Synthesis of 2,3-Dihydrobenzofurans by Mn(OAc)₃-Based Oxidative Cycloaddition of 2-Cyclohexenones with Alkenes. Synthesis of (±)-Conocarpan

Abstract

Oxidative cycloaddition of a 2-cyclohexenone or R-tetralone and an alkene with dried Mn(OAc) 3 in benzene at 80-140 °C provides a general route to dihydrobenzofurans 15 and dihydronaphthofurans 17. Although the yields are modest, this one-pot reaction provides simple access to these compounds, which have previously been prepared by multistep routes. Oxidative cycloaddition of 2-cyclohexenones with β-methylstyrenes provides a new route to benzofuranoid neolignans, which was applied to the synthesis of conocarpan ( 22). The formation of 2-acetoxyhexanedioic acids 27 and 47 from acetoxylation of 2-cyclohexenones in HOAc, but not in benzene, opens up a new class of Mn(OAc) 3 reactions and explains Watt and Demir's discovery that much higher yields of R′-acetoxy enones are obtained in benzene than in HOAc.In 1976, Williams and Hunter reported that Mn-(OAc) 3 ‚2H 2 O oxidation of enones in HOAc at reflux affords 6-35% of R′-acetoxy enones. 1,2 In a series of papers initiated in 1984, Watt, Demir, and co-workers reported that using Mn(OAc) 3 dried over P 2 O 5 in benzene at reflux for 1 h to 2 d improves the yields of R′acetoxylation to 50-90%. 3 These reactions proceed by kinetic enolization of 2-cyclohexenone (1a) to give Mn(III) enolate 2a, which loses Mn(II) to give R′-keto radical 3a, which is oxidized by a second equivalent of Mn(OAc) 3 to give R′-acetoxy enone 4a. No explanation was provided for the vastly improved yields obtained in benzene.We found that intramolecular trapping of the R′-keto radicals obtained from cyclohexenones by suitably situated double bonds is much faster than acetoxylation, affording good yields of bicyclic dienones in favorable cases. 4 For instance, oxidative cyclization of 5 with 5 equiv of Mn(OAc) 3 and 1 equiv of Cu(OAc) 2 in benzene at reflux for 40 h affords 61% of 6 as a 3.4:1 E/Z mixture. We therefore decided to examine the intermolecular reactions of cyclohexenones and alkenes. Results and DiscussionOxidative Cycloadditions in Benzene. To our surprise, we found that oxidative addition of 2-cyclohexenones 1a-e with methylenecyclohexane (7a) in benzene at 80 °C for 3 d using Mn(OAc) 3 dried over P 2 O 5 in vacuum as described by Watt affords 25-42% of dihydrobenzofurans 15aa-ea and 0-18% of 6-(1-cyclohexenylmethyl)-2-cyclohexenones 12aa-ea (the first letter corresponds to the 2-cyclohexenone (1a-g) and the second to the alkene 7a-c or 19ab). Grisan (15aa), so named because it contains the griseofulvin skeleton, has been prepared twice by multistep routes 5 and is now available in a single step. No monomeric products are formed from 1a and 1-octene under these reaction conditions.The following mechanistic scheme is consistent with these results. Oxidation of cyclohexenone 1 will form R′keto radical 3. Addition of radical 3 to methylenecyclohexane (7a) will give radical 8, which is tertiary and is therefore readily oxidized by Mn(OAc) 3 to cation 11. 2 Loss of a proton from cation 11 will give 2-alkenyl-2-cyclohexenone 12. Cyclization of 11 will give bicyclic cation 10. Loss of ...

Antibacterial activity of extracts and neolignans from Piper regnellii (Miq.) C. DC. var. pallescens (C. DC.) Yunck

“…This procedure allowed the isolation of pure compounds 1 (98.5 mg), 2 (82.9 mg), 5 (55.1 mg), and 6 (181.3 mg) identified as eupomatenoid-6, eupomatenoid-5, eupomatenoid-3, and conocarpan, respectively (Fig. 1), by spectroscopic analysis and by comparison with literature data (Achenbach et al 1987, Chauret et al 1996, Snider et al 1997. Compounds 1, 2, and 6 were methylated with diazomethane to give methyl derivatives 3, 4, and 7, respectively (Fig.…”

Neolignanas e análise do óleo essencial das folhas de Piper regnellii (Miq.) C. DC. var. pallescens (C. DC.) Yunck

“…128-130ºC (lit. : 128-130 ºC) (Snider et al, 1997 (Snider et al, 1997). UV max CHCl 3 , nm (log ): 235 (9,57); 267 (9,79); 305 (9,23).…”

“…As frações FH 40-44 reunidas (328 mg) e cromatografadas em sílica gel 60 (230-400 mesh), utilizando-se como fase móvel hexano:diclorometano: acetato de etila 12:7:1 v/v/v, forneceram a substância 4 (181,3 mg). 1, 2, 3 e 4 foram identifi cadas como eupomatenóide-6, eupomatenóide-5, eupomatenóide-3 e conocarpano (Figura 1) respectivamente após análise de dados fornecidos por métodos espectroscópicos (UV, EI-EM, RMN 1 H, RMN 13 C, H-HCOSY, gNOE, HETCOR e HMBC) e por comparação com dados da literatura (Chauret et al, 1996;Achenbach et al, 1987;Snider et al, 1997;Maxwell et al, 1999).…”

Isolation, synthesis and complement inhibiting activity of the naturally occurring K-76, its analogues and derivatives

“…In a similar fashion, even complex compounds such as 154 (from α-tetralone) bearing the same motif, where made easily available in reasonable yields. 108 Mechanistically, oxidation of the cyclohexenone 145 forms α'-keto radical 146, the addition of which to the olefin furnishes radical 147; being tertiary, 147 is readily oxidized by Mn(OAc) 3 to cation 148, 109 which may lose a proton to give the 2-alkenyl-2-cyclohexenone side product 149. However, cyclization of 148 to the bicyclic cation 150 is also a viable alternative; in such case, loss of a proton will give tetrahydrobenzofuran 151 or a double bond positional isomer.…”