Palladium-catalysed reactions oxidation

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

Palladium-catalysed reactions of dimetallic compounds 358 such as X2B—BX2, R3Sn—SnR3, R3S11—SiR3 or R3Si—SiR3 with halides via oxidative addition and transmetallation are useful for the preparation of carbon main group metal bonds 359. 

The palladium-catalysed addition of aryl, vinyl, or substituted vinyl groups to organic halides or triflates, the Heck reaction, is one of the most synthetically useful palladium-catalysed reactions. The method is very efficient, and carries out a transformation that is difficult by more traditional techniques. The mechanism involves the oxidative addition of the halide, insertion of the olefin, and elimination of the product by a p-hydride elimination process. A base then regenerates the palladi-um(0) catalyst. The whole process is a catalytic cycle. 

The reactions proceed with retention of configuration at phosphorus. Various classical routes to alkylphosphine oxides have been applied in the synthesis of a range of potentially chelating and pincer-like ligands, e.g., (233), the binaphthyl system (234), the hybrid phosphine oxide-N-oxide (235), and the chiral pyridine bis(phosphine oxide) (236). A route to diarylmethylphosphine oxides is afforded by the palladium-catalysed reaction of aryl bromides with tet-rakis(hydroxymethyl)phosphonium chloride in the presence of a base. The diastereoisomeric system (237) has been isolated from the reaction of a cyclic... 

Now the alkene must be moved yet one more time around the ring to prepare the way for another intramolecular Heck reaction. Hydroboration (chapter 17) of 153 is regioselective because of the large N-Boc group and Swem oxidation completes the insertion of the ketone 155. Reduction and elimination use another palladium-catalysed reaction. Conversion to the triflate 157 is followed by Pd-catalysed transfer hydrogenation, the H atom coming from formic acid HC02H. 

Organopalladium compounds can be prepared by electrophilic paUadation, oxidative addition to aryl halides or reaction of Pd(II) with organometalhc reagents. These transformations are all vital for the palladium-catalysed reactions discussed later in this chapter. 

Palladium-Catalysed reactions of haloaryl phosphine oxides modular routes to functionalised ligands... 

PALLADIUM-CATALYSED REACTIONS OF HALOARYL PHOSPHINE OXIDES MODULAR ROUTES TO FUNCTIONALISED LIGANDS... 

The electron-withdrawing effect of typical azines makes chlorine substituents sufficiently reactive that they can participate in palladium-catalysed reactions, even at a pyridine / -position. " a-Activation can serve to allow regioselective reaction in the presence of a /3-halogen (cf. section 2.7.1.1, oxidative addition) and this should be contrasted with lithiation by exchange which shows the opposite regioselectivity. 

This reaction type also has been used to prepare C-inethyl 5-pyrimidine-carboxylic acids l94H(38)1375l. Pyrimidinylzinc halides obtained upon oxidative addition of active zinc to 2- or 4-iodopyrimidines have been shown to be transformed into aiylated pyrimidines by palladium-catalysed reaction [93T(49)9713]. Covalent hydration at the 2- and 4-position of monomethyl- and dimethyl-S-pyrimidinecaiboxylic acids has been investigated [94H(38)137S]. 

It seems highly likely that all palladium-catalysed reactions that commence with an oxidative addition as the first step of the catalytic cycle proceed though a Pd(0) / Pd(ll) mechanism. Thus one needs to conclude that all palladacycles and pincers are converted to some form of Pd(0) in these reactions. In many cases this was shown to be in the form of palladium nanoparticles. However, with the more reactive iodoarenes it is possible that most of the catalyst is in the form of an anionic or neutral monomeric or dimeric palladium species. 

Aryltrimethyl- or tri- -butylstaimanes as common Stille reagents are also successfully homo-coupled under palladium catalysed reactions in the presence of ethyl 2,3-dibromophenylpropionate (443) [26], or more conveniently by oxidation with copper(I) salts, e.g. CuCl [27], or copper(II) salts, e.g. Cu(N03)2 3H20 [28,29], which proceed smoothly at room temperature in tetrahydrofuran or DMF to afford symmetrical biaryls in excellent 3uelds. The Cu(N03)2-mediated homo-coupling works well also with diaryldimethyl(or -butyl)stannanes [30]. Moreover, the reaction can be accomplished with a catalytic amount of copper(II) chloride or manganese(II) bromide (10 mol%) in the presence of iodine as stoichiometric oxidant [31]. For example, compound 443, acting as an oxidant, converts the phenyltri-n-butylstannane (184) to biphenyl (8) in 86% yield [26], Scheme 11. 

The palladium catalysed reaction -follows a rate law which is independent on the substrate concentration, but dependent on the CO pressure. In a later work, a AS =-233 J mol " "K, instead o-f -414, has been reported -for this react i on [1843, tor which it has been confirmed a zero order in substrate and first order in each metallic component and in CO pressure. The carbonyl ation of an intermediate complex forming the isocyanate is considered the rate determinin step in the palladium-catalysed reaction. In this work[183j, the oxidative addition of the nitro compound to the catalyst was considered a more likely rate determining step in the case of the rhodium-catalysed reaction. 

A common ground that is explicitly or implicitly defended in the majority of studies on Mizoroki-Heck reactions is that the limiting stage for the whole cycle is the oxidative addition step. By this criterion, the most important substrates, aryl halides, are subdivided into very reactive (aryl iodides and electron-deficient aryl bromides), less reactive (all other aryl bromides and electron-deficient aryl chlorides) and very unreactive (all other aryl chlorides). As evident as this classification may seem, it is not based on any solid proof. Indeed, if it were really so important, the oxidative addition step should have been characterized by very strong dependence on substituent effects in these substrates. However, this has not been observed in either Mizoroki-Heck reactions or in any other palladium-catalysed reaction of aryl hahdes. The Hammett reaction constant values p, whenever measured, are rather modest in valne [5]. Such values could hardly have accounted for the well-known enormous distance between the reactivity of, for example, a typical activated substrate 7 and a typical deactivated substrate 8 (Figure 2.1). 

The problem of how to make aryl chlorides usable in palladium-catalysed reactions has particularly attracted considerable attention in the last decade [127-129]. The task to use aryl chlorides and to obtain preparatively useful yields and TONs for a wide selection of substrates might only be solved by application of monodentate ligands. These are actively involved in increasing the reactivity of palladium(O) species towards the oxidative addition to the unactivated C(sp )-Cl bond. 

In their enantioselective total synthesis of the alkaloid cephalotaxine (246), Tietze and Schirok [127] used a combination of a Tsuji-Trost and a Mizoroki-Heck reaction (Scheme 8.62). It was necessary to adjust the reactivity of the two palladium-catalysed transformations to allow a controlled process. Reaction of 243a using Pd(PPh3)4 as catalyst led to 244, which furnished 245 in a second palladium-catalysed reaction. In this process, the nucleophilic substitution of the allylic acetate is faster than the oxidative addition of the arylbromide moiety in 243a however, if one uses the iodide 243b, then the yield drops dramatically due to an increased rate of the oxidative addition. 

Triphenylenes have been produced in a palladium-catalysed reaction of ortho-iodobiphenyls with orfho-bromobenzyl alcohols. As ouflined in Scheme 19, the mechanism is likely to involve oxidative addition of the iodobiphenyl to palladium... 

In the palladium-catalysed carbonylation of aryl bromides to yield benzaldehyde derivatives, IV-formylsaccharin is used as the source of the acyl function. A double carbonylation has been observed in the reaction of aryl halides with carbon monoxide and terminal alkenes which yields 4-arylfuranones such as (152). The proposed mechanism involves oxidative addition of the aryl halide to palladium and insertion of the carbon monoxide to give an acyl palladium species. This is followed by coordination and insertion of the alkene. A second carbon monoxide insertion is faster than -hydride elimination and, after intramolecular attack, leads to the product. The palladium-catalysed reaction of aryl iodides with simple ketones such as acetone in the presence of carbon monoxide has been shown to yield 1,3-diketones such as... 

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