Synthesis of 1H-isoindol-3-amine derivatives by iodine-mediated cyclization of 2-vinylbenzamidine derivatives

Article abstract of DOI:10.3987/COM-08-11554

It has been found that the reaction of 2-vinylbenzamidine derivatives, prepared by reacting 2-vinylbenzonitriles with lithium cyclic secondary amides, with iodine in the presence of sodium hydrogen carbonate in acetonitrile resulted in the formation of th

Full text of DOI:10.3987/COM-08-11554

HETEROCYCLES, Vol. 78, No. 3, 2009
669
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 669 - 677. © The Japan Institute of Heterocyclic Chemistry
Received, 19th September, 2008, Accepted, 4th November, 2008, Published online, 5th November, 2008
DOI: 10.3987/COM-08-11554
SYNTHESIS OF 1H-ISOINDOL-3-AMINE DERIVATIVES BY
IODINE-MEDIATED CYCLIZATION OF 2-VINYLBENZAMIDINE
DERIVATIVES
Kazuhiro Kobayashi,* Mai Horiuchi, Shuhei Fukamachi, and Hisatoshi
Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan
Abstract - It has been found that the reaction of 2-vinylbenzamidine derivatives,
prepared by reacting 2-vinylbenzonitriles with lithium cyclic secondary amides,
with iodine in the presence of sodium hydrogen carbonate in acetonitrile resulted
in the formation of the corresponding 1-iodomethyl-1H-isoindole-3-amine
derivatives in reasonable overall yields based on the starting 2-vinylbenzonitriles.
We have also found that transformation of these 1-iodomethyl derivatives into
1-sulfenylmethyl derivatives could be achieved in good yields on treatment with
various sodium thiolates.
INTRODUCTION
In a recent paper, we described that the reaction of 2-vinylbenzylideneimine derivatives, which were
easily prepared by reacting 2-lithiostyrene derivatives with nitriles, with iodine in the presence of
sodium hydrogen carbonate afforded the corresponding 3-substituted 1-iodomethyl-1H-isoindole
derivatives.1 As an extension of this work, we wish to report here a convenient synthesis of
1H-isoindol-3-amine derivatives via iodine-mediated cyclization of 2-vinylbenzamidine derivatives,
which can be easily prepared by reacting 2-vinylbenzonitrile derivatives with lithium amides, derived
from cyclic secondary amines, such as pyrrolidine, piperidine, and 4-methylpiperazine. To the best of
our knowledge, the synthesis of 1H-isoindol-3-amine derivatives has only been achieved by
ring-contraction of 1H-2,4-benzodiazepine derivatives,2 and no general and simple methods for their
preparation have not been available so far.
RESULTS AND DISCUSSION
The synthesis of 1H-isoindol-3-amine derivatives (3) and (4) from 2-vinylbenzonitriles 1 was conducted

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HETEROCYCLES, Vol. 78, No. 3, 2009
as illustrated in Scheme 1. Thus, 2-vinylbenzonitriles (1) were allowed to react with lithium amides,
derived from cyclic secondary amines, such as pyrrolidine, piperidine, and 4-methylpiperazine, at –78
˚C in THF to afford the corresponding 2-vinylbenzamidine derivatives (2). It should be noted that no
reactions were observed for the addition of morpholin-4-yllithium and lithium dialkylamides, such as
LDA and lithium diethylamide, to the nitrile carbon of the starting 2-vinylbenzonitriles, and almost
quantitative amounts of the starting materials were recovered. Presumably, the lack of nucleophilicity of
these lithium amides prevents the addition. Moreover the reactions of 2-(1-arylvinyl)benzonitriles with
the above-mentioned lithium amides, derived from cyclic secondary amines, resulted in the formation of
intractable mixtures of products. This may be attributable to the liability of these 2-cyanostyrenes to
oligomerization under the reaction conditions.
R1
R1
R1
I
N
NH
I2, NaHCO3
MeCN, 0 ˚C
1) THF, -78 ˚C
2) H2O
+
LiN
X
N
N
CN
X
X
1a R1 = Me
1b R1 = Et
1c R1 = n-Pr
1d R1 = n-Bu
3
2
R1
SR2
N
NaSR2, DMF, rt
N
X
4
Scheme 1
After usual aqueous work up, these amidines were used in the next step without any purification. Thus,
treatment of these crude amidines with iodine (3 molar amounts) in the presence of sodium
hydrogencarbonate (3 molar amounts) in acetonitrile at 0 ˚C afforded, after usual aqueous workup
followed by purification using column chromatography on neutral alumina, the 5-exo cyclization
products, 1-iodomethyl-3H-isoindol-3-amine derivatives (3) in reasonable overall yields from
2-vinylbenzonitriles (1), as listed in Table 1. While these products were purified by column
chromatography on neutral alumina, no hydrolysis seemed to take place during purification. No traces of
the 6-endo cyclization products (1-aminoisoquinoline derivatives) were detected.
Next, substitution of the iodo moieties of 3 with various sodium thiolates was examined. The reactions

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671
were conveniently performed by stirring solutions of 3 and various sodium thiolates, generated from the
respective thiols and sodium hydride, in DMF at room temperature overnight to afford
1-sulfenylmethyl-1H-isoindol-3-amines (4) in the yields summarized in Table 1. As can be seen from
Entries 4 and 6, heterocyclic thiolates, such as 4,6-dimethylpyrimidine-2-thiolate and pyridin-2-thiolate,
exhibited the satisfactory reactivity toward this substitution to yield the corresponding 1-sulfenylmethyl
derivatives (4d) and (4f) in fair-to-good yields.
Table 1. Preparation of 1,1-Disubstituted 1H-Isoindol-3-amine Derivatives (3) and (4)
Entry
1
X
nil
CH2
NMe
nil
CH2
NMe
nil
CH2
NMe
nil
3 (Yield/%)a
3a (36)
3b (31)
3c (34)
3d (38)
3e (38)
3f (34)
3g (40)
3h (36)
3i (36)
3j (38)
3k (37)
R2
Bn
4 (Yield/%)b
4a (70)
4b (77)
4c (92)
4d (62)
4e (80)
4f (76)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
Ph
(CH2)2OH
4,6-dimethylpyrimidin-2-yl
CH2CO2Et
pyridin-2-yl
naphthalen-2-yl
4-ClC6H4
4g (96)
4h (87)
4i (84)
4j (83)
4k (82)
p-Tol
4-ClC6H4
p-Tol
10
11
CH2
aIsolated yields from 1. bIsolated yields.
In summary, we have developed the first procedure for the general preparation of 1,1-disubstituted
1H-isoindol-3-amine derivatives from α-substituted 2-vinylbenzonitriles using iodine mediated
cyclization. Although the yields of the cyclization products are not so high, the ease of operations as
well as the ready availability of the starting materials 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. H NMR
spectra were determined using SiMe4 as an internal reference in CDCl3 with a JEOL ECP500 FT NMR
spectrometer operating at 500 MHz. 13C NMR spectra were determined using SiMe4 as an internal
reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz in CDCl3. Low- and high-
resolution mass spectra were recorded on a JEOL JMS-AX505 HA spectrometer. Thin-layer
chromatography (TLC) was carried out on Merck Alumina 60 Neutral F254 or Merck Kieselgel 60 PF254.
Column chromatography was carried out on Merck Alumina, Activated, Neutral, Activity I or Merck
Kieselgel 60 (0.063–0.200 mm). All of the solvents used were dried over the appropriate drying agents
and distilled under argon prior to use.

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Starting Materials. 2-(1-Methylethenyl)benzonitrile (1a),2,4 2-(1-ethylethenyl)benzonitrile (1b),2,4
2-pentanoylbenzonitrile,5 and 1-(2-bromophenyl)-1-butanone6 were prepared by the appropriate reported
procedures. All other chemicals used in this study were commercially available.
2-Butanoylbenzonitrile. This compound was prepared by treating 1-(2-bromophenyl)-1-butanone4 with
CuCN under the conditions reported by Friedman et al.7 in 60% yield; a white solid; mp 42–44 ˚C
1
(hexane–Et2O); IR (KBr) 2220, 1693 cm–1; H NMR δ 1.02 (3H, t, J = 7.3 Hz), 1.80 (2H, sext, J = 7.3
Hz), 3.00 (2H, t, J = 7.3 Hz), 7.64 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.70 (1H, ddd, J = 7.8, 7.3, 1.4 Hz),
7.82 (1H, dd, J = 7.8, 1.4 Hz), 7.92 (1H, dd, J = 7.8, 1.4 Hz). Anal. Calcd for C11H11NO: C, 76.28; H,
6.40, N, 8.09. Found: C, 76.22; H, 6.38; N, 8.08.
2-(1-Butylethenyl)benzonitrile (1c). This compound was prepared by the reaction of
2-butanoylbenzonitrile with methylenetriphenylphosphorane in DME at 0 ˚C in 51 % yield; Rf 0.47 (1:2
1
CH2Cl2–hexane, silica gel); IR (neat) 2226, 1636 cm–1; H NMR δ 0.93 (3H, t, J = 7.3 Hz), 1.42 (2H,
sext, J = 7.3 Hz), 2.49 (2H, t, J = 7.3 Hz), 5.20 (1H, s), 5.36 (1H, d, J = 1,4 Hz), 7.32–7.36 (2H, m), 7.53
(1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.66 (1H, dd, J = 7.8, 0.9 Hz). Anal. Calcd for C12H13N: C, 84.17; H,
7.65, N, 8.18. Found: C, 84.06; H, 7.72; N, 8.16.
2-(1-Butylethenyl)benzonitrile (1d). This compound was prepared by the reaction of
2-pentanoylbenzonitrile5 with methylenetriphenylphosphorane in DME at 0 ˚C in 54% yield; Rf 0.50
1
(1:1 CH2Cl2–hexane, silica gel); IR (neat) 2226, 1634 cm–1; H NMR δ 0.89 (3H, t, J = 7.3 Hz),
1.33–1.40 (4H, m), 2.51 (2H, t, J = 7.3 Hz), 5.19 (1H, s), 5.35 (1H, d, J = 1.4 Hz), 7.33 (1H, d, J = 7.8
Hz), 7.35 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.54 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.66 (1H, d, J = 7.8 Hz).
Anal. Calcd for C13H15N: C, 84.28; H, 8.16, N, 7.56. Found: C, 83.97; H, 8.37; N, 7.54.
Typical Procedure for the Preparation of 1-Iodomethyl-1H-isoindole Derivatives (3).
1-Iodomethyl-1-methyl-3-(pyrrolidin-1-yl)-1H-isoindole (3a). To a stirred solution of pyrrolidine
(0.28 g, 4.0 mmol) in THF (8 mL) at –78 ˚C was added butyllithium (1.6 M in hexane; 4 mmol)
dropwise. After 15 min, a solution of 1a (0.29 g, 2.0 mmol) in THF (3 mL) was added, and stirring was
continued for an additional 3 h at the same temperature before the reaction was quenched by adding
water (15 mL). The organic materials were extracted with CH2Cl2 three times (15 mL each), and the
combined extracts were washed with brine, dried over anhydrous Na2SO4, and evaporated. The crude
amidine derivative (2a) was used in the next reaction without any purification. Thus, the crude 2a was
dissolved in MeCN (6 mL), and to this solution at 0 ˚C was added successively NaHCO3 (0.50 g, 6.0
mmol) and iodine (1.5 g, 6.0 mmol) under stirring. After stirring was continued for 1 h at the same
temperature, 10% aqueous Na2S2O3 was added until the color of iodine disappeared. The solution was
adjusted to pH 10 by adding 5% aqueous NaOH and extracted with CH2Cl2 three times (15 mL each).
The combined extracts were washed with brine, dried over anhydrous Na2SO4, and evaporated. The
residue was subjected to column chromatography on alumina to afford 3a (0.26 mg, 36%); a yellow

HETEROCYCLES, Vol. 78, No. 3, 2009
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solid; mp 75–77 ˚C (pentane); IR (KBr) 1599 cm–1; 1H NMR δ 1.62 (3H, s), 1.97 (4H, br s), 3.57 (1H, d,
J = 9.6 Hz), 3.63 (1H, d, J = 9.6 Hz), 3.76 (4H, br s), 7.31 (1H, dd, J = 7.8, 7.3 Hz), 7.36 (1H, t, J = 7.3
13
Hz), 7.43 (1H, d, J = 7.3 Hz), 7.64 (1H, d, J = 7.8 Hz); C NMR δ 18.90, 24.86, 25.51, 48.66, 69.85,
121.87, 122.51, 127.49, 128.31, 134.74, 156.96, 161.82; MS (CI) m/z 341 [(M+1)+, 100]. Anal. Calcd
for C14H17IN2: C, 49.43; H, 5.04, N, 8.23. Found: C, 49.28; H, 5.20; N, 8.08.
1-Iodomethyl-1-methyl-3-(piperidin-1-yl)-1H-isoindole (3b): a yellow oil; Rf 0.37 (CH2Cl2); IR (neat)
1
1598 cm–1; H NMR δ 1.64 (3H, s), 1.74 (6H, br s), 3.60 (4H, br s), 3.66 (2H, s), 7.33–7.41 (2H, m),
7.46 (1H, d, J = 7.3 Hz), 7.60 (1H, d, J = 7.8 Hz); MS (EI) m/z 354 (M+, 13), 227 (37), 213 (100).
HR-MS Calcd for C15H19IN2: M, 354.0593. Found: m/z 354.0585.
1-Iodomethyl-1-methyl-3-(4-methylpiperazin-1-yl)-1H-isoindole (3c): a yellow oil; Rf 0.45 (1:1
THF–C6H6); IR (neat) 1597 cm–1; 1H NMR δ 1.65 (3H, s), 2.36 (3H, s), 2.58–2.61 (4H, m), 3.66 (2H, s),
3.69–3.71 (4H, m), 7.36 (1H, td, J = 7.3, 1.4 Hz), 7.40 (1H, td, J = 7.3, 1.4 Hz), 7.46 (1H, d, J = 7.3 Hz),
7.59 (1H, d, J = 7.3 Hz); MS (EI) m/z 369 (M+, 3.8), 242 (34), 228 (100). HR-MS Calcd for C15H20IN3:
M, 369.0702. Found: m/z 369.0695.
1-Ethyl-1-iodomethyl-3-(pyrrolidin-1-yl)-1H-isoindole (3d): a yellow solid; mp 79–81 ˚C
(hexane–THF); IR (KBr) 1597 cm–1; 1H NMR δ 0.55 (3H, t, J = 7.3 Hz), 2.02–2.15 (6H, m), 3.62 (1H, d,
J = 9.8 Hz), 3.69 (1H, d, J = 9.8 Hz), 3.80–3.82 (4H, m), 7.36 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.39 (1H,
td, J = 7.3, 1.4 Hz), 7.44 (1H, d, J = 7.8 Hz), 7.68 (1H, d, J = 7.3 Hz); MS (EI) m/z 354 (M+, 7.6), 325
(31), 227 (49), 213 (100). Anal. Calcd for C15H19IN2: C, 50.86; H, 5.41; N, 7.91. Found: C, 50.83; H,
5.43; N, 7.90.
1-Ethyl-1-iodomethyl-3-(piperidin-1-yl)-1H-isoindole (3e): a yellow oil; Rf 0.38 (CH2Cl2); IR (neat)
1
1597 cm–1; H NMR δ 0.52 (3H, t, J = 7.3 Hz), 1.70–1.75 (6H, m), 2.03–2.16 (2H, m), 3.57–3.62 (4H,
m), 3.68 (2H, s), 7.33–7.40 (3H, m), 7.59 (1H, d, J = 7.3 Hz); MS (EI) m/z 368 (M+, 10), 339 (31), 241
(37), 227 (100). HR-MS Calcd for C16H21IN2: M, 368.0749. Found: m/z 368.0745.
1-Ethyl-1-iodomethyl-3-(4-methylpiperazin-1-yl)-1H-isoindole (3f): a yellow oil; Rf 0.44 (1:1
1
THF–C6H6); IR (neat) 1597 cm–1; H NMR δ 0.52 (3H, t, J = 7.3 Hz), 2.03–2.17 (2H, m), 2.36 (3H, s),
2.58–2.60 (4H, m), 3.66 (2H, s), 3.68–3.71 (4H, m), 7.34–7.40 (3H, m), 7.58 (1H, d, J = 7.3 Hz); MS
(EI) m/z 383 (M+, 1.7), 326 (7.8), 312 (100). HR-MS Calcd for C16H22IN3: M, 383.0858. Found: m/z
383.0847.
1-Iodomethyl-1-propyl-3-(pyrrolidin-1-yl)-1H-isoindole (3g): a pale-yellow solid; mp 65–67 ˚C
(hexane–THF); IR (KBr) 1599 cm–1; 1H NMR δ 0.60–0.71 (1H, m), 0.76 (3H, t, J = 7.3 Hz), 1.09–1.19
(1H, m), 1.98–2.11 (6H, m), 3.61 (1H, d, J = 9.7 Hz), 3.68 (1H, d, J = 9.7 Hz), 3.76–3.84 (4H, m),
7.34–7.40 (3H, m), 7.67 (1H, d, J = 7.3 Hz); MS (EI) m/z 368 (M+, 2.0), 325 (28), 241 (100). Anal.
Calcd for C16H21IN2: C, 52.18; H, 5.75; N, 7.61. Found: C, 52.12; H, 5.80; N, 7.60.
1-Iodomethyl-3-(piperidin-1-yl)-1-propyl-1H-isoindole (3h): a yellow oil; Rf 0.31 (CH2Cl2); IR (neat)

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1597 cm–1; H NMR δ 0.60–0.69 (1H, m), 0.75 (3H, t, J = 7.3 Hz), 1.02–1.12 (1H, m), 1.68–1.78 (6H,
m), 1.96–2.12 (2H, m), 3.57–3.61 (4H, m), 3.68 (2H, s), 7.33–7.40 (3H, m), 7.58 (1H, d, J = 7.3 Hz);13C
NMR δ 14.34, 17.83, 18.18, 24.89, 25.66, 39.86, 49.35, 73.24, 121.70, 122.38, 127.42, 128.23, 135.82,
155.65, 166.42; MS (CI) m/z 383 [(M+1)+, 100]. Anal. Calcd for C17H23IN2: C, 53.41; H, 6.06; N, 7.33.
Found: C, 53.36; H, 6.14; N, 7.05.
1-Iodomethyl-3-(4-methylpiperazin-1-yl)-1-propyl-1H-isoindole (3i): a yellow oil; Rf 0.30 (1:3
THF–C6H6); IR (neat) 1597 cm–1; 1H NMR δ 0.61–0.70 (1H, m), 0.76 (3H, t, J = 7.3 Hz); 1.01–1.11 (1H,
m), 1.95–2.12 (2H, m), 2.36 (3H, s), 2.56–2.61 (4H, m), 3.66–3.72 (6H, m), 7.34–7.40 (3H, m), 7.57
(1H, d, J = 7.3 Hz); MS (CI) m/z 398 [(M+1)+, 100]. Anal. Calcd for C17H24IN3: C, 51.39; H, 6.09; N,
10.58. Found: C, 51.37; H, 6.20; N, 10.49.
1-Butyl-1-iodomethyl-3-(pyrrolidin-1-yl)-1H-isoindole (3j): a yellow oil; Rf 0.40 (1:3 THF–C6H6); IR
(neat) 1599 cm–1; 1H NMR δ 0.59–0.65 (1H, m), 0.77 (3H, t, J = 7.3 Hz), 1.07–1.24 (3H, m), 1.99–2.12
(6H, m), 3.61 (1H, d, J = 9.6 Hz), 3.68 (1H, d, J = 9.6 Hz), 3.80–3.82 (4H, m), 7.36 (1H, td, J = 7.3, 1.4
Hz), 7.39 (1H, td, J = 7.3, 1.4 Hz), 7.44 (1H, d, J = 7.3 Hz), 7.68 (1H, dd, J = 7.3, 1.4 Hz);13C NMR δ
13.90, 19.08, 22.90, 25.50, 26.82, 37.61, 48.67, 72.81, 121.88, 122.27, 127.37, 128.11, 135.77, 155.73,
162.17; MS (CI) m/z 383 [(M+1)+, 100]. Anal. Calcd for C17H23IN2: C, 53.41; H, 6.06; N, 7.33. Found:
C, 53.28; H, 6.20; N, 7.08.
1-Butyl-1-iodomethyl-3-(piperidin-1-yl)-1H-isoindole (3k): a yellow oil; Rf 0.18 (CH2Cl2); IR (neat)
1
1597 cm–1; H NMR δ 0.55–0.64 (1H, m), 0.76 (3H, t, J = 7.3 Hz), 0.99–1.07 (1H, m), 1.11–1.21 (2H,
m), 1.69–1.76 (6H, m), 1.98–2.13 (2H, m), 3.58–3.62 (4H, m), 3.68 (2H, s), 7.34–7.40 (3H, m), 7.59
(1H, d, J = 7.3 Hz); MS (EI) m/z 396 (M+, 0.5), 339 (18), 269 (100). HR-MS Calcd for C18H25IN2: M,
396.1062. Found: m/z 396.1077.
Typical procedure for the Preparation of 1-Sulfenylmethyl-1H-isoindole Derivatives (4).
1-Benzylsulfanylmethyl-1-methyl-3-(pyrrolidin-1-yl)-1H-isoindole (4a). To a stirred suspension of
NaH (60% in oil; 4.0 mg, 0.10 mmol) in DMF (2 mL) at 0 ˚C was added BnSH (12 mg, 0.10 mmol);
after 15 min, the temperature was raised to rt. To this mixture was added a solution of 3a (34 mg, 0.10
mmol) in DMF (1 mL), and stirring was continued for 3 h before the reaction was quenched by adding
water (10 mL). The organic materials were extracted with CH2Cl2 three times (10 mL each), and the
combined extracts were washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue
was subjected to column chromatography on alumina to afford 4a (24 mg, 70%); a pale-yellow oil; Rf
0.43 (1:1 THF–hexane); IR (neat) 1597 cm–1; 1H NMR δ 1.72 (3H, s), 2.01–2.03 (4H, m), 2.93 (1H, d, J
= 12.8 Hz), 2.97 (1H, d, J = 12.8 Hz), 3.63 (2H, s), 3.82 (4H, br s), 7.17–7.21 (3H, m), 7.24 (2H, d, J =
7.3 Hz), 7.32–7.36 (2H, m), 7.41 (1H, dd, J = 7.3, 1.4 Hz), 7.70 (1H, dd, J = 7.8, 1.4 Hz); MS (CI) m/z
337 [(M+1)+, 100]. Anal. Calcd for C21H24N2S: C, 74.96; H, 7.19; N, 8.33. Found: C, 74.97; H, 7.40; N,
8.08.

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1-Methyl-1-phenylsulfanylomethyl-3-(piperidin-1-yl)-1H-isoindole (4b): a pale-yellow oil; Rf 0.29
(CH2Cl2); IR (neat) 1595 cm–1; 1H NMR δ 1.61 (3H, s), 1.68–1.70 (6H, m), 3.45 (2H, s), 3.47–3.52 (4H,
m), 7.08 (1H, t, J = 7.3 Hz), 7.16 (2H, t, J = 7.3 Hz), 7.21 (2H, dd, J = 7.3, 1.4 Hz), 7.28–7.33 (2H, m),
7.41 (1H, dd, J = 7.8, 1.4 Hz), 7.59 (1H, d, J = 7.3 Hz); MS (CI) m/z 337 [(M+1)+, 100]. Anal. Calcd for
C21H24N2S: C, 74.96; H, 7.19; N, 8.33. Found: C, 74.85; H, 7.05; N, 8.26.
2-{[1-Methyl-3-(4-methylpiperazin-1-yl)-1H-isoindol-1-yl]methylsulfanyl}ethanol
(4c):
a
pale-yellow oil; Rf 0.32 (2:1 THF–hexane); IR (neat) 3356, 1597 cm–1; 1H NMR δ 1.48 (3H, s), 2.27 (3H,
s), 2.37 (1H, s), 2.48–2.49 (1H, m), 2.59–2.63 (4H, m), 2.73–2.77 (1H, m), 3.18 (1H, d, J = 13.7 Hz),
3.26 (1H, d, J = 13.7 Hz), 3.67–3.79 (6H, m), 7.24–7.38 (3H, m), 7.62 (1H, d, J = 7.8 Hz); MS (CI) m/z
320 [(M+1)+, 100]. Anal. Calcd for C17H25N3OS: C, 63.91; H, 7.89; N, 13.15. Found: C, 63.76; H, 7.92;
N, 13.12.
1-(4,6-Dimethylpyrimidin-2-yl)sulfanylmethyl-1-ethyl-3-(pyrrolidin-1-yl)-1H-isoindole (4d):
a
1
pale-yellow oil; Rf 0.36 (2:1 THF–hexane); IR (neat) 1597 cm–1; H NMR δ 0.50 (3H, t, J = 7.3 Hz),
1.99–2.02 (4H, m), 2.09–2.18 (2H, m), 2.32 (6H, s), 3.61 (1H, d, J = 12.8 Hz), 3.78–3.81 (4H, m), 4.07
(1H, d, J = 12.8 Hz), 6.56 (1H, s), 7.22 (1H, td, J = 7.3, 1.4 Hz), 7.23 (1H, ddd, J = 7.8, 7.3, 1.4 Hz),
7.47 (1H, dd, J = 7.3, 1.4 Hz), 7.63 (1H, dd, J = 7.8, 1.4 Hz); MS (EI) m/z 366 (M+, 5.2), 337 (8.6), 213
(100). Anal. Calcd for C21H26N4S: C, 68.82; H, 7.15; N, 15.29. Found: C, 68.50; H, 7.18; N, 15.03.
Ethyl 2-{[1-Ethyl-3-(piperidin-1-yl)-1H-isoindol-1-yl]sulfanylmethyl}acetate (4e): a pale-yellow oil;
Rf 0.22 (1:10 THF–hexane); IR (neat) 1732, 1595 cm–1; 1H NMR δ 0.44 (3H, t, J = 7.3 Hz), 1.23 (3H, t,
J = 7.3 Hz), 1.68–1.73 (6H, m), 1.95–2.02 (1H, m), 2.08–2.16 (1H, m), 3.04 (1H, d, J = 14.7 Hz), 3.14
(1H, d, J = 14.7 Hz), 3.15 (1H, d, J = 11.0 Hz), 3.22 (1H, d, J = 11.0 Hz), 3.56–3.58 (4H, m), 4.12 (2H,
q, J = 7.3 Hz), 7.31–7.35 (2H, m), 7.39 (1H, dd, J = 7.3, 1.4 Hz), 7.58 (1H, dd, J = 7.3, 1.4 Hz); MS (EI)
m/z 360 (M+, 8.0), 226 (100). Anal. Calcd for C20H28N2O2S: C, 66.63; H, 7.83; N, 7.77. Found: C, 66.48;
H, 7.88; N, 7.80.
1-Ethyl-3-(4-methylpiperazin-1-yl)-1-[(pyridin-2-yl)sulfanylmethyl]-1H-isoindole
(4f):
a
1
pale-yellow oil; Rf 0.31 (2:1 THF–hexane); IR (neat) 1595 cm–1; H NMR δ 0.46 (3H, t, J = 7.3 Hz),
2.05–2.12 (1H, m), 2.17–2.24 (1H, m), 2.32 (3H, s), 2.51–2.57 (4H, m), 3.58–3.67 (4H, m), 3.83 (1H, d,
J = 12.9 Hz), 3.84 (1H, d, J = 12.9 Hz), 6.89 (1H, dd, J = 7.3, 4.6 Hz), 6.99 (1H, dd, J = 8.7, 6.4 Hz),
7.23–7.29 (2H, m), 7.33 (1H, td, J = 7.3, 1.8 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.54 (1H, d, J = 7.3 Hz), 8.36
(1H, d, J = 4.6 Hz); MS (EI) m/z 366 (M+, 5.3), 284 (100). Anal. Calcd for C21H26N4S: C, 68.82; H, 7.15;
N, 15.29. Found: C, 68.76; H, 7.45; N, 14.98.
1-[(Naphthalen-2-yl)sulfanylmethyl]-1-propyl-3-(pyrrolidin-1-yl)-1H-isoindole (4g): a pale-yellow
1
oil; Rf 0.30 (1:1 THF–hexane); IR (neat) 1597 cm–1; H NMR δ 0.56–0.66 (1H, m), 0.75 (3H, t, J = 7.3
Hz), 1.06–1.16 (1H, m), 1.84–1.90 (4H, m), 1.95–2.15 (2H, m), 3.51 (1H, d, J = 12.4 Hz), 3.60–3.70
(5H, m), 7.28–7.42 (6H, m), 7.56 (1H, s), 7.63–7.64 (2H, m), 7.69 (1H, d, J = 7.3 Hz), 7.73 (1H, d, J =

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HETEROCYCLES, Vol. 78, No. 3, 2009
7.8 Hz); MS (EI) m/z 400 (M+, 1.1), 227 (100). Anal. Calcd for C26H28N2S: C, 77.96; H, 7.05; N, 6.99.
Found: C, 77.73; H, 7.00; N, 6.74.
1-[(4-Chlorophenyl)sulfanylmethyl]-1-propyl-3-(pyrrolidin-1-yl)-1H-isoindole (4h): a pale-yellow
1
oil; Rf 0.29 (1:7 THF–hexane); IR (neat) 1595 cm–1; H NMR δ 0.56–0.65 (1H, m), 0.74 (3H, t, J = 7.3
Hz), 1.00–1.08 (1H, m), 1.64–1.73 (6H, m), 1.90–2.11 (2H, m), 3.41 (1H, d, J = 12.8 Hz), 3.45–3.51
13
(5H, m), 7.12 (4H, s), 7.28–7.33 (3H, m), 7.58 (1H, d, J = 7.3 Hz); C NMR δ 14.18, 16.80, 24.74,
25.60, 40.50, 44.81, 49.15, 75.25, 121.81, 122.26, 127.03, 127.97, 128.48, 130.82, 131.38, 135.98,
136.79, 155.41, 166.22; MS (CI) m/z 399 [(M+1)+, 100]. Anal. Calcd for C23H27ClN2S: C, 69.24; H,
6.82; N, 7.02. Found: C, 69.23; H, 6.85; N, 6.86.
1-[(4-Methylphenyl)sulfanylmethyl]-3-(4-methylpiperazin-1-yl)-1-propyl-1H-isoindole
(4i):
a
pale-yellow oil; Rf 0.34 (1:2 THF–hexane); IR (neat) 1595 cm–1; 1H NMR δ 0.57–0.68 (1H, m), 0.74 (3H,
t, J = 7.3 Hz), 0.98–1.08 (1H, m), 1.91–2.11 (2H, m), 2.26 (3H, s), 2.34 (3H, s), 2.54 (4H, t, J = 5.0 Hz),
3.43 (1H, d, J = 12.8 Hz), 3.45 (1H, d, J = 12.8 Hz), 3.54–3.65 (4H, m), 6.97 (2H, d, J = 7.8 Hz), 7.10
(2H, d, J = 7.8 Hz), 7.28–7.33 (2H, m), 7.37 (1H, dd, J = 7.3, 1.4 Hz), 7.56 (1H, d, J = 7.3 Hz); MS (CI)
m/z 394 [(M+1)+, 100]. Anal. Calcd for C24H31N3S: C, 73.24; H, 7.94; N, 10.68. Found: C, 73.14; H,
8.22; N, 10.58.
1-Butyl-1-[(4-chlorophenyl)sulfanylmethyl]-3-(pyrrolidin-1-yl)-1H-isoindole (4j): a pale-yellow oil;
1
Rf 0.32 (1:3 THF–C6H6); IR (neat) 1597 cm–1; H NMR δ 0.51–0.62 (1H, m), 0.74 (3H, t, J = 7.3 Hz),
1.05–1.22 (3H, m), 1.93–2.09 (6H, m), 3.41 (1H, d, J = 12.8 Hz), 3.51 (1H, d, J = 12.8 Hz), 3.69–3.81
(4H, m), 7.10 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.29–7.38 (3H, m), 7.68 (1H, d, J = 7.3 Hz);
13C NMR δ 13.94, 22.87, 25.45, 25.65, 38.49, 45.41, 48.51, 75.03, 121.92, 122.23, 127.08, 128.02,
128.30, 128.40, 130.94, 131.31, 136.93, 155.64, 161.93; MS (CI) m/z 399 [(M+1)+, 100]. Anal. Calcd
for C23H27ClN2S: C, 69.24; H, 6.82; N, 7.02. Found: C, 69.05; H, 6.65; N, 7.03.
1-Butyl-1-[(4-methylphenyl)thiomethyl]-3-(piperidin-1-yl)-1H-isoindole (4k): a pale-yellow oil; Rf
1
0.21 (1:2 Et2O–hexane); IR (neat) 1595 cm–1; H NMR δ 0.44–0.53 (1H, m), 0.67 (3H, t, J = 7.3 Hz),
0.89–0.97 (1H, m), 1.02–1.12 (2H, m), 1.60–1.65 (6H, m), 1.87–2.01 (2H, m), 2.19 (3H, s), 3.35 (1H, d,
J = 12.4 Hz), 3.38 (1H, d, J = 12.4 Hz), 3.40–3.45 (4H, m), 6.90 (2H, d, J = 7.8 Hz), 7.03 (2H, d, J = 7.8
Hz), 7.19–7.26 (2H, m), 7.29 (1H, d, J = 7.3 Hz), 7.50 (1H, d, J = 7.8 Hz); MS (EI) m/z 392 (M+, 2.4),
255 (100). Anal. Calcd for C25H32N2S: C, 76.48; H, 8.22; N, 7.14. Found: C, 76.38; H, 8.26; N, 7.07.
ACKNOWLEDGEMENTS
We thank Mrs. Miyuki Tanmatsu of this University for determining mass spectra and performing
combustion analyses.

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REFERENCES
1. K. Kobayashi, M. Horiuchi, M. Tanmatsu, and H. Konishi, Heterocycles, 2008, 75, 1779.
2. W. J. Houlihan, L. Kelly, J. Pankuch, J. Koletar, L. Brand, A. Janowsky, and T. A. Kopajtic, J.
Med. Chem., 2002, 45, 4097.
3. I. M. Dordor and J. M. Mellor, J. Chem. Soc., Perkin Trans. 1, 1984, 1253.
4. K. Kobayashi, K. Hashimoto, T. Shiokawa, O. Morikawa, and H. Konishi, Synthesis, 2007, 824.
5. P. J. Wagner and E. J. Siebert, J. Am. Chem. Soc., 1981, 103, 7329.
6. L. A. Elson, C. S. Gibson, and J. D. A. Johnson, J. Chem. Soc., 1930, 1128.
7. L. Friedman and H. Shechter, J. Org. Chem., 1961, 26, 2522.