Synthesis of 3‐Halogenated Flavonoids via Electrophile‐Promoted Cyclization of 2‐(3‐Aryl‐2‐propynoyl)anisoles

Abstract

Treatment of 2-(1-aryl-3-propynoyl) anisoles 1 with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) gave the 3-halogenated flavones and their related molecules in moderate yields.Keywords: Electrophiclic cyclization; Flavonoids.Flavonoids are a series of the earliest discovered natural products, which occur in most families of higher plant kingdom. As a major class of plant components, over 4000 flavonoid compounds have been identified 1 that exhibit a variety of pharmacological activities, including antiflammatic, antioxidant, antithrombogentic, antiviral, anticarcinogenic and antiproliferative effects. 2 Some flavonoids have also been demonstrated to possess the binding affinities for the estrogen receptor.3 Despite an abundance of flavonoids from natural sources, it is still of interest to obtain them by synthesis since novel biological activities are continuously discovered for these compounds and their derivatives. 4 Herein, we report a new synthetic method to obtain 3-halogenated flavonoids 2 by electrophile-promoted cyclization of 2-(3-substituted 2-propynonyl)anisoles 1 (Eq. 1), and which had no investigation about the route.(1)The synthesis of flavone precursor 1a is summarized in Scheme I. Treatment of salicyclic aldehyde (3) with methyl iodide in DMF for 12 h produced 2-methoxybenzaldehyde (4) in 92% yield. Compound 4 was reacted with lithium phenylacetylide (from treatment of 1.0 eq. phenylacetylene with 1.2 eq. n-BuLi in THF) at 0°C for 2 h to yield the alcohol 5a in 85% yield. Oxidation of 3a with MnO 2 afforded the 2-(3-phenyl-2-propynonyl)anisoles 1a in 96% yield.Several sets of conditions for the cyclization reaction have been tested and the results are summarized in Table 1.Compound 1a was first treated with 3 equivalents of iodine, N-iodosuccinimide (NIS), NBS, or NCS in refluxing CH 2Cl2. No product was isolated in all reactions even after the reaction time was extended to 24 h. Only the starting materials were recovered. When the solvent CH 2Cl2 was replaced by DMF, reaction of 1a with NIS at 100°C for 2 h gave the undesired product 7aa in 50% yield. Treatment of 1a with NBS under the same reaction conditions gave 3-bromoflavone 6ab in 36% yield together with addition product 7ab in 30% yield. Reaction of 1a with NCS gave 3-chloroflavone 6ac in 57% yield along with the addition adduct 7ac in 15% yield. The structure of compound 6ac was unambiguously determined by X-ray crystallography (Fig. 1). The results confirmed that the electrophilic cyclization of 2-(3-phenyl-2-propynoyl)anisole takes a 6-endo pathway instead of a 5-exo pathway to generate 3-chloroflavone (6ac). Under the same reaction conditions, reaction of 1a with iodine gave neither addition adduct nor the cyclization adduct. Moreover, DMSO

Light-Driven Switching between Intramolecular Proton-Transfer and Charge-Transfer States

“…All of the chemicals used for synthesis were procured from Sigma-Aldrich. The compounds were synthesized using the procedure followed for similar kinds of molecules. , A brief synthetic procedure and the characterization data are provided below.…”

“…Methoxylation of 4-N,N-diethylaminosalicylaldehyde was carried out in DMF with methyl iodide in the presence of KOH (Scheme S2). 50 The compound was purified by the crystallization in methanol and confirmed by NMR (Figures S3 and S4) and HRMS. 1 H NMR (600 MHz, CDCl 3 , δ ppm): 10.10 (s, 1H), 7.69 (d, 1H), 6.27 (d, 1H), 6.01 (s, 1H), 3.87 (s, 3H), 3.43 (q, 4H), 1.22 (t, 6H).…”

Synthesis and Transformation of Halochromones

“…This method was originally used to directly 3-iodinate flavones [66]. Electrophile-promoted cyclization with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) can also afford the corresponding 3-haloflavones 16 in moderate yields [67]. The latter cyclization reaction is quite sensi- Scheme 2.…”