A facile synthesis of 1,1-disubstituted isoindoline derivatives by intramolecular iodoamination of 2-vinylbenzylamine derivatives

Article abstract of DOI:10.3987/COM-07-11072

The intramolecular iodoamination of N-(2-vinylbenzyl)acetamide derivatives, derived from α-substituted 2-vinylbenzonitriles in two steps, afforded the corresponding 2-acetyl-l-iodomethylisoindoline derivatives, which were transformed into the 1-methyl or

Full text of DOI:10.3987/COM-07-11072

HETEROCYCLES, Vol. 71, No. 8, 2007
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HETEROCYCLES, Vol. 71, No. 8. 2007, pp. 1827 – 1835. © The Japan Institute of Heterocyclic Chemistry
Received, 4th April, 2007, Accepted, 17th May, 2007, Published online, 18th May, 2007. COM-07-11072
A FACILE SYNTHESIS OF 1,1-DISUBSTITUTED ISOINDOLINE
DERIVATIVES BY INTRAMOLECULAR IODOAMINATION OF
2-VINYLBENZYLAMINE DERIVATIVES
Kazuhiro Kobayashi,* Shizuka Kondo, Kenichi Hashimoto, Shuhei Fukamachi,
Osamu Morikawa, and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Abstract- The intramolecular iodoamination of N-(2-vinylbenzyl)acetamide
derivatives, derived from α-substituted 2-vinylbenzonitriles in two steps, afforded
the corresponding 2-acetyl-1-iodomethylisoindoline derivatives, which were
transformed into the 1-methyl or 1-sulfenylmethyl derivatives by tributyltin
hydride reduction or substitution by sodium thiolates, respectively, in reasonable
yields.
We have recently demonstrated that 3,3-disubstituted isoindolin-1-ones could be prepared by
intramolecular iodoamination1 of α-substituted secondary 2-vinylbenzamides.2 As an extension of this
synthesis, we now wish to report a new and convenient synthesis of 1,1-disubstituted isoindoline
derivatives by iodoamination of N-(2-vinylbenzyl)acetamide derivatives, which can be readily prepared
from α-substituted 2-vinylbenzonitriles. Isoindoline derivatives have attracted synthetic attention3 for
their biological activities.4 The derivatives having no substituents both at the 1- and 3-positions have
been prepared by reduction of phthalimides with appropriate reducing agents.5 However, there have
been few reports on the synthesis of 1,1-disubstituted isoindoline derivatives, though Buchwald et al.
have reported a synthesis of 1-substituted isoindoline-1-carboxylic acid esters by palladium-catalyzed
intramolecular α-arylation of N-(2-bromobenzyl)-α-amino acid ester derivatives.3d
The synthesis of 1,1-disubstituted isoindoline derivatives was conducted by the process illustrated in
Scheme 1. Thus, α-substituted 2-vinylbenzonitriles (1) were treated with LAH, and the resulting
benzylamine derivatives were then acetylated with acetic anhydride in pyridine to give the
corresponding α-substituted 2-(acetylaminomethyl)styrenes (2) in good overall yields. Treatment of
these compounds with iodine in the presence of sodium hydrogencarbonate in acetonitrile resulted in a

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HETEROCYCLES, Vol. 71, No. 8, 2007
clean regioselective conversion to the intramolecular 5-exo iodoamination products,
1-iodomethylisoindolines (3), in good yields. The resulting 1-iodomethyl derivatives (3) thus formed
were then reduced with tributyltin hydride to give the 1-methyl derivatives (4) in good yields.
1
1
R
R
1
CH I
2
R
2
2
2
R
R
R
I , NaHCO
2 3
1) LAH, Et O, 0 ˚C
2
NAc
NHAc
MeCN, 0 ˚C
2) Ac O, Py, rt
2
CN
3a 87%
3b 88%
3c 75%
3d 87%
3e 71%
1
2a 80%
2b 82%
2c 76%
2d 83%
2e 75%
1
2
a R = Ph, R = H
1
2
1
Me
b R = 4-MeOC H , R = H
6
4
R
1
2
c R = Me, R = H
1
n-Bu SnH
3
2
NAc
d R = Et, R = H
2
C H , rt
6
6
1
e R = Me, R = OMe
4a 73%
4b 78%
4c 76%
4d 84%
Scheme 1
Nucleophilic substitution reactions of the iodomethylisoindoline derivatives (3) were then examined.
The sulfenylation with sodium thiolates proceeded cleanly to afford the corresponding 1-sufenylmethyl
derivatives (5),6 as shown in Scheme 2. The yields and reaction conditions of the sulfenylation are
summarized in Table 1, which indicates the yields are generally good. Unfortunately, however,
attempted substitution of 3 with sodium acetanilide or sodium acetate resulted in vain.
The structures of the products prepared in this study were assigned from their spectral and analytical
data. It was found that in cases where the substituent R1 was phenyl or 4-methoxyphenyl, each of the IH
NMR spectra of compounds 3a, 3b, 4a, 4b, 5a, and 5b was observed as a mixture of two rotamers (see
Experimental).
3
1
CH SR
2
R
3
2
R SH, NaH
R
3
NAc
DMF
5
Scheme 2

HETEROCYCLES, Vol. 71, No. 8, 2007
1829
Table 1: Preparation of 1-(Sulfenylmethyl)isoindoline Derivatives (5)
Entry
3
R3 in R3SH
Ph
Temp
80 ˚C
100 ˚C
60 ˚C
60 ˚C
60 ˚C
rt
Time/min
5 (Yield/%)a
5a (81)
5b (64)
5c (79)
1
2
3
4
5
6
7
3a
3b
3c
3c
3c
3d
3e
45
30
10
40
40
15
15
Ph
Ph
pyridin-2-yl
4,6-dimethylpyrimidin-2-yl
5d (66)
5e (69)
5f (90)
Bn
Bn
rt
5g (69)
aIsolated yields.
In conclusion, we have demonstrated herein the utility of the iodoamination strategy for the synthesis of
1,1-disubstituted isoindoline derivatives, which have been hard to prepare by conventional methods. The
ready availability of the starting materials and the ease of operations make the present method attractive.
EXPERIMENTAL
The melting points were determined on a Laboratory Devices MEL-TEMP II melting-point apparatus
1
and are uncorrected. The IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer. The H
NMR spectra were determined using SiMe4 as an internal reference in CDCl3 with a JEOL ECP500 FT
NMR spectrometer operating at 500 MHz or a JEOL LA400 FT NMR spectrometer operating at 400
MHz. Low-resolution mass spectra (EI) were recorded on a JEOL AUTOMASS 20 spectrometer
(Center for Joint Research and Development, this University). Thin-layer chromatography (TLC) was
carried out on Merck Kieselgel 60 PF254. Column chromatography was performed using Merck Kieselgel
60 (0.063–0.200 mm). All of the solvents used in the reactions were dried over appropriate drying
agents and distilled under argon prior to use.
Starting Materials. 2-Bromophenyl(4-methoxyphenyl)methanone7 and 1-(2-bromo-5-methoxyphenyl)-
ethanone8 were prepared by appropriate reported methods. For the preparation of 2-(1-phenylvinyl)-
benzonitrile (1a),9 2-(1-methylvinyl)benzonitrile (1c),10 and 2-(1-ethylethenyl)benzonitrile (1d), see refs.
11 and 12.
2-(4-Methoxybenzoyl)benzonitrile. This compound was prepared by treating 2-bromophenyl-
(4-methoxyphenyl)methanone7 with CuCN in DMF under the conditions reported by Friedman et al.13 in
1
99% yield; a yellow oil; Rf 0.29 (THF–hexane, 1:2); IR (neat) 2228, 1651 cm–1; H NMR (500 MHz) δ
3.90 (s, 3H), 6.97 (d, J = 8.7 Hz, 2H), 7.61–7.65 (m, 2H), 7.69 (ddd, J = 7.8, 7.3, 1.4 Hz, 1H), 7.79–7.84
(m, 3H). Anal. Calcd for C15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found: C, 75.75; H, 4.73; N, 5.74.
2-[1-(4-Methoxyphenyl)vinyl]benzonitrile (1b). This compound was prepared by treating
2-(4-methoxybenzoyl)benzonitrile with methylenetriphenylphosphorane under conditions for the
preparation of 1a reported by us12 in 77% yield; a yellow oil; Rf 0.51 (THF–hexane, 1:3); IR (neat) 2226,
1607 cm–1; 1H NMR (500 MHz) δ 3.81 (s, 3H), 5.35 (s, 1H), 5.78 (s, 1H), 6.86 (d, J = 9.1 Hz, 2H), 7.19

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(d, J = 9.1 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.42 (td, J = 7.3, 1.4 Hz, 1H), 7.57 (ddd, J = 7.8, 7.3, 1.4
Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H). Anal. Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C,
81.59; H, 5.77; N, 5.90.
2-Acetyl-4-methoxybenzonitrile. This compound was prepared by treating 1-(2-bromo-5-
methoxyphenyl)ethanone8 with CuCN in DMF under the conditions for the preparation of
2-propanoylbenzonitrile reported by us11 in 71% yield; a pale-yellow solid; mp 75–77 ˚C
(hexane–CH2Cl2); IR (KBr) 2216, 1680 cm–1; 1H NMR (400 MHz) δ 2.70 (s, 3H), 3.92 (s, 3H), 7.10 (dd,
J = 8.6, 2.6 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H). Anal. Calcd for C10H9NO2: C,
68.56; H, 5.18; N, 8.00. Found: C, 68.50; H, 5.17; N, 7.98.
4-Methoxy-2-(1-methylvinyl)benzonitrile (1e).
This compound was prepared by treating
2-acetyl-4-methoxybenzonitrile with methylenetriphenylphosphorane under conditions for the
preparation of 1a reported by us12 in 62% yield; a pale yellow oil; Rf 0.15 (CH2Cl2–hexane, 1:3); IR
(neat) 2220, 1603 cm–1; 1H NMR (500 MHz) δ 2.18 (dd, J = 1.4, 0.9 Hz, 3H), 3.86 (s, 3H), 5.25 (s, 1H),
5.36 (qd, J = 1.4, 0.9 Hz, 1H), 6.84–6.86 (m, 2H), 7.58 (d, J = 9.2 Hz, 1H). Anal. Calcd for C11H11NO: C,
76.28; H, 6.40; N, 8.09. Found: C, 75.97; H, 6.55; N, 7.86.
Typical Procedure for the Preparation of N-(2-Vinylbenzyl)acetamides (2). N-[2-(1-
Phenylvinyl)phenylmethyl]acetamide (2a). To a stirred suspension of LAH (93 mg, 2.4 mmol) in Et2O
(2.5 mL) at 0 ˚C was added a solution of 1a (0.25 g, 1.2 mmol) in Et2O (2.5 mL) dropwise. After 1h,
five portions of several drops each of saturated aqueous Na2SO4 were added at 15 min intervals to
decompose excess LAH. After 15 min, anhydrous MgSO4 was added to the mixture and stirring was
continued for an additional 20 min. Filtration through a Celite® pad followed by evaporation of the
solvent gave a residue (0.23 g), which was dissolved in 0.5 mL each of pyridine and Ac2O and was
allowed to stand overnight at room temperature under stirring. After removal of the excess pyridine and
Ac2O under reduced pressure, the residue was purified by preparative TLC on silica gel (AcOEt–hexane,
1:2) to give 2a (0.24 g, 80%); a pale-yellow solid; mp 256–257 ˚C (hexane–CH2Cl2); IR (KBr) 3263,
1643, 1611 cm–1; 1H NMR (500 MHz) δ 1.75 (s, 3H), 4.20 (d, J = 5.5 Hz, 2H), 5.16 (br s, 1H), 5.25 (d, J
= 1.4 Hz, 1H), 5.81 (d, J = 1.4 Hz, 1H), 7.26–7.40 (m, 9H). Anal. Calcd for C17H17NO: C, 81.24; H,
6.82; N, 5.57. Found: C, 81.40; H, 6.85; N, 5.51.
N-{2-[1-(4-Methoxyphenyl)ethenyl]phenylmethyl}acetamide (2b): a white solid; mp 105–106 ˚C
1
(hexane–CH2Cl2); IR (KBr) 3265, 1647, 1605 cm–1; H NMR (500 MHz) δ 1.78 (s, 3H), 3.80 (s, 3H),
4.21 (d, J = 6.0 Hz, 2H), 5.13 (d, J = 1.4 Hz, 1H), 5.25 (br s, 1H), 5.72 (d, J = 1.4 Hz, 1H), 6.84 (d, J =
9.2 Hz, 2H), 7.20 (d, J = 9.2 Hz, 2H), 7.24–7.39 (m, 4H). Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81;
N, 4.98. Found: C, 76.75; H, 6.93; N, 5.04.
N-[2-(1-Methylvinyl)phenylmethyl]acetamide (2c): a white solid; mp 83–84 ˚C (hexane–Et2O); IR
(KBr) 3246, 1638 cm–1; 1H NMR (500 MHz) δ 2.00 (s, 3H), 2.06 (d, J = 0.9 Hz, 3H), 4.46 (d, J = 5.5 Hz,

HETEROCYCLES, Vol. 71, No. 8, 2007
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2H), 4.86 (quint, J = 0.9 Hz, 1H), 5.24 (d, J = 0.9 Hz, 1H), 5.62 (br s, 1H), 7.14–7.34 (m, 4H). Anal.
Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 75.97; H, 8.14; N, 7.45.
N-[2-(1-Ethylvinyl)phenylmethyl]acetamide (2d): a white solid; mp 42–43 ˚C (hexane–Et2O); IR
1
(KBr) 3256, 1639 cm–1; H NMR (500 MHz) δ 1.05 (t, J = 7.3 Hz, 3H), 2.00 (s, 3H), 2.34 (qt, J = 7.3,
0.9 Hz, 2H), 4.43 (d, J = 5.5 Hz, 2H), 4.87 (q, J = 0.9 Hz, 1H), 5.22 (q, J = 0.9 Hz, 1H), 5.60 (br s, 1H),
7.09–7.13 (m, 1H), 7.22–7.28 (m, 2H), 7.31–7.34 (m, 1H). Anal. Calcd for C13H17NO: C, 76.81; H, 8.43;
N, 6.89. Found: C, 76.43; H, 8.32; N, 7.12.
N-[4-Methoxy-2-(1-methylvinyl)phenylmethyl]acetamide (2e): a white solid; mp 77–79 ˚C
(hexane–Et2O); IR (KBr) 3314, 1632 cm–1; 1H NMR (400 MHz) δ 1.97 (s, 3H), 2.04 (s, 3H), 3.77 (s, 3H),
4.38 (d, J = 5.2 Hz, 2H), 4.86 (s, 1H), 5.22 (s, 1H), 5.54 (br s, 1H), 6.69 (d, J = 2.6 Hz, 1H), 6.79 (dd, J
= 8.4, 2.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H). Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 71.20; H, 7.90; N, 6.37.
Typical Procedure for the Preparation of 1-Iodomethylisoindolines (3). 1-(1-Iodomethyl-1-
phenylisoindolin-2-yl)ethanone (3a). To a stirred solution of 1a (0.63 g, 2.5 mmol) in MeCN (15 mL)
containing NaHCO3 (0.64 g, 7.6 mmol) at 0 ˚C was added I2 (1.9 g, 7.6 mmol) in portions. Stirring was
continued for 30 min, and then 10% aqueous Na2S2O3 was added until the color of I2 had disappeared.
After the organic solvent was evaporated, the resulting mixture was extracted with Et2O twice (20 ml
each). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and
evaporated. The residue was purified by preparative TLC on SiO2 (AcOEt–hexane, 1:2) to give 3a (0.82
1
g, 87%); a pale-yellow solid; mp 164–165 ˚C (hexane–CH2Cl2); IR (KBr) 1655 cm–1; H NMR (500
MHz; observed as a 9:1 mixture of rotamers) δ 1.79 (s, 0.3H), 2.23 (s, 2.7H), 4.23 (d, J = 9.6 Hz, 1H),
4.34 (d, J = 11.5 Hz. 0.1H), 4.41 (d, J = 11.5 Hz, 0.1H), 4.98 (d, J = 13.7 Hz, 0.9H), 5.04 (d, J = 13.7 Hz,
0.9 H), 5.25 (d, J = 9.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 0.1H), 6.94 (d, J = 7.8 Hz, 0.9H), 7.17–7.36 (m,
8H). MS m/z 377 (M+, 0.97), 250 (25), 236 (80), 194 (100). Anal. Calcd for C17H16NOI: C, 54.13; H,
4.28; N, 3.71. Found: C, 54.11; H, 4.29; N, 3.66.
1-[1-Iodomethyl-1-(4-methoxyphenyl)isoindolin-2-yl]ethanone (3b): a white solid; mp 134–135 ˚C
1
(hexane–CH2Cl2); IR (KBr) 1653, 1609 cm–1; H NMR (500 MHz; observed as a 9:1 mixture of
rotamers) δ 1.81 (s, 0.3H), 2.20 (s, 2.7H), 3.75 (s, 2.7 H), 3.79 (s, 0.3H), 4.16 (d, J = 10.1 Hz, 1H), 4.31
(d, J = 10.5 Hz, 0.1H), 4.36 (d, J = 10.5 Hz, 0.1H), 4.94 (d, J = 13.3 Hz, 0.9H), 5.00 (d, J = 13.3 Hz,
0.9H), 5.27 (d, J = 10.1 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1.8 H), 6.85 (d, J = 8.7 Hz, 0.2H), 6.93 (d, J = 7.3
Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.25–7.36 (m, 3H); MS m/z 407 (M+, 5.3), 266 (34), 224 (100). Anal.
Calcd for C18H18NO2I: C, 53.09; H, 4.46; N, 3.44. Found: C, 53.08; H, 4.51; N, 3.38.
1-(1-Iodomethyl-1-methylisoindolin-2-yl)ethanone (3c):
a
white solid; mp 123–124 ˚C
(hexane–Et2O); IR (KBr) 1638 cm–1; 1H NMR (500 MHz) δ 1.95 (s, 3H), 2.20 (s, 3H), 3.56 (d, J = 10.1
Hz, 1H), 4.74 (d, J = 13.7 Hz, 1H), 4.79 (d, J = 10.1 Hz, 1H), 4.85 (d, J = 13.7 Hz, 1H), 7.11–7.15 (m,

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1H), 7.24–7.27 (m, 1H), 7.33–7.39 (m, 2H); MS m/z 315 (M+, 0.10), 300 (0.62), 258 (4.4), 174 (87), 132
(100). Anal. Calcd for C12H14INO: C, 45.73; H, 4.48; N, 4.44. Found: C, 45.59; H, 4.78; N, 4.39.
1-[1-Ethyl-1-(iodomethyl)isoindolin-2-yl]ethanone (3d): a white solid; mp 71–72 ˚C (hexane–Et2O);
1
IR (KBr) 1645 cm–1; H NMR (500 MHz) δ 0.62 (t, J = 7.3 Hz, 3H), 1.79 (dq, J = 14.6, 7.3 Hz, 1H),
2.22 (s, 3H,), 2.89 (dq, J = 14.6, 7.3 Hz, 1H), 3.53 (d, J = 9.6 Hz, 1H), 4.69 (d, J = 13.7 Hz, 1H), 4.74 (d,
J = 9.6 Hz, 1H), 4.85 (d, J = 13.7 Hz, 1H), 7.07 (dd, J = 8.7, 2.8 Hz, 1H), 7.26 (dd, J = 8.7, 2.8 Hz, 1H),
7.33–7.39 (m, 2H); MS m/z 329 (M+, 0.38), 300 (93), 258 (100). Anal. Calcd for C13H16INO: C, 47.43; H,
4.90; N, 4.26. Found: C, 47.08; H, 4.86; N, 4.35.
1-(1-Iodomethyl-6-methoxy-1-methylisoindolin-2-yl)ethanone (3e): a white solid; mp 134–135 ˚C
(hexane–Et2O); IR (KBr) 1648 cm–1; 1H NMR (500 MHz) δ 1.94 (s, 3H), 2.18 (s, 3H), 3.53 (d, J = 10.1
Hz, 1H), 3.83 (s, 3H), 4.67 (d, J = 13.3 Hz, 1H), 4.76 (d, J = 10.1 Hz, 1H), 4.77 (d, J = 13.3 Hz, 1H),
6.61 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.2, 2.3 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H); MS m/z 345 (M+, 4.5),
288 (4.6), 204 (88), 162 (100). Anal. Calcd for C13H16INO2: C, 45.23; H, 4.67; N, 4.06. Found: C, 45.21;
H, 4.73; N, 3.75.
Typical Procedure for the Preparation of 1,1-Disubstituted Isoindolines (4). 1-(1-Methyl-1-
phenylisoindolin-2-yl)ethanone (4a). A solution of 3a (0.28 g, 0.74 mmol) and n-Bu3SnH (0.45 g, 1.5
mmol) in benzene (4 mL) was stirred at rt for 40 min before the solvent was evaporated. The residue
was purified by column chromatography on silica gel (AcOEt–hexane, 1:2) to give 4a (0.14 g, 73%); a
white solid; mp 148–150 ˚C (hexane–Et2O); IR (KBr) 1645 cm–1; 1H NMR (500 MHz; observed as a 6:4
mixture of rotamers) δ 1.75 (s, 1.2H), 2.07 (s, 1.2H), 2.150 (s, 1.8H), 2.155 (s, 1.8H), 4.98 (d, J = 11.9
Hz, 0.4H), 4.99 (d, J = 16.5 Hz, 0.6H), 5.06 (d, J = 11.9 Hz, 0.4H), 5.14 (d, J = 16.5 Hz, 0.6H), 6.82 (d,
J = 7.8 Hz, 0.6H), 6.92 (d, J = 7.3 Hz, 0.4H), 7.15–7.34 (m, 8H); MS m/z (%) 251 (M+, 100). Anal.
Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.11; H, 6.81; N, 5.55.
1-[1-(4-Methoxyphenyl)-1-methylisoindolin-2-yl)ethanone (4b): a white solid; mp 137–138 ˚C
1
(hexane–CH2Cl2); IR (KBr) 1641, 1614 cm–1; H NMR (500 MHz; observed as a 6:4 mixture of
rotamers) δ 1.77 (s, 1.2H), 2.03 (s, 1.2H), 2.13 (s, 1.8H), 2.14 (s, 1.8H), 3.75 (s, 1.2H), 3.79 (s, 1.8H),
4.94 (d, J = 13.7 Hz, 0.4H), 4.95 (d, J = 16.5 Hz, 0.6H), 5.02 (d, J = 13.7 Hz, 0.4H), 5.12 (d, J = 16.5 Hz,
0.6H), 6.79 (d, J = 9.2 Hz, 0.8H), 6.80 (d, J = 7.8 Hz, 0.4H), 6.85 (d, J = 8.7 Hz, 1.2H), 6.92 (d, J = 7.3
Hz, 0.6H), 7.15–7.33 (m, 5H); MS m/z 281 (M+, 100). Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N,
4.98. Found: C, 76.63; H, 6.74; N, 4.88.
1-(1,1-Dimethylisoindolin-2-yl)ethanone (4c): a white solid; mp 74–75 ˚C (hexane–Et2O); IR (KBr)
1653 cm–1; 1H NMR (500 MHz) δ 1.75 (s, 6H), 2.15 (s, 3H), 4.78 (s, 2H), 7.17 (d, J = 7.3 Hz, 1H), 7.22
(d, J = 7.3 Hz, 1H), 7.28 (td, J = 7.3, 1.4 Hz, 1H), 7.32 (td, J = 7.3, 1.4 Hz, 1H); MS m/z 189 (M+, 4.2),
174 (41), 132 (100). Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.05; H, 8.06; N,
7.41.

HETEROCYCLES, Vol. 71, No. 8, 2007
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1-(1-Ethyl-1-methylisoindolin-2-yl)ethanone (4d): a pale-yellow oil; Rf = 0.23 (AcOEt–hexane, 1:2);
1
IR (neat) 1651 cm–1; H NMR (500 MHz) δ 0.50 (t, J = 7.3 Hz, 3H), 1.68 (dq, J = 14.6, 7.3 Hz, 1H),
1.71 (s, 3H), 2.17 (s, 3H), 2.82 (dq, J = 14.6, 7.3 Hz, 1H), 4.72 (d, J = 13.7 Hz, 1H), 4.80 (d, J = 13.7 Hz,
1H), 7.11 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.28 (td, J = 7.3, 1.4 Hz, 1H), 7.32 (dd, J = 7.8,
7.3 Hz, 1H); MS m/z 203 (M+, 0.17), 174 (50), 132 (100). Anal. Calcd for C13H17NO: C, 76.81; H, 8.43;
N, 6.89. Found: C, 76.79; H, 8.50; N, 6.51.
General Procedure for the Preparation of 1-(Sulfenylmethyl)isoindolines (5). To a stirred
suspension of NaH (60% in oil; 1.0 mmol) in DMF (2 mL) at 0 ˚C was added a thiol (1.0 mmol). After
15 min, one of compounds 3 (1.0 mmol) in DMF (6 mL) was added and the mixture was stirred for the
time at the temperature indicated in Table 1. The resulting mixture was treated with saturated aqueous
NH4Cl (10 mL) and extracted with Et2O four times (10 mL each). The combined extracts were washed
with water three times (10 mL each) and then brine once (10 mL), and dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue, which was purified by preparative TLC on silica gel
(AcOEt–hexane, 1:2) to give pure product.
1-(1-Phenyl-1-phenylthiomethylisoindolin-2-yl)ethanone (5a): a white solid; mp 100–101 ˚C
1
(hexane–CH2Cl2); IR (KBr) 1657 cm–1; H NMR (500 MHz; observed as a 8:2 mixture of rotamers) δ
1.61 (s, 0.6H), 1.93 (s, 2.4H), 3.90 (d, J = 12.8 Hz, 1H), 4.95 (d, J = 13.3 Hz, 0.8H), 5.00 (d, J = 13.3 Hz,
0.8H), 5.01 (d, J = 12.8 Hz, 1H), 5.08 (d, J = 16.1 Hz, 0.2H), 5.18 (d, J = 16.1 Hz, 0.2 Hz), 6.79 (d, J =
7.8 Hz, 0.2H), 6.83 (d, J = 7.8 Hz, 0.8H), 7.09 (m, 13H); MS m/z 359 (M+, 4.1), 250 (14), 209 (36), 191
(100). Anal. Calcd for C23H21NOS: C, 76.85; H, 5.89; N, 3.90. Found: C, 76.77; H, 5.90; N, 3.90.
1-[1-(4-Methoxyphenyl)-1-phenylthiomethylisoindolin-2-yl)ethanone (5b): a white solid; mp
1
120–121 ˚C (hexane–CH2Cl2); IR (KBr) 1651, 1611 cm–1; H NMR (500 MHz; observed as a 8:2
mixture of rotamers) δ 1.63 (s, 0.6H), 1.92 (s, 2.4H), 3.75 (s, 2.4H), 3.78 (s, 0.6H), 3.84 (d, J = 12.8 Hz,
1H), 4.92 (d, J = 13.8 Hz, 0.8H), 4.98 (d, J = 13.8 Hz, 0.8H), 5.01 (d, J = 12.8 Hz, 1H), 5.05 (d, J = 16.0
Hz, 0.2H), 5.16 (d, J = 16.0 Hz, 0.2H), 6.76–6.85 (m, 3H), 7.09–7.35 (m, 10H); MS m/z 389 (M+, 0.04),
266 (51), 224 (100). Anal. Calcd for C24H23NO2S: C, 74.00; H, 5.95; N, 3.60; S, 8.23. Found: C, 73.64;
H, 6.01; N, 3.58; S, 8.14.
1-[1-Methyl-1-(phenylthiomethyl)isoindolin-2-yl]ethanone (5c): a white solid; mp 94–95 ˚C
(hexane–Et2O); IR (KBr) 1659 cm–1; 1H NMR (500 MHz) δ 1.85 (s, 3H), 1.88 (s, 3H), 3.25 (d, J = 13.3
Hz, 1H), 4.54 (d, J = 13.3 Hz, 1H), 4.72 (s, 2H), 7.07 (d, J = 7.3 Hz, 1H), 7.10 (d, J = 6.9, 2.3 Hz, 1H),
7.15–7.21 (m, 4H), 7.23–7.27 (m, 2H), 7.30 (td, J = 7.3, 0.9 Hz, 1H); MS m/z 297 (M+, 0.27), 174 (62),
132 (100). Anal. Calcd for C18H19NOS: C, 72.69; H, 6.44; N, 4.71; S, 10.78. Found: C, 72.43; H, 6.43; N,
4.71; S, 10.76.
1-[1-Methyl-1-(pyridin-2-yl)thiomethylisoindolin-2-yl]ethanone (5d): a pale-yellow solid; mp 85–88
˚C (hexane–CH2Cl2); IR (KBr) 1651 cm–1; 1H NMR (500 MHz) δ 1.91 (s, 3H), 2.10 (s, 3H), 3.87 (d, J =

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HETEROCYCLES, Vol. 71, No. 8, 2007
13.3 Hz, 1H), 4.57 (d, J = 13.3 Hz, 1H), 4.77 (d, J = 13.7 Hz, 1H), 4.83 (d, J = 13.7 Hz, 1H), 6.87 (ddd,
J = 6.9, 5.0, 0.9 Hz, 1H), 6.94 (dd, J = 6.9, 1.4 Hz, 1H), 7.12–7.22 (m, 4H), 7.31 (ddd, J = 8.2, 7.3, 1.8
Hz, 1H), 8.33 (dt, J = 3.7, 0.9 Hz, 1H); MS m/z 298 (M+, 0.27), 174 (62), 132 (100). Anal. Calcd for
C17H18N2OS: C, 68.42; H, 6.08; N, 9.39; S, 10.75. Found: C, 68.17; H, 6.05; N, 9.36; S, 10.50.
1-[1-(4,6-Dimethylpyrimidin-2-yl)thiomethyl-1-methylisoindolin-2-yl]ethanone (5e): a white solid;
mp 152–154 ˚C (hexane–CH2Cl2); IR (KBr) 1643 cm–1; 1H NMR (500 MHz) δ 1.93 (s, 3H), 2.14 (s, 3H),
2.31 (s, 6H), 3.97 (d, J = 13.3 Hz, 1H), 4.53 (d, J = 13.3 Hz, 1H), 4.76 (d, J = 13.3 Hz, 1H), 4.87 (d, J =
13.3 Hz, 1H), 6.54 (s, 1H), 7.12–7.20 (m, 3H), 7.23 (dd, J = 6.4, 1.8 Hz, 1H); MS m/z 327 (M+, 0.16),
174 (55), 132 (100). Anal. Calcd for C18H21N3OS: C, 66.02; H, 6.46; N, 12.83; S, 9.79. Found: C, 66.02;
H, 6.44; N, 12.82; S, 9.54.
1-(1-Benzylthiomethyl-1-ethylisoindolin-2-yl)ethanone (5f): a white solid; mp 104–105 ˚C
(hexane–Et2O); IR (KBr) 1647 cm–1; 1H NMR (500 MHz) δ 0.53 (t, J = 7.3 Hz, 3H), 1.69 (dq, J = 14.6,
7.3 Hz, 1H,), 2.18 (s, 3H), 2.80 (dq, J = 14.6, 7.3 Hz, 1H), 2.86 (d, J = 13.3 Hz, 1H), 3.33 (d, J = 13.3
Hz, 1H), 3.34 (d, J = 13.3 Hz, 1H), 3.93 (d, J = 13.3 Hz, 1H), 4.74 (d, J = 13.7 Hz, 1H), 4.88 (d, J = 13.7
Hz, 1H), 7.03 (dd, J = 8.2, 2.7 Hz, 1H), 7.12 (d, J = 8.2, 1.4 Hz, 2H), 7.19 (tt, J = 7.3, 1.4 Hz, 1H),
7.22–7.27 (m, 3H), 7.29–7.33 (m, 2H); MS m/z 325 (M+, 0.40), 188 (95), 146 (100). Anal. Calcd for
C20H23NOS: C, 73.81; H, 7.12; N, 4.30. Found: C, 73.66; H, 7.14; N, 4.28.
1-(1-Benzylthiomethyl-6-methoxyisoindolin-2-yl)ethanone (5g): a white solid; mp 104–105 ˚C
1
(hexane–CH2Cl2); IR (KBr): 1650 cm–1; H NMR (500 MHz) δ 1.77 (s, 3H), 2.15 (s, 3H), 2.84 (d, J =
13.3 Hz, 1H), 3.34 (d, J = 13.3 Hz, 1H), 3.39 (d, J = 13.3 Hz, 1H), 3.79 (s, 3H), 3.93 (d, J = 13.3 Hz,
1H), 4.72 (d, J = 12.8 Hz, 1H), 4.81 (d, J = 12.8 Hz, 1H), 6.57 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.2, 2.3
Hz, 1H), 7.14–7.25 (m, 6H); MS m/z 341 (M+, 0.28), 204 (94), 162 (100). Anal. Calcd for C20H23NO2S:
C, 70.35; H, 6.79; N, 4.10. Found: C, 70.28; H, 7.01; N, 3.98.
ACKNOWLEDGEMENTS
We thank Mrs. Miyuki Tanmatsu of this Department for determining mass spectra and performing
combustion analyses.
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