Cycloaddition reactions phenol ethers

We decided to investigate one final substrate that contained our desired side chain for the intramolecular Diels-Alder cycloaddition as well as a small and removable cyano group. Our synthesis is outlined in Scheme 11. Phenol 53 was alkylated with chloroacetonitrile, then condensed to form 2-cyano benzo-furan 54. Subsequent quatemarization to 56 was accomplished with sodium hydride and a bromocrotcMiate (55) electrophile. Following phenol ether deprotection and reduction of the benzylic ketone with sodium borohydride, we were in a position to evaluate the dearomatization step. Unfortunately, all attempts to access the quinone epoxide 58 under classic or modified Adler-Becker reaction conditions failed. With these results, we closed the book on the second chapter in our vinigrol saga and went back to the drawing board. 

With key intermediate 252 in hand, Hudlicky turned his attention to the crucial oxidative dearomatizationyiniramo-lecular [4+2] cycloaddition sequence (Scheme 12.45). Thus, the carbonyl moiety in 252 was converted to the requisite terminal alkene via reaction with methyltriphenylphospho-nium bromide, before the MOM ether was cleaved under acidic conditions. Reaction of the free phenol in cyclization precursor 253 with lead tetraacetate resulted in the desired arene oxidation and isolation of cycloaddition product 255 in 50% yield, via intermediary formed dienone 254. Interestingly, 255 was formed as sole cycloaddition product, and the product of the endocyclic cycloaddition reaction was only observed once in minor amounts, probably because of unfavorable steric interactions. 

Mannich reaction of A, A -bis(methoxymethyl)diaza-18-crown-6 with 4-chloro-2-(l/f-pyrazol-3-yl)phenol gave the N-linked bis(3-(5-chloro-2-hydroxy)pyrazol-l-ylmethyl)-substituted diazacrown ether, which interacted with various metal ions and was evaluated by calorimetric titration <1999JOC8855>. Intramolecular nitrilimine cycloadditions were exploited in the preparation of a number of azacrown ethers having a medium or large ring annulated to pyrazole units <1997T3005>. 

Fluoride-induced fragmentation reactions were used in two stages of a synthesis of hexahydrocannabi-nol methyl ether (144 Scheme 52). One of the phenolic hydroxy functions in the resorcinol derivative (140) was selectively liberated from the SEM ether to give the diol (141), which was converted to the bis (trimethylsilyl) ether (142). Subsequent treatment with CsF resulted in a 1,4-elimination to the o-quinone methide (143) intermediate, which underwent an intramolecular [4 -i- 2] cycloaddition to give the product in good yield. 

Nevertheless, the application of alkoxy-functionalized 1,3-dienes is of increasing interest. 1-Alkoxy-functionalized 1,3-butadienes led directly to arene derivatives such as 22 via the cycloaddition/elimination route (Scheme 13.12) [13]. The arene is formed under the reaction conditions of cobalt catalysis upon elimination of trimethyl-silanol from the labile dihydroaromatic intermediate. When 2-alkoxy-functionalized 1,3-butadienes are employed, 3,4-disubstituted phenol derivatives such as 23 are readily available by DDQ oxidation of the dihydroaromatic intermediate. The DDQ oxidation conditions led in several cases to direct desilylation of the enol ether or the desilylation takes place during column chromatography on (nondeactivated) silica gel. 

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