Ethylenes Heck reactions

The Pd-catalysed Heck reaction performed with thiourea as the Ugand exhibit good activities for some catalysts. As for carbene ligands [104], steric hindrance improves catalytic results. Thus, thioureas wearing bulky substituents afford the formation of air- and moisture-stable Pd complexes [105]. For example, the catalyst obtained with 2mol% Pd(dba)2 and Ar,M -dimesitylene-ethylene thiourea (Scheme 24) was still active even after 2 months in an air atmosphere. 

Analogously, over the years, Arai and co-workers have investigated silica-supported ethylene glycol as a catalyst-philic phase, which contained a metal precursor, for C-C bond-forming reactions, such as the Heck reaction. They describe a multiphasic system with an organic phase (solvent) that contains only reactants and products without any catalyst. The products could be recovered by simple filtration, and the catalyst recycled many times without deactivation, since it did not precipitate, thus making the catalytic system stable and reusable (Figure 6.7). °... 

Three different methodologies have been employed to extend the use of the Heck reaction to the synthesis of PPV, and they are presented in Scheme 45. Method A uses ethylene gas that is bubbled through a solution of previously activated Pd(0) catalyst, and an appropriately substituted dibromo- or diiodo-ben-... 

The intramolecular Heck reaction (type d cyclization) has been used to access 3-benzazepine derivatives from o-bromobenzyl substituted /3-amino ester precursors in excellent yields. A key feature though was the use of microwave irradiation in the poly(ethylene glycol), PEG3400, as the solvent <2007EJ0201>. 

Kiji, J., Okano, T. and Hasegawa, T. (1995) Palladium-catalyzed arylation of ethylene (the Heck reaction) under aqueous conditions. J. Mol. Catal. A Chem.,... 

Chandrasekhar S, Narsihmulu C, Sultana SS et al (2002) Poly(ethylene glycol) (PEG) as a reusable solvent medium for organic synthesis. Application in the Heck reaction. Org Lett 4(25) 439)M401... 

Several commercial products have been produced via Heck reactions on a scale in excess of one ton year"1 [43]. The sunscreen agent 2-ethylhexyl-p-methoxycinna-mate has been synthesized on a pilot scale by using Pd/C as the catalyst [44]. Albermarle produces Naproxen via a Heck reaction of 2-bromo-6-methoxy-naphthalene with ethylene, followed by carbonylation of the product [45]. A key step in the production of Singulair (montelukast sodium), a leukotriene receptor antagonist for treatment of asthma, is Heck reaction of methyl 2-iodobenzoate with an allylic alcohol to give a ketone [43]. 

The transition metal-catalysed coupling of aryl halides with alkenes (alkenyla-tion of aromatic halides) is referred to as the Heck reaction [66-75]. Heitz et al. [76-82] were the first to utilise the Heck reaction to synthesise high molecular weight poly(arylene vinylene)s by the self-coupling of bromostyrene [scheme (2)] or the cross-coupling of dibromoarene with ethylene [scheme (4)] or divi-nylarene [scheme (5)]. 

Alkenes without allylic H atoms—such as ethylene, acceptor-substituted ethylenes, and styrene—can be alkenylated and arylated by Heck reactions in a clearly predictable fashion. These alkenes can be alkenylated to provide 1,3-dienes, a,/3,y,S-unsaturated carbonyl compounds (Figures 13.27 and 13.28), a,j8,y,8-unsaturated carboxyl compounds (Figures 13.27 and 13.28), as well as aryl-substituted 1,3-dienes. Moreover, the same alkenes can be arylated to give styrenes, a./l-unsaturated /3-arylated carbonyl compounds, or a./l-unsaturated /3-arylated carboxyl compounds (Figure 13.26) and stilbenes (Figure 13.29). 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

There are very numerous synthetic applications of the Heck reaction, notably in the coupling of naphthyl bromide with ethylene to give a precursor to naproxen 88... 

Ethylene is the most reactive alkene, and the rates of reaction can decrease with the size and number of alkene snbstitnents. However, the rate-limiting step can be the initial oxidative addition of R-X with Pd°, making alkene structure less important in the overall rate. SnccessM snbstitution is general for monosnbstitnted aUcenes and common even with 1,2-disnbstitnted alkenes. Trisubstitnted alkenes are largely nseless in the Heck reaction the intermediate R-Pd-X species... 

Poly(ethylene glycol) (PEG) was used as a soluble polymeric support in the efficient preparation of the 2-benzazepine 58 via a phosphine-free palladium-catalysed Heck reaction from 57 <06T10456>. 

The total synthesis of the potent anticancer macrocyclic natural product lasiodiplodin was achieved in the laboratory of A. Furstner. The key macrocyclization step was carried out by the alkene metathesis of a styrene derivative, which was prepared in excellent yield via an intermolecular Heck reaction between an aryl triflate and high-pressure ethylene gas. 

An interesting approach to overcome these limits and thus combine the advantages of homogeneous and heterogeneous catalysis is that of supported liquid phase catalysts (SLPC or SLP). In SLPC the organometallic complex active components are dissolved in a small quantity of liquid phase dispersed in the form of an isle or film on the surface of supports. A SLPC has been applied successfully for several chemical transformations [113], particularly in the Wacker-type ethylene oxidation to acetaldehyde and vinyl acetate production by ethylene acetoxylation [114], and in other reactions catalyzed by Pd-complexes such as the Heck reaction [115]. 

The obvious limitation of this reaction so far is in the electrophile as we have suggested naturally electrophilic enones as ideal partners for aryl or vinyl palladium o-complexes. In fact, complexation with palladium makes all alkenes electrophilic and nucleophilic addition can in principle occur to a simple alkene while it and the nucleophile are both bound to the palladium atom. Such reactions are known for aryl halides. Even ethylene itself does satisfactory Heck reactions and its reaction with the bromopyridine 132 is the basis for a large scale process leading to a drug.21... 

The application of ethylene in Heck reactions often shows different activities from other alkenes, because of Wacker-type side reactions. It was found, however, that iodo- and acceptor-substituted bromoarenes are cleanly converted in aqueous media to the corresponding styrenes utilizing a palladium-TPPMS complex [13], Furthermore, high purity o- and p-vinyltoluenes were prepared on a large scale (in... 

The Mizoroki-Heck reaction was carried out in water/scCOz and ethylene glycol /scC02 using the typical sulfonated triphenylphosphine ligand TPPTS [56]. The reaction is claimed to occur under monophasic conditions although this seems unlikely under the C02 pressures and temperatures with the amounts of catalyst and co-solvent employed. Catalyst recycling was achieved by phase separation after... 

Coupling. In the synthesis of ArCH=CH2 and ArCH=CHAr from ethylene hy the Heck-reaction hoth steps can he catalyzed by palladacycle 1. ... 

F Zhao, M Shirai, M Aral. Heterogeneous catalyst system for Heck reaction using supported ethylene glycol phase Pd/TPPTS catalyst with inorganic base. J Mol Catal A Chem 154 39-44, 2000. 

Heck reaction. The sodium salt of a disulfonated triphenylphosphine serves as ligand for the Pd-catalyzed Heck reaction when the latter is conducted in a mixture of toluene and ethylene glycol. ... 

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