Furans hydroxyalkylation

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

Furan, 2,5-dialkoxy-2-( 1 -hydroxyalkyl)-2,5-dihydro-ring expansion, 1, 425 Furan, 2,5-dialkoxytetrahydro-pyrrole synthesis from, 4, 330 Furan, 2,4-dialkyl-synthesis, 4, 661, 685 Furan, 2,5-dialkyl-... 

A wide vanety of nucleophiles, such as 1-alkylpyrroles, furans, thiophenls [51], phenols [52], anilmes [55, 54], indoles [55], CH-acidic compounds [56, 57], as well as organolithium [56], Gngnard [57, 59], organocadmiura, and organozmc compounds [56], undergo C-hydroxyalkylation with trifluoropynivates to yield derivatives of a-trifluoromethyi a-hydroxy acids. 

Florio achieved a general method for the synthesis of hydroxyalkyl 1,3-dihydrobenzo[c]furans from o-lithiated aryloxiranes and carbonyl compounds, and an example is depicted in the following scheme <06JOC3984>. 

Synthetically even more versatile trifunctional intermediates result from the addition of carbonyl compounds onto methyl 2-siloxycyclopropanecarboxylates 92). Benzo-phenone, titanium tetrachloride, and 162, for instance, provide an excellent yield of the a-hydroxyalkylated y-oxoester 174, which predominates in the equilibrium with its cyclic hemiacetal 176 (y-lactol). It can undergo elimination to the unsaturated ester 175, but as Scheme 7 illustrates, 174/176 can also serve as the starting material to several highly substituted furan(one) derivatives. 

Scheme 7. Synthesis of Furan(one) Derivatives from Hydroxyalkylation Product 1741176 obtained from Cyclopropane 162...

In addition to furan, other heterocycles have been examined." Thiophene undergoes efficient photocycloaddition with benzaldehyde to afford a single exo photoproduct (183) in 60% yield. As reported by Jones and coworkers,the photolysis of IV-methylpyrrole in the presence of aldehydes or ketones yields the corresponding 3-hydroxyalkyl derivative (184), even when the reaction mixture is free from any trace of acid. In order to use the pyrrole nucleus for stereoselective alkaloid synthesis (cf. caesalpinine, 185) in the fashion developed with the furan nucleus, pyrrole substituents that stabilize the presumed intermediate bicyclic oxetane must be discovered. 

The most popular Pd-catalyzed method for the production of furans and benzofurans involves reactions of alkynols. Acyclic alkynols are converted into furans, while benzene substituted alkynols are transformed into benzofurans. The use of this strategy is widespread for the synthesis of benzofurans however, it is occasionally used for the syntheses of furans. For example, intramolecular alkoxylation of alkyne 189 proceeds via an alkenylpalladium complex and subsequent carbonylation to form furan 190 [156, 157]. In addition, 3 -hydroxyalkyl-benzo[/)J furans were prepared by Bishop et al. via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis [158]. In a related series of experiments, Qing demonstrated that alkynes 191 could be efficiently converted into furans 192 [159]. 

Heterocyclic compounds such as furan, thiophene, and pyrrole are subject to oxidation. Similar to secondary allyUc alcohols, 2-(l-hydroxyalkyl) derivatives of these heterocychc compounds are also good substrates for kinetic resolution using a titanium-tartrate and TBHP system (Scheme 15). 

In contrast to many furan syntheses, this method uses 2-(2-hydroxyalkyl)phenoIs containing a leaving group at the benzylic carbon atom. Thus, 2-(I-isopropyl-thio-2-hydroxy)phenol cyclizes on heating with concentrated hydrochloric acid, but when 2-(2-hydroxyethyl)phenol was similarly treated, cyclization did not occur. When R = H, 2-unsubstituted benzofurans are obtained in good yield minor modifications were made in the synthesis of the 2-phenyl derivatives, and... 

An interesting application of this oxidizing agent is in the formation of spiroisoxazolines from o-hydroxyarylacetoxime derivatives, as well as the more well-known transformation of 2-(l-hydroxyalkyl)furans to the pyranones. The cycloamination of an aromatic compound bearing a sulfonamide side chain provides access to A-heterocycles. 

Moreover, the bromo-lithium exchange in irans-configured R, S ) ori/io-bromophenyloxazolinyloxirane 100, followed by reactions with carbonyl compounds, proved to be a useful approach for making oxazolinyl-substituted hydroxyalkyl l,3-dihydrobenzo[c] furans 101 with dr up to 98 2 (Scheme 28) (2007JOC6316). 

Preliminary activation of the Lewis basic oxetane oxygen with Bp3 Et20 of ori/jo-hydroxyalkylated phenyl oxetane (i .)-(+)-106, obtained by subjecting (il)-(+)-105 to ortho-lithhtion followed by trapping with acetone, induced an almost quantitative 5-exo-tet cycHzation at the phenyl-substituted carbon atom to give the enantiomericaUy enriched (er 96 4) l,3-dihydrobenzo[c]furan (—)-107 (Scheme 29). 

Pavlakos E, Georgiou T, Tofi M et al (2009) y-Spiroketal y-lactones from 2-(y-hydroxyalkyl)furans syntheses of cpi-pyrenolides D and crassalactone D. Org Lett 11 4556-4559... 

Furans may undergo hydroxyalkylation with activated aldehydes (e.g., 12) as well as aminoalkylation with iminium cations (e.g.,—>13) ... 

With ketones like acetone, hydroxyalkylation in general is followed by alkylation of further hetarene units thus, a condensation product 14 from acetone and two molecules of furan [6] and the cyclotetramer 15 from acetone and four molecules of furan are known ... 

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