Nucleophilic substitution palladium catalysis

Direct nucleophilic displacement of halide and sulfonate groups from aromatic rings is difficult, although the reaction can be useful in specific cases. These reactions can occur by either addition-elimination (Section 11.2.2) or elimination-addition (Section 11.2.3). Recently, there has been rapid development of metal ion catalysis, and old methods involving copper salts have been greatly improved. Palladium catalysts for nucleophilic substitutions have been developed and have led to better procedures. These reactions are discussed in Section 11.3. 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

The triflate 125 is formed from the hydroxy precursor (Equation 131) and undergoes a variety of nucleophilic substitution processes <2006TL4437>, including Suzuki and Stille couplings (Equations 132 and 133, respectively). Amination of 125 with aliphatic amines occurs under thermal conditions, using either conventional or microwave heating (Equation 134), but the reactions of 125 with less reactive amines require palladium catalysis (Equation 135). 

Allyl carbonates can be cleaved by nucleophiles under palladium(O) catalysis. Allyl carbonates have been proposed for side-chain protection of serine and threonine, and their stability under conditions of /VT moc or /V-Boc deprotection has been demonstrated [107]. Prolonged treatment with nucleophiles (e.g., 20% piperidine in DMF, 24 h) can, however, lead to deprotection of Alloc-protected phenols [108,109]. Carbohydrates [110], tyrosine derivatives [107], and other phenols have been protected as allyl ethers, and deprotection could be achieved by palladium-mediated allylic substitution (Entry 9, Table 7.8). 9-Fluorenyl carbonates have been used as protected intermediates for the solid-phase synthesis of oligosaccharides [111]. Deprotection was achieved by treatment with NEt3/DCM (8 2) at room temperature. 

Arasabenzene, with chromium, 5, 339 Arcyriacyanin A, via Heck couplings, 11, 320 Arduengo-type carbenes with titanium(IV), 4, 366 with vanadium, 5, 10 (Arene(chromium carbonyls analytical applications, 5, 261 benzyl cation stabilization, 5, 245 biomedical applications, 5, 260 chiral, as asymmetric catalysis ligands, 5, 241 chromatographic separation, 5, 239 cine and tele nucleophilic substitutions, 5, 236 kinetic and mechanistic studies, 5, 257 liquid crystalline behaviour, 5, 262 lithiations and electrophile reactions, 5, 236 as main polymer chain unit, 5, 251 mass spectroscopic studies, 5, 256 miscellaneous compounds, 5, 258 NMR studies, 5, 255 palladium coupling, 5, 239 polymer-bound complexes, 5, 250 spectroscopic studies, 5, 256 X-ray data analysis, 5, 257... 

While the major use for palladium catalysis is to make carbon-carbon bonds, which are difficult to make using conventional reactions, the success of this approach has recently led to its application to forming carbon-heteroatom bonds as well. The Overall result is a nucleophilic substitution at a vinylic or aromatic centre, which would not normally be possible. A range of aromatic amines can be prepared direcdy from the corresponding bromides, iodides, or triflates and the required amine in the presence of palladium(O) and a strong alkoxide base. Similarly, lithium thiolates couple with vinylic triflates to give vinyl sulfides provided lithium chloride is present. 

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. 

Allylic substitutions are among the most important carbon-carbon bond-forming reactions in organic synthesis. Palladium-catalyzed allylic substitutions and their asymmetric version have been extensively studied and widely used in a variety of total syntheses [78]. The palladium catalysis mostly requires soft nucleophiles such as malonate carbanions to achieve high stereo- and regioselectivity. 

Such substitutions follow the same mechanistic route as the displacement of halide from 2- and 4-halo-nitrobenzenes, i.e. the nucleophile first adds and then the halide departs. By analogy with the benzenoid situation, the addition is facilitated by (i) the electron-deficiency at a- and y-carbons, further increased by the halogen substituent, and (ii) the ability of the heteroatom to accommodate negative charge in the intermediate thus produced. A comparison of the three possible intermediates makes it immediately plain that this latter is not available for attack at a p-position, and thus p nucleophilic displacements are very much slower - for practical purposes they do not occur (see, however, reactions with palladium catalysis, 4.2)... 

To reduce the strain associated with cyclization, we next stndied acyclic piperidine precursors as nucleophiles to ultimately intercept the Mazzocchi, discovery, and cyanohydrin approaches. Diethyl glutaconate 35 coupled readily with fluoro-4-nitroarenes 30a or 30b to give 36 (95%, HPLC Scheme 3.12)." ° Again, however, ring closure to 37 did not proceed by either S Ar (36a, X = F) or palladium catalysis (36b, X = Br). The newly formed ally lie anion of 36 presumably delocalized into the nitroaromatic ring to generate electron-rich character inhibiting subsequent nucleophilic S Ar substitution or the oxidative addition required to enter palladium catalysis pathways. 

Nucleophilic aromatic substitution and palladium catalysis compared... 

Allylic aeetates or carbonates can undergo nucleophilic substitutions via palla-dium(0)-catalysis (11). In this paper, we report on the extension of this reaction to unsaturated fatty aeids by the preparation of allyl carbonates and acetates of oleic, linoleic, and 10-undecenoic acid and their substitution with carbon- and heteroatom-nucleophiles by palladium(0)-catalysis. In this way, different substituents can be in-trodueed into the alkyl chain of fatty acids. This leads to fatty acid derivatives in which the properties of biologically active compounds may possibly be combined with the amphiphilic property of the fatty acid. 

The decarboxylative acylation of ortho-substituted benzoic acids involving nucleophilic addition to nitriles occurs under palladium catalysis (Scheme 4.35) [40]. 

In a related catalytic procedure, run in the presence of a stoichiometric amount of lithium chloride (eq 10), it is possible to obtain cfj-l-acetoxy-4-chloro-2-alkenes with high 1,4-selectivity and in high chemical yield. A selective nucleophilic substitution of the chloro group in the chloroacetate, either by palladium catalysis or by classical methods (eq 10), and subsequent elaboration of the acetoxy group, offer a number of useful transformations. The methodology has been applied to, for example, a synthesis of a naturally occurring 2,5-disubstituted pyrrolidine, some tropane alkaloids, and perhydrohistrionicotoxin. ... 

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