Benzyl ethers cycloaddition reactions

As expected, other enol ethers work well in these procedures. For example, Jones and Selenski find that implementation of method F, which occurs by addition of MeMgBr to benzaldehyde 5 in the presence of dihydropyran (DHP) at 78 °C affords a 66% yield of the corresponding tricyclic ketal 59 with better than 50 1 endo diastereoselectivity (Fig. 4.31).27 On the contrary, Lindsey reports use of method H with the benzyl alcohol 35 and diethylketene acetal. The cycloaddition reaction occurs almost instantaneously upon deprotonation of the benzyl alcohol 35 by f-butyl-magnesium bromide in the presence of the ketene acetal and yields the corresponding benzopyran ortho ester 60 in a 67% yield.29... 

Alkenes are scavengers that are able to differentiate between carbenes (cycloaddition) and carbocations (electrophilic addition). The reactions of phenyl-carbene (117) with equimolar mixtures of methanol and alkenes afforded phenylcyclopropanes (120) and benzyl methyl ether (121) as the major products (Scheme 24).51 Electrophilic addition of the benzyl cation (118) to alkenes, leading to 122 and 123 by way of 119, was a minor route (ca. 6%). Isobutene and enol ethers gave similar results. The overall contribution of 118 must be more than 6% as (part of) the ether 121 also originates from 118. Alcohols and enol ethers react with diarylcarbenium ions at about the same rates (ca. 109 M-1 s-1), somewhat faster than alkenes (ca. 108 M-1 s-1).52 By extrapolation, diffusion-controlled rates and indiscriminate reactions are expected for the free (solvated) benzyl cation (118). In support of this notion, the product distributions in Scheme 24 only respond slightly to the nature of the n bond (alkene vs. enol ether). The formation of free benzyl cations from phenylcarbene and methanol is thus estimated to be in the range of 10-15%. However, the major route to the benzyl ether 121, whether by ion-pair collapse or by way of an ylide, cannot be identified. 

Intramolecular cycloaddition of fV-benzyl-substituted 3-O-allylhexose nitrones furnishes chiral oxepane derivatives. The regioselectivity of the cycloaddition depends on several factors such as (1) the structural nature of the nitrone, (2) substitution and stereochemistry at 3-C of the carbohydrate backbone, and (3) substitution at the terminus of the O-allyl moiety. A mixture of an oxepane and a pyran is formed in the intramolecular oxime olefin cycloaddition of a 3-O-allyl carbohydrate-derived oxime <2003T4623>. The highly stereoselective synthesis of oxepanes proceeds by intramolecular nitrone cycloaddition reactions on sugar-derived methallyl ethers <2003TA3899>. 

The principle of dick chemistrf presented by Hawker et al. (see Section 2.3.5) offers an efficient and versatile method of functionalisation. For example, it utilises [3+2]-cycloaddition of azide-functionalised reagents with ethyne end groups of a dendrimer precursor to prepare dendrimers with triazole-functionalised end groups. The mild reaction conditions, almost quantitative reaction, and not least the tolerance towards numerous functional groups permit the use of widely differing molecular frameworks (e.g. poly(benzyl ether), POPAM dendrimer structures or hyperbranched polyesters) and different functionalised azides... 

Interestingly, 716, in which a p-methoxybenzyl ether replaces the benzyl ether as a protecting group, undergoes the [3 + 2] cycloaddition with dimethyl acetylene dicarboxylate to provide exclusively and in 48% yield the cycloadduct 717, whose absolute configuration was established by an NOE difference spectral analysis of a synthesized pyrrolidine derivative. The reaction of 716 with methyl crotonate provides a 10 1 separable mixture of cycloadducts 718 which are converted to the pyrrolidine 719 [215] (Scheme 157). 

The low yields, which are observed among styrenyl adducts, reflect a combination of the poor reactivity of the styrene at the low temperature of the reaction. For example, the combination of t-butyl Grignard with the 2,4-bis-OBoc-benzyl alcohol 15 affords the corresponding benzopyran 50 in only 50% yield even when carried out in the presence of 5-10 equivalents of the styrene (method H, Fig. 4.27).27 Yields for substituted benzopyran styrene adducts are still lower (method G, Fig. 4.27). For example, addition of methyl lithium to 2,4-bis-OBoc-benzylaldehyde 5 followed by the addition of the dienophile and magnesium bromide affords benzopyran 51 in a paltry 27% yield. Method F is entirely ineffective in these cases, because the methyl Grignard reagent competes with the enol ether and with styrene 1,4-addition of methyl supercedes cycloaddition. 

Figure 3.42 a General reaction scheme for the thermal Huisgen cycloaddition b the copper-catalyzed reaction between phenyl propargyl ether (phenyl 2-propynyl ether) and benzyl azide. The catalytic reaction is performed in the presence of a reductant (sodium ascorbate) and gives just one of the product isomers in high yield. 

Possible competitive reactions (e.g., cycloadditions on the double bond) proceed only very slowly with diazotoluene dibenzyl ether is produced by the reaction with water so that strictly anhydrous conditions are not necessary. Similarly, the presence of traces of water does not interfere with the esterification with the aid of N,N -dicyclohexyl-0-benzylisourea, which reacts with water with the production of benzyl alcohol. The reagent is synthesized from dicyclohexylcarbodiimide and benzyl alcohol with copper(I) chloride as the catalyst. The esterification proceeds according to Scheme 5.16. 

The first example of the enantioselective cycloaddition of chiral enol ethers to o-quinone methides, derived from a protected salicylaldehyde by reaction with a Grignard reagent, generates three chiral centres in a one-pot process and provides chiral chromans 30. These products can be manipulated to give other chiral chromans and chromenes and are a source of chiral aliphatic benzylic carbon sites <04JOC9196, 04SL1101>. 

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