T. Prisinzano et al. / Bioorg. Med. Chem. 9 (2001) 613±619
617
Et2O), mp 177±179 ꢀC: H NMR(CD OD): d 1.3 (s,
(m, 5H, ±CH, Ar±CH2, N(CH3)CH2), 3.3 (bs, H2O), 7.0
(s, 2H, Ar±H), 11.1 (bs, 1H). Anal. calcd for
C19H31N HCl 0.25H2O: C, 72.58; H, 10.42; N, 4.54.
Found: C, 72.51; H, 10.27; N, 4.61.
1
3
9H, ±C(CH3)3), 2.4 (s, 6H, Ar±CH3), 4.3 (s, 2H, ±CH2),
7.1 (s, 2H, Ar±H), 7.3 (s, 1H, Ar±H), 8.6 (m, 2H, Ar±
.
H). Anal. calcd for C17H23N2 HCl: C, 69.96; H, 8.29; N,
9.60. Found: C, 70.02; H, 8.01; N, 9.59.
.
.
2-(4-tert-Butyl-2,6-dimethylbenzyl)-1-methyl-1,2,5,6-tet-
rahydropyridine hydrochloride (11). A solution of
2-(4-tert-Butyl-2,6-dimethylbenzyl)pyridine hydrochloride
(9). A suspension of 20 (4.3 g, 13.0 mmol) and 10% Pd/
C (0.3 g) in absolute EtOH (90 mL) was hydrogenated in
a Parr apparatus at 40 psi for 4 h. The catalyst was
removed by ®ltration and the solvent was removed
under reduced pressure. The residue was suspended in
H2O (100 mL) and made alkaline (pH 13) with 50%
NaOH and extracted with EtOAc (3Â100 mL). The
EtOAc solution was dried (MgSO4), and the solvent
removed under reduced pressure aording 3.0 g (92%) of
2-(4-tert-butyl-2,6-dimethylbenzyl)pyridine as a brown
oil. HCl(g)/saturated anhydrous Et2O was added to a
solution of the oil (0.5 g) in anhydrous Et2O. The pre-
cipitate was collected and recrystallized from absolute
EtOH/anhydrous Et2O to give 0.5 g (90%) of 9, mp 184-
phenyl lithium (1.8 M in cyclohexane:anhydrous Et2O
(7:3) (3.5 mL, 6.4 mmol) was added rapidly to 16 (1.0 g,
3.2 mmol) at 25 ꢀC. The reaction mixture was stirred
vigorously at rt for 2 h and then poured into an ice
(50 g)- H2O (50 mL) mixture. The aqueous mixture was
extracted with Et2O (2Â100 mL). The combined Et2O
portion was extracted with 5% HCl (3Â50 mL). The
combined acid extracts were made alkaline (pH 13) by
the addition of 50% NaOH. The aqueous mixture was
extracted with Et2O (3Â75 mL). The Et2O solution was
dried (MgSO4) and the solvent was removed under
reduced pressure. The crude oil was puri®ed by ¯ash
chromatography using petroleum ether:acetone (1:1) to
aord 0.7 g (81%) of a yellow oil. Excess HCl(g)/satu-
rated anhydrous Et2O was added to a solution of the oil
(0.2 g) in anhyd Et2O, the precipitate was collected and
recrystallized from absolute MeOH/anhyd Et2O to
aord 0.2 g (90%) of 11 as a white solid, mp 230±
187 ꢀC. H NMR(CDCl ) d 1.3 (s, 9H, ±C(CH3)3), 1.5
1
3
(bs, H2O), 2.2 (s, 6H, Ar±CH3), 4.7 (s, 2H, Ar2CH2), 7.1
(m, 2H, Ar±H), 7.1 (m, 1H, Ar±H), 7.8 (m, 1H, Ar±H),
8.2 (m, 1H, Ar±H), 8.8 (m, 1H, Ar-H). Anal. calcd for
ꢀ
1
.
.
C18H23N HCl 0.25H2O: C, 73.45; H, 8.39; N, 4.76.
Found: C, 73.78; H, 8.31; N, 4.74.
234 C. H NMR(DMSO- d6) d 1.2 (s, 9H, ±C(CH3)3),
2.3 (s, 8H, ArCH2, Ar±CH3), 2.6±3.0 (m, 3H, NCH3),
3.1±3.4 (m, 2H), 3.35 (s, H2O), 3.5±3.7 (m, 2H), 3.9±4.0
(bs, 1H), 5.0±5.2 (m, 1H, CCH), 5.8±6.0 (m, 1H,
C=CH), 7.0 (s, 2H, Ar±H), 11.4 (s, 1H, HCl); 13C NMR
(DMSO-d6) d 20.9, 21.3, 30.4, 31.5, 34.2, 40.3, 49.1, 59.9,
123.3, 125.6, 129.8, 136.8, 149.2. Anal. calcd for C19
2-(4-tert-Butyl-2,6-dimethylbenzyl)piperidine hydrochloride
(10a). A suspension of 9 (1.0g, 4.0 mmol) and PtO2
(0.1 g, 0.4 mmol) in a mixture of absolute EtOH (25 mL)
and concentrated HCl (1 mL) was hydrogenated in a Parr
apparatus at 25psi for 2 h. The catalyst was removed by
®ltration and the solvent was removed under reduced
pressure. The crude solid was recrystallized from abso-
lute EtOH/anhydrous Et2O to aord 1.0 g (85%) of 10a
.
.
H29N HCl 0.25H2O: C, 73.05; H, 9.84; N, 4.48. Found:
C, 73.23; H, 9.74; N, 4.53.
2-(4-tert-Butyl-2,6-dimethylbenzyl)-1,4,5,6-tetrahydro-
pyrimidine hydrochloride (12). A mixture of 1424 (2.0 g,
10 mmol) and trimethylenediammonium bis-p-toluene-
sulfonate29 (2.1g, 5 mmol) and 1,3-diaminopropane (0.4g,
5 mmol) was heated in an oil bath at 200 ꢀC for 1 h with
the evolution of ammonia gas. After cooling the residue to
rt, H2O (50 mL) was added. The mixture was made alka-
line (pH 13) by the addition of 15% NaOH (ꢁ50mL). The
aqueous mixture was extracted with CH2Cl2 (3Â50 mL).
The CH2Cl2 solution was washed with saturated NaCl
(100 mL), dried (MgSO4), and the solvent was removed
under reduced pressure aording a crude solid. Excess
HCl(g)/saturated anhydrous Et2O was added to a solu-
tion of the solid in anhydrous Et2O, and the precipitate
was collected by ®ltration and recrystallized from abso-
lute EtOH/anhyd Et2O to aord 1.6 g (54%) of 12 as a
white solid, mp 282±284 ꢀC. 1H NMR(DMSO- d6) d 1.3
(s, 9H, C(CH3)3), 1.8 (m, 2H, CH2CH2CH2), 2.3 (s, 6H,
Ar±CH3), 3.3 (m, 4H, ±NHCH2), 3.9 (s, 2H, ArCH2),
7.1 (s, 2H, Ar±H), 9.5 (m, 2H, ±NH). Anal. calcd for
as a white solid, mp 274±277 ꢀC. H NMR(DMSO- d6)
1
d 1.2 (s, 9H,-C(CH3)3), 1.3±1.7 (m, 6H, ±(CH2)3), 2.3 (s,
6H, Ar±CH3), 2.8±3.3 (m, 5H, ±CH, Ar±CH2, NHCH2),
3.3 (bs, H2O), 7.0 (s, 2H, Ar±H), 9.2±9.5 (m, 2H). Anal.
.
.
calcd for C18H29N HCl 0.25H2O: C, 71.97; H, 10.23; N,
4.66. Found: C, 72.25; H, 10.06; N, 4.69.
2-(4-tert-Butyl-2,6-dimethylbenzyl)-1-methylpiperidine
hydrochloride (10b). Sodium cyanoborohydride (0.1 g,
2.0 mmol) was added to a mixture of 10a (0.3 g, 1.0 mmol)
and 37% formaldehyde (0.4mL, 5.5 mmol) in MeCN
(10 mL) at rt. Glacial acetic acid was added to maintain
the pH at 7. The reaction mixture was allowed to stir at
rt for 12 h. The solvent was removed under reduced
pressure and 2 N KOH (50 mL) was added to the residue.
The aqueous mixture was extracted with Et2O (3Â50mL).
The Et2O solution was dried (MgSO4) and the solvent was
removed under reduced pressure. The crude oil was pur-
i®ed by ¯ash chromatography (silica gel, 30g) using
CH2Cl2:MeOH (9:1) to aord 0.2 g (73%) of 2-(4-tert-
butyl-2,6-dimethylbenzyl)-1-methylpiperdine as a clear
oil. Excess HCl(g)/saturated anhydrous Et2O was added
to a solution of the oil (0.2 g) in anhydrous Et2O, and
the precipitate was collected and dried to aord 0.2 g
.
C17H26N2 HCl: C, 69.25; H, 9.23; N, 9.50. Found: C,
69.33; H, 9.25; N, 9.55.
1-(4-tert-Butyl-2,6-dimethylbenzyl)-1-methyl-1,2,5,6-tet-
rahydropyridinium chloride (16). A solution of 1-
methyl-1,2,5,6-tetrahydropyridine (1.0 g, 10.0 mmol)
and 1323 (2.5 g, 12.0 mmol) in dry acetone (10 mL) was
allowed to stir at rt for 18 h. The reaction mixture was
(90%) of 10b, mp 262±265 ꢀC. H NMR(DMSO- d6)
1
d 1.2 (s, 9H, ±C(CH3)3), 1.2±1.9 (m, 6H, ±(CH2)3), 2.3
(s, 6H, Ar±CH3), 2.8 (d, J=4.4 Hz, 3H, NCH3), 3.0-3.3