L. Guandalini et al. / Bioorg. Med. Chem. 13 (2005) 799–807
805
(m, 2H); 3.48–3.57 (m, 2H); 7.37–7.42 (m, 1H); 7.56 (d,
1H, J = 8.4Hz); 7.71 (s, 1H, H-8); 7.84 (d, 1H,
J = 8.4Hz); 8.18 (d, 1H, J = 8.8Hz); 8.64 (m, 1H, H-2)
ppm. Anal. (C14H19IN2) C, H, N.
solvent was evaporated, obtaining a mixture of the title
compound and 6-(but-3-en-1-ynyl)quinoline 14, which
was separated by flash chromatography (using abs.
EtOH/CH2Cl2/Et2O/Pet. ether/NH4OH 180:360:360:
900:9.9 as eluent). The aqueous layer was alkalinized
and extracted again with CH2Cl2; after drying (Na2SO4)
and removal of the solvent, the title compound (2.98g)
was obtained as a yellowish oil.
6.1.6.4. N,N,N-Trimethyl(quinolin-5-yl)methanamin-
ium iodide (10). 50% yield. Mp 200°C. [1H] NMR
(200MHz, D2O, d): 2.94 (s, 9H, +N(CH3)3); 4.82 (m,
2H, CH2N); 7.49 (dd, J = 6.6Hz, 4.4Hz, 1H, H-3);
7.62–7.71 (m, 2H), 7.98 (dd, 1H, J = 6.0Hz, 4.0Hz),
8.50 (d, 1H, J = 8.1Hz, H-8), 8.69 (d, 1H, J = 4.4Hz,
H-2). Anal. (C13H17IN2) C, H, N.
Compound 13 (total yield 73%) [1H] NMR (400MHz,
CDCl3, d) 2.62 (t, 2H, J = 6.4Hz, CH2C„C), 2.98 (t,
2H, J = 6.4Hz, CH2N), 7.40 (dd, 1H, J = 8.3Hz,
4.2Hz, H-3), 7.69 (dd, 1H, J = 8.7Hz, 1.8Hz, H-7),
7.89 (d, 1H, J = 1.4Hz, H-5), 8.02 (d, 1H, J = 8.7Hz,
H-8), 8.10 (d, 1H, J = 7.9Hz, H-4), 8.89 (dd, 1H,
J = 4.0Hz, 1.6Hz, H-2) ppm. [13C] NMR (50MHz,
CDCl3, d) 24.68 (t), 42.64 (t), 81.71 (s), 89.50 (s),
121.70 (d), 122.05 (s), 128.05 (s), 129.52 (d), 130.98
(d), 132.48 (d), 135.68 (d) 147.53 (s), 150.78 (d) ppm.
Anal (C13H12N2) C, H, N.
6.1.7. 4-(Quinolin-6-yl)-3-butyn-1-ol (11). To a solution
of 6-bromoquinoline (1.73g, 8.32mmol) and 3-butyn-
1-ol (1.16g, 16.6mmol) in anhydrous Et3N (20mL), pal-
ladium-tetrakis(triphenylphosphine) (0.38g) and CuBr
(0.14g) were added and the mixture heated at 90°C
for 70min. After cooling, the mixture was partitioned
between a saturated solution of NH4Cl and Et2O; the
aqueous layer was made alkaline and extracted with
Et2O. After drying (Na2SO4) and removal of the solvent
under vacuum, the title compound was obtained in 82%
yield as a white solid. Mp 70–71°C. [1H] NMR
(400MHz, CDCl3, d) 2.53 (br s, 1H, OH), 2.76 (t, 2H,
J = 6.3Hz, CH2C„C), 3.88 (br s, 2H, CH2O), 7.39
(dd, 1H, J = 8.3Hz, 4.2, H-3), 7.66 (d, 1H, J = 8.7Hz,
H-7), 7.86 (s, 1H, H-5), 8.01 (d, 1H, J = 8.7Hz, H-8),
8.07 (d, 1H, J = 8.2Hz, H-4), 8.88 (d, 1H, J = 4.2Hz,
H-2) ppm. [13C] NMR (50MHz, CDCl3, d) 23.88 (t),
60.78 (t), 81.42 (s), 88.23 (s), 121.55 (d), 121.99 (s),
127.87 (s), 128.84 (d), 130.86 (d), 132.52 (d), 135.91
(d), 146.89 (s), 15.033 (d) ppm. GC-MS (EI) M (%):
197 (47), 167 (47), 166 (100), 140 (24), 139 (30), 63
(22). Anal. (C13H11NO) C, H, N.
Compound 14 (19% yield) [1H] NMR (200MHz,
CDCl3, d) 5.56 (dd, 1H, J = 2.2, 11.0Hz, @CHH), 5.76
(dd, 1H, J = 17.4Hz, 2.2Hz, @CHH), 6.03 (dd, 1H,
J = 17.4Hz, 10.6Hz, CH@), 7.33 (dd, 1H, J = 8.4Hz,
4.4Hz, H-3), 7.68 (dd, 1H, J = 8.8Hz, 1.8Hz, H-7),
7.86 (d, 1H, J = 1.5Hz, H-5), 8.00 (d, 1H, J = 8.4Hz,
H-8), 8.02 (dd, 1H, J = 8.1Hz, 1.5Hz, H-4), 8.89 (dd,
1H, J = 4.0Hz, 1.6Hz, H-2) ppm. Anal (C13H9N) C,
H, N.
6.1.10. 6-(3,4-Dihydro-2H-pyrrol-5-yl)quinoline (15). To
a solution of 13 (2.98g, 15.2mmol) in CH3CN (90mL)
and H2O (20mL), PdCl2 (0.43g) was added and the mix-
ture heated at 80°C for 3.5h. After cooling, the mixture
was treated with Et2O, washed first with a saturated
water solution of NaCl and then with dil NH4OH, dried
(Na2SO4) and evaporated, obtaining the title compound
in 67% yield. Yellow solid, mp 115–120. This compound
was used as such for the following step.
6.1.8. 4-(Quinolin-6-yl)-3-butynyl methanesulfonate (12).
To a solution of 11 (0.2g, 1.05mmol) and pyridine
(0.7mL) in amylene-stabilized CHCl3 (3mL), cooled at
0°C, methanesulfonyl chloride (1.14g, 1.2equiv) was
added dropwise and the mixture was allowed to warm
to room temperature. After 2h stirring at this T, the
mixture was treated with water and extracted in CHCl3.
The organic solvent was evaporated, the residue was
treated with 0.1M HCl and extracted with Et2O; the
aqueous layer was alkalinized with NaOH 10% and ex-
tracted again with CHCl3. Drying (Na2SO4) and re-
moval of the solvent gave the title compound as an oil
in 96% yield. [1H] NMR (400MHz, CDCl3, d) 2.95 (t,
2H, J = 6.7Hz, CH2C„C), 3.10 (s, 3H, CH3SO3), 4.44
(t, 2H, J = 6.7Hz, CH2O), 7.41 (dd, 1H, J = 8.3Hz,
4.2Hz, H-3), 7.68 (dd, 1H, J = 8.6Hz, 1.7Hz, H-7),
7.90 (d, 1H, J = 1.4Hz, H-5), 8.03 (d, 1H, J = 8.7Hz,
H-8), 8.10 (d, 1H, J = 8.3Hz, H-4), 8.91 (dd, 1H,
J = 4.4Hz, 1.6Hz, H-2) ppm. Anal. (C14H13NO3S) C,
H, N.
[1H] NMR (400MHz, CDCl3, d) 2.12 (m, 2H, C–CH2–
C), 3.08 (m, 2H, CH2C@), 4.15 (m, 2H, CH2N), 7.44
(dd, 1H, J = 8.2Hz, 4.2Hz, H-3), 8.12 (d, 1H,
J = 8.8Hz, H-7), 8.18 (d, 1H, J = 1.5Hz, H-5), 8.21 (d,
1H, J = 7.8Hz, H-8), 8.32 (dd, 1H, J = 8.8Hz, 1.9Hz,
H-4), 8.95 (dd, 1H, J = 4.2Hz, 1.6Hz, H-2) ppm. [13C]
NMR (50MHz, CDCl3, d) 22.86 (t), 35.05 (t), 61.86
(t), 121.65 (d), 127.79 (d), 127.94 (s), 128.38 (d), 129.72
(d), 132.84 (s), 136.77 (d), 149.22 (s) 151.33 (d), 172.70
(s) ppm.
6.1.11. 6-(Pyrrolidin-2-yl)quinoline (16). To a solution of
compound 15 (0.05g, 0.26mmol) in absolute ethanol
(100mL), cooled at ꢀ70°C, NaBH4 (0.03g, 0.79mmol)
was added portionwise. The reaction was allowed to
warm to room temperature, then the mixture was con-
centrated under vacuum, treated with NaOH 0.1M
and extracted with CH2Cl2. After drying (Na2SO4)
and removal of the solvent, 0.05g of a residue was ob-
tained, which was purified by transformation into the
oxalate salt by treatment with oxalic acid in ethyl ace-
tate. Mp 192–194°C. Yield 72%.
6.1.9. 4-(Quinolin-6-yl)-3-butyn-1-amine (13). A mixture
of 12 (7.12g, 0.026 mol) and NH3 (130mL, 33% in
water) in isopropanol (100mL) was heated at 60°C for
18h. The solvent was removed under vacuum and the
residue partitioned between H2O and CH2Cl2; the or-
ganic layer was collected and dried (Na2SO4), then the