G. L. Grunewald et al. / Bioorg. Med. Chem. 7 (1999) 869±880
877
58.1%); mp 290±291 ꢀC; [a]2d0=+29ꢀ (c 10, MeOH).
recrystallized from MeOH/EtOAc to yield the title
compound as yellow crystals (55 mg, 44.1%); mp=283±
285 ꢀC; [a]2d0= 66ꢀ (c 10.5, MeOH); 1H NMR
(CD3OD) d 7.52 (s, 1H, ArH-8), 7.42 (d, J=8.2 Hz, 1H,
ArH-6), 7.14 (d, J=8.2 Hz, 1H, ArH-5), 4.62 (q,
J=6.9 Hz, 1H, H-1), 3.62±3.56 (m, 1H, H-3), 3.07 (dd,
J=4.5 Hz, J=17.4 Hz, 1H, H-4), 2.85 (dd, J=11.7 Hz,
J=17.4 Hz, 1H, H-4), 1.72 (d, J=6.9 Hz, 3H, 1-CH3),
1.49 (d, J=6.6 Hz, 3H, 3-CH3); 13C NMR (CD3OD,
salt) d 135.4, 113.3, 131.1, 130.9, 128.7, 121.0, 52.7, 50.4,
33.4, 18.2, 17.8; CIMS m/z (relative intensity) 242
(M++2, 100), 240 (M+, 100), 226 (25), 224 (25). Anal.
.
Anal. calcd for C11H14NO2 HBr: C, 46.01; H, 5.26; N,
9.76. Found: C, 45.97; H, 5.22; N, 9.38.
trans-(1R,3R)-(+)-1,3-Dimethyl-7-nitro-1,2,3,4-tetrahydro-
.
isoquinoline hydrobromide (16 HBr). The same reaction
conditions used for the synthesis and puri®cation of 14
were employed for the synthesis of 16 using the racemic
mixture of THIQs 12 and 13 (350 mg, 2.17 mmol) as the
starting material. Compound 16 was isolated from the
racemic mixture of 16 and 17 by one recrystallization
with R-( )-mandelic acid in EtOH/hexanes. The
hydrobromide salt was formed in the manner described
.
calcd for C11H14NBr HBr: C, 41.15; H, 4.71; N, 4.36.
Found: C, 41.48; H, 5.07; N, 4.15.
.
previously to yield 16 HBr as white needles (414 mg,
66.6%); mp 293±294 ꢀC; [a]2d0=+8.3ꢀ (c 0.10, MeOH);
1H NMR (CD3OD) d 8.26 (d, J=2.2 Hz, 1H, ArH-8),
8.18 (dd, J=2.2 Hz, J=8.5 Hz, 1H, ArH-6), 7.53 (d,
J=8.5 Hz, 1H, ArH-5), 4.90±4.83 (m, 1H, H-1), 3.91±
3.87 (m, 1H, H-3), 3.32 (dd, J=4.8 Hz, J= 18.1 Hz, 1H,
H-4), 2.96 (dd, J=10.2 Hz, J=18.1 Hz, 1H, H-4), 1.72 (d,
J=6.9 Hz, 3H, 1-CH3), 1.49 (d, J=6.6 Hz, 3H, 3-CH3).
cis-(1R,3S)-(+)-1,3-Dimethyl-7-bromo-1,2,3,4-tetrahydro-
.
isoquinoline hydrobromide (19 HBr). The synthesis of 19
was performed in the same manner as 18 using the
hydrobromide salt of 15 (235 mg, 0.819 mmol) as the
starting material. The hydrobromide salt of the title
compound was isolated as yellow crystals (151 mg,
57.4%); mp 282±284 ꢀC; [a]2d0=+64ꢀ (c 10.5, MeOH).
.
Anal. calcd for C11H14NO2 HBr: C, 46.01; H, 5.26; N,
9.76. Found: C, 46.06; H, 5.00; N, 9.93.
.
Anal. calcd for C11H14NBr HBr: C, 41.15; H, 4.71; N,
4.36. Found: C, 41.14; H, 5.00; N, 4.20.
trans-(1S,3S)-( )-1,3-Dimethyl-7-nitro-1,2,3,4-tetrahydro-
.
isoquinoline hydrobromide (17 HBr). The same condi-
trans-(1R,3R)-(+)-1,3-Dimethyl-7-bromo-1,2,3,4-tetra-
.
hydroisoquinoline hydrobromide (20 HBr). The synthesis
tions that were used for the isolation of 16 were
employed for the isolation of 17 using the racemic mix-
ture of 16 and 17 (290 mg, 1.80 mmol) crystallized with
S-(+)-mandelic acid in EtOH/hexanes. Compound
of 20 was performed and puri®ed in the same manner as
18 using the racemic mixture of the hydrobromide salts
of 16 and 17 (305 mg, 1.06 mmol) as the starting mate-
rial. The racemic mixture of 20 and 21 was isolated as
their HBr salts to give a yellow crystal (165 mg, 48.5%).
Compound 20 was isolated by one crystallization of the
racemic mixture of 20 and 21 (34.9 mg, 0.145 mmol)
with R-( )-mandelic acid in EtOH/hexanes. The dia-
stereomeric salt was isolated and the free base 20 was
reformed. The HBr salt was formed in the manner
.
17 HBr was formed in the manner described previously
and isolated as white needles (272 mg, 52.7%); mp 293±
294 ꢀC; [a]2d0= 15ꢀ (c 0.10, MeOH). Anal. calcd for
.
C11H14NO2 HBr: C, 46.01; H, 5.26; N, 9.76. Found: C,
46.14; H, 5.03; N, 9.65.
cis-(1S,3R)-( )-1,3-Dimethyl-7-bromo-1,2,3,4-tetrahydro-
.
isoquinoline hydrobromide (18 HBr). In a 250 mL Parr
.
shaker bottle, 14 HBr (115 mg, 0.40 mmol was dissolved
.
described previously to yield the title compound 20 HBr
as o-white crystals (14.4 mg, 25.3%); mp 240±242 ꢀC;
[a]2d0=+9.0ꢀ (c 0.10, MeOH); 1H NMR (CD3OD) d
7.46 (d, J=2.0 Hz, 1H, ArH-8), 7.40 (dd, J=2.0 Hz,
J=8.2 Hz, 1H, ArH-6), 7.12 (d, J=8.2 Hz, 1H, ArH-5),
4.69 (q, J=6.9 Hz, 1H, H-1), 3.90±3.78 (m, 1H, H-3),
3.13 (dd, J=4.8 Hz, J=17.5 Hz, 1H, H-4), 2.78 (dd,
J=10.5 Hz, J=17.5 Hz, 1H, H-4), 1.65 (d, J=6.9 Hz,
3H, 1-CH3), 1.45 (d, J=6.3 Hz, 3H, 3-CH3); 13C
NMR (CD3OD, salt) d 135.6, 131.3, 131.1, 130.2, 129.6,
120.7, 50.5, 45.1, 32.8, 19.7, 17.6 Anal. calcd for
in MeOH (50 mL). PtO2 (30 mg) was added and the
mixture was hydrogenated at 50 psi for 4 h. The reaction
mixture was ®ltered and the solvent removed. The resi-
due was dissolved in ice-cold 48% HBr(aq) (0.2 mL) and
water (0.7 mL). To this mixture, a solution of sodium
nitrite (30 mg, 0.435 mmol) in water (0.7 mL) was added
dropwise. After 30 min, excess HNO2 was destroyed by
the addition of urea (a negative starch-iodide test was
obtained at this time). The resultant solution was added
to a well stirred mixture of CuBr (172 mg, 1.20 mmol),
48% HBr (0.4 mL) and water (1 mL) at 35 ꢀC. After this
addition, the reaction mixture was warmed to 75±80 ꢀC
and stirred at this temperature for 1.5 h. The reaction
mixture was cooled to room temperature and stirred
overnight. The solution was adjusted to pH >10 with
25% NaOH(aq). EtOAc (50 mL) was added to solubilize
the product and the blue copper salts were removed by
®ltration through Celite. The Celite was washed with
EtOAc (2Â20 mL). The ®ltrate was extracted with ethyl
acetate (3Â50 mL), the combined organic extracts dried
over anhydrous Na2SO4 and evaporated to give a yel-
lowish oil. This crude product was dissolved in CH Cl2
and a methanolic HBr solution was added to form2the
HBr salt. The solvent was removed and the residue
.
C11H14NBr HBr: C, 41.15; H, 4.71; N, 4.36. Found: C,
41.14; H, 5.00; N, 4.20.
trans-(1S,3S)-( )-1,3-Dimethyl-7-bromo-1,2,3,4-tetrahydro-
.
isoquinoline hydrobromide (21 HBr). Compound 21 was
isolated using the same conditions that were used for
the isolation of 20, except the racemic mixture of 20 and
21 (67.9 mg, 0.282 mmol) was recrystallized with S-(+)-
mandelic acid in EtOH/hexanes. The diastereomeric salt
was isolated and the free base 21 reformed. The hydro-
bromide salt of 21 was made in the same manner as
.
described earlier to yield 21 HBr as o-white crystals
(16.3 mg, 18.0%); mp 241±243 ꢀC; [a]d20= 12.0 (c 0.22,
.
MeOH). Anal. calcd for C11H14NBr HBr: C, 41.15; H,
4.71; N, 4.36. Found: C, 41.30; H, 4.36; N, 4.24.