Halides, aryl, with active compounds

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

Tertiary and aromatic nitroso compounds react with aryl Grignard or aryl-lithium reagents giving the corresponding hydroxylamines . This reaction is useful for preparation of alkyl- and aiylhydroxylamines (e.g. 109, equation 80 and 110, equation 81) and can be considered as complementary to arylation of hydroxy lamines with activated aryl halides. It has been used for functionalization of cyclophanes with the hydroxy amino group. The main limitation of the reaction is the relatively restricted choice of available aliphatic nitroso components, so most of reactions were done with 2-nitroso-2-methylpropane. There is no literature data about the possibility of removal of the tert-butyl group from these compounds. 

In 2002, Furstner and coworkers reported that aryl halides react with Grignard reagents under the conditions previously used for the coupling of alkenyl halides. They proposed that the active iron species is Fe(MgX)2, a complex described by Bogdanovic and coworkers ° a few years earlier (Scheme 30). This iron(-II) species is formed by addition of four equivalents of the Grignard compounds to FeCl2. 

The coupling of aryl halides with active methylene compounds, such as mal-onitriles and cyanoacetates, is of increasing interest due to its inherent difficulty and the interest of the resulting products as synthetic intermediates in the preparation of bio active [36,37], heterocyclic [38,39] or conducting compounds [40]. Bulky NHCs have been found to be excellent ligands in the coupling of aryl halides with malonitrile [41] in hot pyridine using NaH as base (Scheme 7). 

There is presumably more than a subtle difference between the reactions of alkyl and aryl halides with organocopper compounds, as a straightforward nucleophilic displacement of aryl halide by the d electrons of a copper species is hardly likely. Simple aryl halides are nearly all inert to the usual nucleophiles, such as alkoxides, unless strongly activated by electron-attracting groups in the ortho and para positions. However, coordination of the halogen to copper may be sufficient to... 

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. 

Aryl triflates were shown to react directly with secondary amines in A -methylpyr-rolidine solvent using microwave irradiation. Activated halides can be converted to diethylamino compounds ArX ArNMc2 by treatment with HMPA. Anihne derivatives react with activated aromatic rings, in the presence of tetrabutylammo-... 

A general method makes use of Barbier conditions combined with ultrasonication. The organic halide, RX, bis(tributyltin) oxide, and magnesium powder are caused to react in THF, in the presence of 1,2-dibromoethane, in an ultrasonic cleaning bath at about 35 °C for one hour.16 The presence of a surface-active compound in the bath assists cavitation. The reactions proceed in good yield with alkyl, vinyl, allyl, benzyl, aryl, and heteroaryl halides (usually bromides). 

Phenols, much like anilines, represent important synthons for the constraction of biologically active compounds and functional materials. " Moreover, the phenol moiety itself is present in a number of top selling pharmaceuticals with diverse function selected examples are depicted in Figure 3. The use of water, or related MOH salts, as nucleophiles in palladium-catalyzed cross-couplings involving (hetero)aryl halides conceptually represents a mild and selective route to phenols that is complementary to more established phenol syntheses, " " including oxidative protocols. However, the difficulties associated with realizing such transformations mirror those... 

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