Efficient Entry to Polysubstituted Pyrrolizidines, Indolizidines and ­Quinolizidines via a Sequential Reaction Process

Abstract

A sequential S_N2-Michael addition-Michael addition ­reaction process between ω-iodo-α,β-alkynoates and δ- or γ-amino α,β-unsaturated esters is developed, which affords polysubstituted pyrrolizidines, indolizidines or quinolizidines in good yields.

cascade reactions - pyrrolizidines - indolizidines - quinolizidines

References and Notes

1 Ma D. Zhu W. Org. Lett.  2001,  3:  3927 

2 Zhu W. Dong D. Pu X. Ma D. Org. Lett.  2005,  7:  705 

3 Zhu W. Cai G. Ma D. Org. Lett.  2005,  7:  5545 

4 Jurczak J. Golebiowski A. Chem. Rev.  1989,  89:  149 ; and references cited therein

5

General Procedure for Reaction of Iodides 1 with δ- or γ-Amino α,β-Unsaturated Esters 2: A mixture of 1 (0.22 mmol), 2 (0.23 mmol), anhyd K₂CO₃ (95 mg), and 4 Å MS (40 mg) in 3 mL of MeCN was refluxed until the starting materials disappeared as monitored by TLC. The cooled solution was concentrated and partitioned between brine and Et₂O. The organic phase was dried over MgSO₄ and concentrated. The residue was purified via chromatography to give 3.

6

Selected data for 3a: [α]_D ¹⁸ +138.0 (c 0.75, CHCl₃). IR (film): 1734, 1664, 1573 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.18-4.02 (m, 4 H), 3.28 (t, J = 3.6 Hz, 1 H), 3.22-3.18 (m, 1 H), 3.12-3.10 (m, 1 H), 3.03-2.99 (m, 1 H), 2.81 (dt, J = 18.0, 6.5 Hz, 1 H), 2.64 (dd, J = 14.0, 3.4 Hz, 1 H), 2.36 (dd, J = 14.0, 8.8 Hz, 1 H), 2.02-1.96 (m, 1 H), 1.82-1.61 (m, 5 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 0.88 (d, J = 8.7 Hz, 3 H), 0.77 (d, J = 6.9 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.6, 166.7, 162.4, 161.2, 95.5, 73.2, 60.1, 58.1, 44.9, 40.7, 38.0, 24.8, 23.4, 20.0, 17.3, 15.8, 14.8, 14.4. MS: m/z = 323 [M⁺]. ESI-HRMS: m/z calcd for C₁₈H₂₉NO₄Na: 346.1979 [M + Na]⁺; found: 346.1989.

7

Selected data for 3h: [α]_D ¹⁴ +53.6 (c 0.95, CHCl₃). IR (film): 2934, 1730, 1675, 1552 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.31-7.21 (m, 8 H), 7.12-7.10 (m, 2 H), 4.74 (d, J = 12.6 Hz, 1 H), 4.56 (d, J = 12.6 Hz, 1 H), 4.18-4.09 (m, 4 H), 3.74-3.73 (m, 1 H), 3.48 (d, J = 9.6 Hz, 1 H), 3.41-3.36 (m, 1 H), 3.28 (dt, J = 17.0, 5.0 Hz, 1 H), 3.07-2.99 (m, 1 H), 2.83-2.74 (m, 3 H), 2.61 (dd, J = 13.2, 4.7 Hz, 1 H), 2.52 (dt, J = 11.9, 5.0 Hz, 1 H), 2.38 (dd, J = 16.4, 11.0 Hz, 1 H), 1.69-1.64 (m, 1 H), 1.56-1.47 (m, 3 H), 1.29-1.19 (m, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.0, 169.2, 154.7, 139.0, 138.9, 129.0 (2 C), 128.5 (2 C), 128.3 (2 C), 127.4 (2 C), 127.3, 126.5, 93.0, 75.9, 70.1, 66.2, 60.2, 58.8, 52.6, 38.1, 36.9, 33.8, 27.8, 23.3, 20.5, 14.6, 14.3. MS (EI): m/z = 491 [M⁺]. ESI-HRMS: m/z calcd for C₃₀H₃₇NO₅Na: 514.2586 [M + Na]⁺; found: 514.2564.

8

Selected data for 3m: [α]_D ¹⁸ -12.3 (c 0.5, CHCl₃). IR (film): 2930, 1728, 1665, 1574 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 6.88 (q, J = 7.5 Hz, 1 H), 5.90 (d, J = 15.5 Hz, 1 H), 4.22-4.03 (m, 6 H), 3.47 (q, J = 3.9 Hz, 1 H), 3.22-3.16 (m, 1 H), 3.09-2.96 (m, 2 H), 2.86-2.74 (m, 3 H), 2.52-2.47 (m, 2 H), 2.29 (dd, J = 15.6, 9.9 Hz, 1 H), 1.79-1.74 (m, 2 H), 1.65-1.59 (m, 2 H), 1.31-1.19 (m, 9 H). MS (EI): m/z = 393 [M⁺]. ESI-HRMS: m/z calcd for C₂₁H₃₂NO₆: 394.2252 [M + H]⁺; found: 394.2224.

For some recent references for elaborating these molecules, see:

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