Intramolecular a-arylation

Salcedo A, Neuville L, Rondot C, Retailleau P, Zhu J (2008) Palladium-catalyzed domino intramolecular A-arylation/intermolecular C-C bond formation for the synthesis of functionalized benzodiazepinediones. Org Lett 10 857-860... 

The intramolecular Heck reaction is a powerful method for the synthesis of constrained tertiary and quaternary carbon centers and has been applied as a key step in the synthesis of a number of pyridine alkaloids. Mann et al. have accessed the bicyclononane core structure of huperzine A 150 in moderate yield by intramolecular Heck reaction of bromopyridine 151 (Equation 117). Another notable application of this methodology is the intramolecular a-arylation of the amide enolate generated from 152 to give the carbon skeleton of cytosine <20040BC1825> (Equation 118). 

Pandey, G., Karthikeyan, M., and Mumgan, A. (1998) New intramolecular a-arylation strategy of ketones by the reaction of silyl enol ethers to photosensitized electron transfer generated arene radical cations construction of benzannulated and benzospiroannulated compounds. Journal of Organic Chemistry, 63, 2867-2872. 

Muratake et al. reported the intramolecular a-arylation of ketones [55,56]. Thus, polycyclic compounds are readily obtained from aromatic keto-bromides and keto-triflates (Eq. 16). Bromo-amides can give the corresponding cycliza-tion products (Eq. 17) [52]. Related intramolecular vinylation reactions to give aliphatic polycyclic compounds have also been reported (Eq. 18) [57,581. The intramolecular cyclization of aromatic halo-ketones under carbon monoxide, which proceeds by mechanism C, gives the corresponding a-acylated products (Eq.l9) [321. 

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 e.g. R = PhCH = Me, R = Me, R = H, R = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladium-mediated intramolecular A-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis <06TL3423>. 

Ketones. Although Ni-catalyzed cychzation of iodoaryl-containing lithium enolates shown in Scheme might represent the first example of this class of reactions, subsequent studies have been performed mainly with Pd catalysts. The syntheses of spiro-fused oligocyclic models for fredericamycin A by Ciufolini and co-workers provided some prototypical examples of Pd-catalyzed cycUzalion via intramolecular a-arylation of ketones (Scheme 20). Under appropriate conditions, bromoaryl-containing monoketones can also be converted to spiro-fused bicycles and oligocycles (Scheme 20). 

Regioselective C-H activation is often used for intramolecular biaryl preparations in Pd-mediated transformations. Thus concise syntheses of a large collection of alkaloids have been reported using variations of this approach (239-241), which differ mainly in terms of the functionalization of the precursor, palladium catalysts, and ligands. An efficient synthesis of racemic y-lycorane was recently disclosed whereby the key step is the intramolecular a-arylation of a cyclohexanone derivative (242). Some heterocycKc synthetic precursors (e.g. substituted indoles, quinolines, quinolones, phenanthridines, and phenanthridinones) have also been prepared en route to the alkaloids [hippadine, trisphaeridine (70), and crin-asiadine] via Pd- and Cu-mediated reactions (243,244). 

Scheme 2.19 Organocatalytic asymmetric intramolecular a-arylation reactions of aldehydes reported by (a) Nicolaou, and (b) MacMillan, respectively.

Muratake and Natsume reported intramolecular a-arylations of ahphatic ketones using PdCl2(PPh3)2 and CS2CO3, forming a variety of carbocycHc compounds (Scheme 3.21) [227]. 

Scheme 3.21 Intramolecular a-arylation of aliphatic ketones by Muratake and Natsume [227],...

Soon afterward, MacMillan and co-workers [142, 143] also reported enantio-selective intramolecular a-arylation of aldehydes via organo-SOMO catalysis. [Fe(Phen)3l [PFsl 3, instead of CAN, as a single-electron oxidant together with designed imidazolidinone catalysts LXVIII and LXIX were found to be optimal for reaction efficiency and enantioselectivity (Scheme 8.35). Moreover, ortho selectivity, when 1,3-disubstituted aromatic systems were used, was observed. Methodologies presented by Nicolaou and MacMillan represent a useful tool for the total synthesis of various naturally occurring compounds, such as dimethyl calamenene, tashiromine, and so on. 

Chiral imidazolium tetrafluoroborates 32, 64, and 65 were synthesized and tested as ligands in the palladium-catalyzed intramolecular a-arylation of N-(2-bromoaryl)-Af-alkyl-2-arylpropanamides (Scheme 3.34) [36]. However, only... 

Figure 4.24 Asymmetric oxindole synthesis via intramolecular a-arylations.

A new mode of oxidative organocatalytic activation has been reported, termed organo-SOMO catalysis, which has been successfully applied using an enantioselective intramolecular a-arylation of aldehydes via catalytic oxidative radical cyclization (Eq. 9.25) [101]. In this approach, the exposure of an aryl-tethered aldehyde (124) to a chiral secondary amine catalyst 125 and a suitable oxidant leads to enantio-enriched 126 ... 

In 2011, Murakami and coworkers [82] reported that chiral NHC ligands having a 2,2 -bisquinoline-based Cj symmetric skeleton were efficient ligands in the palladium-catalyzed intramolecular a-arylation of amides to afford 3,3-disubstituted oxindoles with good yield and enantioselectivity (Scheme 8.44). The two fused rings attached to the NHC core played an important role in the reaction mechanism. 

In 2010, Dorta and coworkers [83] reported a new synthetic strategy to access functionalizable 3-allyl oxindoles bearing a chiral quaternary carbon stereocenter via a direct palladium-catalyzed a-arylation protocol. This elegant methodology, previously accessible only via a two-step procedure involving a Pd-catalyzed intramolecular a-arylation followed by an asymmetric Pd-catalyzed allylic alkylation [84], afforded impressive reactivities, and high chemoselectivities and enantioselectivities were also achieved in the synthesis of oxindoles using a new chiral Pd-NHC catalyst (Scheme 8.45). 

In 2009, Ackermann and coworkers reported a palladium catalyst derived from an air-stable secondary phosphane oxide (l-Ad)2P(0)H that enables efficient intramolecular a-arylations of amides with aryl chlorides. Good yields were obtained for several oxindole derivatives. The interesting fact was that they discovered an unprecedented intramolecular palladium-catalyzed a-arylation route to azaoxindoles (Scheme 8.50) [90]. 

Scheme 8.54 Intramolecular a-arylation for the synthesis of oxindoles, as described by Bolm and coworkers [96].

Shortly after, the development of the intramolecular variant of this reaction was reported by Gaertzen and Buchwald [106]. A simple and flexible route to obtain dihydroisoindole and tetrahydroisoquinoline carboxylic acid derivatives was developed using the palladium-catalyzed intramolecular a-arylation of readily available a-amino acid esters (Scheme 8.58). The construction of quaternary carbon centers that tolerate a number of different substituents around the enolate center, including phenyl or bulky isopropyl groups, was reported. A number of different Af-substituents including alkyl, aryl, or carboxyl groups could be employed [106]. 

Sol and Serrano [108] employed a palladium/triphenylphosphane-based catalyst system in the intramolecular a-arylation of fl-(2-iodoanilino) esters, tiffording the corresponding indoline products in low to good yields (Scheme 8.60). [Pd(PPh3) j and potassium phenoxide as base were the conditions applied to obtain indoline-3-carboxylic acid derivatives. 

Figure 8.8 Types of ligands used for the Cul-catalyzed intermolecular and intramolecular a-arylation of activated methylene or methine compounds with aryl halides [114-116].

There has been a summary of computational and experimental studies of the use of palladium complexes with A -heterocyclic carbenes (NHCs) in the asymmetric coupling of -hybridized carbon-hydrogen bonds with aryl halides. It has been shown that the electronic and catalytic properties of NHCs fused to porphyrins may be modified by varying the inner metal in the porphyrin. A DPT study of the use of palladium-NHC complexes in the asymmetric intramolecular a-arylation of 2-bromoaryl amides to give 3,3-disubstituted oxindoles (101) has been reported. The likely pathway involves insertion of the palladium into the arene-bromine bond to form a palladacycle which deprotonates to give an (9-enolate. Conversion into the C-enolate followed by reductive elimination gives the product. The intramolecular reaction of 0 a cyclopropane carbon-hydrogen bond in a 2-bromoanilide derivative has been used to form cyclopropyloxindoles, (102), in a palladium-catalysed, silver-mediated reaction. 

Even shorter, and certainly less conventional, is the synthesis of (—)-tashiromine ent-929) by MacMillan s group (Scheme 121). " This route rehed on the ortho-selective intramolecular a-arylation of the pyrrole-aldehyde 979 mediated by the chiral amine catalyst 980 in conjunction with ceric ammonium nitrate as a single-electron oxidant in a process that MacMillan has termed organo-SOMO catalysis. The reaction is thought to proceed via an imine intermediate that undergoes oxidation to the radical... 

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