3
4
2
5
8
anhydrous sodium sulfate, and the solvent removed under
reduced pressure to leave an orange oil. Chromatography on
silica, and elution with 4 : 6 diethyl ether–‘petroleum ether’ gave
unchanged 9 (37.8 mg, 36%) and 19 as a colourless oil (92.5 mg,
CDCl ) 24.6/24.8 (C , C ), 36.5/36.8 (C , C ), 42.8 (C ), 49.3
3
7
1
6
5Ј
4Ј
3Ј
(C ), 58.6 (C ), 66.8 (C ), 124.2 (C ), 136.9 (C ), 142.7 (C ),
2Ј
6Ј
ϩ
148.2 (C ), 149.0 (C ); m/z 236/238 (M , 19/6%), 207/209 (3/1),
193/195 (15/5), 179/181 (30 : 10), 165 (4), 149 (11), 117 (12), 97
(100), 77 (14), 69 (44); C H ClN requires m/z 236.1077;
6
2
1
1%; 97% based on consumed 9), νmax 3045br w, 2980br w,
13
17
2
940 m, 1695s, 1440br m, 1415 m, 1330w, 1270br m, 1250br m,
observed m/z, 236.1081.
Ϫ1
160br w, 895w cm ; δ (250 MHz) 1.4–1.8/2.0–2.3 (series of
H
2,3,4,5,8
7
m, 10H, H
), 3.19 (m, H ), 4.20/4.31 (2 × br d, J = 6.3 Hz,
N-Benzyl-7ꢁ-(6Ј-chloro-3Ј-pyridyl)-9-azabicyclo[4.2.1]nonane
20. Hydrogen bromide (30% in acetic acid; 230 µL) was injected
into a Reacti-vial containing 19 (12.4 mg, 33.5 µmol) and the
mixture was stirred at RT for 3 days. Water (3 mL) was added,
the solution was basified with dil. aq. sodium hydroxide, and
sodium chloride was added to saturate the aqueous layer. The
mixture was extracted with dichloromethane (5 × 2 mL), the
combined extract was dried over anhydrous sodium sulfate, and
the solvent evaporated to leave an oil (9.4 mg) which contained
3 together with a second compound. The mixture was subjected
to preparative TLC on silica, with dichloromethane–methanol–
ammonia (35% aq. solution, specific gravity 0.880) (90 : 10 : 3)
6
1
2
H ), 4.58/4.66 (2 m, H ), 5.13/5.17 (2 × ABq, J = 12.3 Hz,
CH Ph), 7.11–7.42 (series of m, 6H, ArH and H ), 7.73 (m,
H ), 8.21 (d, J ≈ 2.4 Hz, H ); δ (63 MHz) 24.1/24.2 (C , C ),
3
5
Ј
2
4
Ј
2Ј
3
4
C
2
5
8
7
2.9/33.0/34.1 (C , C ), 40.2/41.4 (C ), 46.7/47.8 (C ), 56.2/56.7
1 6 5Ј
(
(
1
3
C ), 64.1/64.3 (C ), 66.7/66.8 (CH Ph), 124.5 (C ), 127.5–128.5
2
4Ј
complex, aryl CH), 135.1/135.2 (C ), 136.4/136.5 (aryl C),
3Ј 2Ј 6Ј
41.2/141.4 (C ), 148.0 (C ), 149.5 (C ), 153.8 (C᎐O); m/z 370/
ϩ
72 (M , 12/4%), 279/281 (3/1), 262 (15), 235/237 (17/6), 183
(
12), 96 (25), 91 (100), 77 (5); C H ClN O requires m/z
21 23 2 2
3
70.1443; observed m/z, 370.1448.
ꢁ-(6Ј-Chloro-3Ј-pyridyl)-8-azabicyclo[3.2.1]octane (2; homo-
6
as developer. The compound eluted first (R ≈ 0.85) was shown
f
epibatidine). Iodotrimethylsilane (63 µL, 0.44 mmol) was
injected into a solution of 18 (35.3 mg, 0.099 mmol) in CHCl3
to be the N-benzylated compound 20 (5.5 mg; 50%): δH (250
7α
MHz) 1.4–1.8 (series of m, 6H), 1.8–2.1 (m, 4H), 3.03 (m, H ),
6
1
(
20 ml). Methanol (5 mL; acidified with gaseous HCl) was then
3.15 (m, H ), 3.53 (m, H ), 3.90 (s, CH Ph), 7.10–7.31 (series of
2
5Ј 4Ј
added and the solvent removed using a rotary evaporator; this
was followed by the addition of methanol (5 mL; basified with
gaseous ammonia) after which the solvent was again removed.
The residue was taken up in chloroform and the precipitate
removed by filtration to yield a yellow oil after evaporation.
Purification by flash column chromatography, and elution with
diethyl ether–‘petroleum ether’ (in ratios ranging from 1 : 9 to
m, 6H, aryl H, H ), 7.60 (dd, J = 8, 2 Hz, H ), 8.20 (d, J = 2 Hz,
2Ј 3 4 2 5
H ); δ (63 MHz) 24.8/25.0 (C , C ), 33.7/34.3 (C , C ), 41.3
C
8
7
1
6
5Ј
(C ), 48.1 (C ), 53.7 (C ), 60.6 (C ), 123.9 (C ), 126.7 (aryl CH),
128.1 (2 × aryl CH), 137.2 (C ), 140.3 (aryl C), 143.4 (C ),
148.3 (C ), 148.6 (C ); m/z 326/328 (M , 47 : 16%), 283/285
(11 : 4), 269/271 (21 : 7), 235/237 (9 : 3), 187 (38), 96 (34),
91 (100); C H ClN requires m/z 326.1545; observed m/z,
4
Ј
3Ј
2Ј
6Ј
ϩ
20
23
2
3
2
1
7
2
3
: 2), afforded 2 (17.2 mg, 78%), νmax 3045w, 2920s, 2870w,
850m, 1584w, 1560m, 1454s, 1405m, 1390m, 1290w, 1265s,
326.1550. The second compound to be eluted (R ≈ 0.6) (2 mg,
f
25% yield) was 3 contaminated with some 20 and was further
purified by flash chromatography with the same elution con-
ditions to yield a pure sample of 3.
140m, 1100s, 1084w, 862m, 840w, 825m, 805w, 790w, 735br s,
Ϫ1
00s cm ; δ (250 MHz) 1.5–1.9 (series of m, 8H, incl. NH),
H
7β
6β
.16 (dd, J = 13.2, 9.4 Hz, H ), 3.08 (dd, J = 9.1, 5.0, Hz, H ),
.26 (br s, H ), 3.62 (m, H ), 7.15 (d, J = 8.2 Hz, H ), 7.67 (dd,
5
1
5Ј
Attempted direct preparation of N-benzyl-7ꢁ-(6Ј-chloro-3Ј-
pyridyl)-9-azabicyclo[4.2.1]nonane 20. The N-benzyl alkene 21
(44.8 mg, 0.21 mmol) was treated with 2-chloro-5-iodopyridine
(166 mg, 0.69 mmol, 2.3 eq.) followed by tetrakis(triphen-
ylphosphine)palladium(0) (314 mg, 0.27 mmol, 1.3 eq.), DMF
(350 µL), piperidine (125 µL, 108 mg, 1.26 mmol, 6 eq.) and
formic acid (48 µL, 58 mg, 1.25 mmol, 6 eq.) as described above
and heated in a Reacti-vial at 95 ЊC for 48 h. Work-up and
chromatography on silica using 3 : 7 diethyl ether–‘petroleum
ether’ containing ammonia gave only unchanged 21.
4
Ј
2Ј
J = 8.2, 2.5 Hz, H ), 8.20, (d, J = 2.5 Hz, H ); δ (63 MHz) 17.6
C
3
2
4
7
6
1
5
(
1
2
C ), 32.7/33.3 (C , C ), 39.3 (C ), 44.3 (C ), 55.6 (C ), 62.7 (C ),
5Ј 4Ј 3Ј 2Ј 6Ј
24.0 (C ), 137.1 (C ), 142.6 (C ), 148.2 (C ), 148.8 (C ); m/z
ϩ
22/224 (M , 12/3%), 193/195 (3/1), 179/181 (9/3), 155 (5), 127
ϩ
(
4), 107 (4), 91 (10), 83 (100), 68 (18); C H ClN [M ] requires
12
15
2
m/z 222.0924; observed m/z, 222.0924.
A sample of (±)-18 was resolved using chiral HPLC on a
semi-preparative Chiralpak AD column, eluted with 30%
ethanol in hexane; samples were obtained in >99% ee as shown
by analytical chiral HPLC. Pure samples of (ϩ)-2 and (Ϫ)-2
were then obtained by separate deprotection using iodotri-
N-Methyl-6ꢁ-(3Ј-pyridyl)-8-azabicyclo[3.2.1]octane 23. To a
stirred solution of 18 (54 mg, 0.151 mmol) in THF (5 mL) at
Ϫ78 ЊC was added LAH (23 mg, 0.604 mmol). The reaction
mixture was allowed to warm slowly to ambient temperature.
Analysis by TLC after 1.5 h showed only starting material.
Further LAH (23 mg) was added at 0 ЊC and the reaction
mixture allowed to warm to RT but TLC analysis still indicated
that starting material was present after a further 2.5 h. Stirring
was continued overnight, after which time no starting material
remained. The reaction was quenched by the addition of the
minimum quantity of water-saturated diethyl ether at 0 ЊC. The
suspension was dried with anhydrous sodium sulfate and
filtered through Celite. The inorganic residues were washed
with ethyl acetate and the solvent evaporated off using a rotary
evaporator to yield a crude yellow oil. Purification by column
chromatography on silica using 3 : 7 diethyl ether–‘petroleum
ether’ yielded 23 as a pale yellow oil (18 mg, 58%). νmax 2930s,
2870w, 2860m, 1575w, 1460br m, 1425m, 1325br w, 1015br w,
1
9.2
methylsilane as described above. (ϩ)-18 [α] ϩ61.0 (c 0.0159
D
19.9
19.0
MeOH); (Ϫ)-18 [α]D Ϫ61.4 (c 0.0174 MeOH); (ϩ)-2 [α]D
ϩ31.0 (c 0.008 MeOH). Insufficient material was available for
reliable measurements on (Ϫ)-2.
7
ꢁ-(6Ј-Chloro-3Ј-pyridyl)-9-azabicyclo[4.2.1]octane (3; di-
homoepibatidine). Iodotrimethylsilane (210 µL, 295 mg, 1.48
mmol, 5.1 eq.) was injected into a solution of 19 (107 mg, 0.29
mmol) in dry CH Cl (5 mL). The contents were mixed and
stored for 30 min. Methanol (5 mL; acidified with gaseous HCl)
was then added and the solvent removed using a rotary evap-
orator; this was followed by the addition of methanol (5 mL;
basified with gaseous ammonia) after which the solvent was
again evaporated off under reduced pressure. The residue was
purified by chromatography on silica using 4 : 6 diethyl ether–
2
2
‘petroleum ether’ to yield 3 (45 mg, 66%) as a colourless oil. A
preliminary small-scale reaction gave a quantitative crude yield
of 3 as shown by NMR integration against an internal standard
but the deprotection reaction was not further optimised; δH
Ϫ1
850br s cm ; δH (400 MHz) 1.17 (m, 1H), 1.26 (m, 1H), 1.66
(m, 1H), 1.80 (m, 1H), 1.96–2.11 (series of m, 3H), 2.24 (dd,
7
β
5
(
250 MHz; CD Cl ) 1.5–1.9 (series of m, 9H incl. NH), 2.05 (m,
J = 13.1, 9.3 Hz, H ), 2.52 (s, 3H, NCH ), 3.16 (br s, H ), 3.19
3
6β 1
2
2
7α
2
H), 3.05 (br ddd, J ≈ 9.2, 6.6, 2.0 Hz, H ), 3.43 (br dd, J = 5.3,
(dd, J = 9.3, 5.0 Hz, H ), 3.34 (m, H ), 7.21 (br dd, J = 8.0, 4.6,
5Ј 4Ј
6
1
5Ј
2
.0 Hz, H ), 3.85 (m, H ), 7.27 (d, J = 8.2 Hz, H ), 7.61 (dd,
<1 Hz, H ), 7.80 (ddd, J = 8.0, 2.2, ≈1 Hz, H ), 8.43 (br dd,
2Ј 6Ј
4Ј
2Ј
J = 8.2, 2.5 Hz, H ), 8.23 (d, J = 2.5 Hz, H ); δ (63 MHz,
J = 4.6, ≈1, <1 Hz, H ), 8.58 (br d, J = 2.2, <1 Hz, H ); δ (106
C
C
J. Chem. Soc., Perkin Trans. 1, 2001, 1044–1050
1049