P-quinone methide

Diao, L. Yang, C. Wan, P. Quinone methide intermediates from the photolysis of hydroxybenzyl alcohols in aqueous solution. J. Am. Chem. Soc. 1995, 117, 5369-5370. 

Gauvin, R. M. Rozenberg, H. Shimon, L. J. W. Ben-David, Y. Milstein, D. Osmium-mediated C—H and C—C bond cleavage of a phenolic substrate p-quinone methide and methylene arenium pincer complexes. Chem. Eur. J. 2007, 13, 1382-1393. 

Chiang, Y. Kresge, A. J. Zhu, Y. Flash photolytic generation and study of p-quinone methide in aqueous solution. An estimate of rate and equilibrium constants for heterolysis of the carbon-bromine bond in p-hydroxybenzyl bromide. J. Am. Chem. Soc. 2002, 124, 6349-6356. 

Iverson, S. L. Hu, L. Q. Vukomanovic, V. Bolton, J. L. The influence of the para-alkyl substituent on the isomerization of o-quinones to p-quinone methides potential hioac-tivation mechanism for catechols. Chem. Res. Toxicol. 1995, 8, 537-544. 

Bolton, J. L. Shen, L. p-Quinone methides are the major decomposition products of catechol estrogen o-quinones. Carcinogenesis 1996, 17, 925-929. 

Combination of an Ri, radical with an Ra radical yields the single p-qninone methide dimer (V). Here the quinone methide cannot become stabilized by an intramolecnlar addition reaction. Instead, nucleophilic attack of its y-carbon atom occurs by a hydroxyl ion from the medium, for example aromatization and protonation of the phenoxido ion thus formed give rise to guaiacylglycerol- 3-coniferyl ether (VI), again in racemic form dc-spite its two asymmetric carbon atoms. Since attack by the extraneous hydroxyl ion can occur on either side of C-y of the p-quinone methide (V), complete equilibration of the specific hydrogens from the original conifcryl alcohol moiety in the lower half of (V) presumably occurs (sec formulae on p. 131). 

In another case, 4-alkylphenols can be transformed with the help of the flavoenzyme vanillyl alcohol oxidase (VAO) to either (R)-l-(4 -hydroxyphenyl) alcohols or to 1 -(4 -hydroxyphenyl)alkenes. Both products pass through a common intermediate, the p-quinone methide, which then either is attacked by water or rearranges. The product spectrum can be controlled by medium engineering in organic solvents such as acetonitrile and toluene, more ris-alkene but not trans-alkene, and less alcohol, are produced (van den Heuvel, 2001). A similar shift in cis/trans-alkene was achieved by the addition of monovalent anions that bind specifically close to the active site. 

This chapter will focus on o- and p-quinone methides and will be divided into two parts. The first will present methods for generating quinone methides in photochemical and solvolysis reactions and will emphasize how the structure and stability of quinone methides dictates the pathways for their formation. The second section will discuss the results of experiments to characterize the reactivity of quinone methides with nucleophilic reagents, and the broader implications of these results. The scope of this presentation will reflect our interests, and will focus on studies carried out at Buffalo. We considered briefly writing a comprehensive chapter on quinone methides, but abandoned this idea when we learned of Steven Rokita s plans to edit a 12-chapter text, which presents an extremely comprehensive coverage of the chemistry and biochemistry of quinone methides.9... 

There are many additional reports of the o- and p-quinone methides in photosolvolysis reactions ... 

The net effect of this cyclohexadiene/phenyl ring insertion at the carbonyl group is to cause an increase in the overall equilibrium constant for the addition of solvent water, from A dd = 2.3 x 103 for hydration of formaldehyde154 to A dd = 4.0 x 107 for hydration of the p-quinone methide l,3 so that Kj = AT. dd/Aiadd = 1.7 x 104 for transfer of the elements of water from formaldehyde hydrate to 1 (Scheme 43). We have proposed that the relatively small driving force of 6 kcal/mol for this transfer of water from CH2(OH)2 to 1 represents the balance between larger opposing effects3 ... 

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. 

Cyclization of quinone methides.2 p-Quinone methides, particularly those substituted at the 2- and 6-positions, are stable enough to be characterized by IR and NMR, and can be generated in fairly high yield by oxidation of a phenol with Ag,0 (10 equiv.) in CH2C12. When substituted by a suitable terminator, these quinonemethides can undergo Lewis-acid-catalyzed cyclization. Suitable terminators that can survive the initial oxidation include allylsilanes and 3-keto esters. In the latter case, the initial product undergoes oxidation to afford a cyclohexenone. 

Trimethylphenol (221) was oxidized with dioxygen catalyzed by CuCl2-2H20 to afford 3,5-dimethyl-4-hydroxybenzaldehyde (222) and 2,6-dimethyl-p-benzoquinone (223) in low yields. However, the use of acetone oxime as an additive caused a dramatic change to afford both 222 and 223 in 91.5 and 6.5% yields, respectively . These oxidation products are formed from p-quinone methide 225 through 2,6-dimethyl-4-(hexyloxymethyl)phenol (224) (Scheme 45). 

Hydoxyphenyl)-2-(4-hydroxyphenyl)ethane (539) was oxidized with DDQ (1 equiv.) in benzene (room temp., 24 h) to afford both benzofuran (540) and dihydrobenzofuran (541) (27 and 22%, respectively). With 2 equivalents of DDQ the yield of the former increased and that of 541 decreased (Scheme 100). The p-quinone methide 542 is recognized as a plausible reaction intermediate. ... 

Allyl-2,6-dimethoxyphenol (139) underwent rapid oxidation with Ag20 in benzene or CHCI3 (room temp., 6-9 min) to the extended p-quinone methide 778 in quantitative yield (Scheme 155) . This compound is unstable, but isolatable in a pure state. 

Highly reactive quinone methide can be utilized as intermediates in organic synthesis. From the viewpoint of biomimetic synthesis, silybin (782) bearing a benzodioxane skeleton was synthesized in 44.5% yield, together with isosilybin (784) (33.5%), by AgiO-mediated oxidation of equimolar amounts of 27 ,37 -dihydroquercetin (783) and coniferyl alcohol (298) in benzene-acetone. The p-quinone methide 785 must be generated as a reactive intermediate (Scheme 156) °. 

A similar mechanism operates in quinone methides with an amino substituent in the methide group. The p-quinone methide 22 has a C=C barrier of 14.5 kcal mol" and a C—N barrier of 114 kcal mol ... 

Time-resolved resonance Raman spectroscopy of 25 in 50% aqueous CH3CN proved that the final product 26 appears with a rate constant of 2.1 x 109 s 1 following pulsed excitation of 25.207 The appearance of 26 was slightly delayed with respect to the decay of (25), A = 3.0 x 109s, that was determined independently by optical pump probe spectroscopy in the same solvent. The intermediate that is responsible for the delayed appearance of 26, t 0.5 ns, is attributed to the triplet biradical 327.462 It shows weak, but characteristic, absorption bands at 445 and 420 nm, similar to those of the phenoxy radical. ISC is presumably rate limiting for the decay of 327, which cyclizes to the spiro-dienone 28. The intermediate 28 is not detectable its decay must be faster than its rate of formation under the reaction conditions. Decarbonylation of 28 to form p-quinone methide (29) competes with hydrolysis to 26 at low water concentrations. Hydrolysis of 29 then yields p-hydroxybenzyl alcohol (30) as the final product. 

Konschin, H., J. Jakobsons, and S. M. Shevchenko. 1980. A theoretical and experimental investigation of Z. E. Stereoisomerism in some simple lignin p-quinone methides. J. Mol. Struct. 238 231-244. 

Shevchenko, S. M., T. J. Elder, S. G. Semenov, andM. Ya.Zarubin. 1995. Conformational effects on the electronic structure and chemical reactivity of lignin model p-quinone methides and benzyl cations. Res. Chem. Inter. 21(3-5) 413 23. 

The formation of the isomers of the quinonemethide (131) by irradiation of the corresponding o-hydroxybenzyl alcohol has been described. A further study on the formation and reactivity of quinone methides has reported the flash photolysis of the phenol derivative (132) in perchloric acid solution. This affords the p-quinone methide (133). Irradiation of the benzene derivative (134) results in the formation of the quinodimethane (135). A two-colour laser method... 

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>. 

RCONH2 - RCN. The dehydrai tions employs Ag20, molecular sieves Condensation with thiocarhomy with Ag20 renders such compounds re p-Quinone methides. 4-Alkylp stances. It is a useful way to induce eye matic ring. 

Cyclohexadienones, not unexpectedly, can been employed to obtain alkylphenolic systems. Thus a solution of the p-quinone methide depicted when slowly introduced in tetrahydrofuran solution over 2 hours into samarium(ll) iodide at 35°C followed by work-up with sodium bicarbonate solution gave a 67% yield of (E)-2-(3,5-dimethyl-4-hydroxyphenyl)cyclopentanol. The Smij was obtained by treating samarium during 1 hour with methylene diiodide in tetrahydrofuran at 0"C and reacting for a further hour (ref.9). 

Oxidative phenol-benzyl coupling. The key step in a new total synthesis of ( )-picropodophyllone (3) involves oxidation of the phenol 1 with thallium(III) trifluoroacetate in the presence of BF3 etherate in CH2CI2 at 20°. After work-up, which included bisulfite reduction and methylation, the diester (2) was obtained in 55% yield. Some evidence suggests that the cyclization proceeds through a p-quinone methide (a). 

In a rather curious reaction, 2,6-di-(-butylphenol is reported to react with a reagent generated from treatment of A(,A( -diethyl hexahydrodiazocin-2-one (25) with oxalyl chloride to afford the p-quinone methide (26) (Equation (2)) <84MI 922-03). 

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