Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7901
water (50 mL). Diethyl ether (50 mL) was added, and the layers
were separated. The organic layer was extracted with 10% HCl,
and the aqueous extracts were combined, neutralized with
NaHCO3 (s), and basified to pH 11-12 with NH4OH. The
aqueous solution was then extracted with CH2Cl2, dried
(MgSO4), and evaporated to give crude 6-m eth yl-4â-p r op ion yl-
3â-p-tolyl-6-a za bicyclo[3.2.2]n on a n e (8) which was essen-
tially pure by 1H NMR. The crude mixture was chromatographed
(10:9:1 pentane/Et2O/Et3N (Rf ) 0.65)) to give the title product
Hz, 1 H), 3.00 (m, 2 H), 2.30 (s, 3 H), 2.28-2.10 (m, 4 H), 2.06
(br s, 1 H), 1.96-1.66 (m, 5 H), 0.73 (t, J ) 7.3 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ 215.0, 141.3, 135.9, 129.2, 127.6, 65.2,
49.7, 44.7, 43.2, 41.7, 36.9, 29.2, 28.8, 26.0, 20.9, 7.12; IR
(neat): 3368, 3018, 2932, 1701, 1514, 1459 cm-1; MS m/e (rel
int): 271 (M+, 36), 214 (100). Anal. Calcd for C18H25NO: C, 79.66;
H, 9.28; N, 5.16. Found: C, 79.60; H, 9.29; N, 5.06.
6-Me t h yl-4â-p r op ion yl-3R-p -t olyl-6-a za b icyclo[3.2.2]-
n on a n e [13a ]. A solution of 12a (46 mg, 0.17 mmol) in 5 mL
acetonitrile was prepared and HCHO (37% solution, 75 uL, 0.87
mmol) added. The mixture was stirred for 5 min and NaCNBH3
(16 mg, 0.25 mmol) added. The mixture was stirred for 1 h and
HOAc (3 mL) slowly added over 30 min. The mixture was then
added to 25 mL of NaHCO3 (sat, aq) and the mixture neutralized
with NH4OH (50 mL). The aqueous layer was extracted with
CH2Cl2, dried (MgSO4), and evaporated to give crude 13a , which
was chromatographed (20:1 Et2O/Et3N) to give the title com-
pound as a colorless oil. Yield: 33 mg (0.12 mmol, 68%). 1H NMR
(400 MHz, CDCl3) δ 7.11 (d, J ) 8.1 Hz, 2 H), 7.05 (d, J ) 8.1
Hz, 2 H), 3.63 (dd, J ) 12.1, 11.7, 6.6 Hz, 1 H), 3.22 (d, J ) 10.6
Hz, 1 H), 2.81 (d, J ) 12.1 Hz, 1 H), 2.69 (br s, 1 H), 2.41 (s, 3
H), 2.41 (d, overlap, 1 H), 2.28 (s, 3 H), 2.20 (m, 3 H), 2.05 (m,
2 H), 1.93 (m, 1 H), 1.62 (m, 3 H), 0.80 (t, J ) 7.3 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ 213.6, 141.6, 135.6, 129.1, 127.8, 63.7,
58.2, 54.6, 46.0, 45.0, 41.4, 33.5, 29.9, 26.6, 23.4, 20.9, 7.58; IR
(neat) 2932, 2862, 1702, 1513, 1493 cm-1; MS m/e (rel int): 285
(M+, 20), 228 (100). Anal. Calcd for C19H27NO: C, 79.95; H, 9.53;
N, 4.91. Found: C, 79.75; H, 9.58; N, 4.81.
1
as a white crystalline solid. Yield: 99 mg (0.35 mmol, 67%). H
NMR (500 MHz, CDCl3) δ 7.22 (d, J ) 7.9 Hz, 2 H), 7.03 (d, J )
7.9 Hz, 2 H), 3.31 (dd, J ) 5.8, 5.5 Hz, 1 H), 3.19 (dd, J ) 5.8,
5.5 Hz, 1 H), 3.14 (ddd, J ) 10.7, 2, 2 Hz, 1 H), 3.09 (ddd, J )
13.4, 4.8, 4.6 Hz, 1 H), 2.82 (dd, J ) 13.1, 13.1 Hz, 1 H), 2.46
(dd, J ) 10.1, 2.7 Hz, 1 H), 2.35 (m, 1 H), 2.28 (s, 3 H), 2.36 (s,
3 H), 2.22 (m, 1 H), 2.11 (br s, 1 H), 2.05 (m, 2 H), 1.82-1.60 (m,
3 H), 0.82 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
210.7, 141.3, 134.8, 128.5, 127.9, 62.3, 58.7, 57.8, 45.4, 38.9, 35.3,
35.2, 29.7, 22.1, 20.9, 20.7, 7.6; IR (KBr): 3019, 2943, 1712, 1513
cm-1; MS m/e (rel int): 285 (M+, 34), 228 (90), 82 (100). Anal.
Calcd for C19H27NO: C, 79.95; H, 9.53; N, 4.91. Found: C, 79.66;
H, 9.57; N, 4.86. Upon quenching at room temperature with
either HCl (aq) or 1 M HCl solution in Et2O, both 8 and the
trans-substituted isomer 9 are formed as well as the ring-opened
cycloheptene 10.
6-Me t h yl-4R-p r op ion yl-3â-p -t olyl-6-a za b icyclo[3.2.2]-
n on a n e [9]: 1H NMR (500 MHz, CDCl3) δ 7.11 (d, J ) 7.9 Hz,
2 H), 7.05 (d, J ) 7.9 Hz, 2 H), 3.31 (m, 2 H), 3.04 (dd, J ) 10.7,
5.8 Hz, 1 H), 2.69 (d, J ) 10.7 Hz, 1 H), 2.66 (d, J ) 10.7 Hz, 1
H), 2.51 (s, 3 H), 2.34 (m, 1 H), 2.29 (s, 3 H), 2.10 (m, 3 H), 1.98-
1.70 (m, 5 H), 0.75 (t, J ) 7.0 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 212.8, 141.9, 135.7, 129.1, 127.7, 58.6, 57.8, 57.6, 44.3,
43.8, 40.6, 36.6, 29.9, 21.9, 21.4, 20.9, 7.3; IR (neat): 3020, 2930,
1701, 1513, 1459 cm-1; MS m/e (rel int): 285 (M+, 24), 228 (100).
Anal. Calcd for C19H27NO: C, 79.95; H, 9.53; N, 4.91. Found:
C, 80.07; H, 9.42; N, 5.00.
5-(N-Met h yla m in om et h yl)-1-p r op ion yl-7-p -t olyl-cyclo-
h ep ten e [10]: 1H NMR (500 MHz, CDCl3) δ 7.09 (d, J ) 8.2
Hz, 2 H), 7.05 (d, J ) 8.2 Hz, 2 H), 7.02 (dd, J ) 6.5, 6.5 Hz, 1
H), 4.20 (dd, J ) 10.4, 6.7 Hz, 1 H), 2.78 (m, 1 H), 2.65 (m, 1 H),
2.49 (m, 1 H), 2.37 (s, 3 H), 2.28 (s, 3 H), 2.36 (m, 3 H), 2.27 (m,
1 H), 1.96 (m, 2 H), 1.84 (m, 1 H), 1.76 (m, 1 H), 1.45 (m, 1 H),
0.94 (t, J ) 7.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 202.7,
144.5, 142.1, 139.5, 135.4, 129.1, 127.0, 58.3, 44.6, 36.9, 36.5,
35.2, 31.2, 29.5, 23.8, 20.9, 8.51; IR (neat): 3325, 3046, 3017,
2971, 1670, 1636, 1511, 1449 cm-1; HRMS calcd for C19H27NO
285.2093; found 285.2095.
2â-P r op ion yl-3â-p-tolylbicyclo[3.2.1]octa n e [5b] a n d 2R-
P r op ion yl-3â-p-tolylbicyclo [3.2.1]octa n e [6b]. A flame-dried
flask was charged with CuBr‚SMe2 (650 mg, 3.20 mmol), and a
solution (Aldrich, 1.0 M) of p-TolMgBr in Et2O (6.7 mL, 6.7
mmol) was added. The mixture was stirred at room temperature
for 15 min and cooled to 0 °C under argon. A solution of 4b (110
mg, 0.67 mmol) in 10 mL of dry THF was added dropwise over
5 min. The reaction was stirred for 24 h while warming to room
temperature. The mixture was cooled to -78 °C, and a 1 M
solution of HCl in Et2O (10 mL) was slowly added while keeping
the internal temperature below -70 °C. The mixture was
allowed to warm to 0 °C and poured into water (50 mL). Diethyl
ether (50 mL) was added, and the layers separated. The aqueous
layer was extracted with ethyl ether, and the combined extracts
were dried (MgSO4), filtered, and evaporated to give a greenish
3R-(4-Isopr open ylph en yl)-4â-pr opion yl-6-azabicyclo[3.2.2]-
n on a n e [12b] (70% from 11): 1H NMR (500 MHz, CDCl3) δ 7.38
(d, J ) 7.9 Hz, 2 H), 7.18 (d, J ) 8.2 Hz, 2 H), 5.35 (s, 1 H), 5.05
(s, 1 H), 3.45 (ddd, J ) 12.5, 12.2, 5.5 Hz, 1 H), 3.30 (d, J ) 11.6
Hz, 1 H), 3.09 (dd, J ) 11.3, 3.7 Hz, 1 H), 3.01 (m, 2 H), 2.31-
2.15 (m, 3 H), 2.13 (s, 3 H), 2.07 (br s, 1 H), 1.96-1.67 (m, 6 H),
0.74 (t, J ) 7.3 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 214.7,
143.6, 142.7, 139.1, 127.6, 125.5, 111.9, 65.1, 49.8, 44.7, 43.0,
41.6, 39.9, 29.2, 28.9, 26.0, 21.7, 7.1; IR (neat): 3367, 3084, 3025,
2971, 1702, 1627, 1458 cm-1. Anal. Calcd for C20H27NO: C,
80.76; H, 9.15; N, 4.71. Found: C, 80.60; H, 9.29; N, 4.55.
3R-(4-Isop r op en ylp h en yl)-6-(4-n itr op h en ylsu lfon yl)-4â-
p r op ion yl-6-a za bicyclo[3.2.2]n on a n e [13b]. A solution of 12b
(49 mg, 0.16 mmol), K2CO3 (46 mg, 0.33 mmol) in acetone (4
mL) was prepared, and 4-nitrobenzenesulfonyl chloride (45 mg,
0.18 mmol) was added. The reaction was stirred for 24 h and
diluted with 10 mL of NaHCO3 (satd/aq) and 5 mL of Et2O. The
layers were separated, and the aqueous layer was extracted with
Et2O. The organic layers were combined, dried (MgSO4), and
evaporated to give a yellow solid. The crude material was
chromatographed (1:1 pentane/Et2O) to give the title compound
as a white solid. Yield: 42 mg, 0.087 mmol, 53%). Mp ) 182-
1
184 °C. H NMR (500 MHz, CDCl3) δ 8.41 (d, J ) 8.5 Hz, 2 H),
8.14 (d, J ) 8.8 Hz, 2 H), 7.37 (d, J ) 8.2 Hz, 2 H), 7.37 (d, J )
7.9 Hz, 2 H), 5.34 (s, 1 H), 5.05 (s, 1 H), 4.35 (d, J ) 4.0 Hz, 1
H), 3.58 (d, J ) 10.7 Hz, 1 H), 3.34 (ddd, J ) 12.5, 12.5, 6.1 Hz,
1 H), 3.25 (dd, J ) 10.4, 3.4 Hz, 1 H), 2.92 (d, J ) 11.9 Hz, 1 H),
2.32 (m, 3 H), 2.20 (m, 1 H), 2.12 (s, 3 H), 1.95 (m, 1 H), 1.82 (m,
1 H), 1.65 (m, 3 H), 0.86 (t, J ) 7.3 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 210.6, 150.1, 144.5, 142.6, 142.4, 139.5, 129.0, 127.6,
125.8, 124.3, 112.2, 63.0, 51.7, 46.7, 43.1, 40.2, 35.2, 28.9, 28.7,
24.7, 21.7, 7.36; IR (KBr): 3104, 3025, 2971, 2935, 1716, 1529
cm-1; MS m/e (rel int): 482 (M+, 1.6), 464 (1.2), 425 (2.4), 296
(100). Anal. Calcd for C26H30N2O5S: C, 64.71; H, 6.27; N, 5.81.
Found: C, 64.49; H, 6.34; N, 5.79.
solid. This was chromatographed (50:1 pet. ether/Et2O (Rf
)
0.24)) to give a 28:72 mixture of 5b and 6b as a colorless oil.
Yield: 70 mg (0.27 mmol, 41%). Repeated chromatography
provided 6b: 1H NMR (500 MHz, CDCl3) δ 7.08 (d, J ) 8.0 Hz,
2 H), 7.03 (d, J ) 8.0 Hz, 2 H), 3.16 (td J ) 11.5, 5.5 Hz, 1 H),
2.86 (dd, J ) 11.5, 2.0 Hz, 1 H), 2.45-2.29 (m, 3 H), 2.27 (s, 3
H), 1.95 (ddd, J ) 17.5, 15.0, 7.0 Hz, 1 H), 1.90-1.81 (m, 1 H),
1.76-1.42 (m, 1 H), 0.81 (t, J ) 7.0 Hz, 3H); MS m/e (rel int) for
the mixture of 5b and 6b: 256 (M+, 51), 227 (64), 199 (49), 105
(100). Anal. Calcd for C18H24O as the mixture of 5b and 6b: C,
84.32; H, 9.44. Found: C, 84.23; H, 9.55.
4â-P r op ion yl-3R-p-tolyl-6-a za bicyclo[3.2.2]n on a n e [12a ]
(45% yield from 11): 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J )
8.0 Hz, 2 H), 7.06 (d, J ) 8.0 Hz, 2 H), 3.40 (ddd, J ) 12.5, 12.5,
5.5 Hz, 1 H), 3.29 (d, J ) 11.4 Hz, 1 H), 3.08 (dd, J ) 11.4, 4.0
6-Me t h yl-2R-p r op ion yl-3â-p -t olyl-6-a za b icyclo[3.2.2]-
n on a n e [15]. A three-necked flask was charged with CuBr‚SMe2
(538 mg, 2.62 mmol) under argon, and a solution of p-tolyl-
magnesium bromide (Aldrich, 1.0 M in Et2O, 13 mL, 13 mmol)
was added, giving a green solution. The mixture was stirred for
10 min and then cooled to 0 °C. A solution of 14 (248 mg, 1.3
mmol) in 10 mL of dry THF was added dropwise over 5 min.
The reaction was stirred overnight while slowly warming to room
temperature. The reaction mixture was cooled to -78 °C, and a
solution of anhydrous HCl (40 mL, 1.0 M in Et2O) was added at
a rate in order to keep the reaction temperature below -65 °C.
The mixture was allowed to warm to -40 °C and poured over
ice. The layers were separated, and the organic layer was
extracted with 10% HCl. The aqueous solutions were combined,