Synthesis of substituted amino-cycloalkyl[b]thieno-[3,2-e]pyridines

Article abstract of DOI:10.1002/jhet.5570450333

(Chemical Equation Presented) An efficient two respectively three steps procedure for the synthesis of cycloalkyl[b]thieno[3,2-e]-pyridine amines was developed and in general good to very good yields were obtained.

Full text of DOI:10.1002/jhet.5570450333

May-Jun 2008
853
Synthesis of Substituted Amino-Cycloalkyl[b]thieno-
[3,2-e]Pyridines
Pierre Seck, ¹* David Thomae, ² Gilbert Kirsch²*
¹ Laboratoire de Chimie, Faculté des Sciences, de la Technologie et de la Communication, Université du
Luxembourg,
162a, avenue de la Faïencerie, 1511 Luxembourg, Luxembourg
E-mail : pierre.seck@uni.lu
² Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843,
1 Boulevard Arago, 57070 METZ, France.
Received November 13, 2007
NH2
R2
S
R2
CN
R2
R1
O
R1
R1
NH2
S
n
N
An efficient two respectively three steps procedure for the synthesis of cycloalkyl[b]thieno[3,2-e]-
pyridine amines was developed and in general good to very good yields were obtained.
J. Heterocyclic Chem., 45, 853 (2008).
INTRODUCTION
cations of Tacrine, we wanted to synthesize a series of
thiophene analogues, since it is widely recognized that
thiophene is a bioisostere of benzene. As few analogues
based on the thieno[2,3-b]quinoline (III) and the thieno-
[3,2-b]quinoline (IV) moieties have been described [2],
we have chosen to prepare parallel to the synthesis of
Alzheimer’s disease is a form of dementia of older
people that looks to become a major problem in the
coming decade [1]. One possible treatment is to inhibit
acetylcholinesterase to maintain as long as possible the
neurotransmission by acetylcholine which is hindered by
the formation of ß amyloïd plaques. The first acetyl-
cholinesterase inhibitor used in this context was Tacrine
(I) sold under the name of COGNEX® (Figure 1). The
hydroxyl derivative of Tacrine is Velnacrine (II). In order
to investigate the biological effects of structural modifi-
Scheme I
O
R2
CN
R1
S
N
H
Method A
NH2
R
NH2
2 (a-b)
Method A
ii
i
S
N
n
N
NH2
O
R2
R2
S
CN
III
iii
I Tacrine R=H
II Velnacrine R= OH
R1
R1
Method B
S
N
NH2
NH2
R
NH2
3 (a-b)
1 (a-d)
S
S
R2
v
Method B
iv
n
N
n
N
R1
V
IV
NH2 OH
NH2
R2
R2
n= 0,1,2 R=H R2=Ar R1=H
R2=Ar
R1=H
n=1
R=OH
R1
R1
S
S
N
n
N
NH2
R2
S
4 (a-b)
5 (a-d)
R1
n
N
-R1-R2- = - (CH2)4-
n= 1
b
d
R1=R2=CH3
n= 1
a
c
VI
n= 1
n= 1
R=H R1=R2=CH3
R=H -R1-R2- = (CH2)4
n= 0,1,2 R=H R1=H R2= p-CH3O-Ph
n= 0,1,2 R=H R1=H R2= p-Cl-Ph
R1=H
R1=H
R2= p-CH3O-Ph
n= 0, 1, 2
R2= p-Cl-Ph
n= 0, 1, 2
n= 1
n= 1
R=OH R1=R2=CH3
R=OH -R1-R2- = (CH2)4
Reagents and conditions: i cyclohexane-1,3-dione, p-toluene-
sulfonic acid, toluene, reflux, ii CuCl, base, DMF, reflux, iii AlCl3,
cyclohexane-1,3-dione, (CH2)2Cl2, reflux, iv AlCl3, cyclohexane-
1,3-dione, (CH2)2Cl2, reflux, v LiAlH4, THF, reflux.
Figure 1

854
P. Seck, D. Thomae, G. Kirsch
Vol 45
substituted cycloalkyl[b]thieno[2,3-e]pyridine amines (V)
[3], the hitherto unknown substituted cycloalkyl[b]thieno-
[3,2-e]pyridine amines (VI) (Figure 1) The proposed
synthesis is shown in Scheme I.
The Friedländer reaction allowed by another single step
the very rapid access to the target molecules with good
yields. Biological evaluation of the synthesized
compounds, using Ellman’s tests on acetylcholinesterase
inhibition [7] is underway.
RESULTS AND DISCUSSION
EXPERIMENTAL
The synthesis started from substituted 2-amino-3-
thiophenecarbonitriles 1 which were prepared in one or
two steps from the corresponding ketones via a Gewald
reaction [4] (Scheme II).
Melting points were determined on a Stuart SMP3 apparatus
and are uncorrected. IR spectra were recorded neat from 4400 to
600 cm -1 on an Perkin Elmer FT-IR Baragon 1000PC equipped
with a Graseby-Specac golden gate and treated with the
Spectrum (Perkin-Elmer) software version 5.3.1. ¹H and ¹³C
NMR spectra were recorded on a Bruker AC 250 MHz
spectrometer in CDCl3 if not stated otherwise. The coupling
constants are in Hz. Ms spectra were recorded on an Agilent
Technologies GC-MS instrument equipped with a 7683 injector,
6890N gas chromatograph and a 5973 mass selective detector.
The mass spectrometer was operated in EI mode at 70 eV and
ms spectra were recorded from m/z 50 to 650.
The first approach to the Tacrine derivatives 3 was
made by applying a method developed by Tabarrini et al
[5] (Scheme I/method A). In the first step, thiophenes 1
were condensed with cyclohexan-1,3-dione in refluxing
toluene in the presence of p-toluenesulfonic acid to give
the corresponding enamines 2 in various yields. These
enamines were cyclized in the presence of cuprous
chloride and either potassium carbonate or sodium
methanolate in refluxing DMF to give the ketones 3. The
latter were easily reduced by lithium aluminium hydride
to the thiophene analogues of Velnacrine 4.
General procedure to obtain the substituted 2-Amino-3-
thiophenecarbonitriles 1(a-d) (Fig. 2).
WAY A (GEWALD reaction). 0.10 mol (1 equiv.) of ketone
and 0.10 mol of malonic acid dinitrile were dissolved in 150 mL
absolute ethanol. 0.11 mol sulfur powder and 10 mL morpholine
were added. The mixture was heated at reflux with good stirring.
After approx. 2 hours, it was cooled to RT and poured into 300
mL ice-water. The precipitation was filtered of, washed with
cold water and dried. It was purified either by recrystallization in
isopropanol or by silica gel column chromatography using
dichloromethane as eluent
Scheme II
WAY A
R2
CN
NH2
R2
R1
O
CN
CN
i
1/8 S8
R1
S
WAY B. First step: 0.10 mol (1 equiv.) of ketone and 0.10
mol of malonic acid dinitrile were dissolved in 100 mL benzene.
0.10 mol ammonium acetate and 0.30 mol acetic acid were
added and the reaction mixture was refluxed up to 6 hours in a
Dean-Stark apparatus. After cooling to RT, the mixture was
diluted with 100 mL water and the acetic acid was neutralized
with a 10% solution of sodium bicarbonate. The organic layer
was separated, dried on anhydrous sodium sulfite, filtered and
the solvent was evaporated to give the product which was
directly used in the next step.
WAY B
CN
R2
R1
O
CN
CN
ii
R2
R1
CN
R2
CN
Second step: (GEWALD reaction). 25 mmol of the product
obtained by step 1 (substituted 1,1-dicyanoprop-1-ene) were
dissolved in 60 mL DMF. 25 mmol of sulfur powder were added
as well as some droplets of morpholine. After a very short
heating (less than 10 minutes), up to 120ºC, the reaction mixture
was cooled to RT then poured into ice-water. The precipitation
was collected by filtration, washed with cold water, dried and
purified either by recrystallization in isopropyl alcohol or by
iii
R1
NH2
S
Reagents and conditions: i morpholine, ethanol, reflux, ii CH3COOH /
CH3COONH4, Bz, reflux, iii morpholine, DMF, RT or reflux.
In a second approach using Friedländer conditions [6]
(Scheme I/method B), ketones 3 were obtained in
comparable yields than by method A. These conditions
allowed us to conduct the direct condensation of
monocyclanones as well as 1,3-cyclanediones. In this
way, the preparation of Tacrine analogues 5 was possible
by only two or three steps and the introduction of a range
of ring sizes could also be achieved.
silica gel column chromatography using
dichloromethane/ethyl acetate (95:5) as eluent.
a mixture of
2-Amino-4,5-dimethyl-3-thiophencarbonitrile (1a). Yield:
72%; red-brownish needles; mp 138ºC (isopropanol); Lit: mp:
141-142°C [8]; ir: 3432 and 3217 (NH2), 2188 (CN), 1606
1
(NH2), 1377 (CH3), 1305 (NH2) cm-1; H nmr: δ 2.06 (s, 3H,
CH3), 2.15 (s, 3H, CH3), 4.56 (s, 2H, NH2); 13C nmr: δ 12.39,
12.76, 90.56, 115.94, 117.17, 129.58, 159.17; ms: m/z (M)+ =
(C7H8N2S)+ = 152 (100%).
In conclusion substituted 2-amino-3-thiopohenecarbo-
nitriles have been synthesized in only one or two steps.
2-Amino-4,5,6,7-tetrahydrobenzo[b]-3-thiophenecarbo-
nitrile (1b) Yield: 95%; ocher needles; mp: 144ºC

May-Jun 2008
Synthesis of Substituted Amino-Cycloalkyl[b]thieno-[3,2-e]Pyridines
855
(isopropanol); Lit: mp: 147-148°C [4b] ; ir: 3443 and 3304
(NH2), 2195 (CN), 1614 (NH2), 1443 and 1431 (CH2), 1330
mmol) were added to a solution of 2 (10.4 mmol) in dry DMF
(20 mL) and the mixture was heated at 80-90ºC for 4 h. After
cooling, the reaction mixture was poured into ice-water (150
mL) containing sodium tartrate (10%). The obtained precipitate
was filtered off and extracted several times with a mixture of
methanol/ethyl acetate (1:1). The organic extracts were dried on
anhydrous sodium sulphate, filtered and the solvent was
evaporated to give a solid which was purified by silica gel
column chromatography using a mixture of dichloromethane/
methanol (9:1) as eluent.
4-Amino-2,3-dimethyl-7,8-dihydrothieno[2,3-b]quinolin-
5(6H)-one (3a). Yield: 63%; brownish needles; mp 204ºC
(dichloromethane/methanol 9:1); ir: 3410 and 3216 (NH2), 2952
and 2864 (CH3), 1636 (CO), 1589 (NH2), 1423 and 1371 (CH3),
1328 (NH2) cm-1; 1H nmr: δ 1.65 (s, 1H of NH2 linked by
hydrogen-bonding to CO), 2.09 (m, 2H, -CH2-CH2-CH2-); 2.39
(s, 3H, CH3), 2.51 (s, 3H, CH3), 2.67 (m, 2H, =C-CH2-); 3.03
(m, 2H, -CH2-CO-), 5.29 (s, 1H of NH2 linked by hydrogen-
bonding to CO); 13C nmr: δ 13.30, 14.74, 21.41, 29.67, 39.91,
112.55, 122.20, 125.30, 129.55, 152.64, 161.17, 161.79, 202.36;
ms: m/z (M)+ = (C13H14ON2S)+ = 246 (100%). Anal. Calcd. for
C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C, 63.41; H,
5.50; N, 11.38.
1
(NH2) cm-1; H nmr: δ 1.78 (t, 4H, 2×CH2), 4.64 (s, 2H, NH2),
2.49 (m, 4H, 2xCH2); 13C nmr: δ 22.10, 23.34, 23.72, 24.10,
88.45, 115.59, 120.50, 132.27, 160.15; ms : m/z (M)+
(C9H10N2S)+ = 178 (100%).
=
2-Amino-4-(4-methoxyphenyl)-3-thiophenecarbonitrile (1c).
Yield: 89%; ocher needles; mp 161ºC (dichloromethane/
ethylacetate 95:5); Lit: mp: 141-142 [9] ir: 3448 and 3207
(NH2), 2193 (CN), 1607 (NH2), 1248 and 1173 (OCH3 on the
phenyl), 736 (disubstituted phenyl); 1H nmr: δ 3.86 (s, 3H,
OCH3), 4.90 (s, 2H, NH2), 6.30 (s, 1H, CH), 7.00 (d, 2H, Ph-H,
J=8.5), 7.58 (d, 2H, Ph-H, J=8.5); 13C nmr: δ 55.34, 77.22,
104.80, 114.18, 115.90, 126.83, 128.38, 139.74, 159.61, 163.23;
ms : m/z (M)+ = (C12H1OON2S)+ = 230 (100%).
2-Amino-4-(4-chlorophenyl)-3-thiophenecarbonitrile (1d).
Yield: 90%; orange needles; mp 164ºC (dichloromethane/
ethylacetate 95:5); ir: 3301 and 3201 (NH2), 2216 (CN), 1642
1
(NH2), 815 (disubstituted phenyl) cm-1; H nmr: δ 5.40 (s, 2H,
NH2), 6.90 (s, H, CH), 7.00 (d, Ph-H, J=8.5), 7.30 (d, 2H, Ph-H,
J=8.5); 13C nmr: δ 83.71, 104.07, 115.55, 127.80, 128.06,
132.19, 134.52, 136.89, 165.15; ms : m/z (M)+ = (C11H7N2SCl)+
= 234 (100%). Anal. Calcd. for C11H7ClN2S: C, 56.29; H, 3.01;
N, 11.94. Found: C, 56.14; H, 3.09; N, 11.87.
11-Amino-2,3,4,7,8,9-hexahydro[1]benzothieno[2,3-b]-
quinolin-10(1H)-one (3b) Yield: 58%; brown needles; mp
223ºC (dichloromethane/methanol 9:1); ir: 3387 and 3217
(NH2), 2941 (CH2), 1636 (CO), 1587 (NH2), 1426 (CH2), 1311
General procedure to obtain substituted 2-[(3-Oxo-1-
cyclohexen-1yl) amino]-3-thiophenecarbonitriles 2 (a-b).
1
(NH2) cm-1; H nmr: δ 1.28 (s, 1H, NH2 linked by hydrogen-
1st Step of method A/Scheme I. A suspension of a substituted
2-amino-3-thiophencarbonitrile 1 (0.02 mol), cyclohexane-1,3-
dione (0.02 mol) and p-toluenesulfonic acid (0.67 mmol) in dry
toluene (20 mL) were refluxed for 4 h in an Dean-Stark
apparatus. The reaction mixture was then chilled to 0ºC and the
crystallized product was collected by filtration, washed with
cold toluene followed by cold cyclohexane, dried and
recrystallized (ethanol/diethyl ether 1:1).
bonding to CO), 1.89 (m, 4H, 2×CH2), 2.07 (m, 2H, -CH2-CH2-
CH2-), 2.66 (m, 2H, =C-CH2-), 2.77 (m, 2H, -CH2-CO-), 3.02
(m, 6H, 3×CH2), 5.01 (s, 1H, NH2 linked by hydrogen-bonding
to CO); 13C nmr: 21.04, 21.66, 22.26, 22.54, 25.44, 26.57, 39.95,
107.88, 118.14, 127.37, 132.67, 152.74, 161.85, 162.62, 202.05;
ms: m/z (M)+ = (C15H16ON2S)+ = 272 (100%). Anal. Calcd. for
C15H16N2OS: C, 66.15; H, 5.92; N, 10.29. Found: C, 66.24; H,
5.83; N, 10.39.
General procedure to obtain the substituted amino-7,8-
dihydrothieno [2,3-b] quinolinols 4 (a-b) (Scheme I). A
solution of LiAlH4 (1.6 mmol) in dry THF (20 mL) was added
dropwise to a solution of 3 (1 mmol) under argon atmosphere.
After the addition, the reaction mixture was refluxed for 1h, then
quenched by 2 mL of HCl 10%. The mixture was then made
basic with NaOH 30% and extracted with ethylacetate (3×20
mL). The combined organic layers were dried on anhydrous
sodium sulfate, filtered and evaporated to give a solid, which
was purified by silica gel column chromatography using a
mixture of dichloromethane/methanol (9:1) as eluent.
4-Amino-2,3-dimethyl-5,6,7,8-tetrahydrothieno[2,3-b]-
quinolin-5-ol (4a). Yield : 83% ; ocher crystalline powder; mp
182ºC (dichloromethane/methanol 9:1); ir: 3507 and 3383
(NH2), 3118 (OH), 2937and 2864 (CH3), 1589 (NH2), 1438 and
1383 (CH3), 1278 (NH2), 1066 (OH) cm-1; 1H nmr: δ 1.20 (m,
4H, 2×CH2), 1.60 (s, 3H, CH3), 1.91 (m, 3H, CH2+OH), 2.13 (s,
3H, CH3), 4.14 (m, 1H, CH-OH), 4.96 (2H, NH2); 13C nmr: δ
13.09, 14.27, 17.74, 29.15, 32.83, 62.83, 113.24, 118.81, 124.67,
126.13, 149.34, 153.46, 158.67; ms: m/z (M)+ = (C13H16ON2S)+
= 248 (100%). Anal. Calcd. for C13H16N2OS: C, 62.87; H, 6.49;
N, 11.28. Found: C, 63.02; H, 6.50; N, 11.18.
4,5-Dimethyl-2-[3-oxo-1-cyclohexen-1-yl)amino]-3-thio-
phenecarbonitrile (2a). Yield: 68%; yellow-greenish needles;
mp 211ºC (ethanol/diethyl ether 1:1); ir: 3187 (NH), 2955
(CH3), 2224 (CN), 1603 (CO), 1589 (NH), 1358 (CH3), 1242
1
(NH) cm-1; H nmr: δ 2.05 (m, 2H, -CH2-CH2-CH2-), 2.16 (s,
6H, 2xCH3), 2.38 (m, 2H, =C-CH2-), 2.54 (m, 2H, -CH2-CO-),
5.70 (s, 1H, NH), 6.96 (s, 1H, =CH-CO-); 13C nmr: δ 12.50,
12.86, 21.55, 28.75, 36.41, 103.34, 103.96, 114.10, 128.14,
130.93, 146.76, 160.67, 198.56; ms : m/z (M)+= (C13H14ON2S)+
= 246 (100%). Anal. Calcd. for C13H14N2OS: C, 63.39; H, 5.73;
N, 11.37. Found: C, 63.54; H, 5.55; N, 11.38.
2-[3-Oxo-1-cyclohexen-1-yl)amino]-4,5,6,7-tetrahydro-1-
benzo[b]thiophen-3-carbonitrile (2b). Yield: 62%; yellow
needles; mp 200ºC (ethanol/diethyl ether 1:1); ir: 3188 (NH), 2924
(CH2)4, 2211 (CN), 1614 (CO), 1589 (NH), 1447 (CH2)4, 1247
1
(NH) cm-1; H nmr: δ 1.83 (m, 4H, 2×CH2), 2.07 (m, 2H, -CH2-
CH2-CH2-), 2.38 (m, 2H, =C-CH2-), 2.58 (m, 6H, -CH2 -CH2-CH2-
CO-), 5.70 (s, 1H, NH), 6,92 (s, 1H, =CH-CO-); 13C nmr : δ 21.61,
21.92, 22.26, 22.54, 25.44, 26.57, 36.47, 102.49, 102.69, 113.81,
131.54, 133.37, 147.77, 161.63, 198.83; ms : m/z (M)+
=
(C15H16ON2S)+ = 272 (100%). Anal. Calcd. for C15H16N2OS: C,
66.15; H, 5.92; N, 10.29. Found: C, 66.13; H, 5.87; N, 10.34.
General procedure to obtain the substituted amino-7,8-
dihydrothieno [2,3-b] quinolinones 3 (a-b).
11-Amino-1,2,3,4,7,8,9,10-octahydro[1]benzothieno[2,3-b]-
quinolin-10-ol (4b). Yield: 43%; yellow-brown needles; mp
128ºC (dichloromethane/methanol 9:1); ir: 3503 and 3380
(NH2), 3115 (OH), 2928 (CH2)4, 1611 (NH2), 1444 (CH2)4, 1304
2nd Step of method A/Scheme I. Sodium methanolate or
potassium carbonate (2.2 mmol) and cuprous chloride (10.4

856
P. Seck, D. Thomae, G. Kirsch
Vol 45
(NH2), 1068 (OH) cm-1; 1H nmr: δ 1.72 (m, 4H, 2×CH2), 2.27 (s,
1H, NH2 linked by hydrogen-bonding to OH), 2.44 (m, 6H,
3×CH2), 2.68 (m, 4H, 2×CH2), 4.43 (m, 1H, CH-OH), 5.16 (s,
1H, NH2 linked by hydrogen-bonding to OH); 13C nmr: δ 17.78,
22.06, 22.17, 25.25, 25.89, 32.81, 33.22, 62.80, 113.25, 117.68,
2H, =C-CH2-), 3.0 (m, 2H, -N=C-CH2-), 3.86 (s, 3H, OCH3), 4.3
(s, 2H, NH2), 6.9 (s, 1H, thiophene proton), 7.0 (d, 2H, 2×CH,
J=8.5), 7.4 (d, 2H, 2×CH, J=8.5); 13C nmr: δ 22.78, 22.81, 22.95,
33.21, 55.38, 110.46, 113.99, 115.92, 120.15, 129.67, 130.50,
134.40, 147.18, 154.34, 155.34, 159.50; ms: m/z (M)+
=
129.39, 133.37, 149.28, 153.51, 159.23; ms: m/z (M)+
=
(C18H18ON2S)+ = 310 (100%). Anal. Calcd. for C18H18N2OS: C,
69.65; H, 5.84; N, 9.02. Found: C, 69.73; H, 5.87; N, 9.32.
4-Amino-3-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-cyclo-
hepta[b]thieno[3,2-e]pyridine (5c/n=2). Yield 95%; orange
needles; mp 195ºC (dichloromethane/methanol 9:1); ir: 3462
and 3363 (NH2), 2919 and 2842 (CH2)5, 1624 (NH2), 1434
(CH2)5, 1170 (OCH3), 775 (disubstituted phenyl); 1H nmr: δ 1.85
(m, 6H, 3×CH2), 2.6 (m, 2H, =C-CH2-), 3.1 (m, 2H, -N=C-CH2-
), 3.9 (s, 3H, OCH3), 4.4 (s, 2H, NH2), 6.9 (s, 1H, thiophene
(C15H18ON2S)+ = 274 (100%). Anal. Calcd. for C15H18N2OS: C,
65.66; H, 6.61; N, 10.21. Found: C, 65.83; H, 6.49; N, 10.36.
General procedure to obtain the substituted cycloalkyl[b]-
thieno[3,2-e]pyridine amines 5 (a-d) by Friedländer reaction
(method B /Scheme I). Aluminium chloride (3.4 mmol for
monocyclanones and 6.8 mmol for cyclohexa-1,3-diones) was
suspended in dry 1,2-dichloroethane (10 mL per mmol of AlCl3 )
at RT under argon. The corresponding thiophene 1 (2 mmol) and
the ketone (1.7 mmol) were added and the reaction mixture was
heated under reflux up to 18 h for a monocyclanone and up to 36
h for a cyclohexa-1,3-dione. When the reaction was completed
(monitoring by TLC) a mixture of THF/water (2:1) was added at
RT and sodium hydroxide was added until the solution became
basic. After stirring for at least 30 minutes, the mixture was
extracted with dichloromethane (3×30 mL). The combined
organic layers were dried on anhydrous sodium sulfate; the
solvents are evaporated to give a brownish solid which was
purified by silica gel column chromatography using
dichloromethane/methanol (9:1) as eluant.
proton), 7.0 (d, 2H, 2×CH, J=8.5), 7,4 (d, 2H, 2×CH, J=8.5); 13
C
nmr: δ 25.24, 26.60, 27.12, 32.15, 39.04, 55.37, 113.91, 116.00,
120.12, 129.62, 130.62, 130.63, 134.70, 146.24, 153.99, 159.50,
161.88; ms: m/z (M)+ = (C19H20ON2S)+ = 324 (100%). Anal.
Calcd. for C19H20N2OS: C, 70.34; H, 6.21; N, 8.63. Found: C,
70.25; H, 6.34; N, 8.79.
4-Amino-3-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]-
thieno[3,2-e]pyridine (5d/n=0). Yield 95%; orange needles; mp
176ºC (dichloromethane/methanol 9:1); ir: 3473 and 3308
(NH2), 2946 and 2840 (CH2)3, 1635 (NH2), 1455 (CH2)3, 818
1
(Cl), 761 (disubstituted phenyl); H nmr: δ 2.28 (m, 2H, -CH2-
CH2-CH2-), 2.75 (m, 2H, =C-CH2-), 3.1 (m, 2H, -N=C-CH2-),
4.15 (s, 2H, NH2), 6.9 (s, 1H, thiophene proton), 7.4 (m, 4H,
4×CH); 13C nmr: δ 22.87, 26.79, 34.39, 115.73, 115.91, 120.25,
128.72, 130.57, 133.42, 134.15, 135.88, 145.04, 164.42, 166.31;
ms: m/z (M)+ = (C16H13N2SCl)+ = 300 (100%). Anal. Calcd. for
C16H13ClN2S: C, 63.89; H, 4.36; N, 9.31. Found: C, 63.87; H,
4.56; N, 9.52.
4-Amino-3-(4-chlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]-
quinoline (5d/n=1). Yield 83%; orange needles; mp 179ºC
(dichloromethane/methanol 9:1); ir: 3488 and 3340 (NH2),
2935 and 2859 (CH2), 1627 (NH2), 1447 (CH2)4, 831 (Cl), 766
(disubstituted phenyl); 1H nmr: δ 1.9 (m, 4H, 2×CH2), 2.45 (m,
2H, =C-CH2-), 3.0 (m, 2H, -N=C-CH2-), 4.2 (s, 2H, NH2), 6.9
(s, 1H, thiophene proton), 7.4 (m, 4H, 4×CH); 13C nmr: δ
22.56, 22.72, 22.93, 33.18, 110.64, 115.43, 120.39, 128.74,
130.59, 133.40, 134.17, 135.86, 146.91, 155.58, 158.41; ms:
m/z (M)+ = (C17H15N2SCl)+ = 314 (100%). Anal. Calcd. for
C17H15ClN2S: C, 64.85; H, 4.80; N, 8.90. Found: C, 64.81; H,
4.76; N, 9.02.
4-Amino-2,3-dimethyl-5,6,7,8-tetrahydrothieno[2,3-b]-
quinoline (5a). Yield 95%; grey needles; mp 169ºC (dichloro-
methane/methanol 9:1); ir: 3506 and 3301 (NH2), 2922 and 2857
(CH3) and (CH2), 1636 (NH2), 1428 (CH3), 1279 (NH2) cm-1; 1H
nmr: δ 1.89 (m, 6H, 3×CH2), 2.39 (s, 3H, CH3), 2.50 (s, 3H,
CH3), 2.88 (m, 2H, CH2), 4.56 (s, 2H, NH2); 13C nmr: δ 13.48,
14.58, 23.06, 26.82, 32.92, 41.98, 110.93, 115.73, 123.36,
128.46, 146.77, 153.76, 157.97; ms: m/z (M)+ = (C13H16N2S)+ =
232 (100%). Anal. Calcd. for C13H16N2S: C, 67.20; H, 6.94; N,
12.06. Found: C, 67.20; H, 7.02; N, 12.35.
11-Amino-1,2,3,4,7,8,9,10-octahydro[1]benzothieno[2,3-b]-
quinoline (5b). Yield 92%; brown needles; mp 218ºC (dichloro-
methane/methanol 9:1); ir: 3473 and 3361 (NH2), 2924 and 2845
1
2(CH2)4, 1609 (NH2), 1431 (CH2), 1277 (NH2) cm-1; H nmr: δ
1.90 (m, 8H, 4×CH2), 2.45 (m, 4H, 2×CH2), 2.75 (m, 2H, CH2),
2.88 (m, 2H, CH2), 4.56 (s, 2H, NH2); 13C nmr: δ 22.86, 22.97,
23.06, 25.65, 26.81, 33.10, 43.47, 110.89, 117.93, 125.73,
131.79, 132.57, 146.64, 153.92, 158.87; ms: m/z (M)+
=
(C15H18N2S)+ = 258 (100%). Anal. Calcd. for C15H18N2S: C,
69.73; H, 7.02; N, 10.84. Found: C, 69.58; H, 7.06; N, 10.90.
4-Amino-3-(4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta-
[b]thieno[3,2-e]pyridine (5c/n=0). Yield 83%; beige needles;
mp 216º (dichloromethane/methanol 9:1); ir: 3477 and 3368
(NH2), 2951 and 2832 (CH2), 1610 (NH2), 1455 (CH2), 1175
(OCH3), 755 (disubstituted phenyl); 1H nmr: δ 2.20 (m, 2H, -CH2-
CH2-CH2-), 2.75 (m, 2H, =C-CH2-), 3.1 (m, 2H, -N=C-CH2-), 3.9
(s, 3H, OCH3), 4.2 (s, 2H, NH2), 6.9 (s, 1H, thiophene proton), 7.0
(d, 2H, 2×CH, J=8.5), 7.4 (d, 2H, 2×CH, J=8.5); 13C nmr: δ 22.90,
26.75, 34.36, 55.35, 113.56, 113.93, 115.67, 116.20, 119.39,
129.67, 130.46, 134.37, 145.30, 159.45, 164.09; ms: m/z (M)+ =
(C17H16ON2S)+ = 296 (100%). Anal. Calcd. for C17H16N2OS: C,
68.89; H, 5.44; N, 9.45. Found: C, 68.74; H, 5.88; N, 9.50.
4-Amino-3-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclo-
hepta[b]thieno[3,2-e]pyridine (5d/n=2). Yield 86%; orange
needles; mp 175ºC (dichloromethane/methanol 9:1); ir: 3489
and 3382 (NH2), 2913 and 2846 (CH2)5, 1622 (NH2), 1455
1
(CH2)5, 824 (Cl), 755 (disubstituted phenyl). H nmr: δ 1.8 (m,
6H, 3×CH2), 2.65 (m, 2H, =C-CH2-), 3.1 (m, 2H, -N=C-CH2-),
4.3 (s, 2H, NH2), 6.95 (s, 1H, thiophene proton), 7.4 (m, 4H,
4×CH); 13C nmr: δ 25.18, 26.48, 26.99, 32.05, 39.05, 116.13,
116.23, 120.78, 128.61, 130.65, 133.69, 134.11, 135.76, 145.91,
159.77, 162.09; ms: m/z (M)+ = (C18H17N2SCl)+ = 328 (100%).
Anal. Calcd. for C18H17ClN2S: C, 65.74; H, 5.21; N, 10.78.
Found: C, 65.81; H, 5.32; N, 10.65.
Acknowledgements Authors want to thank the University
Paul Verlaine-METZ (France) and the University of
Luxembourg (Grand-Duchy of Luxembourg) for supporting this
work; Mrs. Véronique Poddig from the University Paul
Verlaine-METZ for recording the NMR spectra and Dr Serge
Schneider, Dr Brice Appenzeller and Dr Marc Schuman from
4-Amino-3-(4-methoxyphenyl)-5,6,7,8-tetrahydro[2,3-b]-
quinoline) (5c/n=1). Yield 85%; orange needles; mp 162ºC
(dichloromethane/methanol 9:1); ir: 3474 and 3331 (NH2), 2926
and 2863 (CH2), 1630 (NH2), 1441 (CH2), 1176 (OCH3), 769
1
(disubstituted phenyl); H nmr: δ 1.9 (m, 4H, 2×CH2), 2.45 (m,

May-Jun 2008
Synthesis of Substituted Amino-Cycloalkyl[b]thieno-[3,2-e]Pyridines
857
Ber. 1966, 99, 94.
the Laboratory of Toxicology of the Laboratoire National de
Santé (Luxembourg) for recording the IR and MS spectra.
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