T. Putkonen et al. / Tetrahedron 59 (2003) 8589–8595
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H, 8.13; N, 12.56; MS (EI): m/z 111 (Mþ), 83 (100%), 55;
IR, n/cm21: 3320 (NH2), 1670 (CvO); NMR dH (400 MHz;
DMSO-d6): 6.70 (2H, br s, NH2), 4.91 (1H, s, 2-H), 2.25
(2H, t, J¼6 Hz, 6-H), 2.01 (2H, t, J¼6 Hz, 4-H), 1.78 (2H,
quintet, J¼6 Hz, 5-H); NMR dC (100 MHz; DMSO-d6):
194.3 (CvO), 167.0 (C-3), 97.5 (C-2), 35.9 (C-6), 27.9
(C-4), 21.5 (C-5).
30.5 (C-8, keto), 30.4 (C-8, enol), 25.0 (C-7, keto), 19.9
(C-7, enol).
4.2.4. 10-[20-(30-Indolyl)-ethyl]-6-methoxycarbonyl-5-
oxo-5,6,7,8-tetrahydroquinolinium bromide 5. Ester 4
(820 mg, 4 mmol) was alkylated with tryptophyl bromide
(895 mg, 4 mmol) at 1008C for 2 h. The crude product was
washed several times with CH2Cl2 to give salt 5 (1.54 g,
90%) as yellow powder (enol). IR, n/cm21: 3170 (NH),
1660 (CO2CH3); NMR dH (400 MHz; CD3OD): 8.60 (1H, d,
J4,3¼8 Hz, 4-H), 8.58 (1H, d, J2,3¼6.5 Hz, 2-H), 7.82 (1H,
dd, J3,2¼6.5 Hz, J3,4¼8 Hz, 3-H), 7.35 (1H, d, J¼8 Hz, 70-
H), 7.26 (1H, 0d, J¼8 Hz, 40-H), 7.10 (1H, 0t, J¼8 Hz, 60-H),
6.98 (1H, s, 2 -H), 6.96 (1H, t, J¼8 Hz, 5 -H), 4.95 (2H, t,
J¼6 Hz, b-H), 3.84 (3H, s, –OCH3), 3.46 (2H, t, J¼6 Hz,
a-H), 3.08 (2H, t, J8,7¼8 Hz, 8-H), 2.29 (2H, t, J¼8 Hz,
7-H); NMR dC (100 MHz; CD3OD): 172.6 (–CO2CH3),
158.9 (C-8a), 157.90(C-5), 146.8 (C-2), 139.8 (C-4), 138.1
(C-6), 132.2 (C-7a ), 128.2 (C-3a0), 126.6 (C-3), 1250.2
(C-20), 123.1 (C-60), 120.6 (C-50), 118.2 (C-40), 112.8 (C-7 ),
109.4 (C-30), 101.2 (C-4a), 60.2 (C-b), 53.0 (–CO2CH3),
27.3 (C-a), 25.9 (C-8), 19.3 (C-7).
4.2.2. 7,8-Dihydroquinoline-5(6H)-one 3. A solution of
1,1,3,3-tetraethoxylpropane (10 mL, 40 mmol), 3-amino-
cyclohex-2-enone 2 (4.6 g, 40 mmol) and a catalytical
amount of p-toluenesulfonic acid hydrate in DMF (17 mL)
was heated under reflux for 18 h. The solvent was distilled
in vacuo, the residue neutralized with NaHCO3, extracted
with CH2Cl2 and dried (Na2SO4). Column chromatography
(silica gel, 2% MeOH in CH2Cl2) gave the title compound
(2.06 g, 35%) as light yellow oil. HRMS calcd for C9H9NO:
m/z 147.0684. Found: m/z 147.0610; MS (EI): m/z 147
(Mþ), 119 (100%), 91; IR, n/cm21: 1690 (CvO); NMR dH
(400 MHz): 8.68 (1H, dd, J2,4¼2 Hz, J2,3¼5 Hz, 2-H), 8.28
(1H, dd, J4,2¼2 Hz, J4,3¼8 Hz, 4-H), 7.29 (1H, dd,
J3,2¼5 Hz, J3,4¼8 Hz, 3-H), 3.17 (2H, t, J¼6.5 Hz, 6-H),
2.71 (2H, t, J¼6.5 Hz, 8-H), 2.22 (1H, quintet, J¼6.5 Hz,
7-H); NMR dC (100 MHz): 197.8 (CvO), 163.6 (C-8a),
153.5 (C-2), 134.9 (C-4), 128.1 (C-4a), 122.2 (C-3), 38.5
(C-6), 32.5 (C-8), 21.8 (C-7).
4.2.5. 10-[20-(30-Indolyl)-ethyl]5-oxo-1,4,5,6,7,8-hexa-
hydroquinoline-6-carboxylic acid methyl ester 6. Sodium
dithionite (750 mg, 4.3 mmol, 6.2 equiv.) was added in
small portions during 20 minutes to the solution of bromide
4.2.3. 5-Oxo-5,6,7,8-tetrahydroquinoline-6-carboxylic
acid methyl ester 4. 7,8-Dihydroquinoline-5(6H)-one 3
(1.76 g, 12 mmol) was added to a stirred suspension of
sodium hydride (1.4 equiv. washed with hexane) in
dimethyl carbonate (10 mL). A few drops of dry methanol
were added to initiate the reaction. The reaction mixture
turned lilac and was refluxed for 5 h. It was allowed to cool
to room temperature and neutralized with 2N HCl. The
mixture was extracted with CH2Cl2, dried (Na2SO4) and
crystallized to yield a pale yellow crystalline solid (2.21 g,
90%), mp 678C (hexane, enol). CHN-anal. calcd for
C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.41;
H, 5.32; N, 6.76; MS (EI): m/z 205 (Mþ), 190, 173, 146,
145, 117 (100%), 91; IR, n/cm21: 3280 (OH, enol), 1740
(CO2CH3, keto), 1650 (CO2CH3, enol), 1620 (CvO, keto);
NMR dH (400 MHz): 12.30 (1H, s, OH, enol), 8.71 (1H, dd,
J2,4¼2 Hz, J2,3¼5 Hz, 2-H, keto), 8.49 (1H, dd, J2,4¼2 Hz,
J2,3¼5 Hz, 2-H, enol), 8.30 (1H, dd, J4,2¼2 Hz, J4,3¼8 Hz,
4-H, keto), 8.03 (1H, dd, J4,2¼2 Hz, J4,3¼7.5 Hz, 4-H,
enol), 7.32 (1H, dd, J3,2¼5 Hz, J3,4¼8 Hz, 3-H, keto), 7.23
(1H, dd, J3,2¼5 Hz, J3,4¼7.5 Hz, 3-H, enol), 3.85 (3H, s,
–OCH3, enol), 3.79 (3H, s, –OCH3, keto), 3.67 (1H, dd,
J6ax,7eq¼5 Hz, J6ax,7ax¼10 Hz, 6ax-H, keto), 3.28 (1H, ddd
J8eq,7ax¼5 Hz, J8eq,7eq¼6 Hz, J8eq,8ax¼18 Hz, 8eq-H, keto),
3.17 (1H, ddd, J8ax,7eq¼5 Hz, J8ax,7ax¼9 Hz, J8ax,8eq¼18
Hz, 8ax-H, keto), 3.03 (2H, t, J¼8 Hz, 8-H, enol), 2.69 (2H,
t, J¼8 Hz, 7-H, enol) 2.57 (1H, dddd, J7ax,8eq¼5 Hz,
J7ax,8ax¼9 Hz, J7ax,6ax¼10 Hz, J7ax,7eq¼14 Hz, 7ax-H,
keto), 2.43 (1H, dddd, J7eq–6ax¼5 Hz, J7eq–8ax¼5 Hz,
J7eq–8eq¼6 Hz, J7eq–7ax¼14 Hz, 7eq-H, keto); NMR dC
(100 MHz): 192.8 (CvO, keto), 172.7 (–CO2CH3, enol),
170.0 (–CO2CH3, keto), 163.3 (C-8b, enol), 162.8 (C-8b,
keto), 159.4 (C-5, enol), 154.0 (C-2, keto), 150.4 (C-2,
enol), 135.6 (C-6, enol), 135.6 (C-4, keto), 131.5 (C-4,
enol), 122.4 (C-3, keto), 121.8 (C-3, enol), 97.5 (C-4b), 53.8
(C-6, keto), 52.5 (–CO2CH3, keto), 51.8 (–CO2CH3, enol),
salt 5 (300 mg, 0.7 mmol) and NaHCO3 (940 mg,
11.2 mmol, 16 equiv.) in 50 mL aqueous MeOH (1:2;
H2O–MeOH). The mixture was stirred for 18 h at room
temperature and evaporated under vacuum. The residue was
extracted several times with CH2Cl2, dried over Na2SO4 and
evaporated under vacuum to give nearly pure product 6
(235 mg, 95%) as yellow amorphous solid. To avoid
dissociation, the product was not purified. HRMS calcd
for C21H22N2O3: m/z 350.1630. Found: m/z 350.1600; MS
(EI): m/z 350 (Mþ), 319, 291, 220, 144, 130 (100%); IR,
n/cm21: 3270 (NH), 1735 (CO2CH3), 1610 (CvO); NMR
dH (400 MHz): 8.31 (1H, s, NH), 7.57 (1H, d, J¼8 Hz,
400-H), 7.37 (1H, d, J¼8 Hz, 70-H), 7.20 (1H, t, J¼8 Hz,
60-H), 7.13 (1H, t, J¼8 Hz, 50-H), 7.03 (1H, d, J¼2.5 Hz,
2 -H), 5.78 (1H, br d, J2,3¼8 Hz, 2-H), 5.02 (1H, ddd,
J3,4¼4, 4 Hz, J3,2¼8 Hz, 3-H), 3.70 (3H, s, –OCH3), 3.53
(2H, t, J¼7 Hz, b-H), 3.19 (1H, dd, J6ax,7eq¼5 Hz,
J6ax,7ax¼8.5 Hz, 6ax-H), 3.08 (2H, def d, 4-H), 3.02 (2H, t,
J¼7 Hz, a-H), 2.2–2.3 (1H, m, 8eq-H), 1.9–2.1 (2H, m,
7ax-H, 8ax-H), 1.75–1.85 (1H, m, 7eq-H); NMR dC
(100 MHz): 189.7 (CvO), 171.5 (–CO2CH3), 155.6
(C-8a), 136.3 (C-7a0), 128.9 (C-2), 127.0 0 (C-3a0), 1220.6
(C-20), 122.3 (C-60), 119.7 (C-50), 118.1 (C-4 ), 111.6 (C-3 ),
111.4 (C-70), 107.8 (C-3), 104.7 (C-4a), 52.0 (–CO2CH3),
51.2 (C-6), 50.2 (C-b), 25.7 (C-a), 23.7 (C-7), 23.6 (C-8),
21.5 (C-4).
4.2.6. Compound 7. Ester 6 (690 mg, 2.0 mmol) was
dissolved in HCl/MeOH (240 mL) and stirred for 65 h. The
solvent was evaporated and the residue was neutralized with
aq. NaHCO3 and extracted with CH2Cl2. Purification (silica
gel, 5% MeOH–CH2Cl2) gave two isomers (585 mg, 85%)
of the title product as amorphous yellow solid. The overall
yield of two reactions (5!7) was 80%. HRMS calcd for
C21H22N2O3: m/z 350.1630. Found: m/z 350.1669; MS (EI):
m/z 350 (Mþ, 100%), 291, 169, 156; IR, n/cm21: 3260