Synthesis of 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol derivatives

Article abstract of DOI:10.1002/jhet.5570440631

(Chemical Equation Presented) This paper describes the synthesis of 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol derivatives (3a-h) and 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline (8a) in good yield by three-step procedures starting from 2-am

Full text of DOI:10.1002/jhet.5570440631

Nov-Dec 2007
1439
Synthesis of 4-Amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol
Derivatives
Yang-Heon Song* and Jinmoo Seo
Department of Chemistry, Mokwon University
Daejeon 302-729, South Korea
Received February 16, 2007
O
NH2 OH
O
CN
CN
NH
+
NH2
S
O
R
S
N
R
S
R
This paper describes the synthesis of 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol derivatives
(3a-h) and 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline (8a) in good yield by three-step procedures
starting from 2-aminothiophene-3-carbonitrile and 5-substituted cyclohexane-1,3-dione.
J. Heterocyclic Chem., 44, 1439 (2007).
NH2 OH
NH2
R
NH2
R
Alzheimer’s disease (AD), the most common form of
dementia among elderly people, is a progressive and
degenerative disorder of the brain with a loss of memory and
cognition [1]. The deficiency in cholinergic neuro-
transmission is believed to be one of the major causes of the
decline in cognitive and mental functions associated with
AD [2,3]. One rationale therapeutic approach to amplify
cholinergic neurotransmission is to inhibit acetyl- choline
esterase (AChE). The AChE inhibitors currently on market
for the symptomatic treatment of AD are Tacrine (THA,
Cognex®) [4], Donepezil (Aricept®) [5], Rivastigmine
(Exelon®) [6] and Galanthamine (Reminyl®) [7].
A
S
N
R
N
N
2
1
3
a, R = H, A = NR1
b, R = OH, A = S
a: R = H, b: R= Me,
c: R = di-Me, d: R = i-Pr,
e: R = Ph, f: R = p-Tolyl,
a, Tacrine R = H
b, Velnacrine R = OH
g: R = p-ClPh, h: R = p-MeOPh
Figure 1
was obtained, according to modified Gewald reaction, by
the reaction of 1,4-dithiane-2,5-diol and malononitrile
with a catalytic amount of piperidine. Marked improve-
ments in yield could be made when boiling acetonitrile as
reaction solvent was used in place of DMF. Compound
5a-h, 5-substituted cyclohexane-1,3-dione were prepared
by previously known procedures [13,14] or purchased.
The condensation of 4 with 5 under typical conditions for
enamine formation (refluxing dry toluene in the presence
of catalytic amounts of p-toluenesulfonic acid and
following azeotropic removal of water by Dean-Stark
trap) gave the enamino ketones 6a-h, 2-(3-oxocyclohex-1-
enylamino)thiophene-3-carbonitrile derivatives in good
yield. The enamino ketones 6a-h were then cyclized in
refluxing THF in the presence of K2CO3 and CuCl to give
thienoquinolinones 7a-h, 4-amino-7,8-dihydrothieno[2,3-
b]quinolin-5(6H)-one derivatives. It was noteworthy that
a stoichiometric CuCl has to be used to run the reaction
effectively and to obtain a higher yield, while, in the past,
a catalytic amount of CuCl has been used as catalyst in
this type of reaction [10,15-16]. The cyclization reaction
of 6 moisten with small amounts of THF in the presence
of K2CO3 and CuCl was also attempted by using the
microwave assisted method [17], but it was found to yield
instead an inseparable mixture of compounds.
Various analogues and homologues of Tacrine (1a), the
first AChE inhibitor approved by FDA for treatment of
AD in 1993, have been synthesized and studied to
enhance biological potency and to reduce serious side
effects such as hepatotoxcity, which often forces patients
to discontinue treatment. For instance, compounds 2a-b
[8,9] have been synthesized and investigated, which are
structurally related to 1a or Velnacrine (1b) [10], for the
development of new AChE inhibitors.
Therefore, on the basis of the concept of bioisosterism
as an approach for the improvement of biologically active
drugs, it seemed to be suitable to prepare compounds 3a-
h, 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol
derivatives, which have hitherto not been reported in the
chemical literature. Only 3a has ever been reported in a
patent [11], but no spectroscopical data were represented.
Compounds 3a-h have the structure that was modified by
replacement of a benzene ring by a thiophene in chemical
mimic, and by changing the C-3 methylene unit of
cylohexane ring in 1b, known as a less toxic analogue of
1a. This paper describes the facile synthesis of 3a-h and
8a, 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline.
The synthetic routes to 3 are shown in Scheme 1. The
starting material 4, 2-aminothiophene-3-carbonitrile [12]

1440
Y.-H. Song and J. Seo
Vol 44
Scheme 1
NH2
O
O
O
CN
CN
B
A
+
S
N
R
NH2
O
R
S
S
NH
R
7a-h
5a-h
4
6a-h
C
D
NH2
NH2 OH
O
H
Ref. 19
OH
+
+
five steps
-
S
S
NH3
N
R
N
R
2 SnCl6
S
8a
3a-h
R = a: H, b: Me, c : di-Me, d: i-Pr,
e: Ph, f: p-Tolyl, g: p-ClPh,
h: p-MeOPh
Reagents: A: p-TsOH/toluene, reflux; B: K2CO3, CuCl/THF, reflux;
C: LiALH4/THF, H+, 30% NaOH, D: NH2NH2, KOH/ethylene glycol, reflux
was checked on thin-layer chromatography of Merck Kieselgel
60F254 and purified by column chromatography Merck silica gel
(70-230 mesh). The H-nmr spectra were recorded on Bruker
The carbonyl of 7a was transformed into methylene group
by modified Wolff-Kishner reduction (hydrazine hydrate and
KOH under hot ethylene glycol) [18] to give 8a in 71%
yield. Klemm et al. have first reported the preparation of
compound 8a in five steps [19], from the reaction of 2-
hydroxymethylenecyclohexanone (which was stabilized by
conversion to the methyl ether) with 2-aminothiophene salt,
and successive N-oxidation, nitration and reduction reaction.
However, the overall reaction pathway for 8a was extremely
poor (<1% overall yield) and not scaleable route. Thus, the
synthetic way we report here might be very useful and new
alternative synthetic route to 8a.
Finally, the reduction reaction of compounds 7a-h 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 3a-h, 4-amino-5,6,7,8-tetrahydrothieno[2,3-
b]quinolin-5-ol derivatives in quantitative yields. The
compounds 3b and 3d-h were formed with two
diastereomers, and major products were cis compounds.
Since the hydrogens on the alicyclic rings of 3b and 3d-h
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
[20]. The investigation for the AChE inhibition of all
compounds is under way and will be published elsewhere.
1
DRX-300 FT-NMR spectrometer (300 MHz) with Me4Si as
internal standard and chemical shifts are given in ppm (ꢀ). The ir
spectra were taken on a Perkin Elmer Paragon 500 FT-IR
spectrophotometer. Electron ionization mass spectra were
recorded on a HP 59580 B spectrometer. Elemental analyses
were performed on a Carlo Erba 1106 elemental analyzer.
General Procedure for the Preparation of 2-(3-Oxocyclo-
hex-1-enylamino)thiophene-3-carbonitrile Derivatives (6a-h).
A suspension of 2-aminothiophene-3-carbonitrile (0.03 mole),
the appropriate 1,3-cyclohexanedione (0.03 mole) and p-toluene
sulfonic acid monohydrate (0.10 g) in dry toluene (20 ml) was
refluxed for 5-6 hours, and the water was collected in a Dean-
Stark trap. After cooling, the reaction mixture was filtered off.
The filtrate was evaporated to dryness, and the residue was
chromatographed on a silica gel column by eluting with a 20:80
v/v ethyl acetate/chloroform mixture.
2-(3-Oxocyclohex-1-enylamino)thiophene-3-carbonitrile (6a).
This compound was obtained from 1,3-cyclohexanedione in
1
72% yield, mp 157-158°; H-nmr (deuteriochloroform): 7.02 (s,
2H, thiophene protons), 5.79 (s, 1H, vinyl proton, H-2), 2.59 (t,
2H, H-6), 2.42 (t, 2H, H-4), 2.21 (quintet, 2H, H-5); ms: (m/z)
218 (M+), 190, 123. Anal. Calcd. for C11H10N2OS: C, 60.53; H,
4.62, N, 12.83. Found: C, 60.80; H, 4.51; N, 12.69.
2-(5-Methyl-3-oxocyclohex-1-enylamino)thiophene-3-carbo-
nitrile (6b). This compound was obtained from 5-methylcyclo-
hexane-1,3-dione in 83% yield, mp 155-156°; 1H-nmr (deuterio-
chloroform): 7.01 (s, 2H, thiophene protons), 5.76 (s, 1H, vinyl
proton, H-2), 2.58-2.22 (m, 4H, H-4 and H-6), 2.20-2.02 (m, 1H,
H-5), 1.13 (d, 3H, CH3); ms: (m/z) 232 (M+), 190, 123. Anal.
Calcd. for C12H12N2OS: C, 62.04; H, 5.21, N, 12.06. Found: C,
61.86; H, 5.10; N, 11.89.
EXPERIMENTAL
2-(5,5-Dimethyl-3-oxocyclohex-1-enylamino)thiophene-3-
carbonitrile (6c). This compound was obtained from 5,5-
dimethylcyclohexane-1,3-dione in 85% yield, mp 173-174°; H-
Melting points were determined in capillary tubes on Büchi
apparatus and are uncorrected. Each compound of the reactions
1

Nov-Dec 2007
Synthesis of 4-Amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol Derivatives
1441
nmr (deuteriochloroform): 7.01 (dd, 2H, thiophene protons),
5.81 (s, 1H, vinyl proton, H-2), 2.42 (s, 1H, H-6), 2.27 (s, 1H,
H-4), 1.13 (s, 6H, (CH3)2); ms: (m/z) 246 (M+), 190, 123, 67.
Anal. Calcd. for C13H14N2OS: C, 63.39; H, 5.73, N, 11.37. (m,
1H, H-6), Found: C, 63.46; H, 5.57; N, 11.22.
2-(5-Isopropyl-3-oxocyclohex-1-enylamino)thiophene-3-car-
bonitrile (6d). This compound was obtained from 5-isopropyl-
cyclohexane-1,3-dione in 70% yield, mp 138-139°; 1H-nmr
(deuteriochlo- roform): 7.01 (s, 2H, thiophene protons), 5.77 (s,
1H, vinyl proton, H-2), 2.45 2.10 (dd, 1H, H-4), 1.65 (m, 2H, H-
5 and isopropyl CH) 1.13 (s, 6H, (CH3)2); ms: (m/z) 260 (M+),
190, 123. Anal. Calcd. for C14H16N2OS: C, 64.58; H, 6.19, N,
10.76. Found: C, 63.16; H, 5.97; N, 10.84.
H-7); ms: (m/z) 218 (M+), 202. Anal. Calcd. for C11H10N2OS: C,
60.53; H, 4.62, N, 12.83. Found: C, 60.44; H, 4.43; N, 12.89.
4-Amino-7,8-dihydro-7-methylthieno[2,3-b]quinolin-5(6H)-
one (7b). This compound was obtained from 2-(5-methyl-3-
oxocyclohex-1-enylamino)thiophene-3-carbonitrile in 68%
yield, mp 219-220°; 1H-nmr (deuteriochloroform): 7.26 and 7.20
(d and d, 2H, thiophene protons), 3.09 (d, 2H, H-8), 2.79 (d, 2H,
H-6), 2.40 (m, 1H, H-7), 1.14 (d, 3H, CH3); ms: (m/z) 232 (M+),
216, 201. Anal. Calcd. for C12H12N2OS: C, 62.04; H, 5.21, N,
12.06. Found: C, 61.88; H, 5.16; N, 12.14.
4-Amino-7,8-dihydro-7,7-dimethylthieno[2,3-b]quinolin-5-
(6H)-one (7c). This compound was obtained from 2-(5,5-
dimethyl-3-oxocyclohex-1-enylamino)thiophene-3-carbonitrile
1
in 80% yield, mp 221-222°; H-nmr (deuteriochloroform): 7.26
2-(3-Oxo-5-phenylcyclohex-1-enylamino)thiophene-3-car-
bonitrile (6e). This compound was obtained from 5-phenyl-
cyclohexane-1,3-dione in 66% yield, mp 180-181°; 1H-nmr
(deuteriochloroform): 7.34 (s, 5H, phenyl protons), 7.04 (d, 2H,
thiophene protons), 6.63 (s, 1H, vinyl proton, H-2), 3.45 (m, 1H,
H-5), 2.94-2.59 (m, 4H, H-4 and H-6); ms: (m/z) 294 (M+), 190,
131, 123. Anal. Calcd. for C17H14N2OS: C, 69.36; H, 4.79, N,
9.52, S, 10.89. Found: C, 69.19; H, 4.89; N, 9.33, S, 10.75.
2-(3-Oxo-5-p-tolylcyclohex-1-enylamino)thiophene-3-car-
bonitrile (6f). This compound was obtained from 5-p-
(d, 2H, thiophene protons), 2.98 (s, 2H, H-8), 2.55 (s, 2H, H-6),
1.11 (s, 6H, (CH3)2); ms: (m/z) 246 (M+), 230, 216. Anal. Calcd.
for C13H14N2OS: C, 63.39; H, 5.73, N, 11.37. Found: C, 63.12;
H, 5.79; N, 11.34.
4-Amino-7,8-dihydro-7-isopropylthieno[2,3-b]quinolin-5-
(6H)-one (7d). This compound was obtained from 2-(5-
isopropyl-3-oxocyclohex-1-enylamino)thiophene-3-carbonitrile
1
in 70% yield, mp 172-173°; H-nmr (deuteriochloroform): 7.21
(d, 2H, thiophene protons), 3.24 (d, 2H, H-8), 2.78 (d, 2H, H-6),
2.43 (m, 1H, H-7), 1.65 (m, 1H, isopropyl CH), 1.00 (s, 6H,
(CH3)2); ms: (m/z) 260 (M+), 244, 217. Anal. Calcd. for
C14H16N2OS: C, 64.58; H, 6.19, N, 10.76. Found: C, 64.62; H,
6.25; N, 10.87.
1
tolylcyclohexane-1,3-dione in 65% yield, mp 209-210°; H-nmr
(deuteriochloroform): 7.26-7.09 (m, 6H, phenyl and thiophene
protons), 5.87 (s, 1H, vinyl proton, H-2), 3.42-2.65 (m, 5H, H-4,
H-5 and H-6), 2.35(s, 3H, CH3); ms: (m/z) 308 (M+), 190, 123,
67. Anal. Calcd. for C18H16N2OS: C, 70.10; H, 5.23, N, 9.80, S,
10.40. Found: C, 69.88; H, 5.39; N, 9.73, S, 10.22.
4-Amino-7,8-dihydro-7-phenylthieno[2,3-b]quinolin-5(6H)-
one (7e). This compound was obtained from 2-(3-oxo-5-
phenylcyclohex-1-enylamino)thiophene-3-carbonitrile in 65%
yield, mp 227-228°; 1H-nmr (deuteriochloroform): 7.38-7.22 (m,
7H, phenyl and thiophene protons), 3.46 (m, 1H, H-7), 3.29 (m,
2H, H-8), 2.94 (m, 2H, H-6); ms: (m/z) 294 (M+), 278, 201.
Anal. Calcd. for C17H14N2OS: C, 69.36; H, 4.79, N, 9.52. Found:
C, 69.22; H, 4.76; N, 9.49.
2-(5-(4-Chlorophenyl)-3-oxocyclohex-1-enylamino)thio-
ph- ene-3-carbonitrile (6g). This compound was obtained from
5-(4-chlorophenyl)cyclohexane-1,3-dione in 75% yield, mp 165-
1
166°; H-nmr (deuteriochloroform): 7.35-7.29 (dd, 4H, phenyl
protons), 7.05(s, 2H, thiophene protons), 6.63 (s, 1H, vinyl
proton, H-2), 3.45 (m, 1H, H-5), 2.94-2.59 (m, 4H, H-4 and H-
6); ms: (m/z) 328 (M+), 190, 123. Anal. Calcd. for
C17H13ClN2OS: C, 62.10; H, 3.98, N, 8.52. Found: C, 61.84; H,
3.86; N, 8.59.
4-Amino-7,8-dihydro-7-p-tolylthieno[2,3-b]quinolin-5(6H)-
one (7f). This compound was obtained from 2-(3-oxo-5-p-
tolylcyclohex-1-enylamino)thiophene-3-carbonitrile in 75%
yield, mp 225-226°; 1H-nmr (deuteriochloroform): 7.42-7.20 (m,
6H, phenyl and thiophene protons), 3.48 (m, 1H, H-7), 3.34 (m,
2H, H-8), 2.90 (m, 2H, H-6), 2.35 (s, 3H, CH3); ms: (m/z) 308
(M+), 292, 201. Anal. Calcd. for C18H16N2OS: C, 70.10; H, 5.23,
N, 9.08. Found: C, 70.04; H, 5.22; N, 9.14.
2-(5-(4-Methoxyphenyl)-3-oxocyclohex-1-enylamino)thio-
phene-3-carbonitrile (6h). This compound was obtained from
5-(4-methoxyphenyl)cyclohexane-1,3-dione in 70% yield, mp
179-180°; 1H-nmr (deuteriochloroform): 7.15-6.86 (dd, 4H,
phenyl protons), 6.99 (s, 2H, thiophene protons), 5.84 (s, 1H,
vinyl proton, H-2), 3.77 (s, 1H, OCH3), 3.45 (m, 1H, H-5), 2.81-
2.64 (m, 4H, H-4 and H-6); ms: (m/z) 324 (M+), 190, 123, 67.
Anal. Calcd. for C18H16N2OS: C, 66.64; H, 4.97, N, 8.64. Found:
C, 66.84; H, 4.92; N, 8.55.
4-Amino-7-(4-chlorophenyl)-7,8-dihydrolthieno[2,3-b]-
quinolin-5(6H)-one (7g). This compound was obtained from
2-(5-(4-chlorophenyl)-3-oxo-cyclohex-1-enylamino)thiophene-
1
3-carbonitrile in 70% yield, mp 222-223°; H-nmr (deuterio-
General Procedure for the Preparation of 4-Amino-7,8-
dihydrothieno[2,3-b]quinolin-5(6H)-one Derivatives (7a-h). A
suspension of the appropriate 2-(3-oxocyclohex-1-enyl-
amino)thiophene-3-carbonitrile (0.01 mole), K2CO3 (2.0 mmole)
and CuCl (0.01 mole) in dry THF(10 ml) was refluxed for 5-6
hours. 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.
chloroform): 7.34-7.23 (m, 6H, phenyl and thiophene
protons), 3.48 (m, 1H, H-7), 3.36 (m, 2H, H-8), 2.91 (m, 2H,
H-6); ms: (m/z) 328 (M+), 312, 201. Anal. Calcd. for
C17H13ClN2OS: C, 62.10; H, 3.98, N, 8.52. Found: C, 61.88;
H, 4.02; N, 8.44.
4-Amino-7,8-dihydro-7-(4-methoxyphenyl)thieno[2,3-b]-
quinolin-5(6H)-one (7h). This compound was obtained from 2-
(5-(4-methoxyphenyl)-3-oxo-cyclohex-1-enylamino)thio-phene-
3-carbonitrile in 72% yield, mp 191-192°; 1H-nmr (deuterio-
chloroform): 7.23 (d, 2H, thiophene protons), 6.90 (m, 4H,
phenyl protons), 3.78 (s, 3H, OCH3), 3.33 (s, 1H, H-7), 3.20 (d,
2H, H-8), 2.88 (d, 2H, H-6); ms: (m/z) 324 (M+), 308 201. Anal.
Calcd. for C18 H16N2O2S: C, 66.64; H, 4.97, N, 8.64. Found: C,
66.57; H, 4.90; N, 8.47.
4-Amino-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-one (7a).
This compound was obtained from 2-(3-oxocyclohex-1-enyl-
1
amino)thiophene-3-carbonitrile in 60% yield, mp 200-201°; H-
nmr (deuteriochloroform): 7.25 and 7.20 (d and d, 2H, thiophene
protons), 3.10 (t, 2H, H-8), 2.70 (t, 2H, H-6), 2.13 (quintet, 2H,

1442
Y.-H. Song and J. Seo
Vol 44
dihydro-7-p-tolylthieno[2,3-b]quinolin-5(6H)-one in 94% yield,
mp 138-140°; 1H-nmr (dimethyl-d6 sulfoxide): 7.55 (d, J2,3 = 5.9
Hz, 1H, thiophene H-2), 7.10 (d, 1H, thiophene H-3), 7.00 (d,
J2’,3’ = 7.5 Hz, 2H, phenyl H-2’), 6.68 (d, 2H, phenyl H-3’), 5.19
(m, 1H, H-5), 3.20 (s, 3H, CH3), 2.85-2.62 (m, 3H, H-7 and H-
8), 1.83 (m, 2H, H-6); ms: (m/z) 310 (M+), 292, 277. Anal.
Calcd. for C18H18N2OS: C, 69.65; H, 5.84, N, 9.02. Found: C,
69.48; H, 5.88; N, 9.18.
General Procedure for the Preparation of 4-Amino-5,6,
7,8-tetrahydrothieno[2,3-b]quinolin-5-ol Derivatives (3a-h).
A solution of LiAlH4 in Et2O (2.0 ml of 1.0 M, 2.0 mmole) was
added dropwise to a solution of the appropriate 4-amino-7,8-
dihydrothieno[2,3-b]quinolin-5(6H)-one (2.0 mmole) in dry
THF (10 ml) maintained at 0° under nitrogen. After stirring at
room temperature for 2-3 hours, the reaction solution was
quenched by adding 10% HCl, followed by washing with 30%
NaOH to make free base and extracted with ethyl acetate. The
combined organic layers were evaporated to dryness, and the
residue was purified by silica gel column chromatography
eluting with a 40:60 v/v ethyl acetate/chloroform mixture.
4-Amino-7-(4-chlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]-
quinolin-5-ol (3g). This compound was obtained from 4-amino-
7-(4-chlorophenyl)-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-one
in 93% yield, mp 133-134°; 1H-nmr (dimethyl-d6 sulfoxide):
7.57-7.10 (m, 6H, thiophene and phenyl protons), 5.09 (m, 1H,
H-5), 3.12-2.65 (m, 3H, H-7 and H-8), 1.98 (m, 2H, H-6); ms:
(m/z) 330 (M+), 302, 287. Anal. Calcd. for C17 H15 ClN2OS: C,
61.72; H, 4.57, N, 8.47. Found: C, 61.55; H, 4.50; N, 8.60.
4-Amino-5,6,7,8-tetrahydro-7-(4-methoxyphenyl)thieno-
[2,3-b]quinolin-5-ol (3h). This compound was obtained
from 4-amino-7,8-dihydro-7-(4-methoxyphenyl)-thieno[2,3-
b]quinolin-5(6H)-one in 90% yield, mp 136-137°; 1H-nmr
(dimethyl-d6 sulfoxide): 7.54 (d, J2,3 = 6.0 Hz, 1H, thiophene
H-2), 7.33 (d, 1H, thiophene H-3), 7.24 (d, J2’,3’ = 7.5 Hz,
2H, phenyl H-2’), 6.90 (d, 2H, phenyl H-3’), 5.39 (m, 1H,
H-5), 3.73 (s, 3H, OCH3), 2.92-2.65 (m, 3H, H-7 and H-8),
1.92 (m, 2H, H-6); ms: (m/z) 326 (M+), 308, 293. Anal.
Calcd. for C18H18N2O2S: C, 66.23; H, 5.56, N, 8.58. Found:
C, 66.01; H, 5.45; N, 8.66.
4-Amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol (3a).
This compound was obtained from 4-amino-7,8-dihydro-thieno-
[2,3-b]quinolin-5(6H)-one in 85% yield, mp 227-229° (dec) (lit
1
[11] 226°); H-nmr (dimethyl-d6 sulfoxide): 7.49 (d, J2,3 = 6 Hz,
1H, thiophene H-2), 7.30 (d, 1H, H-3), 4.96 (m, 1H, H-5), 4.72
(brs, 1H, exchanges with D2O, OH), 2.62 (m, 2H, H-8), 2.04-
1.74 (m, 4H, H-6 and H-7); ms: (m/z) 220 (M+), 202, 201, 187.
Anal. Calcd. for C11H12N2OS: C, 59.97; H, 5.49, N, 12.72.
Found: C, 60.28; H, 5.42; N, 12.84.
4-Amino-5,6,7,8-tetrahydro-7-methylthieno[2,3-b]quino-
lin-5-ol (3b). This compound was obtained from 4-amino-7,8-
dihydro-7-methylthieno[2,3-b]quinolin-5(6H)-one in 92% yield,
mp 158-159°; 1H-nmr (dimethyl-d6 sulfoxide): 7.51 (d, J2,3 = 5.9
Hz, 1H, thiophene H-2), 7.30 (d, 1H, H-3), 4.96 (m, 1H, H-5),
2.81 (m, 2H, H-8), 2.40 (m, 1H, H-7), 1.45 (m, 2H, H-6), 1.08
(d, 3H, CH3); ms: (m/z) 234 (M+), 216, 201, 187. Anal. Calcd.
for C12H14N2OS: C, 61.51; H, 6.02, N, 11.96. Found: C, 61.33;
H, 6.10; N, 12.20.
Preparation of 4-Amino-5,6,7,8-tetrahydrothieno[2,3-b]-
quinoline (8a). A mixture of 0.65 g (3.0 mmole) of 4-amino-
7,8-dihydro- thieno[2,3-b]quinolin-5(6H)-one (7a), 0.60 g
(12.0 mmole) of hydrazine hydrate, and 0.67 g (12.0 mmole)
of potassium hydroxide in 30 ml of ethylene glycol was
4-Amino-5,6,7,8-tetrahydro-7,7-dimethylthieno[2,3-b]-
quinolin-5-ol (3c). This compound was obtained from 4-amino-
7,8-dihydro-7,7-dimethylthieno[2,3-b]quinolin-5(6H)-one in
refluxed for
8 hours. After the starting material was
1
89% yield, mp 163-164°; H-nmr (dimethyl-d6 sulfoxide): 7.39
consumed, the reaction mixture was concentrated by
removing water and ethylene glycol by distillation. The
concentrate was allowed to reach room temperature 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
0.43 g (71%) of 8a, mp 150-151° (lit [19] 150-152°). The
spectroscopical data were identical with those reported
previously [19].
(d, J2,3 = 5.9 Hz, 1H, thiophene H-2), 7.17 (d, 1H, H-3), 5.03 (m,
1H, H-5), 2.51 (d, 1H, AB system, H-8), 2.33 (d, 1H, AB
system, H-8), 1.82 (dd, J = 6.0 and 13 Hz, 1H, H-6), 1.49 (dd, J
= 5.5 and 13 Hz, 1H, H-6), 0.99 (s, 6H, (CH3)2); ms: (m/z) 248
(M+), 230, 215. Anal. Calcd. for C13H16N2OS: C, 62.87; H, 6.49,
N, 11.28. Found: C, 62.72; H, 6.44; N, 11.40.
4-Amino-5,6,7,8-tetrahydro-7-isopropylthieno[2,3-b]quino-
lin-5-ol (3d). This compound was obtained from 4-amino-7,8-
dihydro-7-isopropyllthieno[2,3-b]quinolin-5(6H)-one in 94%
yield, mp 174-175°; 1H-nmr (dimethyl-d6 sulfoxide): 7.52 (d, J2,3
= 5.9 Hz, 1H, thiophene H-2), 7.26 (d, 1H, H-3), 4.83 (m, 1H,
H-5), 2.66 (d, 1H, AB system, H-8), 2.50 (d, 1H, AB system, H-
8), 1.70-1.42 (m, 4H, H-6, H-7 and isopropyl CH), 0.99 (d, 6H,
(CH3)2); ms: (m/z) 262 (M+), 244, 229. Anal. Calcd. for
C14H18N2OS: C, 64.09; H, 6.91, N, 10.68. Found: C, 63.88; H,
6.94; N, 10.47.
Acknowledgement. The authors thank KBSI(Korea Basic
Science Institute) for providing mass and elemental analysis
data.
REFERENCES AND NOTES
*
Address reprint requests to Prof. Yang-Heon Song: Depart-
4-Amino-5,6,7,8-tetrahydro-7-phenylthieno[2,3-b]quinolin-
5-ol (3e). This compound was obtained from 4-amino-7,8-
dihydro-7-phenylthieno[2,3-b]quinolin-5(6H)-one in 92% yield,
mp 157-158°; 1H-nmr (dimethyl-d6 sulfoxide): 7.55 (d, J2,3 = 5.9
Hz, 1H, thiophene H-2), 7.35-7.2 (m, 6H, H-3 and phenyl
protons), 4.98 (m, 1H, H-5), 2.97 (m, 2H, H-8), 2.88 (d, 1H, H-
7), 1.98 (m, 2H, H-6); ms: (m/z) 296 (M+), 278, 263, 187. Anal.
Calcd. for C17H16N2OS: C, 68.89; H, 5.44, N, 9.45. Found: C,
69.02; H, 5.41; N, 9.60.
ment of Chemistry, Mokwon University Daejeon 302-729, South Korea.
E-mail:yhsong@mokwon.ac.kr
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Nov-Dec 2007
Synthesis of 4-Amino-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-5-ol Derivatives
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