Betti Reaction of Cyclic Imines with Naphthols and Phenols – Preparation of New Derivatives of Betti's Bases

Abstract

A large library of aminocycloalkylphenols and -naphthols is obtained by the Betti reaction between activated phenols and naphthols and five- and six-membered cyclic imines. Due to the formation of an intramolecular hydrogen bond in the transition state, the attack takes place regioselectively at the position adjacent to the hydroxy group of the aromatic compounds. X-ray crystallography and chirooptical methods (electronic circular dichroism) were used to ascertain the ab-solute configuration of two aminoalkylnaphthols obtained, after resolution of the corresponding racemates with (R,R)-tartaric acid. In addition, some aminoalkylnaphthols and -phenols were alkylated at the nitrogen atom to obtain N-methylated products in good yields

An Efficient One‐Step Synthesis of Piperidin‐2‐yl and Pyrrolidin‐2‐yl Flavonoid Alkaloids through Phenolic Mannich Reactions

“…Although naphthols have been used in the phenolic Mannich reaction, [3][4][5] simple phenols have been considered to be not reactive enough. We were thus pleased to find that not only naphthols ( Table 2, Entries 1-9) but also electronrich phenols (Table 2, Entries 10-22) and simple phenols ( Table 2, Entries 23-26) participated in this reaction to afford the corresponding adduct in good to excellent yields.…”

“…[4] Very recently, Cimarelli and co-workers reported the Mannich reaction of naphthols or activated phenols with cyclic imines. [5] To the best of our knowledge, there are only two reports dealing with the reaction of a flavonoid with cyclic imines. In both cases, no systematic studies were carried out, and the desired products were obtained in low yields (Ͻ10 and 30 %) and low regioselectivities (about 1:1).…”

“…Although the phenolic Mannich reaction is known, [3] most of the reported methods use naphthols or activated phenols as nucleophiles; cyclic imines have been rarely used as the electrophilic partner. [4,5] The Mannich reaction between naphthols and 3,4-dihydroisoquinoline under solvent-free or micro- external reagent afforded the C-6 alkylated product exclusively. The same reaction in water in the presence of NaOH provided the C-8 alkylated flavonoid as a major product.…”

“…Although no biosynthetic studies have been carried out, it is proposed that the N-methyl-Δ 1 -pyrrolidinium ion, which is in turn derived from ornithine, is the common precursor of the N-methylpyrrolidine moiety of isoficine (3), ficine (5), and phylospadine (6). [2] The phloroglucinol motif is embedded in most natural flavonoid alkaloids, as exemplified by the structures of 1-6.…”

Copper-Catalyzed Direct Oxidative α-Arylation of Pyrrolidine with Phenols and Naphtols

“…An ideal procedure for the direct α-arylation of pyrrolidines would be based on readily available, non-functionalized pyrrolidines and arylating agents as well as simple catalytic systems. Based on our interest in copper-catalyzed oxidative reactions [20] and C-H functionalization [21], we envisioned that a copper-catalyzed aerobic oxidation of pyrrolidine 15 should yield to the corresponding cyclic imine 27 [22] which could then be trapped in situ by electron-rich arenes [23] to afford the corresponding α-aryl-pyrrolidines 28 without the need for protecting or directing groups (Scheme 2). While this strategy might seem counterintuitive due to the known propensity of the transient imine 27 to undergo trimerization [24] and electron-rich arenes to dimerize in the presence of copper complexes and an oxidant [25], some reports from the literature in conjunction with technical adjustments might enable the successful development of such a direct arylation.…”