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

14.6 Control of Atropisomerism 533

for good asymmetric induction. These data show that the N-ethylaniline derivative 221l is the best candidate. The authors have proposed a mechanistic explanation for the observed asymmetric induction that involves the formation of a diketone/copper diamine complex 223. Chirality transfer then depends on minimizing unfavorable steric interactions between the appendages of the chiral auxiliaries (Scheme 58).

Scheme 58. Mechanistic speculation on the copper/chiral pyrrolidinemediated oxidative dimerization of 68f.

In the same vein, Koslowski and co-workers have published a study using chiral 1,5- diazadecalin complex 225, a species that directs binaphthol formation with excellent enantioselectivity [149]. The use of CuI or Cu(OTf ) as a copper source in this procedure contributes to the excellent yields (85 %) and high enantiomeric excesses (@90 %) (Scheme 59). Substituents on the nitrogens of 225 or changes in the copper source resulted in lower yields and/or lower enantioselectivities. Other naphthol substrates have been subjected to these conditions, but both the yields and enantioselectivities were diminished, showing the importance of the ester moiety with regard to the e ciency of the reaction (Table 40).

Scheme 59. The e ect of the copper source on the enantioselectivity of the dimerization of 68f, as mediated by chiral amine 225.

The authors have initiated a mechanistic inquiry into this reaction, and unlike Nakajima, they propose that AraAr bond formation proceeds through a radical addition of one aryl moiety with its unperturbed partner. This speculation extended to a model explaining the

53414 Oxidative Aryl-Coupling Reactions in Synthesis

Tab. 40. Substituent e ects on the enantioselective oxidative dimerization of 2-naphthol derivatives mediated by copper salts and chiral amine 225.

Substrate	Cu Source	Solvent	Yield (%)	ee (%)a
68a	CuCl	CH2Cl2	80b	13
68t	CuCl	CH3CN/(ClCH2)2	NR	ND
68r	CuCl	(ClCH2)2	77c	38
68u	CuI	CH3CN/(ClCH2)2	79	90

a Measured by chiral HPLC; b Using air at rt for 5 d.

c Using air at rt for 24 h.

sense of stereoselection (Scheme 60). Complex 226 favors approach of the second unit of 68f from the less hindered face of the Cu-complexed aryl radical, leading preferentially to the (R)-biaryl product 69f.

Scheme 60. Mechanistic speculation on the origins of enantioselection upon oxidative dimerization of 68f in the copper/225 system.

14.7

Conclusion

From the recent work published on oxidative arylic coupling reactions, it is clear that at least some of the issues highlighted in the introduction have found solutions. Studies detailing either the chemo-, regio-, or stereoselectivity of biaryl bond formation show that by using the tools of organic and inorganic chemistry, it is now possible to achieve a biomimetic approach to biaryl synthesis in a more e cient way. Further progress should lead to the development of even more selective and general methods that more closely approximate the success with which nature fashions the link between two aromatic units.

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539

15

Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals – A Useful Tactic in Organic Synthesis

Ste´phane Quideau

Abstract

The oxidative activation of arenes is a powerful and versatile synthetic tactic that enables dearomatization to give useful synthons. Central to this chemistry are hydroxylated arenes or arenols, the phenolic functions of which can be exploited to facilitate the dearomatizing process by two-electron oxidation. Suitably substituted arenols can hence be converted, with the help of oxygenor carbon-based nucleophiles, into ortho-quinone monoketals and ortho-quinols. These 6-oxocyclohexa-2,4-dienones are ideally functionalized for the construction of many complex and polyoxygenated natural product architectures. Today, the inherent and multiple reactivity of arenol-derived ortho-quinone monoketals and orthoquinols species is finding numerous and, in many cases, biomimetic applications in modern organic synthesis.

15.1

Introduction

ortho-Quinols and ortho-quinone monoketals are cyclohexa-2,4-dienone derivatives 1a–d bearing one or two singly-bonded oxygen functions at their tetrahedral 6-position (Figure 1). Strictly speaking, ortho-quinols are 6-hydroxy-substituted cyclohexa-2,4-dienones 1b, while derivatives 1c/d of their 6,6-dihydroxy variants can be viewed as derivatives of ortho-quinone monohydrates 1e. ortho-Quinone monoketals are diether derivatives 1c (R ¼ alkyl) of these monohydrates.

An abundance of information on the various preparation modes and reactivity features of all types of ortho-quinol derivatives can be found in the literature on the chemistry of cyclohexadienones [1, 2]. A few review articles have also been dedicated to the specificities of their chemistry and uses in organic synthesis [3–6]. This chapter specifically addresses the oxidative dearomatization of hydroxylated arenes (i.e. arenols) as a versatile and powerful tactic for the preparation of ortho-quinol derivatives, utilization of which continues to attract more and more adepts engaged in the various facets of modern organic and bioorganic synthesis. This first section is intended to aid the reader in putting the chemistry of ortho-quinol derivatives in their general organic and bioorganic context (Section 15.1). A brief overview of today’s most commonly employed oxidative methods for dearomatizing arenols (Section

Modern Arene Chemistry. Edited by Didier Astruc

Copyright 8 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30489-4

540 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 1

15.2) is followed by a presentation of contemporary applications of ortho-quinols and orthoquinone monoketals in natural products synthesis (Section 15.3).

15.1.1

How to Prepare ortho-Quinols and ortho-Quinone Monoketals

ortho-Quinone monoketals are traditionally considered and often used in synthesis as monoprotected, ‘‘blocked’’ or ‘‘masked’’ forms of ortho-quinones. Direct nucleophilic addition to one carbonyl function of ortho-quinones 2a or cycloaddition with ortho-quinone methides 2b can, in principle, lead to all types of ortho-quinol derivatives (Figure 2), but these addition processes are only of preparative value with the most stable ortho-quinones [7–9]. Partial hydrolysis of ortho-quinone bisketals to monoketals can constitute an alternative methodology (Section 15.2.1), but an adequate level of regioselectivity for preparative purposes is difficult to achieve and the method is again limited to the most stable species [5, 10, 11]. Hence, considerations of all the available possibilities inevitably point to the direct dearomatization of suitably substituted arenols as the most promising route to ortho-quinone monoketals and ortho-quinols.

Reductive alkylation of 2-methoxybenzoates [12–14], carbon alkylation of the alkali metal salts of arenols [15–19], and sigmatropic rearrangements such as the Claisen reaction of allyl

Fig. 2

15.1 Introduction 541

Fig. 3

and propargyl aryl ethers [17, 20] and the Mo at–Olofson reaction of arenoxysulfonium ylides [21–26] are, when directed toward substituted positions, dearomatizing reactions that o er direct routes to cyclohexa-2,4-dienones. Their implementation in the preparation of ortho-quinol derivatives has remained limited [27]. Nevertheless, other avenues are available for arenols because their electron-richness makes them ideal candidates for oxidative dearomatization processes [28].

Arenols 4 and their conjugate arenolate bases are both (a) oxygenand (b) carbon-based nucleophiles, which react with a wide range of electrophilic reagents (Figure 3). Their reactions with soft electrophiles can lead directly to cyclohexadienone derivatives; this is the case, for example, with electrophilic halogenation, which e ectively occurs at the electronrich carbon centers (4 ! 5b) [29, 30].

Reactions with harder electrophilic reagents do not usually mediate immediate dearomatization, since the electrophilic attack occurs predominantly at the oxygen center (4 ! 5a). However, when these reagents are equipped with a core atom or a chemical function whose nucleofugality can be turned on, subsequent dearomatizing bond-forming processes can be achieved with (5a ! 1a–d) or without (5a ! 6 ! 1a–d) the help of an appropriate elec- tron-displacing species (Nu). As alluded to above, the key to an e cient preparation of orthoquinols and ortho-quinone monoketals does not simply reside in the ability to dearomatize the starting arenol, but in the capacity to control the attack of the electron-displacing species at the substituted 2-position. A regiocontrolling device is necessary to prevent competition from para attack, which would lead to cyclohexa-2,5-dienone systems. One can envisage several solutions for this requisite. Non-oxidative pericyclic reactions, such as the Claisen sigmatropic [3,3] rearrangement, are mechanistically well suited for imposing both dearomatization and ortho-selective bond formation [27]. Another solution requires the presence of an electron-releasing group at the substituted 2-position of the starting arenol (e.g. R ¼ alkoxy).

54215 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Such a substituent often su ces to ensure regioselective introduction of an electron-rich species at this position, even when it is the most hindered locus (Figure 3). This is particularly appropriate for reactions following an ionic-type mechanism with intermolecular delivery of the nucleophile (Nu). Thus, 2-alkylarenols 4 can be transformed by oxidative nucleophilic substitution, through intermediates 5 or 6, into 6-carbo-6-oxocyclohexa-2,4-dienone ortho-quinol derivatives using an oxygen-based nucleophile, whereas 2-alkoxyarenols can similarly react with either carbonor oxygen-based nucleophiles to furnish either 6-carbo-6- oxoor 6,6-dioxocyclohexa-2,4-dienone derivatives 1a–d.

15.1.2

Why Bother with ortho-Quinols and ortho-Quinone Monoketals?

15.1.2.1 Synthetic Reactivity of ortho-Quinols and ortho-Quinone Monoketals ortho-Quinone monoketal and ortho-quinol cyclohexa-2,4-dienones 1a–d have been less utilized in synthesis than their para cross-conjugated cyclohexa-2,5-dienone counterparts 1g (Figure 1). The ortho and para quinonoids do share several reactivity features, but the chemistry of ortho species is often more capricious and demands some special considerations. The di erence between the linear and the experimentally more stable cross-conjugated systems cannot alone account for the reactivity di erences observed between ortho and para compounds [2, 31]. ortho-Quinone monoketals and ortho-quinols do exhibit additional reactivity features due to the vicinal positioning of their oxygen functions. This arrangement of electronegative oxygen atoms weakens the bearing C1 aC6 bond, and the dienone system is predisposed toward dimerization as it can behave both as a dienic and as a dienophilic partner in Diels–Alder cycloaddition. The preparation conditions and substitution pattern must be carefully chosen in order to avoid premature ring-opening, dimerization, or rearomatization events (Section 15.3). ortho-Quinone monoketals are masked forms of ortho-quinones in which one carbonyl unit is protected as a ketal function. The two vicinal oxygen functions and the two conjugated carbon–carbon double bonds are thus clearly di erentiated from one another (see 1c, Figure 1). In comparison to the reactivity of ortho-quinones, that of the linearly conjugated enone system of their monoketals is attenuated for easier control in synthetic manipulations. Another particularly interesting feature of these synthons is their electrophilic reactivity. These quinone ketals are indeed susceptible to direct and conjugate attacks by various types of nucleophiles (Section 15.3.3) [6], in contrast to their aromatic parents, which are more readily transformed through electrophilic aromatic substitution. orthoQuinone monoketals can be viewed as masked aryl cation intermediates (see 1f, Figure 1), allowing synthetic operations formally equivalent to an otherwise non-trivial nucleophilic aromatic substitution of their parent arenes. ortho-Quinone monoketals do share this reactivity feature with their para counterparts [32, 33], but substitution is conceivable at the five sp2 ring carbons depending on the type of nucleophilic attack (see 1f, Figure 1). Conversion into quinone ketals constitutes a means of rendering arenols amenable to further ring transformations, including carbon–carbon bond-forming events by nucleophilic attack. A last but not least feature of ortho-quinol derivatives paradoxically resides in the structural motif that is the principal cause of the complications encountered in their synthetic uses, that is their adjacent oxygenated ring carbons. It is not always trivial to introduce such functionalities on a pre-established cyclic hydrocarbon network. The various possibilities