Palladium Catellani reaction

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... 

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],... 

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. 

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. 

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 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... 

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

The total synthesis of (+)-linoxepin 76 was completed by use of a Eleck reaction to form the oxepine ring in the last step (13AGE5305). Notably, a palladium-catalyzed Catellani reaction was used to prepare precursor 74 and this is the first time that this reaction has been used in the synthesis of a complex natural product. 

The most common application of transition metals in organic synthesis, however, is in cross-coupling reactions. Copper plays an important role in this field, as does palladium. An interesting example of the latter was recently published by the group of Tautens [39]. They performed a Catellani reaction that combined aryl iodide 138, alkyl iodide 139, and tert-butyl acrylate 140 under formation of linoxepin precursor 148. The precursor was then transformed to the desired product under optimized conditions in a three-step sequence that harbored another Heck-type coupling (Scheme 14.18). 

Based on a transformation described by Catellani and coworkers [61], the Lautens group [62] developed a three-component domino reaction catalyzed by palladium for the synthesis of benzo annulated oxacycles 6/1-114 (Scheme 6/1.30). As substrates, these authors used a m-iodoaryl iodoalkyl ether 6/1-113, an alkene substi-... 

Since the first X-ray crystal structure of a palladium(IV) complex was published by Canty [29, 30], a number of groups have undertaken the study of these relatively uncommon intermediates. In an effort to elucidate the role of palladium(IV) and palladium(II) intermediates in the reaction mechanism, Catellani prepared a number of isolable palladacycle complexes in both the (II) and (IV) oxidation states using 1,10-phenanthroline as the ligand (Scheme 8) [31]. Catellani successfully isolated palladium(IV) palladacycle 22, which was subsequently characterized by... 

Under the reaction conditions, phenylacetylene was found to be a much more reactive coupling partner than arylboronic acids in the analogous Suzuki-Miyaura coupling, as in addition to the desired product (38), alkynylation and further addition reactions occurred with a variety of transient palladium(II) species (Scheme 27). Despite these undesired side reactions, Catellani was able to fine-tune the reaction conditions to form predominantly product 38 or 39. The formation of the desired product 38 (and suppression of product 39) is promoted by acceleration of norbomene carbopalladation by KOAc [47] and by using an excess of alkyl halide affording several structurally similar unsymmetrical alkyne products in good yields (Scheme 28). 

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

Catellani and coworkers [26] reported a remarkable palladium-catalyzed/norbor-nene-mediated domino reaction where aryl iodides were alkylated at the ortho positions followed by a Heck reaction to afford the 0,0-dialkylvinylarenes 81 (Scheme 3.21). Multiple bonds are formed in a single reaction from simple starting materials. 

An intriguing variation of Catellani s reaction accomplished a selective crosscoupling of two different aryl halides and methyl acrylate (Scheme 5) [8,9], It was suggested that a difference in the rates of oxidative additions of the two differentially substituted aryl halides with the palladium(0) and the palladium(ll) complexes accounted for the reported reactivity. However, the mechanistic ratiraiale invoking palladium(IV) intermediates have not been supported by either an experiment or computations. 

M. Catellani and G. P. Chiusoli, J. Organomet. Chem., 1983, 250, 509-515. The Termination Step in Palladium-Catalyzed Insertion Reactions. 

R. Noyori, M. Uchiyama, H. Kato, S. Wakabayashi, and Y. Hayakawa, Pure Appl. Chem., 1990, 62, 613-622. Organometallic Methodologies for Nucleic Acid Synthesis. M. Catellani, G. P. Chiusoli, and M. Costa, Pure Appl. Chem., 1990, 62, 623-630. Some Palladium-Catalyzed Carbon-Carbon Bond Formation Reactions. 

The carbonylative cyclization of 2-iodophenols with norbornadiene or norbornene was also carried out. In 1989, Catellani s group studied the annulation of 2-iodophenol with norbornadiene to coumarin (Scheme 3.11a). ° In this method, the elimination of cyclopentadiene via retro-Diels-Alder reaction was involved in the formation of the terminal product. Fiaud and co-workers reported the palladium-catalyzed carbonylative cyclization of 2-iodophenol with norbornene in 1997 (Scheme 3.11b). They reported that the selectivity for the production of the two regioisomers can be controlled. Catellani and co-workers studied the intramolecular cyclization of ort/zo-iodophenyl 3-butenoate to 4-methylcoumarin with a palladium catalyst. 85% of 4-methylcoumarin was produced in the presence of benzonitrile and carbon monoxide, which is compulsory (Scheme 3.12a). Silva, Costa and their co-workers reported a tandem process for the synthesis of coumarins from 2-iodophenols and enoates with the assistance of a palladium catalyst (Scheme 3.12b). The general scope of this Heck-lactonization involves E- and Z-enoates as substrates. It was shown that this reaction is sensitive to steric hindrance around the double bound in... 

In 2012, a palladium-catalyzed ring opening of aminocyclopropyl Ugi adducts was presented. Dihydropyridine and benzoazepinone derivatives were produced in moderate yields (Scheme 3.35a). Catellani and co-workers reported a palladium-catalyzed synthesis of substituted phenanthridine derivatives in 2008. Selectively substituted phenanthridine derivatives were obtained by a facile reaction of o-allqrlated aiyl iodides, o-bromoar-enesulfonylanilines and activated olefins in the presence of palladium and norbornene as catalysts. The reaction takes place under mild conditions to give the products in satisfactory yields using readily available starting materials (Scheme 3.35b). 

In 2004, a new palladium-catalyzed method for synthesising 6-phenan-thridinones and heterocyclic condensed quinolones was reported by Ferraccioli, Catellani and their co-workers. ° The reaction was based on consecutive palladium-catalyzed regioselective aryl-aryl and JV-aryl coupling of electron-rich o-iodoarenes with o-bromobenzamides and/or their heterocyclic analogues. Moderate to good yields of the products can be formed and a palladium(iv) metallacycle was proposed as the reaction intermediate (Scheme 3.68a). Later on, the group found that the same product can be... 

Meanwhile, Catellani, Derat and their co-workers developed the synthesis of dihydrodibenzoazepine and dibenzoazepine derivatives from 2-bromoanilines and aryl iodides. The process was based on the sequential reaction of three components, an aryl iodide, a bromoaniline, and either norbornene or norbornadiene in the presence of palladium as the catalyst (Scheme 4.13c). Whereas the use of norbornene leads to dihydrodibenzoazepine derivatives, norbornadiene allows an additional step consisting of a retro-Diels-Alder reaction, thus leading to the parent dibenzoazepines. 

In essence, these domino-coupling reactions form cyclohexadiene fragments from three two-carbon fragments. The 1 2 coupling of norbomene and iodobenzene discovered by Catellani and Chiusoli can also be adopted to couple norbomene with /3-bro-mostyrene.f hi an attempt to apply this Pd-catalyzed [2+2 + 2] assembly for an alternative and more productive access to Hopf s trifoliaphane, a 1 2 mixture of [2.2]paracyclophan-l-ene and l-bromo[2.2]paracyclophan-l-ene was tfeated with palladium acetate under Jeffery conditions. The main product was the hydrocarbon consisting of three [2.2]paracyclophane units linked by a common bicyclo[3.3.0]octene unit (Scheme Apparently, the key intermediate formed via a palladacycle preferen-... 

Catellani and Lautens have independently reported unique palladium/ norbornene-catalyzed reactions of aryl halides, which mechanistically involve a reversible alkene insertion/p-carbon elimination process [11]. For example, iodobenzene reacted with 1-iodobutane and methyl acrylate to form the multiply-alkylated benzene 29 (Scheme 7.9) [12]. The following mechanism is proposed oxidative addition of phenyl iodide onto palladium generates phenylpalladium(ll) iodide. A double bond of norbornene inserts into the C-Pd bond to form an alkylpalladium species, which cleaves a C-H bond nearby to form the palladacycle 25. -Butyl iodide then reacts with 25 to form the Pd(IV) intermediate 26, which undergoes reductive elimination. Repetition of the cyclometalation/alkylation process leads to the formation of 27. Then, P-carbon elimination affords the arylpalladium species 28 together with norbornene. Subsequently, a Heck-type reaction takes place with methyl acrylate, giving rise to 29. 

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