Catellani reactions

The palladium catalysed sequential alkylation-alkenylation of 5-iodoquinoline leads to the formation of the quinolooxepin ring system (5.20.), The process, closely related to the Catellani reaction,19 runs through an ort/zo-alkylation - Heck reaction sequence. The preparation of a series of benzoxepines has also been achieved in this manner, starting from such iodobenzene derivatives, where one of the or/7 o-positions was blocked by substitution.20... 

Scheme 2 Generalized reaction mechanism of the Catellani reaction...

The first step of the Catellani reaction involves the oxidative addition of a palladium(O) species into an aryl halide bond to generate an arylpalladium(II) species [5, 6], Catellani s initial reports employed the pre-formed phenyl-norbomylpalladium(II) dimer [7] (PNP dimer) (10, Fig. 1) as a pre-catalyst which could directly enter the catalytic cycle and generate a palladium(O) species after one catalyst turnover [4],... 

Once palladacycle formation has occurred, a number of possibilities exist for its reaction. A side product often seen in Catellani reactions is cyclobutane (21) formation resulting from a reductive elimination of the palladacycle (Scheme 7). In fact, under optimized conditions it is possible to achieve good yields of the cyclobutane products [26], However, the focus of this section will be to examine the reaction of the palladacycle with alkyl and aryl halides. 

The final step of the Catellani reaction involves the reaction of an ortho, ortho -disubstituted arylpalladium(II) species such as 8 where palladium is present at the ipso position. This arylpalladium(II) species can be subjected to a variety of reactions in order to terminate the reaction, and re-enter the catalytic cycle. These reactions and their applications to synthesis will be discussed in the subsequent sections. 

Scheme 15 Generalized Catellani reaction sequence and key reactive intermediates...

While optimizing the reaction conditions, Lautens found that cyanation took place with many intermediates in the Catellani reaction sequence, as all non-palladacycle palladium(II) species in the sequence underwent cyanation (Scheme 29). Through optimization experiments, the target product could be obtained in good to excellent yields from either tethered or intermolecular alkyl bromides and iodides (Scheme 30). As alkyl chlorides are more widely commercially available, lower in cost, and more stable than the corresponding alkyl bromides or iodides, Lautens reported a method to incorporate alkyl chlorides as reaction partners. This study eventually led to the use of benzyl chlorides, a-chloroesters, and a-chloroamides as coupling partners, which were far too reactive as the analogous bromides or iodides. 

Lautens has applied the direct arylation strategy to enable the coupling of a variety of heteroaromatics as the terminal step of the Catellani reaction sequence. A variety of /V-bromoalkyl nitrogen heterocycles including indoles [77-79], azaindoles [78], pyrroles [78, 80], pyrazoles [80, 81], and indazoles [81] have successfully undergone an ortfto-alkylation/direct arylation reaction to afford a wide variety of heterocyclic products in good to excellent yields (Scheme 33). The reaction conditions... 

While Ferraccioli, Catellani, and Lautens had success in developing ortho-functionalization/amination reactions, there are still improvements to be made in this area of research. To date, there have been no reports of an intermolecular animation reaction as part of the Catellani reaction sequence. Although challenging, this reaction would allow access to interesting polysubstituted IV-arylamines, and should be a goal of future research. 

The hydrogenolysis of arylpalladium(II) species is a widely used reaction for the dehydrohalogenation of arenes. In combination with the Catellani reaction sequence, hydrogenolysis of a complex of type 36 leads to a meto-substituted arene product. In Catellani s stoichiometric investigations of the orf/io-alkylation [43] and orf/to-arylation [88, 89] of the PNP dimer, H2 or NaBH4 were used for reduction of the resultant o,o -disubstituted arylpalladium(II) species (Scheme 38). 

The use of norbomene as a scaffold for aromatic C-H functionalization, a process we dubbed the Catellani Reaction, is a useful and mechanistically interesting method for the polyfunctionalization of aromatic molecules. Through the development and study of palladium complexes with norbomene, a powerful synthetic method has emerged which has been proven useful primarily through the research efforts of Catellani and Lautens. Future studies in this area should focus on expanding the already wide variety of products available, and to develop and/or utilize new reactions which can be performed on either the palladacycle intermediate or terminal arylpalladium(II) species. 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

The Catellani Reactions using Norbomene as a Template for ortAo-Substitution... 

As the initial discovery of this reaction, tremendous progress has been made in unlocking its synthetic utility. Reviews on the mechanistic and synthetic aspects of the Catellani reaction have been written by the Lautens group [27, 28] and the Catellani group [29, 30], This section focuses on the recent developments in this area since 2009. 

The proposed mechanism involves the initial formation of the palladacycle 118 via the Catellani reaction sequence between the aryl iodide and norbornene (Scheme 3.32). Coordination of the aziridine 125 followed by oxidative addition of the N-C single bond by Pd leads to the intermediate 129. The fission of N-C single bond is commonly observed in transition-metal-catalyzed reactions with aziridines. Chemoselective C-C bond formation gives 130, which on decarbopalladation affords palladacycle 131 and extrudes norbornene. Reductive elimination furnishes... 

The reaction of norbornene with iodobenzene or bromobenzene in the presence of [Pd(PPh3)4] as the catalyst leads to pentacycle 83 (Scheme 11.29) [6, 31, 90-94], This process is known as the Catellani reaction. The parent transformation involves an insertion of the phenylpalladium(II) complex into the double bond of norbornene to give (Ti -phenyl)norbornyl palladium(II) complex 84, which then undergoes intramolecular paUadation to form 85. Further reaction of this paUadacycle with iodobenzene leads to 83. Biphenyl, tetracycle 86, and more complex derivatives 87 and 88, have also been isolated in this reaction [90, 93c, 94], Benzocyclobutenes... 

There are always exceptions, a multi-bond forming example of which is the Catellani reaction, see ... 

Scheme 19.10 Palladium-catalyzed C-H alkylation via the Catellani reaction.

---