Heterocycles palladium acetate

The Suzuki reaction has been successfully used to introduce new C - C bonds into 2-pyridones [75,83,84]. The use of microwave irradiation in transition-metal-catalyzed transformations is reported to decrease reaction times [52]. Still, there is, to our knowledge, only one example where a microwave-assisted Suzuki reaction has been performed on a quinolin-2(lH)-one or any other 2-pyridone containing heterocycle. Glasnov et al. described a Suzuki reaction of 4-chloro-quinolin-2(lff)-one with phenylboronic acid in presence of a palladium-catalyst under microwave irradiation (Scheme 13) [53]. After screening different conditions to improve the conversion and isolated yield of the desired aryl substituted quinolin-2( lff)-one 47, they found that a combination of palladium acetate and triphenylphosphine as catalyst (0.5 mol %), a 3 1 mixture of 1,2-dimethoxyethane (DME) and water as solvent, triethyl-amine as base, and irradiation for 30 min at 150 °C gave the best result. Crucial for the reaction was the temperature and the amount of water in the... 

Another compound 9 with three heterocyclic rings linearly fused (5 5 5) with two heteroatoms has been prepared from 1,1 -carbonyl diindole 297 <2001T5199>. Palladium-mediated coupling of the 2- and 2 -positions of 297 afforded the 1,1 -carbonyl-2,2 -biindolyl 9. 1,1 -Carbonyl diindole 297 was in turn obtained in 41% yield from 1,1 -carbonyldiimidazole 296 by reaction with indole in DMSO at 125 °C. The palladium-catalyzed coupling step afforded the desired product 9 in low yield and required a stoichiometric amount of palladium acetate. Therefore, it was felt prohibitively expensive. Addition of various co-oxidants (Ac20, Mn02, and Cu(OAc)2, etc) to make the reaction catalytic in palladium did not result in any improvement of the yield of 18 (Scheme 53). 

In contrast to the carbamates, N-tosyl carbamates 18 reacted fast (1-2 h) with LiBr in the presence of copper(II)-oxygen and catalytic amounts of palladium acetate yielding oxazolidinones 19 (Scheme 17.10). The rate enhancement is due to the presence of two electron-withdrawing substituents on nitrogen and is, again, responsible for the diminished diastereoselectivity of the reaction. Attempts to prepare the homologous six-membered heterocycles gave only poor yields. 

Electron-rich heterocycles can also be coupled with olefins in the presence of a suitable palladium(II) catalyst. The oxidative coupling requires the use of a stoichiometric amount of palladium however, unless a suitable oxidising agent is added to the reaction. In an early example N-sulphonylated pyrrole was reacted with 1,4-naphthoquinone in the presence of an equimolar amount of palladium acetate to give the coupled product in good yield (6.92.).124... 

Iodination (I2/NaOH) of l,6-naphthyrid-5-one (47) gives the iodo derivative (48) (70% yield). This compound is converted to 5-chloro-8-iodo-l,6-naphthyridine (49) by the action of phosphorus oxychloride (64% yield). Heterocycle (49) undergoes a Heck reaction with ethyl acrylate in the presence of palladium acetate as a catalyst giving compound (51) (47% yield). Similarly, heterocycle (50) (obtained in 98% yield by treating compound (49) with sodium methoxide) gives ester (52) (88% yield) in a Heck reaction <86CPB2018>. 

In the search of new non-peptide glycoprotein GPIIb/GPIIIa antagonists, heterocyclic scaffolds such as oxazolepiperidine have been explored. Such framework has both acidic and basic functionalities, which may confer the pharmacological properties to the desired molecule. The Heck reaction of bromooxazolopyridines 104 with methyl acrylate in the presence of palladium acetate afforded methylpropenoate-oxazolopyridines 105 in 70 and 88% yields, respectively [60]. 

Palladium(II)-promoted alkenylation involving a-bromo sulfonamide has been utilized to construct the bridgehead bicyclic sultam 193 <04OL1313>. Treatment of 192 with palladium acetate in DMF containing K2CO3, tri-2-furylphosphine and 4A molecular sieves at 100 C furnishes 193. Subsequent bromination with NBS and elimination with DBU give rise to conjugated diene 194. When irradiated at 350 nM, 194 is isomerized via a two-photon process to the structurally novel spiro heterocycle 198. 

Indoles or heterocycles containing an indole skeleton were the first products to be prepared by intramolecular heterocyclic Mizoroki-Heckreaction. In 1977, the first intramolecular Mizoroki-Heck reaction was reported by Mori et al. [7], who prepared indole 3 by cyclization of (Fl-methyl 4-(N-(2-bromophenyl)acetamido)but-2-enoate (1) in the presence of palladium acetate, triphenylphosphine and iVA/ A A -tetramethylethylenediamine (Scheme 6.4). 

Direct metallation of aromates can be conveniently performed with palladium acetate. The reaction is also of application with heterocycles [57] (example 2) ... 

Arylation of Thiazoles and Oxazoles. The protocol that was previously developed for the C-H activation of azine and diazine (V-oxides with aryl triflates was used to effect the arylation of flve-membered ring heterocycles, such as oxazoles and thiazoles. In contrast to another protocol that was previously reported by the same group, the transformation did not require an V-oxide function. However, in order to direct the arylation at the C4-position, to prevent the formation of a mixture of regioisomers, and to minimize the generation of diarylated products, a C5-chloride was used as a blocking group. The procedure, which is promoted by palladium acetate and di-tert-butyl(methyl)phosphonium tetrafluoroborate, uses an aryl bromide as the electrophile. 

Arylation of Other Heterocycles. Y)i-tert-hutyl(methyl)phosphonium tetrafluoroborate has also been used for the C-H arylation reaction of other heterocycles. For exart5)le, the direct C5-arylation of imidazo[l,5-a]pyrazines was disclosed using this ligand, in combination with palladium acetate as the catalyst (eq 24). ... 

Methyl glyoxylate adducts of iV-Boc-protected allylic amines cyclize in the presence of a catalytic amount of palladium acetate and excess copper(II) acetate to 5-(l-alkenyl)-2-(methoxycarbonyl)oxazolidines (eq 5). These heterocycles are easily converted to unsaturatedIV-Boc protected /3-amino alcohols through anodic oxidation and mild hydrolysis. 

Arene Amination. Alternative methods for the A-arylation of N-H-containing heterocycles that proceed directly with arenes (i.e., where aryl halides are not required) have emerged in the literature. In a recently reported procedure, a succinimide derivative was iV-arylated using palladium acetate as the catalyst, tri-ferf-butylphosphine as the ligand, and (diacetoxyiodo)benzene as a stoichiometric oxidant. This reaction allows the formation of ster-ically controlled products with monosubstituted arenes, yielding mainly meta- and / ara-arylated products and di- and trisubsti-tuted arenes, mostly providing the products of arylation at the meta-position (eq 15). ... 

C-H Activation. Tri-terf-butylphosphine, combined with palladium acetate, acts as an effective catalytic system for the direct Ar-H arylation of heterocycles. This system has been applied for the functionalization of various five- and six-membered ring heterocycles containing one or more heteroatoms. A base (CS2CO3,... 

Other classes of heterocycles that have been arylated using the C-H activation method and involving palladium acetate and tri-tert-butylphosphonium tetrafluorohorate include the quinoline N-oxides (eq 25) and the thiazoleiV-oxides (eq 26). In the case of quinoline (V-oxides, the regioselectivity of arylation is as expected and leads to the corresponding 2-aryl derivatives. However, in the case of thiazole IV-oxides, the nature of the phosphine has a dramatic influence on the regioselectivity of the arylation process, with tri-terf-butylphosphine providing the product of C5 arylation. 

Palladium-catalyzed Direct Arylation of Indoles and Thiophenes. Five-membered ring heterocycles possessing only one heteroatom and no Af-oxide function can also be arylated using palladium(II) complexes, a phosphine ligand, and an inorganic base. In one example, a tandem palladium-catalyzed Heck coupling reaction and direct intramolecular C2 arylation reaction on a )V-(2-chlorobenzyl)-5-bromoindole was reported (eq 30). The procedure, which is catalyzed by palladium acetate, uses tn-tert-butylphosphonium tetrafluoroborate as a ligand and ferf-butyl acrylate as the alkene for the Heck reaction (eq 30). ... 

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