Quinones intramolecular cycloaddition

Unexpectedly, a completely different reaction took place in the oxidation of 2-(l-propenyl)phenol (111) with PdCh. Carpanone (112) was obtained in one step in 62% crude yield. This remarkable reaction is explained by the formation of o-quinone, followed by the radical coupling of the side-chain. Then the intramolecular cycloaddition takes place to form carpanone[131]. 

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>. 

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>. 

As depicted in Scheme 41, an intramolecular cycloaddition of the furan 2,3-double bond of a furan tethered to a cyano-substituted benzocyclobutene via an intermediate quinone dimethide was used for the synthesis of the tetracyclic core of halenaquinol and halenaquinone <2001SL1123, 2002T6097>. The reaction proceeded via an OT,7i9-transition state to produce the cycloadduct 72 exclusively. A related chemistry is shown in Equation (56), in... 

Saegusa s group (81JA5250) found that [o-[(trimethylsilyl)alkylamino]-benzyljtrimethylammonium halide underwent the fluoride-anion induced 1,4-elimination under mild conditions to generate an o-quinone methide N-alkylamine intermediate. They performed the formal synthesis of gephyro-toxin 434 on the basis of an intramolecular cycloaddition of the o-quinone methide A-alkylamine 426 (83TL2881). Treatment of azadiene precursor 425... 

Both inter- and intramolecular cycloaddition modes have been explored and utilized in the synthesis of natural products. Successful intermolecular cycloaddition depends upon making an appropriate selection of solvent, supporting electrolyte, oxidation potential, and current density. This is nicely illustrated in the equations portrayed in Schemes 22 and 23. For example, in methanol the controlled-potential oxidation of phenol 251 affords a high yield (87%) of 252, the adduct wherein methanol has intercepted the reactive intermediate [62]. In contrast, another constant-current electrolysis afforded an 83% yield of quinone 253 when the reaction was conducted in acetonitrile, rather than in methanol. 

The intramolecular cycloaddition of o-quinone methide N-alky1imines with alkenes to form six-membered nitrogen rings is well documented but the intermolecular reaction is less well characterised. Ito et al. have now shown that the o-quinone methide N-alkylimines (182), generated in situ by treatment of the corresponding N-trimethylsilyltrimethylammonium salts (181) with fluoride ion, react with the electron-deficient alkenes (183)... 

With the exception of the abundant o-quinone methide Uterature (62), there is only a single example of a diene exocycUc to a ring [59]. The use of the very reactive o-quinone methide diene, for intramolecular cycloaddition, was introduced by Oppolzer in 1971 (64). Initially, these were prepared by thermolysis of a preformed benzocyclobutene [60, 61]. Later, Vollhardt demonstrated that 1,5 diacetylenes could serve as precursors to benzocyclo-butenes and thus, to o-quinone methides [62]. Since that time, several other methods for the generation of o-quinone methides have been developed [63-68], some of which allow generation of the o-quinone methide under very mild reaction conditions. These methods also allow the incorporation of more complex functionality in the ring system. 

Harrowven and coworkers disclosed a short synthesis of (-)-elisapterosin B (60) and (-)-colombiasin (61) combining the Moore rearrangement and intramolecular cycloaddition reactions (Scheme 8.20) [27b]. The bicyclic quinone 126 was generated from 125 via a domino 4 i-e conrotatory ring opening 125 126/6x-e disrotatory electrocyclization... 

Photochemical 2 + 2 cycloadditions can also take place intramolecularly if a molecule has two double bonds that are properly oriented. " The cyclization of the quinone dimer shown above is one example. Other examples are... 

Another rare kind of 6-electron ionic cycloaddition is that between a pentadienyl cation and an alkene. A telling example is the key step 2.66 — 2.67 in a synthesis of gymnomitrol 2.68, where the nature of the pericyclic step is heavily disguised, but all the more remarkable for that. Ionization of the acetal gives the cationic quinone system 2.66. That this is a pentadienyl cation can be seen in the drawing of a canonical structure on the left, with the components of the pericyclic cycloaddition emphasized in bold. Intramolecular [4+2] cycloaddition takes place, with the pentadienyl cation as the 4-electron component and the cyclopentene as the 2-electron component. Th is reaction is an excellent example of how a reaction can become embedded in so much framework that its pericyclic nature is obscured. 

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-plienyl-l-aza-2-cyanobuta-l,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Diliydro-4//-1,2-oxazines have been shown to be usefiil as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-l,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(f-butyldimethylsilyloxy)-l-azabuta-1,3 -diene (107) reacts with halobenzo-quinones, naphthoquinones, and A-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with A-(cinnamylidcnc)tritylaminc produces the 3,4-adduct whereas with A -(cinnamylidcnc)bcnzylidinc the 1,2-adduct is produced.190... 

A review of photo-cycloadditions of dienones and quinones has been published.41 The first example of a Lewis acid-catalysed 2 + 2-cycloaddition of styrene with naphthoquinone has been reported.42 FMO methods have been used to investigate the effect of substituents on the regiochemistry of the 2 + 2-photo-cycloaddition of a, fi-unsaturated carbonyl compounds with substituted alkenes.43 Evidence has been presented for the presence of a triplet exciplex intermediate in the photo-cycloaddition of 4,4-dimethylcyclohexenone to 1,1-diphenylethylene.44 The intramolecular 2-1-2-photo-cycloaddition of 2-acyloxy-3-hexenoylcyclohexenones (26) is highly diastereo-selective yielding the tricyclic adduct (27) (Scheme 10).45... 

Molecular electrostatic potentials have been used to explain the regioselectivity exhibited in the Diels-Alder cycloaddition reactions between 1-trimethylsilyloxy-butadiene and the quinones 5-formyl-8-methyl-1,4-naphthoquinone, 5-methoxy-7-methyl-1,4-phenanthrenequinone, and 5,6,7-trimethyl-1,4-phenanthrenequinone.128 The intramolecular Diels-Alder reaction of masked o-benzoquinones (123) with a variety of dienes provides adducts (124) which rearrange to functionalized ris-decal ins (125) with complete stereocontrol of up to five stereocentres. This methodology ... 

The formation and intramolecular dipolar cycloaddition of azomethine ylides formed by carbenoid reaction with C=N bonds has recently been studied by the authors group.84 Treatment of 2-(diazoace-tyl)benzaldehyde O-methyl oxime (176) with rhodium(II) octanoate in the presence of dimethyl acetylenedicarboxylate or N-phenylmaleimide produced cycloadducts 178 and 179, respectively. The cycloaddition was also carried out using p-quinone as the dipolarophile. The major product isolated corresponded to cycloadduct 180. The subsequent reaction of this material with excess acetic anhydride in pyridine afforded diacetate 181 in 67% overall yield from 176. The latter compound incorporates the basic dibenzofa, d -cyclohepten-5,10-imine skeleton found in MK-801,85 which is a selective ligand for brain cyclidine (PCP) receptors that has attracted considerable attention as a potent anticonvulsive and neuro-protective agent.86,87... 

Discrepancies between different researchers derive from the character inter-or intramolecular of the interactions presumably controlling the reactive conformation. Thus, in most of the cases, the population of the different rotamers in the sulfinylated substrate (only governed by intramolecular interactions) is the only factor considered for explaining the observed 7r-facial selectivity. This explanation (static conformational polarization) was formulated by Koizumi and used by many authors to justify the behavior of vinyl sulfoxides acting as dienophiles and dipolarophiles. A second explanation assumes that the interactions of the two reagents in the transition states determine a different reactivity of the rotamers around the C-S bond. This intermolecular factor can become the most important one in the control of the 7r-facial selectivity of the cycloadditions, and therefore the tendency expected from conformational stability criteria was not observed in those cases where the most reactive conformation is not the most populated one. This dynamic conformational polarization has been used just to explain some of the results obtained for sulfinyl quinones and sulfinyl dienes (unexplainable with the above model) but it can be applied to many other cases. 

Fluoride-induced fragmentation reactions were used in two stages of a synthesis of hexahydrocannabi-nol methyl ether (144 Scheme 52). One of the phenolic hydroxy functions in the resorcinol derivative (140) was selectively liberated from the SEM ether to give the diol (141), which was converted to the bis (trimethylsilyl) ether (142). Subsequent treatment with CsF resulted in a 1,4-elimination to the o-quinone methide (143) intermediate, which underwent an intramolecular [4 -i- 2] cycloaddition to give the product in good yield. 

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