Synthesis of thiophene analogues of the tacrine series

Article abstract of DOI:10.1055/s-2007-965944

3-Amino-2-cyanothiophenes condensed with cyclanones and afforded analogues of Velnacrine in two or three steps. Condensation under Friedlander's conditions gave tacrine analogues in one step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965944

PAPER
1027
Synthesis of Thiophene Analogues of the Tacrine Series
S
ynthesis of
T
hiop
a
hene
A
nalo
v
gues of the
T
i
acrine
d
Series Thomae,a Gilbert Kirsch,*a Pierre Seckb
a
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, Université Paul Verlaine-
Metz, 1 Boulevard Arago, 57070 Metz, France
Fax +33(3)87325801; E-mail: kirsch@univ-metz.fr
Laboratoire de Chimie, Faculté des Sciences, de la Technologie et de la Communication Université du Luxembourg, 162a avenue de la
Faïencerie, 1511 Luxembourg, Luxembourg
b
Received 29 November 2006; revised 11 January 2007
O
Abstract: 3-Amino-2-cyanothiophenes condensed with cyclanones
and afforded analogues of Velnacrine in two or three steps. Conden-
sation under Friedländer’s conditions gave tacrine analogues in one
step.
CN
S
Ar
N
H
R1
Method A
i
ii
Method A
S
Key words: Alzheimer’s disease, tacrine analogues, Friedländer
reaction, condensation, aminothiophene carbonitrile
2a,b
NH2
N
O
CN
iv
Method B
S
Ar
Ar
Alzheimer’s disease is a form of dementia of older people
that looks set to be a major problem in the coming de-
cade.1 One possible treatment is to inhibit acetylcholin-
esterase, which plays a role in the formation of the b-
amyloid plaque. The first acetylcholinesterase inhibitor
used in this context was tacrine (I), sold under the name
COGNEX® (Figure 1). The hydroxy derivative of tacrine
is velnacrine (II). In order to investigate the biological ef-
fects of structural modifications of tacrine, we wanted to
synthesize a series of thiophene analogues, since it is
widely recognized that thiophene is a bioisostere of ben-
zene. As few analogues (III, IV) based on the thieno[2,3-
b]quinoline moiety and 9-amino-5,6,7,8-tetrahydro-
thieno[3,2-b]quinoline have been described,2 we chose to
NH2
R1
R1
3a,b
1a–d
v
iii
Method B
NH2
NH2 OH
S
S
Ar
Ar
n
N
N
4a,b
R1
R1
5a–d n = 0
6a–d n = 1
7a–d n = 2
Scheme 1 Reagents and conditions: i) cyclohexan-1,3-dione,
PTSA, toluene, reflux; ii) CuCl, base, DMF, reflux; iii) LiAlH4, THF,
reflux; iv) AlCl3, cyclohexan-1,3-dione, DCE, reflux; v) AlCl3, cyclic
ketone, DCE, reflux.
NH2
R2
NH2
N
R
prepare the hitherto unknown substituted thieno[3,2-
b]quinoline series 4–7. The proposed synthesis is shown
in Scheme 1.
R1
S
N
R1 = H or C1 to C4 alkyl group
R2 = H
I (tacrine; R = H)
II (velnacrine; R = OH)
The synthesis started from 3-amino-2-cyano-5-arylthio-
phenes (1), which were prepared from the corresponding
b-chloroacrylonitrile by a previously described method
(Scheme 2).4–10 The yields obtained in the preparation of
a range of thiophenes 1 are shown in Table 1.
III
R
1 = Ph
R2 = Ph
NH2
N
R
NH2
S
S
The first approach to the tacrine derivatives 3 was made
by applying a method developed by Tabarini et al.
(Scheme 1; Method A).11 In the first step, thiophenes 1
were condensed with cyclohexan-1,3-dione, in refluxing
Ar
n
R1
N
4–7
IV
n = 0, 1, 2 R = H
n = 1
R = OH R1 =H
R1 = H or Me
Ar
S
Ar
R1
O
Ar
R1
Cl
CN
Figure 1 Strucure of tacrine (I), velnacrine (II), thiophene analogues
(III and IV) and the target thiophene analogues 4–7.
R1
iv
i, ii, iii
CN
NH2
1
SYNTHESIS 2007, No. 7, pp 1027–1032
Advanced online publication: 20.02.2007
DOI: 10.1055/s-2007-965944; Art ID: Z24706SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7
Scheme 2 Reagents and conditions: i) POCl3, DMF, 60 °C, 5 h; ii)
hydroxylamine chloride, EtOH; iii) Ac2O; iv) Na2S·9H2O, DMF,
ClCH2CN, NaOEt.

1028
D. Thomae et al.
PAPER
Table 1 Formation of Thiophenes 1
Entry
b-Choroacrylonitrile
Thiophene 1
Yield (%)a
S
Cl
a
93
CN
CN
NH2
O
O
S
b
c
95
95
95
Cl
CN
CN
NH2
Cl
Cl
S
Cl
CN
CN
NH2
O
O
S
d
Cl
CN
CN
NH2
a Crude product, analytically pure and used without further purification.
yses were determined with a LECO CHNS 932 elemental analyzer.
HRMS were determined on a Micromass Autospec 3F instrument.
toluene in the presence of p-toluenesulfonic acid, to give
the corresponding enamines 2 in various yields. Enamines
2 were cyclized in the presence of cuprous chloride and ei-
ther sodium methanolate or potassium carbonate, in re-
fluxing DMF, to give the ketones 3 (Table 2). The latter
were easily reduced by lithium aluminum hydride to the
thiophene analogues of velnacrine 4.
In a second approach, using Friedländer’s conditions,11 it
was found that ketone 3 could be obtained directly from 1
(Scheme 1; Method B), with better yields than the two-
step procedure. These conditions also allowed us to con-
duct the direct condensation of cyclanones as well as 1,3-
diones. In this way, the rapid preparation of tacrine ana-
logues 5a–d was possible and, furthermore, the introduc-
tion of a range of ring sizes could also be achieved
(Table 3).
Synthesis of 3-Amino-5-arylthiophenecarbonitriles 1a–d;
General Procedure
A suspension of Na2S·9H2O (0.06 mol, 1 equiv) in DMF (80 mL)
was heated at 40 °C for 30 min. b-Chloroacrylonitrile (0.06 mol, 1
equiv) dissolved in DMF (20 mL) was added and the solution was
heated at 50 °C for 50 min. Chloroacetonitrile (0.06 mol, 1 equiv)
in DMF (1 mL) was added and the solution was stirred at 50 °C for
90 min. A solution of NaOEt (0.06 mol, 1 equiv) in absolute EtOH
(40 mL) was added and the solution was stirred at 50 °C for 30 min
(the reaction was monitored by TLC). The reaction mixture was
then cooled to r.t. and poured into ice-water (150 mL). The precip-
itate was filtered and washed with cold H2O to give the product
which was used directly in the next step. A sample was taken and
purified either by recrystallization (isopropanol) or by column chro-
matography for analysis.
3-Amino-5-(4-methylphenyl)-2-thiophenecarbonitrile (1a)
Purified by column chromatography (CH2Cl2).
In conclusion, 3-amino-5-aryl-2-thiophenecarbonitriles
have been synthesized in four steps. The Friedländer reac-
tion allowed very rapid access to the target molecules with
good yields. Biological evaluation of the synthesized
compounds, using Ellman’s tests on acetylcholinesterase
inhibition,13 are underway.
Yield: 93%; yellow solid; mp 195–197 °C.
1H NMR (250 MHz, CDCl3): d = 2.40 (s, 3 H, CH3), 4.91 (s, 2 H,
NH2), 6.75 (s, 1 H, CH), 7.18 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.42 (d,
J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 21.32, 74.79, 115.70, 116.37,
125.97, 129.88, 130.22, 139.71, 148.89, 158.44.
Melting points were determined on a Stuart SMP3 apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded on a Bruker
Anal. Calcd for C12H10N2S: C, 67.26; H, 4.70; N, 11.07. Found: C,
67.35; H, 4.67; N, 10.99.
AC 250 MHz spectrometer in CDCl3 or DMSO-d6. Elemental anal-
Synthesis 2007, No. 7, 1027–1032 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiophene Analogues of the Tacrine Series
1029
Table 2 Yields of Formation of 2 and 3 from Thiophenes 1
Entry Enamine 2
Yield
Entry
Ketone 3
Yield (%) Overall
(%)
yield (%)
from 1
Method A
O
NH2
N
O
CN
S
a
11c
a
S
81a
38b
9
N
H
O
NH2
O
CN
S
S
b
71
b
27
O
O
N
N
H
Method B
NH2
O
a
S
80
85
80
85
N
NH2
O
S
b
O
N
a CuCl, NaOMe, DMF, reflux.
b CuCl, K2CO3, DMF, reflux.
Table 3 Yields of the Friedländer Reaction
Thiophene
Cyclanones
Tacrine analogue
Product
Yield (%)
NH2
N
n = 0; 5a
n = 1; 6a
n = 2; 7a
87
88
80
S
S
CN
n
O
n
NH2
O
NH2
n = 0; 5b
n = 1; 6b
n = 2; 7b
98
97
97
S
S
CN
O
n
O
O
O
n
N
NH2
Cl
NH2
n = 0; 5c
n = 1; 6c
n = 2; 7c
88
89
85
S
S
CN
Cl
n
n
n
N
NH2
O
NH2
n = 0; 5d
n = 1; 6d
n = 2; 7d
76
89
98
S
S
O
CN
n
N
NH2
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D. Thomae et al.
PAPER
3-Amino-5-(4-methoxyphenyl)-2-thiophenecarbonitrile (1b)
Yield: 95%; brown solid; mp 204–206 °C (isopropanol).
1H NMR (250 MHz, DMSO-d6): d = 3.78 (s, 3 H, CH3), 6.49 (s, 2 H,
NH2), 6.80 (s, 1 H, CH), 6.98 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.52 (d,
J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 21.97, 28.23, 36.91, 55.93,
94.25, 102.17, 114.01, 115.30, 119.86, 124.69, 128.06, 148.37
150.08, 161.12, 161.84, 196.75.
Anal. Calcd for C18H16N2O2S: C, 66.65; H, 4.97; N, 8.64. Found: C,
67.01; H, 5.14; N, 8.37.
13C NMR (63 MHz, DMSO-d6): d = 55.85, 74.24, 115.04, 115.18,
Preparation of 9-Amino-2-(4-aryl)-6,7-dihydrothieno[3,2-
b]quinolin-8(5H)-ones 3a,b; General Procedure (Method A)
NaOMe or K2CO3 (2.2 mmol) and CuCl (10.4 mmol) were added to
a solution of 2 (10.4 mmol) in anhyd DMF (5 mL) and the mixture
was heated at 80–90 °C for 4 h. After cooling, the reaction mixture
was poured into ice-water containing sodium tartrate (15 mmol).
The precipitate obtained was filtered and extracted several times
with a mixture MeOH–EtOAc (1:1). The organic solution was dried
(Na2SO4), filtered and the solvent was evaporated to give a solid
which was purified by column chromatography (CH2Cl2–MeOH,
9:1).
116.43, 125.27, 127.61, 148.75, 158.50, 160.71.
Anal. Calcd for C12H10N2OS: C, 62.59; H, 4.38; N, 12.16. Found:
C, 62.32; H, 4.56; N, 12.47.
3-Amino-5-(4-chlorophenyl)-2-thiophenecarbonitrile (1c)
Yield: 95%; brown solid; mp 184–186 °C (isopropanol).
1H NMR (250 MHz, DMSO-d6): d = 6.58 (s, 2 H, NH2), 6.94 (s,
1 H, CH), 7.48 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.61 (d, J = 7.5 Hz,
2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 75.50, 116.04, 116.76, 127.82,
129.75, 131.42, 134.37, 147.06, 158.36.
Friedländer Reaction; General Procedure (Method B)
Anal. Calcd for C11H7ClN2S: C, 56.29; H, 3.01; N, 11.94. Found: C,
56.42; H, 3.15; N, 11.74.
AlCl3 (3.4 mmol for cyclanones, 6.8 mmol for 1,3-cyclohexanedi-
one) was suspended in anhyd DCE (10 mL/mmol of AlCl3) at r.t.
under argon. The corresponding thiophene 1 (2 mmol) and the ke-
tone (1.7 mmol) were added and the reaction mixture was heated
under reflux for 12 h. When the reaction was complete (monitored
by TLC), a mixture of THF–H2O (2:1) was added at r.t. and NaOH
(10%) was added dropwise until the solution became basic. After
stirring for 30 min, the mixture was extracted with CH2Cl2 (3 × 30
mL) and the combined organic layers were dried (Na2SO4), filtered
and the solvent was evaporated to give a solid which was purified
by column chromatography (CH2Cl2–MeOH, 9:1).
3-Amino-5-(4-methoxyphenyl)-2-thiophenecarbonitrile (1d)
Purified by column chromatography (CH2Cl2).
Yield: 70%; yellow solid; mp 186–188 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.73 (s, 3 H, CH3), 3.01 (s, 3 H,
CH3O), 5.16 (s, 2 H, NH2), 6.18 (d, J = 7.5 Hz, 2 H, 2 × CH), 6.56
(d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 12.38, 55.71, 114.66, 116.81,
123.54, 123.80, 125.42, 130.54, 143.19, 157.18, 160.14.
9-Amino-2-(4-methylphenyl)-6,7-dihydrothieno[3,2-b]quino-
lin-8(5H)-one (3a)
Column chromatography gave a brown solid; mp 220–222 °C.
Anal. Calcd for C13H12N2OS: C, 63.91; H, 4.95; N, 11.47. Found:
C, 63.69; H, 4.56; N, 11.12.
Yield: 81% (Method A; NaOMe used as base).
Preparation of 5-Aryl-3-[(3-oxo-1-cyclohexen-1-yl)amino]-2-
thiophenecarbonitriles 2a,b; General Procedure (Method A)
A suspension of 1 (0.02 mol), cyclohexan-1,3-dione (0.02 mol) and
PTSA·H2O (0.67 mmol) in anhyd toluene (20 mL), was refluxed for
4 h in a Dean–Stark apparatus. The reaction mixture was then
chilled to 0 °C and the product was filtered off, washed with cold
toluene followed by cold cyclohexane, dried and recrystallized
(EtOH–Et2O, 1:1).
Yield: 80% (Method B).
1H NMR (250 MHz, DMSO-d6): d = 2.00 (m, 2 H, CH2), 2.34 (s,
3 H, CH3), 2.50 (m, 2 H, CH2), 2.60 (m, 2 H, CH2), 2.94 (s, 2 H,
NH2), 7.31 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.64 (s, 1 H, CH), 7.69 (d,
J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 21.38, 21.94, 22.33, 34.30,
115.46, 121.60, 126.42, 130.41, 130.76, 132.95, 139.72, 149.48,
151.72, 158.41, 164.55, 201.92.
5-(4-Methylphenyl)-3-[(3-oxo-1-cyclohexen-1-yl)amino]-2-
thiophenecarbonitrile (2a)
Yield: 11%; orange solid; mp 232–234 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.91 (m, 2 H, CH2), 2.19 (m,
2 H, CH2), 2.33 (s, 3 H, CH3), 2.54 (m, 2 H, CH2), 5.25 (s, 1 H,
CHCO), 7.33 (d, J = 7.5 Hz, 2 H, CH), 7.56 (s, 1 H, CH), 7.61 (d,
J = 7.5 Hz, 2 H, CH), 9.42 (s, 1 H, NH).
Anal. Calcd for C18H16N2OS: C, 70.10; H, 5.23; N, 9.08. Found: C,
70.26; H, 5.12; N, 8.77.
9-Amino-2-(4-methoxyphenyl)-6,7-dihydrothieno[3,2-b]quino-
lin-8(5H)-one (3b)
Column chromatography gave a brown solid; mp 228–230 °C.
13C NMR (63 MHz, DMSO-d6): d = 21.38, 21.97, 28.23, 36.93,
94.85, 102.23, 113.93, 120.58, 126.39, 129.36, 130.47, 140.36,
148.36, 150.12, 161.77, 196.68.
Yield: 38% (Method A; K2CO3 used as base).
Yield: 85% (Method B).
1H NMR (250 MHz, CDCl3): d = 1.80 (s, 2 H, NH2), 2.18 (m, 2 H,
CH2), 2.70 (m, 2 H, CH2), 3.14 (m, 2 H, CH2), 3.87 (s, 3 H, CH3),
6.98 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.58 (s, 1 H, CH), 7.64 (d, J = 7.5
Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 21.38, 21.99, 34.07, 55.90,
106.63, 115.27, 116.86, 120.47, 126.08, 127.99, 149.23, 151.43,
158.41, 160.78, 164.23, 201.52.
Anal. Calcd for C18H16N2OS: C, 70.10; H, 5.23; N, 9.08. Found: C,
69.89; H, 5.23; N, 9.21.
5-(4-Methoxyphenyl)-3-[(3-oxo-1-cyclohexen-1-yl)amino]-2-
thiophenecarbonitrile (2b)
Yield: 71%; yellow solid; mp 224–226 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.90 (m, 2 H, CH2), 2.19 (m,
2 H, CH2), 2.53 (m, 2 H, CH2), 3.79 (s, 3 H, CH3), 5.25 (s, 1 H,
CHCO), 7.01 (d, J = 7.5 Hz, 2 H, CH), 7.49 (s, 1 H, CH), 7.61 (d,
J = 7.5 Hz, 2 H, CH), 9.41 (s, 1 H, NH).
HRMS: m/z calcd for C18H16N2O2S: 324.0932; found: 324.0930.
8-Amino-2-(4-methylphenyl)-6,7-dihydro-5H-cyclopen-
ta[b]thieno[2,3-e]pyridine (5a)
Yield: 87% (Method B); mp 180–182 °C.
Synthesis 2007, No. 7, 1027–1032 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiophene Analogues of the Tacrine Series
1031
1H NMR (250 MHz, DMSO-d6): d = 2.04 (m, 2 H, CH2), 2.33 (s,
3 H, CH3), 2.77 (m, 2 H, CH2), 2.85 (m, 2 H, CH2), 6.26 (s, 2 H,
NH2), 7.27 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.60 (s, 1 H, CH), 7.64 (d,
J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 21.32, 23.06, 27.93, 34.37,
114.67, 116.36, 120.65, 126.04, 130.26, 131.54, 138.65, 144.22,
145.37, 157.08, 164.43.
10-Amino-2-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-cyclo-
hepta[b]thieno[2,3-e]pyridine (7b)
Yield: 97% (Method B); mp 190–192 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.73 (m, 2 H, CH2), 1.75 (m,
2 H, CH2), 2.48 (m, 2 H, CH2), 2.74 (m, 2 H, CH2), 3.08 (m, 2 H,
CH2), 3.85 (s, 3 H, CH3), 4.14 (s, 2 H, NH2), 6.96 (d, J = 9.0 Hz,
2 H, 2 × CH), 7.49 (s, 1 H, CH), 7.64 (d, J = 9.0 Hz, 2 H, 2 × CH).
Anal. Calcd for C17H16N2S: C, 72.82; H, 5.75; N, 9.99. Found: C,
72.57; H, 5.59; N, 9.98.
13C NMR (63 MHz, DMSO-d6): d = 25.40, 27.09, 28.01, 32.31,
32.55, 55.82, 115.12, 115.31, 117.20, 120.28, 126.94, 127.54,
144.053, 146.04, 154.81, 162.39.
9-Amino-2-(4-methylphenyl)-5,6,7,8-tetrahydrothieno[3,2-
b]quinoline (6a)
HRMS: m/z calcd for C19H20N2OS: 324.1296; found: 324.1308.
Yield: 88% (Method B); mp 186–188 °C.
8-Amino-2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopen-
ta[b]thieno[2,3-e]pyridine (5c)
Yield: 88% (Method B); mp 189–191 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.78 (m, 2 H, CH2), 1.80 (m,
2 H, CH2), 2.33 (s, 3 H, CH3), 2.55 (m, 2 H, CH2), 2.77 (m, 2 H,
CH2), 6.20 (s, 2 H, NH2), 7.27 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.57 (s,
1 H, CH), 7.64 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 21.29, 22.91, 23.05, 23.75,
32.94, 110.17, 111.88, 120.13, 126.15, 130.28, 131.41, 138.85,
144.85, 147.44, 154.46, 154.80.
1H NMR (250 MHz, DMSO-d6): d = 2.06 (m, 2 H, CH2), 2.79 (t,
2 H, CH2), 2.86 (m, 2 H, CH2,), 6.27 (s, 2 H, NH2), 7.52 (d, J = 7.5
Hz, 2 H, 2 × CH), 7.71 (s, 1 H, CH), 7.79 (d, J = 7.5 Hz, 2 H,
2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 27.94, 31.20, 34.42, 114.93,
116.88, 122.16, 127.79, 129.71, 133.24, 133.48, 142.45, 145.31,
157.11, 164.87.
Anal. Calcd for C18H18N2S: C, 73.43; H, 6.16; N, 9.51. Found: C,
73.41; H, 5.84; N, 9.66.
HRMS: m/z calcd for C16H13ClN2S: 300.0487; found: 300.0497.
10-Amino-2-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]thieno[2,3-e]pyridine (7a)
Yield: 80% (Method B); mp 188–190 °C.
9-Amino-2-(4-chlorophenyl)-5,6,7,8-tetrahydrothieno[3,2-
b]quinoline (6c)
Yield: 89% (Method B); mp 190–192 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.53 (m, 2 H, CH2), 1.58 (m,
2 H, CH2), 1.78 (m, 2 H, CH2), 2.33 (s, 3 H, CH3), 2.75 (t, 2 H,
CH2), 2.92 (m, 2 H, CH2), 6.12 (s, 2 H, NH2), 7.27 (d, J = 7.5 Hz,
2 H, 2 × CH), 7.58 (s, 1 H, CH), 7.64 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 21.25, 25.30, 26.93, 27.84,
32.17, 32.30, 115.41, 117.40, 120.56, 126.04, 130.21, 131.39,
138.68, 144.45, 146.30, 154.07, 162.10
1H NMR (250 MHz, DMSO-d6): d = 1.77 (m, 4 H, CH2), 2.50 (m,
2 H, CH2), 2.78 (m, 2 H, CH2), 6.15 (s, 2 H, NH2), 7.54 (d, J = 7.5
Hz, 2 H, 2 × CH), 7.69 (s, 1 H, CH), 7.79 (d, J = 7.5 Hz, 2 H,
2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 22.86, 23.05, 23.75, 33.19,
110.34, 116.26, 121.88, 127.78, 129.64, 133.08, 133.50, 142.73,
147.12, 154.81, 155.39.
Anal. Calcd for C19H20N2S: C, 73.99; H, 6.54; N, 9.08. Found: C,
73.48; H, 6.84; N, 9.27.
HRMS: m/z calcd for C17H15ClN2S: 314.0644; found: 314.0651.
8-Amino-2-(4-methoxyphenyl)-6,7-dihydro-5H-cyclopen-
ta[b]thieno[2,3-e]pyridine (5b)
Yield: 98% (Method B); mp 180–182 °C.
10-Amino-2-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[b]thieno[2,3-e]pyridine (7c)
Yield: 85% (Method B); mp 191–193 °C.
1H NMR (250 MHz, DMSO-d6): d = 2.21 (m, 2 H, CH2), 2.85 (m,
2 H, CH2), 3.07 (m, 2 H, CH2), 3.85 (s, 3 H, CH3), 6.28 (s, 2 H,
NH2), 6.96 (d, J = 8.8 Hz, 2 H, 2 × CH), 7.50 (s, 1 H, CH), 7.64 (d,
J = 8.8 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 23.05, 27.93, 34.35, 55.77,
114.58, 115.09, 116.12, 119.80, 126.87, 127.52, 144.21, 145.40,
157.14, 160.12, 164.25.
1H NMR (250 MHz, DMSO-d6): d = 1.58 (m, 2 H, CH2), 1.60 (m,
2 H, CH2), 1.81 (m, 2 H, CH2), 2.78 (m, 2 H, CH2), 2.94 (m, 2 H,
CH2), 6.14 (s, 2 H, NH2), 7.54 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.71 (s,
1 H, CH), 7.79 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 25.36, 26.99, 27.90, 32.21,
32.84, 115.64, 117.92, 122.39, 127.44, 127.76, 129.64, 133.19,
142.43, 146.05, 154.48, 162.70.
HRMS: m/z calcd for C17H16N2OS: 296.0983; found: 296.0982.
HRMS: m/z calcd for C18H17ClN2S: 328.0800; found: 328.0797.
9-Amino-2-(4-methoxyphenyl)-5,6,7,8-tetrahydrothieno[3,2-
b]quinoline (6b)
Yield: 97% (Method B); mp 186–188 °C.
8-Amino-2-(4-methoxyphenyl)-3-methyl-6,7-dihydro-5H-cyclo-
penta[b]thieno[2,3-e]pyridine (5d)
Yield: 76% (Method B); mp 207–209 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.79 (m, 2 H, CH2), 1.80 (m,
2 H, CH2), 2.25 (m, 2 H, CH2), 2.78 (m, 2 H, CH2), 3.82 (s, 3 H,
CH3), 6.16 (s, 2 H, NH2), 7.06 (d, J = 8.8 Hz, 2 H, 2 × CH), 7.50 (s,
1 H, CH), 7.71 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 22.95, 23.15, 23.73, 33.30,
55.74, 109.94, 115.04, 115.53, 119.90, 126.84, 127.49, 144.11,
146.88, 155.13, 155.36, 160.07.
1H NMR (250 MHz, DMSO-d6): d = 2.38 (s, 3 H, CH3), 2.71 (m,
2 H, CH2), 2.80 (m, 2 H, CH2), 2.88 (m, 2 H, CH2), 3.80 (s, 3 H,
CH3O), 6.21 (s, 1 H, NH2), 7.09 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.52
(d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 12.96, 23.05, 27.82, 34.30,
55.70, 114.85, 114.96, 115.73, 127.24, 127.95, 130.45, 130.55,
138.13, 145.41, 159.52, 163.48
HRMS: m/z calcd for C18H18N2OS: 310.1140; found: 310.1160.
HRMS: m/z calcd for C18H16N2OS: 310.1139; found: 310.1146.
Synthesis 2007, No. 7, 1027–1032 © Thieme Stuttgart · New York

1032
D. Thomae et al.
PAPER
9-Amino-2-(4-methoxyphenyl)-5,6,7,8-tetrahydrothieno[3,2-
9-Amino-2-(4-methoxyphenyl)-3-methyl-5,6,7,8-tetrahydro-
thieno[3,2-b]quinoline (6d)
b]quinolin-8-ol (4b)
Yield: 98% (Method B); mp 210–212 °C.
Yield: 72%; brown solid; mp 225–228 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.68 (m, 2 H, CH2), 1.81 (m,
2 H, CH2), 2.37 (s, 3 H, CH3), 2.65 (m, 2 H, CH2), 2.83 (m, 2 H,
CH2), 3.83 (s, 3 H, CH3O), 6.06 (s, 1 H, NH2), 7.06 (d, J = 7.5 Hz,
2 H, 2 × CH), 7.71 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 12.86, 23.23, 23.71, 33.43,
36.45, 55.69, 110.30, 114.79, 115.24, 127.33, 128.07, 130.21,
130.42, 137.92, 146.94, 154.57, 159.50.
1H NMR (250 MHz, DMSO-d6): d = 1.55 (m, 2 H, CH2), 2.11 (m,
2 H, CH2), 2.37 (m, 2 H, CH2), 3.39 (s, 3 H, CH3O), 4.23 (m, 1 H,
CHO), 5.46 (s, 1 H, OH), 6.19 (s, 2 H, NH2), 6.94 (s, 1 H, CH), 6.52
(d, J = 7.5 Hz, 2 H, 2 × CH), 7.18 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 18.54, 33.32, 33.52, 55.82,
63.37, 112.75, 115.13, 116.31, 119.85, 126.70, 127.65, 145.21,
148.53, 155.76, 156.40, 160.27.
Anal. Calcd for C19H20N2OS: C, 70.34; H, 6.21; N, 8.63. Found: C,
70.22; H, 6.04; N, 8.87.
HRMS: m/z calcd for C18H18N2O2S: 326.1089; found: 326.1089.
Acknowledgment
10-Amino-2-(4-chlorophenyl)-3-methyl-6,7,8,9-tetrahydro-5H-
cyclohepta[b]thieno[2,3-e]pyridine (7d)
We thank the ‘Ministère de l’Education Nationale, de l’Enseigne-
ment Supérieur et de la Recherche’ for a PhD grant to D.T. We
thank also the Université du Luxembourg for financial support to
P.S.
Yield: 98% (Method B); mp 211–213 °C.
1H NMR (250 MHz, DMSO-d6): d = 1.68 (m, 2 H, CH2), 1.74 (m,
2 H, CH2), 1.81 (m, 2 H, CH2), 2.37 (s, 3 H, CH3), 2.65 (m, 2 H,
CH2), 2.83 (m, 2 H, CH2), 3.83 (s, 3 H, CH3O), 6.06 (s, 1 H, NH2),
7.06 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.71 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 12.62, 12.87, 27.00, 27.87,
30.49, 32.20, 55.77, 114.88, 115.79, 116.92, 130.57, 132.06,
132.18, 138.52, 146.56, 152.87, 159.64, 161.40.
References
(1) Francotte, P.; Grandorge, E.; Boverie, S.; De Tullio, P.;
Pirotte, B. Curr. Med. Chem. 2004, 11, 1757.
(2) Chaki, H.; Yamabe, H.; Sugano, M.; Morita, S.; Bessho, T.;
Tabata, R.; Saito, K.-I.; Egawa, M.; Tobe, A.; Morinaka, Y.
Bioorg. Med. Chem. 2004, 12, 2199.
(3) Marco, J. L.; De Los Rios, C.; Garcia, A.; Villarroya, M.;
Carreiras, C.; Martins, C.; Eleutério, A.; Morreale, A.;
Orozco, M.; Luque, F. J. Bioorg. Med. Chem. 2004, 12,
2199.
HRMS: m/z calcd for C20H22N2S: 338.1452; found: 338.1484.
Preparation of 9-Amino-2-aryl-5,6,7,8-tetrahydrothieno[3,2-
b]quinolin-8-ols 4a,b; General Procedure
A solution of LiAlH4 (1.6 mmol) in anhyd THF (20 mL) was added
dropwise to a solution of 3 (1 mmol) in anhyd THF (20 mL) main-
tained at 0 °C under argon atmosphere. After the addition, the reac-
tion mixture was refluxed for 1 h, then quenched by the addition of
10% HCl (2 mL). The mixture was made basic with 30% NaOH
and extracted with EtOAc (3 × 20 mL). The combined organic lay-
ers were dried (Na2SO4) and evaporated to dryness to give a solid
which was purified by column chromatography (CH2Cl2–MeOH,
9:1).
(4) Ren, W.-Y.; Rao, K.; Kein, R. J. Heterocycl. Chem. 1986,
23, 1757.
(5) Vega, S.; Gil, M. S. J. Heterocycl. Chem. 1991, 28, 1757.
(6) Hartmann, H.; Liebscher, J. Synthesis 1984, 275.
(7) Hartmann, H.; Liebscher, J. Synthesis 1984, 276.
(8) Liebscher, J.; Neumann, B.; Hartmann, H. J. Prakt. Chem.
1983, 325, 915.
(9) Hartmann, H.; Liebscher, J. Synthesis 1979, 241.
(10) Migianu, E.; Kirsch, G. Synthesis 2002, 1096.
(11) Tabarini, O.; Ceccetti, V.; Temperani, A.; Filipponi, E.;
Lamperti, M. G.; Fravolini, A. Bioorg. Med. Chem. 2001, 9,
2921.
(12) (a) Leon, R.; Marco-Contelles, J.; Garcia, A. G.; Villarroya,
M. Bioorg. Med. Chem. 2005, 13, 1167. (b) Marco, J. L.;
De Los Rios, C.; Carreiras, C.; Baños, J. E.; Badia, A.;
Vivas, N. M. Bioorg. Med. Chem. 2001, 9, 727. (c) Grau,
A. M.; Marco, J. L. Bioorg. Med. Chem. 1997, 24, 3165.
(13) Ellman, G. L.; Courtney, K. D.; Andres, V.; Feather-Stone,
R. M. Biochem. Pharmacol. 1961, 7, 88.
9-Amino-2-(4-methylphenyl)-5,6,7,8-tetrahydrothieno[3,2-
b]quinolin-8-ol (4a)
Yield: 75%; brown solid; mp 225–227 °C.
1H NMR (250 MHz, CDCl3 + DMSO-d6): d = 1.47 (m, 2 H, CH2),
1.88 (m, 2 H, CH2), 2.05 (m, 2 H, CH2), 2.71 (s, 3 H, CH3), 4.38 (m,
1 H, CHO), 5.48 (s, 1 H, OH), 6.40 (s, 2 H, NH2), 6.95 (s, 1 H, CH),
6.72 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.06 (d, J = 7.5 Hz, 2 H, 2 × CH).
13C NMR (63 MHz, DMSO-d6): d = 18.33, 21.35, 32.93, 33.15,
63.11, 112.95, 116.58, 119.93, 126.232, 130.32, 131.18, 139.11,
146.04, 149.04, 154.95, 155.34.
Anal. Calcd for C18H18N2OS: C, 69.65; H, 5.84; N, 9.02. Found: C,
69.70; H, 5.70; N, 8.79.
Synthesis 2007, No. 7, 1027–1032 © Thieme Stuttgart · New York