Quinone methide ring

Two model p-quinone methide ring systems of kendomycin were obtained by oxidation with 2,2-dimethyldioxirane (DMDO) and NalO, respectively. The demonstrated chemistry paves the way for the to synthesis of kendomycin <04OL3131>. Anodic oxidation of 2,3-dihydrobenzol )]furan derivatives was also utilized to synthesize 2-fluoro-and 2,3-difluoro-2,3-dihydrobenzo[fc]furan derivatives <04JOC5302>. 

Scheme 10. Mechanislic possibililies for PF condensalion. Mechanism a involves an SN2-like attack of a phenolic ring on a methylol. This attack would be face-on. Such a mechanism is necessarily second-order. Mechanism b involves formation of a quinone methide intermediate and should be Hrst-order. The quinone methide should react with any nucleophile and should show ethers through both the phenolic and hydroxymethyl oxygens. Reaction c would not be likely in an alkaline solution and is probably illustrative of the mechanism for novolac condensation. The slow step should be formation of the benzyl carbocation. Therefore, this should be a first-order reaction also. Though carbocation formation responds to proton concentration, the effects of acidity will not usually be seen in the reaction kinetics in a given experiment because proton concentration will not vary.

Wan s group showed that the observed photodehydration of hydroxybenzyl alcohols can be extended to several other chromophores as well, giving rise to many new types of quinone methides. For example, he has shown that a variety of biphenyl quinone methides can be photogenerated from the appropriate biaryl hydroxybenzyl alcohols.32,33 Isomeric biaryls 27-29 each have the benzylic moiety on the ring that does not contain the phenol, yet all were found to efficiently give rise to the corresponding quinone methides (30-32) (Eqs. [1.4—1.6]). Quinone methides 31 and 32 were detected via LFP and showed absorption maxima of 570 and 525 nm, respectively (in 100% water, Table 1.2). Quinone methide 30 was too short lived to be detected by LFP, but was implicated by formation of product 33 that would arise from electrocyclic ring closure of 30 (Eq. 1.4). 

Uchida and Irie have reported a photochromic system based on ESIPT to an alkene carbon.82 They observed that vinylnaphthol 121 isomerizes to the ring-closed 123 when irradiated with 334 nm light ( = 0.20, Eq. 1.34). The reaction is photoreversible since irradiation of 123 (at400 nm) regenerates the starting vinylnaphthol. The authors proposed a mechanism in which ESIPT from the naphthol OH to the [3-alkenyl carbon gives intermediate o-quinone methide 122, which undergoes subsequent electrocyclic... 

Pyrans and napthopyrans (chromenes) are photochromic compounds that undergo photochemically induced electrocyclic ring opening to give colored ortho-quinone methides.95-98 For example, chromene 153 opens on irradiation to give 154 (Eq. 1.41). 

Quinone methides 156 and 157 were generated on irradiation of the cis and trans forms of 155, respectively (Eqs. 1.42 and 1.43).99 100 The mechanism is believed to involve a radical ring opening of the cyclopropane ring, followed by hydrogen or methyl migration. 

Shi, Y. Wan, P. Solvolysis and ring closure of quinone methides photogenerated from biaryl systems. Can. J. Chem. 2005, 83, 1306-1323. 

Sugimoto, H. Nakamura, S. Ohwada, T. Generation and application of o-quinone methides bearing various substituents on the benzene ring. Adv. Synth. Catal. 2007, 349, 669-679. 

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... 

SCHEME 7.14 Cyclopropyl quinone methide formation upon reductive activation. The CC-1065 A-ring is shown in the inset. 

In a recent study, we showed that the more flexible pyrido[l,2-a]indole-based cyclopropyl quinone methide is not subject to the stereoelectronic effect.47 Scheme 7.17 shows an electrostatic potential map of the protonated cyclopropyl quinone methide with arrows indicating the two possible nucleophilic attack sites on the electron-deficient (blue-colored) cyclopropyl ring. The 13C label allows both nucleophile attack products, the pyrido[l,2-a]indole and azepino [l,2-a]indole, to be distinguished without isolation. The site of nucleophilic is under steric control with pyrido [1,2-a]indole ring formation favored by large nucleophiles. 

The results of the methanolic solvolysis study shown in Fig. 7.15 reveals that nucleophilic attack on the cyclopropyl quinone methide by methanol affords the pyrido[1,2-a]indole (73 ppm) and azepino[l,2-a]indole (29ppm) trapping products. Initially, nucleophilic attack on the cyclopropane ring affords the hydroquinone derivatives (see Scheme 7.17) that oxidizes to the quinones upon aerobic workup. 

FIGURE 7.16 Trapping of the phosphate of 5 -dGMP by the pyrido [1,2-a] indole quinone methide. The 13C-NMR shows most trapping with ring retention, labeled pyrido, with trace amounts of ring expansion, labeled azepino. ... 

The global fitting studies revealed that the hydroquinone species shown in Scheme 7.5 affords the quinone methide at rates of 1-2 x 10 3 min-1 that are independent of both pH (from 7 to 9.5) and the concentration of buffers used to hold pH. We interpreted this observation as protonation of the C-5 center followed by the slow loss on the nitrogen-leaving group. The anionic C-5 center of the electron-rich hydroquinone ring would be very basic resulting in complete protonation near neutrality. 

Lemus, R. L. Skibo, E. B. Studies of extended quinone methides. Design of reductive alkylating agents based on the quinazoline ring system, j. Org. Chem. 1988, 53, 6099-6105. 

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