Allyl with etherification

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>. 

The nonracemic a-menthyloxymethoxy allylic stannanes 71 and 72 were obtained from crotonaldehyde by addition of Bu SnLi and etherification with (—)-menthyloxymethyl... 

In carbohydrate chemistry, the preparation of ethers that are stable in the presence of acids, bases, and aqueous alkali is an important analytical and synthetic tool. The methods used for the etherification of hydroxyl groups51 generally employ reactions of unprotected sugars and glycosides with methyl, allyl, benzyl, triphenylmethyl, and alkylsilyl halides in the presence of a variety of aqueous and nonaqueous bases. 

Etherification with 7r-Allylmetals Generated from Allylic Alcohol Derivatives 657... 

Etherification with Addition to the Central Carbon of a vr-Allyl Species 664... 

Etherification with 7r-Ally I metals Generated from Allylic Alcohol Derivatives... 

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... 

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... 

Blocking the C-l OH of D-fructose and L-sorbose (Scheme 25) was effected in excellent yields through regioselective isopropylidene acetalation of the free ketoses, followed by etherification (benzylation or allylation) of the remaining primary alcohol. Acid-catalyzed hydrolysis of the isopropylidene groups and condensation with HSCN efficiently produced a sole fused bicyclic OZT. 

Etherification to produce cyanoethyolated, benzylated or allylated wood surfaces does not result in an improvement in UV resistance, but the latter two treatments have been found to improve the performance of clear coatings on the modified substrate (Kiguchi, 1990b). Kalnins (1984) methylated wood by pre-treating with concentrated aqueous... 

Catalysts lacking phosphorus ligands have also been used as catalysts for allylic substitutions. [lr(COD)Cl]2 itself, which contains a 7i-accepting diolefin ligand, catalyzes the alkylation of allylic acetates, but the formation of branched products was only favored when the substitution reaction was performed with branched allylic esters. Takemoto and coworkers later reported the etherification of branched allylic acetates and carbonates with oximes catalyzed by [lr(COD)Cl]2 without added ligand [47]. Finally, as discussed in Sect. 6, Carreira reported kinetic resolutions of branched allylic carbonates from reactions of phenol catalyzed by the combination of [lr(COE)2Cl]2 and a chiral diene ligand [48]. 

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... 

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. 

Although the Ir-catalyzed aUyhc substitution was developed only recently, several applications in the areas of medicinal and natural products chemistry have aheady been reported. In many syntheses the allylic substitution has been combined with a RCM reaction [71]. Examples not directed at natural products targets have aheady been described in Sections 9.4 and 9.5. It has also been mentioned that this strategy had previously been used in conjunction with aUyhc substitutions catalyzed by other transition metals (Figure 9.5). This was pioneered by P. A. Evans and colleagues, who used Rh-catalyzed allylic amination (compound A in Figure 9.5) [72] and etherification (compound B) [73], while Trost and coworkers demonstrated the power of this concept for Pd-catalyzed aUyhc alkylations (compound C) [74] and Alexakis et al. for Cu-catalyzed (compound D) aUyhc alkylations [75]. 

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.

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. 

Examination of the stereospecificity of the etherification indicated that the reaction was subject to a dramatic halide effect (Tab. 10.9). Treatment of enantiomerically enriched allylic carbonate (R)-53 (94% ee) under optimized conditions furnished the allyl ether (R)-54 in 84% yield (2° 1° >99 1), although with poor enantiospecificity (41% cee ... 

Etherification. The reaction of alkyl halides with sugar polyols in the presence of aqueous alkaline reagents generally results in partial etherification. Thus, a tetraallyl ether is formed on reaction of D-mannitol with allyl bromide in the presence of 20% sodium hydroxide at 75°C (124). Treatment of this partial ether with metallic sodium to form an alcoholate, followed by reaction with additional allyl bromide, leads to hexaallyl D-mannitol (125). Complete methylation of D-mannitol occurs, however, by the action of dimethyl sulfate and sodium hydroxide (126). A mixture of tetra- and pentabutyloxymethyl ethers of D-mannitol results from the action of butyl chloromethyl ether (127). Completely substituted trimethylsilyl derivatives of polyols, distillable in vacuo, are prepared by interaction with trimethylchlorosilane in the presence of pyridine (128). Hexavinylmannitol is obtained from D-mannitol and acetylene at 25.31 MPa (250 atm) and 160°C (129). 

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