Quinone methides cycloaddition

Talley o-Quinone methide cycloaddition controlled by remote chiral center [85JOC1695]... 

Amouri and coworkers also demonstrated that the nucleophilic reactivity of the exocyclic carbon of Cp Ir(T 4-QM) complex 24 could be utilized to form carbon -carbon bonds with electron-poor alkenes and alkynes serving as electrophiles or cycloaddition partners (Scheme 3.17).29 For example, when complex 24 was treated with the electron-poor methyl propynoate, a new o-quinone methide complex 28 was formed. The authors suggest that the reaction could be initiated by nucleophilic attack of the terminal carbon of the exocyclic methylene group on the terminal carbon of the alkyne, generating a zwitterionic oxo-dienyl intermediate, followed by proton transfer... 

The coordinated quinone methide Jt-system of complex 24 can also undergo cycloaddition (Scheme 3.17). When 24 was reacted with /V-methylmaleimide, a [3+2] cycloaddition took place to give the tricyclic iridium complex 29. The closest example to this unprecedented reactivity pattern is a formal [3 + 2] cycloaddition of /)-quinone methides with alkenes catalyzed by Lewis acids, although in that reaction the QMs serve as electron-poor reagents. 36... 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

The pyrano[3,2-c][l]benzopyran system is available from the reaction between salicylaldehyde and 5-phenylthio-4-penten-l-ols which proceeds by an intramolecular cycloaddition of an o-quinone methide desulfurisation is facile (Scheme 29) <00TL2643>. Mild conditions have been established for the synthesis of (-)-hexahydrocannabinol 50 from the olivetol derivative 49 which also involves a quinone methide (Scheme 30) <00SC1431>. 

Scheme 7 [4 -I- 2] - Cycloaddition with anodically generated quinone methide.

Cycloaddition Anodically generated phe-noxy cations, o-quinones, and o-quinone methides react with olefins to bicyclic and tricyclic annelated compounds in stereoselective cycloadditions [250-252]. In the synthesis of a Euglobal skeleton, a quinone methide has been generated in situ by anodic oxidation mediated by DDQ. The cycloaddition was promoted by the use of lithium perchlorate... 

There are a number of examples of the synthesis of chromans using o-quinone methides as the heterodiene in a hDA reaction. Both pyrano[3 -c]-benzopyrans and cyclopenta[c][l]benzopyrans result from an intramolecular cycloaddition of a substituted o-quinonemethide generated under mild conditions. In the former case, salicylaldehyde and an unsaturated alcohol yield the rra/is-fused tetrahydropyranobenzopyran (Scheme 10) <99JOC9507>. However, the latter synthesis (Scheme 11) is less selective <99BCJ73>. 

The JACS paper describes the total synthesis of the more highly oxygenated (-)-tetracycline 16. To this end, the alcohol S was carried on to the enone 10. Opening of the cyclobutane 11 to the o-quinone methide followed by Diels-Alder cycloaddition to 10 delivered the endo adduct 12. 

The anion derived from 2,3-dimethyl-l,4-naphthoquinone behaves as a quinone methide and undergoes a [l,4]-cycloaddition with the benzoquinone (193). The product is the xanthene derivative (194) (70JCS(C)722). There is no indication of the formation of the isomeric xanthene. A [l,3]-cycloaddition occurs simultaneously which leads to the fluorene derivative (195). 

The polar 1,4-cycloaddition of alkenes with 2-hydroxy-5-nitrobenzyl chloride in the presence of tin(IV) chloride yields 6-nitrochromans (69TL5279). The quinone methide, which is protonated under these conditions, undergoes stereospecific syn addition of the alkene. Although in most cases the reaction is regiospecific, ds-pent-2-ene yields a mixture of isomers. 

The formation of the chromanochromans (286) during the reaction of the phenolic Mannich bases and 2-chloroprop-2-enonitrile probably arises through the decomposition of the base to a quinone methide and dimethylamine (80JOC3726). The initial product, a substituted 4//-chromene (285), undergoes a further [4+2]-cycloaddition to give the final product (Scheme 77). 

It is pertinent at this point to refer briefly to the sources of quinone methides, though these have been reviewed (B-74M122400). The general approach used in chroman syntheses involves the thermal elimination of HX from an -substituted phenol. Commonly the eliminated molecules are water, methanol or dimethylamine (287 X = OH, OMe, NMe2, respectively). However, these methods are not entirely suitable because the eliminated molecules may promote side reactions. In the case of 1,2-naphthoquinone 1-methide, the thermal dissociation of the spirodimer (288) is a better source than the other methods. Its formation represents another example of dimerization by a [4+2]-cycloaddition, since it is prepared by heating l-dimethylaminomethyl-2-naphthol in dodecane or xylene with careful exclusion of moisture (73JCS(P1)120,81CJC2223). 

Cycloaddition of styrene with p-quinone methides.2 In the presence of this Lewis acid, p-quinone methides and styrenes undergo a formal [3 +2]cycloaddi-tion to form dihydro-lff-indenes. The reaction shows some stereoselectivity. Thus the geometry of the (E)-styrene is largely retained (17 1) and only two of the four possible products are formed. Presumably, any electron-rich alkene could participate in this cycloaddition. 

Treatment of v/-butyl 4-formyl-l,3-phenylene dicarbonate 116 with methyl magnesium bromide forms the ortho-quinone methide 117, which undergoes a [4+2]-cycloaddition with ( )-4-(pyrrolidin-l-yl)but-3-en-2-one. Elimination of pyrrolidine from the resulting benzopyran then provides l-(4//-chromen-3-yl)ethanone in moderate yield (Scheme 38) <2002JOC6911>. 

The reaction of benzyne with aromatic aldehydes proceeds via nucleophilic attack of the carbonyl oxygen onto the benzyne to give the zwitterionic intermediate 172 followed by cyclization to the benzoxete intermediate. Cycloreversion then forms an ortho-quinone methide, which undergoes a [4+2] cycloaddition with a second molecule of the benzyne to form the xanthene (Scheme 56) <20040L4049>. 

The one-pot reaction of 0-BOC protected salicylaldehydes and salicyl alcohols with electron-rich alkenes and a Grignard reagent involves a diastereoselective cycloaddition to an o-quinone methide and offers access to a wide range of 4-substituted chromans <02JOC6911>. 

Benzyl cations generated from benzyl alcohols or quinone methides by the action of S11CI4 undergo [3-(-31-cycloaddition of allylsilanes leading to tetrahydronaphthalenes.1 With secondary and tertiary benzyl cations, a competing [3 + 2]-pathway forms dihydro(177)indenes. 

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