An Efficient Acid-Catalysed 5-endo-dig Cyclisation Method for Pyrrole Synthesis

Abstract

Exposure of the γ-ynyl-β-hydroxy-α-amino esters 14 and 16, derived from condensations between conjugated ynals and ynones 11 and the tin(II) enolate of N-tosylglycinate 12, to 0.5 equivalents of toluenesulfinic or sulfonic acid in hot toluene induces smooth 5-endo-dig cyclisation and dehydration to give good to excellent yields of the pyrroles 15 and 17.

pyrrole - 5-endo-dig cyclisation - γ-ynyl-β-hydroxy-α-amino esters

References

<A NAME="RD20703ST-1">1</A> Knight DW. Redfern AL. Gilmore J. J. Chem. Soc., Perkin Trans. 1  2002,  622 

<A NAME="RD20703ST-2">2</A> For an excellent overview, see: Li JJ. Gribble W. Palladium in Heterocyclic Chemistry, Tetrahedron Organic Chemistry Series   Vol. 20:  Pergamon Press; Oxford: 2000. 

<A NAME="RD20703ST-3A">3a</A> Wang JJ. Scott AI. Tetrahedron Lett.  1995,  36:  7043 

<A NAME="RD20703ST-3B">3b</A> Wang JJ. Scott AI. Tetrahedron Lett.  1996,  37:  3247 

<A NAME="RD20703ST-4">4</A> Schlummer B. Hartwig JF. Org. Lett.  2002,  4:  1471 

<A NAME="RD20703ST-5">5</A> Haskins CM. Knight DW. Chem. Commun.  2002,  2724 

<A NAME="RD20703ST-6">6</A> Gridley JJ. Coogan MP. Knight DW. Malik KMA. Sharland CM. Singkhonrat J. Williams SM. Chem. Commun.  2003,  2550 

<A NAME="RD20703ST-7">7</A> Kazmaier U. Grandel R. Eur. J. Org. Chem.  1998,  1833 ; and references cited therein

<A NAME="RD20703ST-8">8</A>

Ethyl 5-(propen-2-yl)-1-(4-toluenesulfonyl)pyrrole-2-carboxylate ( 15c). A typical procedure is as follows: The amino-ester 14c (0.100 g, 0.29 mmol) was dissolved in toluene (10 mL) containing p-toluenesulfinic acid (0.027 g, 0.15 mmol) and the resulting solution stirred at reflux for 6 h. The cooled solution was then diluted with water (20 mL) and evaporated. The residue was dissolved in Et₂O (50 mL) and the resulting solution washed with 2 M aq KOH (2 × 10 mL) and brine (10 mL) then dried (MgSO₄), filtered and evaporated. Column chromatography of the residue (SiO₂; 10-15% Et₂O-hexanes) separated the pyrrole 15c as a viscous oil (0.072 g, 76%), which showed the following spectroscopic data. IR (film): 1732, 1598, 1495, 1446, 1304, 1192, 1020, 914, 815 cm^-1. ¹H NMR (400 MHz, CDCl₃):
δ = 1.28 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃), 1.91 (br. app. s, 3 H, CH₃), 2.34 (s, 3 H, Ar-CH₃), 4.26 (q, J = 7.1 Hz, 2 H, OCH ₂CH₃), 4.86 (app. s, 1 H, =CH), 5.11 (app. s, 1 H, =CH), 5.96 (d, 1 H, J = 3.5 Hz, 4-H), 6.75 (d, 1 H, J = 3.5 Hz, 3-H), 7.19 (d, J = 8.3 Hz, 2 H, 2 × ArCH), 7.72 (d, J = 8.3 Hz, 2 H, 2 × ArCH). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 20.9, 22.9 (all CH₃), 62.6 (OCH₂), 114.2 (4-CH), 119.4 (=CH₂), 122.8 (3-CH), 128.2, 129.8 (both 2 × ArCH) and 160.9 (CO). MS (APcI): m/z (%) = 334 (100) [M+ H⁺]. HRMS: m/z [M ] calcd for C₁₇H₂₀NO₄S: 334.1113; found [M + H⁺]: 334.1114.

<A NAME="RD20703ST-9">9</A> Journet M. Cai DW. DiMichele LM. Larsen RD. Tetrahedron Lett.  1998,  39:  6427 

<A NAME="RD20703ST-10">10</A> For a review of electrophile-driven 5-endo cyclisation methods, see: Knight DW. In Progress in Heterocyclic Chemistry   Gribble GW. Gillchrist TL. 2002.  Vol. 14: