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Vicinal aminoalcohols are widespread structural motifs in bioactive molecules. We report the development of a new dioxazolone reagent containing a p‐nitrophenyldifluoromethyl group, which 1. displays a good safety profile; 2. shows a remarkably high reactivity in the oxime‐directed iridium(III)‐catalyzed amidation of unactivated C(sp3)−H bonds; 3. leads to amide products which can be hydrolyzed under mild conditions. The amidation reaction is mild, general and compatible with both primary C−H bonds of tertiary and secondary alcohols, as well as secondary C−H bonds of cyclic secondary alcohols. This method provides an easy access to free 1,2‐aminoalcohols after efficient and mild cleavage of the oxime directing group and activated amide., A safe and bench‐stable dioxazolone reagent was developed for the oxime‐directed iridium(III)‐catalyzed amidation of unactivated C(sp3)−H bonds in tertiary and secondary alcohol‐based substrates. The amidation reaction is mild, general and compatible with both primary and secondary C−H bonds.

The implications of the use of surfactant TPGS-750-M in water as a micellar reaction medium on the concomitant aqueous waste streams and their sustainable disposal have been studied. Biodegradabili...

A robust and sustainable C(sp2)–C(sp3) cross-electrophile coupling was developed via nickel/copper synergistic catalysis under micellar conditions. This protocol provided a general method to access alkylated arenes with good to excellent yields on a very large scale.

The technology of surfactant chemistry is employed for amide bond construction via the reaction of acyl chlorides with amines in 2 wt % TPGS-750-M aqueous solution. Specifically, this highly effici...

The development of a kilogram scale protocol for a Suzuki–Miyaura cross-coupling step toward the synthesis of the drug candidate LSZ102 is described. Particularly, the use of the surfactant TPGS-75...

With a growing toolbox of surfactant-mediated chemistry in water and an increased number of scaled-up transformations has come tremendous learning [for example, see: Lipshutz, B. H.; et al. The Hydrophobic Effect Applied to Organic Synthesis: Recent Synthetic Chemistry “in Water”. Chem.- Eur. J. 2018, 24 (26), 6672–6695]. These opportunities now reside within a few expert groups, and while all of the details are far from fully understood or still under development, substantial know-how has been gained in both reaction process and synthesis design. Herein we share some of the fundamental principles inherent to micellar catalysis and illustrate them on a particularly challenging case involving a Suzuki–Miyaura cross-coupling. The complete structures of the active pharmaceutical ingredient (API) and the intermediates are not fully disclosed for confidentiality reasons but can nevertheless serve as illustrative of the importance of factors that, unlike traditional chemistry in organic solvents, can be crucial to a successful outcome (e.g., lipophilicity). The API used as an example for this discussion bears significant commonality with a large number of other targets associated with the formation of a biphenyl array as well as the presence of an amide and products resulting from nucleophilic aromatic substitutions (SNAr). Hence, we look to utilize these prior learnings and can now rapidly apply them to the design of optimal conditions for several other important transformations.

We present a short overview of the way Novartis chemists interact and collaborate with the academic chemistry community in Switzerland. This article exemplifies a number of collaborations, and illustrates opportunities to foster research synergies between academic and industrial researchers. It also describes established programs available to academic groups, providing them access to Novartis resources and expertise.

A robust and sustainable C(sp2)-C(sp3) cross-electrophile coupling was developed via nickel/copper synergistic catalysis under micellar conditions. This protocol provided a general method to access alkylated arenes with good to excellent yields on a very large scale.

International audience; Although pyrimidines are not among the most reactive partners in intramolecular inverse-electron demand [4ps+2ps] reactions with alkynes, they could be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-aza-indazole by a one-pot Diels-Alder cascade that starts from a pyrimidine substituted in the 2-position by an (alkynyl)hydrazone. The safety of the process and the environmental impact were thoroughly evaluated. Eventually, a selection of cross-coupling reactions of 17 was studied and allowed the introduction of carbon-and nitrogen-based nucleophiles at the C5-position in good to excellent yields.

Although pyrimidines are not among the most reac-tive partners in intramolecular inverse-electron de-mand [4πs+2πs] reactions with alkynes, they could be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-aza-indazole by a one-pot Diels–Alder cascade that starts from a pyrimidine substituted in the 2-position by an (alkynyl)hydrazone. The safety of the process was carefully studied by DSC studies. Eventually, a selection of cross-coupling reactions of 17 was studied and allowed the introduction of carbon- and nitrogen-based nucleophiles at the C5-position in good to excellent yields.

Substituted benzothiazoles play an important role in medicinal chemistry due to their pharmacological properties. Their 2-substituted derivatives are often prepared from 2-chlorobenzothiazoles, which in turn can be synthesized from the 2-mercapto precursor using sulfuryl chloride. In practice, this seemingly straightforward and widely used reaction can be impeded by poor reproducibility and low reaction yields. In this communication, we report that the simple addition of water to the reaction leads to remarkable improvements in reaction efficiency. We attribute this effect to the formation of acid through partial hydrolysis of sulfuryl chloride. This hypothesis is supported by the observation that improved yields were also obtained in the presence of some anhydrous acidic additives. The simple combination of sulfuryl chloride and water reproducibly provides excellent yields for a range of chlorinated products.

The paper presents the most recent advances in applications of alternative medium to replace polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMAc) or N-methyl-2-pyrrolidone (NMP). Focus is made on the use of nonionic designer surfactant (e.g. TPGS-750-M) in water instead of traditional organic solvents. Much attention is given to its applications to several commonly used transformations in active pharmaceutical ingredient (API) synthesis, such as amidation reactions, Suzuki–Miyaura cross-couplings, nitro group reductions, and aromatic nucleophilic substitutions. Case studies of successful uses to attain improved green processes are included. Future directions and most recent results using tailor-made reagents suitable for micellar environments are given.

An operationally simple and general process for the safe and selective reduction of nitro groups utilizing ppm Pd supported on Fe nanomaterials in aqueous solution of designer surfactant TPGS-750-M has been developed and successfully carried out at a 100 mmol scale. Preferred use of KBH4 as the hydride source, at ambient temperature and pressure, lends this process suitable for a standard reaction vessel alleviating the need for specialized hydrogenation equipment. Calorimetry data parallel those expected for a classical nitro group reduction when measuring the heat of reaction (−896 to −850 kJ/mol).

A robust and general protocol for a sustainable copper‐free Sonogashira cross coupling under micellar aqueous reaction conditions with high turnover was developed. By using the commercially available catalyst CataCXium A Pd G3 and THF as co‐solvent, various alkyne substrates were efficiently cross‐coupled with a broad range of aryl halides, providing improved yields and low catalyst loadings. The reaction parameters were optimized to render the process operationally simple, robust and scalable. The method gives access to alkynylated arenes, heterocyclic compounds, and monofunctionalized products from dihalogenated substrates with an improved selectivity achieved by the micellar aqueous reaction conditions.

Mimicking an enzyme's exquisite activity and selectivity is a long-standing goal for sustainable chemical method development in aqueous media. The use of interface-rich aqueous systems, such as single-chain polymers, micelles and vesicle membranes recently emerged as strategy to emulate the compartmentalization of natural systems. In aqueous solution, aggregates such as micelles or microemulsion droplets are formed, providing reaction environments different from bulk solutions that frequently improve selectivity and accelerate reaction rates for a wide array of chemical transformations. We present here selected examples of interface-rich aqueous systems and discuss the advantages they offer for chemical synthesis. In particular metal-catalyzed cross-coupling reactions are highlighted and future challenges to perform reactions in interface-rich aqueous media are discussed.

A counter-intuitive observation has been made that addition of an organic solvent to a reaction mixture being used under micellar conditions is the key to success. This empirical approach has since proven to be particularly general in a variety of transformations, ranging from C–C cross-couplings (Heck, Sonogashira, Suzuki), oxidations, and reductions, thus providing a sustainable alternative to some of the undesirable solvents classically used.

A general selective and environmentally friendly method for the formation of amide bonds using a surfactant in water as medium is described. The use of readily available 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) and hydroxybenzotriazol (HOBt) as a coupling system, N-methylmorpholine (NMM), and TPGS-750-M represents mild conditions allowing for chemoselective amidation of unprotected amino alcohols. Comparative results with classical polar aprotic solvents such as dimethylformamide or acetonitrile are presented.

During our evaluation of the potential of surfactant technology, we rapidly experienced a straightforward and highly advantageous technology, which we applied on-scale. This resulted into significant benefits across our entire synthetic route, not just from an environmental standpoint but also from an economic and productivity perspective. To name a few: reduction of organic solvent use, reduction of water use, reduction of metric such as PMI, reduction of cost, reduction of cycle time, milder reaction conditions, improved yields, and improved process performances. Quantatively, the differences for some of these virtues approached 50% in favor of surfactant technology, all of which realised in multi-purpose facilities already within the infrastructure of standard pharmaceutical or chemical organizations. All of these benefits were achieved using a catalytic amount of a nonionic designer surfactant (e.g. TPGS-750-M) in water instead of traditional organic solvents.

We report a micellar protocol for Suzuki–Miyaura cross-coupling of heteroaryl boronic esters with aryl or heteroaryl halides. The micellar catalysis enables this coupling reaction to run under mild conditions, which avoids the decomposition of heteroaryl boronate esters and allows for high chemoselectivity for cross-coupling reaction with 6-chloropridine-2-boronic ester. The micellar protocol expands the scope of the cross-coupling reaction with challenging heteroaryl boronic esters and complements the existing cross-coupling methods for construction of heterobiaryl building blocks.

Hydrogen isotope exchange (HIE) is one of the most attractive tools for the introduction of deuterium or tritium to an organic compound. Herein, iridium complexes with N,P-ligands, highly active catalysts for asymmetric double bond reductions, have been tested for their HIE capabilities. Electron-rich ligands, containing dicyclohexylphosphines or phosphinites, have been identified as excellent ligands for efficient deuterium incorporation. Substrates with strong directing groups, that is, pyridines, ketones, and amides, as well as weak ligating units, such as, nitro, sulfones, and sulfonamides, could be labeled efficiently. With the addition of tris(pentafluorophenyl) borane to the reaction mixture, also highly deactivating nitrile substituents were well tolerated in the reaction. Based on the excellent results obtained with the chiral ThrePhox ligand, a structurally simpler, achiral ligand was developed. The iridium complex containing this ligand, proved to be a powerful catalyst for HIE reactions.

The impact of varying percentages of an organic solvent added to reactions run in aqueous nanomicelles as the reaction medium has been investigated. Issues such as rates of reaction, percent conversion, and yield, as well as various practical aspects (e.g., effect on stirring, etc.), are discussed, leading to an operationally simple method for the general improvement of potentially problematic systems across a broad range of reaction types, in particular for reactions run at scale.

A Cu(I)-catalyzed asymmetric aziridination of styrenes with a chiral N-tosyloxycarbamate has been developed. Double stereodifferentiation was observed and both the N-tosyloxycarbamate substituent and the bis(oxazoline) ligand have a significant effect on the yields and diastereoselectivities. The best results for the aziridination were obtained with electron-deficient styrenes. Subsequent ring-opening reactions of styrene-derived aziridines at the benzylic position were observed with various oxygen and nitrogen nucleophiles under Lewis acid catalysis affording the corresponding products with complete inversion of stereochemistry. The strategy was used to synthesize the β-blocker, (R)-nifenalol.

Studies regarding the copper-catalyzed enantioselective aziridination of styrenes with N-tosyloxycarbamates are presented. Catalyst, ligand, and reagent optimization will be discussed. Chiral aziridines were obtained in good yields and modest-to-good levels of stereochemical induction.

Das Museum ist bis heute, auch wenn man es angesichts von Marketingzwangen, Werbelogos und Umsatz getriebenen Events nicht mehr so recht glauben will, eine alte Bildungseinrichtung. Ihre Ursprunge reichen zuruck bis ins ausgehende Mittelalter. Damals drang die Bildungsidee in die Sammlungsgeschichte ein, und zwar uber zwei unterscheidbare Wege: uber die mittelalterliche Schatzkammer und uber die mittelalterliche Gelehrtenstube. Aus beiden ging durch diesen Einfluss jener neue Typ von Privatsammlung hervor, in dem man den Ausgangspunkt der neuzeitlichen Museumsentwicklung sehen darf. Der Aufsatz zeichnet – nach einer kritischen Anmerkung zum Stand der Museumshistoriographie – die Hauptlinien dieser Entwicklung in einfachen Strichen nach.

The enantioselective total synthesis of (+)-desoxygaliellalactone was achieved in six steps starting from 4-tert-butyldimethylsilyloxybutanal. This synthesis featured a one-pot copper-catalyzed methylenation-Diels-Alder cyclization. The challenging methylenation of aldehyde 4 was studied under various reaction conditions. Whereas Wittig reaction conditions led to byproducts resulting from decomposition of the sensitive butenolide moiety, the mild copper-catalyzed methylenation reaction produced the desired triene in good yield.

Die Wissenschaft kann die Praxis nicht 'anleiten'. Sie ist bestenfalls eine kritische Instanz. Sie produziert skeptisches Wissen, erinnert an vergessene Zusammenhänge, bricht Vorurteile auf und erlaubt sich in praktischen Fragen, auch wenn sie nicht darum gebeten wurde, gelegentlich Vorschläge zu machen. So will ich es auch hier halten: ein paar Erinnerungen an die Entstehungsgründe der Museumspädagogik, ein paar, wie ich hoffe, klärende Hinweise auf das gegenwärtige Dilemma der Museumspädagogen und zum Schluss ein paar Vorschläge, die sich auf die Zukunft beziehen. Das Ganze hat die Form von sieben Thesen und ist relativ knapp gehalten.

The lithiation of nine anisylpyridines has been studied. While usual reagents did not react or gave addition products on pyridine ring, the BuLi-LiDMAE (LiDMAE=Me2N(CH2)2OLi) superbase induced exclusive pyridino directed metallation. The usefulness of this new reaction allowed the efficient preparation of a range of alpha functional pyridylphenols. A successful subsequent cyclisation of an appropriate isomer into corresponding benzofuropyridine was also performed.

Die Dinge unserer Lebenswelt lassen sich bei aller Vielfalt allesamt als Zeichen betrachten. Sie verweisen als Indizien, Exempel, Modelle und Metaphern auf anderes und sind insofern Teil des symbolischen Universums, in dem die Menschen sich bewegen mussen. Fur die jeweils Heranwachsenden hat dieses symbolische Universum immer den Charakter eines fremden, ratselhaften Textes, der als Bedingung ihrer kulturellen Existenz gelesen und verstanden werden will. Alles Lernen wird unter dieser Voraussetzung zu einer semiologischen Anstrengung. Die Neuankommlinge mussen die Bedeutung der Dinge entziffern, um sie handhaben und nutzen zu konnen. Der Aufsatz versucht dieser These Plausibilitat zu verschaffen. Er macht einen Vorschlag zur Klassifikation der Zeichendinge und skizziert dann die Rolle, die ein gewandeltes Museum als institutionelle Lesehilfe bei der Entzifferung der Kultur spielen konnte.

The objective for this research is to develop LEVIII SULEV technology for midsize passenger cars with SCR equipped diesel engines. The key for SULEV is to lower NOx over the whole emission cycle. From the engine control standpoint, this paper describes a unique NOx reduction technology with three-way conversion reaction until the SCR is heated up. Operating the engine at stoichiometric A/F allows a high conversion efficiency of both NOx and HC using a DOC. Furthermore, it allows rapid heat up of the SCR due to exothermal effect and reduced mass flow. The control system regulates the airflow in order to achieve stoichiometric A/F by controlling EGR flow as first priority. The amount of fuel is determined by the advanced torque control modelled by combustion efficiency so that the A/F can be controlled to stoichiometry maintaining driver requested torque. In combination with the unique SCR system, the FTP75 and US06 emissions test results for NOx + NMHC are below the proposed LEVIII SULEV regulation by a reasonable margin [1]. Stoichiometric mode is activated to control the NOx before the SCR is activated and when SCR efficiency is dropping at high exhaust flow; Stoichiometric mode supplement for lack of efficiency of SCR to achieve the LEV III targets. Fuel consumption penalty is minimized by a unique stoichiometric A/F control concept where AF target is achieved mostly with EGR control. The base structured engine control has advanced model-based functions such as air management with simultaneous control of VGT/EGR/throttle, torque structure, temperature and pressure estimator and precise A/F control, which are the main enablers to realize stoichiometric control.

The aziridination of styrenes (I) carrying electron.withdrawing groups with chiral N-tosyloxycarbamate (II) gives the aziridines (III) with good to excellent diastereoselectivity.

Compared to (Z)-methylstyrene (VI), other substituted (Z)-alkenes such as indene, dihydronaphthalene and ethylstyrene provide the desired aziridines as 1:1 mixtures of diastereomers.

The first stereoselective rhodium-catalyzed intermolecular aziridination and C–H amination of alkenes to produce chiral carbamate-protected aziridines and allylic amines is described. Good yields and diastereoselectivities were achieved using a readily available chiral N-tosyloxycarbamate and stoichiometric amount of the alkene substrate. Furthermore the protecting group is easy to cleave under mild reaction conditions.

Studies regarding the copper-catalyzed enantioselective aziridination of styrenes with N-tosyloxycarbamates are presented. Catalyst, ligand, and reagent optimization will be discussed. Chiral aziridines were obtained in good yields and modest-to-good levels of stereo chemical induction.