6632 J . Org. Chem., Vol. 65, No. 20, 2000
Della and Smith
extracted with ether (2×). The combined ether extracts were
dried (Na2SO4), and the solvent was removed in vacuo to yield
1-ethyl-1,2,5,6-tetrahydropyridine (16) as an amber oil: 1H
NMR (CDCl3) δ 5.8-5.64 (m, 2H), 2.95 (m, 2H), 2.55 (t, J )
5.7 Hz, 2H), 2.46 (t, J ) 7.2 Hz, 2H), 2.19 (m, 2H), 1.12 (t, J
) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 125.2, 125.1, 52.2, 49.7,
26.2, 12.1. HRMS calcd for C7H13N 111.1048, found 111.1051.
At t em p t ed Cycliza t ion of 1-(2-P h en ylselen oet h yl)-
1,2,5,6-tetr a h yd r op yr id in e (15). A 0.025 M solution of 15
(0.2 g, 0.75 mmol) in toluene was deoxygenated and heated
under reflux. A solution of Bu3SnH (0.66 g, 2.3 mmol) in
toluene (3 mL) containing AIBN (cat.) was added over 3 h.
The progress of reaction was monitored by GC and, upon
completion, the solution was cooled and extracted with 5% HCl.
The aqueous extracts were washed with hexane, and the
solution was basified (K2CO3) and extracted with dichlo-
romethane. The organic extract was dried (Na2SO4) and
evaporated to give an amber oil (0.07 g, 83%) which was
identified as 1-ethyl-1,2,5,6-tetrahydropyridine 16.
30.8, 28.2, 27.5, 21.3, 20.3, 14.2, 14.1.; HRMS calcd for C10H17
NO2+ 183.1259, found 183.1258.
-
1-(2-Br om oeth yl)-4-car beth oxy-1-m eth yl-1,2,5,6-tetr ah y-
dr opyr idin iu m Br om ide (35). 4-Carbethoxy-1-methyl-1,2,5,6-
tetrahydropyridine (34) (1.0 g, 5.9 mmol) was treated with
BrCH2CH2Cl as described in the general procedure and the
product recrystallized from ethanol/ether to furnish the salt
35 (1.9 g, 92%) as colorless crystals: mp 156-158 °C; 1H NMR
(CDCl3/DMSO-d6) δ 6.80 (s, 1H), 4.40 (m, 2H), 4.21 (q, J ) 7.2
Hz, 2H), 3.98-3.93 (m, 5H), 3.77 (m, 1H), 3.25 (s, 3H), 2.69
(m, 2H), 1.29 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3/DMSO-d6)
δ 164.0, 127.2, 62.6, 60.8, 58.7, 56.2, 47.1, 22.2, 20.2, 14.0. Anal.
Calcd for C11H19Br2NO2: C, 37.1; H 5.36; N, 3.92. Found: C,
36.70; H, 5.32; N, 3.95.
1-Eth yl-4-ca r beth oxy-1-m eth yl-1,2,5,6-tetr a h yd r op yr i-
d in iu m Br om id e (38). 4-Carbethoxy-1-methyl-1,2,5,6-tet-
rahydropyridine (34) (0.5 g, 3.0 mmol) was stirred with
bromoethane at room temp for 12 h, after which the solvent
was removed and the residue triturated with ether. Recrys-
tallization of the product from ethanol/ether gave 38 as
colorless crystals (0.75 g, 90%): mp 158-160 °C; 1H NMR
(CDCl3/DMSO-d6) δ 6.84 (s, 1H), 4.48 (m, 2H), 4.24 (q, J ) 7.2
Hz, 2H), 3.90 (m, 1H), 3.74 (m, 3H), 3.23 (s, 3H), 2.72 (bs, 2H),
1.45 (t, J ) 7.0 Hz, 3H), 1.32 (t, J ) 7.2 Hz, 3H); 13C NMR
(CDCl3/DMSO-d6) δ 164, 129.2, 127.4, 60.8, 58.7, 58.4, 55.5,
46.5, 20.2, 13.8, 7.6. Anal. Calcd for C11H20BrNO2: C, 47.49;
H, 7.25; N, 5.03. Found: C, 47.47; H, 7.35; N, 4.85.
4-Ca r beth oxy-1-(2-p h en ylselen oeth yl)-1,2,5,6-tetr a h y-
d r op yr id in e (20). Treatment of 4-carbethoxy-1,2,5,6-tetrahy-
dropyridine (7.0 g, 45 mmol) with BrCH2CH2Cl as described
above afforded 4-carbethoxy-1-(2-chloroethyl)-1,2,5,6-tetrahy-
dropyridine (5.3 g, 54%) as an amber oil: 1H NMR (CDCl3) δ
6.83 (m, 1H), 4.15 (q, J ) 7.1 Hz, 2H), 3.57 (t, J ) 6.9 Hz,
2H), 3.19 (q, J ) 3.1 Hz, 2H), 2.79 (t, J ) 6.9 Hz, 2H), 2.63 (t,
J ) 5.7 Hz, 2H), 2.4 (m, 2H), 1.24 (t, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) δ 166.3, 135.8, 128.8, 60.3, 59.0, 52.4, 49.5, 41.0,
24.9, 14.1; HRMS calcd for C10H16ClNO2 217.0870, found
217.0874. Exposure of 4-carbethoxy-1-(2-chloroethyl)-1,2,5,6-
tetrahydropyridine (1.9 g, 8.8 mmol) to PhSeNa as outlined
above yielded 4-carbethoxy-1-(2-phenylselenoethyl)-1,2,5,6-
tetrahydropyridine (20) (2.5 g, 84%) as a colorless oil after
column chromatography of the crude product on alumina (20%
ether/hexane): 1H NMR (CDCl3) δ 7.51-7.48 (m, 2H), 7.28-
7.22 (m, 3H), 6.86 (sept, J ) 1.8 Hz, 1H), 4.18 (q, J ) 7.1 Hz,
2H), 3.17 (q, J ) 3.0 Hz, 2H), 3.06 (m, 2H), 2.78 (m, 2H), 2.6
4-Car beth oxy-1-m eth yl-1-azon iabicyclo[3.2.1]octyl Br o-
m id e (37). A 0.025 M solution of 1-(2-bromoethyl)-4-carb-
ethoxy-1-methyl-1,2,5,6-tetrahydropyridinium bromide (35)
(0.2 g, 0.56 mmol) in 2-methyl-2-butanol was deoxygenated
and heated under reflux. A solution of Bu3SnH (0.18 g, 0.62
mmol) in 2-methyl-2-butanol (1 mL) containing AIBN (cat.)
was added over 15 min and the solution heated for a further
15 min. Workup in the usual mannner yielded a very hygro-
scopic product which by NMR analysis was found to consist
of 4-carbethoxy-1-methyl-1-azoniabicyclo[3.2.1]octyl bromide
(37) (ca. 50:50 endo:exo) only: 1H NMR (CDCl3) δ 4.3-3.9 (m,
14H), 3.75 (d, J ) 17.0 Hz, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.45
(m, 1H), 3.15-3.0 (m, 3H), 2.75 (m, 2H), 2.54-2.36 (m, 2H),
2.2 (m, 3H), 2.1-1.9 (m, 2H), 1.26 (m, 6H); 13C NMR (CDCl3)
δ 171.6, 171.0, 66.6, 64.1, 61.7, 61.3, 60.9, 60.7, 60.5, 59.7, 50.8,
50.5, 40.8, 40.1, 36.4, 36.2, 28.0, 25.3, 20.4, 19.7, 13.51, 13.48;
(t, J ) 5.7 Hz, 2H), 2.41 (m, 2H), 1.27 (t, J ) 7.1 Hz, 3H); 13
NMR (CDCl3) δ 166.4, 136.0, 132.3, 130.1, 128.9, 128.8, 126.7,
C
60.2, 57.6, 52.2, 49.1, 25.0, 24.9, 14.2; HRMS calcd for C16H21
NO2Se 339.0738, found 339.0739.
-
4-Ca r beth oxy-1-eth yl-1,2,5,6-tetr a h yd r op yr id in e (24).
Ethyl isonicotinate (2.0 g, 13 mmol) was treated with bromo-
ethane and the resulting pyridinium salt reduced with NaBH4.23
Distillation of the product (Kugelrohr: 80 °C (0.5 mm)) yielded
1-ethyl-4-carbethoxy-1,2,5,6-tetrahydropyridine (24) (1.8 g,
75%) as a colorless oil: 1H NMR22 (CDCl3) δ 6.9 (m, 1H), 4.19
(q, J ) 7.2 Hz, 2H), 3.15 (q, J ) 3.1 Hz, 2H), 2.6 (q, J ) 5.6
Hz, 2H), 2.5 (q, J ) 7.2 Hz, 2H), 2.43 (m, 2H), 1.25 (t, J ) 7.2
Hz, 3H), 1.15 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 166.5,
136.3, 128.8, 60.2, 52.2, 51.7, 49.2, 25.2, 14.1, 12.1; HRMS calcd
for C10H17NO2 183.1259, found 183.1260.
Tr ea tm en t of 4-Ca r beth oxy-1-(2-p h en ylselen oeth yl)-
1,2,5,6-tetr a h yd r op yr id in e (20) w ith Bu 3Sn H. A 0.025 M
solution of 4-carbethoxy-1-(2-phenylselenoethyl)-1,2,5,6-tet-
rahydropyridine (20) (0.1 g, 0.29 mmol) in toluene was deoxy-
genated and heated under reflux. A solution of Bu3SnH (0.26
g, 0.87 mmol) in toluene (3 mL) containing AIBN (cat.) was
added over 3 h, and the progress of the reaction was monitored
by GC. The solution was cooled and extracted with 5% HCl,
and the aqueous extracts were washed with hexane. The
solution was basified (K2CO3), and extracted with dichlo-
romethane. The organic extracts were dried (Na2SO4) and
evaporated to give an amber oil (0.038 g, 70%) which by NMR
analysis was found to consist of a 80:20 mixture of the amines
23 and 24. Attempts to separate the components (column
chromatography, distillation (80 °C (0.5 mm)), selective bro-
mination, or oxidation of the double bond in the reduced
material followed by distillation) were unsuccessful. The
product was found to decompose readily and must be treated
with care. Treatment of the mixture with methyl iodide gave
a product whose NMR spectrum was identical with that of
37: 1H NMR (CDCl3) δ 4.19 (m, 2H), 3.05-2.2 (m, 8H), 2.0-
1.7 (m, 4H), 1.25 (m, 3H); 13C NMR (CDCl3) δ 174.4, 174.0,
60.4, 60.3, 56.3, 54.0, 52.7, 51.5, 50.8, 45.2, 44.5, 36.6, 36.2,
+
HRMS calcd for C11H20NO2 198.1494, found 198.1489.
1-(2-Br om op r op en yl)-4-ca r b et h oxy-1-m et h yl-1,2,5,6-
tetr a h yd r op yr id in iu m Br om id e (39). Excess 1,2-dibromo-
2-propene was added to 1-methyl-4-carbethoxy-1,2,3,6-tetrahy-
dropyridine (34) in ether and the solution stirred for 1 h. The
precipitate was filtered off and recrystallized (ethanol/ethyl
acetate) to yield 39 as colorless needles (0.4 g, 90%): mp 168-
1
170 °C; H NMR (CDCl3) δ 6.98 (d, J ) 1.8 Hz, 1H), 6.87 (m,
1H), 6.26 (d, J ) 1.8 Hz, 1H), 5.14 (d, J ) 13.6 Hz, 1H), 5.08
(d, J ) 13.6 Hz, 1H), 4.96 (m, 1H), 4.7 (m, 1H), 4.25 (q, J )
7.1 Hz, 2H), 4.16 (m, 2H), 3.49 (s, 3H), 2.8 (m, 2H), 1.32 (t, J
) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 163.8, 135.1, 128.4, 127.5,
116.3, 68.4, 61.3, 59.0, 56.8, 47.4, 20.5, 13.9. Anal. Calcd for
C
12H19Br2NO2: C, 39.05; H, 5.19; N, 3.79. Found: C,39.31; H,
5.33; N,3.78.
4-Ca r beth oxy-1-m eth yl-1-(2-p r op en yl)-1,2,5,6-tetr a h y-
d r op yr id in iu m Br om id e (43). Excess allyl bromide was
added to a solution of 1-methyl-4-carbethoxy-1,2,3,6-tetrahy-
dropyridine (34) in ether and the mixture stirred for 1 h. The
precipitate was isolated by filtration and recrystallized (etha-
nol/ethyl acetate) to yield 43 as colorless needles (0.3 g, 86%):
mp 200-202 °C; 1H NMR (CDCl3) δ 6.87 (m, 1H), 6.1 0(m, 1H),
5.85 (m, 2H), 4.73 (m, 1H), 4.60 (m, 2H), 4.48 (m, 1H), 4.24 (q,
J ) 7.1 Hz, 2H), 4.05 (m, 1H), 3.85 (m, 1H), 3.38 (s, 3H), 2.75
(m, 2H), 1.32 (t, J ) 7.1 Hz, 2H); 13C NMR (CDCl3) 163.8,
130.2, 128.7, 127.5, 123.6, 64.9, 61.1, 58.2, 55.7, 47.2, 20.4, 13.8.
Anal. Calcd for
C12H20BrNO2: C, 49.67; H,6.95; N,4.83.
Found: C,49.81; H,7.05; N,4.86.
Cycliza tion of 1-(2-Br om op r op en yl)-1-m eth yl-4-ca r b-
eth oxy-1,2,5,6-tetr a h yd r op yr id in iu m Br om id e (39). A
0.025 M solution of 1-(2-bromopropenyl)-1-methyl-4-carb-
ethoxy-1,2,5,6-tetrahydropyridinium bromide (39) (0.2 g, 0.54