Pd-Catalyzed Intramolecular Chemoselective C(sp2)-H and C(sp3)-H Activation of N-Alkyl- N-arylanthranilic Acids

Article abstract of DOI:10.1021/acs.orglett.8b03976

A controllable palladium-catalyzed intramolecular C-H activation of N-alkyl-N-arylanthranilic acids has been developed. The methodology allows selective synthesis of 1,2-dihydro-(4H)-3,1-benzoxazin-4-ones and carbazoles from the same starting materials and palladium catalyst. The selectivity is controlled by the oxidant. Silver oxide promotes C(sp3)-H activation/C-O cyclization to provide 1,2-dihydro-(4H)-3,1-benzoxazin-4-ones, while copper acetate contributes to C(sp2)-H activation/decarboxylative arylation to afford carbazoles. This protocol is demonstrated by its wide substrate scope and good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.8b03976

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Intramolecular Chemoselective C(sp2)−H and C(sp3)−
H Activation of N‑Alkyl‑N‑arylanthranilic Acids
Zhe-Yao Hu, Yan Zhang, Xin-Chang Li, Jing Zi, and Xun-Xiang Guo*
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong
University, Shanghai 200240, China
S
* Supporting Information
ABSTRACT: A controllable palladium-catalyzed intramolec-
ular C−H activation of N-alkyl-N-arylanthranilic acids has
been developed. The methodology allows selective synthesis
of 1,2-dihydro-(4H)-3,1-benzoxazin-4-ones and carbazoles
from the same starting materials and palladium catalyst. The
selectivity is controlled by the oxidant. Silver oxide promotes
C(sp3)−H activation/C−O cyclization to provide 1,2-
dihydro-(4H)-3,1-benzoxazin-4-ones, while copper acetate
contributes to C(sp2)−H activation/decarboxylative arylation
to afford carbazoles. This protocol is demonstrated by its wide
substrate scope and good functional group tolerance.
he development of efficient synthetic methodologies for
the construction of heterocycles is one of the most
difficulty in controlling the functionalization of multiple C−H
bonds. The reported examples are shown in Scheme 1a. One is
acid-mediated intramolecular acyl arylation of N,N-disubsti-
tuted anthranilic acids for the synthesis of N-arylacridones.13
T
important topics in organic synthesis. As one of the convenient
and efficient synthetic protocols for the formation of complex
molecules from simple starting materials, transition-metal-
catalyzed C−H functionalization has received much attention,
and many novel methodologies have been developed in the past
decades.1 Although significant achievements have been made,
transition-metal-catalyzed controllably chemoselective C−H
functionalization remains challenging.2
Scheme 1. Strategies for Intramolecular C−H
Functionalization of N,N-Disubstituted Anthranilic Acids
Carboxylic acids are versatile feedstock chemicals, which can
be used for the preparation of numerous complex molecules.3
Recently, considerable effort has been devoted to the develop-
ment of catalytic strategies for the synthesis heterocycles by the
intramolecular C−H functionalization of carboxylic acids. For
example, Wang reported a Pd-catalyzed C−H activation of
phenylacetic acids for the formation of benzofuranones.4
Gilmour developed a photocascade catalysis method for the
synthesis of coumarins from E-cinnamic acids.5 In addition, the
intramolecular C−H lactonization of 2-arylbenzoic acids has
been investigated, and some efficient synthetic protocols, such as
transition-metal catalysts including Pd,6 Cu,7 Ag,8 and
transition-metal-free catalysis,9 photocatalysts,10 and electro-
chemical synthesis11 have been developed. However, the
successful examples of carboxylic acids in the intramolecular
C−H functionalization are very limited. The development of
new types of carboxylic acids for the catalytic synthesis of
heterocycles by intramolecular C−H functionalization is greatly
desired.
As ones of important acids, anthranilic acids, which combined
with an amino and a carboxyl functional group, have been widely
used in organic synthesis.12 However, the reactivity of the
intramolecular C−H functionalization of N,N-disubstituted
anthranilic acids is rarely investigated, possibly due to the
Received: December 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03976
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Another is the iodine reagent mediated intramolecular
cyclization of N,N-disubstituted anthranilic acids for the
preparation of 1,2-dihydro-(4H)-3,1-benzoxazin-4-ones,14 but
these reported reactions are limited to intramolecular C−H
functionalization of N,N-disubstituted anthranilic acids, and
transition-metal-catalyzed C−H activation remains undevel-
oped.
Table 1. Optimization of the Reaction Conditions
b
yield (%)
Given the structure of N,N-disubstituted anthranilic acids, we
became interested in the N-alkyl-N-arylanthranilic acids, which
contain both C(sp3)−H bonds and C(sp2)−H bonds in the
same molecule.15 We envisioned that the selective C(sp3)−H
and C(sp2)−H activation might occur by choosing the suitable
transition-metal catalysts. Furthermore, we might realize
controllable synthesis of two completely different heterocycles
from the same starting materials based on transition-metal-
catalyzed intramolecular selective C−H activation. Therefore,
the exploration of the controllable synthesis from transition-
metal-catalyzed intramolecular selective C−H activation of N-
alkyl-N-arylanthranilic acids is highly desirable but remains
highly challenging.
Herein, we report a novel and efficient palladium-catalyzed
intramolecular cyclization of N-alkyl-N-arylanthranilic acids for
the synthesis of 1,2-dihydro-(4H)-3,1-benzoxazin-4-ones and
carbazoles. To the best of our knowledge, this is the first
transition-metal-catalyzed intramolecular C−H activation of
N,N-disubstituted anthranilic acids and is also the first
controllable palladium-catalyzed intramolecular chemoselective
C−H activation of N-alkyl-N-arylanthranilic acids by simply
switching the oxidants. The methodology allows highly selective
synthesis of 1,2-dihydro-(4H)-3,1-benzoxazin-4-ones and car-
bazoles from the same starting materials and palladium catalyst
(Scheme 1b).
In our initial study, we chose N-methyl-N-phenylanthranilic
acid (1a) as the model starting material to examine the reaction.
As shown in Table 1, the reaction of compound 1a in the
presence of 10 mol % of Pd(OAc)2 with 2 equiv of BQ in DMAc
at 120 °C for 24 h afforded the product 2a and 3a in 11% and 8%
yield, respectively (Table 1, entry 1). Although the oxidants
TBHP and K2S2O8 provided the products 2a and 3a in low
yields (Table 1, entries 2 and 3), AgOAc gave the product 2a in
49% yield with 15% yield of 3a (Table 1, entry 4). Further
screening of silver salts revealed Ag2O as the best one to
selectively give 2a in 45% yield as the major product with a very
small amount of product 3a (Table 1, entry 5). Interestingly, the
use of Cu(OAc)2 as an oxidant selectively provided 3a as the
major product with 40% yield under the same reaction
conditions (Table 1, entry 6). We used Cu(OAc)2 as the
oxidant to optimize other reaction conditions. After optimiza-
tion of the solvent and reaction temperature, it shows the
optimal ones are DMAc and 130 °C, respectively (Table 1,
entries 7−10). We found that 3 equiv of Cu(OAc)2 improved
the yield of product 3a to 57% (Table 1, entry 11). Furthermore,
extension of the reaction time to 72 h greatly improved the yield
of 3a to 71% (Table 1, entry 13). In order to obtain a high yield
of 2a, we used Ag2O as an oxidant to optimize the reaction
conditions. Although the product 2a can be formed in a large
range of reaction temperatures tested between 120 and 50 °C,
the optimal reaction temperature is 70 °C, giving 2a in 80% yield
when the catalyst loading was decreased to 5 mol % (Table 1,
entries 14−19). The solvent screening shows DMAc is the
optimal one (Table 1, entries 19−21). To our delight, the yield
of product 2a was further improved to 85% when 4 mL of DMAc
was used (Table 1, entry 22).
entry
oxidant
BQ
TBHP
K2S2O8
AgOAc
Ag2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
solvent
temp (°C)
2a 3a
1
2
3
4
5
6
7
8
9
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
DMSO
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
120
120
120
120
120
120
120
120
130
140
130
130
130
100
80
60
50
60
70
70
70
70
11
9
3
8
16
2
49
45
3
15
2
40
6
12
27
2
7
46
10
4
40
c
11
c d
3
57
,
12
13
14
15
16
17
3
63
c e
,
3
71
6
58
67
79
59
66
80
53
39
85
6
trace
trace
trace
trace
3
f
18
19
20
21
f
f
f
dioxane
DMAc
3
f g
22 ,
trace
a
Unless otherwise noted, the reactions were performed in a sealed
tube with 1a (0.2 mmol), Pd(OAc)2 (0.02 mmol), and oxidant (0.4
mmol) in solvent (2.0 mL) at 120 °C for 24 h under N2. Isolated
yields. Cu(OAc)2 (0.6 mmol) was used. 48 h. 72 h. Pd(OAc)2
b
c
d
e
f
g
(0.01 mmol) was used. 4 mL of DMAc was used.
With the optimized conditions in hand (entry 22), we
explored the substrate scope of the C(sp3)−H activation/C−O
cyclization process for the preparation of 1,2-dihydro-(4H)-3,1-
benzoxazin-4-ones 2. The results are summarized in Scheme 2. A
variety of N-alkyl-N-arylanthranilic acids can be used in the
present reaction to give the corresponding cyclization products
in good to high yields. Both electron-donating groups and
electron-withdrawing groups on the aryl rings are tolerated in
this reaction. For example, it provided the product 2b with a
methyl group on the aryl ring in 83% yield when compound 1b
was treated in the presence of 5 mol % of Pd(OAc)2 with 2 equiv
of Ag2O in DMAc at 70 °C for 24 h. Under the same reaction
conditions, the product 2e having a chloro group on the same
position was formed in 81% yield. The steric effect of the
substituent R2 was observed. Although meta- and para-
substituted cyclization products 2l and 2m were obtained in
high yields, the ortho-substituted product 2k was formed in 55%
yield. It was found that the N-alkyl-N-arylanthranilic acids with a
substituent on the two aryl rings proceeded well to give the
corresponding cyclization products in high yields (Scheme 2,
products 2q−u). In addition, when the R3 group was extended
to other substituents except H, such as a methyl and a phenyl
group, the reactions also afforded the corresponding product 2v
and 2w in moderate to good yields.
We also examined the substrate scope of the C(sp2)−H
activation/C−C cyclization process for the synthesis of
B
DOI: 10.1021/acs.orglett.8b03976
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of 1,2-Dihydro-(4H)-3,1-benzoxazin-4-
ones
Scheme 3. Scope of Carbazoles
a
a
The reactions were performed in a sealed tube with 1 (0.2 mmol),
Pd(OAc)2 (0.02 mmol), and Cu(OAc)2 (0.6 mmol) in DMAc (2.0
mL) at 130 °C for 72 h under N2. Isolated yields are shown.
b
Pd(OAc)2 (0.03 mmol) was used.
products 3q,s,t). Furthermore, we found that the carbazoles 3v
and 3x were formed in moderate yields when the substituent R4
was an ethyl and a butyl group, respectively.
a
The reactions were performed in a sealed tube with 1 (0.2 mmol),
Based on the above experimental results and related literature
reports, a possible mechanism has been proposed in Scheme 4.
Treatment compound 1a with silver oxide forms a silver
carboxylate complex A.16 Transmetalation with a PdII complex
generates species B, which gives a seven-membered cyclo-
palladated species C by an intramolecular C(sp3)−H
activation.6,17 Subsequently, reductive elimination takes place
to afford product 2a and a Pd0 species. The PdII species is
regenerated by oxidation of the Pd0 species for the catalytic
cycle. When copper acetate is used in the reaction, an arylcopper
species E is generated by copper-mediated decarboxylation of
compound 1a.18 Then transmetalation with a PdII complex
followed by an intramolecular C(sp2)−H activation forms
species G. Finally, reductive elimination occurs to provide
product 3a and a Pd0 species, which can be reoxided to the PdII
complex by copper acetate.
Pd(OAc)2 (0.01 mmol), and Ag2O (0.4 mmol) in DMAc (4.0 mL) at
70 °C for 24 h under N2. Isolated yields are shown. 100 °C.
b
carbazoles 3. As shown in Scheme 3, various carbazoles were
prepared in moderate to high yields by switching the oxidant
from Ag2O to Cu(OAc)2. For example, the palladium-catalyzed
intramolecular cyclization of compound 1a with 3 equiv of
Cu(OAc)2 in DMAc at 130 °C for 72 h afforded carbazole 3a in
71% yield. For the monosubstituted compounds, the substituent
R1 with the electron-donating groups and electron-withdrawing
groups gave the corresponding carbazoles in moderate to high
yields (Scheme 3, products 3b−j). The substituent R2 with an
electron-withdrawing group provided lower yield compared to
the compound with an electron-donating group (Scheme 3,
product 3e with 41% yield vs 3b with 79% yield). We also tested
the compounds with two substituents, and the present method
gave the corresponding products in good yields (Scheme 3,
In conclusion, we demonstrate an efficient method for the
controllable synthesis of 1,2-dihydro-(4H)-3,1-benzoxazin-4-
C
DOI: 10.1021/acs.orglett.8b03976
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ones and carbazoles by palladium-catalyzed intramolecular
chemoselective C(sp2)−H and C(sp3)−H activation of N-
alkyl-N-arylanthranilic acids. The high selectivity is controlled
by simply switching the oxidants. This novel methodology
shows wide substrate scope and good functional group tolerance
and provides the corresponding 1,2-dihydro-(4H)-3,1-benzox-
azin-4-ones and carbazoles in good to high yields.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03976.
Experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra for all compounds
(PDF)
(13) (a) Zhang, E.; Zhang, X.; Wei, W.; Wang, D.; Cai, Y.; Xu, T.; Yan,
AUTHOR INFORMATION
■
́
́
̇
k, A.; Jozwiak, L.;
M.; Zou, Y. RSC Adv. 2015, 5, 5288. (b) Bouzy
Kolendo, A. Yu.; Błazejowski, J. Spectrochim. Acta, Part A 2003, 59, 543.
Corresponding Author
*E-mail: xunxiang_guo@sjtu.edu.cn.
ORCID
̇
(14) (a) Liu, L.; Du, L.; Zhang-Negrerie, D.; Du, Y. RSC Adv. 2015, 5,
29774. (b) Zhang, N.; Cheng, R.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
J. Org. Chem. 2014, 79, 10581.
Xun-Xiang Guo: 0000-0001-9830-3402
Notes
(15) For selective free carboxylic acid directed C(sp3)−H activation,
see: (a) Hu, L.; Shen, P.-X.; Shao, Q.; Hong, K.; Qiao, J. X.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2019, DOI: 10.1002/anie.201813055.
(b) Zhuang, Z.; Yu, C.-B.; Chen, G.; Wu, Q.-F.; Hsiao, Y.; Joe, C. L.;
Qiao, J. X.; Poss, M. A.; Yu, J.-Q. J. Am. Chem. Soc. 2018, 140, 10363.
(c) Shen, P.-X.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. J. Am. Chem. Soc.
2018, 140, 6545.
(16) (a) Baur, A.; Bustin, K. A.; Aguilera, E.; Petersen, J. L.; Hoover, J.
M. Org. Chem. Front. 2017, 4, 519. (b) Rubottom, G. M.; Mott, R. C.;
Juve, H. D., Jr. J. Org. Chem. 1981, 46, 2717.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21172142) and the Science and
Technology Commission of Shanghai Municipality
(18JC1410801).
(17) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion, J.-L.;
Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157.
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DOI: 10.1021/acs.orglett.8b03976
Org. Lett. XXXX, XXX, XXX−XXX