Astruc D. - Modern arene chemistry (2002)(en)

15.1 Introduction 543

Fig. 4

available for the rapid elaboration of complex structural architectures from ortho-quinol derivatives make them ideally functionalized synthons for the construction of polyoxygenated carboand heteropolycyclic skeleta (Figure 4).

15.1.2.2 Biosynthetic Implications of ortho-Quinols and ortho-Quinone Monoketals

Many natural products display structural motifs biosynthetically derived from ortho-quinol precursors, and some even feature ortho-quinol moieties in their final structural arrangement [1, 6]. Asatone (7) and related neolignans can be put forward as classic examples of complex natural products derived from cyclodimerization of oxidatively activated simple phenol precursors (Figure 5); biomimetic syntheses of 7 have accordingly been accomplished by anodic oxidation (Section 15.2.1) and by Pelter oxidation (Section 15.2.2) of the naturally occurring phenol 9 [34, 36].

Fig. 5

544 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 6

A series of new examples has recently emerged in the literature. Aquaticol (10), an unusual cuparane-type bis-sesquiterpene isolated from the medicinal plant Veronica anagallisaquatica, can be derived from a Diels–Alder cyclodimerization of the ortho-quinol 11, itself derived from an enantiospecific oxidative hydroxylation of ( )-d-cuparenol (12) (Figure 5) [37, 38]. Sorbicillinoid members of the vertinoid polyketide class of natural products also present the same chemical filiation inasmuch as they appear to originate biosynthetically from the sorbicillinol (13)-derived ortho-quinol 14 (Figure 6) (Section 15.3.3) [39, 40].

Scyphostatin (20) was isolated in 1997 as a potent inhibitor of neutral sphingomyerinase (N-SMase) [41, 42]. Synthetic studies on this therapeutically important molecule are currently in progress (Section 15.3.3) [43, 44]. Its structure features an epoxycyclohexenone moiety, which could conceivably be made through an oxidative dearomatization approach (Figure 7).

The humulones 23a–d have been known for many years, but they can still be considered as a topical family of natural products (Figure 8). Found in hop resins and brewing hops, these natural ortho-quinols aroused early interest because of their antibiotic and tuberculostatic properties. Oxidative dearomatizing hydroxylation of their phenolic parents 24a–d was used in their synthesis [1].

15.1 Introduction 545

Fig. 7

In addition to the aforementioned prominent biosynthetic implications of ortho-quinol derivatives, one can also propose their more discrete roles in the construction of natural products that feature motifs resulting from CaC and CaO phenolic couplings. Numerous alkaloids, lignans, and polyphenolic tannins can be envisaged as stemming from such coupling processes, traditionally said to derive from phenoxy radical combinations. Since twoelectron oxidation of phenols can produce ortho-quinone derivatives, including monoketals, that are capable of e ciently undergoing selective bond formation, the role of quinone monoketals in biosynthetic scenarios cannot be disregarded. It was the application of this concept in the natural products synthesis arena that allowed Feldman and co-workers to achieve striking advances in complex ellagitannin synthesis [45–50] (see Chapter 14). Generally speaking, the oxidative dearomatization of arenols to give ortho-quinols and orthoquinone monoketals, and their synthetic manipulation by cycloadditions (Section 15.3.1) or by nucleophilic attacks (Section 15.3.3) constitutes a tactic that is unequivocally better adapted to regioand stereoselective bond formation than synthetically disappointing phenoxy radical coupling processes [33, 47, 51].

15.1.2.3 Biomechanistic Implications of ortho-Quinols and ortho-Quinone Monoketals

Many reasons for studying the chemistry of ortho-quinol derivatives lie in their implications in the biomechanisms of naturally occurring compounds [6]. Their putative involvement in the metabolism of a-tocopherol (i.e. vitamin E) [52–54], and in the mode of action of the in-

Fig. 8

54615 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

tercalating antitumor agent N-2-methyl-9-hydroxyellipticinium acetate [55, 56], are just a couple of illustrations of their biological significance [57]. In these and other biomechanisms, in which one-electron oxidation of phenol units has often been claimed to be the central chemical event, two-electron oxidation alternatives leading to arenoxenium species and quinone derivatives, including monoketals, can again be invoked. In the same line of thought, one may be puzzled by the biological dichotomy apparently expressed by catecholic arenols (i.e. 2-hydroxyphenols) in natural systems. Many medicinal virtues of such arenols, well exemplified by numerous plant polyphenols, have been attributed to antioxidant-like, radical-scavenging activities due to the ease of one-electron oxidation to phenoxy radicals. Further oxidation gives rise to highly reactive ortho-quinones that are probably better known for their toxicity than for their medicinal activity [58]. As blocked ortho-quinones, orthoquinone monoketals might instead express an intermediate level of chemical reactivity better suited for the specific molecular interactions that underlie the therapeutic properties of natural phenols under oxidative conditions.

Study of the oxidation chemistry of exifone (25a) constitutes a perfect illustration of the above statement [59, 60]. This pyrogallol benzophenone (Adlone2) was commercialized in France for the treatment of cognitive disorders in the elderly, but it was withdrawn from the market because of its hepatotoxicity, which was attributed to its 3,4-quinone metabolite 26a. Fleury and co-workers found that blocking of 26 in the form of 1,4-benzoxazin-8-one orthoquinols such as 28 led to a twenty-fold decrease in toxicity, together with a five-fold activity enhancement (Figure 9) [59, 60].

15.2

Oxidative Dearomatization of ortho-Substituted Arenols

15.2.1

Anodic Oxidation

Anodic oxidation can be used to dearomatize 2-substituted arenols. The outcome of such an electrochemical transformation is extremely sensitive to the reaction conditions used,

Fig. 9

15.2 Oxidative Dearomatization of ortho-Substituted Arenols 547

Fig. 10

viz. the applied potentials, the reaction medium, and the type of substituents on the aromatic ring [35, 36, 61, 62]. Neutral conditions appear to favor the formation of cationic intermediates such as 6 through two-electron oxidation (Figure 3). These phenoxenium ions can be rapidly quenched in MeOH to furnish ortho-quinone monoketals such as 1c (Figure 3, R ¼ Nu ¼ OMe), but electrolysis of the same starting phenols in a basic medium at a lower oxidation potential predominantly gives dimers resulting from phenoxy radical coupling [35, 36, 62–64]. Such divergent behavior of arenols has been clearly delineated by Yamamura and co-workers, who showed, inter alia, that eugenol (29) is converted to the ortho-quinone monoketal 30 in 68 % yield when electrolyzed in MeOH at a constant current (90 mA, 0.56 mA cm 2, þ750–780 mV vs. SCE) using a platinum anode and LiClO4 as the supporting electrolyte (Figure 10) [36]. However, 29 dimerized to give the biaryl compound 31 in quantitative yield when the electrolysis was performed at a lower oxidation potential (21 mA, 1.5 mA cm 2, þ200–220 mV vs. SCE) in the presence of NaOH (Figure 10) [36].

The electrooxidative methoxylation of aryl methyl ethers in methanolic KOH is another electrochemically-induced dearomatizing technique that is worth recalling here for comparison purposes [6]. Its mechanistic unfolding is di erent from that of the oxidative nucleophilic substitution of free arenols (Figure 3) since it involves radical cation intermediates leading to quinone bisketals as primary electrochemical products. Their hydrolysis to give quinone monoketals has been well developed by Swenton and co-workers [5, 10, 11]. This method, referred to herein as the Swenton oxidation, has demonstrated its utility for preparing para-quinone monoketals, but ortho analogues are harder to produce in this way. Nevertheless, successful experimentation has been described for naphthoquinone monoketals, which are less reactive than benzoquinones because their 4,5-double bond is part of an aromatic ring (Figure 11). Of particular note is the regioselective acid-catalyzed formation of the linearly conjugated system 34, which is invariably favored over the formation of the cross-conjugated regioisomer 35. This preference has been attributed to di erences in charge stabilization of the cationic intermediates leading to these monoketals [10].

Electrooxidative activation is just one of the tools with which synthetic organic chemists can e ect the dearomatization of arenols and their ethers to give cyclohexa-2,4-dienone derivatives. Other methods are based on the utilization of oxidizing reagents that mediate the oxidative nucleophilic substitution of 2-substituted arenols in the presence of appropriate nucleophilic species. These reagents are for the most part all based on metals (Section 15.2.2) or halogens (Section 15.2.3).

548 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 11

15.2.2

Metal-Based Oxidative Activation

Metal-based reagents are often used to promote oneand two-electron oxidations of arenols. Radical-mediated CaO coupling reactions of aryloxy radicals can, of course, lead to orthoquinol derivatives, but the preparative value of such an approach is poor and essentially limited to intramolecular cases. For example, certain bis-phenols such as 36a–c have been spiroannulated in good yields by diradical CaO coupling under favorable one-electron oxidation regimes (Figure 12) [65–67].

Oxidative nucleophilic substitution is, however, a more versatile technique and a much better choice for target-oriented synthesis (Sections 15.1.1 and 15.1.2.2). In 1950, Wessely and co-workers examined the use of lead tetraacetate (LTA) in acetic acid to determine the structure of phenols and, in doing so, they developed their oxidative acetoxylation reaction, referred to herein as Wessely oxidation (Figure 13) [68–76]. If both an orthoand a paraposition are available to accommodate the entry of the acetoxy nucleophile, ortho products often predominate even when the ortho position is already occupied by a resident alkyl (e.g. 40 ! 41a/b) or alkoxy group (Figure 13) [69, 74].

Phenols with a free ortho position can also give rise to ortho-quinone diacetates such as 39a and 41b, in addition to or instead of ortho-quinol acetates such as 41a [1, 6]. Phenols bearing a 2-methoxy group are particularly prone to regioselective Wessely oxidation to give 6-

Fig. 12

15.2 Oxidative Dearomatization of ortho-Substituted Arenols 549

Fig. 13

acetoxy-6-methoxycyclohexa-2,4-dienone derivatives such as 43a/b, which can be isolated in good yields (Figure 14) [71, 76].

Thallium triacetate [77], and later, thallium trinitrate (TNN) in alcoholic solutions were found to mediate similar transformations of arenols into either paraor ortho-quinol derivatives. In particular, McKillop and collaborators extensively studied the use of TNN in MeOH to oxidize 4- and a few 2-substituted phenols; this reaction is referred to herein as the McKillop oxidation (Figure 14) [78, 79]. As expected from Andersson’s observations (Section 15.3.1), the 5-methoxylated ortho-quinone dimethyl monoketal 45a is stable, but the aldehyde 42a gave rise to the Diels–Alder dimer 46 under the conditions of the McKillop oxidation. Interestingly, the same aldehyde furnished a non-dimerizing ortho-quinol acetate 43a under the conditions of the Wessely oxidation (Figure 14). We made similar observations when comparing the oxidative methoxylation of 2-methoxyphenols with our oxidative acetoxylation (Section 15.2.3) [80], thus confirming the role of a 6-acetoxy group in the resistance of cyclohexa-2,4-dienones to undergo [4pþ2p] cyclodimerization (Section 15.3.1).

Many other metals have been used over the years to generate ortho-quinone monoketals and ortho-quinol derivatives [6], but the venerable Wessely oxidation remains to this day the most commonly used metal-based method. For the generation of ortho-quinols by selec-

Fig. 14

550 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 15

tive ortho-hydroxylation of 2-substituted arenols such as 47a–c, one should not forget the selenium-based Barton oxidation, in which oxygenation at the ortho position is ensured by intramolecular delivery from the diphenylseleninic anhydride following reaction of the latter with the phenolate anion (Figure 15) [81, 82]. Acid hydrolysis furnished ortho-quinols that spontaneously dimerized to give bicyclo[2.2.2]octenones 48a–c. Pyrolysis of such dimers can be used to regenerate the ortho-quinol parents in situ [180].

15.2.3

Halogen-Based Reagents

Various electrophilic and oxidizing halogen-based reagents such as bromine, N-bromosucci- nimide, ammonium tribromides, and polyvalent iodine species, have been used to generate ortho-quinol derivatives [6]. For example, the use of phenyltrimethylammonium tribromide is exemplified in Biali’s ongoing investigation of chemical modifications of calixarenes [83, 84]. This oxidizing system is used to generate various monoto tris(spirodienone) derivatives such as 50 from calix[n]arenes such as the spherand-type 49 (Figure 16).

The two halogen-based methods that continue to attract organic chemists the most for the oxidative activation of arenols are the Adler oxidation and the Pelter oxidation (vide infra);

Fig. 16

15.2 Oxidative Dearomatization of ortho-Substituted Arenols 551

Fig. 17

both methods rely on polyvalent iodine reagents [6]. The Adler oxidation is based on the use of sodium periodate (NaIO4) or periodic acid (HIO4) in water, aqueous alcohols, or acetic acid. Initially developed for the determination of phenolic hydroxyl groups in lignins, this oxidation can be used to perform ortho-oxygenation of 2-substituted arenols, thus furnishing ortho-quinols such as 52a/b or their ethers and esters, and it is particularly e cient in promoting the spirocyclization of 2-hydroxymethylphenols 51c/d (Figure 17) [85–96]. This intramolecular version of the Adler oxidation was recently used by Giannis and co-workers to synthesize active spiroepoxide analogues 54a–c of scyphostatin (20) (Figures 7 and 17) [43, 97, 98].

The other method relies on the use of a hypervalent iodine(III) reagent [99–104]. Following in the footsteps of Wessely, Siegel, and Antony [105] first compared the use of LTA to that of phenyliodonium(III) diacetate (PIDA) in acetic acid in performing the oxidative acetoxylation of various alkylphenols. Curiously, they only obtained para-quinol acetates with PIDA, whereas LTA gave ortho-quinol acetates from the same starting phenols. In 1988, Pelter and co-workers reinvestigated the use of PIDA to oxidize phenols in MeOH and thus introduced the PIDA-mediated oxidative methoxylation of phenols, referred to herein as the Pelter oxidation [106–108]. In 1987, Tamura [109] had reported the use of another less nucleophilic hypervalent iodine reagent, phenyliodonium(III) bis(trifluoroacetate) (PIFA), to promote the oxidative alkoxylation of arenols. Tamura’s and Pelter’s applications of this oxidative nucleophilic substitution of arenols were essentially limited to the production of paraquinone dialkyl monoketals, but numerous other workers have since successfully applied it to the preparation of various ortho-quinone monoketals (Section 15.3) [6]. The mechanistic details of the reaction are still under investigation, for they raise an interesting question embedded in the scheme of Figure 3, viz. does the reaction follow a concerted or a stepwise pathway? This was also a much debated question with regard to the Wessely and Adler oxidations that follow similar mechanisms [1, 6, 87, 110]. Both routes are driven by the reduc-

552 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 18

tive conversion of trivalent iodine into monovalent iodine and first imply the formation of the aryloxyiodonium(III) species 56a, which can then either undergo direct nucleophilic attack (route a) or dissociate to furnish a solvated phenoxenium cation 56b (route b) (Figure 18). Pelter and collaborators recently concluded that the process is most likely to proceed via a phenoxenium ion of type 56b (route b) on the basis of the following arguments: (1) the phenyliodonium(III) group is an extremely powerful nucleofuge with a leaving ability about 106 times that of the triflate group; (2) Mulliken charge semiempirical calculations of a series of 2- and 4-substituted phenoxenium cations predict the observed regiochemistry of the nucleophilic attack with accuracy (vide infra), and (3) reactions performed on 2- alkoxyphenols in a chiral environment displayed a complete lack of stereochemical control [108, 111]. As alluded to above, and demonstrated many times experimentally, the regiochemistry of the methanol attack (i.e., ortho-57 vs. para-58) depends more on the electronic nature of the ring substituents than on their steric demand.

Arenols bearing a strong electron-releasing group capable of stabilizing a positive charge at C-2 (e.g. X ¼ OMe) selectively undergo nucleophilic attack at C-2 regardless of the steric situation at C-4 (e.g. Y ¼ H, Me), as well as at C-6. Alkylphenols such as 2,3-dimethylphenol, 3,5-dimethylphenol, 2-benzyl- and 4-benzylphenol, and 2,4,6-tri-tert-butylphenol show a net preference for attack at C-4 [108].

The ortho-quinol acetates used in our own investigations have been prepared by a modification of the Pelter oxidation. Oxidative methoxylation of 2-methoxyarenols according to Pelter, as well as Tamura, Adler, and McKillop oxidations, a ords 6,6-dimethoxycyclohexa-2,4- dienones such as 60, which are particularly prone to dimerization through Diels–Alder cycloaddition (Figure 19). In agreement with Wessely’s early observations, 6-acetoxy analogues of the same starting arenols often do not spontaneously dimerize (Section 15.3.1) and hence can participate in other chemistries [80, 112]. Our oxidative acetoxylation is conveniently performed by simply treating a solution of 2-methoxyarenols such as 59 with PIDA in CH2Cl2 to generate non-dimerizing ortho-quinol acetates such as 62 in high yield (Figure