Single-Pot Preparation of 4-Amino-2-(het)aryl-5-Substituted Thiazoles Employing Functionalized Dithioesters as Thiocarbonyl Precursors.

An effective, diversity oriented, one-pot reaction of 4-amino-2-(het)aryl/alkyl-5-functionalized thiazoles has been disclosed, utilizing aryl/heteroaryl/alkyl dithioesters as thiocarbonyl coupling partners in a modified Thorpe-Ziegler type cyclization. The reaction proceeds at room temperature, under mild conditions, in excellent yields, displaying broad functional group compatibility at 2 and 5 positions of thiazoles. This synthetic strategy has been further expanded for the one-pot construction of two highly potent tubulin polymerization inhibitors, i.e., 2-(het)aryl-4-amino-5-(3,4,5-trimethoxyaroyl) thiazoles, in high yields.

Aza-Annulation of 1,2,3,4-Tetrahydro-ß-carboline Derived Enaminones and Nitroenamines: Synthesis of Functionalized Indolizino[8,7-b]indoles, Pyrido[1,2-a:3,4-b']diindoles, Indolo[2,3-a]quinolizidine-4-ones and Other Tetrahydro-ß-carboline Fused Heterocycles.

Aza-annulation of novel 1,2,3,4-tetrahydro-ß-carboline derived enaminones and nitroenamines with various 1,2- and 1,3-bis electrophiles, such as oxalyl chloride, maleic anhydride, 1,4-benzoquinone, 3-bromopropionyl chloride, itaconic anhydride, and imines (from formaldehyde and primary amines), has been investigated. These methodologies provide simple one-step pathways for efficient construction of highly functionalized tetrahydro-ß-carboline 1,2-fused, five- and six-membered heterocyclic frameworks, such as indolizino[8,7-b]indoles, pyrido[1,2-a:3,4-b']diindoles, indolo[2,3-a]quinolizidines, and pyrimido[1',6':1,2]pyrido[3,4-b]indoles, which are core structures of many naturally occurring indole alkaloids with diverse bioactivity.

Activation of Benzyl Aryl Carbonates: The Role of Cation-π Interactions.

Benzyl aryl carbonates can react with a nucleophile to yield an activated electrophile and an aryloxide anion. Previously, we had utilized this in the synthesis of α-nitro esters from nitroalkanes. To further understand the process of activation of these carbonates by nucleophiles, we have performed kinetic studies on the hydrolysis of carbonates using nucleophiles. Rate constants for the hydrolysis were obtained under pseudo-first-order conditions with DABCO as the nucleophile. A comparison of rate constant for hydrolysis of isobutyl phenyl carbonate with benzyl phenyl carbonate shows that the presence of benzyl group results in a 16-fold acceleration of hydrolysis rate. This indicates that the transition state for activation of carbonate is stabilized by cation-π interactions. A comparison of the rate constant for various aromatic rings indicates that electron-donating substituents on the benzyl groups accelerate the rate of hydrolysis. Studies were also carried out with DMAP as nucleophile and the results are presented. Our studies show that stable carbonates can be activated using nucleophiles. Activated acyl groups generated from acid anhydrides have been used in several enantioselective reactions. Our studies show that carbonates can be stable alternatives to acid anhydrides.