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

Pooja Aggarwal; George Procopiou; Diane Robbins; Gareth Harbottle; William Lewis; Robert A. Stockman

doi:10.1055/s-0031-1290138

LETTER

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

Pooja Aggarwal^a, George Procopiou^a, Diane Robbins^a, Gareth Harbottle^b, William Lewis, Robert A. Stockman*^a
^a School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: Robert.Stockman@Nottingham.ac.uk;
^b Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK

Abstract

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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

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References

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

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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.

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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.