Synthesis of N,N-disubstituted 1-aryl-1,3-dihydro-2H-isoindole-2-carbothioamides

Article abstract of DOI:10.3987/COM-16-13421

A convenient method for the synthesis of N,N-disubstituted 1-aryl-1,3-dihydro-2H-isoindole-2-carbothioamides starting from 2-[aryl(methoxy)methyl]phenyl bromides is described. Thus, the reaction of 1-[aryl(methoxy)methyl]-2-(isothiocyanatomethyl)benzenes, derived from the starting materials by an easily operated five-step sequence under mild conditions, with secondary amines provides the corresponding thiourea derivatives, which cyclize on treatment with methanesulfonic acid to afford the desired products.

Full text of DOI:10.3987/COM-16-13421

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HETEROCYCLES, Vol. 92, No. 5, 2016
HETEROCYCLES, Vol. 92, No. 5, 2016, pp. 844 - 856. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 26th January, 2016, Accepted, 2nd March, 2016, Published online, 10th March, 2016
DOI: 10.3987/COM-16-13421
SYNTHESIS OF N,N-DISUBSTITUTED 1-ARYL-1,3-DIHYDRO-2H-
ISOINDOLE-2-CARBOTHIOAMIDES
Kazuhiro Kobayashi,* Yuuho Shigemura, and Miyuki Tanmatsu
Division of Applied Chemistry, Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan; E-mail: kkoba@chem.tottori-u.ac.jp
Abstract – A convenient method for the synthesis of N,N-disubstituted
1-aryl-1,3-dihydro-2H-isoindole-2-carbothioamides
starting
from
2-[aryl(methoxy)methyl]phenyl bromides is described. Thus, the reaction of
1-[aryl(methoxy)methyl]-2-(isothiocyanatomethyl)benzenes, derived from the
starting materials by an easily operated five-step sequence under mild conditions,
with secondary amines provides the corresponding thiourea derivatives, which
cyclize on treatment with methanesulfonic acid to afford the desired products.
INTRODUCTION
1,3-Dihydro-2H-isoindole-2-carbothioamides have recently attracted much attention in the medicinal
application.1 Although the methods for the preparation of these compounds are commonly based on the
reaction
of
1,3-dihydro-2H-isoindoles
with
isothiocyanates,
the
synthesis
of
1-oxo-1,3-dihydro-2H-isoindole-2-carbothioamides reported by Wan et al.2 consists of the reaction of
phthalaldehyde with thioureas. More recently, Váña et al. reported the unexpected formation of
1,3-dihydro-2H-isoindole-2-carbothioamide derivatives from the reaction of 3-bromoisobenzofuran-
1(3H)-one with thioureas through the corresponding isothiuronium salts.3 However, there have been no
reports on the synthesis of N,N-disubstituted 1,3-dihydro-2H-isoindole-2-carbothioamides. On the other
hand, we previously reported a convenient method for the preparation of N-substituted
3-arylbenzo[c]thiophen-1(3H)-imines,
which
was
based
on
the
reaction
of
2-[aryl(methoxy)methyl]phenyllithiums with isothiocyanates, followed by acid-mediated cyclization of
the resulting thioamide derivatives.4 In this paper, we wish to report an application of this previous
methodology for the synthesis of heterocyclic compounds utilizing these lithium compounds to the
general preparation of N,N-disubstituted 1,3-dihydro-2H-isoindole-2-carbothioamide derivatives.5

HETEROCYCLES, Vol. 92, No. 5, 2016
845
RESULTS AND DISCUSSION
Our synthetic route to N,N-disubstituted 1-aryl-1,3-dihydro-2H-isoindole-2-carbothioamides (8) relies on
the methanesulfonic acid-mediated cyclization of the thiourea derivatives (7), generated in situ from the
reaction of 1-[aryl(methoxy)methyl]-2-(isothiocyanatomethyl)benzenes (6) with secondary amines, as
illustrated in Scheme 1. A five-step sequence was used to convert 2-[aryl(methoxy)methyl]phenyl
bromides (1) into the isothiocyanates (6). Thus, the readily available (see Experimental) starting materials
(1) were treated with butyllithium in THF –78 ˚C to generate the corresponding
2-[aryl(methoxy)methyl]phenyllithiums by the bromine/lithium exchange, which were allowed to react
with 1-formylpiperidine at the same temperature to give 2-[aryl(methoxy)methyl]benzaldehydes (2) in
good to excellent yields, as shown in Table 1. The reduction of these aldehydes with sodium borohydride
in methanol at room temperature afforded the corresponding benzyl alcohol derivatives (3). The yields
were good to excellent as compiled in Table 1 as well. Treatment of these alcohols (3) with thionyl
chloride in the presence of pyridine in dichloromethane at room temperature gave the corresponding
benzyl chloride derivatives (4), which were used in the next step without any purification after aqueous
workup. The chloro substituent in each of 4 was replaced with an azide group using sodium azide (DMF,
room temperature) to afford the corresponding benzyl azide derivatives (5) in good overall yields from 3.
Finally, treatment of these azides with triphenylphosphine in dichloromethane at room temperature,
followed by the reaction of the resulting aza-phosphoranes with carbon disulfide in acetonitrile at the
same temperature, provided the desired isothiocyanates (6) in moderate-to-fair yields.
Ar
Ar
Ar
R1
R2
R1
R2
R1
R2
1. n-BuLi, THF, –78 ˚C
NaBH4, MeOH, rt
OMe
CHO
OMe
OMe
CH2OH
NCHO
2.
, –78 ˚C
Br
2
1
3
Ar
Ar
R1
R2
R1
R2
NaN3, DMF, rt
SOCl2, Py, CH2Cl2, rt
OMe
OMe
CH2N3
CH2Cl
5
4
Ar
Ar
R1
R2
R1
R2
1. Ph3P, CH2Cl2, rt
2. CS2, MeCN, rt
R3 NH, MeCN, rt
2
OMe
OMe
CH2NCS
CH2NHCNR3
2
S
6
7
Ar
R1
R2
S
MsOH, MeCN
N
NR3
2
8
Scheme 1

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HETEROCYCLES, Vol. 92, No. 5, 2016
Table 1. Preparation of isothiocyanates (6)
Entry
1a
1a
1b
1c
1d
1e
1f
2a
2a
2b
2c
2d
2e
2f
Yield/%b
3a
3a
3b
3c
3d
3e
3f
Yield/%b
5a
5a
5b
5c
5d
5e
5f
Yield/%b,c
6a
6a
6b
6c
6d
6e
6f
Yield/%b
1
2
3
4
5
6
90
99
92
95
95
84
92
86
96
93
97
92
84
71
79
72
70
75
60
58
64
54
54
62
a a (R1 = R2 = H, Ar = Ph); b (R 1 = R2 = H, Ar = 4-ClC6H4); c (R 1 = R2 = H, Ar = 4-MeOC6H4); d (R1 =
Cl, R2 = H, Ar = 4-MeOC6H4); e (R1 = OMe, R2 = H, Ar = Ph); f (R1 = R2 = OMe, Ar = Ph). b Yields of
isolated products. c Based on 3.
The reaction of 6 with secondary amines proceeded quickly and cleanly in dichloromethane at room
temperature to generate the corresponding thiourea derivatives (7), as judged from TLC analyses on silica
gel. Initial reactions of these thioureas with various acids (one equivalent), such as concentrated
hydrobromic acid, trifluoromethanesufonic acid and p-toluenesulfonic acid monohydrate, resulted in the
isolation of the products only in low yields (about 10%) from considerably intractable mixtures of
products. Gratifyingly, however, the use of rather less acidic methanesulfonic acid as an acid led to the
production of the desired products (8) in generally moderate yields. The reaction conditions (temperature
and reaction time) as well as the yields of the products are summarized in Table 1. The precursors without
electron-donating methoxy substituents on the benzene rings (e.g. 7a-7f) underwent the cyclization at
room temperature at an appropriate rate (Entries 1-6). Among them the precursors with a 4-chlorophenyl
substituent (e.g. 7e and 7f) required much more reaction time, though the yields were comparable. On the
other side, using those with a methoxy substituent on the one of the two benzene rings (e.g. 7g-7j), the
cyclization proceed quickly even at 0 ˚C. However, in the case of using other than 7h and 7i, which are
carrying a chloro substituent, the yields of the products (8g) and (8j) decreased somewhat (Entries 7 and
10). The reaction of the precursor carrying two methoxy substituents on the benzene ring proceeded at
much lower temperature (–20 ˚C), but the yield of the product (8k) was low. This lowering of the yields
of the products (8g), (8j), and (8k) may come from the lability of these compounds under the reaction
conditions.
13
The thiourea structure of compounds 8 was confirmed on the basis of their C NMR spectra. They
uniformly exhibit signals around δ 190 due to the thiocarbonyl carbon. However, in 1972, Bream and
Schmutz have reported the formation of 3-(dimethylamino)-1-phenyl-1,5-dihydro-2,4-benzothiazepine by
the hydrogen chloride mediated cyclization of N'-({2-[hydroxy(phenyl)methyl]phenyl}methyl)-N,N-
dimethylthiourea.6 So, we again attempted the reaction of one of the thiourea derivatives with
concentrated hydrobromic acid. Thus, the thiourea derivative (7g), derived from 6c and pyrrolidine, was
treated with two equivalents of concentrated hydrobromic acid at room temperature, as shown in Scheme
2. Just after addition of the acid, the spot due to 8g was observed by TLC analysis on silica gel, but this

HETEROCYCLES, Vol. 92, No. 5, 2016
847
disappeared shortly and a product of high polarity appeared. After complete consumption of 7g, the
mixture was worked up and this highly polar product was isolated as described in Experimental.
Elemental analysis and HR-MS spectrum of this product revealed that its molecular formula is same to
that of 8g. Its 13C NMR spectra exhibited no signal around δ 190 and a signal at δ 150.10 newly appeared.
We determined this product to be 1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)-1,5-dihydro-2,4-
1
benzothiazepine (9). This new signal is assignable to C(3), and the other signals and H NMR data are
well consistent with this structure. Treatment of 8g with concentrated hydrobromic acid under the same
conditions gave also the same product. These results indicate that compound 8g is first formed and this
rearranges to 9.
Table 2. Preparation of N,N-disubstituted 1,3-dihydro-1H-isoindole-3-carbothioamides (8)
R22NH
Et2NH
Entry
6
Temp
rt
Time
2 h
2 h
8
Yield/%a
62
58
1
2
6a
6a
6a
6a
6b
6b
6c
6d
6d
6e
6f
8a
8b
8c
8d
8e
8f
pyrrolidine
piperidine
morpholine
piperidine
morpholine
pyrrolidine
Et2NH
rt
rt
rt
rt
3
4
5
6
7
8
2 h
2 h
62
54
60
55
37
50
53
41
overnight
overnight
20 min
30 min
30 min
1 h
rt
0 ˚C
0 ˚C
0 ˚C
0 ˚C
–20 ˚C
8g
8h
8i
9
10
11
pyrrolidine
piperidine
pyrrolidine
8j
8k
10 min
32
a Yields of isolated products based on 6.
OMe
MeO
OMe
1. pyrrolidine, MeCN, rt
concd. HBr
MeCN, rt
S
S
OMe
2. 2 equiv. concd. HBr, rt
N
N
N
N
CH2NCS
8g
9
6c
52% from 6c
72% from 8g
Scheme 2
In summary, we have developed the first method for the synthesis of N,N-disubstituted
1,3-dihydro-2H-isoindole-2-carbothioamide derivatives, which are hard to prepare by previous synthetic
methods. This synthetic route utilized an operationally simple seven-step and six-flask sequence starting
from readily available 2-[aryl(methoxy)methyl]phenyl bromides under mild reaction conditions. Efforts
toward the synthesis of other heterocycles utilizing these starting materials are in progress in our
laboratory and will be reported in due course.

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HETEROCYCLES, Vol. 92, No. 5, 2016
EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are
1
uncorrected. IR spectra were recorded with a Perkin–Elmer Spectrum65 FTIR spectrophotometer. H
13
NMR and C NMR spectra were recorded in CDCl3 (unless state otherwise) using TMS as an internal
reference with a JEOL ECP500 FT NMR spectrometer operating at 500 and 125 MHz, respectively.
High-resolution MS spectra were measured by a Thermo Scientific Exactive spectrometer (ESI, positive)
or a JEOL JMS-T100GCV (EI, TOF; 70eV) spectrometer. 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.
Starting
[methoxy(phenyl)methyl]benzene (1a),4 1-bromo-2-[(4-chlorophenyl)(methoxy)methyl]benzene (1b),4
1-bromo-2-[methoxy(4-methoxyphenyl)methyl]benzene and 1-bromo-4,5-dimethoxy-2-
(1c),4
Materials.
(2-Bromo-5-methoxyphenyl)phenylmethanol,7
1-bromo-2-
[methoxy(phenyl)methyl]benzene (1f)8 were prepared according to the appropriate reported procedure.
n-BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were
commercially available.
1-Bromo-4-chloro-2-[methoxy(4-methoxyphenyl)methyl]benzene (1d). This compound was prepared
by the reaction of 4-MeOC6H4MgBr and 2-bromo-4-chlorobenzaldehydes, followed by O-methylation of
the resulting alcohol, according to the procedure used for the preparation of 1a and 1b.4
(2-Bromo-5-chlorophenyl)(4-methoxyphenyl)methanol: yield: 94%; a colorless oil; Rf 0.32
(AcOEt/hexane 1:5); IR (neat) 3390, 1611 cm–1; 1H NMR δ 2.28 (d, J = 3.4 Hz, 1H), 3.79 (s, 3H), 6.04 (s,
1H), 6.87 (d, J = 8.7 Hz, 2H), 7.13 (dd, J = 8.6, 2.9 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz,
1H), 7.69 (d, J = 2.9 Hz, 1H). HR-MS (EI). Calcd for C14H12BrClO2 (M): 325.9709. Found: m/z 325.9710.
1d: yield: 83%; a white solid; mp 86–88 ˚C (hexane/CH2Cl2); IR (KBr) 1611, 1246, 1076 cm–1; 1H NMR
δ 3.37 (s, 3H), 3.79 (s, 3H), 5.50 (s, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.11 (dd, J = 8.6, 2.3 Hz, 1H), 7.28 (d,
J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H). Anal. Calcd for C15H14BrClO2: C,
52.74; H, 4.13. Found: C, 52.63; H, 4.06.
1-Bromo-4-methoxy-2-[methoxy(phenyl)methyl]benzene (1e). This compound was prepared in 67%
yield by O-methylation of (2-bromo-5-methoxyphenyl)phenylmethanol7 according to the procedure used
for the preparation of 1a and 1b.4 A white solid; mp 81–83 ˚C (hexane/CH2Cl2); IR (KBr) 1233, 1080
1
cm–1; H NMR δ 3.40 (s, 3H), 3.78 (s, 3H), 5.61 (s, 1H), 6.71 (dd, J = 8.6, 2.9 Hz, 1H), 7.11 (d, J = 2.9
Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.33 (dd, J = 8.0, 7.4 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.6
Hz, 1H). Anal. Calcd for C15H15BrO2: C, 58.65; H, 4.92. Found: C, 58.65; H, 4.63.

HETEROCYCLES, Vol. 92, No. 5, 2016
849
Typical Procedure for the Preparation of Aldehydes (2). 2-[Methoxy(phenyl)methyl]benzaldehyde
(2a). To a stirred solution of 1 (0.86 g, 3.1 mmol) in THF (6 mL) at –78 ˚C was added n-BuLi (1.6 M in
hexane; 3.10 mmol) dropwise. After 15 min, N-formylpiperidine (0.35 g, 3.1 mmol) was added and
stirring was continued for an additional 40 min before addition of saturated aqueous NH4Cl (15 mL). The
mixture was warmed to rt and extracted with AcOEt (3 × 15 mL). The combined extracts were washed
with brine (10 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by
column chromatography on SiO2 to give 2a (0.57 g, 81%); a colorless oil; Rf 0.36 (AcOEt/hexane 1:15);
IR (neat) 2823, 2743, 1695 cm–1; 1H NMR δ 3.40 (s, 3H), 6.16 (s, 1H), 7.25 (d, J = 7.4 Hz, 1H), 7.31 (t, J
= 7.4 Hz, 2H), 7.37 (d, J = 7.4 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.68 (d, J = 7.4
Hz, 1H), 7.85 (d, J = 7.4 Hz, 1H), 10.23 (s, 1H). HR-MS (EI). Calcd for C15H14O2 (M): 226.0994. Found:
m/z 226.1003.
2-[(4-Chlorophenyl)(methoxy)methyl]benzaldehyde (2b): a colorless oil; Rf 0.43 (AcOEt/hexane 1:7);
IR (neat) 2823, 2743, 1697 cm–1; 1H NMR δ 3.38 (s, 3H), 6.18 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.32 (d, J
= 8.0 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 7.4
Hz, 1H), 10.16 (s, 1H). HR-MS (EI). Calcd for C15H13ClO2 (M): 260.0604. Found: m/z 260.0610.
2-[Methoxy(4-methoxyphenyl)methyl]benzaldehyde (2c): a colorless oil; Rf 0.44 (AcOEt/hexane 1:7);
IR (neat) 2822, 2745, 1697 cm–1; 1H NMR δ 3.38 (s, 3H), 3.77 (s, 3H), 6.10 (s, 1H), 6.84 (d, J = 8.6 Hz,
2H), 7.27 (d, J = 8.6 Hz, 2H), 7.46 (td, J = 7.4, 1.1 Hz, 1H), 7.61 (ddd, J = 8.0, 7.4, 1.1 Hz, 1H), 7.69 (d,
J = 8.0 Hz, 1H), 7.83 (dd, J = 7.4, 1.1 Hz, 1H), 10.21 (s, 1H). HR-MS (EI). Calcd for C16H16O3 (M):
256.1099. Found: m/z 256.1111.
4-Chloro-2-[methoxy(4-methoxyphenyl)methyl]benzaldehyde (2d):
a
colorless oil; Rf 0.41
(AcOEt/hexane 1:5); IR (neat) 2833, 2740, 1699 cm–1; 1H NMR δ 3.37 (s, 3H), 3.78 (s, 3H), 6.06 (s, 1H),
6.85 (d, J = 9.2 Hz, 2H), 7.26 (d, J = 9.2 Hz, 2H), 7.42 (dd, J = 8.6, 2.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H),
7.76 (d, J = 8.6 Hz, 1H), 10.14 (s, 1H). HR-MS (EI). Calcd for C16H15ClO3 (M): 290.0710. Found: m/z
290.0697.
4-Methoxy-2-[methoxy(phenyl)methyl]benzaldehyde (2e): a white solid; mp 65–67 ˚C (hexane); IR
(KBr) 2825, 2729, 1695 cm–1; 1H NMR δ 3.41 (s, 3H), 3.90 (s, 3H), 6.24 (s, 1H), 6.93 (dd, J = 8.6, 2.9 Hz,
1H), 7.23–7.32 (m, 4H), 7.38 (dd, J = 8.6, 1.7 Hz, 2H), 7.79 (d, J = 8.6 Hz, 1H), 10.04 (s, 1H). Anal.
Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.85; H, 6.36.
4,5-Dimethoxy-2-[methoxy(phenyl)methyl]benzaldehyde (2f):8 a colorless oil; Rf 0.28 (AcOEt/hexane
1
1:3); IR (neat) 2823, 2723, 1678 cm–1; H NMR δ 3.42 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 6.11 (s, 1H),
7.14 (s, 1H), 7.25 (t, J = 7.4 Hz, 1H), 7.31–7.35 (m, 4H), 7.38 (s, 1H), 10.21 (s, 1H).
Typical Procedure for the Preparation Alcohols 3. {2-[Methoxy(phenyl)methyl]phenyl}methanol
(3a). To a stirred solution of 2a (0.56 g, 2.5 mmol) in MeOH (9 mL) at rt was added NaBH4 (94 mg, 2.5

850
HETEROCYCLES, Vol. 92, No. 5, 2016
mmol). After 15 min, saturated aqueous NH4Cl (15 mL) was added and the organic solvent was removed
by evaporation. The resulting mixture was extracted with AcOEt (3 × 15 mL). The combined extracts
were washed with brine (10 mL), dried (Na2SO4), and concentrated by evaporation. The residue was
purified by column chromatography on SiO2 to give 3a (0.51 g, 90%); a colorless oil; Rf 0.36
(AcOEt/hexane 1:5); IR (neat) 3339, 1602 cm–1; 1H NMR δ 2.60 (t, J = 6.3 Hz, 1H), 3.43 (s, 3H), 4.54 (dd,
J = 12.0, 6.3 Hz, 1H), 4.60 (dd, J = 12.0, 6.3 Hz, 1H), 5.55 (s, 1H), 7.25–7.41 (m, 9H). HR-MS (EI).
Calcd for C15H16O2 (M): 228.1150. Found: m/z 228.1156.
{2-[(4-Chlorophenyl)(methoxy)methyl]phenyl}methanol (3b): a colorless oil; Rf 0.31 (AcOEt/hexane
1
1:7); IR (neat) 3399 cm–1; H NMR δ 2.51 (t, J = 6.3 Hz, 1H), 3.41 (s, 3H), 4.55 (dd, J = 12.6, 6.3 Hz,
1H), 4.57 (dd, J = 12.6, 6.3 Hz, 1H), 5.52 (s, 1H), 7.23–7.35 (m, 7H), 7.40 (dd, J = 6.9, 1.7 Hz, 1H).
HR-MS (EI). Calcd for C15H15ClO2 (M): 262.0761. Found: m/z 262.0748.
{2-[Methoxy(4-methoxyphenyl)methyl]phenyl}methanol (3c): a colorless oil; Rf 0.40 (AcOEt/hexane
1:2); IR (neat) 3423, 1611 cm–1; 1H NMR δ 2.56 (t, J = 6.3 Hz, 1H), 3.40 (s, 3H), 3.80 (s, 3H), 4.53 (dd, J
= 12.6, 6.3 Hz, 1H), 4.60 (dd, J = 12.6, 6.3 Hz, 1H), 5.50 (s, 1H), 6.88 (d, J = 9.2 Hz, 2H), 7.24 (d, J =
9.2 Hz, 2H), 7.27–7.33 (m, 3H), 7.39 (dd, J = 8.6, 2.3 Hz, 1H). HR-MS (EI). Calcd for C16H18O3 (M):
258.1256. Found: m/z 258.1262.
{4-Chloro-2-[methoxy(4-methoxyphenyl)methyl]phenyl}methanol (3d): a colorless oil; Rf 0.32
(AcOEt/hexane 1:2); IR (neat) 3412, 1611 cm–1; 1H NMR δ 2.34 (t, J = 6.3 Hz, 1H), 3.39 (s, 3H), 3.81 (s,
3H), 4.47–4.50 (m, 1H), 4.55–4.59 (m, 1H), 5.43 (s, 1H), 6.89 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz,
2H), 7.27 (dd, J = 8.6, 2.3 Hz, 1H), 7.32–7.34 (m, 2H). HR-MS (EI). Calcd for C16H17ClO3 (M): 292.0866.
Found: m/z 292.0865.
{4-Methoxy-2-[methoxy(phenyl)methyl]phenyl}methanol (3e): a colorless oil; Rf 0.35 (AcOEt/hexane
1:2); IR (KBr) 3406, 1611 cm–1; 1H NMR δ 2.50 (t, J = 6.3 Hz, 1H), 3.43 (s, 3H), 3.78 (s, 3H), 4.45–4.49
(m, 1H), 4.51–4.55 (m, 1H), 5.53 (s, 1H), 6.82 (dd, J = 8.0, 2.9 Hz, 1H), 6.85 (d, J = 2.9 Hz, 1H),
7.28–7.31 (m, 2H), 7.34–7.35 (m, 4H). HR-MS (EI). Calcd for C16H18O3 (M): 258.1256. Found: m/z
258.1257.
{4,5-Dimethoxy-2-[methoxy(phenyl)methyl]phenyl}methanol (3f): a white solid; mp 87–89 ˚C
1
(hexane/CH2Cl2); IR (neat) 3468, 1608 cm–1; H NMR δ 2.40 (t, J = 6.3 Hz, 1H), 3.42 (s, 3H), 3.81 (s,
3H), 3.90 (s, 3H), 4.48–4.52 (m, 1H), 4.56–4.60 (m, 1H), 5.51 (s, 1H), 6.78 (s, 1H), 6.93 (s, 1H), 7.29 (t,
J = 7.4 Hz, 1H), 7.33–7.38 (m, 4H). Anal. Calcd for C17H20O4: C, 70.81; H, 6.99. Found: C, 70.64; H,
7.01.
Typical
Procedure
for
the
Preparation
of
Azides
(5).
1-(Azidomethyl)-2-
[methoxy(phenyl)methyl]benzene (5a). To a stirred solution of 3a (0.50 g, 2.2 mmol) in CH2Cl2 (9 mL)
containing pyridine (0.17 g, 2.2 mmol) at rt was added SOCl2 (0.26 g, 2.2 mmol) dropwise. After 40 min,

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the mixture was diluted by adding CH2Cl2 (15 mL) and saturated aqueous NaHCO3 (20 mL) was added.
The layers were separated, and the aqueous was extracted with CH2Cl2 (2 × 10 mL). The combined
organic layers were washed with water (15 mL), dried (Na2SO4), and concentrated by evaporation to
crude chloride, which was dissolved in DMF (10 mL). To this solution was added NaN3 (0.14 g, 2.2
mmol) at rt and the mixture was stirred overnight. Water (20 mL) was added and the resulting mixture
was extracted with AcOEt (3 × 15 mL). The combined extracts were washed with water (3 × 20 mL) and
brine (15 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column
chromatography on SiO2 to give 5a (0.36 g, 70%); a pale-yellow oil; Rf 0.36 (CH2Cl2/hexane 1:3); IR
(neat) 2099, 1601 cm–1; 1H NMR δ 3.40 (s, 3H), 4.30 (d, J = 13.7 Hz, 1H), 4.38 (d, J = 13.7 Hz, 1H), 5.49
(s, 1H), 7.27–7.38 (m, 8H), 7.45 (d, J = 7.4 Hz, 1H). HR-MS (ESI). Calcd for C15H16NO [(M–N2)+H]:
226.1232. Found: m/z 226.1225.
1-(Azidomethyl)-2-[(4-chlorophenyl)(methoxy)methyl]benzene (5b): a colorless oil; Rf 0.50
(AcOEt/hexane 1:7); IR (neat) 2099 cm–1; 1H NMR δ 3.39 (s, 3H), 4.27 (d, J = 13.7 Hz, 1H), 4.38 (d, J =
13.7 Hz, 1H), 5.46 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.34–7.41 (m, 4H). HR-MS
(ESI). Calcd for C15H15ClNO [(M–N2)+H]: 260.0842. Found: m/z 260.0836.
1-(Azidomethyl)-2-[methoxy(4-methoxyphenyl)methyl]benzene (5c): a colorless oil; Rf 0.28
(AcOEt/hexane 1:10); IR (neat) 2098, 1610 cm–1; 1H NMR δ 3.38 (s, 3H), 3.79 (s, 3H), 4.28 (d, J = 13.7
Hz, 1H), 4.35 (d, J = 13.7 Hz, 1H), 5.44 (s, 1H), 6.86 (d, J = 9.2 Hz, 2H), 7.20 (d, J = 9.2 Hz, 2H),
7.32–7.39 (m, 3H), 7.48 (d, J = 7.4 Hz, 1H). HR-MS (ESI). Calcd for C16H18NO2 [(M–N2)+H]: 256.1338.
Found: m/z 256.1326.
1-(Azidomethyl)-4-chloro-2-[methoxy(4-methoxyphenyl)methyl]benzene (5d): a pale-yellow oil; Rf
0.33 (AcOEt/hexane 1:10); IR (neat) 2101, 1611 cm–1; 1H NMR δ 3.37 (s, 3H), 3.80 (s, 3H), 4.23 (d, J =
14.3 Hz, 1H), 4.28 (d, J = 14.3 Hz, 1H), 5.37 (s, 1H), 6.87 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H),
7.25 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 8.6, 2.3 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H). HR-MS (EI). Calcd for
C16H16ClN3O2 (M): 317.0931. Found: m/z 317.0940.
1-(Azidomethyl)-4-methoxy-2-[methoxy(phenyl)methyl]benzene (5e): a colorless oil; Rf 0.38
(AcOEt/hexane 1:10); IR (neat) 2097, 1610 cm–1; 1H NMR δ 3.41 (s, 3H), 3.82 (s, 3H), 4.21 (d, J = 13.7
Hz, 1H), 4.29 (d, J = 13.7 Hz, 1H), 5.47 (s, 1H), 6.84 (dd, J = 8.6, 2.9 Hz, 1H), 7.07 (d, J = 2.9 Hz, 1H),
7.23 (d, J = 8.6 Hz, 1H), 7.27–7.35 (m, 5H). HR-MS (EI). Calcd for C16H17N3O2 (M): 283.1321. Found:
m/z 283.1330.
1-(Azidomethyl)-4,5-dimethoxy-2-[methoxy(phenyl)methyl]benzene (5f): a colorless oil; Rf 0.33
(AcOEt/hexane 1:5); IR (neat) 2101, 1607 cm–1; 1H NMR δ 3.40 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 4.27
(d, J = 13.7 Hz, 1H), 4.32 (d, J = 13.7 Hz, 1H), 5.45 (s, 1H), 6.82 (s, 1H), 6.98 (s, 1H), 7.26–7.35 (m, 5H).
HR-MS (EI). Calcd for C17H19N3O3 (M): 313.1426. Found: m/z 313.1430.

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Typical Procedure for the Preparation of Isothiocyanates (6). 1-(Isothiocyanatomethyl)-2-
[methoxy(phenyl)methyl]benzene (6a). A mixture of 5a (0.27 g, 1.1 mmol) and PPh3 (0.28 g, 1.1 mmol)
in CH2Cl2 (9 mL) was stirred at rt for a day. The organic solvent was removed by evaporation and the
residue was dissolved in MeCN (6 mL). To this solution was added CS2 (0.81 g, 11 mmol) under stirring
and it was continued for 30 min. The solvent and excess CS2 were removed by evaporation. The residue
was purified by column chromatography on SiO2 to give 6a (0.17 g, 60%); a colorless oil; Rf 0.70
(AcOEt/hexane 1:4); IR (neat) 2164, 2097, 1601 cm–1; 1H NMR δ 3.39 (s, 3H), 4.61 (d, J = 16.0 Hz, 1H),
4.73 (d, J = 16.0 Hz, 1H), 5.37 (s, 1H), 7.25–7.43 (m, 9H). HR-MS (EI). Calcd for C16H15NOS (M):
269.0874. Found: m/z 269.0878.
1-[(4-Chlorophenyl)(methoxy)methyl]-2-(isothiocyantomethyl)benzene (6b): a colorless oil; Rf 0.52
(AcOEt/hexane 1:4); IR (neat) 2164, 2095 cm–1; 1H NMR δ 3.38 (s, 3H), 4.58 (d, J = 16.6 Hz, 1H), 4.73
(d, J = 16.6 Hz, 1H), 5.34 (s, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.33–7.44 (m, 4H).
HR-MS (EI). Calcd for C16H14ClNOS (M): 303.0485. Found: m/z 303.0495.
1-(Isothiocyantomethyl)-2-[methoxy(4-methoxyphenyl)methyl]benzene (6c): a colorless oil; Rf 0.49
(AcOEt/hexane 1:3); IR (neat) 2163, 2095, 1611 cm–1; 1H NMR δ 3.37 (s, 3H), 3.80 (s, 3H), 4.62 (d, J =
16.6 Hz, 1H), 4.70 (d, J = 16.6 Hz, 1H), 5.32 (s, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H),
7.36–7.39 (m, 2H), 7.40–7.42 (m, 2H). HR-MS (EI). Calcd for C17H17NO2S (M): 299.0980. Found: m/z
299.092.
1-Chloro-4-(isothiocyantomethyl)-3-[methoxy(4-methoxyphenyl)methyl]benzene (6d): a colorless
1
oil; Rf 0.41 (AcOEt/hexane 1:7); IR (neat) 2171, 2094, 1611 cm–1; H NMR δ 3.37 (s, 3H), 3.80 (s, 3H),
4.57 (d, J = 16.6 Hz, 1H), 4.61 (d, J = 16.6 Hz, 1H), 5.26 (s, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.15 (d, J =
8.6 Hz, 2H), 7.33 (s, 2H), 7.46 (s, 1H). HR-MS (EI). Calcd for C17H16ClNO2S (M): 333.0590. Found: m/z
333.0592.
1-(Isothiocyanatomethyl)-4-methoxy-2-[methoxy(phenyl)methyl]benzene (6e): a white solid; mp
1
38–40 ˚C (hexane/CH2Cl2); IR (KBr) 2163, 2086, 1610 cm–1; H NMR δ 3.41 (s, 3H), 3.82 (s, 3H), 4.52
(d, J = 16.0 Hz, 1H), 4.61 (d, J = 16.0 Hz, 1H), 5.35 (s, 1H), 6.87 (dd, J = 8.6, 2.9 Hz, 1H), 7.00 (d, J =
2.9 Hz, 1H), 7.26–7.35 (m, 6H). Anal. Calcd for C17H17NO2S: C, 68.20; H, 5.72; N, 4.68. Found: C,
68.12; H, 5.87; N, 4.50.
1-(Isothiocyanatomethyl)-4,5-dimethoxy-2-[methoxy(phenyl)methyl]benzene (6f): a colorless oil; Rf
0.30 (AcOEt/hexane 1:5); IR (neat) 2160, 2087, 1608 cm–1; 1H NMR δ 3.40 (s, 3H), 3.88 (s, 3H), 3.92 (s,
3H), 4.57 (d, J = 16.0 Hz, 1H), 4.63 (d, J = 16.0 Hz, 1H), 5.34 (s, 1H), 6.88 (s, 1H), 6.93 (s, 1H), 7.26 (d,
J = 8.0 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.35 (dd, J = 8.0, 7.4 Hz, 2H). HR-MS (EI). Calcd for
C18H19NO3S (M): 329.1086. Found: m/z 329.1094.

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General Procedure for the Preparation of Dihydroisoindoles (8). To a stirred solution of 6 (1.0 mmol)
in CH2Cl2 (10 mL) at rt was added one of the amines (1.0 mmol). After 5 min, MsOH (96 mg, 1.0 mmol)
was added dropwise at the temperature indicated in Table 1 and stirring was continued for the period
indicated in Table 2 before saturated aqueous NaHCO3 (15 mL) was added. The organic solvent was
removed by evaporation and the mixture was extracted with AcOEt (3 × 15 mL). The combined extracts
were washed with brine (10 mL), dried (Na2SO4), and concentrated by evaporation. The residue was
purified by column chromatography on SiO2 to give 8.
N,N-Diethyl-1-phenyl-1,3-dihydro-2H-isoindole-2-carbothioamides (8a): a pale-yellow oil; Rf 0.50
1
(AcOEt/hexane 1:3); IR (neat) 1336, 1149 cm–1; H NMR δ 1.09 (t, J = 7.4 Hz, 6H), 3.35–3.42 (m, 2H),
3.72–3.79 (m, 2H), 4.77 (d, J = 14.9 Hz, 1H), 5.40 (dd, J = 14,9, 2.3 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H),
13
7.03 (d, J = 8.0 Hz, 1H), 7.19–7.28 (m, 8H); C NMR δ 12.82, 46.73, 59.15, 71.47, 122.00, 123.26,
127.03, 127.51, 127.70, 127.76, 128.50, 134.85, 140.90, 142.44, 190.60. HR-MS (ESI). Calcd for
C19H23N2S (M+H): 311.1582. Found: m/z 311.1575. Anal. Calcd for C19H22N2S: C, 73.51; H, 7.14; N, 9.02.
Found: C, 73.46; H, 7.23; N, 8.97.
(1-Phenyl-1,3-dihydro-2H-isoindol-2-yl)(pyrrolidin-1-yl)methanethione (8b): a white solid; mp
1
160–162 ˚C (hexane/CH2Cl2); IR (KBr) 1348, 1147 cm–1; H NMR δ 1.70–1.81 (m, 2H), 1.95–2.04 (m,
2H), 3.48–3.52 (m, 2H), 3.72–3.78 (m, 2H), 4.74 (d, J = 14.3 Hz, 1H), 5.44 (dd, J = 14.3, 2.3 Hz, 1H),
13
6.97 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.19–7.23 (m, 2H), 7.26–7.32 (m, 6H); C NMR δ
25.61, 53.14, 58.85, 71.36, 121.95, 123.18, 126.88, 127.42, 127.62, 127.75, 128.54, 134.77, 141.05,
142.77, 185.53. HR-MS (ESI). Calcd for C19H21N2S (M+H): 309.1425. Found: m/z 309.1440. Anal. Calcd
for C19H20N2S: C, 73.99; H, 6.54; N, 9.08; S, 10.39. Found: C, 73.84; H, 6.32; N, 9.11; S, 10.61.
(1-Phenyl-1,3-dihydro-2H-isoindol-2-yl)(piperidin-1-yl)methanethione (8c): a pale-yellow solid; mp
1
153–155 ˚C (hexane/CH2Cl2); IR (KBr) 1338, 1118 cm–1; H NMR δ 1.49–1.51 (m, 2H), 1.59–1.64 (m,
2H), 1.64–1.72 (m, 2H), 3.34–3.40 (m, 2H), 3.52–3.57 (m, 2H), 4.82 (d, J = 14.9 Hz, 1H), 5.34 (dd, J =
13
14.9, 1.1 Hz, 1H), 6.93 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 7.19–7.29 (m, 8H); C NMR δ 24.43, 25.65,
52.30, 58.67, 71.34, 122.00, 123.28, 126.84, 127.44, 127.70, 127.73, 128.49, 134.90, 140.84, 142.32,
192.09. HR-MS (EI). Calcd for C20H22N2S (M): 322.1504. Found: m/z 322.1505. Anal. Calcd for
C20H22N2S: C, 74.49; H, 6.88; N, 8.69; S, 9.94. Found: C, 74.39; H, 6.75; N, 8.69; S, 9.88.
(Morpholin-4-yl)(1-phenyl-1,3-dihydro-2H-isoindol-2-yl)methanethione (8d): a pale-yellow solid; mp
1
121–123 ˚C (hexane/CH2Cl2); IR (KBr) 1341, 1115 cm–1; H NMR δ 3.25–3.30 (m, 2H), 3.59–3.63 (m,
2H), 3.68–3.73 (m, 2H), 3.76–3.80 (m, 2H), 4.90 (d, J = 14.9 Hz, 1H), 5.38 (d, J = 14.9 Hz, 1H), 6.83 (s,
1H), 7.06 (d, J = 7.4 Hz, 1H), 7.21–7.32 (m, 8H); 13C NMR δ 51.36, 58.69, 66.37, 71.52, 122.11, 123.33,
126.76, 127.71, 127.91, 127.93, 128.63, 134.56, 140.60, 141.89, 192.13. HR-MS (ESI, positive). Calcd

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HETEROCYCLES, Vol. 92, No. 5, 2016
for C19H21N2OS (M+H): 325.1374. Found: m/z 325.1369. Anal. Calcd for C19H20N2OS: C, 70.34; H, 6.21;
N, 8.63. Found: C, 70.46; H, 6.47; N, 8.57.
[1-(4-Chlorophenyl)-1,3-dihydro-2H-isoindol-2-yl](piperidin-1-yl)methanethione (8e): a pale-yellow
1
solid; mp 161–163 ˚C (hexane/CH2Cl2); IR (KBr) 1335, 1089 cm–1; H NMR δ 1.43–1.57 (m, 2H),
1.62–1.68 (m, 2H), 1.69–1.74 (m, 2H), 3.39–3.42 (m, 2H), 3.53–3.58 (m, 2H), 4.78 (d, J = 14.9 Hz, 1H),
13
5.25 (d, J = 14.9 Hz, 1H), 6.98 (s, 1H), 7.02 (d, J = 7.4 Hz, 1H), 7.21–7.43 (m, 7H); C NMR δ 24.44,
25.71, 52.36, 58.51, 70.68, 122.08, 123.23, 127.88, 127.93, 128.55, 128.66, 133.21, 134.93, 140.39,
140.96, 192.14. HR-MS (EI). Calcd for C20H21ClN2S (M): 356.1114. Found: m/z 356.1129. Anal. Calcd
for C20H21ClN2S: C, 67.31; H, 5.93; N, 7.85. Found: C, 67.24; H, 6.09; N, 7.88.
[1-(4-Chlorophenyl)-1,3-dihydro-2H-isoindol-2-yl](morphorin-4-yl)methanethione (8f): a white
1
solid; mp 145–147 ˚C (hexane/CH2Cl2); IR (KBr) 1335, 1108 cm–1; H NMR δ 3.30–3.34 (m, 2H),
3.62–3.66 (m, 2H), 3.71–3.75 (m, 2H), 3.78–3.82 (m, 2H), 4.85 (d, J = 14.9 Hz, 1H), 5.28 (dd, J = 14.9,
13
1.2 Hz, 1H), 6.91 (d, J = 1.2 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 7.20–7.32 (m, 7H); C NMR δ 51.43,
58.43, 66.39, 70.82, 122.14, 123.27, 128.07, 128.10, 128.48, 128.78, 133.46, 134.56, 140.12, 140.49,
192.18. HR-MS (EI). Calcd for C19H19ClN2OS (M): 358.0907. Found: m/z 358.0924. Anal. Calcd for
C19H19ClN2OS: C, 63.59; H, 5.34; N, 7.81. Found: C, 63.51; H, 5.38; N, 7.79.
[1-(4-Methoxyphenyl)-1,3-dihydro-2H-isoindol-2-yl](pyrrolidin-1-yl)methanethione (8g): a colorless
viscous oil; Rf 0.33 (AcOEt/hexane 1:3); IR (neat) 1611, 1344, 1172 cm–1; 1H NMR δ 1.73–1.78 (m, 2H),
1.97–2.00 (m, 2H), 3.46–3.50 (m, 2H), 3.72–3.78 (m, including s at 3.75, combined 5H), 4.71 (d, J = 14.3
Hz, 1H), 5.42 (dd, J =14.3, 1.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 1.7 Hz, 1H), 7.02 (d, J = 7.4
Hz, 1H), 7.18–7.26 (m, 5H); δ 25.56, 53.07, 55.12, 58.60, 70.75, 113.84, 121.87, 123.14, 127.51, 127.69,
128.16, 134.72, 135.02, 141.28, 158.79, 185.42. HR-MS (EI). Calcd for C20H22N2OS (M): 338.1453.
Found: m/z 338.1469. Anal. Calcd for C20H22N2OS: C, 70.97; H, 6.55; N, 8.28. Found: C, 70.76; H, 6.64;
N, 8.20.
6-Chloro-N,N-diethyl-1-(4-methoxyphenyl)-1,3-dihydro-2H-isoindole-2-carbothioamides (8h):
a
colorless viscous oil; Rf 0.46 (AcOEt/hexane 1:5); IR (neat) 1609, 1336, 1114 cm–1; 1H NMR δ 1.11 (t, J
= 6.9 Hz, 6H), 3.36–3.43 (m, 2H), 3.70–3.75 (m, 2H), 3.76 (s, 3H), 4.67 (d, J = 14.3 Hz, 1H), 5.29 (dd, J
=14.3, 1.1 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 6.87 (br s, 1H), 6.98 (s, 1H), 7.18–7.20 (m, 3H), 7.24 (dd, J
= 8.0, 1.1 Hz, 1H); 13C NMR δ 12.81, 46.64, 55.18, 58.37, 70.62, 113.92, 123.23, 123.49, 127.96, 128.40,
133.34, 133.54, 134.04, 143.15, 159.09, 190.72. HR-MS (ESI). Calcd for C20H24ClN2OS (M+H):
375.1298. Found: m/z 375.1293. Anal. Calcd for C20H23ClN2OS: C, 64.07; H, 6.18; N, 7.47. Found: C,
64.07; H, 6.29; N, 7.42.
[6-Chloro-1-(4-methoxyphenyl)-1,3-dihydro-2H-isoindol-2-yl](pyrrolidin-1-yl)methanethione (8i): a
white solid; mp 163–165 ˚C (hexane/CH2Cl2); IR (KBr) 1609, 1343, 1172 cm–1; 1H NMR δ 1.73–1.81 (m,

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2H), 1.98–2.03 (m, 2H), 3.47–3.50 (m, 2H), 3.70–3.75 (m, 2H), 3.76 (s, 3H), 4.65 (d, J = 14.3 Hz, 1H),
5.36 (dd, J = 14.3, 2.3 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 2.3 Hz, 1H), 6.99 (s, 1H), 7.17 (d, J
= 8.0 Hz, 1H), 7.20–7.24 (m, 3H); 13C NMR δ 25.57, 33.12, 55.16, 58.05, 70.52, 113.99, 123.20, 123.43,
127.93, 128.22, 133.21, 133.53, 134.32, 143.24, 159.01, 185.44. HR-MS (EI). Calcd for C20H21ClN2OS
(M): 372.1063. Found: m/z 372.1064. Anal. Calcd for C20H21ClN2OS: C, 64.42; H, 5.68; N, 7.51. Found:
C, 64.21; H, 5.85; N, 7.35.
(6-Methoxy-1-phenyl-1,3-dihydro-2H-isoindol-2-yl)(piperidin-1-yl)methanethione (8j): a pale-yellow
solid; mp 121–123 ˚C (hexane/CH2Cl2); IR (KBr) 1616, 1337, 1116 cm–1; 1H NMR δ 1.50–1.53 (m, 2H),
1.61–1.64 (m, 2H), 1.69–1.73 (m, 2H), 3.34–3.39 (m, 2H), 3.50–3.55 (m, 2H), 3.71 (s, 3H), 4.75 (d, J =
14.3 Hz, 1H), 5.25 (dd, J = 14.3, 1.7 Hz, 1H), 6.55 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 8.6, 2.3 Hz, 1H),
13
6.93 (d, J = 2.3 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.22–7.24 (m, 1H), 7.26–7.31 (m, 4H); C NMR δ
24.44, 25.66, 52.31, 55.36, 58.20, 71.44, 107.97, 114.40, 122.82, 126.88, 126.93, 127.46, 128.50, 142.22
(2 overlapped Cs), 159.55, 191.98. HR-MS (EI). Calcd for C21H24N2OS (M): 352.1609. Found: m/z
352.1613. Anal. Calcd for C21H24N2OS: C, 71.56; H, 6.86; N, 7.95; S, 9.10. Found: C, 71.27; H, 6.67; N,
7.80; S, 8.98.
(6,7-Dimethoxy-1-phenyl-1,3-dihydro-2H-isoindol-2-yl)(pyrrolidin-1-yl)methanethione
(8k):
a
yellow oil; Rf 0.28 (AcOEt/hexane 3:2); IR (neat) 1613, 1331, 1106 cm–1; 1H NMR δ 1.75–1.79 (m, 2H),
1.98–2.00 (m, 2H), 3.47–3.51 (m, 2H), 3.71–3.75 (m, 2H), 3.77 (s, 3H), 3.88 (s, 3H), 4.66 (d, J = 13.7 Hz,
1H), 5.37 (dd, J = 13.7, 2.9 Hz, 1H), 6.49 (s, 1H), 6.76 (s, 1H), 6.92 (d, J = 2.9 Hz, 1H), 7.23–7.32 (m,
5H); 13C NMR δ 14.17, 25.63, 53.15, 55.98, 56.05, 58.87, 71.47, 104.47, 105.61, 126.33, 127.00, 127.43,
128.55, 132.85, 142.84, 149.24, 185.35. HR-MS (ESI). Calcd for C21H24N2NaO2S (M+Na): 391.1456.
Found: m/z 391.1444. Anal. Calcd for C21H24N2O2S: C, 68.45; H, 6.57; N, 7.60. Found: C, 68.30; H, 6.70;
N, 7.71.
1-(4-Methoxyphenyl)-3-(pyrrolidin-1-yl)-1,5-dihydro-2,4-benzothiazepine (9). To a stirred solution of
6c (0.14 g, 0.45 mmol) in MeCN (4 mL) at rt was added pyrrolidine (32 mg, 0.45 mmol). After 5 min,
concentrated HBr (0.15 g, 0.90 mmol) was added dropwise at 0 ˚C. The temperature was raised to rt and
stirring was continued for an additional 2 h before saturated aqueous NaHCO3 (15 mL) was added. The
organic solvent was removed by evaporation and the mixture was extracted with AcOEt (3 × 15 mL). The
combined extracts were washed with brine (10 mL), dried (Na2SO4), and concentrated by evaporation.
The residual solid was purified by recrystallization from hexane/CH2Cl2 to afford 9 (79 mg, 52%); a beige
solid; mp 134–136 ˚C; IR (KBr) 1608, 1586 cm–1; 1H NMR δ 1.73–1.75 (m, 4H), 3.26–3.28 (m, 4H), 3.82
(s, 3H), 4.53 (d, J = 13.7 Hz, 1H), 5.05 (d, J = 13.7 Ha, 1H), 5.95 (s, 1H), 6.88 (d, J = 6.9 Hz, 1H), 6.89
(d, J = 8.6 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.23 (dd, J = 7.4, 6.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.33
13
(d, J = 7.4 Hz, 1H); C NMR (DMSO-d6) δ 24.67, 47.38, 47.99, 50.96, 55.19, 113.98, 127.30, 127.37,

856
HETEROCYCLES, Vol. 92, No. 5, 2016
127.51, 128.91, 129.99, 131.4, 139.01, 139.44, 150.10, 158.78. HR-MS (EI). Calcd for C20H22N2OS (M):
338.1453. Found: m/z 338.1465. Anal. Calcd for C20H22N2OS: C, 70.97; H, 6.55; N, 8.28. Found: C,
70.70; H, 6.54; N, 8.21.
ACKNOWLEDGEMENTS
Financial support provided by JSPS KAKENHI (Grant No. 26410051) is gratefully acknowledged.
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