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Chemical Oxidative CC Bond Formation

Koji Hirano

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka, 565-0871, Japan

1.1 Introduction

Efficient and selective CC bond formation has been one of the longstanding central topics in synthetic organic chemistry because it is the indispensable methodology for the construction of organic skeletons. In general, an overall redox-neutral process using a carbon electrophile and a carbon nucleophile is employed owing to preferable polarity of two coupling fragments (Scheme 1.1a). On the other hand, the CC bond-forming reaction with two different nucleophiles in the presence of suitable chemical oxidants (chemical oxidative CC bond formation) can provide a good alternative to the above overall redox-neutral process particularly when the corresponding carbon electrophile is difficult to prepare (Scheme 1.1b). Moreover, the ultimate direct CC bond-forming reaction of two simple CH fragments without any stoichiometric preactivations (e.g. halogenation and metalation) is also theoretically possible. Additionally, the oxidative strategy often enables otherwise challenging CC bond formations with uniquely high chemo-, regio-, and stereoselectivity. Such complementary features have prompted synthetic chemists to develop numerous strategies for the oxidative CC bond formation. In this chapter, the recently developed oxidative CC bond formations are categorized according to the carbon hybridization state of the coupling fragments, and their scope, limitations, and mechanisms are briefly summarized.

1.2 Oxidative Aryl-Alkenyl Bond Formation

Since the aryl-alkenyl p-conjugation frequently occurs in many pharmaceuticals, biologically active compounds, and functional materials, the aromatic Csp2-alkenyl Csp2 bond formation has been widely explored by many synthetic chemists. The most famous and standard approach is the Mizoroki-Heck reaction with aryl halides and alkenes, in conjunction with a suitable palladium catalyst and base [1, 2]. This reaction is the overall redox-neutral process containing oxidative addition and reductive elimination in the catalytic cycle (Scheme 1.2). Although numerous efforts for development of palladium catalysts and their supporting ligands have allowed various aryl halides, including unactivated aryl chlorides, to be adopted, the alkene fragments are still largely limited to electronically activated a,ß-unsaturated carbonyls and styrenes. Moreover, the preparation of the corresponding aryl halides from the parent arenes (stoichiometric halogenation) is an additional drawback to be addressed. The chemical oxidative coupling approach can be a good solution to the above problems inherent in the classical Mizoroki-Heck reaction. In this section, the oxidative Mizoroki-Heck reaction with arylmetal reagents as aromatic Csp2 fragments and direct aromatic Csp2-alkenyl Csp2 coupling (Fujiwara-Moritani reaction) are mainly presented.

Scheme 1.1 Overall redox-neutral CC bond formation (a) vs. oxidative CC bond formation (b).

Scheme 1.2 General mechanism of palladium-catalyzed overall redox-neutral Mizoroki-Heck reaction of aryl halides with alkenes.

1.2.1 Oxidative Mizoroki-Heck Reaction with Arylmetal Reagents

As mentioned in the above introduction part, the redox-neutral Mizoroki-Heck reaction still suffers from the relatively narrow scope of alkenes. The oxidative Mizoroki-Heck reaction can address the problem probably because of the formation of more reactive, coordinately unsaturated arylpalladium species through transmetalation between PdX2 and arylmetal reagents rather than the oxidative addition of aryl halides (Scheme 1.3).

In 2008, White and coworkers reported the Pd(OAc)2/bis(sulfoxide) catalyst for the oxidative Mizoroki-Heck reaction with arylboronic acids [3]. In the presence of a benzoquinone (BQ) terminal oxidant, unactivated aliphatic terminal alkenes undergo the Mizoroki-Heck-type arylation (Scheme 1.4). Milder reaction conditions are compatible with somewhat labile point chirality derived from a-amino acids as well as functional groups such as a free carboxylic acid. The regioselectivity (internal/terminal) is also well controlled in most cases, but the olefinic position of product (styrenyl/allylic) is highly dependent on the substrate structure and its control still remains a challenging task. A related Pd(IiPr)(OTs)2 catalysis was reported by Sigman and Werner in 2010 (Scheme 1.5): the beneficial point is the use of molecular oxygen as an terminal oxidant, where Cu(OTf)2 is added as a co-oxidant [4]. Also in this case, the reaction proceeds without erosion-of-point chirality. Particularly notable is the high styrenyl/allylic selectivity as well as internal/terminal selectivity in almost all cases.

Scheme 1.3 General mechanism of palladium-catalyzed oxidative Mizoroki-Heck reaction of arylmetal reagents with alkenes.

Scheme 1.4 Pd(OAc)2/bis(sulfoxide)-catalyzed oxidative Mizoroki-Heck reaction of unactivated terminal alkenes. BQ = benzoquinone.

While not aryl-alkenyl bond formation, the group of Sigman subsequently developed the enantioselective oxidative Mizoroki-Heck reaction of internal alkenyl alcohols by using the chiral pyridine-oxazoline hybrid ligand, PyrOx (Scheme 1.6) [5]. The key to success is the redox-relay process: the alkene is migrated toward the alcohol via an iterative ß-H elimination and insertion, and finally converted to the carbonyl functionality by the formal oxidation event. As a result, the regioselective and enantioselective remote arylation of carbonyl compound is possible. This strategy is also applicable to alkenyl aldehydes and enelactams to deliver the remotely arylated enantioenriched a,ß-unsaturated aldehydes and a,ß-unsaturated d-lactams, respectively (Scheme 1.7) [6].

Scheme 1.5 Pd(IiPr)(OTs)-catalyzed oxidative Mizoroki-Heck reaction of unactivated terminal alkenes. Ts = p-toluenesulfonyl, Tf = trifluoromethanesulfonyl.

Scheme 1.6 Palladium-catalyzed enantioselective redox-relay oxidative Mizoroki-Heck reaction of internal alkenyl alcohols and its redox-relay mechanism.

Source: Modified from Mei et al. [5].

1.2.2 Direct Oxidative Mizoroki-Heck Reaction with Arene C-Hs (Fujiwara-Moritani Reaction)

One of the biggest drawbacks in the above Mizoroki-Heck reaction with aryl halides or aryl boronic acids is their tedious preparation from the parent simple arenes. In 1969, Fujiwara et al. reported seminal work on the palladium-catalyzed coupling reaction of simple arenes and alkenes, in the presence of Cu(OAc)2 or AgOAc terminal oxidant, to form the corresponding alkenylarenes directly (Scheme 1.8) [7]. This protocol received significant attention from the viewpoint of organic synthesis because the arene C-H and alkene C-H are directly cross-coupled without any preactivation steps of both starting substrates. Since then, such a transition-metal-promoted "C-H activation" strategy has greatly and rapidly progressed by efforts of many research groups, and the Fujiwara-Moritani reaction is now a powerful synthetic tool for the construction of aryl-alkenyl p-conjugation. However, the disadvantage of early studies on the Fujiwara-Moritani reaction is the inevitable use of excess arene substrates (in many cases solvent amount).

Scheme 1.7 Palladium-catalyzed enantioselective redox-relay oxidative Mizoroki-Heck reaction of alkenyl aldehydes and enelactams.

Source: Modified from Zhang et al. [6a], Yuan and Sigman [6b].

Scheme 1.8 General reaction scheme and mechanism of palladium-catalyzed Fujiwara-Moritani reaction.

Source: Modified from Fujiwara et al. [7a], Jia et al. [7b].

In this context, Yu and coworkers reported the Fujiwara-Moritani reaction with the simple arene as the limiting reagent (1.0?equiv) under Rh(II)/PCy3/Cu(TFA)2/V2O5 oxidative catalysis (Scheme 1.9) [8]. Although the exact role of PCy3 ligand as well as copper and vanadium combined oxidation system still remains to be elucidated, the reaction proceeds smoothly even in the presence of 1?equiv of simple arenes. More recently, the same research group developed the well-defined and robust Pd(OAc)2/hydroxypyridine catalyst for the reaction with much broader simple arenes, including benzene derivatives, heteroaromatics, and even more challenging complex drug-like molecules (Scheme 1.10) [9]. Also in this case, the arene substrate works well even at 1?equiv loading. The well-designed hydroxypyridine ligand is key to success, and its pivotal role in the...