Synthesis of 3-substituted 1-thioacyl- and 1-thiocarbamoylindoles from-substituted 2-isocyanato-β-methoxystyrenes

Article abstract of DOI:10.1055/s-0030-1258177

3-Aryl-1-thioacylindoles were prepared by treating α-aryl-2- isothiocyanato-β-methoxystyrenes with organolithiums or Grignard reagents, followed by hydriodic acid catalyzed cyclization of the resulting adducts. A one-pot synthesis of 1-thiocarbamoylindoles was achieved by hydriodic acid mediated cyclization of the corresponding thiourea intermediates, prepared from α-substituted 2-isothiocyanato-β-methoxystyrenes and secondary amines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258177

PAPER
2985
Synthesis of 3-Substituted 1-Thioacyl- and 1-Thiocarbamoylindoles from
a-Substituted 2-Isocyanato-b-methoxystyrenes
1
-Thioacyl- an
h
d
1-Thiocarb
u
amoylindol
h
s
ei Fukamachi, Seiki Fujita, Kazuya Murahashi, Hisatoshi Konishi, Kazuhiro Kobayashi*
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 19 March 2010; revised 27 April 2010
treatment with sulfur in the presence of a catalytic amount
of selenium under Fujiwara’s conditions,7 reacted with or-
ganolithium compounds at –78 °C or with Grignard
reagents at 0 °C in tetrahydrofuran to give the correspond-
Abstract: 3-Aryl-1-thioacylindoles were prepared by treating a-
aryl-2-isothiocyanato-b-methoxystyrenes with organolithiums or
Grignard reagents, followed by hydriodic acid catalyzed cyclization
of the resulting adducts. A one-pot synthesis of 1-thiocarbamoylin-
doles was achieved by hydriodic acid mediated cyclization of the ing N-2-(1-aryl-2-methoxyethenyl)phenylamides 2 after
corresponding thiourea intermediates, prepared from a-substituted
2-isothiocyanato-b-methoxystyrenes and secondary amines.
aqueous workup. These products were used in the next
step without any purification. The crude amides 2 re-
mained unchanged when treated in 1,2-dichloroethane
containing an equimolar amount of hydriodic acid at room
temperature for one day. However, when a mixture con-
taining a catalytic amount (5 mol%) of hydriodic acid was
Key words: heterocycles, indoles, cyclizations, isothiocyanates,
organometallic reagents
We recently described a novel and quite rapid route to 4- heated to reflux temperature, cyclization took place im-
substituted quinoline-2(1H)-thiones through an electrocy- mediately (within 5 minutes) and gave the desired prod-
clic reaction of a-substituted 2-isocyanatostyrenes, gener- ucts 3 in satisfactory overall yields after aqueous workup
ated in situ from the corresponding isocyanides by followed by purification of the crude products by prepar-
treatment with sulfur in the presence of a catalytic amount ative thin-layer chromatography on silica gel, as summa-
of selenium.1 Here, we report that a-substituted 2-isocy- rized in Table 1 (entries 1–7). Unfortunately, the reactions
anato-b-methoxystyrenes are stable and isolable, and that of 1-isothiocyanato-2-(2-methoxy-1-methylvinyl)benz-
their reaction with nucleophiles, such as organometallic ene (1c) with butyllithium and with ethylmagnesium bro-
compounds or secondary amines, followed by cyclization mide gave rather complex mixtures of products, the
of the resulting adducts mediated by hydriodic acid gives treatment of which with hydriodic acid in refluxing 1,2-
1-thioacyl- and 1-thiocarbamoylindoles, respectively.2 dichloroethane gave only trace amounts of the desired
Although many methods have been developed recently products (entries 8 and 9).
for the construction of indole derivatives,3 the synthesis of
R1
1-thioacyl- and 1-thiocarbamoylindoles remains a more
formidable problem. These types of indole derivatives are
thought to be of potential importance in medicinal chem-
istry. However, few syntheses of these classes of indoles
have been reported, although 4-(1H-indol-1-yl)-4-thioxo-
butan-1-ol has been prepared by treating indole with dihy-
drofuran-2(3H)-thione using ethylmagnesium bromide as
a base,4 and N-{2-[1-(anilinocarbonothioyl)-5-methoxy-
1H-indol-3-yl]ethyl}acetamide has been synthesized by
treating N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide
with phenyl isothiocyanate in the presence of triethyl-
amine as a base.5 Surprisingly, there are few reports on the
conversion of 1-acylindoles into 1-thioacylindoles by
treatment with Lawesson’s reagent.6
R1
OMe
R2
OMe
1) R2M, THF
2) H3O+
N
H
C
S
NCS
1
2
R1
concd HI (cat.)
DCE, reflux
N
R2
C
3
S
Scheme 1 Preparation of 1-thioacylindoles
We then explored the possibility of a one-pot synthesis of
3-substituted 1-thiocarbamoylindoles 5 from a-substitut-
ed 2-isothiocyanate-b-methoxystyrenes 1 and secondary
amines (Scheme 2). An a-aryl-2-isothiocyanato-b-meth-
oxystyrene 1a or 1b was treated with a solution of a sec-
ondary amine in 1,2-dichloroethane at room temperature.
The addition of the amine to the isothiocyanate occurred
immediately. Treatment of the resulting solution of the
adduct 4 with an equimolar amount of concentrated hydri-
odic acid at the reflux temperature for 5 minutes gave the
Our synthetic approach to 3-aryl-1-thioacylindoles 3 be-
gan with a-aryl-2-isothiocyanato-b-methoxystyrenes 1,
and was conducted as shown in Scheme 1. Thus, com-
pounds 1a and 1b, which are readily available from the
corresponding a-aryl-2-isocyano-b-methoxystyrenes by
SYNTHESIS 2010, No. 17, pp 2985–2989
x
x.
x
x
.
2
0
1
0
Advanced online publication: 12.07.2010
DOI: 10.1055/s-0030-1258177; Art ID: F05010SS
© Georg Thieme Verlag Stuttgart · New York

2986
S. Fukamachi et al.
PAPER
Table 1 Preparation of 1-Thioacylindoles 3
Table 2 Preparation of 1-Thiocarbamoylindoles 5
Entry 1
R2M
Temp Product Yield
Entry
1
HNR2
Product
Yield
(%)a
2
(°C)
–78
–78
–78
0
(%)a
50
46
49
43
43
40
47
–
1
2
3
4
5
6
7
8
9
1a (R1 = Ph)
BuLi
3a
3b
3c
3d
3e
3f
1
2
3
4
5
6
1a (R1 = Ph)
HNEt2
5a
5b
5c
5d
5e
5f
71
77
63
82
76
32
1a
PhLi
1a
pyrrolidine
piperidine
morpholine
pyrrolidine
pyrrolidine
1a
4-TolLi
EtMgBr
4-ClC6H4MgBr
MeLi
1a
1a
1a
1a
0
1b (R1 = 4-Tol)
1c (R1 = Me)
1b (R1 = 4-Tol)
–78
–78
–78
0
a Isolated yields based on 1.
1b
BuLi
3g
3h
3i
1c (R1 = Me)
BuLi
In conclusion, we have demonstrated a rapid method for
preparing 1-thioacyl- and 1-thiocarbamoylindoles, which
are difficult to obtain by previous methods. The new
method is based on the addition reaction of an organome-
tallic reagent or a secondary amine to a 2-isothiocyanato-
b-methoxystyrene to give an adduct that undergoes cy-
clization catalyzed or mediated by hydriodic acid. The
new method may be useful in organic synthesis because of
the ease of the operations that are involved and the ready
availability of the starting materials.
1c
EtMgBr
–
a Isolated yields based on 1.
required 3-aryl-1-thiocarbamoylindole 5a–e in generally
good yield after the usual workup and purification by pre-
parative thin-layer chromatography on silica gel (Table 2,
entries 1–5). Reactions using catalytic amounts of concen-
trated hydriodic acid proceeded very slowly, and the cy-
clization was incomplete after three hours. 3-Methyl-1-
(pyrrolidin-1-ylcarbonothioyl)-1H-indole(5f) was also
prepared from 1-isothiocyanato-2-(2-methoxy-1-methyl-
vinyl)benzene (1c) and pyrrolidine under similar reaction
conditions to those described above; however, a rather
complicated mixture was obtained, and the yield of the de-
sired product was considerably lower (entry 6), possibly
because of the susceptibility of the 2-methoxy-1-methyl-
ethenyl moiety to acid hydrolysis.
All melting points were determined on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were re-
corded with a Shimadzu FTIR-8300 spectrophotometer. The H
1
NMR spectra were recorded in CDCl3 using TMS as an internal ref-
erence on a JEOL ECP500 FT NMR spectrometer operated at 500
MHz or a JEOL LA400 FT NMR spectrometer operated at 400
MHz. The 13C NMR spectra were determined by using TMS as an
internal reference with a JEOL ECP500 FT NMR spectrometer op-
erated at 125 MHz. Low-resolution [EI (70 eV) or CI] and high-
resolution (EI, 70 eV) MS spectra were recorded on a JEOL JMS
AX505 HA spectrometer. TLC was carried out on a Merck Kiesel-
gel 60 PF254. Column chromatography was performed using Merck
Kieselgel 60 (0.063–0.200 mm). All the organic solvents were dried
over appropriate drying agents and distilled before use. 1-Isocyano-
2-(2-methoxy-1-phenylvinyl)benzene and 1-isocyano-2-(2-meth-
oxy-1-methylvinyl)benzene were prepared by our previously re-
ported procedure.8 All other chemicals used in this study were
sourced commercially.
R1
R1
OMe
OMe
NR2
DCE
r.t.
HNR2
+
2
NCS
N
H
C
S
2
1
R1
4
concd HI, reflux
N
NR2
C
1-Isocyano-2-[2-methoxy-1-(4-methylphenyl)vinyl]benzene
This compound was prepared by treating 2-isocyanophenyl(4-
methylphenyl)methanone with (methoxymethylene)(triphen-
yl)phosphorane, as described for the preparation of 1-isocyano-2-
(2-methoxy-1-phenylvinyl)benzene.8 A yellow oil was obtained;
yield: 71% (~6:4 mixture of E- and Z-stereoisomers); Rf = 0.47
(Et2O–hexane, 1:3).
2
S
5
Scheme 2 Preparation of 1-thiocarbamoylindoles
Unfortunately, attempts to obtain 1-thioacyl- and 1-thio-
carbamoylindoles with substituents on the benzene ring of
the indole skeleton, such as chloro or methoxy groups,
were unsuccessful because we were unable to prepare the
necessary precursors, such as 5-chloro-2-isothiocyanato-
b-methoxystyrenes or 4,5-dimethoxy-2-isothiocyanato-b-
methoxystyrenes, in sufficiently pure form for use in the
subsequent step.
IR (neat): 2122, 1636 cm–1.
1H NMR (500 MHz): d = 2.32 (s, 3 H), 3.80 (s, 1.8 H), 3.82 (s, 1.2
H), 6.35 (d, J = 2.3 Hz, 0.6 H), 6.66 (d, J = 2.3 Hz, 0.4 H), 7.00–7.44
(m, 8 H).
HRMS (EI, 70 eV): m/z calcd for C17H15NO: 249.1154; found:
249.1161.
Synthesis 2010, No. 17, 2985–2989 © Thieme Stuttgart · New York

PAPER
1-Thioacyl- and 1-Thiocarbamoylindoles
2987
1-Isothiocyanato-2-(2-methoxyvinyl)benzenes 1; General Pro-
cedure
3-Phenyl-1-(phenylcarbonothioyl)-1H-indole (3b)
Orange solid; mp 107–108 °C (hexane).
These compounds were prepared by treating the corresponding iso-
cyanides with S8 in the presence of a catalytic amount of Se under
the conditions reported by Fujiwara et al.7
IR (KBr): 1450, 1375, 1221 cm–1.
1H NMR (500 MHz): d = 7.25 (td, J = 7.3, 0.9 Hz, 1 H), 7.33 (td,
J = 7.3, 0.9 Hz, 1 H), 7.39 (ddd, J = 8.2, 7.3, 1.4 Hz, 1 H), 7.45 (dd,
J = 7.8, 7.3 Hz, 2 H), 7.48 (dd, J = 7.8, 7.3 Hz, 2 H), 7.55 (tt, J =
7.3, 1.4 Hz, 1 H), 7.62 (d, J = 7.8 Hz, 2 H), 7.64 (d, J = 7.8 Hz, 2
H), 7.80 (s, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.87 (d, J = 8.2 Hz, 1 H).
1-Isothiocyanato-2-(2-methoxy-1-phenylvinyl)benzene (1a)
Yellow oil; yield: 80% (~6:4 mixture of E- and Z-stereoisomers);
Rf = 0.53 (benzene–hexane, 1:2).
13C NMR (125 MHz): d = 116.68, 120.37, 124.59, 124.78, 125.11,
127.17, 127.82, 128.03, 128.45, 128.54, 128.93, 130.99, 131.16,
132.81, 137.64, 144.13, 202.89.
IR (neat): 2110, 1634 cm–1.
1H NMR (500 MHz): d = 3.82 (s, 1.8 H), 3.83 (s, 1.2 H), 6.34 (s, 0.4
H), 6.71 (s, 0.6 H), 7.12–7.38 (m, 9 H).
MS (EI, 70 eV): m/z (%) = 313 (28) [M+], 121 (100).
HRMS (EI, 70 eV): m/z calcd for C16H13NOS: 267.0718; found:
267.0734.
Anal. Calcd for C21H15NS: C, 80.48; H, 4.82; N, 4.47. Found: C,
80.23; H, 4.79; N, 4.42.
1-Isothiocyanato-2-[2-methoxy-1-(4-methylphenyl)vinyl]ben-
zene (1b)
Yellow oil; yield: 83%; (~1:1 mixture of E- and Z-stereoisomers);
Rf = 0.52 (Et2O–hexane, 1:9).
IR (neat): 2106, 1636 cm–1.
1H NMR (500 MHz): d = 2.32 (s, 3 H), 3.80 (s, 1.5 H), 3.82 (s, 1.5
H), 7.01–7.28 (m, 9 H).
1-[(4-Methylphenyl)carbonothioyl]-3-phenyl-1H-indole (3c)
Orange solid; mp 149–150 °C (hexane).
IR (KBr): 1605, 1445, 1379, 1244 cm–1.
1H NMR (400 MHz): d = 2.44 (s, 3 H), 7.23–7.26 (m, 3 H), 7.31
(ddd, J = 8.3, 7.3, 1.0 Hz, 1 H), 7.39 (tt, J = 7.3, 1.4 Hz, 1 H), 7.47
(dd, J = 7.8, 7.3 Hz, 2 H), 7.55 (d, J = 8.3 Hz, 2 H), 7.64 (dd, J =
7.8, 1.4 Hz, 2 H), 7.82 (s, 1 H), 7.85 (d, J = 8.3 Hz, 2 H).
HRMS (EI, 70 eV): m/z calcd for C17H15NOS: 281.0874; found:
281.0876.
MS (EI, 70 eV): m/z (%) = 327 (19) [M+], 135 (100).
Anal. Calcd for C22H17NS: C, 80.70; H, 5.23; N, 4.28. Found: C,
80.44; H, 5.47; N, 4.19.
1-Isothiocyanato-2-[(E)-2-methoxy-1-methylvinyl]benzene (1c)
Yield: 40%; yellow oil; Rf = 0.44 (CH2Cl2–hexane, 1:3).
IR (neat): 2116, 1665 cm–1.
1H NMR (500 MHz): d = 1.81 (s, 3 H), 3.57 (s, 3 H), 6.05 (s, 1 H),
7.11–7.12 (m, 2 H), 7.15–7.17 (m, 2 H).
3-Phenyl-1-propanethioyl-1H-indole (3d)
Yellow solid; mp 96–98 °C (hexane).
IR (KBr): 1609, 1447, 1391, 1233 cm–1.
1H NMR (400 MHz): d = 1.51 (t, J = 7.3 Hz, 3 H), 3.38 (q, J = 7.3
Hz, 2 H), 7.37 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.40–7.45 (m, 2 H),
7.50 (dd, J = 7.8, 7.3 Hz, 2 H), 7.64 (s, 1 H), 7.65 (dd, J = 7.8, 1.4
Hz, 2 H), 7.80 (dt, J = 7.8, 0.7 Hz, 1 H), 9.13 (d, J = 8.0 Hz, 1 H).
13C NMR: d = 14.02, 41.36, 118.01, 120.25, 123.68, 124.86, 125.04,
126.11, 127.92, 128.13, 128.96, 130.80, 132.76, 137.79, 209.00.
HRMS (EI, 70 eV): m/z calcd for C11H11NOS: 205.0561; found:
205.0582.
1-Pentanethioyl-3-phenyl-1H-indole (3a); Typical Procedure
A 1.6 M soln of BuLi in hexane (1.4 mmol) was added dropwise to
a stirred solution of isothiocyanate 1a (0.37 g, 1.4 mmol) in THF (3
mL) at –78 °C, and the mixture was stirred for 25 min. Sat. aq
NH4Cl (15 mL) was added and the mixture was extracted with Et2O
(2 × 10 mL). The combined organic extracts were washed with brine
(10 mL), dried (Na2SO4), and concentrated. The residue was dis-
solved in DCE (5 mL), and concd HI (16 mg, 0.070 mmol) was add-
ed. The mixture was refluxed for 5 min then allowed to cool to r.t.
before DCE (10 mL) and sat. aq NaHCO3 (10 mL) were added and
the layers were separated. The aqueous layer was extracted with
DCE (10 mL), and the combined organic extracts were washed with
brine (10 mL), dried (Na2SO4), and concentrated. The residue was
purified by preparative TLC [silica gel, benzene–hexane (1:7)] to
give 3a as a yellow solid; yield: 0.21 g (50%); mp 62–63 °C (hex-
ane).
MS (EI, 70 eV): m/z (%) = 265 (68) [M+], 73 (100).
Anal. Calcd for C17H15NS: C, 76.94; H, 5.70; N, 5.28. Found: C,
76.85; H, 5.73; N, 5.17.
1-[(4-Chlorophenyl)carbonothioyl]-3-phenyl-1H-indole (3e)
Orange needles; mp 162–164 °C (hexane).
IR (KBr): 1449, 1373, 1229 cm–1.
1H NMR (500 MHz): d = 7.28 (ddd, J = 8.3, 7.3, 0.9 Hz, 1 H), 7.34
(ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.39 (t, J = 7.3 Hz, 1 H), 7.42 (d,
J = 8.2 Hz, 2 H), 7.48 (dd, J = 8.2, 7.3 Hz, 2 H), 7.58 (d, J = 8.2 Hz,
2 H), 7.64 (dd, J = 8.2, 1.4 Hz, 2 H), 7.76 (s, 1 H), 7.84 (d, J = 7.8
Hz, 1 H), 7.88 (d, J = 8.3 Hz, 1 H).
13C NMR: d = 116.52, 120.47, 124.72, 125.02, 125.23, 126.97,
127.90, 127.98, 128.70, 128.93, 129.93, 130.93, 132.60, 137.50,
137.53, 142.25, 200.87.
IR (KBr): 1449, 1385, 1357, 1229 cm–1.
1H NMR (400 MHz): d = 1.00 (t, J = 7.3 Hz, 3 H), 1.53 (sext, J =
7.3 Hz, 2 H), 1.91–1.98 (m, 2 H), 3.39 (t, J = 7.8 Hz, 2 H), 7.37 (t,
J = 7.3 Hz, 1 H), 7.40–7.45 (m, 2 H), 7.50 (dd, J = 7.8, 7.3 Hz, 2 H),
7.65 (d, J = 7.8 Hz, 2 H), 7.80 (dd, J = 7.8, 1.4 Hz, 1 H), 7.89 (s, 1
H), 9.14 (d, J = 8.3 Hz, 1 H).
13C NMR (500 MHz): d = 13.83, 22.33, 31.86, 48.45, 117.97,
120.18, 123.71, 124.84, 124.88, 126.05, 127.89, 128.09, 128.93,
130.77, 132.71, 137.79, 207.93.
MS (EI, 70 eV): m/z (%) = 347 (68) [M+], 155 (100).
Anal. Calcd for C21H14ClNS: C, 72.51; H, 4.06; N, 4.03. Found: C,
72.45; H, 4.24; N, 3.91.
1-Ethanethioyl-3-(4-methylphenyl)-1H-indole (3f)
Yellow solid; mp 42–45 °C (hexane–Et2O).
IR (KBr): 1445, 1383, 1236 cm–1.
1H NMR (500 MHz): d = 2.43 (s, 3 H), 3.22 (s, 3 H), 7.31 (d, J = 7.8
Hz, 2 H), 7.37 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H), 7.43 (ddd, J = 8.2,
MS (EI, 70 eV): m/z (%) = 293 (48) [M+], 101 (100).
Anal. Calcd for C19H19NS: C, 77.77; H, 6.53; N, 4.77. Found: C,
77.517; H, 6.413; N, 4.81.
Synthesis 2010, No. 17, 2985–2989 © Thieme Stuttgart · New York

2988
S. Fukamachi et al.
PAPER
7.3, 1.4 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 1
H), 7.90 (br s, 1 H), 9.03 (distorted d, J = 8.2 Hz, 1 H).
13C NMR: d = 21.29, 37.69, 99.91, 117.86, 120.46, 124.01, 124.86,
125.26, 126.10, 127.96, 129.65, 129.67, 131.08, 137.90, 205.37.
MS (CI): m/z (%) = 309 (100) [M + 1]+.
Anal. Calcd for C19H20N2S: C, 73.99; H, 6.54; N, 9.08. Found: C,
73.86; H, 6.51; N, 8.83.
3-Phenyl-1-(pyrrolidin-1-ylcarbonothioyl)-1H-indole (5b)
Pale-yellow solid; mp 53–55 °C (hexane–CH2Cl2).
IR (KBr): 1605, 1449, 1362, 1213 cm–1.
1H NMR (500 MHz): d = 2.07 (br s, 4 H), 3.58 (br s, 2 H), 4.03 (br
s, 2 H), 7.25 (ddd, J = 7.8, 7.3, 1.4 Hz, 1 H), 7.31–7.35 (m, 2 H),
7.44–7.47 (m, 3 H), 7.61 (s, 1 H), 7.66 (dd, J = 8.2, 0.9 Hz, 2 H),
7.89 (d, J = 7.8 Hz, 1 H).
13C NMR (125 MHz): d = 25.68, 53.40, 112.82, 120.43, 120.75,
121.92, 123.55, 124.97, 126.77, 127.75, 127.84, 128.78, 134.08,
134.96, 178.86.
MS (CI): m/z (%) = 266 (100) [M + 1]+.
Anal. Calcd for C17H15NS: C, 76.94; H, 5.70; N, 5.28. Found: C,
76.80; H, 5.75; N, 5.29.
3-(4-Methylphenyl)-1-pentanethioyl-1H-indole (3g)
Yellow solid; mp 43–46 °C (hexane).
IR (KBr): 1447, 1385, 1229 cm–1.
1H NMR (500 MHz): d = 1.00 (t, J = 7.3 Hz, 3 H), 1.53 (sext, J =
7.3 Hz, 2 H), 1.91–1.97 (m, 2 H), 2.44 (s, 3 H), 3.38 (t, J = 7.8 Hz,
2 H), 7.31 (d, J = 7.8 Hz, 2 H), 7.36 (ddd, J = 7.8, 7.3, 0.9 Hz, 1 H),
7.42 (ddd, J = 7.8, 7.3, 1.4 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 2 H), 7.79
(dd, J = 7.8, 0.9 Hz, 1 H), 7.85 (br s, 1 H), 9.12 (distorted d, J = 7.8
Hz, 1 H).
13C NMR: d = 13.83, 21.29, 22.36, 31.92, 48.53, 93.51, 118.01,
120.27, 123.49, 124.85, 124.94, 126.03, 128.00, 129.67, 129.76,
130.99, 137.86, 207.87.
MS (CI): m/z (%) = 307 (100) [M + 1]+.
Anal. Calcd for C19H18N2S: C, 74.47; H, 5.92; N, 9.14. Found: C,
74.24; H, 6.18; N, 8.90.
3-Phenyl-1-(piperidin-1-ylcarbonothioyl)-1H-indole (5c)
Pale-yellow solid; mp 57–60 °C (hexane–CH2Cl2).
MS (CI): m/z (%) = 308 (100) [M + 1]+.
IR (KBr): 1606, 1452, 1354, 1233 cm–1.
Anal. Calcd for C20H21NS: C, 78.13; H, 6.88; N, 4.56. Found: C,
78.01; H, 6.92; N, 4.51.
1H NMR (500 MHz): d = 1.67–1.83 (m, 6 H), 3.66–3.68 (m, 2 H),
4.08 (br s, 2 H), 7.25 (ddd, J = 7,8, 7,3, 1.4 Hz, 1 H), 7.30–7.37 (m,
2 H), 7.45–7.48 (m, 3 H), 7.67 (s, 1 H), 7.67 (d, J = 7.8 Hz, 2 H),
7.88 (d, J = 8.2 Hz, 1 H).
13C NMR: d = 24.27, 26.05, 53.00, 112.41, 120.40, 121.01, 122.20,
125.72, 126.45, 126.84, 127.75, 128.05, 128.80, 134.01, 135.34,
181.14.
3-(4-Methylphenyl)-1-(pyrrolidin-1-ylcarbonothioyl)-1H-in-
dole (5e); Typical Procedure
Pyrrolidine (63 mg, 0.89 mmol) was added to a stirred solution of
isothiocyanate 1b (0.25 g, 0.89 mmol) in DCE (3 mL) at r.t., and the
mixture was stirred for 10 min at r.t. Concd HI (0.20 g, 0.89 mmol)
was added, and the resulting mixture was refluxed for 3 min. The
cooled mixture was treated with sat. aq NaHCO3 (10 mL) and ex-
tracted with DCE (2 × 10 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated. The
residue was purified by column chromatography [silica gel, THF–
hexanes (1:9)] to give 5e as a pale-yellow solid; yield: 0.22 g (76%);
mp 56–59 °C (hexane–Et2O).
MS (CI): m/z (%) = 321 (100) [M + 1]+.
Anal. Calcd for C20H20N2S: C, 74.96; H, 6.29; N, 8.74. Found: C,
74.72; H, 6.41; N, 8.70.
1-(Morpholin-4-ylcarbonothioyl)-3-phenyl-1H-indole (5d)
Pale-yellow solid; mp 47–50 °C (hexane–CH2Cl2).
IR (KBr): 1605, 1451, 1356, 1235 cm–1.
1H NMR (500 MHz): d = 3.79–3.90 (m, 6 H), 4.02 (br s, 2 H), 7.27
(ddd, J = 8.2, 7.3, 1.4 Hz, 1 H), 7.33–7.37 (m, 2 H), 7.47 (dd, J =
8.2, 7.8 Hz, 2 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.66 (dd, J = 8.2, 1.4 Hz,
2 H), 7.68 (s, 1 H), 7.88 (d, J = 8.2 Hz, 1 H).
13C NMR: d = 52.13, 66.44, 112.38, 120.62, 121.63, 122.56, 124.04,
126.45, 127.04, 127.78, 128.33, 128.84, 133.70, 135.10, 182.04.
IR (KBr): 1447, 1362, 1213 cm–1.
1H NMR (500 MHz): d = 1.95–2.16 (m, 4 H), 2.41 (s, 3 H), 3.42–
3.71 (m, 2 H), 3.87–4.12 (m, 2 H), 7.24 (dd, J = 7.8, 7.3 Hz, 1 H),
7.27 (d, J = 8.2 Hz, 2 H), 7.32 (dd, J = 8.2, 7.3 Hz, 1 H), 7.45 (d,
J = 8.2 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.58 (s, 1 H), 7.86 (d,
J = 7.8 Hz, 1 H).
13C NMR: d = 21.19, 25.66, 53.38, 112.82, 120.48, 120.75, 121.84,
123.48, 124.72, 127.66, 128.00, 129.49, 131.10, 134.95, 136.50,
178.95.
MS (CI): m/z (%) = 323 (100) [M + 1]+.
Anal. Calcd for C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found: C,
70.54; H, 5.83; N, 8.53.
MS (CI): m/z (%) = 321 (100) [M + 1]+.
Anal. Calcd for C20H20N2S: C, 74.96; H, 6.29; N, 8.74. Found: C,
73.94; H, 6.36; N, 8.66.
3-Methyl-1-(pyrrolidin-1-ylcarbonothioyl)-1H-indole (5f)
Yellow oil; Rf = 0.35 (Et2O–hexane, 1:4).
IR (neat): 1610, 1446, 1348, 1231 cm–1.
(Diethylamino)(3-phenylindol-1-yl)methanethione (5a)
Yellow oil; Rf = 0.38 (THF–hexane, 1:9).
IR (neat): 1605, 1451, 1358, 1225 cm–1.
1H NMR (500 MHz): d = 1.31 (t, J = 7.3 Hz, 6 H), 3.73–3.79 (m, 4
H), 7.24 (ddd, J = 7.8, 7.3, 1.4 Hz, 1 H), 7.29–7.34 (m, 2 H), 7.39
(d, J = 7.8 Hz, 1 H), 7.45 (dd, J = 8.2, 7.3 Hz, 2 H), 7.55 (s, 1 H),
7.67 (dd, J = 8.2, 1.4 Hz, 2 H), 7.79 (dd, J = 7.8, 0.9 Hz, 1 H).
13C NMR: d = 13.00, 47.74, 111.82, 120.43, 120.82, 121.98, 123.70,
125.67, 126.75, 127.71, 127.74, 128.79, 134.12, 135.52, 181.65.
1H NMR (500 MHz): d = 2.03 (br s, 4 H), 2.29 (d, J = 1.4 Hz, 3 H),
3.78 (br s, 4 H), 7.18 (ddd, J = 8.2, 7.8, 0.9 Hz, 1 H), 7.25 (s, 1 H),
7.26 (td, J = 7.8, 0.9 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 7.53 (d,
J = 7.8 Hz, 1 H).
13C NMR: d = 9.52, 25.43, 53.38, 112.60, 115.01, 119.39, 121.13,
123.14, 125.42, 130.58, 134.50, 179.48.
MS (CI): m/z (%) = 245 (100) [M + 1]+.
Anal. Calcd for C14H16N2S: C, 68.81; H, 6.60; N, 11.46. Found: C,
68.72; H, 6.42; N, 11.40.
Synthesis 2010, No. 17, 2985–2989 © Thieme Stuttgart · New York

PAPER
1-Thioacyl- and 1-Thiocarbamoylindoles
2989
Murphy, J. A. Tetrahedron Lett. 2009, 50, 3290.
Acknowledgment
(f) Kobayashi, K.; Iitsuka, D.; Fukamachi, S.; Konishi, H.
Tetrahedron 2009, 65, 7523. (g) Muzalevskiy, V. M.;
Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe,
G. Tetrahedron 2009, 65, 7553. (h) Ackermann, L.;
Sandmann, R.; Schinkel, M.; Kondrashov, M. V.
Tetrahedron 2009, 65, 8930. (i) Zhou, L.; Doyle, M. P. J.
Org. Chem. 2009, 74, 9222; and pertinent references cited in
these papers.
We thank Mrs. Miyuki Tanmatsu of this university for recording the
mass spectra and performing the combustion analyses.
References
(1) Kobayashi, K.; Fujita, S.; Fukamachi, S.; Konishi, H.
Synthesis 2009, 3378.
(2) A synthesis of 1-acylindoles by hydrochloric acid-mediated
cyclization of N-[2-(2-ethoxyvinyl)phenyl]alkyl amides has
been reported, see: Satoh, M.; Miyaura, N.; Suzuki, A.
Synthesis 1987, 373.
(4) Wang, W.; Rattananakin, P.; Goekjian, P. G. J. Carbohydr.
Chem. 2003, 22, 743.
(5) Doss, S. H.; Mohareb, R. M.; Elmegeed, G. A.; Luoca, N. A.
Pharmazie 2003, 58, 607.
(6) Flitsch, W.; Niehoff, A. Liebigs Ann. Chem. 1989, 239.
(7) Fujiwara, S.; Shin-Ike, T.; Sonoda, N.; Aoki, M.; Okada, K.;
Miyoshi, N.; Kambe, N. Tetrahedron Lett. 1991, 32, 3503.
(8) Kobayashi, K.; Yoneda, K.; Miyamoto, K.; Morikawa, O.;
Konishi, H. Tetrahedron 2004, 60, 11639.
(3) For recent reports, see: (a) Tyrrell, E.; Whiteman, L.;
Williams, N. Synthesis 2009, 829. (b) Bernini, R.; Cacchi,
S.; Fabrizi, C.; Filsti, E.; Sferraze, A. Synlett 2009, 1480.
(c) Hsieh, T. H.; Dong, V. M. Tetrahedron 2009, 65, 3062.
(d) Denmark, S. E.; Baird, J. D. Tetrahedron 2009, 65,
3120. (e) Hisler, K.; Commeyreuc, A. G. J.; Zhou, S.-z.;
Synthesis 2010, No. 17, 2985–2989 © Thieme Stuttgart · New York