Combining Two-Directional Synthesis and Tandem Reactions, Part 17: Expedient Formation of Functionalised Azabicycles

Abstract

Synthesis of a range of functionalised azabicycles from simple linear keto dienoates has been achieved using a tandem enamine formation/Michael addition/aza-Michael addition reaction.

Key words

aziridine - imine - ylide - sulfonium - vinyl

References and Notes

• For examples see:
• 1a Gignoux C. Newton AF. Barthelme A. Lewis W. Alcaraz M.-L. Stockman RA. Org. Biomol. Chem.  2012,  10:  67 
• 1b Roe SJ. Aggarwal P. Stockman RA. Synthesis  2009,  3375 
• 1c Legeay J.-C. Lewis W. Stockman RA. Chem. Commun.  2009,  2207 
• 1d Roe SJ. Stockman RA. Chem. Commun.  2008,  3432 
• 1e Newton AF. Rejzek M. Alcaraz M.-L. Stockman RA. Beilstein J. Org. Chem.  2008,  4:  No. 4 
• 1f Karatholuvhu MS. Sinclair A. Newton AF. Alcaraz M.-L. Stockman RA. Fuchs PL. J. Am. Chem. Soc.  2006,  128:  12656 
• 2 Spande TF. Jain P. Garraffo HM. Pannell LK. Yeh HJC. Daly JW. Fukumoto S. Inamura K. Tokuyama T. Torres JA. Snelling RR. Jones TH. J. Nat. Prod.  1999,  62:  5 
• 3 Daly JW. Witkop B. Tokuyama T. Nishikawa T. Karle IL. Helv. Chim. Acta  1977,  60:  1128 
• 4a For isolation of lepadins (+)-F, (+)-G, and (+)-H, see: Davis RA. Carroll AR. Quinn RJ. J. Nat. Prod.  2002,  65:  454 
• 4b For isolation of lepadins (+)-D, (-)-E, and (-)-F, see: Wright AD. Goclik E. Koening GM. Kaminsky R. J. Med. Chem.  2002,  45:  3067 
• 4c For isolation of (-)-lepadin A, see: Steffan B. Tetrahedron  1991,  47:  8729 
• 4d For isolation of lepadins (-)-B and (-)-C, see: Kubanek J. Williams DE. de Silva ED. Allen T. Andersen RJ. Tetrahedron Lett.  1995,  36:  6189 
• 5 Robbins D. Newton AF. Gignoux C. Legeay J.-C. Sinclair A. Rejzek M. Laxton CA. Yalamanchili SK. Lewis W. O’Connell M. Stockman RA. Chem. Sci.  2011,  2:  2232 

6

Representative Procedure; Synthesis of 2a: To a solution of (2E,11E)-diethyl 7-oxotrideca-2,11-dienedioate (100 mg, 0.32 mmol) in CH₂Cl₂ (10 mL) at -10 ˚C was added TiCl₄ (1 M soln in CH₂Cl₂, 0.64 mL, 0.64 mmol). The mixture was stirred at -10 ˚C for 30 min, then aniline (40.0 µL, 0.48 mmol) was added. The mixture was allowed to warm to r.t., then heated to reflux overnight. The reaction was quenched with sat. aq NaHCO₃ (10 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (3 × 10 mL), the combined organics washed with brine (20 mL), dried over anhyd Na₂SO₄ and concentrated in vacuo. The resulting product was purified using column chromatography on silica gel (PE-EtOAc, 6:1) to give the title compound as a yellow oil (80.0 mg, 65%), as a 3:1 mixture of diastereomers (data for major diastereomer detailed). IR (thin film): 3664, 3008, 1724 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.24-7.30 (m, 2 H), 6.96-7.06 (m, 3 H), 4.16-4.23 (m, 4 H), 4.04-4.15 (m, 1 H), 2.77 (ddd, J = 14.6, 9.6, 4.1 Hz, 1 H), 2.73-2.81 (m, 1 H), 2.59-2.72 (m, 2 H), 2.27-2.44 (m, 2 H), 1.78-1.93 (m, 3 H), 1.62-1.74 (m, 3 H), 1.45-1.61 (m, 3 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.32 (t, J = 7.0 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 172.8, 149.2, 133.9, 128.7, 124.5, 122.5, 116.4, 60.4, 60.3, 58.0, 39.7, 38.7, 36.5, 29.7, 29.3, 28.1, 22.7, 21.0, 14.4, 14.3. MS (ES): m/z (%) = 386 (100) [M + 1], 408 (16). HRMS: m/z [M + H⁺] calcd for C₂₃H₃₂NO₄: 386.2326; found: 386.2335.

7

Data for major diastereomer of products: 2b: IR (thin film): 1730 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.22-7.35 (m, 5 H), 3.98-4.22 (m, 6 H), 3.42-3.53 (m, 1 H), 2.43-2.58 (m, 3 H), 2.19-2.34 (m, 3 H), 1.91-2.10 (m, 3 H), 1.58-1.70 (m, 4 H), 1.14-1.33 (m, 8 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 172.5, 140.6, 135.6, 128.3, 127.5, 126.7, 109.6, 60.26, 53.98, 52.82, 39.12, 37.18, 35.37, 27.84, 27.64, 23.91, 21.90, 19.42, 17.49, 14.64, 14.30. MS (ES): m/z (%) = 400 (100) [M + 1]. HRMS: m/z [M + H⁺] calcd for C₂₄H₃₄NO₄: 400.2482; found: 400.2429. 2g: IR (thin film): 1732, 1641, 1541 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 5.70-5.90 (m, 1 H), 5.17 (d, J = 17.1 Hz, 1 H), 5.08 (d, J = 10.2 Hz, 1 H), 4.10-4.35 (m, 4 H), 3.50 (m, 3 H), 2.50 (m, 3 H), 2.25 (m, 3 H), 2.00 (m, 2 H), 1.80 (m, 2 H), 1.60 (m, 5 H), 1.35 (t, J = 7.2 Hz, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 172.6, 136.5, 134.9, 115.6, 106.5, 60.1, 60.0, 53.7, 53.1, 38.9, 36.8, 36.7, 28.3, 27.0, 24.6, 22.3, 20.2, 14.3, 14.2. MS (ES): m/z (%) = 350 (100) [M + 1]. HRMS: m/z [M + H⁺] calcd for C₂₀H₃₂NO₄: 350.2326; found: 350.2320. 2h: IR (thin film): 1730 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.12 (q, J = 7.2 Hz, 4 H), 4.80 (dd, J = 18.4, 2.4 Hz, 1 H), 3.67 (m, 1 H), 3.62 (dd, J = 18.4, 2.4 Hz, 1 H), 2.50-2.60 (m, 3 H), 2.25-2.35 (m, 4 H), 2.10 (m, 1 H), 1.90 (m, 1 H), 1.70 (m, 1 H), 1.55-1.65 (m, 5 H), 1.47 (m, 1 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.15 (t, J = 7.1 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.6, 172.3, 133.7, 109.6, 81.2, 71.5, 60.2, 60.1, 54.4, 40.3, 38.8, 37.5, 36.7, 28.0, 26.9, 24.8, 22.5, 19.9, 14.3, 14.25. MS (ES): m/z (%) = 348 (100) [M + 1]. HRMS: m/z [M + H⁺] calcd for C₂₀H₃₀NO₄: 348.2175; found: 348.2135. 9: IR (thin film): 1598, 1490, 1446, 1302, 1144 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.96 (t, J = 7.2 Hz, 2 H), 7.88 (t, J = 6.8 Hz, 1 H), 7.67 (m, 1 H), 7.50 (m, 6 H), 7.25 (m, 2 H), 6.95 (m, 3 H), 4.12 (t, J = 3.6 Hz, 1 H), 3.75 (dd, J = 14.2, 8.4 Hz, 1 H), 3.27 (dd, J = 14.2, 2.4 Hz, 1 H), 3.15 (m, 2 H), 2.68 (d, J = 5.6 Hz, 1 H), 2.20-2.40 (m, 2 H), 1.70-2.10 (m, 2 H), 1.48-1.65 (m, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 148.0, 140.8, 139.8, 135.4, 133.8, 133.4, 129.4, 129.1, 128.9, 127.8, 127.6, 124.5, 123.4, 122.8, 117.6, 114.6, 58.6, 56.7, 56.5, 35.3, 28.4, 27.3, 26.7, 22.3, 21.9. MS (ES): m/z (%) = 522 (38.2) [M + 1]. HRMS: m/z [M + H⁺] calcd for C₂₉H₃₂NO₄S₂: 522.1767; found: 522.1755. 10: IR (thin film): 1725, 1601, 1498 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.26 (t, J = 8.0 Hz, 2 H), 6.89 (m, 1 H), 6.70 (t, J = 7.2 Hz, 1 H), 6.60 (d, J = 8.0 Hz. 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.11 (q, J = 7.2 Hz, 2 H), 3.79-3.85 (m, 2 H), 2.58 (m, 3 H), 2.50 (m, 2 H), 2.44 (m, 2 H), 1.90 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.23 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 171.7, 171.0, 147.1, 129.4, 129.2, 128.8, 124.3, 122.1, 117.81, 113.4, 60.8, 60.2, 40.8, 39.6, 28.8, 25.6, 24.4, 14.25, 14.23. MS (ES): m/z (%) = 358 (100) [M + 1]. HRMS: m/z [M + H⁺] calcd for C₂₁H₂₈NO₄: 358.2013; found: 358.2015.