Copper-Catalyzed sp3 C-H Aminative Cyclization of 2-Alkyl-N-arylbenzamides: An Approach for the Synthesis of N-Aryl-isoindolinones

Article abstract of DOI:10.1021/acs.orglett.5b02235

The synthesis of isoindolinones via copper-catalyzed sp³ C-H functionalization of 2-alkyl-N-substituted benzamides is described. This process does not require the preparation of halogenated substitutes, expensive transition metals, or toxic Sn or CO gas. This method provides an efficient approach to generate various functionalized isoindolinones.

Full text of DOI:10.1021/acs.orglett.5b02235

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed sp3 C−H Aminative Cyclization of
2‑Alkyl‑N‑arylbenzamides: An Approach for the Synthesis of N‑Aryl-
isoindolinones
Kanako Nozawa-Kumada, Jun Kadokawa, Takehiro Kameyama, and Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: The synthesis of isoindolinones via copper-catalyzed
sp3 C−H functionalization of 2-alkyl-N-substituted benzamides is
described. This process does not require the preparation of
halogenated substitutes, expensive transition metals, or toxic Sn or
CO gas. This method provides an efficient approach to generate
various functionalized isoindolinones.
mination reactions are crucial for synthesizing natural
mides,9 transition-metal-catalyzed cyclization of 2-halobenza-
Aorganic and medicinally important compounds. Among mides,10 olefination of benzoic amides,11 and Pd-catalyzed
cycloaminocarbonylation.12 However, most of these methods
the many available amination methods, the direct amination of
sp3 C−H bonds has emerged as an attractive route to prepare
require starting materials that are difficult to prepare, expensive
sp3 C−N bonds1 because it does not require prefunctionalized
transition metals, or toxic Sn or CO gas. During the course of
our present study, Kumar et al. reported the transition-metal-
free intramolecular oxidative coupling of 2-alkylbenzamides for
preparing isoindolinones.13 This process employs iodine,
potassium carbonate, and di-tert-butyl peroxide and provides
a route to various N-aryl-isoindolinones. Herein, we report a
new approach for the synthesis of isoindolinones via Cu-
catalyzed sp3 C−H aminative cyclization of 2-alkyl-N-
substituted benzamides.
We began our investigation using 2-methyl-N-phenyl-
benzamide 1a as a substrate to optimize the reaction conditions
(Table 1). The cyclization of 1a was first performed in the
presence of CuI (20 mol %) and di-tert-butyl peroxide (2
equiv) at 100 °C in benzene. Without the addition of ligands,
the reaction did not proceed at all (Table 1, entry 1). Ligands
play a role in enhancing the overall yield, and it was found that
pyridine was the most effective for this reaction (entries 2−4).
Of the solvents investigated, DCE was demonstrated to be the
best (entry 7). A subsequent screening of Cu(I) and Cu(II)
salts revealed that CuI represented the optimum source of
copper for the reaction (entries 7−10). When we tested further
pyridine derivatives as ligands, we found that electron-donating
group substituted pyridines improved the reaction yield (entries
11 and 12 vs 7). Decreasing the amount of copper and ligand
did not affect the reaction, and it was found that a high yield of
2a was still obtained under these conditions (entry 13). Other
oxidants, such as tert-butyl peroxide and tert-butyl peroxyace-
tate, inhibited the reaction (data not shown).
starting materials. Transition-metal-catalyzed nitrene insertion
into C−H bonds is one of the most widely established sp3 C−
H amination procedures.2 However, this process is limited to
the synthesis of secondary amines. Recently, a Kharasch−
Sosnovsky type amination reaction3,4 was developed as an
alternative to the metal-nitrene-based strategies. This reaction is
an amination of allylic,3a benzylic,3b−e and aliphatic3f−h C−H
bonds using peroxide as the oxidant. However, despite its
usefulness, there have been no reports of it being applied to
intramolecular aminative cyclizations.
Isoindolinones with sp3 C−N bonds are found in many
natural and synthetic drug molecules,5 for example, indoprofen
(an anti-inflammatory),6 stachybotrin (an anxiolytic),7 and
staurosporine (a protein kinase C inhibitor)8 (Figure 1). Many
methods have been reported for the synthesis of N-substituted
isoindolinones, such as selective monoreduction of phthali-
Having identified the optimum reaction conditions, we
explored the range of substrates to which this process can be
applied. As shown in Scheme 1, it worked with a wide range of
Received: July 31, 2015
Figure 1. Bioactive and natural isoindolinone derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02235
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
desired products 2b−d with good yields, with the exception of
3-substituted-2-methyl-N-phenylbenzamide (1e). Conversely,
substrates containing halogen atoms produced the isoindoli-
nones 2f−h with slightly reduced yields. Next, we explored
substitution in the aniline ring and found that the process
yielded moderate amounts of the cyclized products 2i−o
regardless of the electronic properties of the aniline ring. 2-
Ethyl-N-phenylbenzamide 1p, which has a secondary benzylic
hydrocarbon, reacted to produce a good yield.
To investigate the reaction mechanism, we performed the
reaction with the addition of radical scavenger TEMPO
(Scheme 2). None of the desired product was detected,
indicating that the reaction might proceed via a radical process.
Further mechanistic studies are currently underway.
Table 1. Effect of Reaction Parameters
a
entry
Cu (mol %)
ligand (mol %)
solvent
yield (%)
1
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
Cu(OAc)2 (20)
CuBr2 (20)
CuBr (20)
CuI (20)
CuI (20)
none
benzene
benzene
benzene
benzene
toluene
DMSO
DCE
trace
15
2
phen (40)
3
bipy (40)
13
4
pyridine (40)
pyridine (40)
pyridine (40)
pyridine (40)
pyridine (40)
pyridine (40)
pyridine (40)
4-MeO-Py (40)
DMAP (40)
DMAP (30)
17
5
22
6
trace
57
7
8
DCE
26
9
DCE
46
Scheme 2. Radical Scavenger Experiment
10
11
12
13
DCE
47
DCE
65
DCE
86
b
CuI (10)
DCE
85 (82)
a
1
Determined by H NMR using 1,1,2-trichloroethane as an internal
b
standard. Isolated yield in parentheses.
In conclusion, the Cu-catalyzed sp3 C−H aminative
cyclization of 2-alkyl-N-arylbenzamides has been developed
using di-tert-butyl peroxide, and various substituted substrates
were found to be suitable for the reaction. This process
provides a powerful approach to synthesize N-aryl-isoindoli-
nones. Further studies to expand the scope of substrates and
broaden the synthetic application to other heterocycles are in
progress.
Scheme 1. sp3 C−H Functionalization of Various 2-Alkyl-N-
a
arylbenzamides
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02235.
Experimental procedures, characterization data, and
spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ykondo@m.tohoku.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support by a Grant-in-Aid
for Scientific Research (B) (No. 23390002), a Grant-in-Aid for
Challenging Exploratory Research (Nos. 25670002, 15K14926)
from Japan Society for the Promotion of Science, a Grant-in-
Aid for Scientific Research on Innovative Areas “Advanced
Molecular Transformations by Organocatalysis” (No.
23105009), and the project “Platform for Drug Discovery,
Informatics, and Structural Life Science” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
a
b
c
1
Isolated yield. Reaction was run at 120 °C. Determined by H
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