Palladium-catalyzed alkoxycarbonylation

Very high regioselectivities (> 99.5% iso) were obtained, using PdCl2(PhCN)2 in combination with (+)-neomethyldiphenylphosphine and toluene-j9-sulfonic acid, under mild conditions (70 °C and 10 bar). More recently, the palladium-catalyzed alkoxycarbonylation and amido-carbonylation of aryl bromides and iodides in [bmim][BF4] and [bmim][PF6] has been described. Enhanced reaction rates were observed compared to conventional media and the ionic liquid-catalyst could be recycled. 

In a similar fashion, palladium-catalyzed alkoxycarbonylation of 54 was effective in producing pyrimdine esters 55 <99T405>. It was noted that dppf along with the use of the alcohols as solvents (rather than solely as reagents) was required for optimal conversion. 

The palladium catalyzed alkoxycarbonylation of alkynyliodonium tosylates 132 in methanol or ethanol in the presence of trialkylamine proceeds under mild conditions to give carboxylates 144 in good yield (Scheme 58) [120]. 

Carbonylphosphine complexes of zero-valent palladium are considerably less stable and more reactive than their Ni counterparts. Most common triphenyl-phosphine complexes of Pd are excellent catalysts for various carbonylation reactions of aryl iodides and bromides [15,129-131 ]. It is conceivable that the palladium-catalyzed alkoxycarbonylation of ArCl proceeds via a mechanism similar to that proposed for the analogous reactions of bromo- and iodoarenes (Scheme 5) [45,159,160,161]. 

Palladium-catalyzed alkoxycarbonylation enables synthesis of a variety of heterocyclic esters that are otherwise not easily prepared. 5-Bromopyrimidine was transformed into 5-ethoxycarbonylpyrimidine in quantitative yield employing the Pd-catalyzed alkoxycarbonylation. The alkoxycarbonylation of 2-chloro-4,6-dimethoxypyrimidine, in turn, led to benzyl 4,6-dimethoxypyrimidine-2-carboxylate (240), whereas alkoxycarbonylation of 2-(chloromethyl)-4,6-dimethoxypyrimidine provided pyrimidinyl-2-acetate 242 [119]. 4,6-Dimethoxypyrimidines 240 and 242 are both important intermediates for the preparation of antihypertensive and antithrombotic drugs. 

Palladium-catalyzed alkoxycarbonylations represent another class of transition metal catalyzed oxycarboration reactions37. This reaction type was recognized early as proceeding via trans addition, while dicarbonylations (see Section 1.5.8.3.3.) involve overall cix addition38 43-95. 

This reaction type can also be applied to tetrahydrofuran formation and its stereoselectivity is markedly influenced by substituents on the chain and at the double bond49,3 -56. Starting from 5-hydroxy-l-heplenes 3, palladium-catalyzed alkoxycarbonylation leads to 2.5-disubstituted tetrahydrofurans 4 in good yield. Tetrahydrofuran formation is sterically unselective when the substituent R1 at the double bond is hydrogen or methyl however, when R1 is a methoxy group, formation of an isomer of type 4A is highly favored (d.r. >95 5)49,55. 

Scheme 2.6 Palladium-catalyzed alkoxycarbonylation of aryl bromides...

There is an impressive number of publications on the application of transition metal-catalyzed carbonylation reactions in total synthesis. In 1980 Tsuji and colleagues applied palladium-catalyzed alkoxycarbonylation in the synthesis of Zearalenone [22] and Curvularin [23]. Starting from the corresponding aryl iodides or benzyl chlorides and alcohols, the parent molecules for Zearalenone and Curvularin were prepared in good yields and finally transferred to the target products by a few more steps (Scheme 10.1). 

Ma and Tian reported the synthesis of (S)-(+)-aM4CPG from 4-hydroxyphen-ylglycine [59-61]. A palladium-catalyzed alkoxycarbonylation of aryl triflates was applied (Scheme 10.9). 

Vinyl halides, as an interesting family of substrates in addition to vinyl triflates, were applied and used in total syntheses as well. In 1997 manoalide as a marine anti-inflammatory sesterterpenoid was synthesized [71, 72]. Palladium-catalyzed alkoxycarbonylation of vinyl iodide was the key step in the synthetic procedure (Scheme 10.11). 

Bicuculline as an effective antagonist of an inhibitory neurotransmitter, y-aminobutyric acid (GABA), many procedures have been developed for its preparation. Orito and colleagues applied palladium-catalyzed alkoxycarbonylation as the key step in its total synthesis (Scheme 10.16) [88]. 

N- [4-[ 1 -Ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glu-tamic acid as an antifolate was synthesized by Gangjee and colleagues [107], and palladium-catalyzed alkoxycarbonylation of aryl triflate was applied. A palladium-mediated carbonylative C-H activation was developed by Sames and team and applied in the total synthesis of teleocidin B4 core (Scheme 10.24) [108]. 

Overman and colleagues reported the total synthesis of ( )-Gelsemine in 2005 [117]. 1.1 % of the overall yield from 3-methylanisole was succeeded via 26 isolated intermediates. Palladium-catalyzed alkoxycarbonylation of vinyl triilate was applied (Scheme 10.31). 

After a long period of neglect of hydroformylation of fatty acid compounds derived from renewable resources, it is once again in the focus of research. In comparison to the pioneering time, smoother reaction conditions have been identified. Also, related methods such as palladium-catalyzed alkoxycarbonylation of fatty acid esters are attracting more and more attention [64]. This methodology mainly produces a,m-diesters, which cannot be produced in good yields by hydroformylation to date. 

Addition of element-element compounds to alkynes has been reviewed.Other insertions of alkynes into palladium-hydride bonds have been identified in Drent s palladium-catalyzed alkoxycarbonylation of alkynes palladium(ii)-alkenyl complexes have been invoked to account for the observed H/D exchange when conducted in GH3OD and to identify the pathway (i.e., through migratory insertion into Pd-H and formation of acyl species by carbonylation) of the overall reaction. ... 

The mechanism for palladium-catalyzed alkoxycarbonylation ofcinnamyl chloride was investigated. An associative mechanism was observed at low pressure, while an insertion mechanism was observed at high pressure or when an excess of ligand (PPh3, P Hx3, or hemilabile P-N ligands 42, respectively) was used [147]. 

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