Rediscovering Cyanogen Gas for Organic Synthesis: Formation of 2-Cyanothiazole Derivatives.

The expeditious synthesis of an API building block, 2-cyanothiazole, from cyanogen gas and a readily available dithiane is reported. A previously undisclosed partially saturated intermediate is formed, which can be further functionalized and isolated by the acylation of the hydroxy group. Dehydration using trimethylsilyl chloride furnished 2-cyanothiazole, which could be further converted to the corresponding amidine. The sequence provided a 55% yield over 4 steps. We envision that this work will spark further interest in cyanogen gas as a reactive and cost-effective synthetic reagent.

Continuous flow as an enabling technology: a fast and versatile entry to functionalized glyoxal derivatives.

We herein report two complementary strategies employing organolithium chemistry for the synthesis of glyoxal derivatives. Micro-mixer technology allows for the generation of unstable organometallic intermediates and their instantaneous in-line quenching with esters as electrophiles. Selective mono-addition was observed via putative stabilized tetrahedral intermediates. Advantages offered by flow chemistry technologies facilitate direct and efficient access to masked 1,2-dicarbonyl compounds while mitigating undesired by-product formation. These two approaches enable the production of advanced and valuable synthetic building blocks for heterocyclic chemistry with throughputs of grams per minute.

Top 200 Drugs by Worldwide Sales 2016.

The poster series of the Top 200 Drugs by Worldwide Sales by G. Sedelmeier and J. Sedelmeier has now been updated with an overview of the top selling drugs in 2016. QuintilesIMS collected sales numbers in 59 countries for all companies.

A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and Esters.

We report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron-deficient olefins via radical addition to efficiently form C-C coupled products in a redox-neutral fashion. The Lewis base catalyst was shown to form a redox-active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in solution.

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2 )-C(sp3 ) Cross-Couplings in Flow.

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high-throughput continuous flow process was developed to perform a dual iridium- and nickel-catalyzed C(sp2 )-C(sp3 ) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine-derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2 )-C(sp3 ) coupling method using boronic esters and cyano heteroarenes under flow conditions.

Continuous Flow as Enabling Technology: Synthesis of Heteroaromatic Sulfinates as Bench Stable Cross-Coupling Partners.

An enabling continuous flow setup for handling of unstable organolithium intermediates and synthesis of heteroaryl sulfinates on a multigram scale is described. The developed continuous flow process allows for the synthesis and simple isolation of heteroaryl sulfinates which are otherwise challenging to access in classical batch mode. The lithium sulfinate salts prepared by this method were shown to be efficient reaction partners in palladium catalyzed C(sp2)-C(sp2) cross-coupling to access medicinally relevant bis-heteroaryl motifs.

Evolution of Small Molecule Kinase Drugs.

The development of small molecule kinase drugs is a rapidly evolving field and represents one of the most important research areas within oncology. This innovation letter provides an overview and analysis of approved kinase drugs according to their WHO registration (INN) dates, primary biological targets, and selectivity and structural similarities, which are also depicted in an associated poster. It also discusses new trends in kinase drug discovery programs such as new kinase targets, novel mechanisms of action, and diverse indications.

Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow.

We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput.

Dichloromethyllithium: Synthesis and Application in Continuous Flow Mode.

A simple and robust procedure for the synthesis and use of thermally unstable dichloromethyllithium in continuous flow mode is described. By utilizing residence times in the range of milliseconds for the generation and electrophilic quench of dichloromethyllithium, the straightforward synthesis of dichlorocarbinols and benzylic pinacol esters was realized at reaction temperatures of -30 °C, whereas typical temperatures in traditional batch mode are below -78 °C. The excellent purity profile obtained from the flow process allows us to directly telescope the exiting flow stream into semibatch quenches for further modifications. All transformations gave the desired products in remarkable purity and yield on gram scale with no need for chromatography.

Flow Chemistry on Multigram Scale: Continuous Synthesis of Boronic Acids within 1 s.

The benefits and limitations of a simple continuous flow setup for handling and performing of organolithium chemistry on the multigram scale is described. The developed metalation platform embodies a valuable complement to existing methodologies, as it combines the benefits of Flash Chemistry (chemical synthesis on a time scale of <1 s) with remarkable throughput (g/min) while mitigating the risk of blockages.