Synthesis of 2,3-dihydro-1H-isoindole-1-thiones via the bromine-lithium exchange between 1-bromo-2-(1-isothiocyanatoalkyl)benzenes and butyllithium

Article abstract of DOI:10.1016/j.tet.2013.10.020

The reaction of 1-bromo-2-(1-isothiocyanatoalkyl)benzenes, which are easily derived from 2-bromophenyl ketones or (2-bromophenyl)methanamine, with butyllithium generates 1-(1-isothiocyanatoalkyl)-2-lithiobenzenes, which immediately underwent intramolecula

Full text of DOI:10.1016/j.tet.2013.10.020

Tetrahedron 69 (2013) 10304e10310
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2,3-dihydro-1H-isoindole-1-thiones via the
bromineelithium exchange between 1-bromo-2-
(
1-isothiocyanatoalkyl)benzenes and butyllithium
*
Kazuhiro Kobayashi , Yuki Yokoi, Tatsuya Nakahara, Naoki Matsumoto
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:
Received 26 August 2013
Received in revised form 7 October 2013
Accepted 9 October 2013
Available online 16 October 2013
The reaction of 1-bromo-2-(1-isothiocyanatoalkyl)benzenes, which are easily derived from 2-
bromophenyl ketones or (2-bromophenyl)methanamine, with butyllithium generates 1-(1-isothio
cyanatoalkyl)-2-lithiobenzenes, which immediately underwent intramolecular cyclization to give rise
to the corresponding 3-substituted and 3,3-disubstituted 2,3-dihydro-1H-isoindole-1-thiones in good
yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2,3-Dihydro-1H-isoindole-1-thiones
Bromineelithium exchange
Isothiocyanate
Isocyanide
Butyllithium
1. Introduction
thione synthesis, as illustrated in Scheme 1. Thus, N-[1-(2-
bromophenyl)alkyl]formamides 2 were prepared in fair-to-good
2
,3-Dihydro-1H-isoindole-1-thiones have been of interest as
yields by the reaction of 2-bromophenyl ketones 1 with formam-
they are efficient building blocks in the synthesis of structurally
ide and formic acid under heating. Their dehydration with phos-
more complex and/or medicinally important molecules.1 The re-
phorous chloride in the presence of triethylamine in THF at 0
afforded the corresponding isocyanides 3aed in good yields. We
then investigate possibility of the alkylation of the carbon to the
ꢀ
C
4
action of 2,3-dihydro-1H-isoindol-1-ones with P S10 or Lawesson’s
reagent has commonly been used for the preparation of 2,3-
a
2
dihydro-1H-isoindole-1-thiones. However, a major drawback of
isocyano function of these compounds and were pleased to find
that the successive treatment of 3aec with LDA and haloalkanes
provided the a,a-disubstituted 2-bromobenzyl isocyanides 3eeh in
this method is the tedious reaction conditions. We envisaged that
the generation of 1-(1-isothiocyanatoalkyl)-2-lithiobenzenes 8 by
the bromineelithium exchange between 1-bromo-2-(1-isothio
cyanatoalkyl)benzenes 4, followed by cyclization through the
intramolecular attack of the carbanion on the isothiocyanato car-
bon, would give the desired 2,3-dihydro-1H-isoindole-1-thiones
fair-to-good yields. Treatment of compounds 3aeh with sulfur in
the presence of a catalytic amount of selenium under Fujiwara’s
3
conditions gave the requisite precursors 4aeh in reasonable
yields.
1
0. We, herein, wish to describe the results of our study, which
We also prepared 1-bromo-2-(1-isothiocyanatoalkyl)benzenes
4j and k from commercially available (2-bromophenyl)methan-
amine 5, as shown in Scheme 2. Treatment of 5 with formic acid in
the presence of acetic anhydride gave N-[(2-bromophenyl)methyl]
formamide (6), which was dehydrated as described above for the
preparation of 3aed to afford 1-bromo-2-(isocyanomethyl)
benzene (7). Conversion of 7 to 4j and k, via the isocyanides 3j
and k, was performed as described above.
provides a new and efficient synthetic route to substituted 2,3-
dihydro-1H-isoindole-1-thiones.
2
. Results and discussion
First, we carried out the preparation of the precursor iso-
thiocyanates 4aeh for the present 2,3-dihydro-1H-isoindole-1-
With the precursor isothiocyanates 4 in hands, we next con-
ducted the transformation of 4 into substituted 2,3-dihydro-1H-
isoindole-1-thiones 10. When these precursor isothiocyanates
*
Corresponding author. Tel./fax: þ81 857 31 5263; e-mail address: kkoba@chem.
ꢀ
tottori-u.ac.jp (K. Kobayashi).
4
were treated with butyllithium in THF at ꢁ78 C, the
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.020

K. Kobayashi et al. / Tetrahedron 69 (2013) 10304e10310
10305
NH2
HCO H, Ac O, 0 ˚C
NHCHO
2
2
Br
Br
81%
5
6
POCl , Et N, THF, 0 ˚C
3
3
NC
Br
7
63%
R
1
. LDA, THF, –78 ˚C
2
. RBr, –78 ˚C
NC
Br
3
j R = Allyl 75%
3k R = Bn 76%
R
S , cat. Se, Et N, r.t.
8
3
NCS
Br
4
j R = Allyl 91%
4k R = Bn 89%
Scheme 2.
i
R3 R4
NCS
R3
R4
R1
R1
R2
n-BuLi
THF, –78 ˚C
NCS
R2
Br
Li
4
8
R3 R4
NH
R3 R3
R1
R2
R1
+
H O
3
NLi
R2
S
S
10
9
i
Scheme 3.
Scheme 1.
bromineelithium exchange occurred to generate the lithium
compounds 8, which underwent cyclization to give the lithium
thiolactamides 9. This sequence proceeded quickly and cleanly, and
after aqueous work up and the subsequent purification by re-
crystallization the desired products 10 were obtained, as illustrated
in Scheme 3. The yields of the products are good as summarized in
Table 1. It should be noted that the reaction of 1-bromo-2-(iso-
thiocyanatomethyl)benzene, derived from 1-bromo-2-(iso-
cyanomethyl)benzene (7), with butyllithium under the same
conditions, expecting the production of 2,3-dihydro-1H-isoindole-
Table 1
Preparation of 2,3-dihydro-1H-isoindole-1-thiones 10
Entry
4
10
Yield/%a
1
2
3
4
1
2
3
4
5
6
7
8
9
4a (R
¼H, R
¼H, R
¼Me, R ¼H)
4
10a
79
94
84
77
87
89
75
84
94
94
83
1
2
3
4b (R ¼H, R ¼H, R ¼Et, R ¼H)
10b
10c
10d
10e
10f
10g
10h
10i
1
2
3
4
4c (R ¼Cl, R ¼H, R ¼Me, R ¼H)
4
1
2
3
4d (R ¼OMe, R ¼OMe, R ¼Me, R ¼H)
1
2
3
4
4e (R ¼H, R ¼H, R ¼Me, R ¼Me)
1
2
3
4
4f (R ¼H, R ¼H, R ¼Me, R ¼Et)
1
2
3
4
4g (R ¼H, R ¼H, R ¼Me, R ¼Allyl)
1
2
3
4
1
-thione, resulted in the formation of an intractable mixture of
products.
Finally, we tried to synthesize 9b-methyl-1,2,3,9b-tetrahy-
4h (R ¼H, R ¼H, R ¼Et, R ¼Allyl)
1 2 3 4
4i (R ¼Cl, R ¼H, R ¼Me, R ¼Bn)
1
2
3
4
1
1
0
1
4j (R ¼H, R ¼H, R ¼Allyl, R ¼H)
10j
10k
1
2
3
4
4k (R ¼H, R ¼H, R ¼Bn, R ¼H)
dropyrrolo[2,1-a]isoindole-5-thione (11), which involves the pyr-
rolizidine structure, in order to demonstrate utility of the present
a
Yields of isolated products.

10306
K. Kobayashi et al. / Tetrahedron 69 (2013) 10304e10310
method. As illustrated in Scheme 4, 1-bromo-2-(4-chloro-1-
isocyano-1-methylbutyl)benzene (3l) was prepared in relatively
good yield by the successive treatment of 1-bromo-2-(1-iso
cyanoethyl)benzene (3a) with LDA and 1-chloro-3-iodopropane
and converted into 1-bromo-2-(4-chloro-1-isocyanato-1-methyl
butyl)benzene (4l) in fair yield under the same conditions as
mentioned above. Treatment of 4l with butyllithium gave the cor-
responding 2,3-dihydro-1H-isoindole-1-thione derivative 10l in
a reasonable yield, cyclization of which with sodium hydride in
as an internal reference with a JEOL ECP500 FT NMR spectrometer
operating at 125 MHz. Low-resolution MS spectra (EI, 70 eV) were
measured by a JEOL JMS AX505 HA spectrometer. High-resolution
MS spectra (DART, positive) were measured by a Thermo Scien-
tific Exactive spectrometer. 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.
ꢀ
DMF at 0 C proceeded very cleanly and smoothly to give the de-
3.2. Starting materials
sired product 11 in excellent yield.
4
1
-(2-Bromophenyl)propan-1-one (1b) and 1-(2-bromo-4,5-
5
dimethoxyphenyl)ethanone (1d) were prepared according to the
appropriate reported procedures. Butyllithium was supplied by
Asia Lithium Corporation. All other chemicals used in this study
were commercially available.
Me
1
. LDA, THF, –78 ˚C
Me
Me
(CH
NC
) Cl
2 3
NC
2
. I(CH ) Cl, –78 ˚C
2
3
Br
Br
3
.2.1. 1-(2-Bromo-5-chlorophenyl)ethanone (1c). This compound
was prepared by the acetylation of 1-bromo-2-chlorobenzene with
AcCl according to the reported procedure. A colorless liquid; R
.23 (AcOEt/hexane 1:20); IR (neat) 1703 cm ; H NMR (500 MHz)
3a
3
l 76%
6
f
ꢁ1 1
0
d
(CH ) Cl
2
3
2.63 (s, 3H), 7.27 (dd, J¼8.6, 2.3 Hz, 1H), 7.43 (d, J¼2.3 Hz, 1H), 7.54
S , cat. Se, Et N, r.t.
8
3
NCS
(
d, J¼8.6 Hz,1H). Anal. Calcd for C
8 6
H BrClO: C, 41.15; H, 2.59. Found:
C, 40.94; H, 2.68.
Br
3.3. Typical procedure for the preparation of formamides 2
4l 69%
3
.3.1. N-[1-(2-Bromophenyl)ethyl]formamide (2a). A mixture of 1-
Me
(CH ) Cl
2
3
(2-bromophenyl)ethanone (1a) (4.0 g, 20 mmol), HCONH
and HCO
room temperature, water (50 mL) was added and the mixture was
2
(9.3 mL),
n-BuLi, THF, –78 ˚C
ꢀ
2
H (6.2 mL) was heated at 180 C for 33 h. After cooling to
NH
extracted with AcOEt (3ꢂ30 mL). The combined extracts were
S
washed with water (20 mL), satd aq NaHCO
3
(3ꢂ20 mL), and then
1
0l 64%
brine (20 mL), dried (Na
residue was purified by column chromatography on silica gel to
afford 2a (2.9 g, 73%); a yellow oil; R 0.10 (AcOEt/hexane 1:2); IR
H NMR (500 MHz) 1.53 and 1.55 (2d,
2 4
SO ), and concentrated by evaporation. The
f
Me
NaH, DMF, 0 ˚C
ꢁ1 1
;
(neat) 3280, 1660 cm
d
N
S
J¼6.9 Hz each, combined 3H), 5.07e5.13 and 5.42e5.48 (2m, com-
bined 1H), 5.97 (br 1H), 7.14 and 7.17 (2t, J¼7.4 Hz each, combined
1H), 7.29e7.35 (m, 2H), 7.56 and 7.58 (2d, J¼7.4 Hz each, combined
13
1
H), 8.18 and 8.20 (2s, combined 1H); C NMR d 21.00, 22.42, 47.97,
1
1 99%
5
1.04, 122.43, 122.82, 126.89, 127.78, 128.17, 128.90, 129.20, 133.27,
133.40, 141.49, 141.89, 160.16, 164.29. Anal. Calcd for C 10BrNO: C,
7.39; H, 4.42; N, 6.14. Found: C, 47.27; H, 4.68; N, 6.01.
Scheme 4.
9
H
4
In summary,
a
convenient route for the preparation of
3.3.2. N-[1-(2-Bromophenyl)propyl]formamide (2b). White nee-
ꢀ
ꢁ1 1
;
substituted 2,3-dihydro-1H-isoindole-1-thiones has been de-
veloped, which relied on the butyllithium-mediated cyclization of
-bromo-2-(1-isothiocyanatoalkyl)benzenes, derived from 2-
bromophenyl ketones or (2-bromophenyl)methanamine by using
easy sequences. This method may find some value in organic syn-
thesis because of its simplicity and the readily availability of the
starting materials.
dles; mp 70e72 C (hexane/Et
NMR (500 MHz)
0.96 and 1.00 (2t, J¼7.4 Hz, each, combined 3H),
1.74e1.97 (m, 2H), 4.80e4.95 and 5.26e5.31 (2m, combined 1H),
6.03e8.22 (m, 6H). Anal. Calcd for C10 12BrNO: C, 49.61; H, 5.00; N,
5.79. Found: C, 49.50; H, 5.04; N, 5.70.
2
O); IR (neat) 3281, 1661 cm
H
d
1
H
3.3.3. N-[1-(2-Bromo-5-chlorophenyl)ethyl]formamide (2c). A yel-
ꢀ
low solid; mp 110e113
1
C
(hexane/CHCl
1.50 and 1.55 (2d, J¼6.9 Hz each,
combined 3H), 5.02e5.08 and 5.35e5.41 (2m, combined 1H), 5.90
3
); IR (KBr) 3310,
ꢁ
1 1
658 cm ; H NMR (500 MHz)
d
3
3
. Experimental
(
br s, 1H), 7.12 and 7.16 (2dd, J¼8.6, 2.9 Hz each, combined 1H), 7.29
.1. General
and 7.31 (2d, J¼2.9 Hz each, combined 1H), 7.48 and 7.50 (2d,
J¼8.6 Hz, each, combined 1H), 8.17 and 8.20 (2s, combined 1H).
All melting points were obtained on a Laboratory Devices MEL-
9 9
Anal. Calcd for C H BrClNO: C, 41.17; H, 3.46; N, 5.34. Found: C,
TEMP II melting apparatus and are uncorrected. IR spectra were
41.04; H, 3.59; N, 5.34.
recorded with a PerkineElmer Spectrum65 FTIR spectrophotome-
1
ter. H NMR spectra were recorded in CDCl
3
using TMS as an in-
3.3.4. N-[1-(2-Bromo-4,5-dimethoxyphenyl)ethyl]formamide (2d). A
ternal reference with a JEOL ECP500 FT NMR spectrometer
operating at 500 MHz or JEOL LA400FTNMR spectrometer operat-
light-brown amorphous; R
f
0.13 (AcOEt/hexane 2:1); IR (KBr)
H NMR (500 MHz)
1.53 (d, J¼6.9 Hz,
3H), 3.86 (s, 3H), 3.88 (s, 3H), 5.04 and 5.35 (2quint, J¼7.4 and
ꢁ
1 1
3279, 1662, 1604 cm
;
d
ing at 400 MHz. 13C NMR spectra were recorded in CDCl
using TMS
3

K. Kobayashi et al. / Tetrahedron 69 (2013) 10304e10310
10307
6
.9 Hz, respectively, combined 1H), 5.96 and 6.19 (2br s, com-
J¼8.0, 7.4, 1.7 Hz, 1H), 7.63 (dd, J¼8.0, 1.7 Hz, 1H), 7.76 (dd, J¼8.0,
bined 1H), 6.79 and 6.82 (2s, combined 1H), 7.01 and 7.02 (2s,
combined 1H), 8.17 and 8.19 (2s, combined 1H). Anal. Calcd for
1.7 Hz, 1H). HRMS calcd for C11
238.0231.
H
13BrN: MþH, 238.0231. Found: m/z
C
11
H
14BrNO
3
: C, 45.85; H, 4.90; N, 4.86. Found: C, 45.51; H, 4.90;
N, 4.63.
3.5.3. 1-Bromo-2-(1-isocyano-1-methylbut-3-enyl)benzene (3g). A
colorless liquid; R 0.46 (Et O/hexane 1:10); IR (neat) 2130,
H NMR (500 MHz, CDCl 2.00 (s, 3H), 2.87 (dd,
f
2
ꢁ1
1
3
.4. 1-Bromo-2-(1-isocyanoethyl)benzenes 3
1642 cm
;
3
) d
J¼14.3, 7.3 Hz, 1H), 3.30 (ddd, J¼14.3, 6.9, 1.1 Hz, 1H), 5.12
(dd, J¼10.3, 1.1 Hz, 1H), 5.18 (ddd, J¼16.8, 2.8, 1.7 Hz, 1H),
5.60e5.69 (m, 1H), 7.18 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H), 7.36 (ddd,
J¼8.0, 7.4, 1.7 Hz, 1H), 7.64 (dd, J¼8.0, 1.7 Hz, 1H), 7.72 (dd, J¼8.0,
These compounds were prepared by dehydration of 2 with
POCl /Et N under conditions reported previously.
3 3
7
3
.4.1. 1-Bromo-2-(1-isocyanoethyl)benzene (3a). A pale-yellow
1.7 Hz, 1H). HRMS calcd for C12
H
13BrN: MþH, 250.0231. Found:
ꢁ
1
1
liquid; R
NMR (400 MHz)
f
0.59 (Et
1.67 (d, J¼6.8 Hz, 3H), 5.22 (q, J¼6.8 Hz, 1H),
.21 (t, J¼7.8 Hz, 1H), 7.42 (t, J¼7.8 Hz, 1H), 7.56 (d, J¼7.8 Hz, 1H),
2
O/hexane 1:5); IR (neat) 2141 cm
;
H
m/z 250.0215.
d
7
7
3.5.4. 1-Bromo-2-(1-ethyl-1-isocyanobut-3-enyl)benzene
pale-yellow liquid; R 0.51 (Et O/hexane 1:10); IR (neat) 2129,
1642 cm ; H NMR (500 MHz)
0.85 (t, J¼7.4 Hz, 3H), 2.03e2.10
(3h). A
1
3
.65 (d, J¼7.8 Hz, 1H);
C
NMR
d
23.79, 53.57 (t,
f
2
d
ꢁ1 1
J¼6.0 Hz), 121.29, 126.90, 128.37, 129.83, 133.07, 137.74, 156.96 (t,
J¼4.8 Hz). HRMS calcd for C
9
H
9
BrN: MþH, 209.9918. Found: m/z
(m, 1H), 2.73e2.82 (m, 2H), 3.41 (dd, J¼14.3, 7.4 Hz, 1H), 5.07 (d,
J¼10.3 Hz, 1H), 5.16 (d, J¼16.6 Hz, 1H), 5.56e5.64 (m, 1H), 7.17 (ddd,
J¼8.0, 7.4, 1.1 Hz, 1H), 7.36 (t, J¼7.4 Hz, 1H), 7.62 (d, J¼7.4 Hz, 1H),
2
09.9908.
3
R
(
.4.2. 1-Bromo-2-(1-isocyanopropyl)benzene (3b). A yellow liquid;
7.72 (dd, J¼8.0, 1.1 Hz, 1H). HRMS calcd for C13
H15BrN: MþH,
ꢁ
1
1
f
0.83 (AcOEt/hexane 1:10); IR (neat) 2140 cm
1.11 (t, J¼7.4 Hz, 3H), 1.80e1.84 (m, 1H), 1.95e2.01 (m,
H), 5.05e5.08 (m, 1H), 7.21 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H), 7.40 (dd,
J¼8.0, 7.4, 1.1 Hz, 1H), 7.56 (dd, J¼8.0, 1.1 Hz, 1H), 7.59 (dd, J¼8.0,
.7 Hz, 1H). HRMS calcd for C10
;
H NMR
264.0388. Found: m/z 250.0391.
500 MHz) d
1
3.5.5. 1-Bromo-4-chloro-2-(1-isocyano-1-methyl-2-phenylethyl)
benzene (3i). A beige oil; R 0.34 (Et O/hexane 1:30); IR (neat)
H NMR (500 MHz)
f
2
ꢁ
1 1
1
2
H11BrN: MþH, 224.0075. Found: m/z
2128 cm
;
d
2.02 (s, 3H), 3.39 (d, J¼14.3 Hz,
24.0059.
1H), 3.73 (d, J¼14.3 Hz, 1H), 7.13 (dd, J¼6.9, 2.3 Hz, 2H), 7.17 (dd,
J¼8.6, 2.3 Hz, 1H), 7.24e7.25 (m, 3H), 7.50 (d, J¼2.3 Hz, 1H), 7.61 (d,
3
.4.3. 1-Bromo-4-chloro-2-(1-isocyanoethyl)benzene (3c). A yellow
J¼8.6 Hz, 1H). HRMS calcd for C16
m/z 333.9976.
H
14BrClN: MþH, 333.9998. Found:
ꢁ
1 1
liquid; R
500 MHz) d
f
0.53 (Et
1.67 (d, J¼6.9 Hz, 3H), 5.17 (q, J¼6.9 Hz, 1H), 7.20 (dd,
J¼8.6, 1.3 Hz, 1H), 7.49 (d, J¼8.6 Hz, 1H), 7.63 (d, J¼2.3 Hz, 1H).
HRMS calcd for C
BrClN: MþH, 243.9528. Found: m/z 243.9509.
2
O/hexane 1:10); IR (neat) 2141 cm
; H NMR
(
3.5.6. 1-Bromo-2-(4-chloro-1-isocyano-1-methylbutyl)benzene
(3l). A pale-yellow liquid; R 0.31 (Et O/hexane 1:15); IR (neat)
H NMR (500 MHz) 1.50e1.59 (m, 1H), 1.85e1.94
9
H
8
f
2
ꢁ
1
1
2129 cm
;
d
3
.4.4. 1-Bromo-2-(1-isocyanoethyl)-4,5-dimethoxy benzene (3d). A
(m, 1H), 2.03 (s, 3H), 2.16e2.22 (m, 1H), 2.87e2.92 (m, 1H),
3.52 (t, J¼6.9 Hz, 2H), 7.20 (ddd, J¼8.0, 7.4, 1.1 Hz, 1H), 7.39 (dd,
J¼8.0, 7.4 Hz, 1H), 7.64 (d, J¼8.0 Hz, 1H), 7.78 (d, J¼8.0 Hz, 1H).
ꢀ
ꢁ1 1
white solid; mp 68e70 C (hexane); IR (neat) 2145, 1603 cm ; H
NMR (500 MHz, CDCl
3
C
5
3
)
d
1.64 (d, J¼6.3 Hz, 3H), 3.88 (s, 3H), 3.93 (s,
H), 5.15 (q, J¼6.3 Hz, 1H), 6.99 (s, 1H), 7.08 (s, 1H). Anal. Calcd for
12BrNO : C, 48.91; H, 4.48; N, 5.19. Found: C, 48.81; H, 4.56; N,
HRMS calcd for
286.0002.
C
12
H
14BrClN: MþH, 285.9998. Found: m/z
11
H
2
.10.
3.6. Bromophenyl isothiocyanates 4
3
.5. Typical procedure for the preparation of 1-bromo-2-(1-
isocyanoalkyl)benzenes 3eei and l
These compounds were prepared by treatment with S
presence of a catalytic amount of Se under Fujiwara’s conditions.
8
in the
3
3.5.1. 1-Bromo-2-(1-isocyano-1-methylethyl)benzene (3e). To a stir-
red solution of LDA (2.0 mmol), generated from i-Pr
2
NH and n-BuLi
3.6.1. 1-Bromo-2-(1-isothiocyanatoethyl)benzene
yellow liquid; R 0.88 (hexane); IR (neat) 2093 cm
(500 MHz)
1.66 (d, J¼6.9 Hz, 3H), 5.36 (q, J¼6.9 Hz, 1H), 7.19 (td,
J¼7.6, 1.5 Hz, 1H), 7.39 (td, J¼7.6, 1.5 Hz, 1H), 7.53 (dd, J¼7.6, 1.5 Hz,
(4a). A pale-
ꢀ
ꢁ1
1
by the standard method, in THF (5 mL) at ꢁ78 C was added a so-
lution of 3a (0.29 g, 1.4 mmol) in THF (2 mL) dropwise. After 20 min,
MeI (0.29 g, 2.0 mmol) was added and stirring was continued an
f
; H NMR
d
13
additional 20 min before satd aq NH
4
Cl and water (10 mL each) was
1H), 7.55 (dd, J¼7.6, 1.5 Hz, 1H); C NMR
126.89, 128.22, 129.64, 133.08 (2C), 139.22. Anal. Calcd for
9 8
C H BrNS: C, 44.64; H, 3.33; N, 5.78. Found: C, 44.61; H, 3.39; N,
d 23.65, 56.51, 121.33,
added. The mixture was warmed to room temperature and
extracted with AcOEt (3ꢂ10 mL). The combined extract was washed
with brine (10 mL), dried (Na
2
SO
4
), and concentrated by evapora-
5.71.
tion. The residue was purified by column chromatography on silica
gel to afford 3d (2.7 g, 87%); a pale-yellow liquid; R 0.43 (AcOEt/
f
3.6.2. 1-Bromo-2-(1-isothiocyanatopropyl)benzene (4b). A colorless
liquid; R 0.50 (hexane); IR (neat) 2082 cm ; H NMR (500 MHz)
f
ꢁ1
1
ꢁ1 1
hexane 1:5); IR (neat) 2133 cm ; H NMR (500 MHz)
d
2.01 (s, 6H),
7
.19 (dd, J¼8.0, 7.4 Hz, 1H), 7.36 (dd, J¼8.0, 7.4 Hz, 1H), 7.65 (d,
d
1.09 (t, J¼7.4 Hz, 3H), 1.85e1.92 (m, 1H), 1.97e2.02 (m, 1H), 5.19
13
J¼8.0 Hz, 1H), 7.71 (d, J¼8.0 Hz, 1H); C NMR
d
29.63, 61.88 (t,
(dd, J¼8.6, 4.0 Hz, 1H), 7.19 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H), 7.38 (ddd,
J¼8.0, 7.4, 1.1 Hz, 1H), 7.48 (dd, J¼8.0, 1.7 Hz, 1H), 7.55 (dd, J¼8.0,
J¼6.0 Hz), 120.29, 127.38, 127.83, 129.58, 135.99, 138.89, 156.72 (t,
J¼4.8 Hz). HRMS calcd for C10
H11BrN: MþH, 224.0075. Found: m/z
1.1 Hz, 1H). Anal. Calcd for C10H10BrNS: C, 46.89; H, 3.93; N, 5.47.
2
24.0065.
Found: C, 46.87; H, 4.01; N, 5.26.
3
.5.2. 1-Bromo-2-(1-isocyano-1-methylpropyl)benzene (3f). A pale-
3.6.3. 1-Bromo-4-chloro-2-(1-isothiocyanatoethyl)benzene (4c). A
ꢁ1
1
ꢁ1 1
yellow liquid; R
NMR (500 MHz)
1
f
0.47 (Et
0.88 (t, J¼7.4 Hz, 3H), 2.00 (s, 3H), 2.08e2.13 (m,
H), 2.61e2.69 (m, 1H), 7.18 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H), 7.36 (ddd,
2
O/hexane 1:15); IR (neat) 2129 cm ; H
pale-yellow liquid; R
NMR (500 MHz)
1.66 (d, J¼6.3 Hz, 3H), 5.33 (q, J¼6.3 Hz, 1H), 7.18
(dd, J¼8.6, 2.9 Hz, 1H), 7.48 (d, J¼8.6 Hz, 1H), 7.50 (d, J¼2.9 Hz, 1H).
f
0.50 (hexane); IR (neat) 2084, 2049 cm ; H
d
d

10308
K. Kobayashi et al. / Tetrahedron 69 (2013) 10304e10310
Anal. Calcd for C
9
H
7
BrClNS: C, 39.08; H, 2.55; N, 5.06. Found: C,
stirred at room temperature for 2 h. The precipitate was filtered off
3
8.72; H, 2.73; N, 5.02.
and the filtrate was concentrated by evaporation. The residue was
ꢀ
dissolved in Ac
this solution was added HCO
stirred for 20 min at the same temperature. Excess Ac
2
O (4.7 mL) and the solution was cooled to 0 C. To
3
.6.4. 1-Bromo-2-(1-isothiocyanatoethyl)-4,5-dimethoxy
0.30 (AcOEt/hexane 1:5); IR (neat) 2100,
1.63 (d, J¼6.9 Hz, 3H), 3.88 (s, 3H),
.93 (s, 3H), 5.27 (q, J¼6.9 Hz, 1H), 6.97 (s, 1H), 6.98 (s, 1H). Anal.
12BrNO S: C, 43.72; H, 4.00; N, 4.64. Found: C, 43.48;
H, 4.03; N, 4.37.
benzene
2
H (7.6 mL) and the mixture was
O and HCO
(4d). A pale-yellow oil; R
f
2
2
H
ꢁ1 1
1603 cm ; H NMR (500 MHz)
d
were removed under reduced pressure and the resulting residual
3
solid was triturated with hexane to give, after filtration, 6 (1.7 g,
ꢀ
Calcd for C11
H
2
81%); a white solid; mp 77e79 C (hexane/CHCl
3
); IR (KBr) 3261,
4.48 and 4.57 (2d, J¼6.1 and
.9 Hz, respectively, combined 2H), 6.09 (br 1H), 7.17 and 7.20 (t and
ꢁ
1 1
1677, 1657 cm ; H NMR (400 MHz)
d
6
3
.6.5. 1-Bromo-2-(1-isothiocyanato-1-methylethyl)benzene (4e). A
dd, J¼7.6 Hz and J¼8.4, 7.6 Hz, respectively, combined 1H),
7.26e7.34 (m, 2H), 7.56 and 7.59 (2d, J¼7.6 and 8.4 Hz, respectively,
combined 1H), 8.18 and 8.21 (2s, combined 1H). Anal. Calcd for
C H BrNO: C, 44.89; H, 3.77; N, 6.54. Found: C, 44.80; H, 3.89; N,
8 8
6.29.
ꢁ
1 1
pale-yellow liquid; R
f
0.30 (hexane); IR (neat) 2077 cm ; H NMR
(
400 MHz)
d
1.98 (s, 6H), 7.16 (td, J¼7.8, 2.0 Hz, 1H), 7.32 (t, J¼7.8 Hz,
13
1
d
H), 7.54 (dd, J¼7.8, 2.0 Hz,1H), 7.64 (dd, J¼7.8, 2.0 Hz,1H); C NMR
29.86, 64.14, 120.83, 127.12, 127.64, 129.41, 132.67, 135.86, 140.57.
10BrNS: C, 46.89; H, 3.93; N, 5.47. Found: C,
6.81; H, 4.03; N, 5.46.
Anal. Calcd for C10
4
H
3.8. 1-Bromo-2-(1-isocyanomethyl)benzene (7)
3
.6.6. 1-Bromo-2-(1-isothiocyanato-1-methylpropyl)benzene (4f). A
This compound was prepared by dehydration of 6 with POCl
3
ꢁ1
1
7
pale-yellow liquid; R
f
0.47 (hexane); IR (neat) 2083 cm ; H NMR
under conditions reported previously; a pale-yellow oil; R
f
0.78
ꢁ
1
ꢁ1 1
(
500 MHz)
.59e2.66 (m, 1H), 7.15 (dd, J¼8.0, 7.4 Hz, 1H), 7.33 (dd, J¼8.0,
.4 Hz, 1H), 7.58 (d, J¼8.0 Hz, 1H); 762 (d, J¼8.0 Hz, 1H). Anal. Calcd
for C11 12BrNS: C, 48.90; H, 4.48, N, 5.18. Found: C, 48.83; H, 4.58;
N, 5.09.
d
0.89 (t, J¼7.4 Hz, 3H), 1.98 (s, 3H), 2.12e2.19 (m, 1H),
(Et O/hexane 1:1); IR (neat) 2152 cm cm ; H NMR (500 MHz)
2
2
7
d
4.74 (s, 2H), 7.26 (t, J¼7.6 Hz, 1H), 7.42 (t, J¼7.6 Hz, 1H), 7.58 (d,
J¼7.6 Hz, 1H), 7.60 (d, J¼7.6 Hz, 1H). HRMS calcd for C
8
H
7
BrN: MþH,
H
195.9762. Found: m/z 195.9753.
3.9. 1-Bromo-2-(1-isocyanobut-3-enyl)benzene (3j)
3
.6.7. 1-Bromo-2-(1-isothiocyanato-1-methylbut-3-enyl)benzene
ꢁ1
(
4g). A colorless liquid; R
f
0.48 (hexane); IR (neat) 2086,1641 cm
1.98 (s, 3H), 2.91 (dd, J¼14.3, 7.4 Hz, 1H), 3.28
dd, J¼14.3, 6.9 Hz, 1H), 5.14 (d, J¼10.3 Hz, 1H), 5.20 (d, J¼17.2 Hz,
H), 5.60e5.69 (m, 1H), 7.16 (ddd, J¼8.0, 7.4, 1.1 Hz, 1H), 7.33 (td,
J¼7.4, 1.1 Hz, 1H), 7.55 (dd, J¼8.0, 1.1 Hz, 1H), 7.63 (d, J¼7.4 Hz, 1H).
Anal. Calcd for C12 12BrNS: C, 51.07; H, 4.29; N, 4.96. Found: C,
0.75; H, 4.34; N, 5.24.
;
This compound was prepared from 7 and 3-bromopropene by
the procedure as described for the preparation of 3e; a colorless
1
H NMR (500 MHz)
d
ꢁ
1 1
(
1
liquid; R
f
0.42 (Et
2
O/hexane 1:10); IR (neat) 2139, 1643 cm
; H
NMR (500 MHz)
d 2.48e2.54 (m, 1H), 2.66e2.69 (m, 1H), 5.16e5.24
(m, 3H), 5.80e5.88 (m,1H), 7.22 (ddd, J¼8.0, 7.4,1.7 Hz,1H), 7.41 (td,
J¼7.4, 1.1 Hz, 1H), 7.57 (dd, J¼8.0, 1.1 Hz, 1H), 7.59 (dd, J¼7.4, 1.7 Hz,
H
5
1H). HRMS calcd for C11
H11BrN: MþH, 236.0075. Found: m/z
236.0072.
3
.6.8. 1-Bromo-2-(1-ethyl-1-isothiocyanatobut-3-enyl)benzene
0.45 (hexane); IR (neat) 2082,
0.84 (t, J¼7.4 Hz, 3H), 2.11e2.16
m, 1H), 2.72e2.77 (m, 1H), 2.86e2.90 (m, 1H), 3.41 (dd, J¼14.3,
.4 Hz, 1H), 5.10 (d, J¼9.7 Hz, 1H), 5.18 (dd, J¼16.6 Hz, 1H),
.54e5.63 (m, 1H), 7.15 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H), 7.33 (ddd, J¼8.0,
.4, 1.1 Hz, 1H), 7.57 (dd, J¼8.0, 1.7 Hz, 1H), 7.61 (dd, J¼8.0, 1.1 Hz,
(4h). A pale-yellow liquid; R
f
3.10. 1-Bromo-2-(1-isocyano-2-phenylethyl)benzene (3k)
ꢁ
1 1
1639 cm ; H NMR (500 MHz) d
(
7
5
7
This compound was prepared from 7 and (bromomethyl)ben-
zene by the procedure as described for the preparation of 3e;
ꢁ
1 1
a colorless oil; R
NMR (500 MHz)
f
0.35 (AcOEt/hexane 1:15); IR (neat) 2139 cm ; H
d
2.94 (dd, J¼13.7, 9.2 Hz, 1H), 3.24 (dd, J¼13.7,
1
H). Anal. Calcd for C13
H
14BrNS: C, 52.71; H, 4.76; N, 4.73. Found: C,
3.8 Hz, 1H), 5.32 (dd, J¼9.2, 3.8 Hz, 1H), 7.21e7.26 (m, 3H),
5
2.77; H, 4.80; N, 4.72.
7.28e7.35 (m, 3H), 7.38 (t, J¼7.6 Hz, 1H), 7.53 (dd, J¼7.6, 1.5 Hz, 1H),
7
.59 (dd, J¼7.6, 1.5 Hz, 1H). HRMS calcd for C15 13BrN: MþH,
H
3
.6.9. 1-Bromo-4-chloro-2-(1-isocyano-1-methyl-2-phenylethyl)
286.0231. Found: m/z 286.0219.
ꢁ1
benzene (4i). A colorless oil; R
f
0.32 (hexane); IR (neat) 2074 cm
;
1
H NMR (500 MHz)
d
1.99 (s, 3H), 3.38 (d, J¼13.7 Hz, 1H), 3.72 (d,
3.11. 1-Bromo-2-(1-isothiocyanatobut-3-enyl)benzene (4j)
J¼13.7 Hz, 1H), 7.08 (dd, J¼7.4, 2.3 Hz, 2H), 7.14 (dd, J¼8.6, 2.3 Hz,
H), 7.24e7.26 (m, 3H), 7.35 (d, J¼2.3 Hz, 1H), 7.60 (d, J¼8.6 Hz, 1H).
Anal. Calcd for C16 13BrClNS: C, 52.41; H, 3.57; N, 3.82. Found: C,
2.34; H, 3.74; N, 3.70.
1
This compound was prepared by treatment of 3j with S
presence of a catalytic amount of Se under Fujiwara’s conditions;
8
in the
3
H
ꢁ1 1
5
f
a colorless liquid; R 0.30 (hexane); IR (neat) 2078, 1642 cm ; H
NMR (500 MHz) 2.55e2.61 (m, 1H), 2.69e2.74 (m, 1H), 5.23e5.31
d
3
.6.10. 1-Bromo-2-(4-chloro-1-isothiocyanato-1-methylbutyl)ben-
(m, 3H), 5.81e5.89 (m, 1H), 7.20 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H), 7.39
(dd, J¼8.0, 7.4 Hz, 1H), 7.49 (dd, J¼8.0, 1.1 Hz, 1H), 7.56 (d, J¼8.0 Hz,
ꢁ1
zene (4l). A colorless liquid; R
f
0.31 (hexane); IR (neat) 2070 cm
;
1
H NMR (500 MHz)
H), 2.20e2.27 (m, 1H), 2.82e2.88 (m, 1H), 3.53 (t, J¼6.3 Hz, 2H),
.17 (ddd, J¼8.0, 7.4,1.1 Hz,1H), 7.35 (ddd, J¼8.0, 7.4,1.1 Hz,1H), 7.60
d
1.58e1.65 (m, 1H), 1.79e1.87 (m, 1H), 2.02 (s,
1H). Anal. Calcd for C11
49.25; H, 3.77; N, 5.11.
H10BrNS: C, 49.27; H, 3.76; N, 5.22. Found: C,
3
7
(
C
dd, J¼8.0, 1.1 Hz, 1H), 7.63 (dd, J¼8.0, 1.1 Hz, 1H). Anal. Calcd for
3.12. 1-Bromo-2-(1-isothiocyanato-2-phenylethyl)benzene
(4k)
12
H13BrClNS: C, 45.23; H, 4.11; N, 4.40. Found: C, 45.18; H, 4.12; N,
4
.30.
This compound was prepared by treatment of 3k with S
8
in the
3
3
.7. N-[(2-Bromophenyl)methyl]formamide (6)
presence of a catalytic amount of Se under Fujiwara’s conditions;
ꢁ1
1
a colorless oil; R
(500 MHz)
2.98 (dd, J¼13.7, 9.2 Hz, 1H), 3.28 (dd, J¼13.7, 3.8 Hz,
1H), 5.45 (dd, J¼9.2, 3.8 Hz, 1H), 7.21 (td, J¼7.6, 1.5 Hz, 1H), 7.25 (d,
f
0.23 (hexane); IR (neat) 2080 cm
; H NMR
A
mixture of (2-bromophenyl)methanamine hydrochloride
d
(
2.2 g, 10 mmol) and Et N (1.2 g, 12 mmol) in Et O (30 mL) was
3
2

K. Kobayashi et al. / Tetrahedron 69 (2013) 10304e10310
10309
J¼7.6 Hz, 2H), 7.28e7.38 (m, 4H), 7.45 (dd, J¼7.6, 1.5 Hz, 1H), 7.58
dd, J¼7.6, 1.5 Hz, 1H). Anal. Calcd for C15 12BrNS: C, 56.61; H, 3.80;
N, 4.40. Found: C, 56.47; H, 3.81; N, 4.30.
C
11
H
13NS: C, 69.07; H, 6.85; N, 7.32. Found: C, 69.77; H, 8.03;
(
H
N, 7.25.
3
.13.7. 3-Methyl-3-(prop-2-enyl)-2,3-dihydro-1H-isoindole-1-thione
ꢀ
3
1
.13. Typical procedure for the preparation of 2,3-dihydro-
H-isoindole-1-thiones 10
(10g). A white solid; mp 119e120 C (hexane/CH
3147, 1643, 1612, 1501, 1340 cm ; H NMR (500 MHz)
2
Cl
2
); IR (KBr)
1.58 (s, 3H),
ꢁ1 1
d
2
.52 (d, J¼14.3, 7.4 Hz, 1H), 2.65 (dd, J¼14.3, 6.9 Hz, 1H), 5.11 (d,
3
.13.1. 3-Methyl-2,3-dihydro-1H-isoindole-1-thione (10a). To a stir-
J¼16.7 Hz, 1H), 5.12 (d, J¼10.9 Hz, 1H), 5.58e5.66 (m, 1H), 7.36 (d,
ꢀ
red solution of 4a (0.18 g, 0.76 mmol) in THF (4 mL) ꢁ78 C was
added n-BuLi (1.6 M in hexane; 0.76 mL). After 10 min, the mixture
was worked up as described for the preparation of 3e. The residual
J¼7.4 Hz, 1H), 7.49 (t, J¼7.4 Hz, 1H), 7.59 (t, J¼7.4 Hz, 1H), 8.03 (d,
1
3
J¼7.4 Hz, 1H), 8.46 (br s, 1H); C NMR
d 24.18, 43.75, 69.16, 120.43,
120.73, 125.73, 128.56, 131.35, 132.08, 137.37, 149.43, 194.01. HRMS
solid was recrystallized from hexane/CH
2
Cl
2
to give 10a (97 mg,
calcd for C12
Calcd for C12
6.46; N, 6.60.
H
14NS: MþH, 204.0847. Found: m/z 204.0845. Anal.
ꢀ
7
9%); a beige solid; mp 139e141 C; IR (KBr) 3140, 1612, 1512,
H13NS: C, 70.89; H, 6.45; N, 6.89. Found: C, 70.62; H,
ꢁ1 1
1253 cm
;
H NMR (500 MHz)
d
1.56 (d, J¼6.9 Hz, 3H), 4.88 (q,
J¼6.9 Hz, 1H), 7.44 (d, J¼7.6 Hz, 1H), 7.51 (t, J¼7.6 Hz, 1H), 7.61 (t,
1
3
J¼7.6 Hz,1H), 8.07 (d, J¼7.6 Hz, 1H), 8.62 (br s, 1H); C NMR
d
18.79,
3.13.8. 3-Ethyl-3-(prop-2-enyl)-2,3-dihydro-1H-isoindole-1-thione
ꢀ
5
9.85, 121.51, 125.53, 128.49, 132.01, 137.96, 146.73, 195.04; MS m/z
(10h). A white solid; mp 144e146 C (hexane/CH
2
Cl
2
); IR (KBr)
0.67 (t,
þ
3140, 1643, 1612, 1504, 1343 cm ; 1H NMR (500 MHz)
ꢁ1
163 (M , 100). Anal. Calcd for C
9
H
9
NS: C, 66.22; H, 5.56; N, 8.58.
d
Found: C, 66.03; H, 5.67; N, 8.46.
J¼7.4 Hz, 3H), 1.94e1.99 (m, 1H), 2.02e2.07 (m, 1H), 2.59 (dd,
J¼13.7, 7.4 Hz, 1H), 2.69 (dd, J¼13.7, 7.4 Hz, 1H), 5.05e5.10 (m, 2H),
5.51e5.59 (m, 1H), 7.33 (d, J¼8.0 Hz, 1H), 7.49 (dd, J¼8.0, 7.4 Hz,
3
.13.2. 3-Ethyl-2,3-dihydro-1H-isoindole-1-thione (10b). A gray
ꢀ
solid; mp 105e107 C (hexane/CH
2
Cl
2
); IR (KBr) 3163, 1613, 1507,
1H), 7.59 (ddd, J¼8.0, 7.4, 1.1 Hz, 1H), 8.04 (d, J¼8.0 Hz, 1H), 8.83 (br
ꢁ
1
1
13
1243 cm ; H NMR (500 MHz)
d
0.99 (t, J¼7.4 Hz, 3H), 1.76e1.84
s, 1H); C NMR
d
7.83, 30.53, 42.52, 72.88, 120.24, 120.94, 125.67,
(
1
1
m, 1H), 2.03e2.12 (m, 1H), 4.78 (t, J¼6.3 Hz, 1H), 7.44 (d, J¼7.4 Hz,
128.53, 131.20, 132.00, 138.52, 147.76, 194.98. HRMS calcd for
H), 7.51 (t, J¼7.4 Hz, 1H), 7.60 (t, J¼7.4 Hz, 1H), 8.07 (d, J¼7.4 Hz,
C
C
13
H
H
16NS: MþH, 218.1003. Found: m/z 218.0995. Anal. Calcd for
H), 8.60 (br s, 1H); 13C NMR
d
9.66, 26.47, 65.42, 121.74, 125.54,
15NS: C, 71.84; H, 6.96; N, 6.44. Found: C, 71.75; H, 7.04; N,
13
þ
128.50, 131.92, 138.49, 145.29, 195.44; MS m/z 177 (M , 100). Anal.
6.42.
Calcd for C10H11NS: C, 67.76; H, 6.25; N, 7.90. Found: C, 67.61; H,
6
.29; N, 7.84.
3.13.9. 5-Chloro-3-methyl-3-phenylmethyl-2,3-dihydro-1H-iso-
ꢀ
indole-1-thione (10i). A white solid; mp 154e156 C (hexane/
ꢁ
1 1
3
.13.3. 5-Chloro-3-methyl-2,3-dihydro-1H-isoindole-1-thione
CH
1.61 (s, 3H), 3.00 (d, J¼13.7 Hz, 1H), 3.14 (d, J¼13.7 Hz, 1H), 7.10
(dd, J¼7.4, 1.7 Hz, 2H), 7.26e7.28 (m, 3H), 7.34 (d, J¼1.1 Hz, 1H), 7.44
2
Cl
2
); IR (KBr) 3124, 1609, 1521, 1328 cm ; H NMR (500 MHz)
ꢀ
(10c). A beige solid; mp 171e173 C (hexane/CH
2
Cl
1.56 (d, J¼6.9 Hz, 3H),
.86 (q, J¼6.9 Hz, 1H), 7.42 (d, J¼1.7 Hz, 1H), 7.48 (dd, J¼8.0, 1.7 Hz,
2
); IR (KBr) 3142,
d
ꢁ
1 1
1
4
1
611, 1515, 1277 cm ; H NMR (500 MHz)
d
13
(dd, J¼8.6,1.1 Hz,1H), 7.89 (d, J¼8.6 Hz,1H), 8.47 (br s,1H); C NMR
13
H), 7.98 (d, J¼8.0 Hz, 1H), 8.40 (br s, 1H); C NMR
d
18.78, 59.51,
d 23.84, 45.70, 69.20, 121.51, 127.08, 127.49, 128.58, 129.22, 130.20,
122.07, 126.82, 129.17, 136.49, 138.70, 148.14, 193.93; MS m/z 197
134.69, 135.76, 138.59, 151.06, 192.80. HRMS calcd for C16
H
15ClNS:
14ClNS:
þ
(
M , 100). Anal. Calcd for C
9
H
8
ClNS: C, 54.68; H, 4.08; N, 7.09.
MþH, 288.0613. Found: m/z 288.0597. Anal. Calcd for C16
H
Found: C, 54.60; H, 4.18; N, 7.00.
C, 66.77; H, 4.90; N, 4.87. Found: C, 66.73; H, 4.95; N, 4.84.
3
.13.4. 5,6-Dimethoxy-3-methyl-2,3-dihydro-1H-isoindole-1-thione
3.13.10. 3-(Prop-2-enyl)-2,3-dihydro-1H-isoindole-1-thione (10j). A
ꢀ
ꢀ
(10d). A pale-yellow solid; mp 192e196 C (decomp.) (hexane/
beige solid; mp 90e91 C (hexane/CH
2
Cl
2
); IR (KBr) 3153, 1642,
2.38e2.44 (m, 1H),
ꢁ
1
1
1612, 1501, 1333 cm ; 1H NMR (500 MHz)
ꢁ1
CH
2
Cl
2
); IR (KBr) 3211, 1614, 1506, 1276 cm ; H NMR (500 MHz)
d
d
1.53 (d, J¼6.9 Hz, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 4.79 (q, J¼6.9 Hz,
2.75e2.80 (m, 1H), 4.84 (dd, J¼8.7, 5.2 Hz, 1H), 5.21e5.24 (m, 2H),
13
1
5
H), 6.86 (s, 1H), 7.49 (s, 1H), 8.65 (br s, 1H); C NMR d 18.97, 56.28,
5.79e5.87 (m, 1H), 7.46 (dd, J¼7.4, 1.1 Hz, 1H), 7.52 (t, J¼7.4 Hz, 1H),
1
3
6.31, 59.37, 103.21, 106.80, 130.97, 140.93, 149.94, 153.36, 194.78;
7.60 (td, J¼7.4, 1.1 Hz, 1H), 8.07 (d, J¼7.4 Hz, 1H), 8.72 (br s, 1H);
C
þ
MS m/z 223 (M , 100). Anal. Calcd for C11
N, 6.27. Found: C, 59.15; H, 5.90; N, 6.23.
2
H13NO S: C, 59.17; H, 5.87;
NMR
d
37.84, 63.24, 119.83, 121.83, 125.66, 128.71, 131.94, 132.39,
þ
138.36, 144.77, 195.61; MS m/z 189 (M , 100). Anal. Calcd for
11
C H11NS: C, 69.80; H, 5.86; N, 7.40. Found: C, 69.90; H, 6.01; N,
3
.13.5. 3,3-Dimethyl-2,3-dihydro-1H-isoindole-1-thione
7.21.
ꢀ
(10e). Colorless needles; mp 138e139 C (hexane/CH
2
d
Cl
1.60 (s,
2
); IR
ꢁ
1 1
(
KBr) 3158, 1612, 1515, 1303 cm
;
H NMR (500 MHz)
3.13.11. 3-Phenylmethyl-2,3-dihydro-1H-isoindole-1-thione (10k). A
pale-yellow solid; mp 138e139 C (hexane/CH
1613, 1503, 1346 cm
ꢀ
6
1
H), 7.38 (d, J¼7.4 Hz, 1H), 7.49 (t, J¼7.4 Hz, 1H), 7.59 (t, J¼7.4 Hz,
2
Cl
2
); IR (KBr) 3140,
13
ꢁ1
1
H), 8.03 (d, J¼7.4 Hz, 1H), 9.02 (br s, 1H); C NMR
d
26.35, 66.82,
;
H NMR (500 MHz)
d
2.85 (dd, J¼13.7,
120.34, 125.75, 128.47, 132.20, 136.74, 150.81, 193.46. HRMS calcd
9.2 Hz, 1H), 3.28 (dd, J¼13.7, 5.4 Hz, 1H), 4.99 (dd, J¼9.2, 5.4 Hz, 1H),
for C10
for C10
N, 7.87.
H
H
12NS: MþH, 178.0687. Found: m/z 178.0683. Anal. Calcd
7.26 (d, J¼6.9 Hz, 2H), 7.30e7.38 (m, 4H), 7.51 (dd, J¼7.6, 6.9 Hz,1H),
13
11NS: C, 67.76; H, 6.25; N, 7.90. Found: C, 67.70; H, 6.17;
7.57 (dd, J¼7.6, 6.9 Hz, 1H), 8.06 (d, J¼7.6 Hz, 1H), 8.31 (br s, 1H);
C
NMR
d
40.11, 65.12, 121.96, 125.74, 127.46, 128.79, 129.06, 131.86,
þ
141.87, 136.28, 138.30, 144.73, 195.54; MS m/z 239 (M , 100). Anal.
3
.13.6. 3-Ethyl-3-methyl-2,3-dihydro-1H-isoindole-1-thione (10f). A
Calcd for C15
5.54; N, 5.94.
H13NS: C, 75.28; H, 5.47; N, 5.85. Found: C, 75.34; H,
ꢀ
white solid; mp 125e128 C (hexane/CH
2
Cl
0.71 (t, J¼7.6 Hz, 3H),
.57 (s, 3H), 1.90e1.99 (m, 2H), 7.32 (dd, J¼7.6, 0.8 Hz, 1H), 7.48 (t,
J¼7.6 Hz, 1H), 7.58 (td, J¼7.6, 0.8 Hz, 1H), 8.04 (d, J¼7.6 Hz,
2
); IR (KBr) 3143, 1612,
ꢁ
1
1
1504, 1343 cm
; H NMR (500 MHz) d
1
3.13.12. 3-(3-Chloropropyl)-3-methyl-2,3-dihydro-1H-isoindole-1-
thione (10l). A pale-yellow solid; mp 107e109 C (hexane/CH
ꢀ
2
Cl
2
);
H), 8.25 (br s, 1H); 1 C NMR
25.68, 128.41, 132.10, 137.67, 149.53, 194.08. HRMS calcd for
14NS: MþH, 192.0847. Found: m/z 192.0842. Anal. Calcd for
3
d
8.32, 24.67, 32.52, 70.29, 120.54,
IR (KBr) 3153, 1611, 1497, 1341 cm
1.23e1.32 (m, 1H), 1.59e1.67 (m including s at 1.61, 4H), 2.13 (t,
J¼8.0 Hz, 2H), 3.38e3.43 (m, 2H), 7.36 (d, J¼7.4 Hz, 1H), 7.50 (dd,
ꢁ1
;
1
H NMR (500 MHz)
1
1
C H
11
d

10310
K. Kobayashi et al. / Tetrahedron 69 (2013) 10304e10310
þ
J¼8.0, 7.4 Hz, 1H), 7.61 (t, J¼7.4 Hz, 1H), 8.04 (d, J¼7.4 Hz, 1H), 8.33
203 (M , 100). Anal. Calcd for C12
Found: C, 70.80; H, 6.71; N, 6.82.
H13NS: C, 70.89; H, 6.45; N, 6.89.
(
br s, 1H); 13C NMR
d
25.49, 26.80, 36.66, 44.56, 69.41, 120.54,
þ
1
25.78, 128.71, 132.41, 137.51, 148.97, 194.14; MS m/z 239 (M , 100).
Anal. Calcd for C12H14ClNS: C, 60.11; H, 5.89; N, 5.84. Found: C,
Acknowledgements
6
0.08; H, 5.91; N, 5.75.
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) 22550035 from Japan Society for the Promotion of
Science. The authors gratefully acknowledge Mrs. Miyuki Tanmatsu
of our university for recording mass spectra and performing com-
bustion analyses.
3
.14. 9b-Methyl-1,2,3,9b-tetrahydropyrrolo[2,1-a]isoindole-5-
thione (11)
To a stirred suspension of NaH (60% in mineral oil; 10 mg,
.25 mmol) in DMF (1.6 mL) at room temperature was added a so-
lution of 10k (55 mg, 0.23 mmol) in DMF (1 mL) dropwise. After
0 min, the mixture was worked up as described for the prepara-
tion of 3d. The residue was purified by column chromatography on
0
References and notes
1
1. (a) Nishio, T.; Okuda, N. J. Org. Chem. 1992, 57, 4000e4005; (b) Hamid, A.; Ou-
lyadi, H.; Daich, A. Tetrahedron 2006, 62, 6398e6404; (c) Sinha, S. H.; Owens, E.
A.; Feng, Y.; Yang, Y.; Xie, Y.; Tu, Y.; Henary, M.; Zheng, Y. G. Eur. J. Med. Chem.
2012, 54, 647e659.
silica gel to give 11 (46 mg, 99%); a yellow oil; R
f
0.36 (AcOEt/hexane
; H NMR (500 MHz)
ꢁ1
1
1
:1); IR (KBr) 1611, 1473, 1410, 1317 cm
2
3
. Nishio, T.; Okuda, N.; Mori, Y.; Kashima, C. Synthesis 1989, 396e397.
. Fujiwara, S.; Shin-Ike, T.; Sonoda, N.; Aoki, M.; Okada, K.; Miyoshi, N.; Kambe, N.
Tetrahedron Lett. 1991, 32, 3503e3506.
d
1.51e1.57 (m including s at 1.55, 4H), 2.05e2.11 (m,1H), 2.43e2.50
(
m, 1H), 2.53e2.64 (m, 1H), 3.68e3.73 (m, 1H), 4.17e4.23 (m, 1H),
4. Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem. 1985, 50, 5782e5789.
5. Choi, Y. L.; Yu, C.-M.; Kim, B. T.; Heo, J.-N. J. Org. Chem. 2009, 74, 3948e3951.
6. Cam-Van, N. T.; Diep, B. K.; Buu-Hoi, N. P. Tetrahedron 1964, 20, 2195e2199.
7
1
7
.38 (d, J¼7.4 Hz, 1H), 7.46 (dd, J¼8.0, 7.4 Hz, 1H), 7.54 (t, J¼7.4 Hz,
13
H), 7.97 (d, J¼8.0 Hz, 1H); C NMR
d 22.86, 27.73, 32.96, 44.05,
7.04, 120.95, 125.55, 128.60, 131.63, 139.46, 149.14, 193.71; MS m/z
7. Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem. Soc. Jpn. 1984, 57, 73e84.