Sequential Strategies to Trigger Mild Dearomative Diels–Alder Cyclizations

Abstract

Dihydronaphthalenes are present in several functional molecules, but their assembly is challenging. However, a sequential strategy can induce the key annullation of an alkyne with a vinylarene under mild conditions. Products form in good yields, with ample functional tolerance via domino nucleophilic substitution and dearomative Diels−Alder and ene reactions. DFT modeling data show that alkali cations are crucial to ensure a smooth dearomative cyclization on the in situ generated intermediates.

Intramolecular Cyclization of Alkynylheteroaromatic Substrates Bearing a Tethered Cyano Group: A Strategy for Accessing Fused Pyridoheterocycles

“…This design leverages the Thorpe−Ingold (or gem-disubstituent) effect, likely increasing the rate of cyclization. 6 The various HAR substrates were synthesized from the common alkyne precursor 8 by a Sonogashira reaction with a variety of iodo-or bromo-HARs 9a−j (Figure 2a). 7 The alkynes 5a−j are thermally stable at and well past room temperature.…”

“…The reaction mixture was stirred at 23 °C for 24 h, and the organic residue was purified by flash column chromatography (hexanes:E-tOAc 4:1) to give yellow cubic crystals (63.2 mg, 43% yield). 1 H NMR (500 MHz, CDCl 3 ): δ 8.21 (ddd, J = 5.2, 0.8, 0.8 Hz, 1H, H6), 7.22 (ddd, J = 5.1, 1.9, 1.2 Hz, 1H, H5), 6 5d). Following general procedure A, alkynylnitrile 8 17 (0.11 g, 0.55 mmol), bromopyridine 9d (94 mg, 0.5 mmol), triethylamine (0.349 mL, 2.5 mmol), THF (5 mL, 0.1 M), Pd(PPh 3 ) 2 Cl 2 (18 mg, 0.025 mmol), and CuI (9 mg, 0.05 mmol) were used to prepare pyridine derivative 5d.…”

“…1 H NMR (500 MHz, CDCl 3 ): δ 8.97 (dd, J = 4.1, 1.6 Hz, 1H, H2), 8.40 (ddd, J = 8.6, 1.7, 0.8 Hz, 1H, H4), 8.26 (td, J = 1.5, 0.9 Hz, 1H, H9), 7.65 (dd, J = 8.6, 4.2 Hz, 1H, H3), 4.87 (d, J = 1.5, 2H, CH 2 ), 3.05 (s, 3H, MsCH 3 ), and 1.88 [s, 6H, C(CH 3 ) 2 ]. 13 3,3-Dimethyl-2-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo [3,4-b]- [1,6]naphthyridine (7b-maj). A solution of nitrile 5b (16.3 mg, 0.06 mmol) and TBD (4 mg, 0.03 mmol) in CHCl 3 (1.18 mL, 0.05 M) was allowed to stir at 23 °C.…”