Palladium chemistry synthetic utility

We believe that this novel new palladium migration chemistry provides a unique new way to generate a wide variety of organopalladium intermediates that will find considerable synthetic utility in the future. 

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions arc strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles arc studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals. 

Another synthetically useful reaction is catalytic allylic alkylation (Eq. 12.81). With this reaction, the X group can be a halogen, as well as other commonly available substrates such as acetate or carbamate. The synthetic utility derives mostly from stereochemical control, which is briefly introduced in the Connections highlight below. This reaction is widespread in organometallic chemistry and has been found to be catalyzed by a variety of metals, including nickel, palladium, platinum, rhodium, iron, ruthenium, molybdenum, and tungsten. 

The [2,3]-Stevens rearrangement is a thermal sigmatropic rearrangement of an ammonium ylide (38) to form unnatural amino acid derivatives 39 (Scheme 12). Traditionally, the ammonium ylides have been formed through alkylation of aminoesters 36 with aUcyl halides 37 to form quaternary salts followed by treatment with base. Although effective, the harsh conditions lead to side products and limited substrate scope. More recently, the coupling of diazoesters 40 and allylic amines 41 in the presence of metals like copper, rhodium, and palladium has been developed for the direct constmction of ammonium ylides 38 via metal carbenoid intermediates. " Although this approach represented an advance over the traditional alkylation chemistry, the use of diazoesters still limits the synthetic utility of these reactions. 

Another variant of the Heck reaction which is important in heterocyclic chemistry utilizes five membered heterocycles as olefin equivalent (2.2.)7 It is not clear whether the process, coined as heteroaryl Heck reaction follows the Heck mechanism (i. e. carbopalladation of the aromatic ring followed by //-elimination) or goes via a different route (e.g. electrophilic substitution by the palladium complex or oxidative addition into the C-H bond). Irrespective of these mechanistic uncertainties the reaction is of great synthetic value and is frequently used in the preparation of complex policyclic structures. 

Another variant of this type reaction has recently been utilized by Novartis to manufacture an intermediate for Prosulfuron (see Table 1.1). The synthetic scheme is shown by reaction 7.32. The soluble palladium-complex-catalyzed C-C coupling between a diazonium salt and a fluoro alkene gives the required intermediate. This is then converted to the final product by standard reactions of synthetic organic chemistry. 

Anthranilic acids are useful reagents in synthetic chemistry, and two new and convenient syntheses have appeared. In one, carbonylation of bromoacetanilides utilizes palladium catalysis, and in the other, oxidation of isatins with hydrogen peroxide in the presence of sodium methoxide provides a ready source of anthranilic esters. 

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