Mechanistic Study of Indolizine Heterocycle Formation by Ruthenium(II)-Assisted Three-Component Cross-Coupling/Cyclization

Abstract

In the presence of the acid HBF 4 , 3-alkenyl-2-phosphonium indolizines 3a−c can be produced respectively by adding PhCCCOCH 3 (2a), CH 3 OCOCCCOOCH 3 (2b), and CH 3 CH 2 CCCOCH 3 (2c) to a mixture of ruthenium complex RuCl 2 (PPh 3 ) 3 and the propargyl alcohol (2-Py)CH(OH)CCH (1). We carefully investigated the mechanism of this reaction by means of structurally characterizing two key intermediates, ruthenium vinyl (4) and ruthenium carbene (5), and by deuterium-labeling experiments. A plausible mechanism is proposed, which involves addition of a proton to an alkyne carbon and the insertion of an alkyne into the Cα bond of an alkenylcarbene group, followed by an α-H elimination and reductive elimination.

1,2-Migration in the reactions of ruthenium vinyl carbene with propargyl alcohols

“…1a,e,f Recently, we reported a convenient route to prepare a stable ruthenium vinyl carbene 1. 5 It was a fused heterocycle different from the reported aromatic metallacycles 6 because of the significant alternation of the bond lengths in the ring. The electron in it was quite localized, so that it was more suitable to be viewed as a 1,3-butadiene moiety.…”

“…The electron in it was quite localized, so that it was more suitable to be viewed as a 1,3-butadiene moiety. 5 Its C γ was easily attacked by nucleophilic reagents to form a series of ruthenapolycyclic complexes [Ru{CHC(PPh 3 )CHR(2-Py)}Cl(PPh 3 ) 2 ]BF 4 [R = OH, OCH 3 , NHPh]. 4g It could also react with alkynones and alkynoates in the presence of an acid, leading to the formation of 3-alkenyl-2-phosphonium indolizine salts.…”

Synthesis of Ruthena-polycyclic Complexes by Ruthenium-Vinylcarbene Complex

“…此类金属杂 环分子内均含有烯基卡宾结构, 可看作一类特殊的烯基 卡宾化合物. 最近, 我们又报道了一种分子内吡啶螯合钌杂 s-顺 丁二烯化合物 1 [13] 图 1 化合物 3 的阳离子晶体结构图 Figure 1 Molecular structure for the cation of 3 Ellipsoids at the 50% probability level. Counteranion and hydrogen atoms in PPh 3 are omitted for clarity.…”

“…Counteranion and hydrogen atoms in PPh 3 are omitted for clarity. [13] 相比明显向低 场移动, 说明其卡宾特征更为明显. [12] 相近.…”

Propylphosphonic acid anhydride–mediated amidation of Morita–Baylis–Hillman–derived indolizine-2-carboxylic acids

“…3 Various methods of synthesising indolizine derivatives have been developed. 4,5 These include transition metal-catalysed cyclo-isomerisation of readily available non-conjugated 2-propargylpyridines 6 ; cycloaddition reactions of 2-cyclopropenylpyridine in the presence of RhCl(PPh 3 ) 3 or CuI 7 ; cyclisation of propargylic pyridines in the presence of iodine, Pd, Cu or other metals in a polar protic solvent 8–10 ; and the Chichibabin indolizine synthesis, involving base-mediated cyclisation of 1-substituted-2-methylpyridinium salts. 11 The application of Morita–Baylis–Hillman (MBH) methodology in the synthesis of indolizines was first reported by our group 12,13 and, in this communication, we now report the use of this approach in the preparation of a range of indolizine-2-carboxamido derivatives and the evaluation of their anti-malarial, anti-trypanosomal and anti-tuberculosis potential and their HIV-1 protease (PR) and integrase (IN) inhibition activity.…”