Palladium‐Catalyzed Regioselective 5‐exo‐O‐Cyclization/Oxidative Heck Cascades from o‐Alkynylbenzamides and Electron‐Deficient Alkenes

Abstract

A Pd‐catalyzed 5‐exo‐selective oxycyclization/oxidative Heck coupling cascade is described, starting from readily available ortho‐alkynylbenzamides and functionalized olefins. The key to a high regioselectivity in the cyclization step is the choice of catalyst and/or additives. Thus, Pd(OAc)2 provides the desired 5‐exo products predominantly, whereas with PdCl2 or Pd(TFA)2, the corresponding 6‐endo products prevail. The subsequent oxidative Heck‐type coupling takes place stereoselectively with the very predominant formation of E isomers, leading to an effective preparation of structurally diverse carbonyl‐substituted allylideneisobenzofuranimines.

Synthesis of 7-alkylidene-7,12-dihydroindolo[3,2-d]benzazepine-6-(5H)-ones (7-alkylidene-paullones) by N-cyclization–oxidative Heck cascade and characterization as sirtuin modulators

“…: 139 °C (Et 2 O). (13), 170 (43), 127 (23), 117 (100), 116 (17), 99 (19), 89 (20). HRMS (EI): Calcd for C 14 H 13 NO 3 243.0895; found, 243.0893.…”

Palladium‐Catalyzed 6‐endo‐Selective Oxycyclization–Alkene Addition Cascades of ortho‐Alkynylarylcarboxamides and α,β‐Unsaturated Carbonyl Compounds

“…4‐[( Z )‐1‐(Butylimino)‐3‐hexyl‐1 H ‐isochromen‐4‐yl]butan‐2‐one (6d): Compound 3d 6a (100 mg, 0.350 mmol) was used in the representative procedure for a reaction time of 15 h. The crude product was purified by flash chromatography (silica gel saturated with Et 3 N; hexanes/EtOAc/Et 3 N, 98:1:1) to afford 6d (107 mg, 86 %) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ): δ = 0.87–0.98 (m, 6 H), 1.31–1.48 (m, 8 H), 1.59–1.69 (m, 4 H), 2.16 (s, 3 H), 2.48 (t, J = 7.5 Hz, 2 H), 2.61–2.68 (m, 2 H), 2.75–2.81 (m, 2 H), 3.45 (t, J = 7.1 Hz, 2 H), 7.20 (d, J = 7.9 Hz, 1 H), 7.25–7.30 (m, 1 H), 7.43–7.48 (m, 1 H), 8.19 (d, J = 7.9 Hz, 1 H) ppm.…”

“…for C 26 H 28 N 2 O 2 [M] + 400.2151; found 400.2153. Alternatively, the reaction was conducted by using compound 3h 6a (57.0 mg, 0.172 mmol), 3‐buten‐2‐one (84 μL, 1.035 mmol), and PdI 2 (3.10 mg, 8.6 μmol; Table 2, Entry 5), and the crude product was purified by flash chromatography (silica gel saturated with Et 3 N; hexanes/EtOAc/Et 3 N, from 92:7:1 to 40:59:1) to afford 7h 2 (39.5 mg, 75 %), 6h (8.5 mg, 15 %), and 8h 8 (20 mg, 62 %).…”

“…4‐[( Z )‐1‐(4‐Chlorophenylimino)‐3‐hexyl‐1 H ‐isochromen‐4‐yl]butan‐2‐one (6i): Compound 3i 6a (100 mg, 0.294 mmol) was used in the representative procedure for a reaction time of 18 h. The crude product was purified by flash chromatography (silica gel saturated with Et 3 N; hexanes/EtOAc/Et 3 N, from 98.5:0.5:1 to 97:2:1) to afford 6i (110 mg, 91 %) as a yellow solid; m.p. 62–63 °C.…”

“…The Heck pathway is followed, for example, by ortho ‐alkynylarylcarboxamides 3 (among other substrates) in palladium‐catalyzed couplings with electron‐deficient alkenes under oxidative conditions (Scheme ). These reactions have been shown to afford either isobenzofuranimine‐6a or isochromenimine‐type6b–6d products (i.e., 4 or 5 , respectively) with high regioselectivity in each case. We now report that, under modified reaction conditions, a new family of products, namely, carbonyl derivatives 6 , can be prepared from the same substrates 3 and methyl vinyl ketone or acrylaldehyde, as a result of the regioselective oxycyclization–formal conjugate addition cascade reactions that take place to the exclusion of the alternative Heck products 4 / 5 (Scheme ).…”