Oxidative Desymmetrization of Isoindolines Realized by tert -Butyl Nitrite (TBN) Initiated Radical sp 3C-H Activation Relay (CHAR)

Article abstract of DOI:10.1055/s-0040-1706010

An oxidative desymmetrization of isoindolines was realized by TBN initiated radical sp ³C-H activation relay (CHAR), providing a series of ω-hydroxylactams in high yields. This reaction exhibits broad substrate scope and functional group tolerance, and even N -alkyl iso-indolines can be well tolerated. The mechanistic study shows that the C-H bond oxidation, dioxygen trapping and intramolecular 1,5-H shift might be the key steps to achieve the oxidative desymmetrization.

Full text of DOI:10.1055/s-0040-1706010

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 1663–1671
paper
1663
en
Z. Sun et al.
Paper
Synthesis
Oxidative Desymmetrization of Isoindolines Realized by tert-Butyl
Nitrite (TBN) Initiated Radical sp3 C–H Activation Relay (CHAR)
Zheng Suna
Yu Shaob
Shuwei Zhanga
Yuxian Zhanga
Yu Yuan*a
O
H
O
O
TBN
O2
N
R
N R
N
R
H
H
OH
R = aryl, alkyl
C–H activation relay
oxidative desymmetrization
24 examples
Xiaodong Jia*a
up to 99% yield
a School of Chemistry and Chemical Engineering, Yangzhou
University, Yangzhou, Jiangsu 225002, P. R. of China
yyuan@yzu.edu.cn
jiaxd1975@163.com
b School of Information Engineering, Yangzhou University,
Huayang West Road 196, Yangzhou, Jiangsu 225127,
P. R. of China
Corresponding Authors
Received: 26.11.2020
Accepted after revision: 14.12.2020
Published online: 18.01.2021
struct the -hydroxylactam structure, some drawbacks still
exist, such as unsatisfactory functional group tolerance, the
generation of overreduction products, and large amount of
waste.6b–f With the development of the direct functionaliza-
tion of C–H bonds,7,8 we wondered whether -hydroxylact-
ams could be obtained by the strategy of oxidative de-
symmetrization, using those unfunctionalized substrates,
isoindolines, and thus avoiding the tedious synthesis of the
starting materials. However, some challenges still exist and
need to be overcome. In the presence of weak oxidizer, only
one side of the -C–H bonds adjacent to the nitrogen atom
can be oxidized, providing isoindolinone derivatives in high
yields.9a–d When over-stoichiometric amount of TBHP were
employed as the oxidizer, isoindolines were smoothly oxi-
dized to phthalimides and no -hydroxylactams were pro-
vided.9e Therefore, appropriate oxidizer and the corre-
sponding reaction conditions are crucial to achieve the syn-
thesis of -hydroxylactams through the oxidative
desymmetrization of isoindolines.
DOI: 10.1055/s-0040-1706010; Art ID: ss-2020-m0538-op
Abstract An oxidative desymmetrization of isoindolines was realized
by TBN initiated radical sp3 C–H activation relay (CHAR), providing a se-
ries of -hydroxylactams in high yields. This reaction exhibits broad
substrate scope and functional group tolerance, and even N-alkyl iso-
indolines can be well tolerated. The mechanistic study shows that the
C–H bond oxidation, dioxygen trapping and intramolecular 1,5-H shift
might be the key steps to achieve the oxidative desymmetrization.
Key words radicals, C–H bond activation, oxidative desymmetriza-
tion, tert-butyl nitrite, isoindolines
Cyclic lactams and imides exist widely in pharmaceuti-
cals, agrochemicals and other medicinally important com-
pounds with diverse biological activities.1,2 For example, in-
doprofen, which bears an isoindolinone skeleton, exhibits
broad physiological activities and can be used for the treat-
ment of rheumatoid arthritis, osteoarthritis, spondylosis
and other conditions.3 As lactam derivatives, -hydroxylac-
tams are also important and versatile building blocks in
natural products and pharmaceuticals.4 In organic synthe-
sis, they can be employed as precursors of N-acyliminium
ions, which are involved in the construction of various
nitrogen-containing heterocycles and alkaloids.4,5
O
O
CO2R
CHO
NH2R'
[H]
N
R
N R
OH
O
Oxidative desymmetrization?
(this work)
H
O
O
Due to the continuing interest in this class of hetero-
cycles, various synthetic procedures for the construction of
-hydroxylactams have been established (Scheme 1).6 The
-hydroxylactam skeleton can be directly constructed
through the condensation of alkyl 2-formylbenzoates and
amines; however, pre-functionalized starting materials are
needed, which restricts their diverse synthesis.6a Although
reductive desymmetrization of phthalimides, using over-
stoichiometric amount of Zn or Sn under acidic conditions
or organometallic hydrides, is an efficient strategy to con-
O2
TBHP
CuCl
N
R
N
R
N
R
additive
H
H
O
Scheme 1 Synthetic strategies to access -hydroxylactams
Recently, our research interests focused on aerobic oxi-
dation of sp3 C–H bonds, and, in this research, the C–H
bonds adjacent to nitrogen were found to be extremely ac-
tive and could be easily oxidized to the corresponding radi-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1663–1671
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1664
Z. Sun et al.
Paper
Synthesis
cal species. Therefore, we proposed that if the active C–H
bond was initially oxidized to a free radical, under aerobic
conditions, the generated radical might be captured by di-
oxygen, giving a peroxide radical. After a subsequent intra-
molecular hydrogen shift, another C–H bond would be acti-
vated and further functionalized. We believe that this strat-
egy, named C–H activation relay (CHAR), might be a new
way to realize C–H bond activation and 1,3-difunctionaliza-
tion (Scheme 2, eq. 1). In 2016, we reported an interesting
synthesis of isatins through the aerobic oxidation of glycine
esters using this strategy.10 So we questioned whether
CHAR could also be used to achieve the oxidative desymme-
trization of isoindolines (Scheme 2, eq. 2). According to our
design, when the C–H bond adjacent to nitrogen atom is ox-
idized to a radical intermediate under aerobic atmosphere,
dioxygen trapping will generate a peroxide radical. Fast in-
tramolecular 1,5-H shift would then occur smoothly, giving
a new radical intermediate. After elimination of water and
further single-electron transfer, the desired -hydroxy-
lactam structure might be constructed. Herein, we reported
an oxidative desymmetrization of isoindolines initiated by
TBN via the process of C–H activation relay (CHAR).
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO); however,
similar a result was obtained (entry 6). Since a small
amount of the nitrated product on the phenyl ring was de-
tected, one equivalent of p-nitrobenzoic acid (p-NBA) was
added to inhibit the TBN initiated nitration (entry 7).12c To
our disappointment, the reaction outcome remained unsat-
isfactory. Several solvents were then screened, and the re-
sults shown that 1,4-dioxane remained the best choice (en-
tries 8 and 9). The results also showed that increasing of the
amount of TBN or elevating the reaction temperature also
do not improve the reaction efficiency (entries 10 and 11).
Since the reaction is rather clean and the formation of by-
products is almost undetectable by TLC, the lower isolated
yield was attributed to the absorption of acidic silica gel
1
column, a conclusion that was supported by the H NMR
yield of the crude reaction mixture (entry 4). To avoid the
silica gel column absorption, the acidic hydroxyl group was
etherified with NaH and MeI, and the desired -methoxy-
lactam 3b was smoothly obtained in 73% isolated yield (en-
try 12). In the presence of MeOH instead of water, the -
Table 1 Optimization of the Reaction Conditions
1) Our design of C–H activation relay
O
H
H
O
H
H
O
O
C–H activation
O
2 trapping
TBN (1.5 equiv)
R1
R2
R1
R2
additives (0.1 equiv)
R1
R2
NaH
MeI
N
Ar
N Ar
N
Ar
solvent, air, 45 °C
OH
O
O
FG
R2
Ar = 4-ClC6H4
OMe
3b
OH
hydrogen shift
1b
2b
R1
R1
R2
2) This work
O
H
Entry
Additive (mol%)
none
Solvent
H2O (mol%)
Yield (%)a
O
[O]
1,5-H shift
O2
N
R
N
R
R
N
R
1
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
–
5
47
54
52
H
O
2
3
4
none
none
none
H
H
OH
R
O
O
10
15
N
R
N
N
57
– H2O
(84)h
OH
5
6
none
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
15
15
15
15
15
15
15
15
15
38b
56
Scheme 2 Our design of C–H activation relay
TEMPO (10)c
p-NBA (10)d
none
With our design in mind, the substrate isoindoline de-
rivative 1b was chosen as a model compound to test the
strategy of oxidative desymmetrization. Considering the re-
action diversity and high activity in the activation of inert
chemical bonds, TBN was employed as the initiator under
air atmosphere (Table 1).11,12 To our delight, in the presence
of 1.5 equivalent of TBN at 45 °C, the desired -hydroxylac-
tams 2b was obtained in 47% yield (entry 1). When 5 equiv-
alents of water was added into the reaction solution, the
yield was increased to 54% (entry 2). Increasing the amount
of water to 10 and 15 equivalents resulted in slightly higher
yields of the -hydroxylactam 2b (entries 3 and 4). Under
O2 atmosphere, the yield of the desired product was re-
duced to 38%, which might be due to overoxidation (entry
5). To improve the reaction efficiency, the model reaction
was performed in the presence of a catalytic amount of
7
55
8
34
9
none
MeCN
17
10
11
12
13
none
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
50e
52f
73g
54g,i
none
none
none
a Isolated yield of 2b.
b Under O2 atmosphere.
c TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy.
d p-NBA = p-nitrobenzoic acid.
e Two equivalents of TBN were added.
f At 60 °C.
g Isolated yield of 3b after methylation.
h The yield in parentheses is crude 1H NMR yield, using 1,3,5-trimethoxyl-
benzene as the internal standard.
i In the presence of 15 mol% MeOH instead of H2O.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1663–1671

1665
Z. Sun et al.
Paper
Synthesis
methoxylactam 3b was isolated in 54% yield, suggesting
that the presence of water is beneficial to enhance the reac-
tion efficiency (entry 13).
process. When methyl group was connected on the phenyl
ring of isoindoline, a mixture of two regioisomers 3z and
3z′ was obtained in 31% yield, and oxidation on the methyl
group was observed, reducing the reaction outcome.
With the best reaction conditions established, the reac-
tion scope and limitations were then evaluated. Overall, N-
substituted isoindolines 1a–x gave the corresponding -
methoxylactams in good to excellent yields (Scheme 3). Ini-
tially, various para-groups on the N-phenyl ring were test-
ed. Halogen groups including Cl, Br, and F, gave the corre-
sponding products 3b–d in higher yields than the N-phenyl
product (3a). The presence of ester and acyl functional
groups, which could be used in further transformations, did
not affect the reaction efficiency, providing the desired
product 3e and 3f in 68% and 48% yields, respectively. The
strong electron-withdrawing group CF3 enhanced this C–H
bond oxidation, and the corresponding -methoxylactam
3g was isolated in nearly quantitative yield. When this reac-
tion was scaled up to 10 mmol, the desired product was iso-
lated in 88% yield. In contrast, electron-donating substitu-
ent tert-butyl reduced the yield to 49% (3h). This is proba-
bly because when the N-aryl group is electron-rich, the
desired C–H bond oxidation will be disturbed by TBN initi-
ated direct nitration on the N-phenyl ring. When ortho-sub-
stituted substrates were tested, moderate to good yields
were obtained (3i–j), and even biphenyl-2-amine derived
isoindoline was smoothly tolerated, giving the expected
product 3k in 62% yield. When the halogen atoms were
connected on the meta-position, the reaction occurred
smoothly, giving the desired products 3l–o in 78–99%
yields. It is worth noting that the iodo-substituted sub-
strates are not well tolerated in transition-metal initiated
C–H bond activation, but reacted under the developed con-
ditions to give the product 3o, which could be further func-
tionalized to construct more complex molecules. The reac-
tion of various 2,4-disubstituted isoindolines were also per-
formed under the standard reaction conditions, and slightly
diminished reaction yields were observed (3p–r; 33–60%),
which might be due to the steric hindrance of the ortho-
groups. Since the N-aryl groups could dramatically stabilize
the generated radical intermediate, in most cases, the pres-
ence of these groups is crucial to accomplish an efficient C–
H bond activation. Therefore, N-alkyl isoindolines were in-
vestigated under the optimized reaction conditions, and, to
our delight, not only linear but also bulky alkyl groups were
well tolerated in this oxidative desymmetrization, giving
the desired -methoxylactams 3s–w in moderate yields
(33–66%).13 For N-cyclopropylisoindoline 1x, the O-methyl-
ation step led to fragmentation of the cyclopropyl ring,
therefore, the expected product 2x was isolated in only 33%
O
H
TBN (1.5 equiv)
H2O (15 equiv)
NaH
MeI
N
R
N
R
1,4-dioxane, air, 45 °C
OMe
H
1
3
R = Cl, 3b (73%)
R = Br, 3c (63%)
R = F, 3d (76%)
R = CO2Me, 3e (68%)
R = Ac, 3f (48%)
R = CF3, 3g (99%, 88%a)
R = tBu, 3h (49%)
O
O
N
R
N
OMe
OMe
3a (59%)
O
R
O
R
N
O
F
N
OMe
N
OMe
R = Cl, 3i (75%)
R = Br, 3j (46%)
R = Ph, 3k (62%)
R = Cl, 3l (78%)
R = Br, 3m (85%)
R = F, 3n (99%)
R = I, 3o (92%)
OMe
3p (60%)
O
O
O
Cl
N
N
Cl
N
OMe
OMe
3r (56%)
OMe
3s (34%)
3q (33%)
O
O
O
Ph
N
N
N
OMe
3t (30%)
O
OMe
3u (46%)
O
OMe
3v (66%)
O
O
Ph
N
N
N
Bn
3
N
Ph
OMe
OH
OMe
3y (37%)
OMe
2x (33%, 49%b
)
3w (33%)
3z and 3z' (1.2:1, 31%)
Scheme 3 Substrate scope. a 10 mmol scale. b Crude yield based on 1H
NMR analysis.
To gain mechanistic insight into this transformation a
series of control experiments were performed (Scheme 4).
In the absence of dioxygen, the C–H bond oxidation was to-
tally inhibited, and the starting material 1a was fully recov-
ered (eq. 1). This result suggested that the presence of diox-
ygen is crucial to initiate the sp3 C–H activation. Then, 2
equivalents of TEMPO was added as a radical inhibitor, and
no reaction occurred, which supported the conclusion that
this reaction is mediated by a radical intermediate (eq. 2).
To reveal the origin of the oxygen atom, the standard reac-
tion was conducted in the presence of H218O, and, after
methylation, 3a′ was isolated in 68% yield, in which only
one 18O atom was incorporated into the desired product (eq.
3). Since two oxygen atoms were incorporated in the target
-methoxylactam, Brönsted acid catalyzed Friedel–Crafts
reaction was performed after the C–H bond oxidation, us-
ing anisole as a nucleophile (eq. 4). The Friedel–Crafts prod-
uct 4 was isolated in 63% yield as a mixture of regioisomers,
in which no 18O atom was incorporated. These results con-
1
yield (49% crude H NMR yield), probably due to the silica
gel column absorption. When N-benzylisoindoline 1y was
employed, a competitive 1,5-H shift on the benzyl position
disturbed the desired reaction process, and only 37% yield
of 3y was obtained.14 This result also supported the conclu-
sion that the C–H oxidation was mediated by a 1,5-H shift
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1663–1671

1666
Z. Sun et al.
Paper
Synthesis
firmed that the oxygen atom in the methoxyl group comes
from water via hydrolysis of the acyliminium ion. On the
other hand, the oxygen atom in the carbonyl group origi-
nates from dioxygen, implying the existence of a peroxide
intermediate (B, Scheme 4). Next, the reaction of the 1:1
mixture of the 1a and 1a-d4 was performed under the opti-
mized conditions (eq. 5); the KIE value of 5.2 supported the
conclusion that cleavage of the C−H bond adjacent to nitro-
gen atom might be involved in the rate-determining step.
trapped by the persistent nitro radical, giving intermediate
E. Finally, the nitrite anion is excluded, forming an iminium
ion F, which is subsequently trapped by water to provide
the desired product.
In summary, we have developed an efficient oxidative
desymmetrization of isoindolines to -hydroxylactams.
This transformation features a TBN initiated sp3 C–H bond
functionalization under aerobic conditions, in which the C–
H activation relay (CHAR) is the key step to accomplish the
desymmetric oxidation. It is worth noting that this method
provides a direct way to construct the pharmaceutically
and synthetically important -hydroxylactam skeleton
from unfunctionalized starting materials. The transition-
metal free and mild reaction conditions as well as good
functional group tolerance also highlight its potential appli-
cations in the synthesis of heterocyclic compounds. Further
applications of this reaction and mechanistic studies are
under way in our laboratory.
standard conditions
1) 1a
2) 1a
no reaction
no reaction
argon
standard conditions
TEMPO (2 equiv)
O
TBN (1.5 equiv)
H218O (15 equiv)
NaH, MeI
68%
3) 1a
3a' (68%)
Ph
N
1,4-dioxane, air, 45 °C
18OMe
O
TBN (1.5 equiv)
H218O (15 equiv)
p
-TsOH
4)
5)
N
Ph 4 (63%)
1a
1a
1,4-dioxane, air, 45 °C
MeOPh
TBN were purchased from commercial sources and used without fur-
ther purification. Flash chromatography was carried out with silica
gel (200–300 mesh). Analytical TLC was performed with silica gel
GF254 plates, and the products were visualized by UV detection. 1H
and 13C NMR (400 MHz, 600MHz and 100 MHz, 150MHz respectively)
spectra were recorded in CDCl3. Chemical shifts () are reported in
ppm using TMS as internal standard, and spin-spin coupling con-
stants (J) are given in Hz. High-resolution mass spectra (HRMS) were
measured with an electrospray ionization (ESI) apparatus using time
of flight (TOF) mass spectrometry.
Ar
D
D
Ar = 4- and 2-MeOC6H4
standard conditions
KIE = 5.2
N
D
Ph
2a
d-2a
+
+
D
1a-d4
Scheme 4 Control experiments
OBut
O
N
Substrate Preparation
O2
OBut
– HOBut
O
O
H
NO2
A solution of 1,2-bis(bromomethyl)benzene (10 mmol) and anilines
(12 mmol) in toluene (10 mL) was mixed fully, then N,N-diisopropy-
lethanamine (24 mmol) was added dropwise under argon atmo-
sphere. The reaction solution was stirred under 110 °C. After comple-
tion (reaction monitored by TLC with UV visualization), the solvent
was removed under reduced pressure. The products were separated
by silica gel column chromatography eluted with petroleum ether/
acetone (v/v 20:1) to afford the products.
O2
N
R
N
R
N
R
H
H
H
A
B
OH
O
O
1,5-H shift
NO2
N
R
N
R
– H2O
C
D
O
O
O
H2O
– H+
TBN Initiated Oxidative Desymmetrization of Isoindolines; Gener-
al Procedure 1
N
R
N
R
N R
–
– NO2
ONO
OH
E
F
A solution of 1 (0.5 mmol) and H2O (7.5 mmol) in 1,4-dioxane (5 mL)
was mixed fully, then TBN (0.75 mmol) was added dropwise under air
atmosphere. The reaction solution was stirred at 45 °C. After comple-
tion (reaction monitored by TLC with UV visualization), the solvent
was removed under reduced pressure. The reaction mixture was used
in the methylation step without further purification.
Scheme 5 Proposed mechanism
Based on the control experiments and on previous prec-
edent of TBN initiated reactions,12 a possible mechanism
was proposed to rationalize the product formation (Scheme
5). In the presence of dioxygen, a tert-butoxyl radical is gen-
erated by -fragmentation of TBN, followed by intermolec-
ular H-abstraction, generating radical intermediate A. This
radical is then captured by dioxygen, affording a peroxide
radical B. Next, the other C–H bond adjacent to nitrogen
atom is further activated by the intramolecular 1,5-H shift,
giving radical C. After water elimination, radical D might be
Methylation of the Product 2; General Procedure 2
The reaction mixture was dissolved in anhydrous THF (5 mL), then
MeI (1.5 mmol) and NaH (1.5 mmol) were added dropwise, sequen-
tially. The reaction solution was stirred at 45 °C. After completion (re-
action monitored by TLC with UV visualization), the solvent was re-
moved under reduced pressure. The products were separated by silica
gel column chromatography eluted with petroleum ether/acetone
(v/v 10:1) to afford the products.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1663–1671

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Z. Sun et al.
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Synthesis
Oxidative Desymmetrization of Isoindolines in the Presence of
H218O
Following General Procedures 1 and 2 in the presence of H218O (15
13C NMR (101 MHz, CDCl3):  = 166.7, 160.1 (d, JCF = 245.3 Hz), 139.6,
133.3 (d, J = 2.0 Hz), 132.9, 132.7, 130.4, 124.0, 123.6 (d, JCF = 8.0 Hz),
123.4, 115.9 (d, JCF = 22.4 Hz), 87.5, 49.2.
HRMS (ESI): m/z calcd for C15H12FNO2 + Na+: 280.0750; found:
equiv), the corresponding product 3a′ was isolated in 68% yield.
HRMS (ESI): m/z calcd for C15H13NO18O + Na+: 264.0881; found:
280.0740.
264.0880.
Methyl 4-(1-Methoxy-3-oxoisoindolin-2-yl)benzoate (3e)
Compound 3e purified by TLC (petroleum ether/acetone, 15:1).
Yield: 68% (101 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.07 (d, J = 8.8 Hz, 2 H), 7.99 (d, J = 8.9
Hz, 2 H), 7.89 (d, J = 7.5 Hz, 1 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.61–7.52 (m,
2 H), 6.50 (s, 1 H), 3.89 (s, 3 H), 2.85 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.8, 166.6, 141.6, 139.4, 133.2,
132.5, 130.6, 130.5, 126.0, 124.1, 123.5, 119.8, 86.8, 52.0, 48.9.
HRMS (ESI): m/z calcd for C17H15NO4 + Na+: 320.0899; found:
320.0898.
Performed by following General Procedure 1 in the presence of H218O
(15 equiv). The solvent was removed under reduced pressure, then
anisole (15 equiv) and p-TsOH (0.2 mmol) were added and the reac-
tion mixture was stirred at 80 °C for 12 hours. After completion (reac-
tion monitored by TLC with UV visualization), the solvent was re-
moved under reduced pressure. The product 4 was separated by silica
gel column chromatography eluted with petroleum ether/acetone
(v/v 10:1).
HRMS (ESI): m/z calcd for C21H17NO2
+
H+: 316.1332; found:
316.1345.
3-Methoxy-2-phenylisoindolin-1-one (3a)
2-(4-Acetylphenyl)-3-methoxyisoindolin-1-one (3f)
Compound 3f was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 48% (68 mg); yellow solid; mp 99–100 °C.
1H NMR (400 MHz, CDCl3):  = 8.06–7.95 (m, 4 H), 7.89 (d, J = 7.5 Hz, 1
H), 7.67 (t, J = 7.4 Hz, 1 H), 7.63–7.53 (m, 2 H), 6.51 (s, 1 H), 2.85 (s, 3
H), 2.58 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 197.0, 166.8, 141.7, 139.4, 133.3,
133.1, 132.4, 130.6, 129.5, 124.1, 123.6, 119.8, 86.7, 48.8, 26.4.
HRMS (ESI): m/z calcd for C17H15NO3 + Na+: 304.0950; found:
304.0945.
Compound 3a was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 59% (71 mg); red oil.
1H NMR (400 MHz, CDCl3):  = 7.91 (d, J = 7.4 Hz, 1 H), 7.81 (d, J = 8.1
Hz, 2 H), 7.71–7.63 (m, 1 H), 7.61–7.55 (m, 2 H), 7.44 (t, J = 7.6 Hz, 2
H), 7.22 (t, J = 7.5 Hz, 1 H), 6.46 (s, 1 H), 2.90 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.7, 139.7, 137.3, 132.9, 132.8,
130.3, 129.1, 125.3, 123.9, 123.4, 121.7, 87.2, 49.1.
HRMS (ESI): m/z calcd for C15H13NO2 + Na+: 262.0844; found:
262.0832.
2-(4-Chlorophenyl)-3-methoxyisoindolin-1-one (3b)
Compound 3b purified by TLC (petroleum ether/acetone, 10:1).
Yield: 73% (100 mg); yellow solid; mp 160–162 °C.
1H NMR (400 MHz, CDCl3):  = 7.89 (d, J = 7.2 Hz, 1 H), 7.80 (d, J = 8.5
Hz, 2 H), 7.64 (d, J = 7.2 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 2 H), 7.41–7.33 (m,
2 H), 6.41 (s, 1 H), 2.87 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.6, 139.5, 136.0, 133.0, 132.6,
130.4, 130.3, 129.1, 123.9, 123.4, 122.4, 87.1, 49.0.
HRMS (ESI): m/z calcd for C15H12ClNO2 + Na+: 296.0454; found:
296.0449.
3-Methoxy-2-(4-(trifluoromethyl)phenyl)isoindolin-1-one (3g)
Compound 3g was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 99% (152 mg); yellow solid; mp 56–59 °C.
1H NMR (400 MHz, CDCl3):  = 8.05 (d, J = 8.5 Hz, 2 H), 7.89 (d, J = 7.5
Hz, 1 H), 7.71–7.64 (m, 3 H), 7.62–7.57 (m, 2 H), 6.50 (s, 1 H), 2.87 (s, 3
H).
13C NMR (101 MHz, CDCl3):  = 166.8, 140.6, 139.4, 133.3, 132.4,
130.5, 126.5 (d, JCF = 32.5 Hz), 126.2 (q, JCF = 3.8 Hz), 124.1 (d, JCF
271.8 Hz), 124.1, 123.5, 120.3, 86.9, 48.9.
HRMS (ESI): m/z calcd for C16H12F3NO2 + Na+: 330.0718; found:
=
330.0706.
2-(4-Bromophenyl)-3-methoxyisoindolin-1-one (3c)
Compound 3c purified by TLC (petroleum ether/acetone, 10:1).
Yield: 63% (100 mg); red solid; mp 158–160 °C.
1H NMR (400 MHz, CDCl3):  = 7.89 (d, J = 7.4 Hz, 1 H), 7.76 (d, J = 8.9
Hz, 2 H), 7.69–7.62 (m, 1 H), 7.60–7.55 (m, 2 H), 7.52 (d, J = 9.0 Hz, 2
H), 6.42 (s, 1 H), 2.87 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.6, 139.4, 136.5, 133.0, 132.6,
132.1, 130.4, 124.0, 123.4, 122.7, 120.7, 118.1, 87.1, 49.0.
HRMS (ESI): m/z calcd for C15H12BrNO2 + Na+: 339.9949; found:
339.9938.
2-(4-(tert-Butyl)phenyl)-3-methoxyisoindolin-1-one (3h)
Compound 3h was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 49% (72 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.91 (d, J = 7.4 Hz, 1 H), 7.70 (d, J = 8.6
Hz, 2 H), 7.65–7.54 (m, 3 H), 7.45 (d, J = 8.7 Hz, 2 H), 6.43 (s, 1 H), 2.91
(s, 3 H), 1.33 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 166.7, 148.3, 139.7, 134.5, 133.0,
132.6, 130.3, 125.9, 123.8, 123.4, 121.5, 87.3, 49.1, 34.4, 31.3.
HRMS (ESI): m/z calcd for C19H21NO2 + Na+: 318.1470; found:
318.1470.
2-(4-Fluorophenyl)-3-methoxyisoindolin-1-one (3d)
Compound 3d purified by TLC (petroleum ether/acetone, 15:1).
Yield: 76% (98 mg); red solid; mp 123–125 °C.
1H NMR (400 MHz, CDCl3):  = 7.90 (d, J = 7.4 Hz, 1 H), 7.79–7.74 (m, 2
H), 7.68–7.63 (m, 1 H), 7.62–7.54 (m, 2 H), 7.11 (t, J = 8.7 Hz, 2 H), 6.39
(s, 1 H), 2.90 (s, 3 H).
2-(2-Chlorophenyl)-3-methoxyisoindolin-1-one (3i)
Compound 3i was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 75% (102 mg); yellow solid; mp 89–90 °C.
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1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 7.4 Hz, 1 H), 7.66 (dd, J = 7.2,
1.0 Hz, 1 H), 7.62–7.56 (m, 2 H), 7.52–7.54 (m, 1 H), 7.43–7.32 (m, 3
H), 6.35 (s, 1 H), 3.11 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.9, 140.8, 133.9, 132.9, 132.7,
132.1, 130.6, 130.2, 129.5, 127.7, 124.3, 123.8, 88.6, 51.3.
Yield: 99% (127 mg); red solid; mp 70–73 °C.
1H NMR (400 MHz,CDCl3):  = 7.90 (d, J = 7.5 Hz, 1 H), 7.74 (dt, J =
11.3, 2.3 Hz, 1 H), 7.68–7.63 (m, 2 H), 7.58 (ddd, J = 8.4, 7.1, 1.9 Hz, 2
H), 7.36 (td, J = 8.3, 6.7 Hz, 1 H), 6.90 (tdd, J = 8.3, 2.5, 0.8 Hz, 1 H), 6.43
(s, 1 H), 2.88 (s, 3 H).
HRMS (ESI): m/z calcd for C15H12ClNO2 + Na+: 296.0454; found:
296.0445.
13C NMR (101 MHz, CDCl3):  = 166.7, 162.9 (d, JCF = 244.6 Hz), 139.4,
139.0 (d, JCF = 10.5 Hz), 133.1, 132.5, 130.4, 130.1 (d, JCF = 9.3 Hz),
124.0, 123.4, 116.2 (d, JCF = 3.0 Hz), 111.7 (d, JCF = 21.2 Hz), 108.4 (d,
JCF = 26.2 Hz), 87.1 (d, JCF = 3.0 Hz), 48.9.
HRMS (ESI): m/z calcd for C15H12FNO2 + Na+: 280.0750; found:
280.0738.
2-(2-Bromophenyl)-3-methoxyisoindolin-1-one (3j)
Compound 3j was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 46% (73 mg); red solid; mp 105–107 °C.
1H NMR (600 MHz, CDCl3):  = 7.95 (s, 1 H), 7.76–7.64 (m, 2 H), 7.60
(d, J = 6.1 Hz, 2 H), 7.49–7.36 (m, 2 H), 7.29 (s, 1 H), 6.35 (s, 1 H), 3.14
(s, 3 H).
13C NMR (151 MHz, CDCl3):  = 167.0, 140.8, 135.6, 133.8, 132.8,
132.1, 130.2, 129.9, 128.4, 124.4, 123.8, 123.1, 88.8, 51.7.
2-(3-Iodophenyl)-3-methoxyisoindolin-1-one (3o)
Compound 3o was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 92% (168 mg); red solid; mp 166–168 °C.
1H NMR (400 MHz, CDCl3):  = 8.23 (s, 1 H), 7.94–7.86 (m, 1 H), 7.87–
7.78 (m, 1 H), 7.66 (ddd, J = 7.6, 2.8, 1.4 Hz, 1 H), 7.62–7.50 (m, 3 H),
7.13 (td, J = 8.1, 2.4 Hz, 1 H), 6.42 (s, 1 H), 2.89 (s, 3 H).
HRMS (ESI): m/z calcd for C15H12BrNO2 + Na+: 339.9949; found:
339.9954.
13C NMR (101 MHz, CDCl3):  = 166.5, 139.5, 138.6, 134.0, 133.1,
132.5, 130.5, 130.4, 129.8, 124.0, 123.5, 120.3, 94.3, 87.0, 49.1.
HRMS (ESI): m/z calcd for C15H12INO2 + Na+: 387.9810; found:
387.9804.
2-(Biphenyl-2-yl)-3-methoxyisoindolin-1-one (3k)
Compound 3k was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 62% (98 mg); yellow solid; mp 101–103 °C.
1H NMR (400 MHz, CDCl3):  = 7.91–7.89 (m, 1 H), 7.56–7.49 (m, 2 H),
7.46 (m, 4 H), 7.37–7.33 (m, 3 H), 7.33–7.21 (m, 3 H), 5.35 (s, 1 H),
2.85 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 168.1, 140.7, 139.2, 132.3, 132.2,
131.1, 129.9, 129.8, 128.6, 128.5, 128.4 (two 13C), 127.5, 124.0, 123.5,
51.3.
2-(2-Fluoro-4-methylphenyl)-3-methoxyisoindolin-1-one (3p)
Compound 3p was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 60% (81 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.92 (d, J = 7.4 Hz, 1 H), 7.70–7.62 (m, 1
H), 7.61–7.54 (m, 2 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.09–6.99 (m, 2 H), 6.37
(s, 1 H), 3.00 (s, 3 H), 2.38 (s, 3 H).
HRMS (ESI): m/z calcd for C21H17NO2 + Na+: 338.1157; found:
338.1164.
13C NMR (101 MHz, CDCl3):  = 166.7, 157.5 (d, JCF = 249.9 Hz), 140.7,
139.7, 139.8, 132.6, 132.3, 130.1, 128.5 (d, JCF = 2.1 Hz), 125.3 (d, JCF
3.1 Hz), 124.1, 123.6, 117.2 (d, JCF = 19.9 Hz), 88.3, 50.3, 21.1.
HRMS (ESI): m/z calcd for C16H14FNO2 + Na+: 294.0906; found:
=
2-(3-Chlorophenyl)-3-methoxyisoindolin-1-one (3l)
Compound 3l was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 78% (106 mg); yellow solid; mp 137–139 °C.
294.0909.
1H NMR (400 MHz, CDCl3):  = 7.93 (s, 1 H), 7.89 (d, J = 7.3 Hz, 1 H),
7.76 (d, J = 8.2 Hz, 1 H), 7.71–7.64 (m, 1 H), 7.62–7.55 (m, 2 H), 7.34 (t,
J = 8.1 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 6.43 (s, 1 H), 2.88 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.6, 139.4, 138.6, 134.7, 133.1,
132.5, 130.5, 130.0, 125.1, 124.0, 123.5, 121.2, 119.0, 87.1, 49.0.
2-(2-Chloro-4-methylphenyl)-3-methoxyisoindolin-1-one (3q)
Compound 3q was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 33% (47 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.93 (d, J = 7.4 Hz, 1 H), 7.69–7.62 (m, 1
H), 7.55–7.60 (m, 2 H), 7.35 (d, J = 1.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H),
7.17 (dd, J = 8.0, 1.3 Hz, 1 H), 6.31 (s, 1 H), 3.11 (s, 3 H), 2.38 (s, 3 H).
HRMS (ESI): m/z calcd for C15H12ClNO2 + Na+: 296.0454; found:
296.0449.
13C NMR (101 MHz, CDCl3):  = 167.1, 140.8, 140.0, 132.6, 132.4,
132.2, 131.0, 130.8, 130.1, 128.5, 124.3, 124.0, 123.7, 88.6, 51.3, 21.0.
HRMS (ESI): m/z calcd for C16H14ClNO2 + Na+: 310.0611; found:
310.0614.
2-(3-Bromophenyl)-3-methoxyisoindolin-1-one (3m)
Compound 3m was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 85% (135 mg); brown solid; mp 67–70 °C.
1H NMR (400 MHz, CDCl3):  = 8.07 (s, 1 H), 7.89 (d, J = 7.4 Hz, 1 H),
7.80 (dd, J = 8.0, 0.8 Hz, 1 H), 7.64 (d, J = 7.2 Hz, 1 H), 7.61–7.53 (m, 2
H), 7.33–7.25 (m, 2 H), 6.42 (s, 1 H), 2.87 (s, 3 H).
2-(4-Chloro-2-methylphenyl)-3-methoxyisoindolin-1-one (3r)
Compound 3r was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 56% (80 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.90–7.92 (m, 1 H), 7.69–7.63 (m, 1 H),
7.61–7.56 (m, 2 H), 7.33 (d, J = 2.4 Hz, 1 H), 7.28–7.24 (m, 1 H), 7.18
(d, J = 8.4 Hz, 1 H), 6.10 (s, 1 H), 3.13 (s, 3 H), 2.25 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.6, 139.5, 138.7, 133.1, 132.5,
130.4, 130.3, 128.0, 124.0 (two 13C), 123.5, 122.7, 119.5, 87.1, 49.0.
HRMS (ESI): m/z calcd for C15H12BrNO2 + Na+: 339.9949; found:
339.9940.
13C NMR (101 MHz, CDCl3):  = 166.7, 141.0, 138.6, 133.8, 132.6,
132.0, 131.2, 130.2, 129.1, 127.0, 126.9, 124.2, 123.6, 89.6, 18.3.
2-(3-Fluorophenyl)-3-methoxyisoindolin-1-one (3n)
Compound 3n was purified by TLC (petroleum ether/acetone, 10:1).
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HRMS (ESI): m/z calcd for C16H14ClNO2 + Na+: 310.0611; found:
13C NMR (101 MHz, CDCl3):  = 167.7, 141.3, 140.3, 133.1, 131.9,
310.0608.
129.9, 128.4, 128.3, 125.9, 123.4, 123.4, 86.3, 49.2, 39.4, 33.4, 29.7.
HRMS (ESI): m/z calcd for C18H19NO2 + Na+: 304.1314; found:
304.1326.
2-Methoxy-2-propylisoindolin-1-one (3s)
Compound 3s was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 34% (35 mg); yellow oil.
2-Cyclopropyl-3-hydroxyisoindolin-1-one (2x)
Compound 2x was purified by TLC (petroleum ether/acetone, 10:1).
1H NMR (400 MHz, CDCl3):  = 7.80 (d, J = 7.1 Hz, 1 H), 7.58–7.52 (m, 1
H), 7.52–7.46 (m, 2 H), 5.86 (s, 1 H), 3.76–3.68 (m, 1 H), 3.21–3.14 (m,
1 H), 2.85 (s, 3 H), 1.78–1.53 (m, 2 H), 0.94 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 167.7, 140.3, 133.2, 131.8, 129.9,
123.4, 123.3, 86.2, 49.0, 41.1, 21.4, 11.4.
Yield: 33% (31 mg); yellow solid; mp 158–161 °C.
1H NMR (400 MHz, CDCl3):  = 7.51–7.48 (m, 3 H), 7.36 (t, J = 6.8 Hz, 1
H), 5.65 (s, 1 H), 2.81–2.63 (m, 1 H), 1.05–1.04 (m, 1 H), 0.96–0.68 (m,
3 H).
HRMS (ESI): m/z calcd for C12H15NO2 + Na+: 228.1001; found:
13C NMR (101 MHz, CDCl3):  = 168.6, 143.6, 132.2, 131.6, 129.7,
228.0996.
123.1, 123.1, 83.1, 23.1, 5.6, 4.9.
HRMS (ESI): m/z calcd for C11H11NO2 + Na+: 212.0688; found:
212.0683.
2-Butyl-3-methoxyisoindolin-1-one (3t)
Compound 3t was purified by TLC (petroleum ether/acetone, 10:1).
2-Benzyl-3-methoxyisoindolin-1-one (3y)
Compound 3y was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 37% (47 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.86 (d, J = 6.8 Hz, 1 H), 7.60–7.50 (m, 2
H), 7.50–7.44 (m, 1 H), 7.39–7.33 (m, 2 H), 7.33–7.28 (m, 2 H), 7.28–
7.22 (m, 1 H), 5.70 (s, 1 H), 5.17 (d, J = 14.7 Hz, 1 H), 4.20 (d, J = 14.7
Hz, 1 H), 2.87 (s, 3 H).
Yield: 30% (33 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.80 (d, J = 7.1 Hz, 1 H), 7.58–7.53 (m, 1
H), 7.52–7.46 (m, 2 H), 5.86 (s, 1 H), 3.84–3.71 (m, 1 H), 3.23–3.16 (m,
1 H), 2.85 (s, 3 H), 1.67–1.59 (m, 2 H), 1.41–1.30 (m, 2 H), 0.93 (t, J =
7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 167.6, 140.3, 133.2, 131.8, 129.9,
123.4, 123.3, 86.2, 49.0, 39.2, 30.2, 20.2, 13.7.
HRMS (ESI): m/z calcd for C13H17NO2 + Na+: 242.1157; found:
13C NMR (101 MHz, CDCl3):  = 167.7, 143.9, 136.5, 132.5, 131.0,
242.1151.
129.8, 128.7, 128.4, 127.7, 123.5, 123.4, 81.1, 42.7.
HRMS (ESI): m/z calcd for C16H15NO2 + Na+: 276.0995; found:
276.0998.
2-Cyclohexyl-3-methoxyisoindolin-1-one (3u)
Compound 3u was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 46% (46 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.79 (d, J = 7.3 Hz, 1 H), 7.58–7.52 (m, 1
H), 7.48 (t, J = 7.4 Hz, 2 H), 6.00 (s, 1 H), 4.06–3.95 (m, 1 H), 2.87 (s, 3
H), 2.03–1.64 (m, 8 H), 1.47–1.33 (m, 2 H), 1.31–1.13 (m, 2 H).
3-Methoxy-5-methyl-2-phenylisoindolin-1-one and 3-Methoxy-6-
methyl-2-phenylisoindolin-1-one and (3z and 3z′)
The mixture of compounds 3z and 3z′ was purified by TLC (petroleum
ether/acetone, 10:1).
Yield: 31% (39 mg); yellow oil.
13C NMR (101 MHz, CDCl3):  = 167.6, 140.4, 133.2, 131.8, 129.7,
123.3, 123.1, 85.7, 51.9, 48.8, 31.2, 30.4, 26.0, 25.9, 25.4.
HRMS (ESI): m/z calcd for C15H19NO2 + Na+: 268.1314; found:
268.1311.
1H NMR (400 MHz, CDCl3):  = 7.69–7.59 (m, 4.3 H), 7.50 (d, J = 7.6 Hz,
1.2 H), 7.45 (d, J = 7.7 Hz, 1 H), 7.42 (s, 1 H), 7.38–7.26 (m, 7.2 H),
7.17–7.12 (m, 3.4 H), 6.27 (s, 1 H), 6.24 (s, 1.2 H), 2.44 (s, 3 H), 2.28 (s,
3.9 H).
13C NMR (101 MHz, CDCl3):  = 166.89, 166.76, 143.75, 143.17,
140.39, 140.16, 137.24, 133.69, 131.32, 130.91, 128.86, 128.83,
128.62, 124.95, 123.96, 123.64, 123.55, 122.92, 121.44, 121.32, 82.88,
82.77, 21.96, 21.37.
HRMS (ESI): m/z calcd for C16H15NO2 + Na+: 276.0995; found:
276.1002.
3-Methoxy-2-phenethylisoindolin-1-one (3v)
Compound 3v was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 66% (88 mg); yellow solid; mp 89–92 °C.
1H NMR (400 MHz, CDCl3):  = 7.81 (d, J = 7.3 Hz, 1 H), 7.59–7.43 (m, 3
H), 7.31–7.15 (m, 5 H), 5.62 (s, 1 H), 4.10–3.97 (m, 1 H), 3.57–3.40 (m,
1 H), 3.04–2.95 (m, 2 H), 2.83 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 167.7, 140.3, 138.7, 133.0, 132.0,
3-(2-Methoxyphenyl)-2-phenylisoindolin-1-one (4a)
Compound 4a was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 23% (36 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.92 (d, J = 6.9 Hz, 1 H), 7.65 (d, J = 7.9
Hz, 2 H), 7.50–7.41 (m, 3 H), 7.33 (d, J = 6.4 Hz, 1 H), 7.26–7.13 (m, 3
H), 6.96 (s, 1 H), 6.73 (s, 3 H), 4.00 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.5, 146.0, 134.2, 132.4, 131.1,
129.3, 128.8, 128.8, 128.5, 128.2, 125.0, 124.0, 123.5, 123.0, 122.8,
114.4, 65.2, 55.2.
129.9, 128.7, 128.6, 126.5, 123.4 (two 13C), 86.6, 49.2, 41.0, 34.4.
HRMS (ESI): m/z calcd for C17H17NO2 + Na+: 290.1157; found:
290.1164.
3-Methoxy-2-(3-phenylpropyl)isoindolin-1-one (3w)
Compound 3w was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 33% (46 mg); yellow solid; mp 95–98 °C.
1H NMR (400 MHz, CDCl3):  = 7.83–7.81 (m, 1 H), 7.59–7.49 (m, 3 H),
7.27–7.13 (m, 5 H), 5.85 (s, 1 H), 3.79–3.86 (m, 1 H), 3.35–3.26 (m, 1
H), 2.86 (s, 3 H), 2.74–2.65 (m, 2 H), 2.05–1.96 (m, 2 H).
HRMS (ESI): m/z calcd for C21H17NO2 + Na+: 338.1157; found:
338.1161.
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2-(4-methoxyphenyl)-2-phenylisoindolin-1-one (4b)
Compound 4b was purified by TLC (petroleum ether/acetone, 10:1).
Yield: 40% (63 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 7.1 Hz, 1 H), 7.57–7.52 (m, 2
H), 7.49 (t, J = 7.5 Hz, 2 H), 7.20–7.25 (m, 3 H), 7.15–7.04 (m, 2 H), 6.78
(d, J = 7.6 Hz, 2 H), 5.98 (s, 1 H), 3.72 (s, 3 H).
(6) (a) Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60,
8591. (b) Ding, G.; Lu, B.; Li, Y.; Wan, J.; Zhang, Z.; Xie, X. Adv.
Synth. Catal. 2015, 357, 1013. (c) Ding, G.; Li, C.; Shen, Y.; Lu, B.;
Zhang, Z.; Xie, X. Adv. Synth. Catal. 2016, 358, 1241. (d) Cabrero-
Antonino, J. R.; Adam, R.; Papa, V.; Holsten, M.; Junge, K.; Beller,
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13C NMR (101 MHz, CDCl3):  = 167.3, 134.4, 131.7, 130.0, 129.7,
129.1, 128.8, 128.8, 128.1, 126.6, 123.7, 113.8, 113.7, 113.4, 55.2, 51.6.
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Jiao, N. Acc. Chem. Res. 2017, 50, 1640. (b) Yi, H.; Zhang, G.;
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HRMS (ESI): m/z calcd for C21H17NO2 + Na+: 338.1157; found:
338.1159.
Funding Information
This work was financially supported by National Natural Science
Foundation of China (NNSFC, No. 21562038) for supporting our re-
search. The authors also thank Natural Science Foundation of Jiangsu
(8) Recent progress of C–H bond functionalization: (a) Yang, X.;
Zhu, Y.; Xie, Z.; Li, Y.; Zhang, Y. Org. Lett. 2020, 22, 1638.
(b) Anand, D.; Sun, Z.; Zhou, L. Org. Lett. 2020, 22, 2371.
(c) Zhao, X.; Liang, S.; Fan, X.; Yang, T.; Yu, W. Org. Lett. 2019, 21,
1559. (d) Yu, Z.; Zhang, Y.; Tang, J.; Zhang, L.; Liu, Q.; Li, Q.; Gao,
G.; You, J. ACS Catal. 2020, 10, 203. (e) Roque, J. B.; Kuroda, Y.;
Jurczyk, J.; Xu, L.-P.; Ham, J. S.; Göttemann, L. T.; Roberts, C. A.;
Adpressa, D.; Saurí, J.; Joyce, L. A.; Musaev, D. G.; Yeung, C. S.;
Sarpong, R. ACS Catal. 2020, 10, 2929. (f) Liu, S.; Shen, T.; Luo, Z.;
Liu, Z.-Q. Chem. Commun. 2019, 55, 4027. (g) Wu, J.; Zhou, Y.;
Zhou, Y.; Chiang, C.-W.; Lei, A. ACS Catal. 2017, 7, 8320.
(h) Prusinowski, A. F.; Twumasi, R. K.; Wappes, E. A.; Nagib, D. A.
J. Am. Chem. Soc. 2020, 142, 5429. (i) Tang, S.; Zeng, L.; Lei, A.
J. Am. Chem. Soc. 2018, 140, 13128. (j) Wang, H.; Zhang, D.;
Bolm, C. Angew. Chem. Int. Ed. 2018, 57, 5863. (k) Hu, X.-Q.;
Chen, J.-R.; Xiao, W.-J. Angew. Chem. Int. Ed. 2017, 56, 1960.
(l) Wang, H.; Li, Y.; Lu, Q.; Yu, M.; Bai, X.; Wang, S.; Cong, H.;
Zhang, H.; Lei, A. ACS Catal. 2019, 9, 1888. (m) Yuan, P.-F.;
Zhang, Q.-B.; Jin, X.-L.; Lei, W.-L.; Wu, L.-Z.; Liu, Q. Green Chem.
2018, 20, 5464.
Province (BK20161328) for financial support.
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were detected. We think that when intermediate B (Scheme 5)
was generated, a series of competitive reactions, such as direct
elimination to N-alkylisoindolin-1-one, over-oxidation of inter-
mediate D to N-alkylphthalimide and hydrolysis of iminium
intermediate F might occur, leading to decline of the yields of
the desired product.
(13) Analysis of the reaction solution of 1u by GC-MS showed that,
besides the desired product, N-alkylisoindolin-1-one and N-
alkyphthalimide as well as the C–N bond cleaved side-products
(14) Benzoic acid together with a small amount of benzaldehyde
were detected by GC-MS analysis.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1663–1671