Heterocouplings

For the development of the oxidative homocoupling reaction, in 1955 Chodkiewicz and Cadiot explored a Cu(I)-catalyzed heterocoupling reaction of terminal alkynes with 1-bromoalkyne in the... 

Nickel-bpy and nickel-pyridine catalytic systems have been applied to numerous electroreductive reactions,202 such as synthesis of ketones by heterocoupling of acyl and benzyl halides,210,213 addition of aryl bromides to activated alkenes,212,214 synthesis of conjugated dienes, unsaturated esters, ketones, and nitriles by homo- and cross-coupling involving alkenyl halides,215 reductive polymerization of aromatic and heteroaromatic dibromides,216-221 or cleavage of the C-0 bond in allyl ethers.222... 

The electrochemistry of cobalt-salen complexes in the presence of alkyl halides has been studied thoroughly.252,263-266 The reaction mechanism is similar to that for the nickel complexes, with the intermediate formation of an alkylcobalt(III) complex. Co -salen reacts with 1,8-diiodo-octane to afford an alkyl-bridged bis[Co" (salen)] complex.267 Electrosynthetic applications of the cobalt-salen catalyst are homo- and heterocoupling reactions with mixtures of alkylchlorides and bromides,268 conversion of benzal chloride to stilbene with the intermediate formation of l,2-dichloro-l,2-diphenylethane,269 reductive coupling of bromoalkanes with an activated alkenes,270 or carboxylation of benzylic and allylic chlorides by C02.271,272 Efficient electroreduc-tive dimerization of benzyl bromide to bibenzyl is catalyzed by the dicobalt complex (15).273 The proposed mechanism involves an intermediate bis[alkylcobalt(III)] complex. 

Trost s group examined the possibility of carrying out cross-coupling reactions of alkynes and transformed this into a very powerful synthetic method. Either homocoupling or perhaps, more interesting, heterocoupling procedures were performed using catalytic amounts of a palladium salt (Equation (191)). 

Application in organic synthesis of pentacoordinated triorganodifluorosilicate anions, such as [Bu4N][Ph3SiF2] 825, have been extended to palladium(0)-catalyzed cross coupling reactions (solvents DMF, TFIF, dioxane) with arene halides (Scheme 111).825 This method is tolerant to various palladium(O) catalysts and provides excellent yields of mainly heterocoupled products and only small amounts of homocoupled byproducts. 

A radical tandem cyclization, consisting of two radical carbocyclizations and a heterocoupling reaction, has been achieved by electrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, for example, triquinanes, starting from carboxylic acids which are accessible in few steps (Scheme 6) [123]. The selectivity for the formation of the tricyclic, bi-cyclic, and monocyclic product depending on the current density could be predicted by applying a mathematical simulation based on the proposed mechanism. 

Radical cyclizations of this type can be also achieved in chemical radical chain reactions [124, 125], often in a wider scope. The anodically initiated cyclization, however, has advantages. It avoids tin hydride, which is mostly used as coreagent in chemical radical chain cyclizations and because the toxicity of tin organics makes these reactions less attractive for the synthesis of pharmaceuticals. In chemical radical chain reactions, which involve in most cases an addition and an atom-transfer reaction, one C,C- and one C,H- or C,X bond is being formed, while in anodic addition followed by heterocoupling two C,C bonds are being formed, where the second one is established simply and in wide variety by the appropriate choice of the coacid. 

The conversion of aromatic compounds comprises coupling, nuclear and ben-zylic substitution, and in some cases, addition. Homo- and in a more limited scope, heterocoupling is achieved for unsubstituted and substituted aromatic compounds in direct or indirect anodic processes. Chemically, there is a limited variety of expensive oxidation reagents available, but a large scope of transition... 

A reaction of type ii (heterocoupling) occurred for (74) in satisfactory yield when... 

Scheme 43 Intermolecular cathodic heterocoupling of ketones with oximes Rh R alkyl, cycloalkyl, yields 43-98%.

Intermolecular coupling reactions can take place either through a reaction between an electrogenerated reagent and another suitable species (heterocoupling reaction)... 

Scheme 86 Cathodic heterocoupling of ketones with methyl acrylate.

Scheme 149 Cathodic heterocoupling of aryl halides and pyridyl halides.

Scheme 150 Cathodic heterocoupling of aryl halide and pyrimidine halide.

Fig. 47 Stereoselective 5-exo-trig-cyclization and heterocoupling to a prostaglandine precursor [246].

Unsaturated carboxylic acids can be de-carboxylated to alkyl radicals that undergo an intramolecular addition. The S-exo-trig-cyclization of fi-allyloxy radicals, generated from an appropriate carboxylic acid, combined with a final heterocoupling has been applied to synthesize a precursor of prostaglandine PGF2q (Fig. 47) [246] and a branched carbohydrate (ratio of diastereo-mers 1.8 1) (Fig. 48) [247]. A radical tandem cyclization of a doubly unsaturated monocyclic carbocyclic acid provides a... 

Intramolecular hydrodimerization of activated olefins has been exploited for elegant one-step cyclizations and heterocouplings (Fig. 53) [263, 278, 279]. 

A variety of intramolecular cathodic homo- and heterocouplings and their stereochemistry also with regard to the synthesis of complex natural products is shown in Fig. 54, and has been compiled in Chap. 11 and in Ref. [280]. 

Cathodic heterocoupling of ketones with allylic alcohols takes place at a carbon fiber cathode with high regio- and diastereoselectivity to afford the corresponding... 

Fig. 25. Heterocoupling between an arylhalide and olefin is achieved using dendrimer-en-capsulated catalysts with 100% selectivity for the trans isomer product (R = -H, -NO2 and X = -I,-Br)...

Preliminary results from a study of catalytic activation of the heterocoupling between arylhalides and alkenes using pony-tail-functionalized dendrimer-encapsulated Pd nanoparticles have shown promise. For example, the classic Pd-catalyzed Heck coupling between arylhalides and methacrylate yields predominately (> 97%) the trans-cinnimaldehyde product [176]. On the other hand, the C02-soluble dendrimer nanocomposite exclusively catalyzes the production of the highly unfavored 2-phenyl-acrylic acid methyl ester isomer at 5000 psi and 75 °C (Fig. 27] [177]. 

Understanding the relative rates of both productive heterocoupling and homodimerization reactions allows for the judicious selection of cross-partners that can participate in a highly selective CM reaction, even when equal stoichiometries of reactants are employed. There are five relevant equilibria and 10 rate constants in CM (Scheme 4 the rate constants for olefin E/Z isomerization have been excluded for simplicity). In the simple scenario where all the rates are similar, and the reaction can achieve equilibrium, the expected statistical cross-product yield is 50%. If, however, one olefin (e.g., R CH=CH2), as a consequence of either steric or electronic factors, reacts at a slower rate k- ) than the other reactions, such that k, k/ k-, and it is assumed that the productive cross-... 

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