Journal of Medicinal Chemistry
Article
removed by distillation in vacuo and the residue was purified by silica
gel flash chromatography (EtOAc as eluent) and crystallization. Beige
solid, mp 117−8 °C (CH2Cl2−petroleum ether); 48% yield. 1H NMR
(200 MHz, CDCl3) δ 1.26 (t, 3H, J = 7.5 Hz), 2.40 (q, 2H, J = 7.5
Hz), 4.01 (s, 3H), 4.73 (d, 2H, J = 4.5 Hz), 6.84−6.89 (m, 1H), 7.20
(br s, 1H), 7.31 (d, 1H, J = 8.5 Hz), 7.61−7.65 (m, 2H), 8.54 (d, 1H, J
= 8.5 Hz). 13C NMR (50 MHz, CDCl3) δ 173.9, 156.4, 155.2, 148.0,
131.7, 129.8, 120.7, 119.7, 119.1, 104.3, 55.7, 44.7, 29.7, 9.9. ESI MS
(m/z): 245 (M + H)+.
N-[(1-Benzyl-5-methoxy-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-
propionamide (8a). This product was obtained starting from 6a and
using the above N1-benzylation procedure described for compound 6n.
Flash chromatography: silica gel, EtOAc−cyclohexane 7:3 as eluent
and crystallization. White solid, mp 154−5 °C (CH2Cl2−petroleum
ether); 89% yield. 1H NMR (200 MHz, CDCl3) δ 1.04 (t, 3H, J = 7.5
Hz), 1.85−2.05 (m, 4H), 2.44−2.62 (m, 1H), 2.80−2.96 (m, 1H),
3.26−3.41 (m, 2H), 3.43−3.55 (m, 1H), 3.81 (s, 3H), 4.48 (d, 1H J =
17.0 Hz), 4.64 (d, 1H J = 17.0 Hz), 5.45 (br s, 1H), 6.28 (d, 1H J = 8.0
Hz), 6.32 (d, 1H J = 8.0 Hz), 6.99 (dd, 1H, J1 = J2 = 8.0 Hz), 7.23−
7.37 (m, 5H). 13C NMR (50 MHz, CDCl3) δ 173.9, 157.3, 145.2,
139.7, 128.4, 126.8, 126.7, 126.5, 109.5, 106.2, 98.6, 56.8, 56.5, 55.4,
41.1, 29.5, 23.9, 23.3, 9.7. ESI MS (m/z): 339 (M + H)+.
2ABq, 1H J = 17.4 Hz, 1H, H9A), 6.37 (d, J = 7.8 Hz, 1H, H8), 6.46
(td, 1H, J1 = J2 = 7.2, J3 = 0.6 Hz, H6), 6.81 (bt, 1H, J1 = J2 = 7.8 Hz,
H7), 6.89 (d, 1H, J = 7.2 Hz, H5), 7.12−7.15 (m, 1H, Ph), 7.18−7.24
(m, 4H, Ph). 13C NMR (50 MHz, CDCl3) δ 170.2, 144.6, 139.3,
129.1, 128.7, 127.2, 127.0, 126.7, 122.0, 116.7, 113.1, 57.3, 55.7, 41.6,
23.8, 23.3, 23.1. EI MS (m/z) 294 (M+), 91 (100).
1H NMR and NOESY spectra of compound 8e are depicted in
1
NMR spectrum can be found at page S6 of the Supporting
Information.
Milligram-scale optical resolution of ( )-8e by MPLC, using
triacetylcellulose (TAC) as chiral stationary phase,31 afforded optical
isomers (+)-8e and (−)-8e.
Compound (+)-8e. [α]25 = +74.3 at λ = 365 nm (Hg lamp), (c
0.152 in abs EtOH); tR = 17.09 min [97% enantiomeric purity, as
determined by analytical HPLC analysis on a Chiralcel (Chiralpak)
AD-H column, using hexane−i-PrOH 9:1 as eluent, at 262 nm and a
flow rate = 1.0 mL/min].
Compound (−)-8e. [α]25 −74.8 at λ = 365 nm (Hg lamp), (c 0.096
in abs EtOH); tR = 19.5 min [98% enantiomeric purity; Chiralcel
(Chiralpak) AD-H column, hexane−i-PrOH 9:1 as eluent, at 262 nm
and a flow rate = 1.0 mL/min].
N-(1-Benzyl-6-methoxy-1,2,3,4-tetrahydroquinolin-2-yl-methyl)-
propionamide (8b). This product was obtained starting from 6b and
using the above N1-benzylation procedure described for compound 6n.
Flash chromatography: silica gel, EtOAc/cyclohexane 1:1 as eluent and
crystallization. White solid, mp 147−8 °C (EtOAc−hexane); 78%
N-[(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-
cyclopropanecarboxamide (8f). This product was obtained starting
from 6f and using the above N1-benzylation procedure described for
compound 6n. Flash chromatography: silica gel, cyclohexane−EtOAc
7:3 as eluent and crystallization. White solid, mp 158−9 °C (CH2Cl2−
1
1
yield. H NMR (200 MHz, CDCl3) δ 1.02 (t, 3H J = 7.5 Hz), 1.90−
petroleum ether); 58% yield. H NMR (200 MHz, CDCl3) δ 0.62−
2.05 (m, 4H), 2.72−2.85 (m, 2H), 3.14−3.47 (m, 3H), 3.74 (s, 3H),
4.39 (d, 1H, J = 16.5 Hz), 4.54 (d, 1H, J = 16.5 Hz), 5.45 (br s, 1H),
6.61−6.64 (m, 3H), 7.23−7.39 (m, 5H). 13C NMR (50 MHz, CDCl3)
δ 173.8, 151.6, 139.8, 139.1, 128.7, 127.1, 127.0, 124.0, 115.5, 114.5,
112.9, 57.3, 57.0, 55.7, 41.2, 29.6, 24.2, 23.0, 9.7. EI MS (m/z): 338
(M+), 91 (100).
N-[(1-Benzyl-7-methoxy-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-
propionamide (8c). This product was obtained starting from 6c and
using the above N1-benzylation procedure described for compound 6n.
Flash chromatography: silica gel, EtOAc−cyclohexane 7:3 as eluent
and crystallization. White solid, mp 129−30 °C (EtOAc−petroleum
ether); 90% yield. 1H NMR (200 MHz, CDCl3) δ 1.05 (t, 3H J = 7.5
Hz), 1.90−2.10 (m, 4H), 2.67−2.91 (m, 2H), 3.35 (t, 1H, J = 6.2 Hz),
3.51−3.57 (m, 1H), 3.67 (s, 3H), 4.52 (d, 1H J = 17.2 Hz), 4.64 (d,
1H J = 17.2 Hz), 5.47 (brs, 1H), 6.15 (d, 1H J = 2.0 Hz), 6.23 (dd, 1H
J = 8.2 Hz), 6.94 (d, 1H J = 8.2 Hz), 7.20−7.37 (m, 5H). 13C NMR
(50 MHz, CDCl3) δ 174.0, 159.2, 145.4, 139.1, 129.5, 128.7, 127.0,
126.5, 114.6, 101.2, 99.2, 57.3, 55.4, 55.1, 41.4, 29.5, 23.6, 23.0, 9.7.
ESI MS (m/z): 339 (M + H)+.
N-[(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-
propionamide (8d). This product was obtained starting from 6d and
using the above N1-benzylation procedure described for compound 6n.
Flash chromatography: silica gel, EtOAc−cyclohexane 7:3 as eluent
and crystallization. White solid, mp 108−9 °C (Et2O−petroleum
ether); 92% yield. 1H NMR (200 MHz, CDCl3) δ 1.05 (t, 3H J = 7.5
Hz), 1.92−2.08 (m, 4H), 2.73−2.93 (m, 2H), 3.32−3.40 (m, 2H),
3.43−3.59 (m, 1H), 4.53 (d, 1H J = 17.0 Hz), 4.66 (d, 1H J = 17.0
Hz), 5.47 (br s, 1H), 6.56−6.69 (m, 2H), 6.98−7.05 (m, 2H), 7.21−
7.38 (m, 5H). 13C NMR (50 MHz, CDCl3) δ 173.9, 144.6, 139.3,
129.1, 128.7, 127.3, 127.0, 126.6, 122.1, 116.7, 113.0, 57.5, 55.6, 41.5,
29.6, 23.9, 23.3, 9.7. ESI MS (m/z): 309 (M + H)+.
N-[(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]acetamide
(8e). This product was obtained starting from 6e and using the above
N1-benzylation procedure described for compound 6n. Flash
chromatography: silica gel, EtOAc as eluent and crystallization.
Greyish solid, mp 120−1 °C (Et2O−petroleum ether); 59% yield.
1H NMR (600 MHz, CD3OD) δ 1.84 (tt, 1H J1 = J2 = 4.8, J3 = J4 =
0.71 (m, 2H), 0.83−0.93 (m, 2H), 1.02−1.15 (m, 1H), 1.92−2.01 (m,
2H), 2.72−2.97 (m, 2H), 3.33−3.39 (m, 2H), 3.49−3.56 (m, 1H),
4.54 (d, 1H J = 17.3 Hz), 4.66 (d, 1H J = 17.3 Hz), 5.62 (br s, 1H),
6.56 (d, 1H J = 8.0 Hz), 6.63 (ddd, 1H J1 = 1, J2 = J3 = 7.5 Hz), 6.96−
7.04 (m, 2H), 7.22−7.36 (m, 5H). 13C NMR (50 MHz, CDCl3) δ
173.8, 144.5, 139.3, 129.1, 128.7, 127.2, 126.9, 126.6, 122.0, 116.5,
112.7, 57.5, 55.4, 41.7, 23.9, 23.3, 14.6, 7.1. ESI MS (m/z): 321 (M +
H)+.
N-[(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-
cyclobutanecarboxamide (8g). This product was obtained starting
from 6g and using the above N1-benzylation procedure described for
compound 6n. Flash chromatography: silica gel, cyclohexane−EtOAc
7:3 as eluent and crystallization. Amorphous solid; 54% yield. 1H
NMR (200 MHz, CDCl3) δ 1.69−2.23 (m, 8H), 2.70−2.92 (m, 3H),
3.32−3.38 (m, 2H), 3.48−3.55 (m, 1H), 4.53 (d, 1H J = 17.2 Hz),
4.64 (d, 1H J = 17.2 Hz), 5.38 (br s, 1H), 6.54 (d, 1H J = 8.2 Hz),
6.96−7.04 (m, 2H), 7.23−7.36 (m, 5H arom). 13C NMR (50 MHz,
CDCl3) δ 175.1, 144.6, 139.2, 129.0, 128.7, 127.2, 126.9, 126.5, 122.0,
116.5, 112.7, 57.5, 55.4, 41.5, 39.8, 25.2, 23.9, 23.4, 18.0. ESI MS (m/
z): 335 (M + H)+.
N-[(1-Methyl-5-methoxy-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-
propionamide (8h). This product was obtained starting from 6a and
using the above N1-methylation procedure described for compound 6l.
Flash chromatography: silica gel, EtOAc as eluent and crystallization.
White solid, mp 139−40 °C (CH2Cl2−petroleum ether); 87% yield.
1H NMR (200 MHz, CDCl3) δ 1.15 (t, 3H J = 7.5 Hz), 1.84−1.89 (m,
2H), 2.21 (q, 2H J = 7.5 Hz), 2.40−2.58 (m, 1H), 2.77−2.90 (m, 1H),
3.02 (s, 3H), 3.20−3.50 (m, 3H), 3.80 (s, 3H), 5.63 (br s, 1H), 6.27−
6.33 (m, 2H), 7.08 (dd, 1H J1= J2 = 8.0 Hz). 13C NMR (50 MHz,
CDCl3) δ 174.1, 157.1, 145.8, 127.0, 109.5, 104.7, 98.8, 57.2, 55.4,
40.6, 39.1, 29.7, 22.7, 17.0, 9.8. ESI MS (m/z): 263 (M + H)+.
N-[(1-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl]-
propionamide (8i). This product was obtained starting from 6d and
using the above N1-methylation procedure described for compound 6l.
Flash chromatography: silica gel, CH2Cl2−acetone 9:1 as eluent and
crystallization. White solid, mp 63−4 °C (Et2O−petroleum ether);
95% yield. 1H NMR (400 MHz, CD3OD) δ 1.15 (t, 3H, J = 7.5), 1.81
(dddd, 1H, J1 = 4.5, J2 = 5.0, J3 = J4 = 13.0, H3B), 1.96 (dddd, 1H, J1 =
J2 = 3.0, J3 = 5.5, J4 = 13.0, H3A), 2.23 (q, 2H, J = 7.5), 2.65 (ddd, 1H,
J1 = 3.0, J2 = 5.0, J3 = 16.5 Hz, H4B), 2.86 (ddd, 1H, J = 5.5, 13.0, 16.5
Hz, H4A), 3.01 (s, 3H, N-CH3), 3.19 (m, 1H, H10B), 3.36−3.41 (m,
1H, H10A), 3.43 (dddd, 1H, J = 3.0, 4.5, 5.0, 9 Hz, H2), 6.55 (ddd, 1H J
13.2, H3B), 1.85 (s, 3H, CH3), 1.96 (ddt, 1H J1 = J2 = 3.0, J3 = 5.4, J4 =
13.2 Hz H3A), 2.65 (ddd, 1H, J1 = J2 = 3.6, J3 = 16.2 Hz, H4B), 2.87
(ddd, 1H, J = 5.4, 13.2, 16.2 Hz, H4A), 3.18 (dd, 1H, J = 9.0, 13.2 Hz,
H10B), 3.32 (dd, 1H, J = 4.8, 13.2 Hz, H10A), 3.49 (dq, 1H, J1 = J2 = J3 =
4.2, J4 = 7.8 Hz, H2), 4.52 (1/2ABq, 1H, J = 17.4 Hz, H9B), 4.61 (1/
J
J. Med. Chem. XXXX, XXX, XXX−XXX