Considerable efforts have been undertaken by numerous groups in academia and industry over the past decade to expand the repertoire of coupling reagents in palladium(0)-catalyzed cross-coupling reactions.[1] In particular, alkenyl phosphates and tosylates have proven their worth in various cross-coupling reactions, such as the Stille, [2] Suzuki, [2e,f, 3] Negishi, [2b] Kumada, [2b, 3e, 4] Sonogashira, [2-b,e,f, 5] Buchwald-Hartwig, [4a, 6] carbonyl enolate, [3d] and Heck couplings, [7] as effective alternatives to the less stable and typically more expensive alkenyl triflates and nonaflates. [8] However, the majority of this work has focused on the use of activated vinyl phosphates and tosylates, such as a,b-unsaturated systems or a-heteroatom-substituted alkenes, for which the oxidative-addition step is nonproblematic with palladium(0) catalysts bearing aryl phosphine ligands. Less attention has been devoted to nonactivated counterparts, most likely because of the greater difficulty in carrying out the first step of the catalytic cycle, namely the oxidative addition. [3d, 4, 5, 9] We now report on catalyst systems composed of a palladium complex with a basic, hindered alkyl phosphine that can promote the Heck coupling of nonactivated vinyl tosylates and phosphates with electron-deficient alkenes in good yields, thereby increasing the scope of this important cross-coupling reaction. Furthermore, during these studies we observed an interesting 1,2-isomerization with certain alkenyl tosylates and phosphates under reaction conditions that provide coupling yields as high as 95 %. A mechanistic proposal supported by experimental results and DFT calculations is included.To identify suitable reaction conditions for Heck couplings with nonactivated alkenyl tosylates and phosphates, we examined the use of palladium complexes with the ever increasingly popular bulky electron-rich phosphines.[10] All tosylates and phosphates were prepared from starting ketones by base-promoted proton extraction and reaction with tosyl anhydride (Ts 2 O) or (PhO) 2 POCl, as earlier reported. [4b, 11, 12] Initial coupling attempts were performed between the tosylate 1 and ethyl acrylate (Scheme 1). After examining a variety of reaction conditions, we noted that a combination of [PdCl 2 (cod)] (cod = 1,5-cyclooctadiene; 5 mol %) and the P(tBu) 3 HBF 4 salt [13] (10 mol %) in the presence of dicyclohexylmethylamine (2 equiv) in dimethylformamide (DMF) at 85 8C could furnish the diene 2, albeit in low yield (approximately 5 %). The addition of one equivalent of LiCl, however, had a dramatic effect on the reaction outcome, thus providing a 50 % yield of the diene 2 after 24 hours. [14] Increasing the reaction temperature to 100 8C improved the coupling yield to 66 %. Other reactions conditions, including change of solvent or examination of alternative catalyst combinations, were incapable of promoting the cross-coupling.To probe the scope of these reaction conditions, we examined the Heck coupling of a variety of alkenyl tosylates ...

A catalyst system was identified which promotes the Heck coupling of nonactivated vinyl phosphates with electron deficient alkenes providing a new entry to diene products from simple and readily accessible starting materials. In contrast to our earlier work exploiting P(t-Bu)3 as the ligand in the presence of PdCl2(COD), the application of Buchwald's dialkylbiarylphosphines, X-Phos, effectively promoted the vinylic substitution with a wide range of alkenyl phosphates in the presence of 10 equiv of lithium chloride. Importantly, these reaction conditions suppressed 1,2-migration of the alkenyl palladium(II) intermediate. Further studies are also reported with the catalytic system which encourages isomerization in order to determine the range of vinyl phosphates that may participate in these coupling reactions. The extent of the 1,2-migration was dependent on the C1-substituent where best results were noted for substrates possessing a C1-alkyl quaternary carbon. Hence, with certain members of this class of alkenyl phosphates either the migrated or nonmigrated Heck products may be preferentially synthesized by selection of the phosphine ligand. Finally, competition experiments between an unactivated aryl chloride and a vinyl phosphate with a palladium catalyst possessing either X-Phos or P(t-Bu)3 as ligand demonstrated the ability to carry out Heck coupling reactions selectively with the aryl halide. Oxidative addition of the metal catalyst into the aryl chloride bond rather than the C-O bond of the alkenyl phosphate is therefore preferred.

The development of versatile Suzuki-Miyaura and Negishi cross-couplings with nonactivated alkenyl phosphates and aromatic boronic acids or organozinc reagents was achieved in acceptable to good yields. A series of 1,1-disubstituted alkenes were synthesized using a combination of either Ni(COD)2/Cy3P/K3PO4 or Pd2dba3/DPPF in THF. When working with alkenyl electrophiles in metal-catalyzed cross-couplings, this method lends itself as a less costly and more stable alternative to the corresponding triflate or nonaflate derivatives. In addition, initial studies are presented regarding an efficient 1,2-migration under Negishi coupling conditions.

The use of the N-acetoacetyl protecting group for N-terminal cysteine residue enabled creation of an efficient and mild one-pot native chemical ligation/SEA ligation sequence giving access to large cyclic peptides.

A combination of Ni(COD)(2) and PCy(3) promotes effectively the Suzuki-Miyaura cross coupling of 1-arylalkenyl phosphates with aryl boronic acids with yields attaining 99%.

No abstract

The styryl benzene derivative (E, E)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), well-known for its binding to beta-amyloid peptide fibrils, was synthesized in an efficient manner exploiting two sequential palladium(0)-catalyzed coupling reactions in a 34% overall yield. This is a substantial improvement to the previously reported synthesis of FSB in 1.1%.

Considerable efforts have been undertaken by numerous groups in academia and industry over the past decade to expand the repertoire of coupling reagents in palladium(0)-catalyzed cross-coupling reactions.[1] In particular, alkenyl phosphates and tosylates have proven their worth in various cross-coupling reactions, such as the Stille, [2] Suzuki, [2e,f, 3] Negishi, [2b] Kumada, [2b, 3e, 4] Sonogashira, [2-b,e,f, 5] Buchwald-Hartwig, [4a, 6] carbonyl enolate, [3d] and Heck couplings, [7] as effective alternatives to the less stable and typically more expensive alkenyl triflates and nonaflates. [8] However, the majority of this work has focused on the use of activated vinyl phosphates and tosylates, such as a,b-unsaturated systems or a-heteroatom-substituted alkenes, for which the oxidative-addition step is nonproblematic with palladium(0) catalysts bearing aryl phosphine ligands. Less attention has been devoted to nonactivated counterparts, most likely because of the greater difficulty in carrying out the first step of the catalytic cycle, namely the oxidative addition. [3d, 4, 5, 9] We now report on catalyst systems composed of a palladium complex with a basic, hindered alkyl phosphine that can promote the Heck coupling of nonactivated vinyl tosylates and phosphates with electron-deficient alkenes in good yields, thereby increasing the scope of this important cross-coupling reaction. Furthermore, during these studies we observed an interesting 1,2-isomerization with certain alkenyl tosylates and phosphates under reaction conditions that provide coupling yields as high as 95 %. A mechanistic proposal supported by experimental results and DFT calculations is included.To identify suitable reaction conditions for Heck couplings with nonactivated alkenyl tosylates and phosphates, we examined the use of palladium complexes with the ever increasingly popular bulky electron-rich phosphines.[10] All tosylates and phosphates were prepared from starting ketones by base-promoted proton extraction and reaction with tosyl anhydride (Ts 2 O) or (PhO) 2 POCl, as earlier reported. [4b, 11, 12] Initial coupling attempts were performed between the tosylate 1 and ethyl acrylate (Scheme 1). After examining a variety of reaction conditions, we noted that a combination of [PdCl 2 (cod)] (cod = 1,5-cyclooctadiene; 5 mol %) and the P(tBu) 3 HBF 4 salt [13] (10 mol %) in the presence of dicyclohexylmethylamine (2 equiv) in dimethylformamide (DMF) at 85 8C could furnish the diene 2, albeit in low yield (approximately 5 %). The addition of one equivalent of LiCl, however, had a dramatic effect on the reaction outcome, thus providing a 50 % yield of the diene 2 after 24 hours. [14] Increasing the reaction temperature to 100 8C improved the coupling yield to 66 %. Other reactions conditions, including change of solvent or examination of alternative catalyst combinations, were incapable of promoting the cross-coupling.To probe the scope of these reaction conditions, we examined the Heck coupling of a variety of alkenyl tosylates ...