Quinone methide precursors

SCHEME 2.13 Activation of QMPs (quinone methide precursors) by base catalysis and single-electron reduction (reproduced from Ref. [47] with permission from American Chemical Society). 

FIGURE 9.4 Representative quinone methide precursors for DNA cross-linking.61 66... 

Dyer, R. G. Turnbull, K. D. Hydrolytic stabilization of protected p-hydroxybenzyl halides designed as latent quinone methide precursors. /. Org. Chem. 1999, 64, 7988—7995. 

The yields of polynuclear heterocycles, e.g. (112), available by condensing quinone-methides, e.g. (113), with arylamines are much improved (36- 77%) if the hemi-acetal (114) is used as the quinone-methide precursor in place of the Mannich base (115). ... 

FIGURE 6.16 ortho-Quinone methide 3 stabilization of the zwitterionic rotamer in a complex with /V-methyImorpholine /V-oxide (17). The zwitterionic, aromatic precursor 3a affords the common quinoid form of the o-QM 3 by in-plane rotation of the exocyclic methylene group. 

The geometry of the zwitterions with its exocylic out-of-plane methylene group was quasi-preserved in the recently reported dibenzodioxocine derivative (18) that was formed in rather small amounts by rapidly degrading the NMMO complex at elevated temperatures.45 Strictly speaking, dibenzodioxocine dimer 18 is actually not a dimer of ortho-quinone methide 3, but of its zwitterionic precursor or rotamer 3a (Fig. 6.17). As soon as the out-of-plane methylene group in this intermediate rotates into the ring plane, the o-QM 3 is formed irreversibly and the spiro dimer 9 results... 

FIGURE 6.17 Oxidation of a-tocopherol (1) conventionally leads to its spiro dimer (9) via ortho-quinone methide 3 (path A). The zwitterionic o-QM precursor 3a is stabilized by NMMO in complex 17, which upon rapid heating produces small amounts of new dioxocine dimer 18 (path B). Acid treatment of 18 causes quantitative conversion into spiro dimer 9, via o-QM 3 (path C). 

It was shown that complexes 19 of the zwitterionic precursors of ortho-quinone methides and a bis(sulfonium ylide) derived from 2,5-di hydroxyl 1,4 benzoquinone46 were even more stable than those with amine N-oxides. The bis(sulfonium ylide) complexes were formed in a strict 2 1 ratio (o-QM/ylide) and were unaltered at —78 °C for 10 h and stable at room temperature under inert conditions for as long as 15—30 min (Fig. 6.18).47 The o-QM precursor was produced from a-tocopherol (1), its truncated model compound (la), or a respective ortho-methylphenol in general by Ag20 oxidation in a solution containing 0.50-0.55 equivalents of bis(sulfonium ylide) at —78 °C. Although the species interacting with the ylide was actually the zwitterionic oxidation intermediate 3a and not the o-QM itself, the term stabilized o-QM was introduced for the complexes, since these reacted similar to the o-QMs themselves but in a well defined way without dimerization reactions. 

To assess the trapping of biological nucleophiles, the pyrido[l,2-a]indole cyclopropyl quinone methide was generated in the presence of 5 -dGMP. The reaction afforded a mixture of phosphate adducts that could not be separated by reverse-phase chromatography (Fig. 7.16). The 13C-NMR spectrum of the purified mixture shown in Fig. 7.16 reveals that the pyrido [1,2-a] indole was the major product with trace amounts of azepino[l,2-a] indole present. Since the stereoelec-tronic effect favors either product, steric effects must dictate nucleophilic attack at the least hindered cyclopropane carbon to afford the pyrido[l,2-a]indole product. Both adducts were stable with elimination and aromatization not observed. In fact, the pyrido [1,2-a] indole precursor (structure shown in Scheme 7.14) to the pyrido [l,2-a]indole cyclopropyl quinone methide possesses cytotoxic and cytostatic properties not observed with the pyrrolo [1,2-a] indole precursor.47... 

The Structure of Quinone Methides and Their Precursors Modulate the Reversibility of Reaction... 

The studies described above show that a quinone methide or its aza-analogue quinonimine methide incorporated as a latent electrophilic species into a cyclic lactone or lactam precursor can modify a second nucleophilic residue within the enzyme active site after formation of the acyl-enzyme. Very efficient suicide... 

Cyclobutane-fused pyrimidinones 39, precursors to quinone methide intermediates, have been prepared by reaction of amidines with the cyclopropane ester 38 <06EJOC2753>. 

Loubinoux, B., Gerardin, P., Kilbertus, G. and Miazimbakana, J. (1992). Reaction of wood and cellulose with quinone methides prepared in situ from phenolic precursors. Holzforschung, 46(2), 175-176. 

An interesting variation on the above theme for the biosynthesis of the pavines and isopavines has been proposed by Dyke (169). This proceeds via a quinone methine intermediate. The precursor, a l-benzyltetrahydroisoquinoline-3-car-boxylic acid 165 oxidizes to a quinone methide 166, which then decarboxylates to afford a reactive enamine 167. Cyclization then readily furnishes a pavine. Alternatively, hydration of the enamine 167 at C-4 would ultimately result in formation of an isopavine (Scheme 36). 

An alternate precursor for achieving the same result may be (+)-reticuline (158), which would oxidize to quinone methide 168. Direct cyclization would result in an isopavine skeleton, whereas conversion to the enamine 167 would lead to a pavine. Similarly, a hydroxylation of the methide 168 at C-4 to furnish species 169 would either yield an isopavine by cyclization, or a pavine via the intermediacy of the 1,2-dihydro compound 167 (Scheme 37) (769). 

Aminochromans also arise from the reaction of phenolic Mannich bases with enamines (70JHC1311). The route is attractive for a number of reasons the starting materials are readily available its scope is considerable since the enamines may be aldehyde or ketone based and the Mannich bases may be aromatic or heteroaromatic and the products themselves are precursors of hydroxychromans and 4//-chromenes. Mechanistically, the synthesis proceeds through a quinone methide followed by addition to the enamine and cyclization, which may be a concerted process (Scheme 71). 

Loubinoux, B. Miazimbakana, J. Gerardin, P. Reactivity of new precursors of quinone methides. Tetrahedron Lett. 1989, 30, 1939-1942. 

Dimethyl quinone methide (38a, Ri = CH3,R2 = H) was one of the first spectroscopically characterized simple quinone methides. This quinone methide was generated in alkaline aqueous solution from chloride and acetate precursors H-38a-Cl and H-38a-OAc.68 Stable quinone methides such as 38b-e (Scheme 19) were generated from chloride precursors H-38-C1.169,70... 

The tetramethyl quinone methide 38f has been generated by cleavage of the chloride precursor in dichloromethane, and its reactions with amine bases studied.74... 

Several general synthetic methods have been developed that utilize the novel reactivity of quinone methides generated by oxidation of phenol precursors. Angle and Ranier have generated 2,6-dialkyl or 2,6-dialkoxy-substituted / -quinone methides 51 by oxidation of the corresponding phenols with Ag20. 

These questions were addressed in studies of the reactions ofp-1 and / -Me-1 + in aqueous solution. The quinone methide p-1 was generated by photoheterolysis of neutral 4-hydroxybenzyl acetate in water, and ks = 3.3 s 1 determined for addition of water.52 The O-methylated quinone methide / -Me-l+ was generated as an intermediate of solvolysis of neutral precursors in water,128 and ks = 2.5 x 108 s 1 for addition of water was determined by using the diffusion-limited rate of nucleophile addition of azide anion to / -Me-l+ as a clock for the slower addition reaction of solvent.135,138 These data show that methylation ofp-1 causes an enormous 6 x 107-fold increase in the reactivity of the electrophile with solvent water.52... 

Indeed, also p- and ra-hydroxybenzhydryl alcohols yield the corresponding quinone methides or zwitterions. o-Hydroxymethylanilines are excellent photo-precursors for the generation of o-quinone methide imides [101] (Sch. 4). 

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