A convenient synthesis of 2-alkyl-3-aryl-2,3-dihydro-1H-isoindol-1-ones by the reaction of N-alkyl-N-[(2-bromophenyl)methyl]benzamides with butyllithium

Article abstract of DOI:10.1016/j.tet.2016.06.082

An unprecedented and convenient synthetic approach to 2,3-dihydro-1H-isoindol-1-one (isoindolinone) derivatives has been developed. The key and final step of the method is the reaction of N-alkyl-N-(o-bromobenzyl)benzamides with butyllithium in THF at ?78

Full text of DOI:10.1016/j.tet.2016.06.082

Tetrahedron 72 (2016) 5100e5105
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A convenient synthesis of 2-alkyl-3-aryl-2,3-dihydro-1H-isoindol-1-
ones by the reaction of N-alkyl-N-[(2-bromophenyl)methyl]
benzamides with butyllithium
*
Kazuhiro Kobayashi , Yuuki Chikazawa
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An unprecedented and convenient synthetic approach to 2,3-dihydro-1H-isoindol-1-one (isoindolinone)
derivatives has been developed. The key and final step of the method is the reaction of N-alkyl-N-(o-
bromobenzyl)benzamides with butyllithium in THF at ꢀ78 ꢁC. The corresponding 2-alkyl-3-aryl-2,3-
dihydro-1H-isoindol-1-ones were produced in moderate-to-fair yields, probably via oxidation of the
initially formed corresponding 2H-isoindole derivatives with air during workup.
Received 23 March 2016
Received in revised form 27 June 2016
Accepted 30 June 2016
Available online 1 July 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Isoindolinone
2,3-dihydro-1H-isoindol-1-one
Organolithium
Bromine/lithium exchange
Ring closure
1. Introduction
2. Results and discussion
A
large number of 2,3-dihydro-1H-isoindol-1-one (iso-
Our synthesis of isoindolinones 4 was conducted according to
the sequence illustrated in Scheme 1. The requisite precursors 3
were prepared from o-bromobenzyl azides 1 as follows. Com-
pounds 1 were treated with triphenylphosphine in dichloro-
methane at room temperature overnight, and the resulting mixture
was then allowed to react with aroyl chloride in the presence of
triethylamine to give N-(o-bromobenzyl)benzamides 2 generally in
good yields as compiled in Table 1. Aliphatic acyl chlorides, such as
acetyl chloride and propionyl chloride did not work well in this
acylation reaction. N-Alkylation of 2 was effected with sodium
hydride and alkyl halides in DMF to provide N-alkyl-N-(o-bromo-
benzyl)benzamides 3 in relatively good yield as listed in Table 2.
Compounds 3 were then converted into the desired isoindolinones
4 by treating with butyllithium.
indolinone) derivatives have been reported to exhibit a variety of
biological activities.1 Recently, some synthetic elaborations of
isoindolinone derivatives to more complex and important mole-
cules have been demonstrated.2 Moreover, many biologically im-
portant natural products with the isoindolinone structure have
been isolated from nature.3 Therefore, various synthetic ap-
proaches have been recording,4 and we were interested in de-
veloping a method for the preparation of these heterocycles
which would not only be unprecedented but also be operationally
simple. As one of the studies on our ongoing research program for
the preparation of benzene-fused nitrogen heterocycles utilizing
o-functionalized benzyl azides,5 we found that 2-alkyl-3-aryl-2,3-
dihydro-1H-isoindol-1-ones (3-aryl-1-alkylisoindolinones) 4 can
be prepared through
a
sequential reactions induced by the
The reaction of N-(o-bromobenzyl)-N-methylbenzamide (3a)
was first treated with butyllithium in THF at ꢀ78 ꢁC for 20 min to
give, after quenching by adding water and extractive workup fol-
lowed by purification using column chromatography on silica gel,
2-methyl-2-phenylisoindolin-1-one (4a) in 27% yield. This product
exhibited spectral data (IR and 1H NMR) fully identical to those
reported previously for this compound.7 The yield was improved
(49%) when the reaction time was prolonged to 2 h (Table 2, Entry
1). Further extended reaction times did not improve the yield. A rise
treatment of N-alkyl-N-(o-bromobenzyl)benzamides
3
with
butyllithium.6 Details of the new transformation are reported
herein.
* Corresponding author. Tel./fax: þ81 857 31 5263; e-mail address: kkoba@chem.
tottori-u.ac.jp (K. Kobayashi).
http://dx.doi.org/10.1016/j.tet.2016.06.082
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

K. Kobayashi, Y. Chikazawa / Tetrahedron 72 (2016) 5100e5105
5101
(o-lithiobenzyl)-N-methylbenzamide and 1-bromobutane after the
bromine/lithium exchange, did not be detected in the reaction
mixture. In fact, the use of two equivalents of butyllithium did not
improve the yields. THF was proved to be a superior solvent to
diethyl ether or 1,2-dimethoxyethene (DME); the reactions in these
solvents resulted in the formation of considerably intractable
mixtures of products, from which only trace amounts of 4a was
obtained. Under these reaction conditions, the other eight N-alkyl-
N-(o-bromobenzyl)benzamides (3b to 3i) were similarly converted
into the corresponding isoindolin-1-ones (4b to 4i) in comparable
yields (Table 2, Entries 2e9). These results indicate that both of
electron-donating methoxy and electron-withdrawing chloro
substituents on the benzene rings of 3 did not affect the yields of
the products so much.
An attempt to prepare a 1,2-dihydro-3H-benz[e]isoindol-3-one
derivative was carried out. However, under typical reaction con-
ditions,
N-[(2-bromonaphthalen-3-yl)methyl-N-(phenylmethyl)
benzamide (3j) gave 1-hydroxy-1-phenyl-2-(phenylmethyl)-1,2-
dihydro-3H-benz[e]isoindol-3-one (5) (32%) together with the de-
sired product, 1-phenyl-2-(phenylmethyl)-1,2-dihydro-3H-benz[e]
isoindol-3-one (4j) (19%) (Table 2, Entry 10). This by-product may
be arisen from the autoxidation of 4j probably during aqueous
workup. These products could be easily separated by column
chromatography on silica gel.
Although the mechanism of the formation of 4 from 3 is un-
clear, we assumed that the reaction would proceed through the
pathway depicted in Scheme 2. Thus, N-[(2-lithiophenyl)methyl]
benzamide intermediate 6, generated by the bromine/lithium ex-
change between 3 and butyllithium, cyclizes intramolecularly to
Scheme 1. Preparation of isoindolinones 4.
Table 1
Preparation of N-alkyl-N-[(2-bromophenyl)methyl]benzamides 3
Entry
1
Ar
Ph
2
Yield/%a
74
R4X
3
Yield/%a
1
2
3
4
5
6
7
8
9
1a (R1]R2]R3]H)
2a
MeI
3a
3b
3c
3d
3e
3f
3g
3h
3i
87
92
86
83
70
86
77
76
74
73
BnBr
4-ClC6H4CH2Br
BnBr
MeI
MeI
MeI
MeI
MeI
BnBr
1b (R1]R3]H, R2]Cl)
1c (R1]Cl, R2]R3]H)
1d (R1]OMe, R2]R3]H)
1d
Ph
Ph
Ph
2b
2c
2d
2e
2f
78
84
90
64
90
75
87
2-ClC6H4
4-MeOC6H4
Ph
1d
1e (R1]R2]OMe, R3]H)
1f (R1]H, R2eR3]benzo)
2g
2h
10
Ph
3j
a
Yields of isolated products.
form the lithium oxide intermediate 7. Elimination of lithium
hydroxide gives 2H-isoindole intermediate 8, which was oxidized
with oxygen during workup to give rise to 4. A similar oxidation of
2H-isoindoles to 1,3-dihydro-2H-isoindol-1-ones has been recor-
ded previously.8 Compound 4f is then further oxidized with air to
give 5. Alternatively, the formation of 4 might be trough addition
of lithium hydroxide to 8 at the 3-position producing lithium 1,3-
dihydro-2H-isoindol-1-olate intermediate 9, followed by pro-
tonation and oxidation. However, since the corresponding pro-
tected 1,3-dihydro-2H-isoindol-1-ol derivative was not detected at
all after addition of di-tert-butyl dicarbonate to the mixture ob-
tained from the reaction of 3d with butyllithium, this pathway
could be excluded.
In conclusion, we have developed a novel sequence for the
synthesis of 3-aryl-2-alkyl-2,3-dihydro-1H-isoindol-1-ones from o-
bromobenzyl azides. Although the yields of the products in the final
step are only moderate-to-fair, the attractiveness of the present
procedure lies in its operational simplicity as well as the ready
availability of the starting materials.
Table 2
Preparation of 2-alkyl-3-aryl-2,3-dihydro-1H-isoindol-1-ones 4
Entry
3
R1
R2
R3 Ar
R4
4
Yield/%a
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e Cl
3f
3g OMe
3h OMe
3i
3j
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Me
Bn
4a 49
4b 56
4-ClC6H4CH2 4c
Bn
Me
Me
Me
51
4d 50
4e 44
4f
4g 53
4h 43
4i
4j
OMe
47
2-ClC6H4
4-MeOC6H4 Me
Ph
Ph
OMe OMe
Benzo
Me
Bn
55
10
H
19b
a
Yields of isolated products.
Compound 5 was isolated in 32% yield along with 4j.
b
of the reaction temperature to 0 ꢁC conversely diminished the yield
slightly. In every reaction, not only the starting material but also N-
benzyl-N-methylbenzamide, arisen from the reaction between N-

5102
K. Kobayashi, Y. Chikazawa / Tetrahedron 72 (2016) 5100e5105
3.3. General procedure for the preparation of N-[(2-
bromophenyl)methyl]benzamides 2
A mixture of 1 (3.0 mmol) and PPh3 (0.79 g, 3.0 mmol) in CH2Cl2
(15 mL) was stirred at room temperature overnight. Et3N (0.30 g,
3.0 mmol) and ArCOCl (3.0 mmol) were then added and stirring
was continued for an additional 15 min. The mixture was concen-
trated by evaporation and the residue was subjected to purification
using column chromatography on SiO2 (CH2Cl2) to afford 2.
3.3.1. N-[(2-Bromophenyl)methyl]benzamide (2a). A white solid;
mp 131e133 ꢁC (hexane/CH2Cl2) (lit.,12 133e134 ꢁC). The spectral
(IR and 1H NMR) were identical to those reported previously.12
3.3.2. N-[(2-Bromo-4-chlorophenyl)methyl]benzamide (2b). A white
solid; mp 118e119 ꢁC (hexane/CH2Cl2); IR (KBr) 3307, 1643 cmꢀ1
;
1H NMR
d
4.68 (d, J¼6.3 Hz, 2H), 6.64 (br s, 1H), 7.28 (dd, J¼8.0,
2.3 Hz, 1H), 7.42e7.46 (m, 3H), 7.52 (t, J¼7.4 Hz, 1H), 7.59 (d,
J¼2.3 Hz, 1H), 7.78 (d, J¼7.4 Hz, 2H); 13C NMR
d 43.7, 123.9, 127.0,
128.0, 128.6, 131.3, 131.7, 132.4, 134.0, 134.2, 135.9, 167.3. HRMS (EI)
calcd for C14H11BrClNO (M): 322.9713. Found: m/z 322.9711.
Scheme 2. A plausible pathway to the products 4.
3.3.3. N-[(2-Bromo-5-chlorophenyl)methyl]benzamide (2c). A white
solid; mp 129e131 ꢁC (hexane/CH2Cl2); IR (KBr) 3295, 1639 cmꢀ1
;
3. Experimental
3.1. General
1H NMR
d
4.68 (d, J¼6.3 Hz, 1H), 6.66 (br s, 1H), 7.15 (dd, J¼8.6,
2.3 Hz, 1H), 7.44e7.54 (m, 6H), 7.80 (dd, J¼8.6, 1.7 Hz, 2H); 13C NMR
d
44.0, 121.3, 127.0, 128.7 (2 overlapped Cs), 129.2, 130.1, 131.8, 133.8,
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were
recorded with a PerkineElmer Spectrum65 FTIR spectrophotome-
ter. 1H and 13C NMR spectra were recorded in CDCl3 using TMS as an
internal reference with a JEOL ECP500 FT NMR spectrometer op-
erating at 500 and 125 MHz, respectively. High-resolution MS
spectra were measured by a Thermo Scientific Exactive spectrom-
eter (ESI, positive) or a JEOL JMS-T100GCV (EI, TOF; 70 eV) spec-
trometer. Elemental analyses were performed with an Elementar
Vario EL II instrument. TLC was carried out on Merck Kieselgel 60
PF254. Column chromatography was performed using WAKO GEL C-
200E. All of the organic solvents used in this study were dried over
appropriate drying agents and distilled prior to use.
133.9, 138.9, 167.4. HRMS (ESI) calcd for C14H12BrClNO (MþH):
323.9791. Found: m/z 323.9782.
3.3.4. N-[(2-Bromo-5-methoxyphenyl)methyl]benzamide (2d).13
white solid; mp 100e102 ꢁC (hexane/CH2Cl2); IR (KBr) 3310, 1638,
1601 cmꢀ1; 1H NMR
A
d
3.78 (s, 3H), 4.68 (d, J¼5.7 Hz, 2H), 6.63 (br,
1H), 6.73 (dd, J¼8.6, 2.9 Hz,1H), 7.03 (d, J¼2.9 Hz,1H), 7.42e7.46 (m,
4H), 7.51 (t, J¼7.4 Hz, 1H), 7.79 (d, J¼8.6 Hz, 1H).
3.3.5. N-[(2-Bromo-5-methoxyphenyl)methyl]-2-chlorobenzamide
(2e). A white solid; mp 129e130 ꢁC (hexane/CH2Cl2); IR (KBr) 3308,
1631 cmꢀ1
;
1H NMR
d
3.80 (s, 3H), 4.70 (d, J¼6.3 Hz, 2H), 6.70 (br,
1H), 6.73 (dd, J¼8.6, 2.9 Hz, 1H), 7.08 (d, J¼2.9 Hz, 1H), 7.33 (td,
J¼7.4, 1.7 Hz, 1H), 7.37 (td, J¼7.4, 1.7 Hz, 1H), 7.40 (dd, J¼7.4, 1.7 Hz,
1H), 7.44 (d, J¼8.6 Hz, 1H), 7.70 (dd, J¼7.4, 1.7 Hz, 1H); 13C NMR
3.2. Starting materials
d
44.5, 55.5, 113.9, 115.2, 115.7, 127.1, 130.26, 130.30, 130.7, 131.4,
2-Bromo-1-(bromomethyl)-4-chlorobenzene9 and 1-(azido-
methyl)-2-bromobenzenes 1a,5f 1c10 and 1e10 were prepared by
the appropriate reported procedure. n-BuLi was supplied by Asia
Lithium Corporation. All other chemicals used in this study were
commercially available.
133.3, 134.6, 137.7, 159.2, 166.3. HRMS (EI) calcd for C15H13BrClNO2
(M): 352.9818. Found: m/z 352.9892.
3.3.6. N-[(2-Bromo-5-methoxyphenyl)methyl]-4-methoxybenzamide
(2f). A white solid; mp 129e131 ꢁC (hexane/CH2Cl2); IR (KBr) 3339,
1635, 1606 cmꢀ1 1H NMR
; d 3.78 (s, 3H), 3.85 (s, 3H), 4.66 (d,
3.2.1. Azides 1b, 1d,11 and 1f. These compounds were prepared
from the respective bromides according to the procedure for the
preparation of 1a.5f
J¼6.3 Hz, 2H), 6.55 (br, 1H), 6.72 (dd, J¼8.6, 2.9 Hz, 1H), 6.92 (d,
J¼8.6 Hz, 2H), 7.02 (d, J¼2.9 Hz, 1H), 7.44 (d, J¼8.6 Hz, 1H), 7.76 (d,
J¼8.6 Hz, 2H); 13C NMR
d 44.4, 55.4, 55.5, 113.7, 113.8, 114.9, 116.9,
128.8, 132.3, 133.3, 138.3, 159.2, 162.3, 170.9. HRMS (ESI) calcd for
3.2.1.1. 1-(Azidomethyl)-2-bromo-4-chlorobenzene (1b). Yield:
82%; a colorless oil; Rf 0.21 (hexane); IR (neat) 2105 cmꢀ1; 1H NMR
C
16H17BrNO3 (MþH): 350.0392. Found: m/z 350.0386.
d
4.47 (s, 2H), 7.33 (s, 2H), 7.62 (s, 1H); 13C NMR
d
54.0, 123.9, 128.0,
3.3.7. N-[(2-Bromo-4,5-dimethoxyphenyl)methyl]benzamide (2g). A
white solid; mp 135e136 ꢁC (hexane/CH2Cl2); IR (KBr) 3285, 1635,
130.6, 132.6, 133.6, 134.8. Anal. Calcd for C7H5BrClN3: C, 34.11; H,
2.04; N, 17.05. Found: C, 33.96; H, 2.23; N, 16.96.
1603 cmꢀ1; 1H NMR
d
3.87 (s, 6H), 4.65 (d, J¼6.3 Hz, 2H), 6.60 (br s,
1H), 7.03 (s, 2H), 7.43 (t, J¼7.4 Hz, 2H), 7.50 (t, J¼7.4 Hz, 1H), 7.78 (d,
3.2.1.2. 2-(Azidomethyl)-1-bromonaphthalene (1f). Yield: 81%;
a white solid; mp 27e28 ꢁC (pentane); IR (KBr) 2105 cmꢀ1; 1H NMR
J¼7.4 Hz, 2H); 13C NMR
d 44.1, 56.1, 56.2, 113.6, 113.9, 115.4, 126.9,
128.6, 129.4, 131.5, 134.3, 148.5, 149.1, 167.2. HRMS (ESI) calcd for
d
4.75 (s, 2H), 7.51 (d, J¼8.6 Hz, 1H), 7.56 (ddd, J¼8.0, 6.9, 1.1 Hz, 1H),
C
16H17BrNO3 (MþH): 350.0392. Found: m/z 350.0401.
7.63 (ddd, J¼8.0, 6.9, 1.1 Hz, 1H), 7.85 (d, J¼8.0 Hz, 2H), 8.35 (d,
J¼8.6 Hz, 1H); 13C NMR
d
55.4, 124.1, 126.6, 127.0, 127.4, 127.79,
3.3.8. N-[(1-Bromonaphthalen-2-yl)methyl]benzamide
(2h). A
127.80,128.2,132.3,132.9,134.1. Anal. Calcd for C11H8BrN3: C, 50.41;
H, 3.08; N, 16.03. Found: C, 50.36; H, 3.06; N, 15.95.
white solid; mp 178e180 ꢁC (hexane/CH2Cl2); IR (KBr) 3295,
1639 cmꢀ1; 1H NMR
4.97 (d, J¼6.3 Hz, 2H), 6.73 (br s,1H), 7.43 (dd,
d

K. Kobayashi, Y. Chikazawa / Tetrahedron 72 (2016) 5100e5105
5103
J¼8.0, 7.4 Hz, 2H), 7.49 (t, J¼7.4 Hz, 1H), 7.53 (dd, J¼8.0, 7.4 Hz, 1H),
and 3.08 (2br s, combined 3H), 3.81 (br s, 3H), 4.52 and 4.84 (2br s,
7.60 (d, J¼8.0 Hz, 2H), 7.79e7.84 (m, 4H), 8.32 (d, J¼8.6 Hz, 1H); 13
C
combined 2H), 6.74 (dd, J¼8.6, 2.9 Hz, 1H), 6.85 and 6.92 (2br s,
NMR
d
45.3, 124.0, 126.6, 127.0, 127.1, 127.5, 127.6, 128.08, 128.14,
combined 1H), 7.35e7.48 (m, 6H); 13C NMR
d 33.5, 37.2, 50.6, 55.3,
128.6, 131.6, 132.3, 134.0, 134.1, 135.5, 167.4. HRMS (EI) calcd for
18H14BrBrNO (M): 339.0259. Found: m/z 339.0254.
112.7, 113.8, 114.0, 114.8, 126.5, 126.8, 128.2, 129.6, 129.7, 133.3,
133.5, 135.5, 135.8, 136.6, 159.1, 170.8, 172.3. HRMS (EI) calcd for
C
C16H16BrNO2 (M): 333.0364. Found: m/z 333.0361.
3.4. Typical procedure for the preparation of N-alkyl-N-[(2-
bromophenyl)methyl]benzamides 3
3.4.7. N-[(2-Bromo-5-methoxyphenyl)methyl]-2-chloro-N-methyl-
benzamide (3g). A pale-yellow oil; Rf 0.28 (CH2Cl2/hexane 5:1);
3.4.1. N-[(2-Bromophenyl)methyl]-N-methylbenzamide
(3a). To
a mixture of rotamers; IR (neat) 1646 cmꢀ1; 1H NMR
d 2.82 and 3.09
a stirred suspension of NaH (60% in mineral oil; 44 mg, 1.1 mmol) in
DMF (3 mL) at room temperature was added a solution of 2a
(0.29 g,1.0 mmol) in DMF (2 mL) dropwise. After evolution of H2 gas
had ceased, MeI (75 mg, 1.2 mmol) was added. After 1.5 h, H2O
(20 mL) was added and the mixture was extracted with AcOEt
(3ꢂ10 mL). The combined extracts were washed with H2O
(3ꢂ20 mL) and brine (15 mL), dried (Na2SO4), and concentrated by
evaporation. The residue was purified by column chromatography
on SiO2 to afford 3a (0.26 g, 87%); a colorless oil; a mixture of
(2br s, combined 3H), 3.80 (s, 3H), 4.43, 4.76, and 5.04 (3br, com-
bined 2H), 6.71 and 6.74 (2dd, J¼9.2, 2.9 Hz each, combined 1H),
6.81 and 7.04 (2d, J¼2.9 Hz each, combined 1H), 7.26e7.46 (m, 5H);
13C NMR
d 32.7, 35.8, 50.1, 54.2, 55.4, 113.1, 113.9, 114.1, 114.6, 115.2,
127.0, 127.2, 127.6, 127.7, 129.6, 129.7, 130.1, 130.2,130.3, 130.4,133.3,
133.6, 135.9, 136.0, 159.29, 159.33, 168.7, 169.0. HRMS (EI) calcd for
C16H15BrClNO2 (M): 366.9975. Found: m/z 366.9983.
3.4.8. N-[(2-Bromo-5-methoxyphenyl)methyl]-4-methoxy-N-meth-
rotamers; Rf 0.24 (CH2Cl2); IR (neat) 1638, 1602 cmꢀ1
;
1H NMR
ylbenzamide (3h). A pale-yellow oil; Rf 0.25 (CH2Cl2); a mixture of
d
2.91 and 3.08 (2br s, combined 3H), 4.57 and 4.89 (2br s, com-
rotamers; IR (neat) 1634,1609 cmꢀ1; 1H NMR
d
3.05 (br, 3H), 3.81 (s.
3H), 3.82 (s, 3H), 4.56 and 4.81 (2br, combined 2H), 6.73 (dd, J¼8.6,
2.9 Hz, 1H), 6.89 (br, 3H), 7.45 (br, 3H); 13C NMR
34.5, 38.3, 50.1,
bined 2H), 7.18e7.60 (m, 9H); 13C NMR
d
33.4, 37.2, 50.5, 55.3, 122.5,
123.6, 126.4, 126.9, 127.4, 127.6, 128.2, 128.8, 129.0, 129.5, 129.60,
129.63, 132.7, 132.9, 135.4, 135.5, 135.7, 171.4, 172.3. HRMS (EI) calcd
for C15H14BrNO (M): 303.0259. Found: m/z 303.0249.
d
55.1, 55.3, 113.5, 114.1, 127.7, 128.7, 128.8, 128.86, 128.92, 128.96,
129.00, 129.1, 133.47, 133.49, 136.9, 159.3, 160.7, 170.9, 172.0. HRMS
(EI) calcd for C17H18BrNO3 (M): 363.0470. Found: m/z 363.0464.
3.4.2. N-[(2-Bromophenyl)methyl]-N-(phenylmethyl)benzamide
(3b). A colorless oil; a mixture of rotamers; Rf 0.21 (Et2O/hexane
3.4.9. N-[(2-Bromo-4,5-dimethoxyphenyl)methyl]-N-methyl-
1:2); IR (neat) 1639, 1602 cmꢀ1; 1H NMR
d
4.47 (br s, 2H), 4.72 and
benzamide (3i). A pale-yellow oil; Rf 0.23 (CH2Cl2); a mixture of
4.81 (2br s, combined 2H), 7.12e7.53 (m, 14H); 13C NMR
d
47.4, 52.0,
rotamers; IR (neat) 1636,1602 cmꢀ1; 1H NMR
d
2.89 and 3.06 (2br s,
combined 3H), 3.88 (s, 6H), 4.52 and 4.85 (2br s, combined 2H),
6.72e7.45 (m, 7H); 13C NMR
33.1, 36.8, 49.7, 99.6, 110.3, 112.3,
122.7, 123.7, 126.3, 126.6, 127.0, 127.4, 127.5, 127.8, 128.2, 128.5,
128.8, 129.5, 129.6, 131.11, 132.2, 132.8, 133.0, 135.2, 135.5, 135.6,
136.1, 136.4, 172.2. HRMS (EI). calcd for C21H18BrNO (M): 379.0572.
Found: m/z 379.0588.
d
112.6, 113.8, 115.0, 115.5, 123.8, 125.9, 126.6, 126.7, 127.9, 128.2,
129.4, 129.6, 135.8, 148.5, 148.7, 170.8, 172.1. HRMS (EI) calcd for
C17H18BrNO3 (M): 363.0470. Found: m/z 363.0471.
3.4.3. N-[(2-Bromophenyl)methyl]-N-[(4-chlorophenyl)methyl]ben-
zamide (3c). A white solid; mp 91e93 ꢁC (hexane/CH2Cl2); a mix-
3.4.10. N-[(2-Bromonaphthalen-3-yl)methyl]-N-(phenylmethyl)ben-
ture of rotamers; IR (KBr) 1640, 1601 cmꢀ1; 1H NMR
d
4.42 and 4.48
(2br s, combined 2H), 4.67 and 4.80 (2br s, combined 2H), 7.05e7.55
(m, 13H); 13C NMR
47.0, 47.5, 51.4, 52.1, 122.9, 123.8, 126.5, 126.6,
zamide (3j). Awhitesolid;mp98e100 ꢁC(hexane/CH2Cl2);amixture
of rotamers; IR (neat) 1630 cmꢀ1; 1H NMR
d
4.47 (br s, 1H), 4.73 and
4.75(2brs,combined2H), 5.09(brs,1H), 7.13e8.33(m,16H);13CNMR
d 47.7, 48.2, 52.0, 52.9, 123.0, 124.0, 124.4, 126.5, 126.67, 126.71, 126.8,
d
127.5, 127.7, 127.9, 128.1, 128.3, 128.4, 128.7, 128.77, 128.79, 129.0,
129.7,129.8,131.3,132.5,132.9, 133.1, 133.3,134.7,135.1,135.4, 135.5,
137.2, 167.2, 172.3. Anal. Calcd for C21H17BrClO2: C, 60.82; H, 4.13; N,
3.38. Found: C, 60.42; H, 4.08; N, 3.27.
127.1, 127.5, 127.7, 127.9, 127.96, 128.02, 128.1, 128.2, 128.4, 128.6, 129.7,
132.2, 133.3, 133.7, 134.0, 135.6, 135.7, 136.2, 136.5, 172.4. HRMS (ESI)
calcd for C25H21BrNO (MþH): 430.0807. Found: m/z 430.0805.
3.4.4. N-[(2-Bromo-4-chlorophenyl)methyl]-N-(phenylmethyl)ben-
3.5. Typical procedure for the preparation of 2,3-dihydro-1H-
zamide (3d). A colorless oil; a mixture of rotamers; Rf 0.30 (CH2Cl2/
isoindol-1-ones 4
hexane 2:1); IR (neat) 1642 cmꢀ1
;
1H NMR
d
4.43 and 4,47 (2br s,
combined 2H), 4.70 and 4.78 (2br s, combined 2H), 7.11e7.58 (m,
13H); 13C NMR
47.3, 47.9, 51.9, 52.5, 126.7, 127.0, 127.9, 128.0, 128.1,
3.5.1. 2-Methyl-3-phenyl-2,3-dihydro-1H-isoindol-1-one
(4a). To
d
a stirred solution of 3a (0.23 g, 0.76 mmol) in THF (5 mL) at ꢀ78 ꢁC
was added n-BuLi (1.6 M in hexane; 0.76 mmol) dropwise. After 2 h,
H2O (15 mL) was added and the mixture was extracted with AcOEt
(3ꢂ10 mL). The combined extracts were washed with H2O and
brine (15 mL each), dried (Na2SO4), and concentrated by evapora-
tion. The residue was purified by column chromatography on SiO2
(AcOEt/hexane 1:2) to afford 4a (83 mg, 49%); white solid; mp
100e102 ꢁC (hexane/CH2Cl2) (lit.,7 mp 101 ꢁC). The spectral data (IR
and 1H NMR) were identical to those reported previously.7
128.5,128.7, 129.0,130.1, 130.8,132.7, 133.0,134.1,134.7,135.7,136.2,
136.6, 171.6. HRMS (EI) calcd for C21H17BrClNO (M): 413.0182.
Found: m/z 413.0201.
3.4.5. N-[(2-Bromo-5-chlorophenyl)methyl]-N-methylbenzamide
(3e). A pale-yellow oil; Rf 0.29 (CH2Cl2/hexane 1:1); a mixture of
rotamers; IR (neat) 1639 cmꢀ1
;
1H NMR
d
2.95 and 3.09 (2br s,
combined 3H), 4.52 and 4.84 (2br s, combined 2H), 7.16e7.51 (m,
8H); 13C NMR
33.7, 37.5, 50.6, 53.4, 55.3, 120.3, 121.4, 126.5, 127.0,
d
127.6, 128.4, 128.8, 128.9, 129.0, 129.8, 133.8, 133.9, 134.1, 135.3,
135.5, 137.6, 171.7, 172.4. HRMS (EI). Calcd for C15H13BrClNO (M):
336.9869. Found: m/z 336.9865.
3.5.2. 3-Phenyl-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one
(4b). A white solid; mp 133e135 ꢁC (hexane/CH2Cl2) (lit.,7 mp
136 ꢁC). The spectral data (IR and 1H NMR) were identical to those
reported previously.7
3.4.6. N-[(2-Bromo-5-methoxyphenyl)methyl]-N-methylbenzamide
(3f). A pale-yellow oil; Rf 0.38 (CH2Cl2/hexane 3:1); a mixture of
3.5.3. 2-[(4-Chlorophenyl)methyl]-3-phenyl-2,3-dihydro-1H-iso-
indol-1-one (4c). A pale-yellow solid; mp 120e125 ꢁC (hexane/
rotamers; IR (neat) 1638 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
2.92

5104
K. Kobayashi, Y. Chikazawa / Tetrahedron 72 (2016) 5100e5105
CH2Cl2); IR (KBr) 1694,1640 cmꢀ1; 1H NMR
d
3.74 (d, J¼14.9 Hz,1H),
128.6, 129.1, 137.2, 139.6, 149.8, 152.8, 168.9. HRMS (EI) calcd for
5.22 (s, 1H), 5.31 (d, J¼14.9 Hz, 1H), 7.05e7.06 (m, 2H), 7.10 (d,
C17H17NO3 (M): 283.1208. Found: m/z 283.1208. Anal. Calcd for
J¼8.6 Hz, 2H), 7.25 (d, J¼8.6 Hz, 2H), 7.29e7.39 (m, 4H), 7.43e7.50
C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 71.92; H, 6.12; N,
(m, 2H), 7.94 (dd, J¼8.6, 2.3 Hz, 1H); 13C NMR
d
43.2, 63.6, 123.2,
4.66.
123.7, 127.7, 128.4, 128.76, 128.81, 129.2, 129.8, 131.1, 132.0, 133.4,
135.6, 136.5, 146.2, 168.5. HRMS (EI) calcd for C21H16ClNO (M):
333.0920. Found: m/z 333.0927. Anal. Calcd for C21H16ClNO: C,
75.56; H, 4.83; N, 4.20. Found: C, 75.43; H, 5.06; N, 4.12.
3.5.10. 1-Phenyl-2-(phenylmethyl)-1,2-dihydro-3H-benz[e]isoindol-
3-one (4j). A white solid; mp 175e177 ꢁC (hexane/CH2Cl2); IR (KBr)
1689 cmꢀ1
;
1H NMR
d
3.69 (d, J¼14.9 Hz, 1H), 5.40 (d, J¼14.9 Hz,
1H), 5.60 (s, 1H), 7.13e7.38 (m, 11H), 7.46e7.50 (m, 2H), 7.92 (d,
3.5.4. 5-Chloro-3-phenyl-2-(phenylmethyl)-2,3-dihydro-1H-iso-
J¼8.6 Hz, 1H), 7.98 (d, J¼8.6 Hz, 1H), 8.01 (d, J¼8.6 Hz, 1H); 13C NMR
indol-1-one (4d). A white solid; mp 148e151 ꢁC (hexane/CH2Cl2);
d 43.5, 63.3, 119.9, 123.6, 127.0, 127.4, 127.5, 127.7, 128.3, 128.4, 128.7,
IR (KBr) 1698, 1611 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
3.72 (d,
128.8, 129.1, 129.2, 129.7, 129.7, 135.5, 136.9, 137.4, 143.9, 168.6.
HRMS (EI) calcd for C25H19NO (M): 349.1467. Found: m/z 349.1483.
Anal. Calcd for C25H19NO: C, 85.93; H, 5.48; N, 4.01. Found: C, 85.63;
H, 5.42; N, 3.92.
J¼14.9 Hz, 1H), 5.21 (s, 1H), 5.37 (d, J¼14.9 Hz, 1H), 7.05e7.09 (m,
3H), 7.16 (d, J¼6.9 Hz, 2H), 7.26e7.31 (m, 3H), 7.36e7.39 (m, 3H),
7.43 (dd, J¼8.0, 1.1 Hz, 1H), 7.86 (d, J¼8.0 Hz, 1H); 13C NMR
d 43.9,
63.2, 123.6, 125.0, 127.67, 127.70, 128.4, 128.7, 129.0, 129.3, 129.83,
129.84, 135.9, 136.8, 138.2, 147.8, 167.4. HRMS (EI) calcd for
3.5.11. 1-Hydroxy-1-phenyl-2-(phenylmethyl)-1,2-dihydro-3H-benz
C
C
21H16ClNO (M): 333.0920. Found: m/z 333.0913. Anal. Calcd for
21H16ClNO: C, 75.56; H, 4.83; N, 4.20. Found: C, 75.38; H, 4.96; N,
[e]isoindol-3-one (5). A white solid; mp 187e189 ꢁC (hexane/
CH2Cl2); IR (KBr) 3262, 1675 cmꢀ1 1H NMR
; d 2.96 (s, 1H), 4.09 (d,
4.02.
J¼15.5 Hz, 1H), 4.79 (d, J¼15.5 Hz, 1H), 7.15e7.20 (m, 2H), 7.24e7.27
(m, 6H), 7.36e7.41 (m, 3H), 7.50 (dd, J¼8.0, 6.9 Hz, 1H), 7.85 (d,
J¼8.6 Hz, 1H), 7.88 (d, J¼8.6 Hz, 1H), 7.90 (d, J¼8.6 Hz, 1H), 7.97 (d,
3.5.5. 6-Chloro-2-methyl-3-phenyl-2,3-dihydro-1H-isoindol-1-one
(4e). A yellow solid; mp 94e96 ꢁC (hexane/CH2Cl2); IR (KBr)
J¼8.6 Hz, 1H); 13C NMR
d 42.6, 91.7, 119.2, 124.6, 126.3, 126.9, 127.3,
1686 cmꢀ1
;
1H NMR
d
2.96 (s, 3H), 5.31 (s, 1H), 7.09e7.13 (m, 3H),
7.34e7.38 (m, 3H), 7.42 (dd, J¼8.0, 1.7 Hz, 1H), 7.83 (d, J¼1.7 Hz, 1H);
13C NMR
27.6, 66.3, 123.6, 124.2, 127.3, 128.9, 129.3, 131.8, 133.4,
127.6, 127.9, 128.2, 128.4, 128.5, 128.6, 128.8, 128.9, 130.9, 136.1,
138.25, 138.32, 145.3, 167.9. HRMS (EI) calcd for C25H19NO2 (M):
365.1416. Found: m/z 365.1425. Anal. Calcd for C25H19NO2: C, 82.17;
H, 5.24; N, 3.83. Found: C, 82.00; H, 5.30; N, 3.66.
d
134.6, 136.2, 144.2, 167.3. HRMS (EI) calcd for C15H12ClNO (M):
257.0607. Found: m/z 257.0612. Anal. Calcd for C15H12ClNO: C,
69.91; H, 4.69; N, 5.43. Found: C, 69.56; H, 4.56; N, 5.33.
Acknowledgements
3.5.6. 6-Methoxy-2-methyl-3-phenyl-2,3-dihydro-1H-isoindol-1-one
This work was founded by a grant from Japan Society for the
Promotion of Science (JSPS) KAKENHI (Grant No. 26410051). The
authors gratefully acknowledge Mrs. Miyuki Tanmatsu of our uni-
versity for recording mass spectra and performing combustion
analyses.
(4f). A white solid; mp 115e116 ꢁC (hexane/CH2Cl2); IR (KBr) 1682,
1617 cmꢀ1; 1H NMR
d 2.96 (s, 3H), 3.86 (s, 3H), 5.27 (s, 1H), 7.01 (dd,
J¼8.6, 2.9 Hz, 1H), 7.05 (d, J¼8.6 Hz, 1H), 7.13 (dd, J¼7.4, 1.1 Hz, 2H),
7.31e7.36 (m, 3H), 7.37 (d, J¼2.9 Hz, 1H); 13C NMR
d 27.6, 55.7, 66.2,
106.2, 119.9, 123.8, 127.3, 128.6, 129.8, 133.0, 137.2, 138.4, 160.1,
168.7. HRMS (EI) calcd for C16H15NO2 (M): 253.1103. Found: m/z
253.1103. Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53.
Found: C, 75.82; H, 6.05; N, 5.42.
References and notes
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3.5.7. 3-(2-Chlorophenyl)-6-methoxy-2-methyl-2,3-dihydro-1H-iso-
indol-1-one (4g). A white solid; mp 131e134 ꢁC (hexane/CH2Cl2); IR
(KBr) 1693, 1620 cmꢀ1; 1H NMR
d 2.99 (s, 3H), 3.86 (s, 3H), 6.02 (s,
1H), 6.77 (dd, J¼8.0, 1.7 Hz, 1H), 7.01 (dd, J¼8.0, 2.3 Hz, 1H), 7.17 (t,
J¼7.4 Hz, 1H), 7.16e7.25 (m, 2H), 7.36 (d, J¼2.3 Hz, 1H), 7.49 (d,
J¼7.4 Hz, 1H); 13C NMR
d 27.7, 55.7, 61.7, 106.4, 120.0, 123.7, 127.4,
127.8, 129.5, 130.0, 133.0, 134.0, 135.0, 137.9, 160.3, 168.9. HRMS (EI)
calcd for C16H14ClNO2 (M): 287.0713. Found: m/z 287.0719. Anal.
Calcd for C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87. Found: C, 66.69; H,
4.86; N, 4.79.
3.5.8. 6-Methoxy-3-(4-methoxyphenyl)-2-methyl-2,3-dihydro-1H-
isoindol-1-one (4h). A white solid; mp 133e135 ꢁC (hexane/
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CH2Cl2); IR (KBr) 1686, 1611 cmꢀ1 1H NMR
; d 2.93 (s, 3H), 3.80 (s,
3H), 3.86 (s, 3H), 5.22 (s, 1H), 6.87 (d, J¼9.2 Hz, 2H), 7.00e7.05 (m,
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d 27.4, 55.3, 55.7, 65.7, 106.1,
113.9, 114.4, 119.8, 123.8, 128.7, 129.0, 133.1, 138.6, 159.8, 160.1.
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ꢀ
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1-one (4i). A colorless viscous oil; Rf 0.29 (AcOEt/hexane 2:1); IR
(neat) 1685, 1615 cmꢀ1; 1H NMR
d
2.94 (s, 3H), 3.82 (s, 3H), 3.96 (s,
3H), 5.23 (s, 1H), 6.61 (s, 1H), 7.14 (dd, J¼7.4, 1.1 Hz, 2H), 7.35e7.39
(m, 4H); 13C NMR
27.5, 56.1, 56.3, 66.3, 105.0, 124.0, 126.0, 127.5,
d

K. Kobayashi, Y. Chikazawa / Tetrahedron 72 (2016) 5100e5105
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