Pd catalyzed carbonylation

Formation of carboxylic acids ami their derivatives. Aryl and alkenyl halides undergo Pd-catalyzed carbonylation under mild conditions, offering useful synthetic methods for carbonyl compounds. The facile CO insertion into aryl- or alkenylpalladium complexes, followed by the nucleophilic attack of alcohol or water affords esters or carboxylic acids. Aromatic and a,/ -unsaturated carboxylic acids or esters are prepared by the carbonylation of aryl and alkenyl halides in water or alcohols[30l-305]. 

The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

The carbonylation of aryl iodides in the presence of alkyl iodides and Zn Cu couple affords aryl alkyl ketones via the formation of alkylzinc species from alkyl iodides followed by transmetallation and reductive elimination[380]. The Pd-catalyzed carbonylation of the diaryliodonium salts 516 under mild conditions in the presence of Zn affords ketones 517 via phenylzinc. The a-diketone 518 is formed as a byproduct[381],... 

The reaction of the allylic acetate with a diene system 784 affords the poly-fused ring system 785 by three repeated alkene insertions[487]. An even more strained molecule of the [5.5.5.5] fenestrane 788 has been constructed by a one-pot reaction in a satisfactory yield by the Pd-catalyzed carbonylation-cycliza-tion of 786 without undergoing elimination of /3-hydrogen in the cr-alkylpalla-dium intermediate 787 owing to unfavorable stereochemistry for syn elimination[488]. 

Propargylic alcohols are less reactive and their carbonylation proceeds under severe conditions. The Pd-catalyzed carbonylation of propargyl alcohol in the... 

Pd-catalyzed carbonylation of heteroaryl halides provides a quick entry to heteroaryl carbonyl compounds such as heteroaryl aldehydes, carboxylic acids, ketones, esters, amides, a-keto esters and a-keto amides. In addition, Pd-catalyzed alkoxycarbonylation and aminocarbonylation are compatible with many functional groups, and therefore, are more advantageous than conventional methods for preparing esters and amides [78],... 

Dihydropyrrole triflate 55, which we have encountered earlier in this chapter, undergoes a Pd-catalyzed carbonylation reaction to give ester 158 [53, 81]. A similar carbonylation sequence in the presence of the hydride donor n-BusSnH gives the corresponding aldehyde in 56% yield [81]. 

In the presence of tetramethyltin, 1-bromonauclefine reacts with CO in a Pd-catalyzed carbonylation to give the alkaloid naucletine [202], Dong and Busacca effected a new synthesis of tryptamines and tryptophols via a Rh-catalyzed hydroformylation of functionalized anilines that are prepared by a standard Heck reaction, as shown for the preparation of tryptamine sulfonamide 325 [423]. This reaction is applicable to ring-substituted tryptamines (Cl, Br, F. OMe, CF3). Likewise, the Rh-catalyzed carbonylation of o-alkynylanilines, which were prepared by a Pd-catalyzed Sonogashira coupling, leads to oxindoles (60-86% yields) [424],... 

Carbonylation of chloropyridines is less straightforward than that of bromo- and iodopyridines. The a and y positions are sufficiently activated to undergo facile oxidative addition to Pd(0), whereas the reactivity is greatly diminished at (3 positions. Thus, 2,6-dichloropyridine was converted to the corresponding dimethyl ester in good yield under normal Pd-catalyzed carbonylation conditions [152], and 2-chloropyridine was readily carbonylated to furnish methyl 2-pyridinecarboxylate (191), but 3-chloropyridine gave no carbonylated products under the same conditions [153,154],... 

The Pd-catalyzed carbonylation of 2,6-dibromopyridine in the presence of 2-pyridylamine gave N,lV -di(2-pyridyl)pyridine-2,6-dicarboxamide under relatively high pressure and prolonged reaction time [156]. Partial aminocarbonylation of 2,6-dibromopyridine was more cumbersome—only 55% of the monocarboxamide 195 was isolated in a shorter reaction time accompanied by the corresponding 2,6-dicarboxamide in 32% yield. 

A unique Pd-catalyzed carbonyl insertion reaction of 197 furnished pyrido[2,l-b]quinazoline 198, an antiallergy agent [158]. This particular outcome may be substrate-specific. 

Advantage has been taken of the aforementioned observations in the synthesis of a terthiophene natural product, arctic acid (147) [123]. Pd-catalyzed carbonylation of bromobisthiophene 25, obtained from the Kumada coupling of 2-thienylmagnesium bromide and 2,5-dibromothiophene, gave bithiophene ester 144, which was converted to iodide 145 by reaction with iodine and yellow mercuric oxide. Subsequent propynylation of 145 was then realized using the Sonogashira reaction with prop-l-yne to give bisthienyl alkyne 146, which was subsequently hydrolyzed to 5 -(l-propynyl)-2,2 -bithienyl-5-carboxylic acid (147), a natural product isolated from the root of Arctium lappa. 

Lin and Yamamoto described a Pd-catalyzed carbonylation of benzyl alcohols [131]. Thus, under the agency of palladium catalysis and promotion by HI, 3-thiophenemethanol was carbonylated to give 3-thiopheneacetic acid as a major product along with methylthiophene as a minor one. 

To synthesize pyrazinecarboxylic esters and pyrazinecarboxamides, chloropyrazines were subjected to Pd-catalyzed carbonylation reactions in either alcohols or dialkylamines [44, 45]. 2-Chloro-3,6-dimethylpyrazine (23) was smoothly carbonylated in methanol containing a catalytic amount of Pd(dba)2 and Ph3P to give 2-methoxycarbonyl-3,6-dimethylpyrazine (70). Somewhat lower yields were observed in the preparation of pyrazinecarboxylic diesters under the same conditions. 

Pd-catalyzed carbonylation of 2-chloropyrazine 1-oxide failed, whereas that of 3-chloropyrazine 1-oxide (40) proceeded without deoxygenation of the IV-oxide function to give 3-methoxycarbonylpyrazine 1-oxide (73). This observation was in accord with the failure of Stille reactions of 2-chloropyrazine 1-oxide [9,18]. 

Overman et al. <1996JA9062> and Kibayashi et al. <2002JOC5517> have utilized the same alkynyl intermediate 222 as a substrate in their chemistry (Scheme 47). While the first group uses a nucleophilic attack of the triple bond on the iminium cation 223, the second group performs a regioselective hydrostannylation, followed by Pd-catalyzed carbonylation, to provide the precursor 224 to the cyclization step. 

Propargyl halides [56] and propargyl acetates [57] have also been employed for Pd-catalyzed carbonylation (Scheme 3.22). From the latter substrates, allenylcarboxylic acids were obtained under phase-transfer conditions (with nBu4NBr in aqueous NaOH and 4-methyl-2-pentanone) [56],... 

When the Pd-catalyzed carbonylation of a propargyl carbonate was performed in the presence of an activated methylene or methine pronucleophile, the acylpalla-dium intermediate 38 was trapped by the pronucleophile to give 39 (Scheme 3.24) [59]. 

An a-allenic sulfonamide undergoes Pd-catalyzed carbonylative cyclization with iodobenzene, affording a mixture of isomeric heterocycles (Scheme 16.12) [17]. The coupling reaction of an allene with a PhCOPdl species takes place at the allenyl central catrbon to form a 2-acyl-Jt-allylpalladium complex, which is attacked by an internal sulfonamide group in an endo mode, affording a mixture of isomeric heterocycles (Scheme 16.13). 

Scheme 23 Pd-catalyzed carbonylation of iodophenol with alkynes and allenes...

Rahman MT, Fukuyama T, Kamata N et al (2006) Low pressure Pd-catalyzed carbonylation in an ionic liquid using a multiphase microflow system. Chem Commun 21 2236-2238... 

Lisinopril (S) -1-A - (l-Carboxy-3-phenylpropyl) -L-lysyl] L-proline dihydrate Pd-catalyzed carbonylation, hydroxylation of a double bond, chemical resolution, amidation, A-protection (using trifluoroacetic anhydride), carbonyl activation (using phosgene)... 

The Pd-catalyzed carbonylation of o-vinylaryl bromides using Mo(CO)6 as CO source with microwave irradiation gave indanone 338 and 3-acylaminoindanone 340, which are key intermediates for the synthesis of inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and Plasmepsin I and II (Scheme 46). These polycyclic compounds were obtained in less than 30 min in high yields. The results clearly indicate the power and advantage of this protocol, especially for the combinatorial parallel synthesis of a library of compounds. 

Boots-Hoechst-Celanese process More recently, a shorter three-step catalytic route has been developed and is illustrated in the following scheme. Here, a Pd catalyzed carbonylation reaction is employed in the final step to introduce the carboxyl group. 

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