Synthesis of 9-amino-5,6,7,8-tetrahydrothieno[3,2-b]quinoline and 9-amino-5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol derivatives

Article abstract of DOI:10.1002/jhet.186

(Chemical Equation Presented) The synthesis of 9-amino-5,6,7,8- tetrahydrothieno[3,2-b]quinoline (3) and 9-amino-5,6,7,8-tetrahydrothieno[ 3,2-b]quinolin-5-ol derivatives (4a-g) in good yield by three-step procedures starting from 3-aminothiophene-2-carbonitrile and 5-substituted cyclohexane-1,3-dione is described.

Full text of DOI:10.1002/jhet.186

1132
Synthesis of 9-Amino-5,6,7,8-tetrahydrothieno[3,2-b]quinoline
and 9-Amino-5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol
Derivatives
Vol 46
Yang-Heon Song* and Boung Sun Jo
Department of Chemistry, Mokwon University, Daejeon 302-729, South Korea
*E-mail: yhsong@mokwon.ac.kr
Received January 4, 2009
DOI 10.1002/jhet.186
Published online 2 November 2009 in Wiley InterScience (www.interscience.wiley.com).
The synthesis of 9-amino-5,6,7,8-tetrahydrothieno[3,2-b]quinoline (3) and 9-amino-5,6,7,8-tetrahydro-
thieno[3,2-b]quinolin-5-ol derivatives (4a–g) in good yield by three-step procedures starting from 3-ami-
nothiophene-2-carbonitrile and 5-substituted cyclohexane-1,3-dione is described.
J. Heterocyclic Chem., 46, 1132 (2009).
INTRODUCTION
fail. Gronowitz et al. has prepared 3-bromothiophene-2-
carbaldeyde (6) in low yield from 2,3-dibromothiophene
through its successive treatment butyllithium and DMF
[14]. As shown in Scheme 1, the aldehyde 6 could be
obtained in high yield more conveniently and on a large
scale by selective deprotonation at position-2 of 3-bromo-
thiophene (5) with LDA followed by N-formylpiperidine
quench [15]. The nucleophilic substitution of Br in 6
by sodium azide in DMPU afforded 3-azidothiophene-2-
carbaldehyde (7) in good yield [16].
The conversion of aldehyde in 7 into nitrile was
obtained in high yield by heating 7 with hydroxylamine-
O-sulfonic acid in water. The use of hydroxylamine-O-
sulfonic acid in water instead of hydroxylamine in dry
alumina [17] could lead to a more efficient and clear
route to 3-azidothiophene-2-carbonitrile (8). Finally, the
reduction of azide in 8 to amine without affecting nitrile
group could be achieved by hydrogenation over 10%
Pd-carbon, not using toxic H2S gas, to give 5 in high
yield. Compounds 10a–g, 5-substituted cyclohexane-1,3-
dione, were prepared by previously known procedures
[18,19] or purchased.
Alzheimer’s disease (AD) is characterized by the defi-
cits in the cholinergic system [1,2] and presence of neuro-
fibrillary tangles and amyloid plaques [3,4]. Since the
deficiency in cholinergic neurotransmission is believed to
be one of the major causes of the decline in cognitive and
mental functions associated with AD, cholinergic system
became a target for the design of anti-Alzheimer drugs.
Acetylcholinesterase (AChE) inhibitors such as
tacrine (1a) and donepezil by ‘‘cholinergic hypothesis’’
have been a useful and practical treatment for AD [5,6].
Moreover, the interest for AChE inhibitors has been
greatly renewed due to the recent evidences that AChE
might function to accelerate b-amyloid peptide (Ab) for-
mation and could play a role during amyloid deposition
in AD brain [7,8].
We have recently reported the synthesis of new
4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline
(2a)
and 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol
derivatives (2b) as potential AChE inhibitors as shown
in Figure 1 [9]. Similar analogues based on the substi-
tuted thieno[3,2-b]quinoline and the thieno[2,3-b]quino-
line moiety were also reported [10]. As a continuation
of our previous works on thienopyridine and thienopyri-
midine [9,11,12], we now report the synthesis of 9-
amino-5,6,7,8-tetrahydrothieno[3,2-b]quinoline (3) and
9-amino-5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol (4a–
g) derivatives, which have hitherto not reported.
For the synthesis of 3 and 4, 3-aminothiophene-2-car-
bonitrile (9) as starting material was needed. However,
the only synthetic method for 9 is associated with several
drawbacks, such as use of toxic H2S, low yield, and poor
selectivity [13]. The reaction, in addition, was capricious,
and further scale-up led reaction that would occasionally
The synthetic routes to 3 and 4a–g are shown in
Scheme 1. The condensation of 9 with 10 in the pres-
ence of catalytic amounts of p-toluenesulfonic acid gave
the corresponding enamines 11a–g, 3-(3-oxo-cyclohex-
1-enylamino)thiophene-2-carbonitrile derivatives in good
yield. These enamins were then cyclized in refluxing
THF in the presence of cuprous chloride and potassium
carbonate to give thienoquinolinones 12a–g, 9-amino-
6,7-dihydro-5H-thieno[3,2-b]quinolin-8-one derivatives.
It was noteworthy that a stoichiometric cuprous chloride
has to be used to run the reaction effectively and to
C
V
2009 HeteroCorporation

November 2009
Synthesis of 9-Amino-5,6,7,8-tetrahydrothieno[3,2-b]quinoline
and 9-Amino-5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol Derivatives
1133
stereomers, and major products were cis compounds.
Because the hydrogens on the alicyclic rings of 4c–g
were resolved at 300 MHz, it is possible to determine
all the coupling constants by first-order analysis and to
assign the relative stereochemistry of two diastereomers
[21]. The product compounds 4a–g were assayed on
AChE inhibitory activity by the modified Ellman
method [22]. None of these compounds showed an
improved AChE inhibition (IC50 ꢀ100 lM) as compared
with tacrine (IC50 ¼ 0.40 lM), with compound 4a (IC50
¼ 3.36 lM) being the most active. It showed that the
introduction of alkyl or aryl group at the C-6 of cyclo-
hexane ring resulted in marked decline in activity.
In conclusion, 9-amino-5,6,7,8-tetrahydrothieno[3,
2-b]quinoline and 9-amino-5,6,7,8-tetrahydrothieno[3,
2-b]quinolin-8-ol derivatives have been synthesized in
good yield by three-step procedures.
Figure 1. Tacrine and biosteric analogs.
obtain a higher yield. The carbonyl of 12a was trans-
formed into methylene group by modified Wolff-Kishner
reduction (hydrazine hydrate and KOH under hot ethyl-
ene glycol) [20] to give a new 9-amino-5,6,7,8-tetrahy-
drothieno[3,2-b]quinoline (3) in 57% yield. In another
way, the reduction reaction of compounds 12a–g with
lithium aluminum hydride in dry THF, followed by
work up of aqueous acidification, and by washing with
30% NaOH solution in order to remove the aluminum
salt from the product and to get free amine, provided
the expected compounds 4a–g, 9-amino-5,6,7,8-tetrahy-
drothieno[3,2-b]quinolin-8-ol derivatives in quantitative
yields. The compounds 4c–g were formed with two dia-
EXPERIMENTAL
Melting points were determined in capillary tubes on Bu¨chi
apparatus and are uncorrected. Each compound of the reactions
was checked on thin layer chromatography of Merck Kieselgel
60F254 and purified by column chromatography Merck silica
gel (70–230 mesh). The 1H NMR spectra were recorded on
Bruker DRX-300 FT-NMR spectrometer (300 MHz) with
Me4Si as internal standard and chemical shifts are given in
ppm (d). Electron ionization mass spectra were recorded on a
HP 59580 B spectrometer. Elemental analyses were performed
on a Carlo Erba 1106 elemental analyzer.
Scheme 1. A: LDA/THF, N-formylpiperidne, 0ꢁC; B: NaN3/DMPU, 35ꢁC; C: hydroxylamine-O-sulfonic acid/H2O, 40–50ꢁC; D: H2, Pd-C/ EtOH,
rt; E: p-TsOH/toluene, reflux; F: K2CO3, CuCl/THF, reflux; G: NH2NH2, KOH/ethylene glycol, reflux; H: LiLH4/THF, Hþ, 30% NaOH, rt.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1134
Y.-H. Song and B. S. Jo
Vol 46
Preparation
of
3-aminothiophene-2-carbonitrile
3-(3-Oxo-5-phenylcyclohex-1-enylamino)thiophene-2-car-
bonitrile (11c). This compound was obtained from 5-phenylcy-
clohexane-1,3-dione in 70% yield, mp 189–190ꢁC; 1H NMR
(9). 3-Bromothiophene (5) (0.3 mol) was added to a stirred
solution of lithium diisopropylamide (0.3 mol) in dry THF
(300 mL) at 0ꢁC under nitrogen. After addition of N-formylpi-
peridine (0.3 mol), the reaction solution was stirred for 5 h.
Then, it was poured into 30% aqueous ammonium chloride
solution and extracted with ether. The combined extracts
were dried over magnesium sulfate and evaporated to
dryness to afford 3-bromothiophene-2-carbaldeyde (6) in 86%
yield, bp 115–117ꢁC at 10 mmHg (ref. 13, 113–115ꢁC at
10 mmHg).
A suspension of 6 (0.2 mol) and sodium azide (0.8 mol) in
DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,
100 mL) was stirred at 50ꢁC for 24 h. Then, it was poured
into water and extracted with ether. The combined extracts
were dried over magnesium sulfate and evaporated to dryness
to give 3-azidothiophene-2-carbaldehyde (7) in 83% yield, mp
57–58ꢁC (ref. 12, 56.6–57.2ꢁC; ref. 15, 56–58ꢁC).
A suspension of 7 (0.1 mol) and hydroxylamine-O-sulfonic
acid (0.12 mol) in water (100 mL) was stirred at 50ꢁC for 24
h. After cooling, the precipitate was filtered off and washed
with water, giving 3-azidothiophene-2-carbonitrile (8) in 90%
yield, mp 78–79ꢁC (ref. 12, 77.5–79ꢁC).
A suspension of 8 (0.05 mol) and 10% Pd-carbon (0.3 g) in
ethanol (50 mL) was stirred under hydrogen at room temperature
for 4 h. After completion of the reaction, the reaction mixture
was filtered and evaporated to dryness to give 3-aminothiophene-
2-carbonitrile (9) in 95% yield, mp 49–50ꢁC (ref. 12, 47.5–50ꢁC).
1H NMR (deuteriochloroform): d 7.28 (d, J4, 5 ¼ 5.8 Hz, 1H, H-
5), 6.54 (d, J4, 5 ¼ 5.8 Hz, 1H, H-4), 4.48 (s, 2H, NH2); ms: (m/
z) 124 (Mþ), 110. Anal. Calcd. for C5H4N2S: C, 48.37; H, 3.25;
N, 22.56. Found: C, 48.50; H, 3.40; N, 22.41.
(deuteriochloroform): d 7.56 (d, J4, ¼ 5.8 Hz, 1H, thiophene
5
proton), 7.36–7.20 (m, 6H, thiophene and phenyl protons), 6.43
(s, 2H, NH2), 5.70 (s, 1H, vinyl proton, H-2), 3.45 (m, 1H, H-5),
2.95(dd, 1H, H-6a), 2.68–2.58 (m, 3H, H-4 and H-6b); ms: (m/z)
294 (Mþ), 265, 190, 159, 123. Anal. Calcd. for C17H14N2OS: C,
69.36; H, 4.79; N, 9.52. Found: C, 69.47; H, 4.92; N, 9.38.
3-(3-Oxo-5-p-tolylcyclohex-1-enylamino)thiophene-2-car-
bonitrile (11d). This compound was obtained from 5-p-tolyl-
1
cyclohexane-1,3-dione in 76% yield, mp 238–239ꢁC; H NMR
(deuteriochloroform): d 7.56 (d, J4, 5 ¼ 5.8 Hz, 1H, thiophene
proton), 7.22 (d, J4, 5 ¼ 5.8 Hz, 1H, thiophene proton), 7.20
(s, 4H, phenyl protons), 6.60 (s, 2H, NH2), 5.87 (s, 1H, vinyl
proton, H-2), 3.42 (m, 1H, H-5), 2.89 (dd, 1H, H-6a), 2.66–
2.59 (m, 3H, H-4 and H-6b), 2.35(s, 3H, CH3); ms: (m/z) 308
(Mþ), 279, 190, 162, 123, 67. Anal. Calcd. for C18H16N2OS:
C, 70.10; H, 5.23; N, 9.80. Found: C, 69.92; H, 5.10; N, 9.69.
3-(5-(4-Bromophenyl)-3-oxocyclohex-1-enylamino)thiophene-
2-carbonitrile (11e). This compound was obtained from 5-(4-
bromophenyl)-cyclohexane-1,3-dione in 70% yield, mp 238–
239ꢁC; 1H NMR (deuteriochloroform): d 7.60 (d, J4, 5 ¼ 5.8
0
0
Hz, 1H, thiophene proton), 7.36 (d, J2 , 3 ¼ 7.5 Hz, 2H, phe-
nyl protons), 7.22 (d, J4, ¼ 5.8 Hz, 1H, thiophene proton),
5
7.18 (d, 2H, phenyl protons), 6.80 (s, 2H, NH2), 5.71 (s, 1H,
vinyl proton, H-2), 3.42 (m, 1H, H-5), 2.84 (dd, 1H, H-6a),
2.69–2.59 (m, 3H, H-4 and H-6b); ms: (m/z) 372 (Mþ), 190,
123. Anal. Calcd. for C17H13BrN2OS: C, 54.70; H, 3.51; N,
7.50. Found: C, 54.88; H, 3.70; N, 7.44.
3-(5-(4-Chlorophenyl)-3-oxocyclohex-1-enylamino)thiophene-
2-carbonitrile (11f). This compound was obtained from 5-(4-
chlorophenyl)cyclohexane-1,3-dione in 75% yield, mp 216–
217ꢁC; 1H NMR (deuteriochloroform): d 7.59 (d, J4, 5 ¼ 5.8
General procedure for the preparation of 3-(3-oxocyclo-
hex-1-enylamino)thiophene-2-carbonitrile derivatives (11a–
g). A suspension of 3-aminothiophene-2-carbonitrile (0.03
mol), the appropriate 1,3-cyclohexanedione (0.03 mol) and p-
toluene sulfonic acid monohydrate (0.10 g) in dry toluene (20
mL) was refluxed for 7–8 h, and the water was collected in a
Dean-Stark trap. After cooling, the reaction mixture was fil-
tered off. The filtrate was evaporated to dryness, and the resi-
due was chromatographed on a silica gel column by eluting
with a 20:80 v/v ethyl acetate/chloroform mixture.
0
0
Hz, 1H, thiophene proton), 7.37–7.24 (dd, J2 , 3 ¼ 7.5 Hz, 4H,
phenyl protons), 7.22 (d, J4, ¼ 5.8 Hz, 1H, thiophene pro-
5
ton), 6.32 (s, 2H, NH2), 5.70 (s, 1H, vinyl proton, H-2), 3.43
(m, 1H, H-5), 2.83 (dd, 1H, H-6a), 2.70–2.60 (m, 3H, H-4 and
H-6b); ms: (m/z) 328 (Mþ), 190, 123. Anal. Calcd. for
C17H13ClN2OS: C, 62.10; H, 3.98; N, 8.52. Found: C, 61.92;
H, 3.88; N, 8.63.
3-(5-(4-Methoxyphenyl)-3-oxocyclohex-1-enylamino)thio-
phene-2-carbonitrile (11g). This compound was obtained
from 5-(4-methoxyphenyl) cyclohexane-1,3-dione in 75%
yield, mp 147–148ꢁC; 1H NMR (deuteriochloroform): d 7.56
3-(3-Oxocyclohex-1-enylamino)thiophene-3-carbonitrile
(11a). This compound was obtained from 1,3-cyclohexane-
dione in 70% yield, mp 142–143ꢁC; H NMR (deuteriochloro-
1
form): d 7.54 (d, J4, 5 ¼ 5.8 Hz, 1H, thiophene proton), 7.21
(d, J4, 5 ¼ 5.8 Hz, 1H, thiophene proton), 6.88 (s, 2H, NH2),
5.61 (s, 1H, vinyl proton, H-2), 2.56 (t, 2H, H-6), 2.40 (t, 2H,
H-4), 2.07 (quintet, 2H, H-5); ms: (m/z) 218 (Mþ), 190, 162,
123, 68. Anal. Calcd. for C11H10N2OS: C, 60.53; H, 4.62; N,
12.83. Found: C, 60.72; H, 4.49; N, 12.70.
0
0
(d, J4, 5 ¼ 5.8 Hz, 1H, thiophene proton), 7.36 (d, J2 , 3 ¼ 7.5
Hz, 2H, phenyl protons), 7.21 (d, J4, ¼ 5.8 Hz, 1H, thio-
5
phene proton), 6.92 (d, 2H, phenyl protons), 6.40 (s, 2H,
NH2), 5.70 (s, 1H, vinyl proton, H-2), 3.46 (m, 1H, H-5), 2.84
(dd, 1H, H-6a), 2.70–2.63 (m, 3H, H-4 and H-6b); ms: (m/z)
324 (Mþ), 190, 123, 67. Anal. Calcd. for C18H16ClN2OS: C,
66.64; H, 4.97; N, 8.64. Found: C, 66.75; H, 5.13; N, 8.48.
General procedure for the preparation of 9-amino-6,7-
dihydro-5H-thieno[3,2-b]quinolin-8-one derivatives (12a–
g). A suspension of the appropriate 3-(3-oxocyclohex-1-enyl-
amino)thiophene-2-carbonitrile (0.01 mol), K2CO3 (0.01 mol)
and CuCl (0.01 mol) in dry THF (10 mL) was refluxed for 10
h. After completion of reaction, the warm reaction solution
was filtered off. The filtrate was evaporated to dryness, and the
residue was chromatographed on a silica gel column by eluting
with a 30:70 v/v ethyl acetate/chloroform mixture.
3-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)thiophene-2-
carbonitrile (11b). This compound was obtained from 5,5-
dimethylcyclohexane-1,3-dione in 68% yield, mp 152–
1
153ꢁC; H NMR (deuteriochloroform): d 7.54 (d, J4, 5 ¼ 5.8
Hz, 1H, thiophene proton), 7.22 (d, J4, 5 ¼ 5.8 Hz, 1H, thio-
phene proton), 6.23 (s, 2H, NH2), 5.64 (s, 1H, vinyl proton,
H-2), 2.40 (s, 1H, H-6), 2.26 (s, 1H, H-4), 1.13 [s, 6H,
(CH3)2]; ms: (m/z) 246 (Mþ), 190, 123, 67. Anal. Calcd. for
C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C, 63.50;
H, 5.50; N, 11.44.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
Synthesis of 9-Amino-5,6,7,8-tetrahydrothieno[3,2-b]quinoline
and 9-Amino-5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol Derivatives
1135
(m, 2H, H-5), 2.98–2.89 (m, 2H, H-7); ms: (m/z) 324 (Mþ),
308, 201, 190. Anal. Calcd. for C18 H16N2O2S: C, 66.64; H,
4.97; N, 8.64. Found: C, 66.79; H, 5.08; N, 8.53.
9-Amino-6,7-dihydro-5H-thieno[3,2-b]quinolin-8-one (12a). This
compound was obtained from 3-(3-oxocyclohex-1-enyl-amino)-
thiophene-2-carbonitrile in 55% yield, mp 199–200ꢁC; 1H
Preparation of 9-amino-5,6,7,8-tetrahydrothieno[3,2-b]
quinoline (3). A mixture of 0.65 g (3.0 mmol) of 9-amino-
6,7-dihydro-5H-thieno[3,2-b]quinolin-8-one (12a), 0.60 g (12.0
mmol) of hydrazine hydrate, and 0.67 g (12.0 mmol) of potas-
sium hydroxide in 30 mL of ethylene glycol was refluxed for
8 h. After the starting material was disappeared, the reaction
mixture was concentrated by distillating off water and ethylene
glycol. The concentrate was allowed to reach room tempera-
ture and extracted repeatedly with chloroform. The organic
extract was dried with magnesium sulfate and evaporated. The
residue was purified with silica gel column chromatography
eluting with a 30:70 v/v ethyl acetate/chloroform mixture to
give 0.35 g (57%) of 3, mp 137–138ꢁC; 1H NMR (deuterio-
chloroform): d 7.21 and 7.10 (d and d, 2H, thiophene protons),
4.47 (s, 2H, NH2), 2.99 (m, 2H, H-5), 2.54 (m, 2H, H-8),
1.99–1.84 (m, 4H, H-6 and H-7); ms: (m/z) 204 (Mþ), 190,
161, 135. Anal. Calcd. for C11H12N2S: C, 64.67; H, 5.92; N,
13.71. Found: C, 64.88; H, 6.09; N, 13.60.
General procedure for the preparation of 9-amino-
5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol derivatives (4a–
g). A solution of LiAlH4 in Et2O (2.0 mL of 1.0M, 2.0 mmol)
was added dropwise to a solution of the appropriate 9-amino-
6,7-dihydro-5H-thieno[3,2-b]quinolin-8-one (2.0 mmol) in dry
THF (10 mL) maintained at 0ꢁC under nitrogen. After stirring
at room temperature for 5 h, the reaction solution was
quenched by adding 10% HCl, followed by washing with 30%
NaOH to make free base and extracted with chloroform. The
combined organic layers were evaporated to dryness, and the
residue was purified by silica gel column chromatography elut-
ing with a 50:50 v/v ethyl acetate/chloroform mixture.
NMR (deuteriochloroform): d 7.70 and 7.40 (d and d, J2, 3
¼
5.7 Hz, 2H, thiophene protons), 3.13 (t, 2H, H-5), 2.72 (t, 2H,
H-7), 2.16 (quintet, 2H, H-6); ms: (m/z) 218 (Mþ), 190, 71,
57. Anal. Calcd. for C11H10N2OS: C, 60.53; H, 4.62; N, 12.83.
Found: C, 60.66; H, 4.50; N, 12.94.
9-Amino-6,6-dimethyl-6,7-dihydro-5H-thieno[3,2-b]quinolin-
8-one (12b). This compound was obtained from 3-(5,5-di-
methyl-3-oxocyclohex-1-enylamino)thiophene-2-carbonitrile in
67% yield, mp 255–256ꢁC; 1H NMR (deuteriochloroform): d
7.72 and 7.40 (d and d, J2, 3 ¼ 5.7 Hz, 2H, thiophene protons),
3.01 (s, 2H, H-5), 2.57 (s, 2H, H-7), 1.01 [s, 6H, (CH3)2]; ms:
(m/z) 246 (Mþ), 230, 216. Anal. Calcd. for C13H14N2OS: C,
63.39; H, 5.73; N, 11.37. Found: C, 63.23; H, 5.89; N, 11.48.
9-Amino-6-phenyl-6,7-dihydro-5H-thieno[3,2-b]quinolin-8-
one (12c). This compound was obtained from 3-(3-oxo-5-phe-
nylcyclohex-1-enylamino)thiophene-2-carbonitrile in 65%
yield, mp 189–190ꢁC; 1H NMR (deuteriochloroform): d 7.74
and 7.40 (d and d, J2, ¼ 5.7 Hz, 2H, thiophene protons),
3
7.38–7.25 (m, 5H, phenyl), 3.53 (m, 1H, H-6), 3.34–3.28 (m,
2H, H-5), 2.95–2.91 (m, 2H, H-7); ms: (m/z) 294 (Mþ), 265,
238, 203, 190. Anal. Calcd. for C17H14N2OS: C, 69.36; H,
4.79; N, 9.52. Found: C, 69.48; H, 4.63; N, 9.65.
9-Amino-6-p-tolyl-6,7-dihydro-5H-thieno[3,2-b]quinolin-8-
one (12d). This compound was obtained from 3-(3-oxo-5-p-tol-
ylcyclohex-1-enylamino)thiophene-2-carbonitrile
in
62%
yield, mp 262–263ꢁC; 1H NMR (deuteriochloroform): d 7.74
and 7.41 (d and d, J2, 3 ¼ 5.7 Hz, 2H, thiophene protons), 7.26–
7.18 (m, 4H, phenyl), 3.55 (m, 1H, H-6), 3.33–3.29 (m, 2H, H-
5), 2.95–2.92 (m, 2H, H-7), 2.35 (s, 3H, CH3); ms: (m/z) 308
(Mþ), 292, 201, 135. Anal. Calcd. for C18H16N2OS: C, 70.10; H,
5.23; N, 9.08. Found: C, 70.28; H, 5.33; N, 9.19.
9-Amino-5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol (4a). This
compound was obtained from 9-amino-6,7-dihydro-5H-
thieno[3,2-b]quinolin-8-one in 80% yield, mp 218–219ꢁC; 1H
NMR (dimethyl sulfoxide-d6): d 7.78 and 7.22 (d and d, J2, 3
¼ 5.8 Hz, 2H, thiophene protons), 6.16 (s, 2H, NH2), 5.06 (m,
1H, H-8), 2.78–2.66 (m, 2H, H-5), 1.93–1.70 (m, 4H, H-6 and
H-7); ms: (m/z) 220 (Mþ), 202, 201, 187, 175, 164. Anal.
Calcd. for C11H12N2OS: C, 59.97; H, 5.49; N, 12.72. Found:
C, 60.18; H, 5.33; N, 12.88.
9-Amino-6,6-dimethyl-5,6,7,8-tetrahydrothieno[3,2-b]quino-
lin-8-ol (4b). This compound was obtained from 9-amino-6,6-
dimethyl-6,7-dihydro-5H-thieno[3,2-b]quinolin-8-one in 84%
yield, mp 176–177ꢁC; 1H NMR (dimethyl sulfoxide-d6): d
7.74 and 7.24 (d and d, J2, 3 ¼ 5.8 Hz, 2H, thiophene protons),
5.06 (m, 1H, H-8), 2.80 and 2.58 (d and d, J5a, 5b ¼ 13 Hz,
2H, H-5), 2.10 (dd, J ¼ 5.5 and 13 Hz, 1H, H-7a), 1.74 (dd,
J ¼ 6.0 and 13 Hz, 1H, H-7b), 1.13 (s, 3H, CH3), 0.99 (s, 3H,
CH3); ms: (m/z) 248 (Mþ), 230, 215, 203, 188. Anal. Calcd.
for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C,
62.94; H, 6.40; N, 11.39.
9-Amino-6-(4-bromophenyl)-6,7-dihydro-5H-thieno[3,2-b]qui-
nolin-8-one (12e). This compound was obtained from 3-(5-(4-
bromophenyl)-3-oxocyclohex-1-enylamino)thiophene-2-carbon-
1
itrile in 67% yield, mp 197–198ꢁC; H NMR (deuteriochloro-
form): d 7.74 and 7.42 (d and d, J2, 3 ¼ 5.7 Hz, 2H, thiophene
0
0
protons), 7.45 and 7.19 (d and d, J2 , 3 ¼ 7.5 Hz, 4H, phenyl
H-30and H-20), 3.55 (m, 1H, H-6), 3.40–3.29 (m, 2H, H-5),
2.96–2.89 (m, 2H, H-7); ms: (m/z) 308 (Mþ), 292, 203, 161.
Anal. Calcd. for C18H16N2OS: C, 70.10; H, 5.23; N, 9.08.
Found: C, 70.21; H, 5.40; N, 9.22.
9-Amino-6-(4-chlorophenyl)-6,7-dihydro-5H-thieno[3,2-b]qui-
nolin-8-one (12f). This compound was obtained from 3-(5-(4-
chlorophenyl)-3-oxocyclohex-1-enylamino)thiophene-2-carbon-
1
itrile in 68% yield, mp 204–205ꢁC; H NMR (deuteriochloro-
form): d 7.77 and 7.52 (d and d, J2, 3 ¼ 5.7 Hz, 2H, thiophene
0
0
protons), 7.35 and 7.24 (d and d, J2 , 3 ¼ 7.5 Hz, 4H, phenyl),
3.57 (m, 1H, H-6), 3.38–3.30 (m, 2H, H-5), 2.97–2.90 (m, 2H,
H-7); ms: (m/z) 328 (Mþ), 312, 201. Anal. Calcd. for
C17H13ClN2OS: C, 62.10; H, 3.98; N, 8.52. Found: C, 62.27;
H, 4.14; N, 8.40.
9-Amino-6-phenyl-5,6,7,8-tetrahydrothieno[3,2-b]quinolin
8-ol (4c). This compound was obtained from 9-amino-6-phe-
nyl-6,7-dihydro-5H-thieno[3,2-b]quinolin-8-one in 89% yield,
mp 193–194ꢁC; 1H NMR (dimethyl sulfoxide-d6): d 7.57
(d, J2, 3 ¼ 5.8 Hz, 1H, thiophene proton), 7.41–7.29 (m, 6H,
thiophene and phenyl protons), 5.20 (m, 1H, H-8), 3.19–3.09
(m, 3H, H-5 and H-6), 2.68–2.62 (m, 1H, H-7a), 2.06–2.02
(m, 1H, H-7b); ms: (m/z) 296 (Mþ), 278, 263, 251, 201, 187.
9-Amino-6-(4-methoxyphenyl)-6,7-dihydro-5H-thieno[3,2-b]qui-
nolin-8-one (12g). This compound was obtained from 3-(5-(4-
methoxyphenyl)-3-oxocyclohex-1-enylamino)thiophene-2-car-
bonitrile in 70% yield, mp 244–245ꢁC; 1H NMR (deuterio-
chloroform): d 7.74 and 7.29 (d and d, J2, 3 ¼ 5.7 Hz, 2H, thi-
0
0
ophene protons), 7.24 and 6.90 (d and d, J2 , 3 ¼ 7.5 Hz, 4H,
phenyl), 3.78 (s, 3H, OCH3), 3.55 (m, 1H, H-6), 3.39–3.31
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1136
Y.-H. Song and B. S. Jo
Vol 46
Anal. Calcd. for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45.
Found: C, 69.98; H, 5.53; N, 9.57.
(Mþ), 308, 293, 201. Anal. Calcd. for C18H18N2O2S: C, 66.23;
H, 5.56; N, 8.58. Found: C, 66.34; H, 5.64; N, 8.47.
9-Amino-6-p-tolyl-5,6,7,8-tetrahydrothieno[3,2-b]quinolin-8-ol
(4d). This compound was obtained from 9-amino-6-p-tolyl-6,7-
dihydro-5H-thieno[3,2-b]quinolin-8-one in 78% yield, mp
1
131–132ꢁC; H NMR (dimethyl sulfoxide-d6): d 7.84 and 7.25
REFERENCES AND NOTES
0
(d and d, J2, 3 ¼ 5.7 Hz, 2H, thiophene protons), 7.22 (d, J2 ,
¼ 7.5 Hz, 2H, phenyl H-20), 7.16 (d, 2H, phenyl H-30), 5.18
[1] Perry, E. K.; Perry, R. H.; Blessed, G.; Tomlinson, B. E.
Lancet 1977, 1, 189.
30
(m, 1H, H-5), 3.15–2.98 (m, 3H, H-5 and H-6), 2.60–2.52 (m,
1H, H-7a), 2.32 (s, 3H, CH3), 2.06–2.00 (m, 1H, H-7b); ms:
(m/z) 310 (Mþ), 292, 277, 265, 201. Anal. Calcd. for
C18H18N2OS: C, 69.65; H, 5.84; N, 9.02. Found: C, 69.77; H,
5.70; N, 9.10.
[2] Bartus, R. T.; Dean, R. L., III; Beer, B.; Lippa, A. S.
Science 1982, 217, 408.
[3] Crowther, R. A.; Goedert, M. J Struct Biol 2000, 130, 271.
[4] Reve, R. L.; McPhie, D. L.; Chen, Y. Brain Res 2000, 886, 54.
[5] Marco, J. L.; Carreiras, M. C. Mini Rev Med Chem 2003,
3, 518.
9-Amino-6-(4-bromophenyl)-5,6,7,8-tetrahydrothieno[3,2-
b]quinolin-8-ol (4e). This compound was obtained from 9-
amino-6-(4-bromo-phenyl)-6,7-dihydro-5H-thieno[3,2-b]quino-
[6] Selkoe, D. J. Nature 1999, 399, A23.
´
[7] Inestrosa, N. C.; Alvarez, A.; Perez, C. A.; Moreno, R. D.;
1
lin-8-one in 85% yield, mp 116.5–117.5ꢁC; H NMR (dimethyl
Vicente, M.; Linker, C.; Casanueva, O. I.; Soto, C.; Garrido, J. Neuron
1996, 16, 881.
sulfoxide-d6): d 7.75 (d, J2, 3 ¼ 5.7 Hz, 1H, thiophene proton),
7.50 (d, J2 , 3 ¼ 7.5 Hz, 2H, phenyl H-30), 7.34 (d, 1H, thio-
phene proton), 7.25 (d, 2H, phenyl H-20), 5.13 (m, 1H, H-5),
3.14–3.02 (m, 3H, H-5 and H-6), 2.54–2.49 (m, 1H, H-7a),
2.10–2.03 (m, 1H, H-7b); ms: (m/z) 374 (Mþ), 356, 277, 201.
Anal. Calcd. for C17H15BrN2OS: C, 54.41; H, 4.03; N, 7.46.
Found: C, 54.57; H, 4.13; N, 7.34.
0
0
[8] Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V.
Biochem Pharmacol 2003, 65, 407.
[9] Song, Y.-H.; Seo, J. J Heterocycl Chem 2007, 44, 1439.
[10] (a) Seck, P.; Thomae, D.; Kirch, G. J Heterocycl Chem
2008, 45, 853; (b) Thomae, D.; Kirch, G.; Seck, P.; Synthesis 2007, 7,
1027; (c) Marco, J. L.; de los Rios, C.; Carreiras, M. C.; Banos, J. E.;
Badia, A.; Vivas, N. M. Arch Pharm 2002, 7, 347.
[11] Joe, B. S.; Son, H. Y.; Song, Y.-H. Heterocycles 2008, 75,
4301.
9-Amino-6-(4-chlorophenyl)-5,6,7,8-tetrahydrothieno[3,2-
b]quinolin-8-ol (4f). This compound was obtained from 9-
amino-6-(4-chloro-phenyl)-6,7-dihydro-5H-thieno[3,2-b]quino-
lin-8-one in 88% yield, mp 117–118ꢁC; 1H NMR (dimethyl
sulfoxide-d6): d 7.75 (d, J2, 3 ¼ 5.7 Hz, 1H, thiophene proton),
7.35 (s, 4H, phenyl protons), 7.24 (d, 1H, thiophene proton),
5.16 (m, 1H, H-5), 3.13–3.03 (m, 3H, H-5 and H-6), 2.53–2.48
(m, 1H, H-7a), 2.10–2.03 (m, 1H, H-7b); ms: (m/z) 330 (Mþ),
312, 277, 187, 201, 126. Anal. Calcd. for C17H15ClN2OS: C,
61.72; H, 4.57; N, 8.47. Found: C, 61.83; H, 4.64; N, 8.58.
9-Amino-6-(4-methoxyphenyl)-5,6,7,8-tetrahydrothieno[3,2-
b]quinolin-8-ol (4g). This compound was obtained from 9-
amino-6-(4-methoxy-phenyl)-6,7-dihydro-5H-thieno[3,2-b]qui-
[12] Song, Y.-H. Heterocycl Commun 2007, 13, 33.
[13] Gronowitz, S.; Westerlund, C. Acta Chem Scand B 1975,
29, 224.
[14] Gronowitz, S.; Moses, P.; Hornfeldt, A.-B.; Hakanss, R.
Ark Kemi 1961, 17, 165.
[15] Fuller, L. S.; Iddon, B.; Smith, K. A. J Chem Soc Perkin
Trans 1 1997, 1, 3465.
[16] Bjork, M.; Grivas, S. Heterocycles 2005, 65, 2369.
[17] Sharghi, H.; Savari, M. H. Tetrahedron 2002, 58, 10323.
[18] Yoshimoto, Y.; Kunimoto, K.; Tada, S.; Tomita, T.; Wada,
T.; Seto, E.; Murayama, M.; Shibata, Y.; Nomura, A.; Ohata, K.
J Med Chem 1977, 20, 709.
1
nolin-8-one in 86% yield, mp 170–171ꢁC; H NMR (dimethyl
sulfoxide-d6): d 7.74 (d, J2, 3 ¼ 6.0 Hz, 1H, thiophene H-2),
[19] Frank, R. L.; Hall, H. K., Jr. J Am Chem Soc 1950, 72, 1645.
[20] Huang-Minlon. J Am Chem Soc 1946, 68, 2487.
[21] Katsuura, K.; Snieckus, V. Can J Chem 1987, 65, 124.
[22] Ellman, G. L.; Courtney, K. D.; Andres, V. Jr.;
Featherstone, R. M. Biochem Pharmacol 1961, 7, 88.
7.28–7.23 (m, 3H, thiophene H-3 proton and phenyl H-30),
6.90 (d, J2 , 3 ¼ 7.5 Hz, 2H, phenyl H-20), 5.12 (m, 1H, H-5),
3.77 (s, 3H, OCH3), 3.07–2.99 (m, 3H, H-5 and H-6), 2.53–
2.48 (m, 1H, H-7a), 2.09–2.00 (m, 1H, H-7b); ms: (m/z) 326
0
0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet