Dual Antitubercular and Antileishmanial Profiles of Quinoxaline Di-N-Oxides Containing an Amino Acidic Side Chain.

We present a new category of quinoxaline di-N-oxides (QdNOs) containing amino acid side chains with dual antituberculosis and antileishmanial activity. These compounds were synthesized by combining a regioselective 2,5-piperazinedione opening and a Beirut reaction and were screened for their activity against Mycobacterium tuberculosis and the promastigote and amastigote forms of representative species of the Leishmania genus. Most QdNOs exhibited promising antitubercular activity with IC50 values ranging from 4.28 to 49.95 µM, comparable to clinically established drugs. Structure-activity relationship analysis emphasized the importance of substituents on the aromatic ring and the side chain. Antileishmanial tests showed that some selected compounds exhibited activity comparable to the positive control miltefosine against promastigotes of Leishmania amazonensis and Leishmania donovani. Notably, some compounds were found to be also more potent and less toxic than miltefosine in intracellular amastigote assays against Leishmania amazonensis. The compound showing the best dual antitubercular and leishmanicidal profile and a good selectivity index, 4h, can be regarded as a hit compound that opens up new opportunities for the development of integrated therapies against co-infections.

Photoinduced Palladium-Catalyzed Negishi Cross-Couplings Enabled by the Visible-Light Absorption of Palladium-Zinc Complexes.

A visible-light-induced Negishi cross-coupling is enabled by the activation of a Pd0 -Zn complex. With this photocatalytic method, the scope of deactivated aryl halides that can be employed in the Negishi coupling was significantly expanded. NMR experiments conducted in the presence and absence of light confirmed that the formation of the palladium-zinc complex is key for accelerating the oxidative addition step.

On-demand synthesis of organozinc halides under continuous flow conditions.

Organozinc reagents are versatile building blocks for introducing C(sp2)-C(sp3) and C(sp3)-C(sp3) bonds into organic structures. However, despite their ample synthetic versatility and broad functional group tolerance, the use of organozinc reagents in the laboratory is limited because of their instability, exothermicity and water sensitivity, as well as their labor-intensive preparation. Herein, we describe an on-demand synthesis of these useful reagents under continuous flow conditions, overcoming these primary limitations and supporting widespread adoption of these reagents in synthetic organic chemistry. To exemplify this procedure, a solution of ethyl zincbromoacetate is prepared by flowing ethyl bromoacetate through a column containing metallic zinc. The temperature of the column is controlled by a heating jacket and a thermocouple in close contact with it. Advice on how to perform the procedure using alternative equipment is also given to allow a wider access to the methodology. Here we describe the preparation of 50 ml of solution, which takes 1 h 40 min, although up to 250-300 ml can be prepared with the same column setup at a rate of 30 ml per h. The procedure provides the reagent as a clean solution with reproducible concentration. Organozinc solutions generated in flow can be coupled to a second flow reactor to perform a Reformatsky reaction or can be collected over a flask containing the required reagents for a batch Negishi reaction.

Grignard Reagents on a Tab: Direct Magnesium Insertion under Flow Conditions.

An on-demand preparation of organomagnesium reagents is presented using a new flow protocol. The risks associated with the activation of magnesium are circumvented by a new on-column initiation procedure. Required amounts of solutions with a precise titration were obtained. Telescoped flow or batch reactions allow access to a diverse set of functional groups.

Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into ß-functionalized α-ketoamides.

A sequential three-component process is described, starting from 3-arylmethylene-2,5-piperazinediones and involving a one-pot sequence of reactions achieving regioselective opening of the 2,5-diketopiperazine ring and diastereoselective generation of an aziridine ring. This method allows the preparation of N-unprotected, trisubstituted aziridines bearing a peptide side chain under mild conditions. Their transformation into ß-trifluoroacetamido-α-ketoamide and α,ß-diketoamide frameworks was also achieved in a single step.

Investigation of a lithium-halogen exchange flow process for the preparation of boronates by using a cryo-flow reactor.

Conducting low-temperature organometallic reactions under continuous flow conditions offers the potential to more accurately control exotherms and thus provide more reproducible and scalable processes. Herein, progress towards this goal with regards to the lithium-halogen exchange/borylation reaction is reported. In addition to improving the scope of substrates available on a research scale, methods to improve reaction profiles and expedite purification of the products are also described. On moving to a continuous system, thermocouple measurements have been used to track exotherms and provide a level of safety for continuous processing of organometallic reagents. The use of an in-line continuous liquid-liquid separation device to circumvent labour intensive downstream off-line processing is also reported.

1,3-dipolar cycloadditions from tricyclic hemiaminals. Synthesis of the quinocarcin core through catalyst-free generation of azomethine ylides.

The generation of azomethine ylides from the readily accessible hemiaminals 3 and 8 or from iminium salt 10 was studied. Compounds 8 gave anti- and syn-cycloadducts containing the quinocarcin core through a catalyst-free dehydration process.