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Synlett 2009(17): 2749-2754  
DOI: 10.1055/s-0029-1217999
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Thieme Chemistry Journal Awardees - Where Are They Now? Bridgehead Lithiated 9-Oxabispidines

Matthias Breuning*, Melanie Steiner, David Hein, Christian Hörl, Philipp Maier
Universität Würzburg, Institut für Organische Chemie, Am Hubland, 97074 Würzburg, Germany
Fax: +49(931)8884755; e-Mail: breuning@chemie.uni-wuerzburg.de;
Further Information

Publication History

Received 1 July 2009
Publication Date:
30 September 2009 (online)

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Abstract

Bi- and tricyclic 9-oxabispidines are smoothly deprotonated at -78 ˚C by s-BuLi at one of the bridgehead carbon atoms to give α-lithio ethers, which were trapped with electrophiles in good yields. Rearrangements to ring-contracted N,O-acetals occurred upon warming in the absence of an electrophile. The α-lithio ether intermediates are presumably stabilized by negative hyperconjugation.

Key words

9-oxabispidines - carbanions - rearrangements - lithiation - bicyclic compounds

    References and Notes

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7

The term ‘nonactivated ethers’ refers to ethers that do not form benzyl-, allyl-, or vinyl-stabilized α-lithio ethers upon deprotonation.

19

All new compounds have been characterized by ¹H NMR and ¹³C NMR spectroscopy as well as HRMS spectrometry. Compounds 9b, 9c, and 13A/B could not be separated from the starting materials.
Spectroscopic Data for Selected Compounds
Compound 9a: mp 70 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 2.21 (s, 6 H, 3-Me, 6-Me), 2.41 (d, J = 11.1 Hz, 2 H, 6-H, 8-H), 2.42 (dd, J = 11.1, 4.4 Hz, 2 H, 4-H, 6-H), 2.89 (d, J = 11.1 Hz, 4 H, 2-H′, 4-H′, 6-H′, 8-H′), 3.85 (t, J = 4.3 Hz, 1 H, 5-H). ¹³C NMR (100 MHz, CDCl3): δ = 47.8 (3-Me, 6-Me), 58.4 (NCH2), 58.5 (NCH2), 68.0 (t, J = 21.8 Hz, C-1), 68.4 (C-5). HRMS (ESI+): m/z calcd for C8H16DN2O [M + H]+: 158.1398; found: 158.1398.
Compound 10A/B (ratio A/B = 55:45): mp 35 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 1.36 (m, 3 H A, 3 H B, CH2), 1.56 (m, 1 H A, 1 H B, CH2), 1.70-1.87 (m, 3 H A, 3 H B, CH2, 6-H), 2.19 (s, 3 H A, 3 H B, 11-Me), 2.25 (m, 2 H A, 2 H B, 2-H, 12-H), 2.39 (dd, J = 11.7, 1.3 Hz, 1 H, 10-H A), 2.40 (ddd, J = 11.6, 4.2, 1.6 Hz, 1 H, 10-H B), 2.55 (dd, J = 11.6, 1.5 Hz, 1 H, 8-H A), 2.56 (ddd, J = 11.6, 4.5, 1.7 Hz, 1 H, 8-H B), 2.78-2.95 (m, 4 H A, 4-H B, 6-H′, 8-H′, 10-H′, 12-H′), 3.47 (t, J = 3.5 Hz, 1 H, 1-H A), 3.85 (t, J = 4.1 Hz, 1 H, 9-H B). ¹³C NMR (100 MHz, CDCl3): δ = 24.6 (CH2 A, B), 25.1 (CH2 A, B), 28.2 (CH2 A, B), 47.4 (11-Me A, B), 54.4 (C-12), 54.5 (C-12), 57.2 (C-6 A, B), 57.8 (C-8), 57.9 (C-8), 58.2 (C-10), 58.3 (C-10), 64.9 (C-2), 65.0 (C-2), 68.3 (t, J = 19.8 Hz, C-9 A), 68.7 (C-9 B), 71.4 (t, J = 21.6 Hz, C-1 B), 71.8 (C-1 A). IR (ATR): ν = 2929, 2853, 2784, 1458, 1354, 1283, 1199, 1161, 1119, 1069, 973, 815, 722 cm-¹. HRMS (ESI+): m/z calcd for C11H19DN2O [M + H]+: 198.1711; found: 198.1711.
Compound 11: [α]D ²² +14.9 (c 0.22, MeOH). ¹H NMR (400 MHz, CDCl3): δ = 1.36 (m, 3 H, CH2), 1.56 (m, 1 H, CH2), 1.77 (m, 3 H, CH2, 6-H), 2.19 (s, 3 H, 11-Me), 2.24 (d, J = 11.6 Hz, 1 H, 12-H), 2.26 (m, 1 H, 2-H), 2.39 (dd, J = 11.4, 1.3 Hz, 1 H, 10-H), 2.55 (dd, J = 11.6, 1.4 Hz, 1 H, 8-H), 2.81 (d, J = 11.6 Hz, 1 H, 8-H′), 2.89 (m, 1 H, 6-H′), 2.91 (d, J = 11.7 Hz, 1 H, 10-H′), 2.92 (m, 1 H, 12-H′). ¹³C NMR (100 MHz, CDCl3): δ = 24.8 (CH2), 25.3 (CH2), 28.3 (CH2), 47.5 (11-Me), 54.5 (C-12), 57.3 (C-6), 57.9 (C-8), 58.4 (C-10), 64.9 (C-2), 68.4 (t, J = 22.1 Hz, C-9), 71.6 (t, J = 22.2 Hz, C-1). IR (ATR): ν = 2931, 2754, 1438, 1352, 1288, 1276, 1176, 1135, 1076, 1056, 1023, 788, 752, 721, 699 cm-¹ HRMS (ESI+): m/z calcd for C11H18D2N2O [M + H]+: 199.1774; found: 199.1774.
Compound 12A/B (ratio A/B = 56:44): ¹H NMR (400 MHz, CDCl3): δ = 1.05 (s, 3 H B, 1-Me), 1.10 (s, 3 H A, 9-Me), 1.27-1.86 (m, 7 H A, 8 H B, CH2, 12-H B), 1.91 (br d, J = 10.5 Hz, 1 H, 2-H B), 2.00 (dd, J = 11.4, 2.4 Hz, 1 H, 10-H A), 2.11-2.18 (m, 3 H, 2-H A, 8-H A, 12-H A), 2.15 (s, 3 H, 11-Me), 2.16 (s, 3 H, 11-Me), 2.29 (ddd, J = 11.5, 4.1, 1.7 Hz, 1 H, 10-H B), 2.55 (ddd, J = 11.5, 4.3, 1.8 Hz, 1 H, 8-H B), 2.80 (m, 2 H, 8-H′ A, 8-H′ B), 2.84-2.93 (m, 3 H A, 3 H B, 6-H′, 10-H′, 12-H′), 3.54 (t, J = 3.7 Hz, 1 H, 1-H A), 3.88 (t, J = 4.3 Hz, 1 H, 9-H B). ¹³C NMR (100 MHz, CDCl3): δ = 24.8 (CH2), 25.16 (CH2), 25.24 (2 × CH2), 25.7 (1-Me B), 26.2 (1-Me A), 27.2 (CH2), 28.1 (CH2), 47.32 (11-Me), 47.34 (11-Me), 53.8 (C-12 A), 57.3 (C-6 A), 57.58 (C-6 B or C-10 B), 57.62 (C-6 B or C-10 B), 58.0 (C-8 B), 60.6 (C-12 B), 63.9 (C-8 A), 64.2 (C-2 A), 64.3 (C-10 A), 69.1 (C-9 B), 70.1 (C-9 A), 70.8 (C-2 B), 72.0 (C-1 B), 73.1 (C-1 A). IR (ATR): ν = 2930, 2854, 2758, 1457, 1357, 1286, 1260, 1102, 1055, 812 cm-¹. HRMS (ESI+): m/z calcd for C12H22N2O [M + H]+: 211.1805; found: 211.1805.
Compound 14A/B (ratio A/B = 73:27): ¹H NMR (400 MHz, CDCl3): δ = 1.10-1.65 (m, 4 H A, 4 H B, CH2), 1.70-1.95 (m, 3 H A, 3 H B, CH2, 6-H), 2.10-2.45 (m, 5 H, 2-H A, 10-H A, 12-H A, 10-H B, 12-H B,), 2.25 (s, 3 H, 11-Me A), 2.27 (s, 3 H, 11-Me B), 2.56 (dd, J = 11.7, 2.0 Hz, 1 H, 8-H A), 2.59 (br d, J = 10.7 Hz, 1 H, 2-H B), 2.82 (ddd, J = 11.7, 4.3, 1.6 Hz, 1 H, 8-H B), 2.95 (m, 5 H, 6-H′ A, 12-H′ A, 6-H′ B, 8-H′ B, 10-H B), 3.20 (d, J = 11.7 Hz, 1 H, 8-H′ A), 3.30 (d, J = 11.5 Hz, 1 H, 10-H′ A), 3.46 (d, J = 12.2 Hz, 1 H, 12-H′ B), 3.79 (t, J = 4.1 Hz, 1 H, 1-H A), 4.14 (t, J = 4.2 Hz, 1 H, 9-H B), 7.43 (m, 2 H A, 2 H B, PhH), 7.55 (m, 1 H A, 1 H B, PhH), 8.17 (m, 2 H A, PhH), 8.25 (m, 2 H B, PhH). ¹³C NMR (100 MHz, CDCl3): δ = 24.67 (CH2 B), 24.70 (CH2 A), 25.1 (CH2 B), 25.2 (CH2 A), 26.5 (CH2 B), 27.8 (CH2 A), 47.2 (11-Me A), 47.3 (11-Me B), 53.6 (C-12 A), 56.6 (C-12 B), 57.1 (C-6 A), 57.4 (C-10 B), 57.7 (C-8 B), 57.9 (C-6 B), 59.6 (C-8 A), 59.8 (C-10 A), 64.0 (C-2 A), 65.5 (C-2 B), 69.3 (C-9 B), 72.9 (C-1 A), 80.5 (C-9 A), 81.9 (C-1 B), 127.9 (PhH A), 128.0 (PhH B), 130.3 (PhH A), 130.6 (PhH B), 132.7 (PhH A), 132.8 (PhH B), 135.2 (PhH A), 135.5 (PhH B), 199.1 (C=O B), 200.7 (C=O A). IR (ATR): ν = 2934, 2852, 2763, 1674, 1446, 1266, 1099, 1054, 708, 689, 665 cm-¹. HRMS (ESI+): m/z calcd for C18H25N2O2 [M + H]+: 301.1911; found: 301.1910.
Compound rac-17: ¹H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H, 5-Me), 2.06 (d, J = 11.1 Hz, 1 H, 4-H), 2.21 (s, 3 H, 3-Me), 2.25 (dd, J = 11.0, 1.8 Hz, 1 H, 2-H), 2.42 (s, 3 H, 6-Me), 2.54 (dd, J = 11.1, 1.8 Hz, 1 H, 2-H′), 2.76 (d, J = 11.1 Hz, 1 H, 4-H′), 3.03 (dd, J = 8.3, 1.7 Hz, 1 H, 7-H), 3.05 (dd, J = 8.3, 5.4 Hz, 1 H, 7-H′), 4.32 (dq, J = 5.4, 1.8 Hz, 1 H, 1-H). ¹³C NMR (100 MHz, CDCl3): δ = 20.2 (5-Me), 37.1 (6-Me), 45.0 (3-Me), 57.8 (C-7), 58.2 (C-2), 62.3 (C-4), 73.0 (C-1), 92.7 (C-5). IR (ATR): ν = 2925, 2853, 1662, 1456, 1258, 1015, 854, 793 cm-¹. HRMS (ESI+): m/z calcd for C8H17N2O [M + H]+: 157.1335; found: 157.1335.

20

A dilithiation of 10A/B followed by dideuteration, which would also explain the quantitative formation of 11, but without relying on a high kinetic isotope effect, can be excluded since otherwise 11 should also had been formed in the lithiation-deuteration of 4.

22

The Following Procedure is Representative: Rearrangement of Compound 4
s-BuLi (3.30 mL, 4.59 mmol, 1.39 M in cyclohexane) was added at -78 ˚C to a solution of 4 (300 mg, 1.52 mmol) in anhyd Et2O (10 mL). The reaction mixture was warmed to r.t. within 16 h, quenched with H2O (30 mL), and extracted with CH2Cl2 (10 × 30 mL). The combined organic layers were dried over MgSO4 and evaporated. Column chroma-tography (basic alumina, activity V, n-pentane-EtOAc = 6:1) delivered an inseparable 58:42 mixture of 18A and 18B (137 mg, 698 µmol, 46%) as a colorless oil. ¹H NMR (400 MHz, CDCl3): δ = 1.07 (m, 1 H, 3-H A), 1.18-1.40 (m, 4 H, 3-H′ A, 3-H B, 4-H A, 4-H B), 1.26 (s, 3 H, 1-Me B), 1.29 (s, 3 H, 9-Me A), 1.46-1.60 (m, 4 H, 3-H′ B, 5-H A, 5-H′ A, 5-H B), 1.66 (m, 1 H, 5-H′ B), 1.77 (m, 2 H, 4-H′ A, 4-H′ B), 1.88 (dd, J = 10.9, 2.3 Hz, 1 H, 2-H B), 2.03 (m, 1 H, 6-H A, 6-H B), 2.11 (dt, J = 11.7, 2.0 Hz, 1 H, 2-H A), 2.17 (d, J = 11.2 Hz, 1 H, 8-H A), 2.38 (dd, J = 11.4, 1.8 Hz, 1 H, 8-H B), 2.40 (s, 3 H, 11-Me B), 2.44 (s, 3 H, 10-Me A), 2.53 (dd, J = 11.1, 2.0 Hz, 1 H, 8-H′ B), 2.62 (dd, J = 8.9, 6.5 Hz, 1 H, 10-H B), 2.68 (d, J = 11.2 Hz, 1 H, 8-H′ A), 2.70 (m, 2 H, 6-H′ A, 6-H′ B), 2.91 (dd, J = 8.7, 6.4 Hz, 1 H, 11-H A), 3.15 (d, J = 8.8 Hz, 1 H, 11-H′ A), 3.41 (d, J = 9.0 Hz, 1 H, 10-H′ B), 3.97 (d, J = 6.5 Hz, 1 H, 1-H A), 4.27 (dt, J = 6.5, 2.0 Hz, 1 H, 9-H B). ¹³C NMR (100 MHz, CDCl3): δ = 18.3 (1-Me B), 19.8 (9-Me A), 24.1 (C-4 A), 24.2 (C-4 B), 24.9 (C-5 B), 25.4 (C-5 A), 26.3 (C-3 B), 26.7 (C-3 A), 37.5 (10-Me A), 40.7 (11-Me B), 54.3 (C-6 A), 55.16 (C-6 B, C-11 A), 58.8 (C-8 B), 60.1 (C-10 B), 62.3 (C-8 A), 63.3 (C-2 A), 71.4 (C-2 B), 72.2 (C-9 B), 76.9 (C-1 A), 93.5 (C-9 A), 96.0 (C-1 B). IR (ATR): ν = 2925, 2852, 2793, 1730, 1442, 1377, 1331, 1258, 1181, 1132, 823, 719, 607 cm-¹ HRMS (ESI+): m/z calcd for C11H21N2O [M + H]+: 197.1648; found: 197.1648.

23

¹³C NMR and HRMS also indicate the formation of a small amount of a trideuterated species, the structure of which is unknown.