Nucleophilic substitution using palladium

Helquist et al. [129] have reported molecular mechanics calculations to predict the suitability of a number of chiral-substituted phenanthrolines and their corresponding palladium-complexes for use in asymmetric nucleophilic substitutions of allylic acetates. Good correlation was obtained with experimental results, the highest levels of asymmetric induction being predicted and obtained with a readily available 2-(2-bornyl)-phenanthroline ligand (90 in Scheme 50). Kocovsky et al. [130] prepared a series of chiral bipyridines, also derived from monoterpene (namely pinocarvone or myrtenal). They synthesized and characterized corresponding Mo complexes, which were found to be moderately enantioselective in allylic substitution (up to 22%). 

Nucleophilic Substitution of xi-Allyl Palladium Complexes. TT-Allyl palladium species are subject to a number of useful reactions that result in allylation of nucleophiles.114 The reaction can be applied to carbon-carbon bond formation using relatively stable carbanions, such as those derived from malonate esters and (3-sulfonyl esters.115 The TT-allyl complexes are usually generated in situ by reaction of an allylic acetate with a catalytic amount of fefrafcz s-(triphenylphosphine)palladium... 

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. 

In Section 8.2.3.2, we discussed arylation of enolates and enolate equivalents using palladium catalysts. Related palladium-phosphine combinations are very effective catalysts for aromatic nucleophilic substitution reactions. For example, conversion of aryl iodides to nitriles can be done under mild conditions with Pd(PPh3)4 as a catalyst. 

Lamaty and coworkers described a straightforward combination of three Pd-cata-lyzed transformations first, an intermolecular nucleophilic substitution of an al-lylic bromide to form an aryl ether second, an intramolecular Heck-type transformation in which as the third reaction the intermediate palladium species is intercepted by a phenylboronic acid [124]. Thus, the reaction of a mixture of 2-iodophenol (6/1-253), methyl 2-bromomethylacrylate 6/1-254 and phenylboronic acid in the presence of catalytic amounts of Pd(OAc)2 led to 3,3-disubstituted 2,3-di-hydrobenzofuran 6/1-255 (Scheme 6/1.66). In addition to phenylboronic acid, several substituted boronic acids have also been used in this process. 

Starting with bromoallenes 133, nucleophilic substitution supported by the use of cuprous cyanide lead to cyanoallenes of type 134 (Scheme 7.22) [126, 131, 181]. Pro-pargyl precursors and also cumulenes of type 133 can be utilized for palladium-catalyzed aminocarbonylation to give allenic amides 135 (cf. Section 7.2.6) [182]. 

Nucleophilic substitution at the 3-carbon of 4//-l,4-benzothiazine 195 was achieved using a palladium catalyst (Equation 10) <1999TL6373>, whereas in compounds 196 <1972CPB1325> and 197 <2005BMC141> nucleophilic attack occurred because the 2,3-double bonds were conjugated to electron-withdrawing groups at the 2-position (Scheme 16). 

Substitution of halopurines at C-2 and C-6 has become a well-developed synthetic process, with a wide variety of nucleophilic aromatic substitution and palladium-catalyzed C-N or C-O hond formations exemplified in the literature. The use of selective, sequential substitution reactions on polyhalopurine scaffolds is the basis of an increasing number of combinatorial syntheses of polysubstituted purines, both in solution and on solid phase. The introduction of N-, 0-, or S-substituents has often been combined with transition metal-catalyzed C-C bond-forming reactions (see Section 10.11.7.4.2) and selective N-alkylation (see Section 10.11.5.2.1) to provide versatile routes to purines with multiple, diverse substituents. 

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). 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

Palladium-catalyzed nucleophilic substitutions of activated allylic alcohols have been investigated using a bicyclic phosphine as the chiral element. Reactions have been reported with racemic acyclic allylic acetates <1999TL7791> and cycloalkenyl carbonates <2001TL1297> using the phosphine 203, with good to excellent enantiomeric excesses. 

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. 

Ionic liquids can be used as replacements for many volatile conventional solvents in chemical processes see Table A-14 in the Appendix. Because of their extraordinary properties, room temperature ionic liquids have already found application as solvents for many synthetic and catalytic reactions, for example nucleophilic substitution reactions [899], Diels-Alder cycloaddition reactions [900, 901], Friedel-Crafts alkylation and acylation reactions [902, 903], as well as palladium-catalyzed Heck vinylations of haloarenes [904]. They are also solvents of choice for homogeneous transition metal complex catalyzed hydrogenation, isomerization, and hydroformylation [905], as well as dimerization and oligomerization reactions of alkenes [906, 907]. The ions of liquid salts are often poorly coordinating, which prevents deactivation of the catalysts. 

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