Coupling of Acid Chlorides

Acid chlorides may also be used as substrates. Oxidative addition generates an acyl paUadium(H) complex that may decarbonylate leading to by-products. This may be avoided by running the reaction under an atmosphere 

A corollary of this is that if a Stille coupling of a vinyl or aryl halide is carried out under an atmosphere of CO, then a ketone will be produced. This is discussed in Section 4.1. 

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Palladium-Catalyzed Coupling of Acid Chlorides with Organotin Reagents (E)-Ethyl-4-(4-n1trophenyl)-4-oxo-2-butenoate A, F. Renaldo, J, W. Labadie, and J. K. Stille, Department of Chemistry, Colorado State University, Ft. Collins, CO 80523... 

Palladium, benzylchlorobis(triphenylphosphine)-, trans-, 67, 86 Palladium-catalyzed aryl-aryl coupling, 66, 70 PALLADIUM-CATALYZED ALLYLIC AMINATION, 67,105 PALLADIUM-CATALYZED CHLOROACETOXYLATION, 67, 105 PALLADIUM-CATALYZED COUPLING OF ACID CHLORIDES WITH ORGANOTIN REAGENTS, 67, 86 PALLADIUM-CATALYZED COUPLING OF ARYL HALIDES, 66, 67 PALLADIUM-CATALYZED syn-ADDITION OF CARBOXYLIC ACIDS,... 

Modified Sonogashira Coupling of Acid Chlorides to Alkynones... 

A carbonyl group in conjugation with the triple bond exerts a strong polarization of the alkyne. Thus, Sonogashira coupling of acid chlorides 7 and terminal alkynes... 

Scheme 5 Alkynones 8 by modified Sonogashira cross coupling of acid chlorides 7 and alkynes 4...

Mechanistically, this sequence can be rationalized by initial alkynone formation upon coupling of acid chloride 7 and aUcyne 4 furnishing the alkynone 8, which now can act as a dipolarophile (Scheme 18). The amount of triethylamine is sufficient to deprotonate the l-(2-oxoethyl)pyridinium bromide 25 giving rise to the zwitter-ionic pyridinium ylide 27, an allyl-type dipole suitable for the subsequent 1,3-dipolar cycloaddition to give the dihydroindolizine 28. Under either aerobic or anaerobic conditions in the final cycloaddition step oxidative aromatization directly furnishes the desired indolizines 26. 

Another palladium catalysed reaction that has been successfully performed in water is the direct coupling of acid chlorides with alkynes.Copper is used as a CO catalyst and the choice and use of a surfactant are essential to the success of the reaction (Figure 3.10). 

PALLADIUN-CATALYZED COUPLING OF ACID CHLORIDES UITH ORGANOTIN REAGENTS ETHYL (E )-4- 4-NITROPHENYL)-4-OXO-2-BUTENOATE (2-Buteno1c acid, 4-(4-nitropheny1)-4-oxo-, ethyl ester, (E)-)... 

Ketones can be obtained by coupling of acid chlorides with organostannanes or by carbonylative couplings. The first reaction is one of the older and more general Stille coupling reactionsi i 122 and continues to be used under essentially the original conditions.1 3... 

The palladium-catalyzed coupling of acid chlorides with tetraalkyllead derivatives gave the ketones in high yields under mild conditions (Scheme 13.28) [51]. Even with only 0.6 equiv. tetrahutyllead high yields (78-99%) were obtained. 

Coupling of acid chlorides with (E)-BujSnCH=CHSnBuj 1,4-diketones f The... 

Pd-catalyzed Stille coupling can be extended to coupling of acid chlorides with ([ )- ,2-bis(tributylstannyl)ethene. Unexpectedly, a 1,4-dionc is formed, evidently by reduction of an intermediate enediketone by BuySnCl. Reaction of an a, -unsaturated acid chloride also leads to a 1,4-diketone, as does the reaction of an acid chloride with a /3-stannyl enone. 

While wanning the catalysis mixture to 55 C (Step D, Scheme 1) leads to no other observable reaction intermediates, the generation of intermediate 8 would allow the series of steps shown in Scheme 1. Insertion of the coordinated CO into the palladium-carbon bond would lead to the overall coupling of acid chloride, imine and carbon monoxide in conq>lex 10. The subsequent loss of HCl from 10, either via direct deprotonation or P-H elimination, would form the a-amide substituted ketene 11. The latter is known to be in rapid equilibrium with its cyclic mesoionic l,3-oxazolium-5-oxide tautomeric 12 (14). These steps would lead to the liberation of the Pd(0) catalyst, which can return to the catalytic cycle. 

Interesting coupling reactions can be carried out with alkenyl- and alkynyl-stannanes. Reductive coupling of acid chlorides with ( )-l,2-bis(tri-n-butylstannyl)-... 

Coupling of acid chlorides symmetrical ketones. The reaction of a-mono-substituted acetyl chlorides with 1 equiv. of Fea(CO)9 results in symmetrical ketones in fair yield. This coupling is not observed with other iron carbonyls Ni(CO)2[P(CeH6)3]2 does effeet this coupling, but in lower yield. 

A seemingly simple method for the coupling of acid chlorides to acetylenes which avoids the use of copper acetylides employs mixtures of copper(i) iodide, tri-phenylphosphine, and palladium(ll) chloride as catalysts. By treating terminal acetylenes with dimethylcarbamoyl chloride under these conditions, high yields of 2-alkynamides (159) may be obtained. ... 

Scheme 14.15 Ni/ll-catalysed aqmnmetric reductive cross-coupling of acid chlorides and ben l chlorides.

An alternative approach to multicomponent heterocycle synthesis involves the use of palladium catalysis to construct keto-alkynes for cycloaddition reactions. Muller has demonstrated the power of this approach in the construction of a range of aromatic heterocycles. For example, the palladium-catalyzed coupling of acid chlorides with terminal alkynes provides a method to assemble 36. The trapping of this substrate can provide routes to aromatic heterocycles. As an example, the addition of amidines provides a multicomponent synthesis of pyrimidines (Scheme 6.69) [97]. This same substrate 36 is available via the carhonylative coupling of aryl halides with terminal alkynes, providing a four-component synthesis of pyrimidines (98j. 36 can also be employed in 1,3-dipolar cydoaddition reactions. For example, cydoaddition... 

Scheme 3.29 Reductive coupling of acid chlorides with secondary henzyl chlorides.

The two key catalytic intermediates have been observed by electrospray mass spectrometry [394]. Although the exact role and influence of the base remains unclear [395], the transmetallation is thought to be facilitated by base-mediated formation of the tetracoordinate boronate anion [396], which is more electrophilic than the free boronic acid (Sections 1.5.1 and 1.5.2). A useful carbonylative variant has also been developed to access benzophenones (Equation 70) [397], which can also be produced from the coupling of acid chlorides [398] or anhydrides [399], A variant of this method allows the preparation of a, 3-unsaturated esters from alkenylboronic esters [243]. In all of these reactions, one dreaded limitation with some ortho-substituted and electron-poor arylboronic acids is the possible occurrence of a competitive protolytic de-boronation, which is exacerbated by the basic conditions and the use of a transition metal catalyst (Section 1.5.1). Methods to minimize this side reaction were developed in particular the use of milder alternative bases [400] such as fluoride salts [401], and... 

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