Synthesis of multi-substituted pyridines from ylidenemalononitriles and their emission properties.

Numerous methodologies to obtain pyridines from ylidenemalononitriles are described in the literature. Nevertheless, they are limited to the use of microwave or conventional heat and few lead to 2,3,4 or 2,3,4,5-substituted pyridines as multi-proposal molecular scaffolds or even universal pyridines. Herein, we present a mild and facile solvent-free methodology to obtain a scope of multi-substituted pyridines at room temperature. We also report an example where one of the resulting amino-nicotinonitriles exhibits a preliminary evidence of aggregation-induced emission (AIE).

A Continuous Flow Sulfuryl Chloride-Based Reaction-Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine.

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines emtricitabine and lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm and evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous byproducts in solution and controlling the temperature led to better outcomes. These reactions are ideal candidates for implementation in a continuous mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein we discuss the flow implementation and the final reactor design that led to a system with a 141 g/h throughput.

Increasing Scope of Clickable Fluorophores: Electrophilic Substitution of Ylidenemalononitriles.

Recently, we demonstrated that ylidenemalononitriles (YMs) react with amines to form cyclic amidines and that the starting linear YMs are nonemissive in solution and the cyclic amidines are fluorescent. These turn-on systems were of interest to us because of their potential as biosensors and synthons for accessing functionalized pyridines. While our original method was promising, several limitations persisted, including access to more functionalized and polar-solvent-soluble structures as well as increased control over the rate of cyclization. Herein, we report a new approach that allows the electrophilic substitution of YMs. These substituted YMs exhibit faster turn-on rates, color tunability, access to polar-solvent-soluble species, and increased control over cyclization rate. This allowed us to significantly expand the fluorophore's chemical space.

Continuous Endoperoxidation of Conjugated Dienes and Subsequent Rearrangements Leading to C-H Oxidized Synthons.

We have investigated the continuous flow photooxidation of several conjugated dienes and subsequent rearrangement using a practical and safe continuous-flow homemade engineered setup. End-to-end approaches involving endoperoxidation, Kornblum-DeLaMare rearrangement, and additional rearrangements are comprehensively detailed with optimization, scope, and scale-up to obtain useful hydroxyenones, furans, and 1,4-dicarbonyl building blocks.

Lithocholic acid and derivatives: Antibacterial activity.

In order to develop bioactive lithocholic acid derivatives, we prepared fifteen semi-synthetic compounds through modification at C-3 and/or C-24. The reactions showed yields ranging from 37% to 100%. The structures of all compounds obtained were identified on the basis of their spectral data (IR, MS, 1D- and 2D-NMR). The activity of lithocholic acid and derivatives was evaluated against the growth of Escherichia coli, Staphylococcus aureus, Bacillus cereus and Pseudomonas aeruginosa. The derivative 3α-formyloxy-5ß-cholan-24-oic acid (LA-06) showed the best activity, with MIC values of 0.0790 mM against E. coli (Ec 27) and B. cereus in both cases, and 0.0395 mM against S. aureus (ATCC 12692). Lithocholic acid and the derivatives with MIC⩽1.2 mM were evaluated on the susceptibility of some bacterial pathogens to the aminoglycoside antibiotics neomycin, amikacin and gentamicin was evaluated. There are no previously reported studies about these compounds as modifiers of the action of antibiotics or any other drugs.