4 INTERMOLECULAR APPLICATIONS OF o-QUINONE METHIDES (o-QMs) ANIONICALLY GENERATED AT LOW TEMPERATURES: KINETIC CONDITIONS THOMAS PETTUS AND LIPING PETTUS Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93106, USA 4.1 INTRODUCTION TO o-QMs There existmanyfundamental and philosophical truths in the universe. Among these is the notion that the value of an item is determined by its inherent characteristics and its surrounding environment. For example, a fishing pole near the sea is a useful tool, but when relocated to the desert its usefulness decreases. o-Quinone methides (o-QMs) are highly reactive species with short lifetimes because of the thermodynamic drive to undergo rearomatization. However, the above philosophical truth applies to these highly electrophilic intermediates. In the absence of stabilizing residues, these transient species prove so reactive that the setting in which they are produced dictates the range and scope of their subsequent application. Figure 4.1 shows some of the accepted canonical representation for o-QMs. These depictions should give readers some appreciation regarding the reactivity of o-QMs and impart some credence to the notion that the olefin geometry in an o-QM is fluxional, being determined by the energy difference between competing steric effects (R2 and R1) versus (R2 and O). Quinone Methides, Steven E. Rokita Copyright Ó 2009 John Wiley & Sons, Inc. 89 90 INTERMOLECULAR APPLICATIONS OF o-QUINONE METHIDES (o-QMs) R1 R2 R1 R2 R1 R2 R1 R1 R2 R2 O O O O O favored geometry if biradical zwitterion benzoxete favored geometry if R1 is smaller than valence R1 is larger than the the oxygen atom of tautomer oxygen atom of the the carbonyl carbonyl FIGURE 4.1 Some plausible canonical representation of o-QMs. Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable para-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 thermody- namic 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. 4.2 THERMAL GENERATION CONDITIONS Therefore, most of the nonoxidative generation methods that have evolved can be viewed as a ‘‘crossover’’reaction of sorts whereby one o-QM product is exchanged for another by application of heat. The stereochemistry accruing in the products of these procedures is expectedly subject to thermodynamic control. For example, while exploring a synthetic approach for nomofungin (Fig. 4.2), Funk recently showed that heating 2,2-dimethyl-1,3-benzodioxin to 195C caused expulsion of acetone resulting N N H O 195°C, 27 h N O decalin O O N N H N and dimers 63% yield 10:1 / endo:exo FIGURE 4.2 The Funk crossover strategy for the hexacyclic core of nomofungin. THERMAL GENERATION CONDITIONS 91 MOMO OMOM 1:6 3 M aq. HCl/MeOH O OH O OH HO reflux 2 h H H and dimers FIGURE 4.3 The Snider strategy for the tetracyclic core of the bisabosquals. in the formation of an o-QM intermediate, which subsequently succumbed to a [4 2] reaction with the attached indole.1 Whether or not the intermediate o-QM undergoesþ cycloadditions with itself or some other nucleophile or recombines with acetone proves rather inconsequential as the ultimate product and the stereo- chemical outcome (10:1 endo/exo) are decided by relative thermodynamic stabilities. Moreover, under thermal conditions the o-QM intermediate can evenundergo reaction with extremely unreactive nucleophiles, such as the indole. Another elegant example of the thermal generation and subsequent intramolecular cycloaddition of an o-QM can be found in Snider’s biomimetic synthesis of the tetracyclic core of bisabosquals.2 Treatment of the starting material with acid causes the MOM ethers to cleave from the phenol core (Fig. 4.3). Under thermal conditions, a proton transfer ensues from one of the phenols to its neighboring benzylic alcohol residue. Upon expulsion of water, an o-QM forms. The E or Z geometry of the o-QM intermediate and its propensity toward interception by formaldehyde, water, or itself, again prove inconsequential as the outcome is decided by the relative thermodynamic stabilities among accessible products. Recently, Ohwada has employed benzoxazines as the starting precursor for various b,b-unsubstituted o-QMs (Fig. 4.4).3 In this protocol, the benzoxazine is gently warmed; in some cases, 50C proves sufficient to expel methyl cyanoformate and generate the o-QM intermediate. The initial expulsion is irreversible because methyl cyanoformate is a poor nucleophile. Electron-withdrawing groups within the o-QM species appear to facilitate reaction with less reactive nucleophiles. However, the choice of subsequent conditions depends on the overall reactivity of the nucleophile. Long reaction times and high temperatures (>100C) are necessary in many exam- ples, such as the cycloaddition between an o-QM and nonnucleophilic alkenes. These facts suggest that the product distribution in these high-temperature examples remains under thermodynamic control and enables the products of undesired o-QM side reactions, such as dimerization, to revert and channel into the preferred product. In addition, the conspicuous absence of benzopyrans afforded from o-QMs with b- substituents may suggest that these reactions afford syn/anti ratios as the result of a thermodynamic distribution among isomers. 92 INTERMOLECULAR APPLICATIONS OF o-QUINONE METHIDES (o-QMs) CO2Me CO2Me 50°C N N R O toluene R O (R = electron- and dimers withdrawing group) O N O 2 equiv R ON 6 h, 100°C 62% yield Ph 2 equiv R OhP 12 h, 120°C 69% yield FIGURE 4.4 The Ohwada method of a benzoxazine crossover for o-QM generation. For the remaining discussion, we focus on low-temperature methods for generation of o-QMs (<25C) as reported in the literature since 2001 as well as their subsequent synthetic applications. Surprisingly, only three general procedures adhere to this stringent criterion. All of the methods can be considered as examples of anionic generation of o-QMs. In our opinion, these three procedures are unique because any o-QM intermediate generated in a nonoxidative fashion at low temperature can then be utilized in reactions under kinetic control. For past several decades, kinetically controlled reactions have largely supplanted thermodynamic regimes in synthetic applications because of likelihood of better stereocontrol and greater precision. 4.3 LOW-TEMPERATURE KINETIC GENERATION OF o-QMs 4.3.1 Formation of the o-QMs Triggered by Fluoride Ion There are only a few examples of low-temperature conditions reported to lead to a species behaving as an o-QM. All of these, except for our O-acyl transfer methods that will be discussed later, use a fluoride ion to trigger the formation of the o-QM in an almost instantaneous manner. In these examples, a high concentration of the intended nucleophile is necessary to prevent any side reactions with the o-QM, because given the low-temperature conditions its formation is usually irreversible. The newest protocol, which was reported by Yoshida in 2004, is a testimonyto these issues (Fig. 4.5).4 Treatment of a TMS-aryl compound displaying an ortho-OTf residue with a fluoride ion at 0C causes the formation of a symmetric benzyne, which succumbs to a [2 2] cycloaddition with the carbonyl of various benzaldehydes to form a benzoxete.þ This four-membered ring then undergoes immediate valence LOW-TEMPERATURE KINETIC GENERATION OF o-QMs 93 1 equiv R O R TMS O O OTf H KF/18-c-6 THF, 0 °C R 3 equiv symmetric benzyne 67% yield O 9 9-aryl-xanthene (R = OMe) R FIGURE 4.5 Yoshida fluoride-triggered [2 2] benzoxetane formation and rearrangement. þ isomerization to its corresponding o-QM, which as expected proves highly reactive and indiscriminate in its search for a nucleophile. It could undergo dimerization with itself or the addition of another weak nucleophile. However, since some of the reactive benzyne still remains, it undergoes an immediate [4 2] cycloaddition at low temperature to restore aromaticity and affords the correspondingþ 9-aryl-xanthene. The authors are able to push the reaction to completion by providing three equivalents of the benzyne precursor. Thorough experimentation shows that in order for the reaction to proceed in good yield, the aryl aldehyde must contain an electron-donating group (such as R OMe) to ensure the rapid and complete formation of the benzoxete precedes subsequent¼ formation of the o-QM intermediate, which is most likely the rate-determining step in the cascade. The first of the few low-temperature methods for the formation of an o-QM was a method developed by Rokita.5 It is principally used for reversible DNA alkylation. However, it has recently begun to find its way into some synthetic applications. It utilizes a silylated phenol, which proves vastly more manageable as an o-QM precursor than the corresponding o-hydroxyl benzyl halide (Fig. 4.6). In this kineti- cally controlled process, expulsion of a benzylic leaving group is triggered at low temperature by treatment with a fluoride ion, which causes a b-elimination. The most comprehensive examination of the Rokita kinetic procedure from a synthetic standpoint was carried out by Barrero and coworkers.6 They examined the 1) TBSCl OH OTBDMS O imidazole CHO – 2) NaBH4 X F o 3) PPh3/X2 25 C 2 min physiological pH DNA adduct DNA FIGURE 4.6 The Rokita fluoride-triggered expulsion for generation of an o-QM.