1018 Chem. Res. Toxicol., Vol. 9, No. 6, 1996
Nimkar et al.
mL). The combined organic extracts were dried (MgSO4), and
the solvent was removed in vacuo. The residue was purified
by column chromatography (silica gel, 30% EtOAc/hexanes) to
give the free base 26 (131 mg, 0.64 mmol, 70%) as a yellow oil.
The oxalate salt was recrystallized from CH3CN to afford 125
mg (0.423 mmol, 46%) of product as a light green solid: mp 181
N2‚0.78H2O: C, 62.90; H, 6.68; N, 11.29. Found: C, 62.89; H,
6.63; N, 11.26.
1-Cyclop r op yl-4-(1-m eth yl-2-p yr r yl)-1,2,3,6-tetr a h yd r o-
p yr id in iu m Oxa la te [28‚(COOH)2]. To a solution of the above
cyclopropylpyridinium chloride (54, 150 mg, 0.64 mmol) in CH3-
OH (15 mL) was added NaBH4 (61 mg, 1.60 mmol) at 0 °C. This
mixture was allowed to warm to room temperature and was
stirred for an additional 30 min. After removing the solvent,
the residue was extracted with CH2Cl2 and the extract was
washed with water several times. The product obtained fol-
lowing removal of the CH2Cl2 in vacuo was converted to its
oxalate salt which was recrystallized from 2-propanol/Et2O to
yield 114 mg (0.39 mmol, 55%) of product as pale yellow
needles: mp 179-180 °C; GC (temperature program: 60 °C for
1 min, then 25 °C/min to 275 °C; tR ) 9.1 min)-EIMS of free
base m/ z (%), 202 (55, M•+), 187 (100), 159 (10), 132 (40), 118
(60), 94 (55), 77 (20), and 68 (25); 1H NMR (DMSO-d6) δ 6.71 (s,
1H, ArH), 6.03 (s, 1H, ArH), 5.94 (t, J ) 3.3, 1H, ArH), 5.72 (s
1H, NCH2CH,), 3.59 (s, 5H, CH3, NCH2CH), 3.14 (t, J ) 5.9,
2H, NCH2CH2), 2.48 (s, 1H, NCHCH2), 2.35 (s, 2H, NCH2CH2),
0.69 (m, 4H, NCHCH2). Anal. Calcd for C15H20N2O4: C, 61.63;
H, 6.90; N, 9.58. Found: C, 61.43; H, 6.98; N, 9.35.
°C; UV (0.1 M Na3PO4) λmax ) 277 nm (ꢀ 9900 M-1); GC (tR
)
4.94 min)-EIMS m/ z (%), 205 (40, M•+), 190 (100), 135 (33), and
97 (30); 1H NMR (oxalate salt, DMSO-d6) δ 10.5 (bs, 2H, COOH),
7.40 (dd, J ) 5.1 and 1.1, 1H, ArH), 7.10 (d, J ) 3.4, 1H, ArH),
7.01 (dd, J ) 5.1 and 2.6, 1H, ArH), 6.05-6.07 (m, 1H,
NCH2CH), 3.60 (d, J ) 2.6, 2H, NCH2CH), 3.18 (t, J ) 6.1, 2H,
NCH2CH2), 2.60-2.63 (m, 2H, NCH2CH2), 2.37-2.40 (m, 1H,
NCH), 0.61-0.74 (M, 4H, NCHCH2); 13C NMR (oxalate, DMSO-
d6) δ 163.14 (C), 145.43 (C), 129.00 (C), 127.70 (CH), 124.67
(CH), 123.08 (CH), 117.73 (CH), 51.08 (CH2), 49.10 (CH2), 37.69
(CH), 25.70 (CH2), 4.44 (CH2). Anal. Calcd for C14H17NO4S:
C, 56.93; H, 5.80; N, 4.74. Found: C, 57.04; H, 5.78; N, 4.69.
1-Cyclop r op yl-4-(2-fu r a n yl)-1,2,3,6-tetr a h yd r op yr id in -
iu m Oxa la te [27‚(COOH)2]. Condensation of the furanyl-
lithium reagent 43, prepared by treatment of furan (2.0 g, 29.4
mmol) with n-BuLi (2 M in hexanes, 11.7 mL, 23.3 mmol) in
dry Et2O (15 mL), with 1-cyclopropyl-4-piperidone (39, 200 mg,
1.44 mmol) as described above for the synthesis of 45 gave,
following recrystallization from EtOAc, 185 mg (0.89 mmol, 62%)
of the piperidinol 47: mp 176 °C; GC (temperature program:
60 °C for 2 min then 15 °C/min to 250 °C; tR ) 7.7 min)-EIMS
m/ z (%), 207 (18, M•+), 192 (8), 178 (19), 97 (28), 96 (42), 95
(40), 82 (100), 68 (75), and 55 (33); 1H NMR (CHCl3) δ 7.35 (dd,
J ) 1.8 and 0.9, 1H, ArH), 6.32 (dd, J ) 3.2 and 1.8, 1H, ArH),
6.19 (dm, J ) 3.3, 1H, ArH), 2.72-2.74 (m, 4H, NCH2), 2.03-
2.13 (m, 2H, NCH2CHeqH), 1.94 (dm, J ) 11.9, 2H, NCH2-
CHHax), 1.65 (m, 1H, NCH), 0.42-0.47 (m, 4H, NCHCH2). Acid
catalyzed dehydration of this crude 47 (100 mg, 0.48 mmol) gave
the free base 27 as an oil that was purified by recrystallization
of its oxalate salt from CH3CN to yield a white solid (97 mg,
0.35 mmol, 72%): mp 163 °C; GC (tR ) 3.55 min)-EIMS m/ z
(%), 189 (50, M•+), 174 (100), 105 (15), 91 (26), 77 (23), and 54
(26); UV (0.1 M Na3PO4) λmax ) 264 nm (ꢀ 13 600 M-1); 1H NMR
(oxalate salt, DMSO-d6) δ 7.62 (bs, 1H, ArH), 6.47-6.48 (m, 1H,
ArH), 6.42 (d, J ) 3.2, 1H, ArH), 6.10 (bs, 1H, NCH2CH), 4.50
(bs, 2H, COOH), 3.59 (bs, 2H, NCH2CH), 3.13 (t, J ) 5.8, 2H,
NCH2CH2), 2.48 (bs, 2H, NCH2CH2), 2.33 (bs, 1H, NCH), 0.62-
0.67 (m, 4H, NCHCH2); 13C NMR (oxalate salt, DMSO-d6) δ
162.76 (C), 152.16 (C), 142.93 (CH), 125.07 (C), 114.34 (CH),
111.56 (CH), 106.64 (CH), 50.44 (CH2), 48.72 (CH2), 37.92 (CH),
22.30 (CH2), 3.76 (CH2). Anal. Calcd for C14H17N-
O5‚0.18H2O: C, 59.36; H, 6.17; N, 4.97. Found: C, 59.36; H,
6.16; N, 5.26.
1-Meth yl-4-(2-th ien yl)-1,2,3,6-tetr a h yd r op yr id in e N-Ox-
id e (58). To a solution of 1-methyl-4-(2-thienyl)-1,2,3,6-tet-
rahydropyridine (20, 200 mg, 1.12 mmol) in dry CHCl3 (15 mL)
at 0 °C was added m-chloroperoxybenzoic acid (m-CPBA, 50%,
390 mg, 2.23 mmol) in one portion. After stirring for 15 min,
the reaction mixture was concentrated in vacuo and the residue
was purified by column chromatography (basic alumina, 95%
CHCl3/5% MeOH) to give 58 (149 mg, 0.761 mmol, 70%) as an
oil: 1H NMR (CDCl3) δ 7.05 (d, J ) 5, 1H, ArH), 6.82-6.88 (m,
2H, ArH), 5.80 (brs, 1H, NCH2CH), 3.88 (brs, 2H, NCH2CH),
3.36 (t, J ) 6, 2H, NCH2CH), 3.09 (s, 3H, NCH3), 2.91-2.96
(m, 1H, CHeqH), 2.51-2.56 (m, 1H, CHHax). HR-CIMS. Calcd
for C10H13NSO: 196.0796. Found: 196.0806.
1-Meth yl-4-(2-th ien yl)-2,3-d ih yd r op yr id in iu m P er ch lo-
r a te (63‚HClO4). A mixture of the above N-oxide (149 mg,
0.761 mmol) and trifluoroacetic anhydride (177 mg) was stirred
for 15 min at 0 °C in CH2Cl2 (3 mL) and then was added to
perchloric acid (2.10 mmol) in methanol (10 mL). The resulting
solid was recrystallized from methanol to give 63 (95 mg, 0.342
mmol, 45%) as yellow needles: mp 140-141 °C; UV (pH 7.4
phosphate buffer) λmax ) 386 nm (ꢀ 18 800 M-1); 1H NMR (CD3-
OD) δ 8.35-8.38 (m, 1H, ArH), 7.92 (dd, J ) 5.0 and 1.0, 1H,
ArH), 7.85 (dd, J ) 4.0 and 1.0, 1H, ArH), 7.35 (dd, J ) 5 and
4, 1H, NCH), 6.78 (d, J ) 5.2, 1H, NCHCH), 4.00 (t, J ) 9.2,
2H, NCH2), 3.87 (s, 3H, NCH3), 3.30-3.34 (m, 2H, NCH2CH2);
13C NMR (CD3OD) δ 26.58 (CH2), 46.98 (CH3), 49.08 (CH2),
111.53 (CH), 130.75 (CH), 133.96 (CH), 135.57 (CH). Anal.
Calcd for C10H13NSO4Cl: C, 43.16; H, 4.71; N, 5.04. Found: C,
43.42; H, 4.41; N, 5.06.
4-(1-Met h yl-2-p yr r yl)-1-(2,4-d in it r op h en yl)p yr id in iu m
Ch lor id e (53). A solution of 4-(1-methyl-2-pyrryl)pyridine (40)
(51, 640 mg, 4.10 mmol) and 2,4-dinitrochlorobenzene (820 mg,
4.10 mmol) in anhydrous acetone (10 mL) was heated under
reflux for 24 h. The reaction mixture was concentrated and the
precipitated solid was collected, washed with ice cold acetone,
and recrystallized from CH3OH/Et2O to yield 610 mg (1.19
mmol, 41%) of product as dark yellow needles: mp 241-243
1-Meth yl-4-(2-fu r a n yl)-2,3-d ih yd r op yr id in iu m P er ch lo-
r a te (64‚HClO4). A solution of 1-methyl-4-(2-furanyl)-1,2,3,6-
tetrahydropyridine (100 mg, 0.61 mmol) in dry CH2Cl2 (10 mL)
was cooled to 0 °C in an ice bath, and m-CPBA (50%, 212 mg,
1.2 mmol) was added in one portion. After stirring for 15 min,
the reaction mixture was concentrated in vacuo and the residue
was purified by column chromatography (basic alumina, 95%
CHCl3/5% MeOH) to give 59 (82 mg, 0.46 mmol, 75%) as an oil
which was pure according to TLC and NMR analysis: 1H NMR
(CDCl3) δ 7.39 (brs, 1H, ArH), 6.40 (dd, J ) 2.0 and 2.0, 1H,
ArH), 6.32 (d, J ) 4.5, 1H, ArH), 6.12 (m, 1H, NCH2CH), 4.08
(brs, 2H, NCH2CH), 3.53 (t, J ) 6.3, 2H, NCH2CH2), 3.26 (s,
3H, NCH3), 2.99-3.05 (m, 1H, CHeqH), 2.60-2.66 (m, 1H,
CHHax); 13C NMR (CDCl3) δ 152.11 (C), 142.35 (CH), 124.67 (C),
113.95 (CH), 111.19 (CH), 106.29 (CH), 67.80 (CH2), 64 (CH2),
57.24 (CH3), 23.72 (CH2). HR-CIMS. Calcd for C10H13NO (M
- 16+): 163.0997. Found: 163.0993. A mixture of the N-oxide
(11 mg) and trifluoroacetic anhydride (13 mg) was stirred for
15 min at 0 °C in 3 mL of CH2Cl2. This reaction mixture was
added to 50 mL of methanolic perchloric acid, and 0.7 mL of
the resulting solution was diluted to 10 mL with methanol to
give a final concentration of the dihydropyridinium species 64
of 88 µM: UV (MeOH) λmax ) 382 nm (ꢀ 23 000 M-1).
1
°C; H NMR (CD3OD) δ 9.22 (d, J ) 2.5, 1H, ArH), 8.86 (dd, J
) 8.8 and 2.5, 1H, ArH), 8.27 (d, J ) 3.9, 1H, ArH), 8.80 (d, J
) 7.4, 2H, ArH), 8.25 (dd, J ) 7.4 and 2.4, 2H, ArH), 7.41 (m,
2H, ArH), 6.44 (dd, J ) 6.8 and 2.5, 1H, ArH), 4.10 (s, 3H, CH3).
Anal. Calcd for C16H13ClN4O4: C, 53.27; H, 3.63; N, 15.53.
Found: C, 53.24; H, 3.60; N, 15.46.
1-Cyclop r op yl-4-(1-m et h yl-2-p yr r yl)p yr id in iu m Ch lo-
r id e (54). A solution of cyclopropylamine (133 mg, 2.33 mmol)
and 53 (700 mg, 1.94 mmol) in 1-butanol (40 mL) was heated
under reflux for 24 h and then was evaporated to dryness in
vacuo. The residue was recrystallized from CH3CN/Et2O to
yield 208 mg (0.89 mmol, 38%) of product as pale yellow
hygroscopic needles: mp 131-132 °C; UV (pH 7.4 phosphate
buffer) λmax ) 373 nm (ꢀ 18 800 M-1); 1H NMR (CD3OD) δ 8.69
(d, J ) 6.8, 2H, ArH), 8.01 (d, J ) 7.3, 2H, ArH), 7.20 (d, J )
2.1, 1H, ArH), 7.12 (dd, J ) 5.7 and 1.7, 1H, ArH), 6.33 (dd, J
) 6.8 and 2.6, 1H, ArH), 4.16 (m, 1H, NCHCH2), 3.98 (s, 3H,
CH3), 1.33 (m, 4H, NCHCH2). Anal. Calcd for C13H15Cl-