/N-H Carbonylation of Hydrazides: Access to
Substituted 1,3,4-Oxadiazole-2(3H)-ones. J. Org. Chem. 2015, 80, 5713-5718. (c)
Ji, F.; Li, J.; Li, X.; Guo, W.; Wu, W.; Jiang, H. Carbonylation Access to
Phthalimides Using Self-Sufficient Directing Group and Nucleophile. J. Org.
Chem. 2018, 83, 104-112. (d) Jiang, G.; Wang, S.; Zhang, J.; Yu, J.; Zhang, Z.; Ji,
F. Palladium-Catalyzed Primary Amine-Directed Decarboxylative Annulation of
α-Oxocarboxylic Acids: Access to Indolo[1,2-a]quinazolines Adv. Synth. Catal.
2019, 361, 1798-1802. (e) Wang, S.; Wang, K.; Kong, X.; Zhang,S.; Jiang, G.; Ji.
F. DMF as Methine Source: Copper-Catalyzed Direct Annulation of Hydrazides
to 1,3,4-Oxadiazoles Adv. Synth. Catal. 2019, 361, 3986-3990.
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
10. Shi, R.; Niu, H.; Lu, L.; Lei, A. Pd/Cu-Catalyzed Aerobic Oxidative Aromatic
C-H Bond Activation/N-dealkylative Carbonylation towards the Synthesis of
Phenanthridinones. Chem. Commun. 2017, 53, 1908-1911.
11. Shi, R.; Lu, L.; Xie, H.; Yan, J.; Xu, T.; Zhang, H.; Qi, X.; Lan, Y.; Lei, A. C8-H
Bond Activation vs. C2-H Bond Activation: from Naphthyl Amines to Lactams.
Chem. Commun. 2016, 52, 13307-13310.
12. Shi, R.; Lu, L.; Zhang, H.; Chen, B.; Sha, Y.; Liu, C.; Lei, A.
Palladium/Copper-Catalyzed Oxidative C-H Alkenylation/N-Dealkylative
Carbonylation of Tertiary Anilines. Angew. Chem. Int. Ed. 2013, 52,
10582-10585.
13. (a) Eraslan, E.; Tanyeli, A.; Polat, E.; Yetim, Z. Evodiamine Alleviates Kidney
Ischemia Reperfusion Injury in Rats: A Biochemical and Histopathological Study.
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
J Cell Biochem. 2019, 120, 17159-17166. (b) Wu, Y.; Wang, J.; Zhao, J.; Zhang,
Y.; Sun, Y.; Chen, J.; Wang, J. Gene Regulation Analysis of the Effects of
Rvodiamine on Tongue Squamous Cell Carcinoma. J Cell Biochem. 2019, 120,
15933-15940. (c) Wu. P.; Chen, Y. Evodiamine Ameliorates Paclitaxel-Induced
Neuropathic Pain by Inhibiting Inflammation and Maintaining Mitochondrial
Anti-Oxidant Functions. Human Cell 2019, 32, 251-259. (d) Shen, P.; Zhang, Z.;
Zhu, K.; Gao, H.; Liu, J.; Lu, X.; Li, Y.; Jing, Y.; Yuan, X.; Fu, Y.; Gao, Y.;
Zhang, N. Evodiamine Prevents Dextran Sulfate Sodium-Induced Murine
Experimental Colitis via the Regulation of NF-κB and NLRP3 Inflammasome.
Biomedicine & Pharmacotherapy 2019, 110, 786-795. (e) Jin, H.; Yao, L.; Chen,
K.; Liu, Y.; Wang, Q.; Wang, Z.; Liu, Q.; Cao, Z.; Kenny, J.; Tickner, J.; Wang,
X.; Xu, J. Evodiamine Inhibits RANKL‐Induced Osteoclastogenesis and Prevents
Ovariectomy‐Induced Bone Loss in Mice. J Cell Mol Med. 2019, 23, 522-534.
14. (a) Deng, J.-D.; Lei, S.; Jiang, Y.; Zhang, H.-H.; Hu, X.-L.; Wen, H.-X.; Tan, W.;
Wang, Z. A Concise Synthesis and Biological Study of Evodiamine and its
Analogues. Chem. Commun. 2019, 55, 3089-3092. (b) Wang, Z.-X.; Xiang, J.-C.;
Wang, M.; Ma, J.-T.; Wu, Y.-D.; Wu, A.-X. One-Pot Total Synthesis of
Evodiamine and Its Analogues through a Continuous Biscyclization Reaction. Org.
Lett. 2018, 20, 6380-6383. (c) Hu, X.; Wang, Y.; Xue, J.; Han, T.; Jiao, R.; Li, Z.;
Liu, W.; Xu, F.; Hua, H.; Li, D. Design and Synthesis of Novel Nitrogen
Mustard-Evodiamine Hybrids with Selective Antiproliferative Activity.
Bioorganic & Medicinal Chemistry Letters 2017, 27, 4989-4993. (d) Wei, L.-S.;
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
ACS Paragon Plus Environment