Oxidative coupling/cyclization reaction

The oxidative coupling/cyclization reaction is the intramolecular union of two arenes with formal loss of H2 promoted by a Pd(II) species (typically Pd(OAc)2). In an early example of this transformation, treatment of diphenylamines 1 with Pd(OAc)2 in acetic acid yielded carbazoles 2 [8]. The role of acetic acid in such oxidative cyclization processes is to protonate one of the acetate ligands, which affords a more electrophilic... 

Many anodic oxidations involve an ECE pathway. For example, the neurotransmitter epinephrine can be oxidized to its quinone, which proceeds via cyclization to leukoadrenochrome. The latter can rapidly undergo electron transfer to form adrenochrome (5). The electrochemical oxidation of aniline is another classical example of an ECE pathway (6). The cation radical thus formed rapidly undergoes a dimerization reaction to yield an easily oxidized p-aminodiphenylamine product. Another example (of industrial relevance) is the reductive coupling of activated olefins to yield a radical anion, which reacts with the parent olefin to give a reducible dimer (7). If the chemical step is very fast (in comparison to the electron-transfer process), the system will behave as an EE mechanism (of two successive charge-transfer steps). Table 2-1 summarizes common electrochemical mechanisms involving coupled chemical reactions. Powerful cyclic voltammetric computational simulators, exploring the behavior of virtually any user-specific mechanism, have... 

The reductive coupling/silylation reaction was extended to more complicated polyenes, such as the triene-substituted cyclopentanol 73, which cyclizes to provide 74 with a 72% yield and 6 1 dr after oxidation (Eq. 10) [44], The reaction is chemoselective the initial insertion occurs into the allyl substituent, which then inserts into the less hindered of the two remaining olefins, leaving the most hindered alkene unreacted. 

As expected, reaction of A-aroylpyrroles 28 in the absence of added arene affords the bipyrroles 29 or cyclized product 30 [32, 33], Bipyrrole 31 was prepared via this oxidative coupling reaction [32],... 

Most of the early applications of palladium to indole chemistry involved oxidative coupling or cyclization using stoichiometric Pd(II). Akermark first reported the efficient oxidative coupling of diphenyl amines to carbazoles 37 with Pd(OAc)2 in refluxing acetic acid [45]. The reaction is applicable to several ring-substituted carbazoles (Br, Cl, OMe, Me, NO2), and 20 years later Akermark and colleagues made this reaction catalytic in the conversion of arylaminoquinones 38 to carbazole-l,4-quinones 39 [46]. This oxidative cyclization is particularly useful for the synthesis of benzocarbazole-6,11-quinones (e.g., 40). 

Miki effected Pd-catalyzed cross-coupling between dimethyl 7-bromoindole-2,3-dicarboxylate and both tributylvinyltin and tributyl-1-ethoxyvinyltin to yield the expected 7-vinylindoles [197]. Hydrolysis of the crude reaction product from using tributyl-1-ethoxyvinyltin gave the 7-acetylindole. Sakamoto used dibromide 192, which was prepared by acylation of 7-bromoindole, in a very concise and efficient synthesis of hippadine [36]. The overall yield from commercial materials is 39%. Somewhat earlier, Grigg employed the same strategy to craft hippadine from the diiodoindoline version of 192 using similar cyclization reaction conditions ((Me3Sn)2/Pd(OAc)2), followed by DDQ oxidation (90%) [198]. 

In conclusion, the fantastically diverse chemistry of indole has been significantly enriched by palladium-catalyzed reactions. The accessibility of all of the possible halogenated indoles and several indolyl triflates has resulted in a wealth of synthetic applications as witnessed by the length of this chapter. In addition to the standard Pd-catalyzed reactions such as Negishi, Suzuki, Heck, Stille and Sonogashira, which have had great success in indole chemistry, oxidative coupling and cyclization are powerful routes to a variety of carbazoles, carbolines, indolocarbazoles, and other fused indoles. 

In Pd(II)-catalyzed reactions targeting cydization/oxidative coupling products, the butenolides often were formed as side-products, but only in low yield [81, 82]. The cyclization of a series of 1,2-allenylcarboxylic adds 120 to butenolides 121 was acomplished with 4mol% of CuCl, a comparable cheap catalyst, in methanol (Scheme 15.36) [83]. 

Since enol silyl ethers are readily accessible by a number of methods in a regioselective manner and since the trialkylsilyl moiety as a potential cationic leaving group facilitates the termination of a cyclization sequence, unsaturated 1-trialkylsilyloxy-1-alkenes represent very promising substrates for radical-cation cyclization reactions. Several methods have been reported on the synthesis of 1,4-diketones by intermolecular oxidative coupling of enol silyl ethers with Cu(II) [76, 77], Ce(IV) [78], Pb(IV) [79], Ag(I) [80] V(V) [81] or iodosoben-zene/BFa-etherate [82] as oxidants without further oxidation of the products. 

In all of the cyclization reactions, Moeller has found only a small difference between the use of alkyl and silyl enol ethers. Since both styrenes and enol ethers have similar oxidation potentials, even the styrene moiety could function as the initiator for oxidative cyclization reactions. The anodic oxidation of simple styrene type precursors leads to low yields of cyclized products so that enol ether moiety seems to be the more efficient initiator for intramolecular anodic coupling reactions [93]. 

Intermolecular anodic cyclizations often involve initial coupling of radical-cations followed by a chemical cyclization reaction. An alternative is cyclization by internal nucleophilic addition of some reactant to an intermediate derived by anodic oxidation. 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

Morphine is biosynthesized from norreticuline through intramolecular oxidative coupling of the electron-rich aromatic rings, transformation that is difficult to achieve with chemical oxidizing agents. The most convenient synthesis, illustrated in Scheme 23, consists of partial saturation of the aromatic ring by the Birch reaction followed by an acid-Catalyzed Grewe-type cyclization to form the required tetracyclic skeleton (48). 

There have also been several reports of the cyclization of diynes with amines under the influence of copper(I) chloride (equation 73) (65CB98, 70KGS125, 72TL3487). This is a potentially useful reaction for symmetrically substituted pyrroles, since symmetrical diynes can be obtained by oxidative coupling of alkynes. 

Cyclization reactions can be conducted by methods that remove cyclic radicals by selective radi-cal/radical coupling, oxidation, or reduction. The usual selectivity concerns are operative initial radicals must cyclize, and cyclic radicals must be productively removed. 

Many cyclization reactions via formation of metallacycles from alkynes and alkenes are known. Formally these reactions can be considered as oxidative cyclization (coupling) involving oxidation of the central metals. Although confusing, they are also called the reductive cyclization, because alkynes and alkenes are reduced to alkenes and alkanes by the metallacycle formation. Three basic patterns for the intermolecular oxidative coupling to give the metallacyclopentane 94, metallacyclopentene 95 and metallacyclopentadiene 96 are known. (For simplicity only ethylene and acetylene are used. The reaction can be extended to substituted alkenes and alkynes too). Formation of these metallacycles is not a one-step process, and is understood by initial formation of an tj2 complex, or metallacyclopropene 99, followed by insertion of the alkyne or alkene to generate the metallacycles 94-96, 100 and 101-103 (Scheme 7.1). 

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