Trapping of Hexadehydro-Diels–Alder Benzynes with Exocyclic, Conjugated Enals as a Route to Fused Spirocyclic Benzopyran Motifs

Dedicated with very best wishes to Professor Victor Snieckus on the occasion of his 80^th birthday

Abstract

Exocyclic, conjugated enals react with benzynes generated by heating various triyne-containing substrates to produce spirocyclic benzopyran derivatives. These products are consistent with a mechanistic sequence that involves initial net [2+2] cycloaddition of the benzyne and aldehyde followed by 4π-electrocyclic ring opening and 6π ring closing.

Key words

benzoxetenes - electrocyclizations - spirocycles - arynes - cascades

• References and Notes

• 1a Heaney H. Jablonski JM. Chem. Commun. 1968; 1139
• 1b Heaney H. Jablonski JM. McCarty CT. J. Chem. Soc. Perkin Trans. 1 1972; 2903
• 2a Adam W. Hadjiarapoglou L. Peters K. Sauter M. J. Am. Chem. Soc. 1993; 115: 8603
• 2b Meier H. Molecules 2012; 17: 1548
• 3 Wang T. Hoye TR. J. Am. Chem. Soc. 2016; 138: 13870
• 4 Meng X. Lv S. Cheng D. Hu Q. Ma J. Liu B. Hu Y. Chem. Eur. J. 2017; 23: 6264
• 5 Zhang T. Huang X. Wu L. Eur. J. Org. Chem. 2012; 3507
• 6 Klajn R. Chem. Soc. Rev. 2014; 43: 148 ; and references cited therein
• 7 Saragi TP. I. Spehr T. Siebert A. Fuhrmann-Lieker T. Salbeck J. Chem. Rev. 2007; 107: 1011
• 8 NOE experiments carried out on this mixture of coeluting isomers (toluene-d ₈, 90 °C) failed to reveal the relative configuration between the spirocyclic and methyl ester bearing stereocenters. In particular, the alkene protons enhanced one another in both diastereomers but neither showed a detectable enhancement of the pyrrolidine methine proton.
• 9a Chen J. Palani V. Hoye TR. J. Am. Chem. Soc. 2016; 138: 4318
• 9b Zhang J. Niu D. Brinker VA. Hoye TR. Org. Lett. 2016; 18: 5596
• 10 Representative Procedure for the Formation of Spirocyclic Benzopyran 17a N-(Hepta-3,5-diyn-1-yl)-4-methyl-N-(penta-1,3-diyn-1-yl)benzenesulfonamide (15, 30 mg, 93 μmol) and 2-cycloheptylideneacetaldehyde (16a, 26 mg, 188 μmol, 2 equiv) were added to a glass vial. DCE (5 mL) was added to bring the concentration of the tetrayne to 0.02 M. The vial was sealed with a Teflon-lined cap and placed in an oil bath held at 100 °C. After 15 h at 100 °C, the cooled solution was partitioned between EtOAc and 30% aqueous n-butylamine (to remove excess enal, which had a very similar R_f on silica gel to that of 17a). The EtOAc layer was dried (Na₂SO₄), filtered, and concentrated. Purification of the residue by MPLC (hexanes/EtOAc = 5:1) gave the spirocyclic product 5′-methyl-4′-(prop-1-yn-1-yl)-1′-tosyl-2′,3′-dihydro-1′H-spiro{cycloheptane-1,7′-pyrano[2,3-g]indole} (17a, 30 mg, 65 mol, 70%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.39 (d, J = 8.3 Hz, 2 H, SO₂ArH_ortho ), 7.17 (d, J = 8.5 Hz, 2 H, SO₂ArH_meta ), 6.90 (d, J = 9.9 Hz, 1 H, H1), 5.73 (d, J = 9.9 Hz, 1 H, H2), 3.96 (t, J = 7.4 Hz, CH₂NTs), 2.39 (s, 3 H, SO₂ArCH₃), 2.26 (s, 3 H, ArCH₃), 2.16 (t, J = 7.4 Hz, 2 H, CH₂ CH₂NTs), 2.15–2.08 (non-first-order m, 2 H), 2.02 (s, 3 H, –C≡CCH₃ ), 1.82–1.67 (m, 6 H), 1.63–1.55 (m, 2 H), and 1.53–1.45 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 150.4, 144.1, 136.0, 134.6, 131.3, 130.6, 129.8, 127.8, 126.0, 120.0, 119.9, 116.0, 93.1, 80.4, 76.6, 53.1, 39.1, 29.6, 28.7, 22.0, 21.8, 13.8, and 4.7. IR: 2921, 2856, 1598, 1354, 1164, 1089, 1017, 913 and 814 cm^–1. HRMS (ESI-TOF): m/z calcd for C₂₈H₃₁NNaO₃S⁺ [M + Na]⁺: 484.1917; found: 484.1920.