The Journal of Organic Chemistry
Note
0.50; 0.018 g, 50%) that crystallized in ivory needles from a PE/Et2O
mixture: mp 107−108 °C; IR νmax (KBr) 3124, 2931, 2853, 2801,
1456, 1439, 1321, 1183, 1128, 1099, 1049 cm−1; 1H NMR (400 MHz,
CDCl3) δ 4.27 (dd, J = 8.0 and 5.3 Hz, 1H), 3.98 (ddd, J = 8.6, 5.1,
and 2.7 Hz, 1H), 3.34 (dd, J = 11.4 and 2.6 Hz, 1H), 3.00−2.93 (m,
2H), 2.60 (vbr s, 1H), 2.07−1.93 (m, 2H), 1.83−1.77 (m, 2H), 1.62−
1.55 (m, 2H), 1.36−1.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
87.5 (d), 69.55 (d), 64.2 (t), 52.7 (t), 28.3 (t), 25.2 (d), 24.6 (t), 23.8
(t); HRMS (ESI) m/z calcd for C8H15INO [MH]+ 268.0198, found
268.0196.
1H), 1.87 (m, 2H), 1.58 (m, 2H), 1.51−1.30 (m, 2H); 13C NMR (50
MHz, CD3OD) δ 65.35 (d), 57.4 (d), 54.3 (t), 52.8 (d), 52.2 (t), 27.2
(t), 26.1 (t), 25.6 (t).
(1SR,2SR,8aSR)-1,2-Dihydroxyindolizidine (15) and
(1RS,2RS,8aSR)-1,2-Dihydroxyindolizidine (16). (A) When a
solution of KOH (0.042 g, 0.750 mmol) in H2O (0.4 mL) was
added to a solution of indolizidine 8 (0.055 g, 0.250 mmol) in THF (1
mL), two immiscible phases formed. The reaction mixture was heated
overnight at 40 °C while being magnetically stirred in a screw-cap tube
(Pirex N. 13). The aqueous phase was then separated and washed with
THF (3 × 1 mL), and the combined organic extracts were dried over
anhydrous Na2SO4. The inorganic material was removed by filtration
and washed with THF (2 × 1 mL). Then, aqueous H2SO4 (1 M
solution, 0.37 mL, 0.370 mmol) was added to the organic phase. After
the mixture had been heated at 100 °C while being stirred in a screw-
cap tube (Pirex N. 20) for 7 h, evaporation of the solvent left a crude
that was purified by flash chromatography (41:8:1 CH2Cl2/MeOH/
30% aqueous NH3). The first moving band gave compound 155a,7,27
(Rf = 0.30; 0.027 g, 69%) as a white solid: 1H NMR (400 MHz, D2O)
δ 4.11 (ddd, J = 7.6, 4.0, and 1.8 Hz, 1H), 3.69 (dd, J = 9.0 and 3.9 Hz,
1H), 2.98 (br d, J = 11.0 Hz, 1H), 2.87 (dd, J = 11.1 and 1.8 Hz, 1H),
2.68 (dd, J = 11.3 and 7.4 Hz, 1H), 2.10 (td, J = 11.7 and 3.0 Hz, 1H),
2.02−1.96 (m, 2H), 1.89−1.81 (m, 1H), 1.68 (br d, J = 13.6 Hz, 1H),
1.55−1.43 (m, 1H), 1.36−1.22 (m, 2H); 13C NMR (100 MHz, D2O)
δ 81.35 (d), 74.1 (d), 67.0 (d), 58.7 (t), 51.1 (t), 26.0 (t), 22.4 (t),
21.5 (t); HRMS (ESI) m/z calcd for C8H16NO2 [MH]+ 158.1181,
found 158.1179.
The following band (Rf = 0.20; 0.007 g, 19%) gave a mixture of 10
1
1
and 11 (1.7:1 ratio determined by H NMR): H NMR (400 MHz,
CDCl3)24 δ 4.55 (pq, J = 7.6 Hz, 1H), [4.25 (dd, J = 8.2 and 5.1 Hz,
1H)], [3.98 (ddd, J = 8.6, 5.1, and 2.7 Hz, 1H)], 3.67 (dd, J = 10.1 and
7.4 Hz, 1H), [3.33 (dd, J = 11.3 and 2.6 Hz, 1H)], 3.30 (pt, J = 7.4 Hz,
1H), 3.00−2.91 (m, 4H), 2.10−1.77 (m, 10H), 1.64−1.44 (m, 4H),
1.35−1.20 (m, 4H); 13C NMR (100 MHz, CDCl3)24 δ [87.6 (d)],
73.9 (d), [69.5 (d)], 68.8 (d), 64.35 (t), [64.2 (t)], [52.6 (t)], 52.5 (t),
32.3 (d), 28.45 (t), [28.4 (t)], [25.1 (d)], 25.05 (t), [24.65 (t)], 23.9
(t), [23.8 (t)].
(1SR,2SR,8aRS)-2-Iodooctahydro-1-indolizinol (12) and
(1RS,2RS,8aRS)-1-Iodooctahydro-2-indolizinol (13). A solution
of indolizidine 9 (0.032 g, 0.145 mmol) and NaI (0.045 g, 0.30 mmol)
in acetone (0.9 mL) was stirred at 70 °C in a screw-cap tube (Pirex N.
13) for 5 days. After filtration of the precipitate (NaBr) and
evaporation of the solvent, the reaction crude was purified by flash
chromatography (50:1:1 CH2Cl2/MeOH/30% aqueous NH3). Com-
pound 12 was isolated along with indolizidine 13 (Rf = 0.35; 0.011 g,
28%, 1:1.6 ratio determined by 1H NMR): 1H NMR (400 MHz,
CDCl3)25 δ [4.44 (ddd, J = 6.3, 4.0, and 1.0 Hz, 1H)], 4.30 (br d, J =
3.1 Hz, 1H), 4.02 (pt, J = 7.5 Hz, 1H), 3.82 (dd, J = 10.5 and 7.7 Hz,
1H), [3.59 (dd, J = 9.7 and 3.8 Hz, 1H)], 3.17 (m, 1H), [3.08 (m,
1H)], [2.97 (d, J = 10.3 Hz, 1H)], 2.90 (vbr s, 2H), 2.76 (dd, J = 10.5
and 7.2 Hz, 1H), [2.56 (dd, J = 10.4 and 6.4 Hz, 1H)], 2.41 (m, 1H),
[2.18 (m, 1H)], 2.14 (m, 1H), [2.04−1.94 (m, 2H)], 1.89−1.74 (m,
3H), 1.68−1.52 (m, 4H), 1.38−1.14 (m, 4H); 13C NMR (100 MHz,
CDCl3)25 δ 82.8 (d), [80.1 (d)], [73.6 (d)], 65.75 (d), 64.7 (t), [62.1
(t)], 52.65 (t), [52.6 (t)], [34.3 (d)], [28.3 (t)], [25.0 (t)], 24.7 (t),
24.4 (t), [23.8 (t)], 23.4 (t), 22.7 (d).
The following band gave regioisomeric indolizidine 13 as a white
solid (Rf = 0.21; 0.015 g, 39%): mp 125−126 °C (from PE/Et2O); IR
νmax (KBr) 3118, 2935, 2825, 1449, 1338, 1155, 1027 cm−1; 1H NMR
(400 MHz, CDCl3) δ 4.44 (ddd, J = 6.4, 3.9, and 1.0 Hz, 1H), 3.57
(dd, J = 9.7 and 3.7 Hz, 1H), 3.21, (vbr s, 1H), 3.05 (dt, J = 10.6 and
2.6 Hz, 1H), 2.94 (d, J = 10.1 Hz, 1H), 2.53 (dd, J = 10.3 and 6.4 Hz,
1H), 2.15 (td, J = 9.9 and 2.5 Hz, 1H), 2.01−1.94 (m, 2H), 1.87−1.82
(m, 1H), 1.62−1.50 (m, 2H), 1.29−1.11 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 80.1 (d), 73.5 (d), 62.2 (t), 52.7 (t), 34.7 (d), 28.4
(t), 25.1 (t), 23.9 (t); HRMS (ESI) m/z calcd for C8H15INO [MH]+
268.0198, found 268.0194.
The slowest-moving band afforded 1,2-dihydroxyindolizidine 167,27
(Rf = 0.18; 0.002 g, 5%) as a white solid: 1H NMR (400 MHz, CDCl3)
δ 4.20 (t, J = 6.3 Hz, 1H), 4.02 (m, 2H), 3.86 (d, J = 4.7 Hz, 1H), 3.51
(m, 1H), 3.11 (br d, J = 11.0 Hz, 1H), 2.25 (m, 1H), 2.13−2.04 (m,
2H), 1.85 (br d, J = 12.9 Hz, 1H), 1.73−1.47 (m, 4H), 1.35−1.24 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 80.0 (d), 77.1 (d), 66.8 (d), 61.4
(t), 53.3 (t), 24.7 (t), 24.3 (t), 23.6 (t); HRMS (ESI) m/z calcd for
C8H16NO2 [MH]+ 158.1181, found 158.1177.
(B) As described above, a solution of KOH (0.021 g, 0.375 mmol)
in H2O (0.3 mL) was added to a solution of indolizidine 9 (0.055 g,
0.250 mmol) in THF (1 mL), and the resulting biphasic mixture was
heated overnight at 40 °C while being magnetically stirred in a screw-
cap tube (Pirex N. 13). After separation of the aqueous phase and
anydrification, the organic solution was treated with aqueous H2SO4 (1
M solution, 0.28 mL, 0.280 mmol) and heated while being stirred at
100 °C in a screw-cap tube (Pirex N. 20) for 7 h. After evaporation of
the solvent, the reaction crude was resolved by flash chromatography
(41:8:1 CH2Cl2/MeOH/30% aqueous NH3) to give 1,2-dihydrox-
yindolizidines 155a,7,27 (Rf = 0.30; 0.004 g, 10%) and 167,27 (Rf = 0.18;
0.028 g, 71%), which were identical with the samples previously
obtained.
(1aRS,7aSR,7bSR)-Octahydrooxireno[2,3-a]indolizine (14a).
A solution of KOH (0.018 g, 0.321 mmol) in CD3OD (0.3 mL) was
added to a solution of indolizidine 8 (0.024 g, 0.109 mmol) in the
same solvent (0.6 mL) in an NMR tube and the mixture heated
overnight at 40 °C. Compound 8 disappeared completely, and epoxide
14a21 was the only reaction product:26 1H NMR (400 MHz, CD3OD)
δ 3.62 (br d, J = 3.3 Hz, 1H), 3.47 (d, J = 3.3 Hz, 1H), 3.11 (dd, J =
12.4 and 3.7 Hz, 1H), 2.94 (br s, 2H), 2.92−2.73 (m, 2H), 1.80 (m,
1H), 1.52−1.42 (m, 2H), 1.39 (dt, J = 12.6 and 3.2 Hz, 1H), 1.31 (m,
1H), 1.14 (qd, J = 12.6 and 3.8 Hz, 1H); 13C NMR (50 MHz,
CD3OD) δ 59.8 (d), 57.6 (d), 55.1 (d), 48.85 (t), 46.8 (t), 24.3 (t),
24.2 (t), 21.1 (t).
(1aRS,7aRS,7bSR)-Octahydrooxireno[2,3-a]indolizine (14b).
A solution of KOH (0.006 g, 0.107 mmol) in CD3OD (0.3 mL) was
added to a solution of indolizidine 9 (0.016 g, 0.073 mmol) in the
same solvent (0.6 mL) in an NMR tube and the mixture heated
overnight at 40 °C. The disappearance of compound 9 gave rise to
epoxide 14b as the only reaction product: 1H NMR (400 MHz,
CD3OD) δ 3.52 (m, 2H), 3.18 (d, J = 10.9 Hz, 1H), 2.95 (m, 1H),
2.30 (d, J = 10.9 Hz, 1H), 2.21 (m, 1H), 2.14 (dd, J = 11.5 and 2.1 Hz,
ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C NMR spectra of all new compounds and X-ray
crystal data of 6, 8, and 9. This material is available free of
AUTHOR INFORMATION
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Corresponding Author
ACKNOWLEDGMENTS
■
Mrs. B. Innocenti and Mr. M. Passaponti are acknowledged for
technical support. We thank the Ministry of University and
Research (MIUR, Rome, Italy) for financial support
(PRIN2008BRXNTY).
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dx.doi.org/10.1021/jo201830b|J. Org. Chem. 2011, 76, 9536−9541