Selective and Stepwise Functionalization of the Pyridazine Scaffold by Using Thio-Substituted Pyridazine Building Blocks.

We described a regioselective tri- and tetra-functionalization of the pyridazine scaffold using two readily available building blocks: 3-alkylthio-6-chloropyridazine and 3,4-bis(methylthio)-6-chloropyridazine by performing selective metalations with TMPMgCl ⋅ LiCl and catalyst-tuned cross-coupling reactions with arylzinc halides. Several of the resulting pyridazines were converted into more elaborated N-heterocycles such as thieno[2,3-c]pyridazines and 1H-pyrazolo[3,4-c]pyridazines.

How Can Academia Help Industry Reduce the Footprint of Chemicals Manufacture?

Industrial representatives from the Swiss chemistry ecosystem met to formulate unmet needs in the field of sustainability and share the content of the exchange. The aim is to spark inspiration and trigger ambitious and pre-competitive projects collectively at the interface of the academic and industrial worlds, with the hope to profoundly change the current practices and provide an answer to some of the most urgent environmental challenges.

Exploiting Coordination Effects for the Regioselective Zincation of Diazines Using TMPZnX⋠LiX (X=Cl, Br).

A new method for regioselective zincations of challenging N-heterocyclic substrates such as pyrimidines and pyridazine was reported using bimetallic bases TMPZnX⋅LiX (TMP=2,2,6,6-tetramethylpiperidyl; X=Cl, Br). Reactions occurred under mild conditions (25-70 °C, using 1.75 equivalents of base without additives), furnishing 2-zincated pyrimidines and 3-zincated pyridazine, which were then trapped with a variety of electrophiles. Contrasting with other s-block metalating systems, which lack selectivity in their reactions even when operating at low temperatures, these mixed Li/Zn bases enabled unprecedented regioselectivities that cannot be replicated by either LiTMP nor Zn(TMP)2 on their own. Spectroscopic and structural interrogations of organometallic intermediates involved in these reactions have shed light on the complex constitution of reaction mixtures and the origins of their special reactivities.

Practical and Regioselective Synthesis of C-4-Alkylated Pyridines.

The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.

Use of Renewable Resources Towards the Sustainable Production of Crop Protection Agents.

Today, the production of food accounts for roughly one quarter of anthropogenic greenhouse gas emissions. Since the 1970s, thanks to substantial research and development, the overall yield output in farm fields has increased by ca. 60%, while the net use of crop protection agents per square meter of farm field has been reduced by more than 90%. The development of modern crop protection agents remains an important need as new pests, diseases and weeds continue to affect crops. The vast majority of these effective solutions are manufactured using raw materials that ultimately come from fossil resources. In this article, we are touring within the agrochemical landscape to provide the reader with an overview of concrete examples on how in this industrial field, renewable and sustainable raw materials have been used to produce active ingredients. We are also discussing the opportunities for future development as well as some of the challenges and needs that are emerging.

Direct Amidation of Esters by Ball Milling*.

The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.

Building up a Continuous Flow Platform as an Enabler to the Preparation of Intermediates on Kilogram Scale.

The following outlook describes the strategy we followed at Syngenta R&D to build and develop an effective flow chemistry platform which could fit a precise business purpose. In this account, we give insight into specific chemistry challenges encountered and addressed using continuous flow chemistry. The conclusions of the outlook outline the future of our strategy with a perspective on the technology within our business.

Concise total syntheses of amphidinolides†C and F.

The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4-diketone substructure. This particular motif inspired a synthesis plan predicating a late-stage formation of this non-consonant ("umpoled") pattern by a platinum-catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross-coupling and a macrocyclization by ring-closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other π-systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene-selective cobalt-catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two-directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from D-glutamic acid by an intramolecular oxa-Michael addition and a proline-mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3 Sn-group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate.

Radical and radical-ionic multicomponent processes.

All in one pot! Radical, radical-ionic, and radical-organometallic MCR are highly convergent processes, representing a useful pathway to molecular and structural diversity (see scheme). This concept article highlights recent developments in the field and shows the potential of the strategy for the economical elaboration of various kinds of organic substrates.Progress in multicomponent reactions (MCRs) based on ionic and organometallic processes has recently allowed the synthesis, with high efficiency, of large collections of drug-like molecules. In contrast, MCRs based on cascade radical reactions appear to have attracted, so far, much less interest. This concept article highlights the latest progress in the field and underlines the potential of such an approach. The collected examples demonstrate that radical and radical-ionic MCRs are highly convergent processes leading to useful structural diversity.

Synthesis of fused piperidinones through a radical-ionic cascade.

Azabicyclo[4.3.0]nonanes were assembled, from chiral allylsilanes possessing an oxime moiety, using a stereocontrolled formal [2 + 2 + 2] radical-ionic process. The cascade involves the addition of an alpha-iodoester to the less substituted end of the enoxime which is then followed by a 5-exo-trig cyclization onto the aldoxime function, producing an alkoxyaminyl radical species which finally lactamizes to afford the titled piperidinone. High levels of stereoinduction were observed, demonstrating the ability of a silicon group located at the allylic position to efficiently control the stereochemistry of the two newly created stereogenic centers. When the radical cascade was extended to ketoximes, the resulting sterically hindered alkoxyaminyl radical did not react further with the initiator Et3B to produce the expected nucleophilic amidoborane complex. In sharp contrast, this long-lived radical recombined with the initial alpha-stabilized ester radical to produce a cyclopentane incorporating two ester fragments.

A stereocontrolled access to ring-fused piperidines through a formal [2+2+2] process.

[reaction: see text] A formal [2+2+2] process has been devised that allows the stereocontrolled formation of ring-fused piperidines from allylsilanes possessing an oxime moiety. The cascade involves an intermolecular radical addition of an alpha-iodoacetate onto an allylsilane double bond, which is followed by a 5-exo-trig cyclization onto an oxime and is completed by the formation of the amide bond by nucleophilic attack of the amine onto the ester function.