Etherification, allylic

Although a vast amount of research has been devoted to the asymmetric 7i-allylic subshtuhon of acyclic esters (e.g. 1,3-diphenylpropenyl esters) with carbon and nitrogen nucleophiles, studies on the catalytic asymmehic subshtuhon of cyclic 

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Scheme 1.81 Allylic etherifications with phosphinamidite-thioether ferrocenyl ligand.

Diastereoselective syntheses of dihydrobenzo[f>]furans have been accomplished by a rhodium-catalyzed regioselective and enantiospecific intermolecular allylic etherification of o-iodophenols as a key step, providing the corresponding aryl ally ether 122, which leads to a dihydrobenzo[b]furan by treatment of the intermediate aryl iodide with tris(trimethylsilyl)silane and triethylborane at room temperature in the presence of air <00JA5012>. 

Figure 4 Recently developed ligands for transition metal-catalyzed allylic etherification.

Although palladium catalysts have played the most prominent role in this area, other metals have also been found to catalyze allylic etherification reactions, often providing complementary stereochemical outcomes. A few ruthenium catalyst systems have been used for the O-allylation of phenols,143,144 including an enantioselective version utilizing [Cp Ru(MeCN)3]PF6 that provides promising ee s, albeit with diminished control of regioselectivity (Equation (25)).145... 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

In rare cases, the Pd-catalyzed intramolecular allylic etherification has been extended to the construction of medium-sized rings. Both an 11-membered bis-ether ring (Equation (34))164 and an eight-membered ether ring (Equations (35) and (36))155 have been prepared in this fashion. In the latter case, the choice of ligand dictated the regiochemical outcome. 

Rhodium catalysts have also been used with increasing frequency for the allylic etherification of aliphatic alcohols. The chiral 7r-allylrhodium complexes generated from asymmetric ring-opening (ARO) reactions have been shown to react with both aromatic and aliphatic alcohols (Equation (46)).185-188 Mechanistic studies have shown that the reaction proceeds by an oxidative addition of Rh(i) into the oxabicyclic alkene system with retention of configuration, as directed by coordination of the oxygen atom, and subsequent SN2 addition of the oxygen nucleophile. 

Another Rh-catalyzed protocol that has potentially broad utility has come from the reactions of Cu(i) alkoxides with allylic carbonates.190,191 Under the action of Wilkinson s catalyst modified by P(OMe)3, a variety of primary, secondary, and even tertiary aliphatic alcohols undergo an allylic etherification process with a high degree of retention of regio- and stereochemistry, thus providing expeditious access to a and/or ct -stereogenic ether linkages (Scheme 5).192... 

A two-component bimetallic catalytic system has been developed for the allylic etherification of aliphatic alcohols, where an Ir(i) catalyst acts on allylic carbonates to generate electrophiles, while the aliphatic alcohols are independently activated by Zn(n) coordination to function as nucleophiles (Equation (48)).194 A cationic iridium complex, [Ir(COD)2]BF4,195 and an Ru(n)-bipyridine complex196 have also been reported to effectively catalyze the O-allylation of aliphatic alcohols, although allyl acetate and MeOH, respectively, are employed in excess in these examples. 

Although the majority of allylic etherification reactions have primarily utilized allylic carboxylates or carbonates as electrophiles (and occasionally allylic chlorides), the use of allylic alcohols for this transformation would be more desirable from a practical standpoint. Reported strategies involving Pd catalysis include the use of P(OPh)3 as the ligand197 and Ti(OPf)4198 as an additive for the in situ activation of the hydoxyl group (Equation (49)).199... 

In addition to alkoxides, carbonyl oxygens have occasionally been recruited to function as nucleophiles in allylic etherification processes. The cyclization reactions of ketones containing internal allylic systems occur through O-allylation under Pd catalysis to give rise to vinyl dihydrofurans203 or vinyl dihydropyrans (Equation (51))204,205 in good yields. 

Scheme 7 Allylic etherification catalyzed by [Ir(COD)Cl]2 and a phosphorodiamidite ligand...

Iridium-Catalyzed Allylic Etherification with Catalysts Derived from LI... 

Hartwig et al. demonstrated that the same combination of iridium precursor and phosphoramidite LI also catalyzes allylic etherifications (Scheme 9) [68]. Lithium and sodium aryloxides were shown to react with cinnamyl and hex-2-enyl carbonates to form the branched allylic ethers in high yield, with high branched-to-linear... 

Scheme 9.38 Allylic alcohols via Ir-catalyzed allylic etherification.

Disubstituted dihydrofurans and dihydropyrans were prepared via allylic etherification [68] in a similar manner to dihydropyrroles (cf Section 9.4.6). Thus, diaste-reoisomeric ethers were generated by the reaction of cinnamyl tert-butyl carbonate with the copper alkoxide prepared from (Rj-l-octen-3-ol, depending on which enantiomer of the phosphoramidite ligand was used (Scheme 9.39). Good yields and excellent selectivities were obtained. RCM in a standard manner gave cis- and trans-dihydrofuran derivatives in good yield, and the same method was used for the preparation of dihydropyrans. 

Rhodium-Catalyzed Allylic Etherifications with Phenols and Alcohols... 

Transition metal-catalyzed allylic substitution with phenols and alcohols represents a fundamentally important cross-coupling reaction for the construction of allylic ethers, which are ubiquitous in a variety of biologically important molecules [44, 45]. While phenols have proven efficient nucleophiles for a variety of intermolecular allylic etherification reactions, alcohols have proven much more challenging nucleophiles, primarily due to their hard, more basic character. This is exemphfied with secondary and tertiary alcohols, and has undoubtedly limited the synthetic utihty of this transformation. 

Tab. 10.7 summarizes the results of the application of rhodium-catalyzed allylic etherification to a series of ortho-substituted phenols. The etherification tolerates alkyls, including branched alkanes (entries 1 and 2), aryl substituents (entry 3), heteroatoms (entries 4 and 5), and halogens (entry 6). These results prompted the examination of ortho-disubstituted phenols, which were expected to be more challenging substrates for this type of reaction. Remarkably, the ortho-disubstituted phenols furnished the secondary aryl allyl ethers with similar selectivity (entries 7-12). The ability to employ halogen-bearing ortho-disubstituted phenols should facilitate substitutions that would have proven extremely challenging with conventional cross-coupling protocols. 

This methodology was applied to a two-step sequence for the preparation of enantio-merically enriched dihydrobenzo[h]furans (Scheme 10.11) [46]. Rhodium-catalyzed allylic etherification of (S)-47 (>99% ee), with the sodium anion of 2-iodo-6-methyl-phenol, furnished the corresponding aryl allyl ethers (S)-48/49 as a 28 1 mixture of regioisomers favoring (S)-48 (92% cee). Treatment of the aryl iodide (S)-48 with tris(trimethylsilyl)silane and triethylborane furnished the dihydrobenzo[h]furan derivatives 50a/50b as a 29 1 mixture of diastereomers [43]. 

Tab. 10.7 Regioselective rhodium-catalyzed allylic etherification with ortfio-substituted phenols.

Scheme 10.11 Stereoselective construction of benzo[b]furans using allylic etherification with phenols.

Enantiospecijic Rhodium-QjtalYzed Allylic Alkylation 207 Tab. 10.8 The scope of the regioselective rhodium-catalyzed allylic etherification reaction. 

Tab. 10.8 summarizes the application of rhodium-catalyzed allylic etherification to a variety of racemic secondary allylic carbonates, using the copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol vide intro). Although the allyhc etherification is tolerant of linear alkyl substituents (entries 1-4), branched derivatives proved more challenging in terms of selectivity and turnover, the y-position being the first point at which branching does not appear to interfere with the substitution (entry 5). The allylic etherification also proved feasible for hydroxymethyl, alkene, and aryl substituents, albeit with lower selectivity (entries 6-9). This transformation is remarkably tolerant, given that the classical alkylation of a hindered metal alkoxide with a secondary alkyl halide would undoubtedly lead to elimination. Hence, regioselective rhodium-catalyzed allylic etherification with a secondary copper(l) alkoxide provides an important method for the synthesis of allylic ethers. 

Rhodium-catalyzed allylic etherification could also be extended to the more challenging tertiary alcohols (Eq. 7). Although preliminary attempts revealed that the alkylation of the allylic carbonate 51 was feasible, the reaction required increased catalyst loading (20 mol%), affording the allylic ether 52 in 67% yield (2° 1°=47 1). 

Tab. 10.10 Probing the role of lithium iodide and the copper(l) alkoxide in allylic etherification.

For recent approaches to the transition metal-catalyzed allylic etherification using phenols, see (a) Goux, C. Massacret, M. Lhoste, P. Sinou, D. OrganometaUics 1995, 14, 4585. (b) Trost, B.M. Toste, F.D. 

For recent approaches to transition metal-catalyzed allylic etherification using alcohols, see (a) Trost, B.M. ... 

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