Palladium catalysis electrophilic

The intramolecular arylation of sp3 C-H bonds is observed in the reaction of l-/ r/-butyl-2-iodobenzene under palladium catalysis (Equation (71)) 94 94a 94b The oxidative addition of Arl to Pd(0) gives an ArPdl species, which undergoes the electrophilic substitution at the tert-butyl group to afford the palladacycle. To this palladacycle, another molecule of Arl oxidatively adds, giving the Pd(iv) complex. 

Alkylation and deprotection of N-protected aminomethylphosphonate esters 6 are shown in Scheme 6. The nitrogen is protected as the imine derived from benzophenone or a benz-aldehyde, and a variety of conditions are used for deprotonation and alkylation (Table 2). The benzaldehyde imine of aminomethylphosphonate can be deprotonated with LDA and alkylated with electrophilic halides (entries 1 and 2). For the best yields, saturated alkyl bromides require an equivalent of HMPA as an additive. 36 Allylic esters can be added to the carbanion with palladium catalysis (entries 3-7). 37,38 For large-scale production, phase-transfer catalysis appears to be effective and inexpensive (entries 8-12). 39,40 ... 

Several new leaving groups have been discovered recently which merit special discussion. Allyl sul-fones, surprisingly, function as substrates for palladium catalysis.86 As the sulfone group had previously been proven to be able to stabilize an adjacent carbanion, this result allowed allyl sulfones now to be considered as synthons for 1,1- and 1,3-dipoles (equation 10). That is, the allyl sulfone can be used alternately as a nucleophile and electrophile, greatly extending its synthetic utility. 

The copper-catalysed asymmetric conjugate addition of dialkylzinc leads to homo-chiral zinc enolates.28 These intermediates have been trapped in situ with activated allylic electrophiles, without the need for additional palladium catalysis (Scheme 3). 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

The scope of vinyl metals as sources of nucleophilic vinyl groups is very great. As well as the expected electrophiles such as halogens, alkyl and acyl halides, aldehydes and ketones, unsaturated carbonyl compounds and epoxides, they also combine with aryl and alkenyl halides with palladium catalysis. The usual stereochemical course is retention at the vinyl group. It is necessary to decide whether the vinyl metal is reactive enough or whether it must first be transformed into an ate complex. Since most of these vinyl metals can be converted into each other with retention, this is an unusually versatile group of reagents. 

Halide and triflate leaving groups are also involved with palladium catalysis in the most general of all these reactions with vinyl electrophiles. These use a main group rather than transition metal, chiefly boron or tin, in stoichiometric amounts to mark one molecule as nucleophilic and then... 

The most common means of activating aromatic C-H bonds via palladium catalysis is by electrophilic C-H activation. This proceeds more like a Freidel-Craft type metahation mechanism, followed by rearomatization to form versatile aryl-metal intermediates (Scheme 5) [19]. It can occur with electrophilic palladium(II) catalysts such as Pd(OAc)2, PdCl2, Pd(TFA)2 (Scheme 5a) or on electrophilic aryl-pahadium(II) complexes, that result from oxidative addition of palladium(O) into an aryl halide (Scheme 5b). The resultant aryl-palladium(H) complexes are analogous to those observed in conventional cross-coupling reactions and as such are versatile intermediates in the formation of new C-C bonds. 

Palladium(0)-catalysed coupling of an orf/to-halophenolic ether (thioether) with a terminal alkyne (or with an alkynylboronic ester ) and ring closure promoted with an electrophile - iodine has been most often used - is an excellent method to make both benzothiophenes °° ° and benzofurans. ortfto-AIkynyl-phenols can be comparably closed with palladium catalysis in the presence of copper(II) halides to give the corresponding 3-halo-benzofurans, ° and ortfto-alkynyl pyridin-2- and -3-yl acetates likewise ring close with iodine, generating furopyridines. ... 

Further improvements in palladium catalysis were achieved with a larger excess of benzene as co-solvent, and also with DavePhos (95) as ligand and pivalic acid as additive (Scheme 9.31) [70]. This catalytic system tolerated various valuable functional groups, such as a nitro substituent. These reaction conditions allowed not only for the achievement of better yields of biaryls with aryl bromides as electrophiles, but also improved chemoselectivies of these transformations. Thus, in competition experiments between benzene (87) and fluorobenzene (96), the latter reacted preferentially in a ratio of >11 < 1 (Scheme 9.31) [70],... 

Palladium catalysis promotes the Reformatsky reaction. Heteroaryl iodides are better substrates than bromides and chlorides. Iodine in electrophilic positions in the substrate, but not in the benzenoid position, were active in the Reformatsky reaction (277,278) (Scheme 63). Homo-coupling is the major pathway for iodo derivatives in the benzenoid position, with formation of 3,3 -biquinoline (279) (85CPB4309). 

In cases where a simple alkyl functionality (nonbenzylic or allylic) is desired at the site of C-C bond formation, early strategies largely involved the use of an sp electrophile and sp nucleophile (Scheme 3-6). Although these developments more frequently involved palladium catalysis, various nickel-catalyzed strategies involving either homogeneous or heterogeneous catalysts have also been successfully employed. ... 

Since the reaction can proceed at ambient temperature, some electrophilic functional groups can be present in the alkyl electrophiles, as exempUfied by products 1-3. Further optimizations studies on this catalyst led to the development of N-heterocychc carbene (NHC)-derived palladium catalysts for arylations of alkyl chlorides. In this system, it is assumed that the initial reaction of a precatalyst [Pd(IMes)(NQ)]2 4 and an aryl Grignard reagent should generate a coordinatively unsaturated palladium-carbene complex, which is the actual palladium-catalysis complex with high catalytic activity [9]. 

An important route for the C-H activation of arenes and heteroarenes is through electrophilic metallation of an aromatic ring, followed by reaction with an alkene. There are numerous simple examples with arenes and heteroarenes reacting with alkenes under palladium catalysis." This has been referred to as the dehydro-genative Heck reaction and the oxidative Heck reaction, as well as the Fujiwara reaction, or Fujiwara-Heck reaction. Both benzene 3.4 and its derivatives (Schemes 3.6 and 3.7) and heteroarenes (Schemes 3.8 and 3.9) can be used. While the reaction has been carried out with a stoichiometric amount of palladium, catalytic processes, with an added oxidant are widespread. 

The nucleophilic and electrophilic additions are the most common reactions and have a large number of applications in organic synthesis and palladium catalysis. The nucleophilic additions are more or less easy depending on whether the complex is cationic or neutral. In the latter case, the ancillary ligands must be electron withdrawing (CO, NO), or the allyl group must bear an electron-withdrawing substituent in order to allow the reaction ... 

In the field of homogeneous catalysis, electrophilic metals [palladium(II), plati-num(II), rhodium(II), iridium (I), ruthenium(II), cobalt(I), titanium(II) and gold(I)] activate alkynes under mild conditions [2-8]. When an alkyne behaves as a ligand, there are four orbitals that can participate in the bonding (Fig. 1.1) [4]. The in-plane orbitals, Try and n, are responsible for a donor interaction (M <- L donation) and a 7r-acceptor interaction (M L back-donation) respectively. The orthogonal, out-of-plane orbitals, and n , are engaged in the M <- L 7t donation and the d symmetry M L back-donation respectively. This latter interaction can be neglected, due to the weak overlap of the orbitals. 

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