Hydroesterification Alkoxycarbonylation

16a-Substituted steroidal esters [43] and hydroxyesters [44] were obtained as main products in the reaction of androst-16-ene derivatives with alcohols and a,co-diols, respectively, in the presence of a catalytic amount of (Ph3P)2PdCl2 under 80-120 bar CO pressure. On the contrary, a double bond remained intact even under more severe conditions [43]. 

Hydroesterification of the C—C triple bond of a macrocycle has been used as the key step for the total synthesis of several members of the pseudopterane family possessing significant biological activity such as cytotoxicity or anti-inflammatory activity [45]. As any attempts to convert propargylic alcohol 31 directly into butenolide 34 by conventional methods failed, a new route was developed via atmospheric alkoxycarbonylation of mesylate 32 to allenic ester 33. 

The intramolecular version of hydroesterification was used for the synthesis of steroidal 17-spirolactones such as the aldosterone antagonist eplerenone starting from 17-hydroxy-17-vinyl or 17-hydroxy-17-ethynyl derivatives [46]. 

In the presence of various functional groups in an appropriate distance from the alkenyl or alkynyl moieties, substituted alkenes or alkynes may undergo tandem reactions comprising hydroesterification as one of the individual steps. The bicylic cis-fused lactone core of plakortones, a novel class of activators of cardiac SR-Ca -pumping ATPase, was efficiently accessed by a palladium(II)-mediated cyclization-intramolecular hydroesterification reaction sequence. Cyclization of the starting enediols was carried out using either a small excess of Pd(II) [47] or a catalytic amount of Pd(II) and an excess of Cu(II) as the reoxidant [48], 

The (2 )-methoxymethylidene-l,6-dioxaspiro[4,5]-decane skeleton (36) was constructed in a highly stereoselective manner by a palladium(II)-catalyzed cycliza-tion-alkoxycarbonylation sequence starting from the 3,4-dioxygenated-9-hydroxy-l-nonyn-5-one (35). The use of a catalytic amount of Pd(0) and a high excess of p-benzoquinone was essential to minimize the amount of the active palladium(II) catalyst in the reaction mixture and to prevent intramolecular acetal formation, leading to 37 as a side reaction [49]. 

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In presence of a mild base such as Na2C03 or NaOAc, a hydroesterification to furanones is possible (equation 89).437 RhCl3-3H20 or a binary carbonyl was used as catalyst. Indanont derivatives were obtained as by-products. The mechanism probably involves the formation of ar alkoxycarbonyl intermediate (Scheme 29). 

When the cluster [Pd4(C0)4(02CMe)4]-2MeC02H was dissolved in styrene and treated with methanol under an atmosphere of carbon monoxide, methyl cinnamate was formed.516 This reaction was also believed to occur by an alkoxycarbonyl route. The reaction became catalytic when [Pd(OAc)2] (106) was used in presence of NaOAc and a stoichiometric amount of copper(II) as reoxidant for the palladium(O) formed. Stille and co-workers have investigated this reaction, sometimes called carboalkoxylation, in detail. A basic difference between this reaction and the hydroesterification described above is that the oxidative nature of carboalkoxylation permits double functionalization of a double bond. Thus (E)- and (Z)-2-butene react readily with CO and methanol in the presence of a catalytic amount of PdCl2 and a stoichiometric amount of CuCl2 to give methyl 3-methoxy-2-methylbutanoate (equation 124).517,518... 

Hydroesterification is one of the Reppe reactions in which carbon monoxide, an alcohol, and an alkene react to esters (Scheme 21). This reaction is also called alkoxycarbonylation, hydroalkoxycarbonylation, and hydrocarbalkoxylation. 

The cycle is started with the formation of a Pd-alkoxy complex that reacts with CO to an alkoxycarbonyl intermediate. In the next step, the approach of the olefin and insertion into the carbonyl palladium bond is predicted. In the last step, the starting complex is rebuilt by the addition of an alcohol and the cleavage of the hydroesterification product [59]. 

A useful synthesis of ( )-j -ethoxycarbonylvinylsilanes by palladium-catalyzed regio- and stereospecific hydroesterification (EtOH -I- CO) (or carboethoxylation) of trimethylsilylacetylenes has been reported recently [210]. Alkoxycarbonyl or carbonyl functionalization of vinylsilanes are useful synthetic intermediates [211, 212]. The use of PdCl2(dppf) as a catalyst (with SnCl2 2 H2O as cocatalyst) is found to be superior and gives excellent yields. A key step in the reaction is thought to involve hydropalladation to give 60 or 61. The preference for 60 to 61 is understood... 

Besides the term alkoxycarbonylation, hydroesterification and hydroalkoxycarbony-lation have also been used in the literature to describe this reaction. Furthermore, more specific terms such as methoxycarbonylation can be found. In this chapter, the term alkoxycarbonylation will be used as a general term, and specific terms will be used to unambiguously define which reaction is meant. 

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