Synthesis of 2-Amino-2′-hydroxy-1,1′-biaryls via Cascade Benzannulation and C–N Bond Cleavage Sequence

Abstract

A serendipitous synthesis of N-substituted 2-amino-2′-hydroxy-1,1′-biaryls through an aryne annulation with indolyl β-ketonitrile/ester in a cascade manner is demonstrated. The reaction sequence involves benzyne-mediated [2 + 2] Stoltz-type cycloaddition–cleavage and intramolecular Michael addition followed by C–N bond cleavage under transition-metal-free reaction conditions. Interestingly, while [4 + 2] Diels–Alder reaction is a possible pathway, no traces of the regioisomer was isolated.

Indole Editing Enabled by HFIP‐Mediated Ring‐Switch Reactions of 3‐Amino‐2‐Hydroxyindolines

“…As a similar approach, Manna and co‐workers used tosylhydrazones for constructing pyrazoles [6b] . Another C2‐N1 breaking transformation of indoles featuring aryne insertion to afford naphthols was reported by Adepu and Chandrasekhar very recently [6c] . In 2020, Park and coauthors reported that alkynes and ammonium acetate can serve as an indole editing reagent to afford pyridines [6d] .…”

Poly(ethylene glycol) Dimethyl Ethers (PEGDME): Efficient and Recyclable Solvents for Aryne-Involved Reactions

“…Initially, we investigated the use of PEG as a solvent on our recent cascade of benzannulation reaction. 11 We carried out the cascade benzannulation reaction of N-Boc indole β-ketonitrile 1a with aryne precursor, using PEG-400 as a solvent, without additive at 60 o C and found 3 instead of 4a reported by us as a major product which might be due to the quenching the aryl anion formed after the nucleophilic addition by terminal hydroxy groups of PEG solvent and resulting in the simple arylation reaction (Scheme 1a). To our delight when the same reaction was performed in PEGDME (average molecular weight 240), the annulation product was obtained in 70% yield which showcases the great advantage over a reaction in THF with 18crown-6 (Conditions A and B, Scheme 1b).…”

“…Compound 1b was synthesized from N-methyl-5-bromoindole according to a previously reported procedure. 11 A solution of cyanoacetic acid (244 mg, 2.87 mmol, 1.2 equiv.) and propionic anhydride (4 mL) was heated to 65 °C using an oil bath for 10 min.…”

“…Thus, we chose a higher molecular weight PEG solvent, PEGDME (MW 2000), to study the reusability, and the results are summarized in Table 1. The Truce-Smiles rearrangement of aryne 2 with 4-nitro-Nphenylbenzenesulfonamide (11) was performed using PEGDME (MW 2000) (Table 1, entry 1). After the initial experiment, the reaction mixture was extracted with diethyl ether and the residual PEGDME was subjected to a second run by adding the same substrates.…”

Cascade aryne insertion/vinylogous aldol reaction of vinyl-substituted β-keto/enol carbonyls

“…Domino reactions involving aryne chemistry form another strategy followed for the synthesis of polycyclic organic frameworks. 5,6 Annulation reactions involving aryne α-bond insertion are rarely known, but recently, Wu and co-workers reported the synthesis of substituted naphthalenes by sequential α-bond insertion 7 followed by benzannulation reactions of arynes. 8 We recently reported aromaticity driven access to cycloalkyl fused naphthalenes.…”