Polycyclic N-heterocyclic compounds. 57 Syntheses of fused furo(or thieno)[2,3-b]pyridine derivatives via smiles rearrangement and cyclization

Article abstract of DOI:10.3987/COM-01-9168

An efficient methodology for the synthesis of thieno[2,3-c][2,7]-naphthyridine (6), thieno[2,3-c]isoquinoline (11), furo[2,3-c]isoquinoline (14), [1]benzothieno[3,2-d]thieno[2,3-b]pyridine (21), and [1]benzothieno[3,2-d]furo-[2,3-b]pyridine (26) skeletons from 4-[o-cyanoarylthio(or oxy)]butyronitriles with base via Smiles type rearrangement reaction followed by the cyclization is described.

Full text of DOI:10.3987/COM-01-9168

HETEROCYCLES, Vol. 55, No. 4, 2001, pp. 741-752, Received, 29th January, 2001
POLYCYCLIC N-HETEROCYCLIC COMPOUNDS. 57
SYNTHESES OF FUSED FURO(OR THIENO)[2,3-b]PYRIDINE
DERIVATIVES
CYCLIZATION
VIA
SMILES
REARRANGEMENT
AND
Takashi Hirota,*,a Kei-ichiroh Tomita,a Kenji Sasaki,a Kensuke Okuda,a Masahiko
Yoshida,a and Setsuo Kashinob
a Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-
naka, Okayama, 700-8530, Japan
b Faculty of Science, Okayama University, 3-1-1 Tsushima-naka, Okayama, 700-
8530, Japan
Abstract - An efficient methodology for the synthesis of thieno[2,3-c][2,7]-
naphthyridine (6), thieno[2,3-c]isoquinoline (11), furo[2,3-c]isoquinoline (14),
[1]benzothieno[3,2-d]thieno[2,3-b]pyridine (21), and [1]benzothieno[3,2-d]furo-
[2,3-b]pyridine (26) skeletons from 4-[o-cyanoarylthio(or oxy)]butyronitriles with
base via Smiles type rearrangement reaction followed by the cyclization is
described.
We previously reported a new methodology for the syntheses of thieno(or furo)naphthyridine derivatives
from 4-[o-cyanopyridylthio(or oxy)]butyronitriles with t-BuOK via Smiles rearrangement reaction
followed by the cyclization.1-5 In those reports new tricyclic heterocycles, 5-substituted 8,9-
dihydrothieno[2,3-h][1,6]naphthyridines,1,2,5 5-substituted and non-substituted 1,2-dihydrofuro[3,2-
f][1,7]naphthyridines,3 2,5-disubstituted 8,9-dihydrofuro[2,3-h][1,6]naphthyridines,4 were prepared
efficiently (Figure 1). The bronchodilatory activity of these compounds was also evaluated on the basis of
their relaxation activity to tracheal contraction induced by carbamylcholine chloride as a primary in vitro
assay. Effect of some naphthyridines on carbamylcholine chloride-induced contractions of trachea in the
presence or absence of milrinone or 4-(3-butoxy-4-methoxyphenyl)imidazolidin-2-ones, which are

a inhibitor of phosphodiesterase III or IV, was also evaluated.5 We describe here the successful
application of this reaction employing 4-(3-cyanopropylthio)pyridine-3-carbonitrile (5), 2-(3-cyano-
propylthio)benzonitrile (10), 2-(3-cyanopropoxy)benzonitrile (13), 3-(3-cyanopropylthio)[1]benzo-
thiophene-2-carbonitrile (20), and 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile (25) in which
cyano and 3-cyanopropylthio (or 3-cyanopropoxy) groups are attached on 1,2 positions of the molecule
as a precursor to give fused thieno(or furo)[2,3-b]pyridine derivatives (6, 11, 14, 21, and 26).
2
8
9
1
1
9
3
7
O
S
N
2
3
8
7
N
N
4
6
N
5
5
4
6
NH2
NH2
Figure 1
As shown in Scheme 1, dinitrile (5) was synthesized in several steps from 4-chloropyridine-3-carboxylic
acid (1),6 which was converted to 4-mercaptopyridine-3-carboxylic acid (2) with sodium hydrogen-
sulfide. Then the reaction of 2 with 4-chlorobutyronitrile in the presence of K2CO3 gave nitrile (3). This
compound was transformed to carboxamide (4) via carbonyl chloride by the reaction of SOCl2 followed
SH
Cl
2
7
; X = N
; X = CH
X
N
CO2H
CO2H
1
OH
CN
Y
Y
R
CN
X
X
N
NH2
3
4
5
8
9
; R = CO2H, X = N, Y = S
; R = CONH2, X = N, Y = S
; R = CN, X = N, Y = S
; R = CO2H, X = CH, Y = S
; R = CONH2, X = CH, Y = S
12
6
; X = N, Y = S
11; X = CH, Y = S
14; X = CH, Y = O
10; R = CN, X = CH, Y = S
13; R = CN, X = CH, Y = O
Scheme 1

by ammonolysis with liq. NH3. Compound (4) was dehydrated by POCl3 to give the desired dinitrile (5).
As described in the previous papers,1-5 a solution of 5 in dioxane was refluxed in the presence of t-
BuOK to give the expected 5-amino-1,2-dihydrothieno[2,3-c][2,7]naphthyridine (6) in 52% yield. The
structure assignment of 6 was based upon characteristic spectral and analytical data. That is, the
absorption of CN group could not be found and that of amino group was observed at 3349, 3312, and
3127 cm-1 in its IR spectrum. In the 1H-NMR spectrum broad singlet protons due to the ethylene moiety
were observed at δ 3.41 ppm besides aromatic ring and amino protons.
For further application of this Smiles rearrangement reaction and cyclization, other requisite intermediate
(10) was prepared as shown in Scheme 1. Thiosalicylic acid (7) was employed as a starting material.
Acid (7) was derived to 2-(3-cyanopropylthio)benzoic acid (8) by the reaction with 4-chlorobutyronitrile
in dioxane in the presence of K2CO3. Compound (8) was also transformed to the desired dinitrile (10) via
carboxamide (9) similar to the synthesis of 5 from 3. A solution of 10 in dioxane was refluxed in the
presence of t-BuOK to afford the rearranged and cyclized product, 5-amino-1,2-dihydrothieno[2,3-
c]isoquinoline (11), in 42% yield. The structure assignment of 11 was also based upon characteristic
spectral and analytical data. The IR spectrum of 11 showed no signal due to CN but NH2 group
absorption occurred at 3460 and 3330 cm-1. Broad singlet protons due to ethylene moiety could be also
observed in its 1H-NMR spectrum. For trying a similar reaction using another benzonitrile derivative
(13), the requisite intermediate (13) was prepared by the reaction of commercially available 2-
cyanophenol (12) with 4-chlorobutyronitrile in the presence of K2CO3. A solution of 13 in DMF was
stirred at room temperature in the presence of t-BuOK to give the desired 5-amino-1,2-dihydrofuro[2,3-
c]isoquinoline (14) in 14% yield. The structure of 14 was consisted by the instrumental (IR, 1H-NMR,
and MS spectra) and elemental analytical data. An X-Ray structure analysis also well confirmed the
Scheme 2 ORTEP Drawing of Compound (14)

structure of 14 as shown in Scheme 2. The cyclized product (14) was a new compound, however, some
compounds with the same ring system have been already synthesized.7-10
For the next application of this Smiles rearrangement and cyclization reaction, we employed compound
(20) as a key intermediate dinitrile in which cyano and cyanopropoxy groups are attached to the 2,3-
positions of the π-sufficient thiophene ring. The requisite precursor (20) was prepared from
commercially available trans-cinnamic acid (15) in several steps as shown in Scheme 3. That is, acid
(15) was cyclized to 3-chloro[1]benzothiophene-2-carbonyl chloride (16) by the method of Wright et
CO2H
CO2 Et
CN
CO2Et
SH
S
15
23
22
Y
X
R
Y
CN
N
S
S
CN
S
NH2
16; R = COCl, X = Cl
17; R = CONH2, X = Cl
18; R = CN, X = Cl
19; R = CN, X = SH
24; R = CN, X = OH
20; Y = S
25; Y = O
21; Y = S
26; Y = O
Scheme 3
al.11 3-Chloro[1]benzothiophene-2-carbonitrile (18) was obtained by ammonolysis of chloride (16) with
liq. NH3 followed by dehydration of carboxamide (17) with POCl3. Compound (18) reacted with
thioacetamide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) by the method of Boschelli
et al.12 to give 3-mercapto[1]benzothiophene-2-carbonitrile (19). This mercapto derivative (19)
decomposed during the purification, so that, this compound was used in the next step without further
purification. The desired dinitrile (20) was prepared by the reaction of unpurified 19 with 4-
chlorobutyronitrile in the presence of K2CO3. The reaction of the hot benzene solution of compound (20)
in the presence of t-BuONa gave the desired rearranged and cyclized product (21) in 8% yield. The IR,
1H-NMR, MS spectra, and elemental analysis of 21 well consisted with its structure. As a further
application of this rearranged and cyclized reaction of the [1]benzothiophene derivative, the similar

reaction of dinitrile (25) with base was examined. This compound was prepared from ethyl thio-
salicylate (22) in several steps as shown in Scheme 3. That is, compound (22) was derived to ethyl 2-
cyanomethylthiobenzoate (23) by the reaction with chloroacetonitrile in the presence of K2CO3 and KI.
Compound (23) was cyclized to [1]benzothiophene derivative (24) in the presence of NaH, which was
transformed to the requisite dinitrile (25) by the reaction with 4-chlorobutyronitrile in the presence of
K2CO3 and KI. The dioxane solution of 25 was refluxed with NaH to give the corresponding rearranged
compound, 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine (26) in 26% yield. The
structure of 26 was well consisted with its instrumental and elemental analyses.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro-melting point apparatus, and are
uncorrected. Elemental analyses were performed on a Yanagimoto MT-5 CHN Corder elemental
analyzer. The FAB-MS spectra were measured on a VG 70 mass spectrometer and glycerol or m-
nitrobenzyl alcohol was used as a matrix agent. The IR spectra were recorded on a Japan Spectroscopic
IRA-102 diffraction grating infrared spectrophotometer and frequencies are expressed in cm-1. 1H-NMR
spectra were recorded on a Hitachi R-1500 FT-NMR spectrometer at 60 MHz or a Varian VXR-200
instrument working at 200 MHz with TMS as an internal standard. Chemical shifts are given in ppm (δ)
and J values in Hz.
4- Mercaptopyridine-3-carboxylic Acid (2)
Title compound was obtained by the method of Delarge6 from 4-chloropyridine-3-carboxylic acid (1),
yield 67%, mp 237-239 °C (from water, lit.,6 mp 234-237 °C, lit.,13 mp 236-238 °C, lit.,14 mp 243-
245 °C).
4-(3-Cyanopropylthio)pyridine-3-carboxylic Acid (3)
To a solution of acid (2) (5.00 g, 32.2 mmol) in 2-ethoxyethanol (100 mL) was added 4-
chlorobutyronitrile (3.50 g, 33.8 mmol) and K2CO3 (13.8 g, 100 mmol) and the resulting mixture was
refluxed for 8 h under N2 atmosphere. After evaporation of the reaction mixture, ice water (200 mL) was
added onto the residue and the resulting mixture was acidified (pH 4) with dil. HCl. The precipitated
solid was collected by filtration and the filtrate was extracted with ethyl acetate. The organic layer was
treated as usual. The residue was combined to the above collected solid and recrystallized from methanol
to give 3 as colorless prisms (5.10 g, 71%), mp 198-200 °C. FAB-MS m/z: 223 (MH+). IR (KBr) cm-1:
1
3113 (OH), 2243 (CN), 1701 (CO). H-NMR (60 MHz, DMSO-d6) δ: 2.00 (2H, quin, J = 7.2,

CH2CH2CH2), 2.69 (2H, t, J = 7.2, CH2CN), 3.09 (2H, t, J = 7.2, CH2S), 7.46 (1H, d, J = 5.3, 5-H), 8.54
(1H, d, J = 5.3, 6-H), 8.92 (1H, s, 2-H). Anal. Calcd for C10H10N2O2S·1/10H2O: C, 53.61; H, 4.59; N,
12.50. Found: C, 53.66; H, 4.42; N, 12.34.
4-(3-Cyanopropylthio)pyridine-3-carboxamide (4)
A solution of 3 (4.50 g, 20.2 mmol) in POCl3 (16.5 g, 108 mmol) was refluxed for 1 h. After evaporation
of POCl3, liq. NH3 (10 mL) was added to the residue under cooling and the mixture was allowed to stand
overnight. After evaporation of the mixture the residue was recrystallized from ethyl acetate to give 4 as
1
pale brown needles (3.39 g, 76%), mp 117-119 °C. IR (KBr) cm- : 3348, 3175 (NH), 2244 (CN), 1654,
(CO). This compound was used to the next step without further purification.
4-(3-Cyanopropylthio)pyridine-3-carbonitrile (5)
A solution of 4 (2.30 g, 10.4 mmol) in POCl3 (16.5 g, 108 mmol) was refluxed for 4 h. After evaporation
of POCl3, ice-water (300 mL) was added to the residue and the mixture was neutralized with NaHCO3.
The resulting mixture was extracted with ethyl acetate and the organic layer was treated as usual. The
residue was recrystallized from methanol-n-hexane to give 5 as colorless needles (1.50 g, 71%), mp 84-
86 °C. FAB-MS m/z: 204 (MH+). IR (KBr) cm-1: 2246, 2226 (CN). 1H-NMR (200 MHz, CDCl3) δ: 2.14
(2H, quin, J = 7.0, CH2CH2CH2), 2.62 (2H, t, J = 7.0, CH2CN), 3.26 (2H, t, J = 7.0, CH2S), 7.25 (1H, d,
J = 5.5, 5-H), 8.62 (1H, d, J = 5.5, 6-H), 8.71 (1H, s, 2-H). Anal. Calcd for C10H9N3S·1/5H2O: C, 58.06;
H, 4.58; N, 20.31. Found: C, 58.11; H, 4.63; N, 20.28.
5-Amino-1,2-dihydrothieno[2,3-c][2,7]naphthyridine (6)
To a solution of 5 (600 mg, 2.95 mmol) in dioxane (10 mL) was added t-BuOK (600 mg, 5.35 mmol)
and the resulting mixture was refluxed for 10 min. After evaporation of the solvent, ice water (50 mL)
was added onto the residue. The precipitated solid was collected by filtration and the filtrate was
extracted with ethyl acetate. The organic layer was treated as usual. The residue was combined to the
above collected solid and recrystallized from methanol to give 6 as pale yellow needles (310 mg, 52%),
1
mp > 300 °C. FAB-MS m/z: 204 (MH+). IR (KBr) cm-1: 3349, 3312, 3127 (NH). H-NMR (60 MHz,
DMSO-d6) δ: 3.41 (4H, br s, 1,2-H), 7.55 (2H, br s, D2O exchangeable, NH2), 7.30 (1H, d, J = 6.4, 9-H),
8.47 (1H, d, J = 6.4, 8-H), 9.41 (1H, br s, 6-H). Anal. Calcd for C10H9N3S·1/4H2O: C, 57.81; H, 4.61; N,
20.23. Found: C, 57.99; H, 4.57; N, 20.01.
2-(3-Cyanopropylthio)benzoic Acid (8)

To a solution of thiosalicylic acid (7) (20.1 g, 0.130 mol) in dioxane (100 mL) was added 4-
chlorobutyronitrile (20.2 g, 0.195 mol) and K2CO3 (27.0 g, 0.195 mol) and the resulting mixture was
heated at 80 °C for 20 h. After evaporation of the reaction mixture, ice water (300 mL) was added to the
residue and the resulting mixture was extracted with ethyl acetate. The organic layer was treated as usual
and the residue was recrystallized from ethanol to give 8 as colorless needles (21.3 g, 74%), mp 121-
1
122 °C. FAB-MS m/z: 222 (MH+). IR (KBr) cm-1: 3025 (OH), 2255 (CN), 1650 (CO). H-NMR (200
MHz, CDCl3) δ: 2.10 (2H, quin, J = 7.0, CH2CH2CH2), 2.59 (2H, t, J = 7.0, CH2CN), 3.11 (2H, t, J =
7.0, CH2S), 7.25-7.85 (4H, m, Ar-H), 13.00 (1H, br s, D2O exchangeable, OH). Anal. Calcd for
C11H11NO2S: C, 59.71; H, 5.01; N, 6.33. Found: C, 59.94; H, 4.80; N, 6.26.
2-(3-Cyanopropylthio)benzamide (9)
A solution of 8 (5.00 g, 22.6 mmol) in SOCl2 (26.9 g, 226 mmol) was refluxed for 9 h. After evaporation
of SOCl2, liq. NH3 (100 mL) was added to the residue under cooling and the mixture was allowed to
stand overnight. Saturated NaCl aq. solution was added into the mixture, and the precipitated solid was
collected and recrystallized from acetone to give 9 as pale brown powder (3.89 g, 78%), mp 112-114 °C.
FAB-MS m/z: 221 (MH+). IR (KBr) cm-1: 3450, 3370 (NH), 2225 (CN), 1660 (CO). 1H-NMR (60 MHz,
CDCl3) δ: 1.97 (2H, br quin, J = 7.0, CH2CH2CH2), 2.55 (2H, t, J = 7.0, CH2CN), 3.12 (2H, t, J = 3.4,
CH2S), 6.46 (2H, br s, D2O exchangeable, NH2), 7.23-7.76 (4H, m, Ar-H). Anal. Calcd for C11H12N2OS:
C, 59.98; H, 5.49; N, 12.72. Found: C, 59.88; H, 5.59; N, 12.63.
2-(3-Cyanopropylthio)benzonitrile (10)
A solution of 9 (7.91 g, 35.9 mmol) in POCl3 (55.1 g, 359 mmol) was refluxed for 10 h. After
evaporation of POCl3, ice-water (300 mL) was added to the residue and the mixture was neutralized with
NaHCO3. The resulting mixture was extracted with ethyl acetate and the organic layer was treated as
usual. The residue was recrystallized from ethanol to give 10 as pale brown prisms (4.39 g, 61%), mp
1
61-62 °C. FAB-MS m/z: 203 (MH+). IR (KBr) cm-1: 2245, 2230 (CN). H-NMR (60 MHz, CDCl3) δ:
1.99 (2H, quin, J = 7.0, CH2CH2CH2), 2.58 (2H, t, J = 7.0, CH2CN), 3.17 (2H, t, J = 7.0, CH2S), 7.24-
7.73 (4H, m, Ar-H). Anal. Calcd for C11H10N2S·1/10H2O: C, 64.74; H, 5.04; N, 13.73. Found: C, 64.88;
H, 5.15; N, 13.51.
5-Amino-1,2-dihydrothieno[2,3-c]isoquinoline (11)
To a solution of 10 (500 mg, 2.47 mmol) in dioxane (15 mL) was added t-BuOK (832 mg, 7.42 mmol)
and the resulting mixture was refluxed for 5 min. After evaporation of the solvent, ice water (30 mL) was

added to the residue and the mixture was extracted with ethyl acetate. The organic layer was treated as
usual to give an oily residue that was subjected to a column-chromatography on silica gel. The eluate
with n-hexane-ethyl acetate (4 : 1, v/v) afforded 11 which was recrystallized from ethyl acetate to give
pale yellow needles (205 mg, 42%), mp 121-122 °C. FAB-MS m/z: 203 (MH+). IR (KBr) cm-1: 3460,
1
3330 (NH). H-NMR (200 MHz, CDCl3) δ: 3.40 (4H, br s, 1,2-H), 5.20 (2H, br s, D2O exchangeable,
NH2), 7.28 (1H, td, Jt = 8.0, Jd = 1.0, 8-H), 7.46 (1H, d, J = 8.0, 6-H), 7.59 (1H, td, Jt = 8.0, Jd = 1.0, 7-
H), 7.73 (1H, d, J = 8.0, 9-H). Anal. Calcd for C11H10N2S: C, 65.32; H, 4.98; N, 13.85. Found: C, 65.36;
H, 4.76; N, 13.77.
2-(3-Cyanopropoxy)benzonitrile (13)
To a solution of o-cyanophenol (12, 25 g, 0.21 mol) in DMF (400 mL) was added 4-chlorobutyronitrile
(33 g, 0.33 mol) and K2CO3 (32 g, 0.23 mol) and the resulting mixture was refluxed for 4 h. Ice water (4
L) was added into the reaction mixture. The precipitated solid was collected and recrystallized from
ethanol to give 13 as colorless plates (37 g, 95%), mp 48-49 °C. FAB-MS m/z: 187 (MH+). IR (KBr)
cm-1: 2230, 2180 (CN). 1H-NMR (60 MHz, CDCl3) δ: 2.23 (2H, quin, J = 5.8, CH2CH2CH2), 2.70 (2H,
t, J = 5.8, CH2CN), 4.23 (2H, t, J = 5.8, CH2O), 6.91-7.68 (4H, m, Ar-H). Anal. Calcd for C11H10N2O: C,
70.95; H, 5.41; N, 15.04. Found: C, 70.89; H, 5.43; N, 14.88.
5-Amino-1,2-dihydrofuro[2,3-c]isoquinoline (14)
To a solution of 13 (3.7 g, 20 mmol) in DMF (100 mL) was added t-BuOK (4.5 g, 40 mmol) and the
resulting mixture was stirred at rt for 4 h. Ice water (1 L) was added into the reaction mixture and the
mixture was extracted with ethyl acetate. The organic layer was worked up as usual to give an oily
residue that was subjected to a column-chromatography on silica gel. The eluate with benzene-ethyl
acetate (4 : 1 - 0 : 1, v/v) afforded 14 which was recrystallized from ethyl acetate to give pale brown
prisms (0.52 g, 14%), mp 192-194 °C. FAB-MS m/z: 187 (MH+). IR (KBr) cm-1: 3490, 3330 (NH). 1H-
NMR (200 MHz, CDCl3) δ: 3.33 (2H, t, J = 8.7, 1-H), 4.70 (2H, t, J = 8.7, 2-H), 5.24 (2H, br s, D2O
exchangeable, NH2), 7.21 (1H, td, Jt = 8.2, Jd = 1.4, 7-H), 7.41 (1H, d, J = 8.2, 6-H), 7.54 (1H, td, Jt =
8.2, Jd = 1.4, 8-H), 7.71 (1H, d, J = 8.2, 9-H). Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.04.
Found: C, 71.12; H, 5.49; N, 15.17.
This analytical sample was dried around 100 °C under vaccum.
Crystal structure analysis of 14. Crystal data: C11H10N2O; Mr = 372.43; orthorhombic, space group
P212121, a = 13.479(2), b = 14.321(4), c = 9.118(2) Å, V = 1760(1) Å3; Z = 8; Dc = 1.405 g cm-3. The

crystals were grown from an ethyl acetate solution by slow evaporation. A crystal of size 0.600 x 0.600 x
0.600 mm was examined by using graphite-monochromated Mo Kα radiation (λ= 0.71073 Å). Cell
dimensions were obtained from 25 reflections (21 < 2θ< 23°). In total 2582 reflections were measured
by the ω-2θ scan method, and 2309 of these were unique (Rint= 0.010). Refinements were carried out
including all the hydrogen atoms by using 1790 reflections with I > 3σ(I) within 2θmax of 55°. R = 0.035,
Rw = 0.034, S = 1.38. Asymmetric unit is composed of two molecules with similar conformations.
3-Chloro[1]benzothiophene-2-carbonyl Chloride (16)
Title compound was obtained by the method of Wright et al.11 from trans-cinnamic acid (15), yield 85%,
mp 109-112 °C (from n-hexane, lit.,11 mp 114-116 °C, lit.,15 mp 113.5-115 °C).
3-Chloro[1]benzothiophene-2-carboxamide (17)
To compound (16) (1.01 g, 4.37 mmol) was added liq. NH3 (30 mL) under cooling and the mixture was
allowed to stand for 1 d. Thus obtained solid was recrystallized from ethyl acetate to give 17 as pale
brownish powder (757 mg, 82%), mp 227-228 °C. FAB-MS m/z: 214 ([M+2]H+), 212 (MH+). IR (KBr)
1
cm-1: 3450, 3120 (NH), 1650 (CO). H-NMR (60 MHz, DMSO-d6) δ: 7.52-7.74 (2H, m, 5- and 6-H),
7.87-8.11 (4H, changed to 2H after D2O addition, m, 4- and 7-H and NH2). Anal. Calcd for C9H6NOClS:
C, 51.07; H, 2.86; N, 6.62. Found: C, 50.71; H, 3.00; N, 6.38.
3-Chloro[1]benzothiophene-2-carbonitrile (18)
A solution of 17 (2.12 g, 10.0 mmol) in POCl3 (15.3 g, 100 mmol) was refluxed for 3 h. After
evaporation of POCl3, the residue was recrystallized from n-hexane to give 18 as colorless needles (1.77
1
g, 92%), mp 120-121 °C. FAB-MS m/z: 194 (MH+). IR (KBr) cm-1: 2210 (CN). H-NMR (60 MHz,
DMSO-d6) δ: 7.50-7.66 (2H, m, 5- and 6-H), 7.70-8.02 (2H, m, 4- and 7-H). Anal. Calcd for C9H4NClS·
1/10H2O: C, 55.30; H, 2.17; N, 7.17. Found: C, 55.39; H, 2.34; N, 6.97.
3-Mercapt[1]benzothiophene-2-carbonitrile (19)
To a solution of 18 (5.06 g, 26.2 mmol) and thioacetamide (6.21 g, 82.8 mmol) in DMF (70 mL) was
added DBU (11.8 g, 77.6 mmol) and the mixture was heated at 80 °C for 3 h under N2 atmosphere. After
evaporation of the solvent, the residue was triturated with ethyl acetate. The organic layer was washed
with successive 1N HCl aq. solution and sat. NaCl aq. solution, and then extracted with 1N NaOH aq.
solution. The alkaline aq. layer was acidified with 2N HCl aq. solution. The precipitated solid was
collected to give 19 which was used for the next step without further purification.
3-(3-Cyanopropylthio)[1]benzothiophene-2-carbonitrile (20)

A mixture of 19, K2CO3 (10.8 g, 78.3 mmol) and 4-chlorobutyronitrile (4.01 g, 38.7 mmol) in DMF (70
mL) was heated at 60 °C for 6 h. After filtration of the mixture, the filtrate was evaporated and ice water
(200 mL) was added onto the residue. The resulting mixture was extracted with ethyl acetate. The
organic layer was treated as usual and an oily residue was subjected to a column-chromatography on
silica gel. The eluate with n-hexane-ethyl acetate (9 : 1, v/v) afforded 20 which was recrystallized from
cyclohexane to give pale yellow needles (4.27 g, 64% as overall yield from 18), mp 67-68 °C. FAB-MS
1
m/z: 259 (MH+). IR (KBr) cm-1: 2260, 2220 (CN). H-NMR (200 MHz, CDCl3) δ: 1.95 (2H, quin, J =
7.0, CH2CH2CH2), 2.61 (2H, t, J = 7.0, CH2CN), 3.18 (2H, t, J = 7.0, SCH2), 7.54-7.65 (2H, m, 5- and 6-
H), 7.89 (1H, m, 4-H), 8.05 (1H, m, 7-H). Anal. Calcd for C13H10N2S2·1/10H2O: C, 60.02; H, 3.95; N,
10.77. Found: C, 59.97; H, 3.88; N, 10.72.
5-Amino-1,2-dihydro[1]benzothieno[3,2-d]thieno[2,3-b]pyridine (21)
To a hot solution of 20 (1.00 g, 3.88 mmol) in benzene (200 mL) was added t-BuONa (1.86 g, 19.4
mmol) and the resulting mixture was refluxed for 1 h. After evaporation of the solvent, ice water (30
mL) was added onto the residue and the mixture was extracted with ethyl acetate. The organic layer was
treated as usual to give an oily residue which was subjected to a column-chromatography on silica gel.
The eluate with n-hexane-ethyl acetate (9 : 1, v/v) afforded 21 which was recrystallized from benzene to
give pale yellow needles (80 mg, 8%), mp 207-208 °C. FAB-MS m/z: 259 (MH+). IR (KBr) cm-1: 3450,
1
3280 (NH). H-NMR (200 MHz, CDCl3) δ: 3.59 (2H, t, J = 7.8, 2-H), 3.79 (2H, t, J = 7.8, 1-H), 4.61
(2H, br s, D2O exchangeable, NH2), 7.42-7.62 (2H, m, 8- and 9-H), 7.87 (1H, dd, J = 8.9 and 1.5, 10-H),
8.12 (1H, dd, J = 8.5 and 1.8, 7-H). Anal. Calcd for C13H10N2S2: C, 60.44; H, 3.90; N, 10.84. Found: C,
60.48; H, 4.01; N, 10.74.
Ethyl 2-Cyanomethylthiobenzoate (23)
A mixture of ethyl thiosalicylate (22) (10.2 g, 56.0 mmol), K2CO3 (15.0 g, 109 mmol), KI (503 mg, 3.03
mmol) and chloroacetonitrile (5.10 g, 67.5 mmol) in acetone (200 mL) was stirred at rt for 3 h under
nitrogen atmosphere. After filtration of the mixture, the filtrate was evaporated and ice water (200 mL)
was added onto the residue. The resulting mixture was extracted with benzene. The organic layer was
treated as usual and the residue was recrystallized from cyclohexane to give 23 as colorless needles (10.8
g, 87%), mp 79-81 °C. FAB-MS m/z: 222 (MH+). IR (KBr) cm-1: 2250 (CN), 1680 (CO). 1H-NMR (60
MHz, CDCl3) δ: 1.41 (3H, t, J = 7.0, Me), 3.72 (2H, s, SCH2), 4.40 (2H, q, J = 7.0, OCH2), 7.25-7.68

(3H, m, 3-, 4- and 5-H), 7.91-8.20 (1H, m, 6-H). Anal. Calcd for C11H11NO2S: C, 59.71; H, 5.01; N,
6.33. Found: C, 59.96; H, 5.09; N, 6.27.
3-Hydroxy[1]benzothiophene-2-carbonitrile (24)
A mixture of 23 (9.97 g, 45.1mmol) and NaH (60% oil dispersion, 2.20 g, 55.0 mmol) in ethanol (200
mL) was stirred at rt for 1 h. After filtration of the mixture, the filtrate was evaporated and ice water (200
mL) was added onto the residue. The resulting mixture was extracted with ethyl acetate. The organic
layer was treated as usual a the residue was recrystallized from acetonitrile to give 24 as pale yellow
needles (6.72 g, 85%), mp 160-162 °C. FAB-MS m/z: 176 (MH+). IR (KBr) cm-1: 3170 (OH), 2220
(CN). 1H-NMR (60 MHz, DMSO-d6) δ: 7.42-7.80 (2H, m, 5- and 6-H), 7.80-8.19 (2H, m, 4- and 7-H),
12.25 (1H, br s, D2O exchangeable, OH). Anal. Calcd for C9H5NOS: C, 61.70; H, 2.88; N, 7.99. Found:
C, 61.85; H, 3.11; N, 8.10.
3-(3-Cyanopropoxy)[1]benzothiophene-2-carbonitrile (25)
A mixture of 24 (10.0 g, 57.1 mmol), K2CO3 (15.8 g, 114 mmol), KI (497 mg, 2.99 mmol) and 4-
chlorobutyronitrile (7.08 g, 68.4 mmol) in acetone (200 mL) was refluxed for 24 h. After filtration of the
mixture, the filtrate was evaporated and ice water (200 mL) was added onto the residue. The resulting
mixture was extracted with benzene. The organic layer was treated as usual and the residue was
recrystallized from benzene to give 25 to give colorless needles (10.4 g, 75%), mp 112-114 °C. FAB-MS
1
m/z: 243 (MH+). IR (KBr) cm-1: 2260, 2220 (CN). H-NMR (60 MHz, CDCl3) δ: 2.12-2.86 (4H, m,
CH2CH2CN), 4.80 (2H, t, J = 5.0, OCH2), 7.36-7.98 (4H, m, Ar-H). Anal. Calcd for C13H10N2OS: C,
64.44; H, 4.16; N, 11.56. Found: C, 64.36; H, 4.26; N, 11.58.
5-Amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine (26)
To a solution of 25 (9.95 g, 41.1 mmol) in dioxane (200 mL) were added NaH (60% oil dispersion, 2.05
g, 51.3 mmol) and 3 drops of t-BuOH, and the resulting mixture was refluxed for 5 h. After filtration of
the reaction mixture, the filtrate was evaporated and ice water (200 mL) was added to the residue. The
resulting mixture was extracted with ethyl acetate. The organic layer was treated as usual to give an oily
residue that was subjected to a column-chromatography on silica gel. The eluate with benzene-ethyl
acetate (4 : 1, v/v) afforded 26 which was recrystallized from acetonitrile as pale brown prisms (2.53 g,
26%), mp 269-271 °C. FAB-MS m/z: 243 (MH+). IR (KBr) cm-1: 3450, 3280, 3170 (NH). 1H-NMR (60
MHz, DMSO-d6) δ: 3.54 (2H, t, J = 8.0, 1-H), 4.67 (2H, t, J = 8.0, 2-H), 6.35 (2H, br s, D2O

exchangeable, NH2), 7.37-7.74 (2H, m, 8- and 9-H), 7.90-8.18 (2H, m, 7- and 10-H). Anal. Calcd for
C13H10N2OS: C, 64.44; H, 4.16; N, 11.56. Found: C, 64.64; H, 4.29; N, 11.56.
ACKNOWLEDGEMENTS
A part of this work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (A) (No.
11147217) from the Ministry of Education, Science, Sports and Culture of Japan. We are grateful to The
SC-NMR Laboratory of Okayama University for 200 MHz 1H-NMR experiments.
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