Iodinated Analogs of Trimetoquinol
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3709
was refluxed for 1.5 h. MeOH was evaporated, and a white
precipitate was filtered and dried. Recrystallization from
CHCl3-hexane gave 0.300 g (76%) of white crystals: mp 168-
170 °C (dec); 1H NMR (CDCl3) δ 7.79 (s, 2H, ArH), 6.60 (s,
1H, ArH), 6.58 (s, 1H, ArH), 4.09 (dd, J ) 9.8, 3.8 Hz, 1H,
CH), 3.86 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.17 (m, 1H, CH),
3.04-2.88 (m, 2H, CH), 2.82-2.60 (m, 3H, CH); 13C NMR
(CDCl3) δ 147.66, 147.15, 143.00, 139.68, 129.67, 127.42,
118.18, 111.92, 109.14, 107.09, 56.35, 56.06, 55.85, 41.38,
40.56, 29.35; IR (KBr) 3312 (NH), 1516 (CdC Ar) cm-1. Anal.
(C18H18I3NO2) C, H, N.
1-(4-Aceta m id o-3-iod oben zyl)-6,7-d im eth oxy-2-(tr iflu o-
r oa cetyl)-1,2,3,4-tetr a h yd r oisoqu in olin e (22). To a solu-
tion of isoquinoline 9a (0.52 g, 1 mmol) in hot benzene (15 mL)
was added Ac2O (0.51 g, 5 mmol). The solution was refluxed
for 1 h. The reaction mixture was allowed to cool. White
crystals were filtered. Mother liquor was concentrated, and
hexane was added. Slightly creamy crystals were filtered,
total yield 0.53 g (94%). To get an analytical sample, the
compound was recrystallized from EtOAc-hexane: mp 174-
175 °C; 1H NMR (CDCl3) δ 8.11 (d, J ) 8.3 Hz, 1H, H-5′), 7.52
(d, J ) 1.5 Hz, 1H, H-2′), 7.36 (s, 1H, NH), 7.10 (dd, J ) 8.3,
1.5 Hz, 1H, ArH), 6.60 (s, 1H, ArH), 6.32 (s, 1H, ArH), 5.23 (t,
J ) 6.6 Hz, CH), 3.94 (m, 1H, CH), 3.87 (s, 3H, OMe), 3.72 (s,
3H, OMe), 3.54 (ddd, OMe ) 14.1, 10.4 Hz, 3.8 Hz, 1H, CH),
3.06 (m, 2H, CH), 2.90 (ddd, J ) 15.9, 10.4, 5.2 Hz, 1H, CH),
2.68 (dt, J ) 16.0, 4 Hz, 1H, CH), 2.23 (s, 3H, Ac); 13C NMR
(CDCl3) δ 168.12, 155.90 (q), 148.30, 147.63, 139.63, 137.12,
134.95, 130.53, 126.19, 124.95, 121.73, 116.44 (q), 111.10,
110.17, 89.68, 55.91, 55.33, 40.75, 40.50 (q), 28.51, 24.75; IR
1-(4-Am in o-3,5-d iiod oben zyl)-6,7-d im eth oxy-1,2,3,4-tet-
r a h yd r oisoqu in olin e (20c). A slurry of the isoquinoline 10a
(1.94 g, 3 mmol) in MeOH (260 mL) and K2CO3 (11.2 g) in
H2O (80 mL) was refluxed for 1 h. MeOH was evaporated
under reduced pressure, and crystals were filtered, dried, and
recrystallized from EtOAc-hexane to give the title compound
(1.39 g, 84%): mp 169-171 °C; 1H NMR (CDCl3) δ 7.55 (s,
2H, ArH), 6.61 (s, 1H, ArH), 6.51 (s, 1H, ArH), 4.54 (s, 2H,
NH2), 4.04 (dd, J ) 9.6, 4.0 Hz, 1H, CH), 3.86 (s, 3H, OMe),
3.84 (s, 3H, OMe), 3.18 (m, 1H, CH), 3.03 (dd, J ) 13.8, 4.0
Hz, 1H, CH), 2.92 (ddd, J ) 12.1, 6.8, 5.2 Hz, 1H, CH), 2.82-
2.61 (m, J ) 13.8, 9.6 Hz, 3H, CH); 13C NMR (CDCl3) δ 147.51,
147.05, 144.66, 139.97, 132.36, 130.14, 127.38, 111.88, 109.28,
81.59, 56.79, 56.01, 55.83, 40.87, 40.72, 29.47; IR (KBr) 3416
(KBr) 3395 (NH), 1688 (CdO), 1519 (CdC Ar) cm-1
. Anal.
(C22H22F3IN2O4) C, H, N.
1-(4-Acet a m id o-3-iod ob en zyl)-6,7-d im et h oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e (23). The title compound (0.57 g,
69%) as a glassy solid was obtained from the isoquinoline 22
(0.99 g, 1.76 mmol) in the same manner as 20c: 1H NMR
(CDCl3) δ 8.12 (d, J ) 8.3 Hz, 1H, H-5′), 7.70 (d, J ) 1.7 Hz,
1H, ArH), 7.38 (s, 1H, NH), 7.26 (dd, J ) 8.3, 1.7 Hz, 1H, ArH),
6.63 (s, 1H, ArH), 6.60 (s, 1H, ArH), 4.11 (dd, J ) 9.6, 3.8 Hz,
1H, CH), 3.10-3.25 (m, 2H, CH), 2.92 (m, 1H, CH), 2.63-2.86
(m, 3H, CH2Ar, CH), 2.25 (s, 3H, Ac); 13C NMR (CDCl3) δ
168.19, 147.54, 147.05, 139.31, 137.30, 136.66, 130.12, 129.92,
127.28, 122.25, 111.85, 109.27, 90.50, 56.64, 55.99, 55.79,
41.63, 40.61, 29.30, 24.66; IR (KBr) 3391 (NH), 1676 (CdO),
1515 (CdC Ar) cm-1. Anal. (C20H23IN2O3) C, H, N.
(NH), 3331 (NH), 1607 (NH bend), 1571, 1512 (CdC Ar) cm-1
.
Anal. (C18H20N2I2) C, H, N.
6,7-Dih yd r oxy-1-(3,5-d iiod oben zyl)-1,2,3,4-tetr a h yd r o-
isoqu in olin e Hyd r obr om id e (21a ‚HBr ). The isoquinoline
20a (0.19 g, 0.35 mmol) was demethylated using the same
procedure as 15. Recrystallization from MeOH-ether gave
0.20 g (96%) of the title compound: mp 157-159 °C (dec); 1H
NMR (DMSO-d6) δ 9.13 (bs, 1H, OH), 8.88 (bm, 2H, NH+OH),
8.57 (bm, 1H, NH), 8.02 (t, J ) 1.4 Hz, 1H, ArH), 7.80 (d, J )
1.4 Hz, 2H, ArH), 6.61 (s, 1H, ArH), 6.56 (s, 1H, ArH), 4.63
(bm, 1H, CH), 3.22-3.41 (m, 2H, CH), 3.14 (m, 1H, CH), 2.71-
2.96 (m, 3H, CH); 13C NMR (CD3OD) δ 147.01 and 145.79 (C-6
and C-7), 145.69 (C-4′), 139.18 (C-2′ and C-6′), 141.15 (C-1′),
123.76 and 123.03 (C-4a and C-8a), 116.30 (C-5), 114.21 (C-
8), 96.14 (C-3′ and C-5′), 57.25 (C-1), 41.02 (C-3), 40.08 (CH2-
Ar), 25.60 (C-4); IR (KBr) 3600-2700 (br OH, NH), 1617, 1521
(CdC Ar) cm-1. Anal. (C16H15BrI3NO2) C, H, N.
1-(4-Am in o-3-iodoben zyl)-6,7-dih ydr oxy-1,2,3,4-tetr ah y-
d r oisoqu in olin e Dih yd r och lor id e (24‚2HCl). The title
compound was obtained in the same manner as 21c from the
isoquinoline 23 (0.42 g, 0.90 mmol). The product was recrys-
tallized from MeOH (twice) to give 0.32 g (64%). The com-
pound was dissolved in NaHCO3 solution and extracted with
EtOAc (×5). The solution was dried (MgSO4) and evaporated;
1 M HCl in ether (2 mL) was added to the methanol solution
of the residue. The solution was concentrated and put in a
refrigerator. The white crystals were filtered, washed with
6,7-Dih yd r oxy-1-(3,4,5-t r iiod ob en zyl)-1,2,3,4-t et r a h y-
d r oisoqu in olin e Hyd r obr om id e (21b‚HBr ). The isoquino-
line 20b (0.23 g, 0.35 mmol) was demethylated using the same
procedure as 15. Recrystallization from MeOH-ether gave
0.24 g (97%) of the title compound: mp 210-213 °C (dec); 1H
NMR (MeOH-d4) δ 7.92 (s, 2H, ArH), 6.63 (s, 1H, ArH), 6.56
(s, 1H, ArH), 4.64 (dd, J ) 5.7 and 3.1 Hz, 1H, CH), 3.42-
3.53 (m, 1H, CH), 3.2-3.34 (m, 2H, CH), 2.83-3.07 (m, 3H,
CH); 13C NMR (CD3OD) δ 147.11 and 145.90 (C-6 and C-7),
141.06 (C-2′ and C-6′), 140.21 (C-1′), 123.70 and 122.98 (C-4a
and C-8a), 120.90 (C-4′), 116.31 (C-5), 114.14 (C-8), 108.68 (C-
3′ and C-5′), 57.04 (C-1), 41.01 (C-3), 39.38 (CH2Ar), 25.62 (C-
4); IR (KBr) 3600-2700 (br OH, NH), 1617, 1540 (CdC Ar)
cm-1. Anal. (C16H16BrI2NO2) C, H, N.
1
EtOAc, and dried: dec.p. 186-190 °C; H NMR (DMSO-d6) δ
9.05 (bs, 1H, OH), 7.68 (d, J ) 1.7 Hz, 1H, ArH), 7.16 (dd, J )
8.2, 1.7 Hz, 1H, ArH), 6.94 (d, J ) 8.2 Hz, 1H, ArH), 6.57 (s,
1H, ArH), 6.55 (s, 1H, ArH), 4.46 (m, 1H, CH), 3.27 (m, 1H,
CH), 3.00-3.20 (m, 2H, CH), 2.80-3.00 (m, 2H, CH), 2.74 (dt,
J ) 16.8, 5.9 Hz, CH); 13C NMR (CD3OD) δ 147.00 and 145.76
(C-6 and C-7), 1412.68 (C-2′), 138.21 (C-4′), 136.27 (C-1′),
132.35 (C-6′), 123.82 and 123.10 (C-4a and C-8a), 116.27 (C-
5), 114.33 (C-8), 124.24 (C-5′), 91.49 (C-3′), 57.27 (C-1), 40.90
(C-3), 39.87 (CH2Ar), 25.659 (C-4); IR (KBr) 3600-2300 (br,
OH, NH), 1607 (NH bend), 1526 (CdC Ar) cm-1
(C16H17IN2O2‚2HCl) C, H, N.
. Anal.
1-(4-Acetam ido-3-iodoben zyl)-6,7-bis(ben zyloxy)-2-(ter t-
bu toxyca r bon yl)-1,2,3,4-tetr a h yd r oisoqu in olin e (25a ). To
a cold solution (0 °C) of isoquinoline 9b (0.68 g, 1 mmol) and
Et3N (0.34 g, 3 mmol) in CH2Cl2 (10 mL) was added AcCl (0.16
g, 2 mmol). The cooling bath was removed, and the mixture
was stirred overnight. The solution was washed with water
(2×), dried over MgSO4, filtered, and evaporated. Ether was
added and evaporated again to give a glassy solid (0.65 g,
90%): mp 62-64 °C; 1H NMR (CDCl3) δ (the spectrum consists
of two rotamers of 5:3 ratio) 8.12 and 8.06 (d, J ) 8.2), 7.59-
7.25 (m, 11H, ArH), 7.06 and 6.98 (m, 1H, ArH), 6.70 and 6.65
(s, 1H, ArH), 6.48 and 6.35 (s, 1H, ArH), 5.24-4.87 (m, 5H,
CH2O + CH), 4.12 and 3.73 (m, 1H, CH), 3.27-3.11 (m, 1H,
CH), 2.98-2.60 (m, 3H, CH2Ar + CH), 2.60-2.37 (m, 1H, CH),
2.22 (s, 3H, Ac), 1.43 and 1.31 (s, 9H, t-Bu); IR (KBr) 3389
(NH), 1688 (CdO), 1512 (CdC Ar) cm-1. Anal. (C37H39IN2O5)
C, H, N.
1-(4-Am in o-3,5-d iiod oben zyl)-6,7-d ih yd r oxy-1,2,3,4-tet-
r a h yd r oisoqu in olin e Dih yd r och lor id e (21c‚2HCl). The
isoquinoline 20c (1.21 g, 2.2 mmol) was demethylated in the
same manner as 20b to give 1.14 g (76%) of the dihydrobro-
mide salt: mp 155-157 °C (dec). The product was dissolved
in MeOH, chromatographed (silica gel, EtOAc-NH4OH, 100:
1), and evaporated with EtOH (×5). To an ethanol solu-
tion was added a 1 N etherial solution of HCl (3 mL),
concentrated, precipitated with EtOAc, and recrystallized from
1
MeOH-i-PrOH: mp 176-178 °C (dec); H NMR (DMSO-d6)
δ 9.15 (br s, 1H, OH), 8.89 (br s, 1H, NH2+), 7.68 (s, 2H, H-2′),
6.64 (s, 1H, H-5), 6.55 (s, 1H, H-8), 5.06 (br s, 2H, NH2), 4.47
(m, 1H, H-1), 3.40-2.67 (m, 6H, H-3 + H-4 + CH2Ar); 13C NMR
(CD3OD) δ 147.99 (C-4′), 146.84 and 145.75 (C-6 and C-7),
141.60 (C-2′ and C-6′), 128.78 (C-1′), 123.75 and 123.33 (C-4a
and C-8a), 116.24 (C-5), 114.16 (C-8), 81.86 (C-3′ and C-5′),
57.59 (C-1), 41.07 (C-3), 39.07 (CH2Ar), 25.68 (C-4); IR (KBr)
3600-2500 (br, OH, NH), 1607 (NH bend), 1529 (CdC Ar)
cm-1. Anal. (C16H16I2N2O2‚2HCl‚H2O) C, H, N.
1-(4-(Ben zoyla m in o)-3-iod oben zyl)-6,7-bis(ben zyloxy)-
2-(ter t-b u t oxyca r b on yl)-1,2,3,4-t et r a h yd r oisoq u in olin e
(25b). To a cold solution (0 °C) of isoquinoline 9b (0.68 g, 1