Iodoarenes, Heck reaction

Palladium-catalysed C-C bond formation under Heck reaction conditions, which normally requires anhydrous conditions and the presence of copper(I) salts, is aided by the addition of quaternary ammonium salts. It has been shown that it is frequently possible to dispense with the copper catalyst and use standard two-phase reactions conditions [e.g. 18, 19]. Tetra-/i-butylammonium salts catalyse the palladium-catalysed reaction of iodoarenes with alkynes to yield the arylethynes in high yield [20, 21], whereas the reaction with 3-methylbut-1 -yn-3-ol (Scheme 6.30) provides a route to diarylethynes [22]. Diarylethynes are also formed from the reaction of an iodoarene with trimethylsilylethyne [23], Iodoalkynes react with a,p-unsaturated ketones and esters to produce the conjugated yne-eneones [19],... 

The Heck reaction on polymer-bound iodoarenes is assisted by the addition of a catalytic amount of tetra-n-butylammonium bromide and has been employed in the synthesis of 4-carboxycinnamic esters and amides [33], and 4-aminosulphonyl-cinnamic esters [34], It has also been reported that the presence of an equimolar equivalent of benzyltriethylammonium chloride aids the Pd(II)-mediated reaction of A -acyl-2-iodoanilines with vinylidene carbonate, which leads to A -acyl-2-hydroxy-indolines providing a convenient route to the indoles (80-90%) [35], The catalysed reaction of 2-hydroxy- and 2-tosylaminoiodobenzene with 1,2-dienes produces 1,2-dihydrobenzofurans and 1,2-dihydroindoles, respectively [36]. 

Benzazepinones can be prepared on cross-linked polystyrene by intramolecular Heck reaction (Entry 6, Table 15.35). In the presence of sodium formate, the intramolecular Heck reaction of iodoarenes with alkynes yields methylene benzazepinones (Entry 7, Table 15.35). Surprisingly, when this reaction was performed in solution, the main product (65% yield) was a dehalogenated, non-cyclized benzamide. In the synthesis on cross-linked polystyrene, however, this product was not observed [419]. 

At about the same time, Seddon reported the Heck reactions of bromo-and iodoarenes in a series of /V-hexylpyridinium [C6py] + and N,N dialkylimidazolium based liquids with [PF6] and [BF4] anions.20 The effects of changing the ionic liquid and reaction conditions upon the Heck reaction of iodobenzene with ethyl acrylate were reported using 2 mol% Pd(OAc)2. 

A palladium-mediated annulation of Y-( o-bromoary l)pyrroles across strained alkenes led to the formation of pyrrolo[l,2-a]quinolines <07OL1761>. An intramolecular Heck reaction involving tethered iodoarenes produced an entry to pyrrolo[2,3-t/][2]benzazepin-7-ones, analogues of the pyrrole natural product latonduines <07T867>. A Heck reaction of a 3-iodopyrrole with a 2,3-dihydrofuran provided pyrrole deoxyribonucleosides <07T12747>. 

A major achievement was the discovery that Heck reactions are greatly accelerated in the presence of phase-transfer catalysts using quaternary ammonium salts and solid bases [ Jeffery conditions Pd(OAc)2, MHCO3 (M = K, Na), nBu4NX (X = Br, Cl), DMSO or DMF] [100]. Under these conditions, iodoarenes and iodoalkenes can be coupled to alkenes... 

Bimetallic Pd/Ni [121] andPd/Co [122] systems have exhibited considerable catalytic activity in the Heck reaction of nonactivated chloroarenes with ethyl acrylate, acrylonitrile, and acrylic acid. For instance, ethyl acrylate and acrylonitrile reacted smoothly with chlorobenzene in the presence of Nal and catalytic amounts of NiBr2, Pd2(dba)3, and o-Tol3P in DMF to give E-isomers of ethyl cinnamate and cinnamonitrile, respectively [121]. The reaction occurred via the nickel-catalyzed halogen exchange between ArCl and Nal, followed by the conventional palladium-catalyzed olefination of the iodoarene generated in situ. 

In this context, a functionalized ionic liquid, 1-(2-hydroxyethyl)-3-methyl imidazolium tetrafluoroborate [hemim][BF4], is reported as an efficient and recyclable reaction medium for the palladium catalyzed Heck reaction. The olefination of iodoarenes and bromoarenes with olefins generates the corresponding products in good to excellent yields under phosphine-ffee reaction conditions. After separation of the product, fresh starting materials are charged into the recovered ionic liquid which entraps the palladium catalyst. The reactions still proceed quantitatively for six cycles, without significant loss of catalytic activity. " The effect of both the cation and the anion on the chemical yield is shown in Figure 28. 

Heck reaction. The coupling of iodoarenes with tertiary allylic amines gives the normal jS-aminomethylstyrenes (in EtOH or PhMe) or enamines (in DMF). ... 

Besides this widespread pathway based on the intermediate N-acyliminium ion, several other established methods have been applied to construct the C5/C13 bond of the erythrinane skeleton. Thus, the Heck reaction has proved to be an attractive approach to the target compounds. The synthesis reported by Rigby (Scheme 10) starts with a smooth [1 -I- 4] cycloaddition of certain isocyanides to the vinyl isocyanate 79 affording the required hydroindolone 80. Then the iodoarene moiety has been installed by AT-alkylation with the phenethylmesylat 81 giving the N-alkylated precursor 82. Cyclization of 82 under Heck conditions yields the expected 7,8-dioxoerythrinane 83 as a single diastereomer, which then has been converted to ( )-2-cpi-erythrinitol (84) in twelve additional steps (64). 

On the other hand, even the recently prepared Herrmann-Beller catalystf still requires higher temperatures for efficient coupling rates of the Heck reaction. Interestingly, the complexation of chloroarenes with the Cr(CO)3 fragment activates the arene-chlorine bond considerably toward the oxidative addition. Thus, Cr(CO)3 complexed chloroarenes react about 15 times faster than iodoarenes in Pd-catalyzed cross-couphng reactions under mild conditions, in particular in Pd/Cu-catalyzed cross-couplings with terminal acetylenes in refluxing THF and/or tertiary amines (Scheme 36). ... 

An organometallic reaction which shows a close similarity to the Mizoroki-Heck reaction is the cobalt-catalysed [46] reaction between alkenes and organic halides. The use of [CoCKPPhsls] (59) as catalyst for intermolecular arylations of methyl acrylate (1) and styrene (2) was reported by Iyer [47] (Scheme 10.20). The para-substituted aryl iodides could be employed with this homogeneous catalyst, but the more sterically hindered ortho-substituted iodoarenes failed to undergo the desired substitution reaction. Aryl bromides and chlorides, as well as alkyl-substituted halides, proved unreactive under these reaction conditions. 

Grether and Waldmann [15] developed an enzyme-labile safety catch linker 1 tested in intermolecular Mizoroki-Heck reactions (Scheme 14.1). This linker releases alcohols and amines through enzymatic cleavage of the benzylamide moiety followed by snbsequent lactam formation. After a Mizoroki-Heck reaction performed on an immobilized iodoarene... 

Scheme 14.2 Mizoroki-Heck reaction of an iodoarene attached by an enzyme-labile safety catch linker.

Another attractive three-component procedure involves the versatile triazene linker T1 and generates spirooctene 30 from a Mizoroki-Heck reaction of immobilized iodoarene 29 with bicyclopropylidene in the presence of an acrylate derivative (Scheme 14.9) [27, 28], The triazene moiety can be cleaved to diazonium salts which, in turn, act as substrates for Mizoroki-Heck reactions with various alkenes to give spirooctenes 31. The latter can be obtained without the double bond in the coupled alkene if palladium on charcoal is used instead of palladium acetate, hi this case, the same catalyst promotes the Mizoroki-Heck reaction and the subsequent hydrogenation [28]. 

The aqueous protocol has been applied to combinatorial Heck reactions with resin-bonded iodoarenes, though in such cases water can have a detrimental elfect, which is likely due to folding of hydrophobic polymeric support. 

The use of hydrophilic sulfonated phosphines TPPMS and particularly TPPTSf allowed development of a very mild procedure for Heck reactions of iodoarenes and iodoalkenes, though this protocol requires a large amount of expensive catalyst, which makes this scheme unsuitable for large-scale reactions. The method showed unusual selectivity trends for example, in the reactions with cycloalkenes no migration of double bond was reported. "" Also, a very rare endo-trig-mode of cyclization is favored in the aqueous phosphine-assisted method compared to the normal exo-trig-mode observed in nonaqueous methods (Scheme 35). "" " ... 

In 2001, Mauleon et al. reported an unusual palladium-cascade arylation of a,P-unsaturated phenyl sulfones 23 under Heck reaction conditions [12]. Contrary to the work of Fuchs and others [13], Mauledn et al. described the intermolecular reaction of a,P-unsaturated sulfones with a large excess of iodobenzene (or / -substituted iodoarenes) in the presence of Ag COj as base, which occurred mainly through a complex cascade reaction in which three molecules of iodobenzene and one molecule of vinyl sulfone were involved, forming fused polycyclic compounds 25 rather than the Heck trisubstituted olefin expected. The authors propose a mechanism involving Heck reaction and C-H activation pathways (Scheme 6.5). 

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