Copper-Catalyzed Intramolecular Benzylic C-H Amination for the Synthesis of Isoindolinones

Article abstract of DOI:10.1021/acs.joc.6b01393

A copper-catalyzed intramolecular amination occurs at the benzylic C-H of 2-methylbenzamides to deliver the corresponding isoindolinones of great interest in medicinal chemistry. The mild and abundant MnO₂ works well as a terminal oxidant, and the reaction proceeds smoothly under potentially explosive organic peroxide-free conditions. Additionally, the directing-group-dependent divergent mechanisms are proposed: 8-aminoquinoline-containing benzamides include a Cu-mediated organometallic pathway whereas an aminyl radical-promoted Hofmann-Loffler-Freytag (HLF)-type mechanism can be operative in the case of N-naphthyl-substituted substrates.

Full text of DOI:10.1021/acs.joc.6b01393

Subscriber access provided by UNIV OF NEW ENGLAND
Article
Copper-Catalyzed Intramolecular Benzylic C–
H Amination for the Synthesis of Isoindolinones
Chiaki Yamamoto, Kazutaka Takamatsu, Koji Hirano, and Masahiro Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01393 • Publication Date (Web): 09 Aug 2016
Downloaded from http://pubs.acs.org on August 10, 2016
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CopperꢀCatalyzed Intramolecular Benzylic C–H
Amination for the Synthesis of Isoindolinones
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
Chiaki Yamamoto, Kazutaka Takamatsu, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka
565ꢀ0871, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
A copperꢀcatalyzed intramolecular amination occurs at the benzylic C–H of 2ꢀmethylbenzamides to
deliver the corresponding isoindolinones of great interest in medicinal chemistry. The mild and
abundant MnO works well as a terminal oxidant, and the reaction proceeds smoothly under potentially
2
explosive organic peroxideꢀfree conditions. Additionally, the directingꢀgroupꢀdependent divergent
mechanisms are proposed: 8ꢀaminoquinolineꢀcontaining benzamides include a Cuꢀmediated
organometallic pathway whereas an aminyl radicalꢀpromoted HofmannꢀLofflerꢀFreytag (HLF)ꢀtype
mechanism can be operative in the case of Nꢀnaphthylꢀsubstituted substrates.
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 32
Introduction
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Isoindolinones are one of the prevalent nitrogenꢀcontaining heterocycles in natural and synthetic drug
1
2
3
molecules. Such well known compounds include indoprofen, stachybotrin, and staurosporine.
Additionally, some isoindolinone derivatives show unique biological activities, such as inhibitors for the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
production of tumor necrosis factor, MGRꢀ1 antagonist, antiꢀtumor, and antiꢀinflammatory activities.
Thus, versatile strategies for the construction of the isoindolinone skeleton have been developed by
many synthetic chemists. Traditional but reliable protocols largely rely on prefunctionalized starting
5
materials, as exemplified by hydrosilaneꢀ or tinꢀmediated selective monoreduction of phthalimides and
6
Pdꢀcatalyzed carbonylative cyclization of orthoꢀhalogenated benzylamines.
Moreover, recent
7
advances in CꢀH functionalization can provide more atomꢀ and stepꢀeconomical approaches to the
above target structure: Pdꢀ, Niꢀ, and KOꢀtꢀBuꢀmediated direct cyclizations of orthoꢀhalogenated
8
benzamides (Scheme 1a), Pdꢀcatalyzed carbonylative oxidative cyclization of benzylamines (Scheme
9
1
b), and intramolecular CꢀH/NꢀH coupling of orthoꢀmethylbenzamides in the presence of Cu,
1
0
iodoarene, or iodine promoter combined with organic peroxides (Scheme 1c).
The last scheme is
particularly attractive because the CꢀN forming process occurs in a dehydrogenative manner and toxic
11
CO gas is not necessary.
However, potentially explosive peroxideꢀbased terminal oxidants are still
required. Thus, there remains large demand for further improvements of the catalytic systems.
Herein we report a Cu/Mnꢀcatalyzed intramolecular CꢀH/NꢀH coupling of orthoꢀmethylbenzamides
directed toward the isoindolinones. Trivial, safe, and abundant MnO worked well as the terminal
2
oxidant, and the desired isoindolinoes are obtained in the dehydrogenative manner even without the use
of organic peroxides.
Additionally, the directingꢀgroupꢀdependent divergent mechanisms are
observed: 8ꢀaminoquinolineꢀcontaining benzamides include a Cuꢀmediated organometallic pathway
whereas an aminyl radicalꢀpromoted HofmannꢀLofflerꢀFreytag (HLF)ꢀtype mechanism can be operative
in the case of Nꢀnaphthylꢀsubstituted substrates (Scheme 2).
Scheme 1. C–H Functionalization Approaches to Isoindolinones
ACS Paragon Plus Environment
2

Page 3 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
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
Scheme 2. Cu/Mn-Catalyzed Intramolecular C–H/N–H Coupling of ortho-Methylbenzamides
directed toward Isoindolinones (This Work)
Results and Discussion
1
2
We previously reported an 8ꢀaminoquinolineꢀdirected, Cu(OAc) ꢀmediated oxidative coupling of
2
1
3
benzamides and maleimides, giving the spirosuccinimides.
At an early stage of this study, we
performed the reaction of the orthoꢀmethylbenzamide 1a with Nꢀmethylmaleimide and serendipitously
detected a small but significant amount of the isoindolinone 2a, accompanied by the formation of the
expected spirosuccinimide (Scheme 3). Apparently, the intramolecular amination occurred at the
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 32
benzylic position of the benzamide 1a without participation of the maleimide. The intriguing result
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
prompted us to optimize catalytic conditions for the dehydrogenative cyclization with
2,4,6ꢀtrimethylbenzamide 1b as the model substrate (Table 1). On the basis of our previous work on
14,15
the copperꢀcatalyzed intramolecular aromatic C–H amination,
we first tested an MnO terminal
2
oxidant (2.0 equiv), combined with 20 mol % of Cu(OAc) and 1.0 equiv PivOH, in DMF at 170 ˚C and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
pleasingly found the desired isoindolinone 2b in 35% GC yield (entry 1). The structure of 2b was
16
unambiguously determined by NMR, HRMS, and Xꢀray analysis.
Other oxidants, such as silver salts
and molecular oxygen (air), resulted in the negligible catalyst turnover (entries 2–4). As seen in
14
previous studies, microwave irradiation (ꢀw; 200 ˚C, 1 h) accelerated the reaction and increased the
GC yield to 47% (entry 5). Subsequent screening of acidic additives revealed that the carboxylic acids
generally accelerated the reaction, with 1ꢀAdCOOH proving to be optimal (entries 6–9). Some other
copper carboxylates also promoted the C–H amination with the comparable efficiency, but Cu(OAc)2
1
7
was still found to be best from the viewpoints of cost and availability.
An increase in the amount of
MnO further improved the yield, and in this case 1ꢀAdCOOH could be decreased to 40 mol % (entries
2
1
0–12). Finally, treatment of 1b with 20 mol % Cu(OAc) , 40 mol % 1ꢀAdCOOH, and 6.0 equiv
2
MnO in diglyme for 2 h afforded 2b in 83% yield (entry 13). Additionally notable is that no reaction
2
occurred in the absence of Cu(OAc) , thus confirming the operation of copper catalysis in this
2
transformation (entry 14).
Scheme 3. Initial Finding
ACS Paragon Plus Environment
4

Page 5 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
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
Table 1. Optimization Studies for Copper-Catalyzed Intramolecular Benzylic C–H Amination of
a
Benzamide 1b directed toward Isoindolinone 2b
b
entry
oxidant (equiv)
additive (equiv)
PivOH (1.0)
conditions
yield (%)
(35)
1
2
MnO (2.0)
DMF, 170 ˚C, 16 h, N2
DMF, 170 ˚C, 164 h, N2
2
Ag O (2.0)
PivOH (1.0)
(19)
2
3
4
5
AgOAc (2.0)
PivOH (1.0)
PivOH (1.0)
PivOH (1.0)
DMF, 170 ˚C, 4 h, N2
DMF, 170 ˚C, 14 h, air
DMF, ꢀw, 200 ˚C, 1 h, N2
(18)
(16)
(47)
O (air)
2
MnO (2.0)
2
6
7
8
9
MnO (2.0)
AcOH (1.0)
DMF, ꢀw, 200 ˚C, 1 h, N2
DMF, ꢀw, 200 ˚C, 1 h, N2
DMF, ꢀw, 200 ˚C, 1 h, N2
DMF, ꢀw, 200 ˚C, 1 h, N2
DMF, ꢀw, 200 ˚C, 1 h, N2
(36)
(51)
(27)
(40)
(64)
(66)
2
MnO (2.0)
1ꢀAdCOOH (1.0)
MesCOOH (1.0)
none
2
MnO (2.0)
2
MnO (2.0)
2
1
0
1
MnO (4.0)
1ꢀAdCOOH (1.0)
2
1
MnO (4.0)
1ꢀAdCOOH (0.40) DMF, ꢀw, 200 ˚C, 1 h, N2
2
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 32
1
2
MnO (6.0)
1ꢀAdCOOH (0.40) DMF, ꢀw, 200 ˚C, 1 h, N2
1ꢀAdCOOH (0.40) diglyme, ꢀw, 200 ˚C, 2 h, N2
1ꢀAdCOOH (0.40) diglyme, ꢀw, 200 ˚C, 2 h, N2
(72)
83
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
MnO (6.0)
2
c
14
MnO (6.0)
(0)
2
a
b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reaction conditions: 1b (0.25 mmol), Cu(OAc) (0.050 mmol), oxidant, additive, solvent (1.5 mL).
2
c
GC yields are in parentheses.
Without Cu(OAc)2.
With conditions of entry 13 in Table 1, we initially investigated the effect of the substitution at the 4
position of 2,6ꢀdimethylbenzamide substrates (Scheme 4). Electronꢀneutral as well as
electronꢀdonating substituents were well tolerated to form the corresponding isoindolinones 2c, 2d, and
e, in 80, 80, and 73% yields, respectively. The Cu/Mn catalysis was also compatible with
2
electronꢀwithdrawing halogen functionalities, and we obtained 2f–h in synthetically useful yields with
chloride, bromide, and iodide moieties left intact, which can be useful synthetic handle for further
manipulations. In the case of 2ꢀmethylꢀ6ꢀpentylbenzamide 1i that bears potentially reactive methyl
and methylene benzylic CꢀHs, the reaction occurred exclusively at the methyl C–H to deliver 2i in 55%
yield. Similarly, the 2ꢀisopropylꢀ6ꢀmethylbenzamide 1j afforded the methyl C–H aminated product as
the sole product. On the other hand, expectedly, 2,6ꢀdipentylbenzamide 1k showed moderate
reactivity (13% GC yield of 2j).
ACS Paragon Plus Environment
6

Page 7 of 32
The Journal of Organic Chemistry
Scheme 4. Copper-Catalyzed Intramolecular Benzylic C–H Amination of Various
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
2
,6-Disubstituted Benzamide 1 directed toward Isoindolinone 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1 (0.25 mmol), Cu(OAc) (0.050 mmol), 1ꢀAdCOOH (0.10 mmol), MnO (1.5
2
2
mmol), diglyme (1.5 mL), 200 ˚C, 2 h, microwave irradiation.
We then tested the 2,5ꢀdimethylbenzamide 1l under the standard reaction conditions, however, the
desired product 2l was formed in only 37% GC yield (Scheme 5). Thus, we performed additional
optimization studies. To our delight, the yield was dramatically improved to 65% (76% GC yield) by
using a combination of 20 mol % of Cu(OPiv) and 1.0 equiv of PivOH instead of the
2
Cu(OAc) /1ꢀAdCOOH catalyst system. The second catalyst system was also effective for the
2
methoxyꢀ, chloroꢀ, and bromoꢀsubstituted substrates to furnish 2m–o in acceptable yields. As shown
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 32
in Scheme 4, the methyl benzylic C–H was most reactive: the C–H amination at the methylene C–Hs of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the 2ꢀpentylꢀ and 2ꢀbenzylbenzamides 1p and 1q proceeded insufficiently (2p and 2q).
Scheme 5. Copper-Catalyzed Intramolecular Benzylic C–H Amination of Various
a
2
,5-Disubstituted Benzamide 1 directed toward Isoindolinone 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1 (0.25 mmol), Cu(OPiv) (0.050 mmol), PivOH (0.25 mmol), MnO (1.5
2
2
b
mmol), diglyme (1.5 mL), 200 ˚C, 1 h, microwave irradiation.
Reaction conditions: 1l (0.25 mmol),
Cu(OAc) (0.050 mmol), 1ꢀAdCOOH (0.10 mmol), MnO (1.5 mmol), diglyme (1.5 mL), 200 ˚C, 2 h,
2
2
c
microwave irradiation.
In diglyme (5.0 mL).
Under identical conditions, the methoxyꢀsubstituted quinoline also worked well as the substituent on
the nitrogen: the benzamide 1r underwent the intramolecular C–H amination to afford 2r in 60% yield.
Subsequent demethylation with BBr was followed by oxidation with PhI(TFA) to produce the NH
3
2
1
8
isoindolinone 2rꢀH in 51% yield (Scheme 6).
ACS Paragon Plus Environment
8

Page 9 of 32
The Journal of Organic Chemistry
Scheme 6. Copper-Catalyzed Intramolecular Benzylic C–H Amination of 1r followed by
Deprotection
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To get mechanistic insight, deuterated 1lꢀd was prepared, and some kinetic studies were carried out
3
(Scheme 7). All the following experiments were performed under the conventional heating conditions
with an oil bath (170 ˚C, N ), because under microwaveꢀirradiated conditions the reaction proceeded in
2
the course of the preheating time, and the conversion at an early stage was difficult to trace. When the
reaction stopped in 3 h, the cyclized product 2lꢀd was formed in 34% yield, and the recovered starting
2
1
2
material underwent no H/D scrambling, which was confirmed by H and H NMR analysis.
Additionally, major kinetic isotope effect (KIE) values of 1.9 was obtained from the parallel reactions of
1l and1lꢀd (see the Supporting Information for detailed kinetic profiles). The above outcomes suggest
3
the irreversible and rateꢀlimiting C–H cleavage at the benzylic position. On the other hand, addition of
radical scavengers, TEMPO and 1,4ꢀdinitrobenzene, gave only minor impact on the reaction efficiency
(maximum 36% decrease of the yield), thus indicating that a single electron transfer (SET) mechanism
is unlikely (Scheme 8).
Scheme 7. Deuterium-Labeling Experiments
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 32
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 8. Effects of Radical Inhibitors for 1b
On the basis of literature information and our findings, we propose the reaction mechanism as shown
in Scheme 9. The benzamide 1 initially reacts with the Cu(OR) with the liberation of ROH to form a
2
N,Nꢀbidentately coordinated Cu species 3. Subsequent irreversible and rateꢀlimiting C–H cleavage at
the proximal benzylic position generates the cyclometalated complex 4. The oneꢀelectron oxidation
1
9
(disproportionation)ꢀinduced reductive elimination then occurs via a Cu(III) intermediate 5 to furnish
the observed isoindolinone 2 along with the CuOR. The catalytic cycle is closed by the reoxidation of
20
CuOR into Cu(OR) with MnO and ROH.
Although the exact role of acidic additives, 1ꢀAdCOOH
2
2
and PivOH, is not clear at present, they can accelerate the C–H cleavage step through an
21
acetateꢀligandꢀassisted concerted metalationꢀdeprotonation.
Scheme 9. Plausible Mechanism for 1. R = Ac, 1-AdCO, or Piv.
ACS Paragon Plus Environment
10

Page 11 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
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
We finally investigated the effect of substituents on the nitrogen of benzamide substrate 1 (Scheme
0). Surprisingly, albeit with lower efficiency, the naphthylꢀsubstituted 1bꢀNp also underwent the
1
reaction under conditions of entry 13 in Table 1, which contrasts with other 8ꢀaminoquinolineꢀdirected,
22
copperꢀmediated C–H transformations.
Inspired by this outcome, we prepared a series of
Nꢀsubstituted benzamides and tested their reactivity. As a general trend, the sterically more
demanding aryl group gave better yields: 1bꢀNp and 1bꢀXyl formed the corresponding isoindolinones
2
bꢀNp and 2bꢀXyl in 55 and 39% GC yields, respectively, while simple phenyl and paraꢀsubstituted
phenyl groups largely dropped the yield regardless of their electronic property (2bꢀPh, 2bꢀOMe, and
bꢀCF3). Potentially doubly coordinated Nꢀpyridyl and Nꢀ(pyridyl)methyl as well as aliphatic
tertꢀbutyl substituents delivered only trace amount of the cyclized products (2bꢀPy, 2bꢀCH Py, and
2
2
2
bꢀt-Bu). Although the exact reason is not clear yet, the dihedral angle between the amide CON and
aryl (on nitrogen) planes may play a pivotal role in these cases. The acidity of the amide NH can also
2
3
be important, but it gave secondary effects on the reaction efficiency.
Scheme 10. Effects of Substituents on Nitrogen of Benzamide Substrates
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 32
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Notably, in contrast to the quinolineꢀcontaining 1b, the reaction of 1bꢀNp was relatively largely
inhibited by the radical inhibitors (maximum 76% decrease of the yield; Scheme 11 vs Scheme 8).
Moreover, the unsymmetrical 2ꢀmethylꢀ6ꢀpentylbenzamide derivative 1i-Np showed the different
reactivity from the original 1i: the unique pentacyclic compound 2i-Np’ was formed as a single syn
diastereomer (the relative stereochemistry was assigned by the coupling constant of vicinal protons; J =
1
2.0 Hz), via preferable cyclization at more sterically congested methylene benzylic CꢀH of 1iꢀNp albeit
with lower conversion. The 1j-Np, which is naphthyl analogue to 1j, was also predominantly
converted to the more sterically demanding methine C–H aminated product 2j-Np with concomitant
formation of the pentacyclic 2j-Np’ (Scheme 12). Although the details remain to be elucidated, these
results
suggest
that
a
distinct
mechanism,
namely,
an
aminylꢀradical–mediated
2
4
HofmannꢀLofflerꢀFreytag (HLF)ꢀtype mechanism can be operative in the case of 1bꢀNp (Scheme 13).
Initial binding of 1bꢀNp to Cu(OR) and oxidation (disproportionation) with additional Cu(OR)
2
2
generates a Cu(III)ꢀamide intermediate 7. The homolysis of the Cu(III)–N bond of 7 is followed by a
,5ꢀH shift of an aminyl radical 8 to form a benzyl radical 9. Subsequent one electron oxidation with
1
Cu(OR) and ring closure by an intramolecular nucleophilic attack of the amide nitrogen furnish the
2
ACS Paragon Plus Environment
12

Page 13 of 32
The Journal of Organic Chemistry
2
5
isoindolinone 2bꢀNp together with CuOR.
Final oxidation with MnO /ROH regenerates the starting
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cu(OR) to complete the catalytic cycle. The proposed Cuꢀmodified HLFꢀtype pathway can explain
2
phenomena observed in Schemes 11 and 12: radical scavengers such as TEMPO and 1,4ꢀdinitrobenzene
are detrimental to radical intermediates 8 and 9 (Scheme 11), and the 1,5ꢀH shift predominantly gives
2
6
more stable secondary carbonꢀcentered radicals than primary ones (Scheme 12).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 11. Effects of Radical Inhibitors for 1b-Np
Scheme 12. Reactions of Naphthyl-Containing Unsymmetrical 2-Methyl-6-pentylbenzamide 1i-Np
and 2-Isopropyl-6-methylbenzamide 1j-Np
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 32
Scheme 13. Plausible Mechanism for 1b-Np. R = Ac or 1-AdCO.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conclusion
3
We have developed a copperꢀcatalyzed intramolecular benzylic sp C–H amination of
orthoꢀmethylbenzamides for the synthesis of isoindolinones, which are of potent interest in medicinal
chemistry. The cheap, safe, and abundant MnO works well as a terminal oxidant, and the process
2
does not necessitate potentially explosive organic peroxides, which are indispensable in related
10
precedents.
Additionally, the directingꢀgroupꢀdependent divergent mechanism is proposed: the
8ꢀaminoquinolineꢀcontating substrates include a Cu(I)/(II)/(III) organometallic pathway while a
Cuꢀmodified, aminyl radicalꢀmediated HLFꢀtype mechanism is operative in the case of benzamide that
2
7
bear simpler aryl group on the nitrogen. Although the substrate scope is still somewhat narrow, the
results obtained herein can provide useful information for the design of new and more efficient C–H
activation catalysis based on copper.
Experimental Section
ACS Paragon Plus Environment
14

Page 15 of 32
The Journal of Organic Chemistry
1
13
Instrumentation and Chemicals H and C NMR spectra were recorded at 400 and 100 MHz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
respectively, for CDCl solutions. HRMS data were obtained by APCI using TOF. GC analysis was
3
carried out using a silicon OVꢀ17 column (2.6 mm i.d. x 1.5 m) or a CBPꢀ1 capillary column (0.5 mm
i.d. x 25 m). TLC analyses were performed on commercial glass plates bearing a 0.25 mm layer of
Merck silica gel 60F254. Silica gel was used for column chromatography. Gel permeation
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography (GPC) was performed with a CHCl or an ethyl acetate eluent (UV detector).
3
+
Microwave irradiation was conducted with Initiator (Biotage), and the reaction temperature was
measured by an internal probe. Unless otherwise noted, materials obtained from commercial suppliers
were used as received. Diglyme was freshly distilled from CaH prior to use. Cu(OPiv) was
2
2
2
8
prepared according to the literature.
Preparation of Benzamides 1.
29
Synthesis of 1b. 8ꢀAminoquinoline (2.3 g, 16 mmol) and N,Nꢀdimethyꢀ4ꢀaminopyridine (DMAP;
550 mg, 4.5 mmol) were placed in a 50 mL twoꢀnecked reaction flask, and the flask was flushed with
nitrogen. Anhydrous dichloromethane (20 mL) and Et N (3.0 mL, 18 mmol) were added, and the
3
resulting solution was cooled to 0 °C. 2,4,6ꢀTrimethylbenzoyl chloride (2.5 mL, 15 mmol) was added
dropwise, and reaction mixture was stirred at room temperature for 4 h. The mixture was quenched
with water (30 mL) and extracted with CH Cl (3 x 20 mL). Combined organic phase was dried over
2
2
anhydrous Na SO . After concentration under reduced pressure, silica gel column purification with
2
4
hexane/ethyl acetate (5/1, v/v) afforded 2,4,6ꢀtrimethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1b; 3.0 g, 10
mmol) in 68% yield. Other benzamides 1bꢀNp, 1c, and 1r were prepared by the same procedure.
3
0
Synthesis of 1e.
To a 20 mL microwave vessel, 4ꢀmethoxyꢀNꢀ(8ꢀquinolinyl)benzamide (840 mg,
3
.0 mmol), which was synthesized from the corresponding benzoyl chloride and 8ꢀaminoquinoline by
the same procedure as that for 1b, methyl pꢀtoluenesulfonate (1,8 mL, 12 mmol), Ni(OTf) (210 mg, 0.6
2
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 32
mmol), PPh (310 mg, 1.2 mmol), Na CO (1.3 g, 12 mmol), NaI (1.8 g, 12 mmol) and toluene (10 mL)
3
2
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
were added in a glovebox. The vessel was sealed with a cap and then taken out of the glovebox. The
mixture was stirred for 24 h at 160 °C. The resulting mixture was then filtered through a short pad of
celite. After concentration under reduced pressure, silica gel column purification with hexane/ethyl
acetate
(5/1,
v/v)
followed
by
GPC
(chloroform)
afforded
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
ꢀmethoxyꢀ2,6ꢀdimethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1e; 670 mg, 2.3 mmol) in 76% yield as a white
solid. Other benzamides 1d, 1f, 1g, 1h, and 1j were prepared by the same procedure.
10c
Synthesis of 1i.
To a 100 mL twoꢀnecked reaction flask which was filled with nitrogen,
diisopropylamine (3.5 ml, 25 mmol), anhydrous THF (25 mL), and nBuLi (1.6 M in hexane, 16 mL, 25
mmol) were added dropwise at 0 °C. The solution was stirred at the same temperature for 1 h to
prepare a LDA solution. To another round bottom flask which was flushed with nitrogen, a solution of
2
,6ꢀdimethylbenzoic acid (1.5 g, 10 mmol) in THF (15 mL) was added and cooled to 0 °C. The LDA
solution prepared in advance was transferred via a syringe to the reaction mixture. After stirring the
solution for 1.5 h at 0 °C, nꢀbutyl bromide (3.2 mL, 30 mmol) was added dropwise. The solution was
warmed to room temperature and stirred overnight. The reaction was quenched with 10% HCl aq. (30
mL) and the reaction mixture was extracted with Et O (3 x 60 mL). The combined organic phase was
2
concentrated under vacuum. The crude product was redissolved in Et O (20 mL) and extracted with
2
aqueous 20% KOH (3 x 30 mL) solution. The combined aqueous phase was diluted with ether (30 mL
x 3) and acidified with 2.0 M HCl aq. to pH = 1. The aqueous phase was extracted with Et O (60 mL
2
x 3). The combined organic phase was washed with water (60 mL) and brine (100 mL), and then dried
over Na SO . After the filtration and evaporation, a mixture of monoꢀ and dialkylated benzoic acids
2
4
was obtained, which was used for the next step without further purifications. The obtained crude
benzoic acid was then dissolved in SOCl (8.0 mL) and heated at 100 ˚C overnight. After excess
2
SOCl was removed under reduced pressure at 80 ˚C, the residual oil was dissolved in CH Cl (16 mL).
2
2
2
8
ꢀAminoquinoline (1.2 g, 8.0 mmol), N,Nꢀdimethyꢀ4ꢀaminopyridine (DMAP; 293 mg, 2.4 mmol), and
ACS Paragon Plus Environment
16

Page 17 of 32
The Journal of Organic Chemistry
Et N (1.3 mL, 9.6 mmol) were sequentially added at 0 ˚C, and the solution was stirred for 4 h at room
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
temperature. The resulting mixture was quenched with NH Cl aq. (30 mL) and extracted with CH Cl
2
4
2
(3 x 20 mL). Combined organic phase was dried over anhydrous Na SO . After concentration under
2
4
reduced pressure, silica gel column purification with hexane/ethyl acetate (5/1, v/v) followed by GPC
chloroform) afforded 6ꢀmethylꢀ2ꢀpentylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1i; 898 mg, 2.7 mmol) in 27%
overall yield. The 1iꢀNp was also prepared under similar conditions.
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10c
Synthesis of 1p.
To a 100 mL twoꢀnecked reaction flask which was filled with nitrogen,
diisopropylamine (2.8 ml, 20 mmol), anhydrous THF (20 mL), and nBuLi (1.6 M in hexane, 13 mL, 20
mmol) were added dropwise at 0 °C. The solution was stirred at the same temperature for 1 h to
prepare a LDA solution. To another round bottom flask which was flushed with nitrogen, a solution of
2
,5ꢀdimethylbenzoic acid (1.5 g, 10 mmol) in THF (15 mL) was added and cooled to 0 °C. The LDA
solution prepared in advance was transferred via a syringe to the reaction mixture. After stirring the
solution for 1.5 h at 0 °C, nꢀbutyl bromide (2.2 mL, 20 mmol) was added dropwise. The solution was
warmed to room temperature and stirred overnight. The reaction was quenched with 10% HCl aq. (30
mL) and the reaction mixture was extracted with Et O (3 x 60 mL). The combined organic phase was
2
concentrated under vacuum. The crude product was redissolved in Et O (20 mL) and extracted with
2
aqueous 20% KOH (3 x 30 mL) solution. The combined aqueous phase was diluted with ether (30 mL
x 3) and acidified with 2.0 M HCl aq. to pH = 1. The aqueous phase was extracted with Et O (60 mL
2
x 3). The combined organic phase was washed with water (60 mL) and brine (100 mL), and then dried
over Na SO . After the filtration and evaporation, a mixture of monoꢀ and dialkylated benzoic acids
2
4
was obtained, which was used for the next step without further purifications. The residual solid,
ꢀaminoquinoline (650 mg, 4.5 mmol), N,Nꢀdimethyꢀ4ꢀaminopyridine (DMAP; 550 mg, 4.5 mmol), and
8
1ꢀ(3ꢀdimethylaminopropyl)ꢀ3ꢀethylcarbodiimide hydrochloride (EDCI・HCl; 1.3 g, 6.8 mmol) were
placed in a 50 mL twoꢀnecked reaction flask, and the flask was flushed with nitrogen. Anhydrous
CH Cl (9.0 mL) was added. The resulting solution was cooled to 0 °C and Et N (1.3 mL, 9.0 mmol)
2
2
3
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 32
was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was
quenched with NH Cl aq. (30 mL) and extracted with CH Cl (3 x 20 mL). Combined organic phase
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
2
2
was dried over anhydrous Na SO . After concentration under reduced pressure, silica gel column
2
4
purification with hexane/ethyl acetate (5/1, v/v) followed by GPC (chloroform) afforded
5
ꢀmethylꢀ2ꢀpentylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1p; 860 mg, 2.6 mmol) in 26% overall yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
29
Synthesis of 1l.
2,5ꢀDimethylbenzoic acid (2.3 g, 15 mmol), 8ꢀaminoquinoline (2.4 g, 17 mmol),
(DMAP; 1.8 g, 15 mmol), and
ꢀ(3ꢀdimethylaminopropyl)ꢀ3ꢀethylcarbodiimide hydrochloride (EDCI・HCl; 4.3 g, 23 mmol) were
N,Nꢀdimethyꢀ4ꢀaminopyridine
1
placed in a 50 mL twoꢀnecked reaction flask, and the flask was flushed with nitrogen. Anhydrous
dichloromethane (20 mL) was added to the solution. The resulting solution was cooled to 0 °C, and
Et N (4.2 mL, 30 mmol) was added. The reaction mixture was stirred at room temperature for 18 h.
3
The mixture was quenched with NH Cl aq. (30 mL) and extracted with CH Cl (3 x 20 mL).
4
2
2
Combined organic phase was dried over anhydrous Na SO . After concentration under reduced
2
4
pressure, silica gel column purification with hexane/ethyl acetate (5/1, v/v) afforded
,5ꢀdimethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1l; 3.7 g, 13 mmol) in 89% yield. Other benzamides 1n
2
and 1o were prepared by the same procedure.
Synthesis of 1m. To a 100 mL twoꢀnecked reaction flask charged with 3ꢀbromoꢀ4ꢀmethylanisole
(
1.5 mL, 10 mmol) and anhydrous Et O (61 mL), nBuLi (1.6 M in hexanes, 6.1 mL, 10 mmol) was
2
added dropwise at 0 ºC. After the solution was stirred for 1.5 h, solid dry ice was added slowly. The
reaction mixture was warmed up to room temperature and stirred for additional 30 min. The reaction
was quenched with 10% HCl aq. (60 mL) and washed with Et O (20 mL x 3). The aqueous layer was
2
then acidified with conc. HCl to pH = 1 and extracted with Et O (20 mL x 3). The combined organic
2
layers were washed with brine, dried over anhydrous Na SO , and concentrated under reduced pressure.
2
4
The residual solid, 8ꢀaminoquinoline (720 mg, 5.0 mmol), N,Nꢀdimethyꢀ4ꢀaminopyridine (DMAP; 610
ACS Paragon Plus Environment
18

Page 19 of 32
The Journal of Organic Chemistry
mg, 5.0 mmol), and 1ꢀ(3ꢀdimethylaminopropyl)ꢀ3ꢀethylcarbodiimide hydrochloride (EDCI・HCl; 1.4 g,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7.5 mmol) were placed in a 50 mL twoꢀnecked reaction flask, and the flask was flushed with nitrogen.
Anhydrous CH Cl (10 mL) was added to this solution. The resulting solution was cooled to 0 °C, and
2
2
Et N (1.4 mL, 10 mmol) was added. The reaction mixture was stirred at room temperature for 18 h.
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The mixture was quenched with NH Cl aq. (30 mL) and extracted with CH Cl (3 x 20 mL).
4
2
2
Combined organic phase was dried over anhydrous Na SO . After concentration under reduced
2
4
pressure, silica gel column purification with hexane/ethyl acetate (5/1, v/v) followed by GPC
chloroform) afforded 5ꢀmethoxyꢀ2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1m; 910 mg, 3.1 mmol) in
(
3
1% overall yield.
Synthesis of 1j-Np. A suspension of 2ꢀisopropylꢀ6ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1j; 365
mg, 1.2 mmol) in aq. H SO (40%, 2.5 mL) was heated at 120 ˚C for 24 h. After being cooled to room
2
4
temperature, the mixture was extracted with Et O, and the combined organic layer was dried over
2
anhydrous Na SO . Subsequent filtration and evaporation formed 2ꢀisopropylꢀ6ꢀmethylbenzoic acid
2
4
(205 mg, 1.2 mmol) in 96% yield. The crude 2ꢀisopropylꢀ6ꢀmethylbenzoic acid (303 mg, 1.7 mmol)
was then dissolved in SOCl (2.0 mL) and heated at 100 ˚C overnight. After excess SOCl was
2
2
removed under reduced pressure at 80 ˚C, the residual oil was dissolved in CH Cl (3.5 mL).
2
2
1ꢀAminonaphthalene (243 mg, 1.7 mmol), N,Nꢀdimethyꢀ4ꢀaminopyridine (DMAP; 62 mg, 0.51 mmol),
and Et N (0.28 mL, 2.0 mmol) were sequentially added at 0 ˚C, and the solution was stirred for 4 h at
3
room temperature. The resulting mixture was quenched with NH Cl aq. (30 mL) and extracted with
4
CH Cl (3 x 20 mL). Combined organic phase was dried over anhydrous Na SO . After
2
2
2
4
concentration under reduced pressure, silica gel column purification with hexane/ethyl acetate (5/1, v/v)
followed by GPC (chloroform) afforded 2ꢀisopropylꢀ6ꢀmethylꢀNꢀ(naphthalenꢀ1ꢀyl)benzamide (1j-Np;
181 mg, 0.60 mmol) in 35% yield.
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 32
Synthesis of 1l-d . To a solution of pꢀtoluenesulfonyl chloride (TsCl; 1.5 g, 8.0 mmol) in THF (5.8
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mL), CD OD (580 mg, 16 mmol) and 20% NaOH aq. (4.0 mL) were added at 0 °C. After 4 h, the
3
mixture was diluted with water and extracted with ether. The combined organic phase was washed
with saturated NH Cl aq. and brine. The organic phase was dried over anhydrous Na SO , filtered, and
4
2
4
3
1
concentrated in vacuo to give TsOCD (1.5 g, 7.7 mmol, 96%, >99% D) as a colorless oil.
To a 20
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
mL microwave vessel, 3ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (700 mg, 2.7 mmol), TsOCD (1.0 g, 5.3
3
mmol), Ni(OTf) (95 mg, 0.27 mmol), PPh (140 mg, 0.53 mmol), Na CO (560 mg, 5.3 mmol), NaI
2
3
2
3
(790 mg, 5.3 mmol), and toluene (9.0 mL) were added in a glovebox. The vessel was sealed with a
cap and then taken out of the glovebox. The mixture was stirred for 24 h at 140 °C. The resulting
mixture was then filtered through a short pad of celite. After concentration under reduced pressure,
silica gel column purification with hexane/ethyl acetate (5/1, v/v) followed by GPC (chloroform)
afforded 5ꢀmethylꢀ2ꢀ(methylꢀd )ꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1lꢀd ; 380 mg , 1. 4 mmol, >99% D) in
3
3
5
1 % yield.
Typical Procedure for Copper-Catalyzed Intramolecular Benzylic C–H Amination of
,6-Disubstituted Benzamides 1. The synthesis of 2b is representative (Scheme 4). Cu(OAc) (9.1
2
2
mg, 0.050 mmol), 2,4,6ꢀtrimethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1b; 73 mg, 0.25 mmol),
ꢀadamantanecarboxylic acid (18 mg, 0.10 mmol), and MnO (130 mg, 1.5 mmol) were placed in a 2.0
1
2
mL microwave vessel, and the vessel was flushed with nitrogen. Diethylene glycol dimethyl ether
diglyme, 1.5 mL) was sequentially injected via a syringe. The mixture was irradiated under
(
microwave reactor conditions at 200 °C for 2 h. The resulting mixture was then quenched with water.
The mixture was extracted with ethyl acetate three times, and the combined organic layer was dried over
anhydrous Na SO . After concentration under reduced pressure, silica gel column purification with
2
4
hexane/ethyl acetate (2/1, v/v) afforded 5,7ꢀdimethylꢀ2ꢀ(quinolinꢀ8ꢀyl)isoindolinꢀ1ꢀone (2b; 60 mg, 0.21
mmol) in 83% yield.
ACS Paragon Plus Environment
20

Page 21 of 32
The Journal of Organic Chemistry
5
,7-Dimethyl-2-(quinolin-8-yl)isoindolin-1-one (2b) Purified by column chromatography on silica
1
2
o
1
gel with hexane/ethyl acetate (2:1, v/v) as an eluent; 60 mg (83%); yellow solid; mp 178.5ꢀ180.0 C; H
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (400 MHz, CDCl ) δ 2.44 (s, 3H), 2.75(s, 3H), 5.18 (s, 2H), 7.06 (s, 1H), 7.13 (s, 1H), 7.41 (dd, J
3
=
4.2, 8.3 Hz, 1H), 7.61 (dd, J = 7.5, 8.0 Hz, 1H), 7.81 (dd, J = 1.2. 8.2 Hz, 1H), 7.91 (dd, J = 1.4, 7.4
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1H), 8.20 (dd, J = 1.7, 8.3 Hz, 1H), 8.87 (dd, J = 1.7, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
1
1
2
7.4, 21.8, 53.1, 120.7, 121.3, 126.4, 127.1, 127.3, 128.9, 129.5, 130.9, 135.9, 136.4, 138.0, 141.8,
+
43.5, 144.5, 150.0, 169.7; HRMS (APCI) m/z ([M+H] ) calcd for C H N O: 289.1335, found:
19 17
2
89.1336. Xꢀray quality crystals were grown from dichloromethane/heptane.
7-Methyl-2-(quinolin-8-yl)isoindolin-1-one (2c) Purified by column chromatography on silica gel
o
1
with hexane/ethyl acetate (2:1, v/v) as an eluent; 55 mg (80%); yellow solid; mp 172.3ꢀ173.9 C; H
NMR (400 MHz, CDCl ) δ 2.79 (s, 3H), 5.23 (s, 2H), 7.25 (d, J = 6.4 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H),
3
7
.42 (dd, J = 4.2, 8.3 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.63 (dd, J = 7.5, 8.1 Hz, 1H), 7.82 (dd, J = 1.3,
.2 Hz, 1H), 7.92 (dd, J = 1.4, 7.4 Hz, 1H), 8.21 (dd, J = 1.7, 8.3 Hz, 1H) , 8.88 (dd, J = 1.8, 4.2 Hz,
8
1
3
1H); C NMR (100 MHz, CDCl ) δ 17.5, 53.2, 120.1, 121.4, 126.4, 127.4, 128.9, 129.5, 129.6, 129.9,
3
+
1
31.3, 135.7, 136.4, 138.3, 143.1, 144.5, 150.0, 169.6; HRMS (APCI) m/z ([M+H] ) calcd for
C H N O: 275.1179, found: 275.1184.
18 15
2
5
-(tert-Butyl)-7-methyl-2-(quinolin-8-yl)isoindolin-1-one (2d) Purified by column chromatography
on silica gel with hexane/ethyl acetate (2/1, v/v) as an eluent; 66 mg (80%), yellow solid; mp 65.3ꢀ67.1
o
1
C; H NMR (400 MHz, CDCl ) δ 1.38 (s, 9H), 2.78 (s, 3H), 5.21 (s, 2H), 7.27 (s, 1H), 7.34 (s, 1H),
3
7
.40 (dd, J = 4.2, 8.3 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.80 (dd, J = 1.3, 8.2 Hz, 1H), 7.90 (dd, J = 1.4.
1
3
7
.4 Hz, 1H), 8.18 (dd, J = 1.7, 8.3 Hz, 1H), 8.86 (dd, J = 1.7, 4.2 Hz, 1H); C NMR (100 MHz, CDCl )
3
δ 17.7, 31.4, 35.1, 53.3, 117.0, 121.3, 126.4, 127.2, 127.3 (2C), 128.9, 129.5, 135.9, 136.3, 137.6, 143.2,
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 32
+
1
44.6, 150.0, 155.2, 169.6; HRMS (APCI) m/z ([M+H] ) calcd for C H N O: 331.1805, found:
22
23
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
31,1809.
5
-Methoxy-7-methyl-2-(quinolin-8-yl)isoindolin-1-one (2e) Purified by column chromatography on
silica gel with hexane/ethyl acetate (2:1, v/v) as an eluent; 56 mg (73%); yellow solid; mp 202.6ꢀ204.3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
C; H NMR (400 MHz, CDCl ) δ 2.75 (s, 3H), 3.87 (s, 3H), 5.19 (s, 2H), 6.78 (s, 1H), 6.82 (s, 1H),
3
7
.40 (dd, J = 4.2, 8.3 Hz, 1H), 7.61 (dd, J = 7.5 Hz, 1H), 7.79 (dd, J = 1.3, 8.2 Hz, 1H), 7.91 (dd, J =
1
3
1.4, 7.4 Hz, 1H), 8.19 (dd, J = 1.7, 8.3 Hz, 1H), 8.87 (dd, J = 1.8, 4.2 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 17.6, 53.1, 55.6, 104.9, 116.3, 121.3, 122.6, 126.4, 127.2, 128.8, 129.5, 135.9, 136.4, 140.0,
3
+
144.5, 145.5, 149.9, 162.5, 169.4; HRMS (APCI) m/z ([M+H] ) calcd for C H N O : 305.1285,
1
9
17
2
2
found: 305.1284.
5-Chloro-7-methyl-2-(quinolin-8-yl)isoindolin-1-one (2f) Purified by column chromatography on
silica gel with hexane/ethyl acetate (2/1, v/v) as an eluent; 46 mg (59%), yellow solid; mp 182.5ꢀ184.2
o
1
C; H NMR (400 MHz, CDCl ) δ 2.76 (s, 3H), 5.20 (s, 2H), 7.25 (s, 1H), 7.32 (s, 1H), 7.42 (dd, J =
3
4
8
1
1
.2, 8.3 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.82 (dd, J = 1.3, 8.2 Hz, 1H), 7.90 (dd, J = 1.3. 7.4 Hz, 1H),
1
3
.20 (dd, J = 1.7, 8.3 Hz, 1H), 8.90 (dd, J = 1.7, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 17.2, 52.8,
3
20.5, 121.4, 126.4, 127.6, 128.2, 128.8, 129.5, 130.1, 135.3, 136.4, 137.4, 140.0, 144.3, 144.6, 150.1,
+
68.7; HRMS (APCI) m/z ([M+H] ) calcd for C H ClN O: 309.0789, found: 309.0785.
1
8
14
2
5
-Bromo-7-methyl-2-(quinolin-8-yl)isoindolin-1-one (2g) Purified by column chromatography on
silica gel with hexane/ethyl acetate (2/1, v/v) as an eluent; 41 mg (46%), yellow solid; mp 207.3ꢀ208.9
o
1
C; H NMR (400 MHz, CDCl ) δ 2.76 (s, 3H), 5.21 (s, 2H), 7.41ꢀ7.42 (m, 1H), 7.44 (d, J = 4.2 Hz,
3
1
H), 7.49 (s, 1H), 7.62 (dd, J = 7.5, 8.2 Hz, 1H), 7.83 (dd, J = 1.3, 8.2 Hz, 1H), 7.90 (dd, J = 1.4. 7.4
1
3
Hz, 1H), 8.21 (dd, J = 1.7, 8.3 Hz, 1H), 8.87 (dd, J = 1.7, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
ACS Paragon Plus Environment
22

Page 23 of 32
The Journal of Organic Chemistry
1
1
7.2, 52.7, 121.4, 123.5, 125.8, 126.4, 127.6, 128.7, 128.8, 129.5, 132.9, 135.3, 136.4, 140.2, 144.3,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
44.8, 150.1, 168.8; HRMS (APCI) m/z ([M+H] ) calcd for C H BrN O: 353.0284, found: 353.0286.
1
8
14
2
5
-Iodo-7-methyl-2-(quinolin-8-yl)isoindolin-1-one (2h) Purified by column chromatography on
silica gel with hexane/ethyl acetate (2/1, v/v) as an eluent; 39 mg (39%), yellow solid; mp 231.9ꢀ233.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
C; H NMR (400 MHz, CDCl ) δ 2.73 (s, 3H), 5.19 (s, 2H), 7.43 (dd, J = 4.2, 8.3 Hz, 1H), 7.60ꢀ7.64
3
(m, 2H), 7.71 (s, 1H), 7.83 (dd, J = 1.3, 8.2 Hz, 1H), 7.90 (dd, J = 1.4, 8.4 Hz, 1H), 8.21 (dd, J = 1.7.
13
8
.3 Hz, 1H), 8.87 (dd, J = 1.7, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 17.0, 52.5, 98.3, 121.4,
3
1
26.4, 127.6, 128.9, 129.3, 129.4, 129.5, 135.2, 136.4, 138.8, 140.2, 144.3, 144.8, 150.1, 168.9; HRMS
+
(APCI) m/z ([M+H] ) calcd for C H IN O: 401.0145, found: 401.0147.
1
8
14
2
7
-Pentyl-2-(quinolin-8-yl)isoindolin-1-one (2i) Purified by column chromatography on silica gel
1
with hexane/ethyl acetate (3:1, v/v) as an eluent; 45 mg (55%); yellow oil; H NMR (400 MHz, CDCl )
3
δ 0.87 (t, J = 7.0, 3H), 1.31ꢀ1.43 (m, 4H), 1.68ꢀ1.75 (m, 2H), 3.21 (t, J = 7.8 Hz, 2H), 5.24 (s, 2H), 7.27
(d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.42 (dd, J = 4.2, 8.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H),
7
1
3
1
.62 (dd, J =7.6, 8.0 Hz, 1H), 7.81 (dd, J = 1.4, 8.2 Hz, 1H), 7.93 (dd, J = 1.4, 7.4 Hz, 1H), 8.20 (dd, J =
1
3
.7, 8.3 Hz, 1H), 8.88 (dd, J = 1.7, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 14.1, 22.6, 31.1, 31.3,
3
1.9 53.2, 120.2, 121.4, 126.4, 127.3, 128.9, 129.0, 129.1, 129.5, 131.3, 135.7, 136.4, 143.3, 143.6,
+
44.4, 150.0, 169.3; HRMS (APCI) m/z ([M+H] ) calcd for C H N O: 331.1805, found: 331.1804.
2
2
23
2
7
-Isopropyl-2-(quinolin-8-yl)isoindolin-1-one (2j) Purified by column chromatography on silica gel
o
1
with hexane/ethyl acetate (3:1, v/v) as an eluent; 36 mg (48%); yellow solid; mp 164.9ꢀ166.3 C; H
NMR (400 MHz, CDCl ) δ 1.33 (d, J =6.9 Hz, 6H), 4.48 (septet, J =6.9 Hz, 1H), 5.23 (s, 2H), 7.33 (d, J
3
=
7.4 Hz, 1H), 7.40ꢀ7.44 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.82 (dd, J = 1.0, 8.3
Hz, 1H), 7.93 (dd, J = 1.3, 7.4 Hz, 1H), 8.20 (dd, J = 1.1, 8.2 Hz, 1H), 8.88 (dd, J = 1.7, 4.2 Hz, 1H);
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 32
1
3
C NMR (100 MHz, CDCl ) δ 23.5, 26.8, 53.0, 120.1, 121.4, 124.7, 126.4, 127.3, 128.2, 128.9, 129.5,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
131.7, 135.8, 136.4, 143.1, 144.5, 149.7, 150.0, 169.3; HRMS (APCI) m/z ([M+H] ) calcd for
C H N O: 303.1492, found: 303.1489.
20
19
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2-(5-Methoxyquinolin-8-yl)-5,7-dimethylisoindolin-1-one (2r) Purified by column chromatography
on silica gel with hexane/ethyl acetate (2:1, v/v) as an eluent; 48 mg (60%); yellow solid; mp
o
1
2
6
1
18.9ꢀ220.6 C; H NMR (400 MHz, CDCl ) δ 2.43 (s, 3H), 2.74 (s, 3H), 4.04 (s, 3H), 5.06 (s, 2H),
3
.91 (d, J = 8.3 Hz, 1H), 7.05 (s, 1H), 7.12 (s, 1H), 7.38 (dd, J = 4.2, 8.5 Hz, 1H), 7.76 (d, J = 8.2 Hz,
13
H), 8.60 (dd, J = 1.8, 8.5 Hz, 1H), 8.85 (dd, J = 1.8, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 17.3,
3
21.7, 53.1, 55.9, 103.9, 120.4, 120.6, 121.6, 127.3, 128.4, 129.2, 130.8, 131.1, 137.8, 141.6, 143.5,
+
1
3
45.2, 150.4, 154.6, 169.9; HRMS (APCI) m/z ([M+H] ) calcd for C H N O : 319.1441, found:
2
0
19
2
2
19.1441.
5
,7-Dimethyl-2-(naphthalen-1-yl)isoindolin-1-one (2b-Np) Purified by column chromatography on
silica gel with hexane/ethyl acetate (2:1, v/v) followed by GPC with ethyl acetate as an eluent; 27 mg
o
1
(
(
(
38%); yellow solid; mp 164.2ꢀ165.9 C; H NMR (400 MHz, CDCl ) δ 2.46 (s, 3H), 2.75 (s, 3H), 4.78
3
1
3
s, 2H), 7.13 (d, J = 10.6 Hz, 2H), 7.45ꢀ7.55 (m, 4H), 7.72ꢀ7.74 (m, 1H), 7.87ꢀ7.93 (m, 2H); C NMR
100 MHz, CDCl ) δ 17.2, 21.8, 53.4, 120.8, 123.1, 125.6, 125.7, 126.3, 126.8, 126.9, 128.4, 128.5,
3
+
1
30.7, 131.4, 134.6, 135.5, 138.2, 142.0, 142.8, 169.5; HRMS (APCI) m/z ([M+H] ) calcd for
C H NO: 288.1383, found: 288.1382.
20
18
Typical Procedure for Copper-Catalyzed Intramolecular Benzylic C–H Amination of
2
,5-Disubstituted Benzamides 1 and 2,6-Disubstituted Benzamides 1i-Np and 1j-Np. The
synthesis
of
2l
is
representative.
Cu(OPiv)2
(13
mg,
0.050
mmol),
2,5ꢀdimethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1l; 69 mg, 0.25 mmol), pivalic acid (26 mg, 0.25 mmol), and
ACS Paragon Plus Environment
24

Page 25 of 32
The Journal of Organic Chemistry
MnO (130 mg, 1.5 mmol) were placed in a 2.0 mL microwave vessel, and the vessel was flushed with
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
nitrogen. Diethylene glycol dimethyl ether (diglyme, 1.5 mL) was sequentially injected via a syringe.
The mixture was irradiated under microwave reactor conditions at 200 °C for 1 h. The resulting
mixture was then quenched with water. The mixture was extracted with ethyl acetate three times, and
the combined organic layer was dried over anhydrous Na SO . After concentration under reduced
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
pressure, silica gel column purification with hexane/ethyl acetate (1/1, v/v) afforded
ꢀmethylꢀ2ꢀ(quinolinꢀ8ꢀyl)isoindolinꢀ1ꢀone (2l; 45 mg, 0.16 mmol) in 65% yield.
6
6
-Methyl-2-(quinolin-8-yl)isoindolin-1-one (2l) Purified by column chromatography on silica gel
o
1
with hexane/ethyl acetate (1:1, v/v) as an eluent; 45 mg (65%); yellow solid; mp 167.6ꢀ168.9 C; H
NMR (400 MHz, CDCl ) δ 2.49 (s, 3H), 5.25 (s, 2H), 7.40ꢀ7.45 (m, 3H), 7.64 (dd, J = 7.5, 8.1 Hz, 1H),
3
7
.83 (dd, J = 1.3, 8.3 Hz, 2H), 7.93 (dd, J = 1.4, 7.4 Hz, 1H), 8.21 (dd, J = 1.7, 8.3 Hz, 1H), 8.89 (dd, J
1
3
= 1.8, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 21.4, 53.7, 121.4, 122.4, 124.5, 126.5, 127.5, 128.7,
3
+
1
29.5, 132.7, 132.8, 135.7, 136.4, 137.9, 139.7, 144.3, 150.0, 169.0; HRMS (APCI) m/z ([M+H] ) calcd
for C H N O: 275.1179, found: 275.1177.
18 15
2
6
-Methoxy-2-(quinolin-8-yl)isoindolin-1-one (2m) Purified by column chromatography on silica gel
o
with hexane/ethyl acetate (5/1, v/v) as an eluent; 38 mg (53%), pale yellow solid; mp 163.8ꢀ165.2 C;
1
H NMR (400 MHz, CDCl ) δ 3.90 (s, 3H), 5.21 (s, 2H), 7.18 (dd, J = 2.5, 8.3 Hz, 1H), 7.40ꢀ7.44 (m,
3
2
7
H), 7.49 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.83 (dd, J = 1.3, 8.2 Hz, 1H), 7.93 (dd, J = 1.4,
1
3
.4 Hz, 1H), 8.21 (dd, J = 1.7, 8.3 Hz, 1H), 8.88 (dd, J = 1.8, 4.2 Hz, 1H); C NMR (100 MHz, CDCl )
3
δ 53.5, 55.8, 106.8, 120.4, 121.4, 123.6, 126.5, 127.5, 128.6, 129.5, 133.9, 134.8, 135.7, 136.4, 144.3,
+
150.0, 159.9, 168.9; HRMS (APCI) m/z ([M+H] ) calcd for C H N O : 291.1128, found: 291.1124.
1
8
15
2
2
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 32
6
-Chloro-2-(quinolin-8-yl)isoindolin-1-one (2n) Purified by column chromatography on silica gel
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
with hexane/ethyl acetate (1:1, v/v) as an eluent; 48 mg (65%); yellow solid; mp 159.6ꢀ161.9 C; H
NMR (400 MHz, CDCl ) δ 5.28 (s, 2H), 7.43ꢀ7.48 (m, 2H), 7.58 (dd, J = 2.0, 8.0 Hz, 1H), 7.64 (dd, J =
3
7
.5, 8.1 Hz, 1H), 7.85 (dd, J = 1.4, 7.4 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 8.22
13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(dd, J = 1.7, 8.3 Hz, 1H), 8.88 (dd, J = 1.8, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 53.5, 121.5,
3
1
24.0, 124.5, 126.4, 127.8, 128.7, 129.5, 131.9, 134.2, 134.4, 135.2, 136.4, 140.6, 144.1, 150.1, 167.5;
+
HRMS (APCI) m/z ([M+H] ) calcd for C H ClN O: 295.0633, found: 295.0630.
17 12
2
6
-Bromo-2-(quinolin-8-yl)isoindolin-1-one (2o) Purified by column chromatography on silica gel
o
1
with hexane/ethyl acetate (1:1, v/v) as an eluent; 38 mg (45%); yellow solid; mp 160.9ꢀ162.6 C; H
NMR (400 MHz, CDCl ) δ 5.26 (s, 2H), 7.40ꢀ7.46 (m, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.73 (dd, J = 1.8,
3
8
.0 Hz, 1H), 7.85 (dd, J = 1.2, 8.2 Hz, 1H), 7.93 (dd, J = 1.3, 7.4 Hz, 1H), 8.13 (d, J = 1.7 Hz, 1H), 8.22
13
(
dd, J = 1.7, 8.3 Hz, 1H), 8.88 (dd, J = 1.7, 4.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 53.6, 121.5,
3
1
21.9, 124.4, 126.4, 127.5, 127.8, 128.7, 129.5, 134.7 (2C), 135.1, 136.4, 141.1, 144.1, 150.1, 167.4;
+
HRMS (APCI) m/z ([M+H] ) calcd for C H BrN O: 339.0128, found: 339.0127.
1
7
12
2
(7R*,7aS*)-11-Methyl-7-propyl-7,7a-dihydro-12H-benzo[g]isoindolo[2,1-a]indol-12-one (2i-Np’)
Purified by column chromatography on silica gel with hexane/ethyl acetate (10:1, v/v) followed by GPC
o
1
with chloroform as an eluent; 15.7 mg (19%); yellow solid; m.p. 142.0ꢀ143.6 C; H NMR (400 MHz,
CDCl ) δ 1.15 (t, J = 7.3 Hz, 3H), 1.60ꢀ1.74 (m, 2H), 2.34ꢀ2.50 (m, 2H), 2.84 (s, 3H), 3.11ꢀ3.13 (dt, J =
3
1
2.0, 3.6 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.46ꢀ7.57 (m, 5 H), 7.65 (dd, J =
1
3
0.9, 8.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 8.43 (dd, J = 1.0, 7.6 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
1
4.7, 16.8, 17.8, 29.5, 43.3, 59.1, 116.1, 121.3, 121.9, 123.7, 123.8, 125.9, 126.2, 126.7, 130.4, 130.9,
+
1
31.3, 133.1, 133.3, 134.0, 138.9, 144.2, 166.6; HRMS (APCI) m/z ([M+H] ) calcd for C H NO:
2
3
22
328.1696, found: 328.1703.
ACS Paragon Plus Environment
26

Page 27 of 32
The Journal of Organic Chemistry
1
2
3
,3,7-Trimethyl-2-(naphthalen-1-yl)isoindolin-1-one (2j-Np) Purified by column chromatography
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
on silica gel with hexane/ethyl acetate (9:1 to 5:1, v/v) as an eluent; 14 mg (18%); white solid; mp
o
1
2
03.2ꢀ204.6 C; H NMR (400 MHz, CDCl ) δ 1.38 (s, 3H), 1.68 (s, 3H), 2.78 (s, 3H), 7.26ꢀ7.27 (m,
3
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1H), 7.30 (d, J = 7.6 Hz, 1H), 7.42ꢀ7.57 (m, 5H), 7.74ꢀ7.77 (m, 1H), 7.90ꢀ7.94 (m, 2H); C NMR (100
MHz, CDCl ) δ 17.5, 26.1, 28.0, 64.4, 118.4, 124.0, 125.4, 126.2, 126.7, 127.3, 128.0, 128.4, 129.1,
3
+
1
30.2, 131.6, 132.1, 132.7, 134.8, 138.6, 153.0, 168.7; HRMS (APCI) m/z ([M+H] ) calcd for
C H NO: 302.1539, found: 302.1540.
21
20
7a,11-Dimethyl-7,7a-dihydro-12H-benzo[g]isoindolo[2,1-a]indol-12-one (2j-Np’) Purified by
column chromatography on silica gel with hexane/ethyl acetate (9:1, v/v) followed by GPC with ethyl
o
1
acetate as an eluent; 29 mg (38%); white solid; mp 177.9ꢀ179.3 C; H NMR (400 MHz, CDCl ) δ 1.39
3
(s, 3H), 2.83 (s, 3H), 3.16 (d, J = 15.0 Hz, 1H), 3.46 (d, J = 15.0 Hz, 1H), 7.26ꢀ7.31 (m, 2H), 7.39 (d, J
=
7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.2
1
3
Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 8.43 (dd, J = 1.1, 7.5 Hz, 1H); C NMR (100 MHz, CDCl ) δ 17.7,
3
2
1
3
3.8, 40.8, 60.7, 117.5, 118.3, 122.8, 123.8, 125.6, 125.9, 126.5, 126.8, 128.3, 129.3, 130.6, 131.5,
+
31.9, 133.6, 138.8, 151.2, 166.4; HRMS (APCI) m/z ([M+H] ) calcd for C H NO: 300.1383, found:
21 18
00.1384.
Procedure for Deprotection of 2r. 2ꢀ(5ꢀMethoxyquinolinꢀ8ꢀyl)ꢀ5,7ꢀdimethylisoindolinꢀ1ꢀone (2r;
4
8 mg, 0.15 mmol) was placed in a 20 mL twoꢀnecked reaction flask, and the flask was flushed with
nitrogen. Anhydrous dichloromethane (1.7 mL) was added to the solution. The resulting solution
was cooled to 0 °C, and BBr (1.0 M dichloromethane solution, 0.60 mL, 0.60 mmol) was added. The
3
reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was
quenched with H O at 0 °C (20 mL) and extracted with chloroform (3 x 20 mL). Combined organic
2
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 32
phase was dried over anhydrous Na SO and concentrated under reduced pressure. The residual solid
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and PhI(TFA) (97 mg, 0.23 mmol) were placed in another 20 mL twoꢀnecked reaction flask, and the
2
flask was flushed with nitrogen. Acetonitrile (6.0 mL), THF (1.9 mL), and H O (5.3 mL) were
2
sequentially added at 0 °C. The reaction mixture was stirred at the same temperature for 4 h. The
mixture was quenched with H O at 0 °C (20 mL) and extracted with chloroform/2ꢀPrOH (3/1) (3 x 20
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
mL). Combined organic phase was dried over anhydrous Na SO . After concentration under reduced
2
4
pressure, purification by GPC (chloroform) afforded 5,7ꢀdimethylisoindolinꢀ1ꢀone (2r-H; 12 mg, 0.077
mmol) in 51% overall yield.
5
,7-Dimethylisoindolin-1-one (2r-H) Purified by GPC with chloroform as an eluent; 12 mg (51%);
o
1
yellow solid; mp 164.2ꢀ165.9 C; H NMR (400 MHz, CDCl ) δ 2.40 (s, 3H), 2.68 (s, 3H), 4.34 (s, 2H),
3
13
6
.62 (bs, 1H), 7.01 (s, 1H), 7.06 (s, 1H); C NMR (100 MHz, CDCl ) δ 17.2, 21.7, 44.7, 121.1,
3
+
126.6,130.9, 137.6, 142.0, 144.8, 172.6; HRMS (APCI) m/z ([M+H] ) calcd for C H NO: 162.0913,
1
0
12
found: 162.0914.
Associated Content
Author Information
Corresponding Authors
*
Eꢀmail: k_hirano@chem.eng.osakaꢀu.ac.jp.
*Eꢀmail: miura@chem.eng.osakaꢀu.ac.jp.
Notes
The authors declare no competing financial interest.
ACS Paragon Plus Environment
28

Page 29 of 32
The Journal of Organic Chemistry
Acknowledgment.
This work was supported by JSPS KAKENHI Grant Nos. 15K13696
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(GrantꢀinꢀAid for Exploratory Research), and 15H05485 (GrantꢀinꢀAid for Young Scientists (A)) to
K.H. and 24225002 (GrantꢀinꢀAid for Scientific Research (S)) to M.M.
1
13
1
Supporting Information: Detailed kinetic profiles for the reaction of 1l and 1l-d , H and C{ H}
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
NMR spectra for products, an ORTEP drawing of 2b, and detailed pathways leading to 2i-Np’ and
2
j-Np/2j-Np’. This material is available free of charge via the Internet at http://pubs.acs.org.
References
1) Lawrence, N. J.; Liddle, J.; Bushell, S. M.; Jackson, D. A. J. Org. Chem. 2002, 67, 457.
(
(2) (a) Inoue, S.; Kim, R.; Hoshino, Y.; Honda, K. Chem. Commun. 2006, 1974. (b) Jacolot, M.; Jean,
M.; Tumma, N.; Bondon, A.; Chandrasekhar, S.; van de Weghe, P. J. Org. Chem. 2013, 78, 7169.
(3) Link, J. T.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 552.
(4) (a) Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39, 149. (b) Park, J. S.; Moon,
S. C.; Baik, K. U.; Cho, J. Y.; Yoo, E. S.; Byun, Y. S.; Park, M. H. Arch. Pharmacal Res. 2002, 125,
1
37. (c) Uno, M.; Ban, H. S.; Nakamura, H. Bioorg. Med. Chem. Lett. 2009, 19, 3166. (d) Ghosh, U.;
Bhattacharyya, R.; Keche, A. Tetrahedron 2010, 66, 2148.
5) (a) Das, S.; Addis, D.; Knopke, L. R.; Bentrup, U.; Junge, K.; Brukner, A.; Beller, M. Angew.
(
Chem., Int. Ed. 2011, 50, 9180. (b) Joźwiak, A.; Zagorski, P. M.; Płotka, M. W.; Cal, D. Tetrahedron
Lett. 2014, 55, 2420.
(
6) (a) Cho, C. S.; Ren, W. X. Tetrahedron Lett. 2009, 50, 2097. (b) MarosvölgyiꢀHaskó, D.; Takács,
A.; Riedl, Z.; Kollár, L. Tetrahedron 2011, 67, 1036.
7) For selected reviews and accounts: (a) Campeau, L. C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta
007, 40, 35. (b) Lewis, L. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (c)
(
2
Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (d) Daugulis, O.; Do, H.ꢀQ.; Shabashov, D. Acc. Chem.
Res. 2009, 42, 1074. (e) Chen, X.; Engle, K. M.; Wang, D.ꢀH.; Yu, J.ꢀQ. Angew. Chem., Int. Ed. 2009,
ACS Paragon Plus Environment
29