Synthesis of exo-3-Amino-7-azabicyclo[2.2.1]heptanes
20 min. This solution was filtered and slowly added over 30 min to
at 90–100 °C under N2 for 12 h. Column chromatography (CH2Cl2/
AcOEt, 19:1) gave (Ϯ)-9c as a white solid (546 mg, 81%). A mix-
ture of diastereoisomeric products was also isolated from the chro-
matographic purification (27 mg, 4%). These were not further puri-
fied or characterized. M.p. 127–139 °C. 1H NMR (300 MHz,
CDCl3, 45 °C): δ = 1.43 [s, 9 H, C(CH3)3], 1.43–1.75 (m, 2 H, endo-
H-5, exo-H-6), 1.87–1.98 (m, 1 H, exo-H-5), 2.36–2.44 (m, 1 H,
endo-H-6), 3.26 (dt, J = 1.8, 4.5 Hz, 1 H, H-2), 3.31–3.32 (m, 1 H,
H-3), 3.73 (d, J = 13.5 Hz, 1 H, NHCH2), 3.92 (d, J = 13.5 Hz, 1
a
cooled (0–5 °C) solution of bis(trimethylsilyl)acetylene (6;
13.0 mL, 58.3 mmol) in CH2Cl2 (50 mL). The cooling bath was re-
moved, and the mixture was stirred at 25 °C for 18 h. The reaction
was quenched by pouring into ice-cold 1 HCl (300 mL), and the
organic layer was separated, dried with Na2SO4, and concentrated
to dryness in vacuo. Column chromatography (hexane/AcOEt, 4:1)
simultaneously effected removal of the TMS protecting group to
provide 7 as a brown solid (4.34 g, 30%). M.p. 60–62 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.61 (s, 1 H, HCϵ), 7.72 (d, J = 8.7 Hz, H, NHCH2), 4.33 (d, J = 5.1 Hz, 1 H, H-4), 4.46 (t, J = 4.5 Hz, 1
2 H, Ph), 7.84 (d, J = 8.7 Hz, 2 H, Ph) ppm. 13C NMR (75 MHz,
H, H-1), 7.19 (d, J = 8.4 Hz, 1 H, napht.), 7.46–7.49 (m, 2 H,
CDCl3): δ = 80.0, 82.5, 129.4, 130.5, 133.1, 139.9 ppm. IR (neat): napht.), 7.57–7.68 (m, 5 H, Ph, napht.), 7.76–7.84 (m, 3 H, Ph,
ν = 3228, 3086, 2059, 1920, 1571, 1471, 1393, 1333, 1285, 1184,
napht.) ppm. 13C NMR (75 MHz, CDCl3, 45 °C): δ = 24.6, 26.3,
28.4, 52.0, 57.8, 61.3, 64.5, 74.0, 80.9, 126.0, 126.4, 126.7, 126.8,
127.9, 128.0, 128.3, 129.3, 129.8, 132.8, 133.0, 133.6, 137.0, 139.5,
˜
1156, 1084, 1067, 1012 cm–1. HRMS (EI, 70 eV): calcd. for
C8H5BrO2S+ [M+] 243.9194; found 243.9193.
155.4 ppm. IR (neat): ν = 2974, 1698, 1574, 1509, 1471, 1389, 1364,
˜
tert-Butyl
(1SR,4RS)-2-[(4-Bromophenyl)sulfonyl]-7-azabicyclo-
1309, 1275, 1249, 1144, 1098, 1083, 1067, 1009 cm–1. HRMS (ESI):
calcd. for C28H32BrN2O4S+ [M + H]+ 573.1242; found 573.1234.
C28H31BrN2O4S (571.53): calcd. C 58.84, H 5.47, N 4.90; found C
58.68, H 5.62, N 4.85.
[2.2.1]hepta-2,5-diene-7-carboxylate [(؎)-8]: A mixture of acetylene
7 (800 mg, 3.26 mmol) and N-Boc-pyrrole (1.09 mL, 6.53 mmol)
was heated at 80 °C under N2 for 18 h and with protection from
light. The mixture was cooled to 25 °C and taken up in a minimum
amount of CH2Cl2. Column chromatography (hexane/AcOEt, 3:1)
tert-Butyl (1SR,2SR,3RS,4RS)-2-{[4-(3-Cyclopentylprop-1-yn-1-yl)-
phenyl]sulfonyl}-3-[(2-naphthylmethyl)amino]-7-azabicyclo[2.2.1]-
heptane-7-carboxylate [(؎)-12k]: A solution of (Ϯ)-9c (100 mg,
0.17 mmol) and 3-cyclopentylprop-1-yne (11k; 40 µL, 0.34 mmol)
in HNEt2 (3 mL) was prepared in a Schlenk tube under Ar and
degassed with three freeze–pump–thaw cycles. [PdCl2(PPh3)2]
(12 mg, 0.017 mmol) and CuI (6.7 mg, 0.035 mmol) were added to
the solution at 25 °C. The black mixture was stirred at 55 °C for
13 h, then cooled to 25 °C, filtered over SiO2 (AcOEt), and concen-
trated in vacuo. Purification of the residue by column chromatog-
raphy (hexane/AcOEt, 17:3) yielded (Ϯ)-12k as an off-white solid
(95 g, 93%). M.p. 126–128 °C. 1H NMR (300 MHz, CDCl3, 45 °C):
δ = 1.28–1.77 (m, 8 H, CH2 cyclopentyl), 1.43 [s, 9 H, C(CH3)3],
1.84–1.95 (m, 3 H, H-5, exo-H-6), 2.19 (hept., J = 7.5 Hz, 1 H,
ϵCCH2CH), 2.38–2.49 (m, 3 H, endo-H-6, ϵCCH2), 3.27–3.40 (m,
2 H, H-2, H-3), 3.73 (d, J = 13.2 Hz, 1 H, NHCH2), 3.90 (d, J =
13.2 Hz, 1 H, NHCH2), 4.32 (d, J = 5.1 Hz, 1 H, H-4), 4.45 (t, J
= 4.2 Hz, 1 H, H-1), 7.19 (d, J = 8.1 Hz, 1 H, napht.), 7.43–7.51
(m, 4 H, Ph, napht.), 7.57 (s, 1 H, napht.), 7.72–7.83 (m, 5 H, Ph,
napht.) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.6, 25.4, 25.4,
26.1, 28.3, 32.2, 39.0, 51.8, 57.6, 60.9, 64.2, 73.6, 79.4, 80.6, 95.1,
125.6, 125.9, 126.4 (2 C), 127.5, 127.7, 127.8, 127.9, 130.2, 132.2,
1
yielded (Ϯ)-8 as a beige solid (1.01 g, 75%). M.p. 120–125 °C. H
NMR (300 MHz, CDCl3): δ = 1.28 [br. s, 9 H, C(CH3)3], 5.16 (s,
1 H, H-4), 5.40 (br. s, 1 H, H-1), 6.90 (dd, J = 2.7, 5.4 Hz, 1 H, H-
5), 6.97 (br. s, 1 H, H-6), 7.65–7.75 (m, 5 H, H-3, Ph) ppm. 13C
NMR (75 MHz, CDCl3): δ = 28.1, 67.1, 68.2, 81.7, 129.4, 129.7,
132.9, 138.2, 141.8, 143.5, 153.9 (2 C), 159.1 ppm. IR (neat): ν =
˜
3094, 3017, 2976, 1699, 1571, 1476, 1455, 1387, 1349, 1314, 1278,
1256, 1149, 1117, 1084, 1066, 1018, 1006 cm–1. HRMS (ESI): calcd.
for C17H18BrNNaO4S+ [M + Na]+ 434.0038; found 434.0032.
C17H18BrNO4S (412.30): calcd. C 49.52, H 4.40, N 3.40; found C
49.55, H 4.59, N 3.37.
tert-Butyl
(1SR,4RS)-2-[(4-Bromophenyl)sulfonyl]-7-azabicyclo-
[2.2.1]hept-2-ene-7-carboxylate [(؎)-4]: A suspension of NaBH4
(413 mg, 10.9 mmol) in EtOH (15 mL) was added dropwise to a
solution of [Ni(OAc)2(H2O)4] (2.72 g, 10.9 mmol) in EtOH
(15 mL), and the resulting black slurry was stirred at 25 °C under
N2 for 10 min. A solution of diene (Ϯ)-8 (900 mg, 2.18 mmol) in
THF (9 mL) and 37% HCl (1.88 mL) was added, and stirring was
continued for 16 h under N2. The mixture was filtered through Ce-
lite and washed through with CH2Cl2 (50 mL). The filtrate was
basified to pH 8 with saturated aqueous NaHCO3 solution, and the
organic layer was separated. The cloudy aqueous layer was further
extracted with CH2Cl2 (2ϫ20 mL), and the combined organics
were dried with Na2SO4 and concentrated to dryness in vacuo to
give (Ϯ)-4 as a pale-brown solid that was used without further puri-
fication (900 mg, 100%). M.p. 128–130 °C. 1H NMR (300 MHz,
CDCl3, 45 °C): δ = 1.24 [s, 9 H, C(CH3)3], 1.26–1.47 (m, 2 H, endo-
H-5, exo-H-6), 1.91–2.10 (m, 2 H, exo-H-5, endo-H-6), 4.76 (d, J
= 3.9 Hz, 1 H, H-1), 4.85 (br. s, 1 H, H-4), 7.13 (d, J = 2.1 Hz, 1
H, H-3), 7.71 (d, J = 8.7 Hz, 2 H, Ph), 7.80 (d, J = 8.7 Hz, 2 H,
Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.3, 25.2, 28.1, 61.1,
62.1, 81.0, 129.3, 129.6, 132.9, 139.2, 145.1, 148.7, 154.8 ppm. IR
132.6, 133.2, 136.6, 138.1, 155.2 ppm. IR (neat): ν = 3008, 2936,
˜
2869, 2226, 1702, 1592, 1467, 1367, 1323, 1294, 1272, 1254, 1160,
1143, 1132, 1100, 1084, 914, 876, 844, 816, 775, 759, 745, 662, 634,
622 cm–1. HRMS (MALDI, 3-HPA): calcd. for C36H42N2O4SNa+
[M + Na]+ 599.2938; found 599.2948. C36H42N2O4S (598.79):
calcd. C 72.21, H 7.07, N 4.68; found C 72.08, H 7.01, N 4.59.
tert-Butyl (1SR,2SR,3RS,4RS)-2-{[4-(3-Cyclopentylpropyl)phenyl]-
sulfonyl}-3-[(2-naphthylmethyl)amino]-7-azabicyclo[2.2.1]heptane-
7-carboxylate [(؎)-13k]: Alkyne (Ϯ)-12k (44 mg, 0.073 mmol) and
PtO2 (4.4 mg, 10%) were combined in EtOH (4 mL) and stirred
under a H2 atmosphere (balloon) at 25 °C for 15 h. The mixture
was filtered through Celite, concentrated in vacuo, and purified by
column chromatography (CH2Cl2) to give (Ϯ)-13k as a white solid
(40 mg, 91%). M.p. 98–100 °C. 1H NMR (300 MHz, CDCl3,
45 °C): δ = 0.99–1.12 (m, 2 H, cyclopentyl), 1.27–1.79 (m, 13 H,
endo-5-H, exo-6-H, 11 aliph. H), 1.42 [s, 9 H, C(CH3)3], 1.82–1.95
(neat): ν = 2973 (br.), 1694, 1574, 1471, 1365, 1311, 1145, 1099,
˜
1068, 1083, 1009 cm–1. HRMS (ESI): calcd. for C17H20BrNNaO4S+
[M + Na]+ 436.0194; found 436.0189. C17H20BrNO4S (414.31):
calcd. C 49.28, H 4.87, N 3.38; found C 49.24, H 5.03, N 3.31.
tert-Butyl (1SR,2SR,3RS,4RS)-2-[(4-Bromophenyl)sulfonyl]-3-[(2- (m, 1 H, exo-5-H), 2.41–2.49 (m, 1 H, endo-6-H), 2.68 (t, J =
naphthylmethyl)amino]-7-azabicyclo[2.2.1]heptane-7-carboxylate
[(؎)-9c]: Vinyl sulfone [(Ϯ)-4; 490 mg, 1.18 mmol] and 2-naphthyl-
methylamine (279 mg, 1.77 mmol) were dissolved in CH2Cl2 (3 mL)
and concentrated to dryness in vacuo. The neat residue was heated
7.8 Hz, 2 H, Ar–CH2), 3.32 (dt, J = 1.5, 4.5 Hz, 1 H, 2-H), 3.37–
3.38 (m, 1 H, 3-H), 3.73 (d, J = 13.2 Hz, 1 H, NHCH2), 3.89 (d, J
= 13.2 Hz, 1 H, NHCH2), 4.30 (d, J = 5.1 Hz, 1 H, 4-H), 4.41 (t,
J = 4.5 Hz, 1 H, 1-H), 7.23 (d, J = 8.1 Hz, 1 H, napht.), 7.31 (d, J
Eur. J. Org. Chem. 2009, 1707–1719
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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