Synthesis of Spiro[benzo[d][1,3]oxazine-4,4′-isoquinoline]s via [4+1+1] Annulation of N-Aryl Amidines with Diazo Homophthalimides and O₂

Abstract

Synthesis of spiro[benzo[d][1,3]oxazine-4,4′isoquinoline]s through a unique [4+1+1] annulation of N-aryl amidines with diazo homophthalimides and O 2 is presented. This unprecedented spirocyclization reaction features readily obtainable substrates, structurally and pharmaceutically attractive products, a cost-free and clean oxygen source, sustainable reaction medium, tolerance of a broad spectrum of functional groups, and an interesting reaction mechanism based on sequential C(sp 2 )−H/ C(sp 3 )−H bond cleavage and oxygen insertion.

Concise Synthesis of Spirocyclic Dihydrophthalazines through Spiroannulation Reactions of Aryl Azomethine Imines with Cyclic Diazo Compounds

“…As a result, 3a was partially hydrogenated to give product 6 with good efficiency (Scheme a). Second, coupling reactions of 3f with phenylacetylene, phenol, and styrene were tried, respectively . From these reactions, to our delight, diversely functionalized spirocyclic dihydrophthalazine derivatives 7 , 8 , and 9 with potential applications in pharmaceutical and fine chemical fields were obtained (Scheme b,–d).…”

“…Second, coupling reactions of 3f with phenylacetylene, phenol, and styrene were tried, respectively. 15 From these reactions, to our delight, diversely functionalized spirocyclic dihydrophthalazine derivatives 7, 8, and 9 with potential applications in pharmaceutical and fine chemical fields were obtained (Scheme 6b,−d). Finally, to test if this novel spiroannulation reaction is suitable for scale-up synthetic scenarios, the preparation of 3a was carried out in gram scale.…”

“…White solid (52.5 mg, 70%), mp 167.5−168.1 °C. 1 H NMR (600 MHz, CDCl 3 ): δ 7.94 (d,J = 7.8 Hz,2H),5H),1H) 4, 171.6, 158.7, 138.1, 136.8, 132.9, 130.2, 128.9, 127.8, 126.2, 125.2, 124.1, 131.4, 119.2, 68.8, 42.2, 25.5, 22.7, 13.4 15 To a reaction tube equipped with a stir bar were added 3f (45.1 mg, 0.1 mmol), ethynylbenzene (16.5 μL, 0.15 mmol), PPh 3 (5.2 mg, 0.02 mmol), K 3 PO 4 (25.5 mg, 0.12 mmol), Pd(OAc) 2 (1.1 mg, 0.005 mmol), and DMSO (1 mL). The resulting mixture was then stirred at 80 °C (oil bath) under argon for 24 h. Upon completion, it was diluted with ethyl acetate (20 mL) and washed with water and brine.…”

“…Synthesis of 8. 15 To a reaction tube equipped with a stir bar were added 3f (45.1 mg, 0.1 mmol), phenol (14.1 mg, 0.15 mmol), N,Ndimethyl glycine hydrochloride (4.2 mg, 0.03 mmol), Cs 2 CO 3 (65.2 mg, 0.2 mmol), CuI (1.9 mg, 0.01 mmol), and dioxane (1 mL). The resulting mixture was then stirred at 90 °C (oil bath) under argon for 24 h. Upon completion, it was diluted with ethyl acetate (20 mL) and washed with water and brine.…”

Coupling partner-dependent unsymmetrical C–H functionalization of N-phenoxyacetamides leading to sophisticated spirocyclic scaffolds

“…Inspired by these elegant pioneering studies and continuing our interest on the functionalization of inert chemical bonds, 5,6 in this work we endeavored to design and explore the reactions of N -phenoxyacetamides with diazopyrazolones 7 and diazooxindoles 8 with the aim of obtaining new chemical entities that have potential pharmaceutical and material applications. Serendipitously, we found two unprecedented distinct reaction modes of N -phenoxyacetamides under the catalysis of Rh( iii ).…”