Two synthetic strategies for key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate 1 for orforglipron were demonstrated. The Negishi cross-coupling route was initially scaled up to deliver a total of 36.6 kg of compound 1 to support the production of orforglipron to fund early clinical trials. However, this route was nonenantioselective and required laborious chiral SFC purification to obtain an optically pure intermediate. An enantioselective route featuring Evans auxiliary-assisted asymmetric 1,4-addition successfully produced the desired product without necessitating nonscalable chromatographic purification throughout the synthesis, which was selected for further development into a robust process for large-scale production.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTAcademic-Industrial Collaborations: Merging Paths to ThriveHongli BaoHongli BaoKey Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Center for Excellence in Molecular Synthesis, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. ChinaMore by Hongli Baohttps://orcid.org/0000-0003-1030-5089, Karla Bravo-Altamirano*Karla Bravo-AltamiranoPfizer Worldwide Research and Development Medicine, Eastern Point Road, Groton, Connecticut 06340, United States*Email: [email protected]More by Karla Bravo-Altamiranohttps://orcid.org/0009-0009-3578-403X, Zachary BuchanZachary BuchanDiscovery Chemistry, Small Molecule Discovery and Development, Corteva Agrisciences, 9330 Zionsville Road, Indianapolis, Indiana 46268, United StatesMore by Zachary Buchan, Pablo J. CabreraPablo J. CabreraChemical Research & DevelopmentPfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Pablo J. Cabrera, Sarah J. RyanSarah J. RyanNufarm Limited, Pipe Road, Laverton North, VIC 3026, AustraliaMore by Sarah J. Ryanhttps://orcid.org/0000-0002-9633-5299, Joshua J. Roth*Joshua J. RothDiscovery Chemistry, Small Molecule Discovery and Development, Corteva Agrisciences, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States*Email: [email protected]More by Joshua J. Roth, Fernando Sartillo-PiscilFernando Sartillo-PiscilCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, MéxicoMore by Fernando Sartillo-Piscilhttps://orcid.org/0000-0002-4322-7534, Yasuhiro SawaiYasuhiro SawaiSynthetic Molecule Process Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, JapanMore by Yasuhiro Sawaihttps://orcid.org/0000-0002-6722-2068, Uttam K. Tambar*Uttam K. TambarDepartment of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States*Email: [email protected]More by Uttam K. Tambarhttps://orcid.org/0000-0001-5659-5355, and Cayetana ZarateCayetana ZarateJohnson & Johnson Innovative Medicine, Chemical Process R&D, Cilag AG, Hochstrasse 201, 8200 Schaffhausen, SwitzerlandMore by Cayetana Zaratehttps://orcid.org/0000-0002-4002-6147Cite this: Org. Lett. 2024, 26, 14, 2669–2671Publication Date (Web):April 12, 2024Publication History Received27 March 2024Published online12 April 2024Published inissue 12 April 2024https://doi.org/10.1021/acs.orglett.4c01107Copyright © Published 2024 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views-Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (1 MB) Get e-AlertscloseSUBJECTS:Catalysis,Cross coupling reaction,Organic chemistry,Pharmaceuticals,Photochemical synthesis Get e-Alerts

This article describes the use of tetramethylammonium fluoride tetrahydrate (TMAF·4H2O) for the large-scale preparation of a challenging 4-fluorothiazole. Commercially available TMAF·4H2O was procured on a large scale and rigorously dried by distillation with isopropyl alcohol and then dimethylformamide at elevated temperature. This method of drying provided anhydrous TMAF [TMAF (anh)] containing <0.2 wt % water and <60 ppm isopropanol. The use of TMAF (anh) was essential for production of the 4-fluorothiazole. When the chlorothiazole starting material was treated with other anhydrous fluoride sources, poor conversion of the starting material or potential safety issues were observed. SNAr fluorination using dried TMAF·4H2O was carried out at a 45.1 kg scale at 95–100°C to produce 36.8 kg of 4-fluorothiazole 1b.

AbstractWir berichten über die Synthese von Kaliumacyltrifluoroboraten (KATs) mittels Palladium‐katalysierter Kreuzkupplung von Boronsäuren mit dem Thioimidat‐KAT‐Transferreagenz. Die Kombination von breit erhältlichen Aryl‐ und Vinylboronsäuren mit kommerziellem Thioimidat 1 unter Verwendung von katalytischem PdII und CuII als Additiv erlaubt die Herstellung von KATs in hohen Ausbeuten und mit guter Verträglichkeit für verschiedene funktionelle Gruppen. Das formale Einfügen von CO in Organoboronsäuren kann unter Verwendung eines geringfügig veränderten Vorgehens auch für Boronsäurepinakolester und Kaliumorganotrifluoroborate angewendet werden. Durch die einzigartige Chemie von KATs und Trifluoroboratiminiumionen (TIMs) lassen sich Kreuzkupplungen auch auf die Synthese von Amiden und α‐Aminotrifluoroboraten als Eintopfvariante ausweiten.

Community-based natural resource management (CBNRM) has grown in stature as a key component of many national natural resource and rural development governance systems. Despite their growth, the integrity of CBNRM governance systems has rarely been analysed in a national context. To enhance dialogue about how best to design and deploy such systems nationally, this paper analyses the Australian system in detail. The Australian system was selected because the nation has a globally recognised and strong history of CBNRM approaches. We first contextualise the international emergence of national CBRM governance systems before analysing the Australian system. We find that a theoretically informed approach recognising regions as the anchors in brokering multi-scale CBNRM was applied between 2000 and 2007. Subsequent policy, while strengthening indigenous roles, has tended to weaken regional brokering, Commonwealth–state cooperation and research collaboration. Our findings and consequent emerging lessons can inform Australian policy makers and other nations looking to establish (or to reform existing) CBNRM governance systems. Equally, the research approach taken represents the application of an emerging new theoretical framework for analysing complex governance systems.

We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. Interestingly, traditional SNAr conditions resulted in impurity formation. When the starting material 2 was treated with alkali base in polar aprotic solvents, an undesired product regioisomer was observed. The formation of this regioisomer impurity could be suppressed by using a less polar solvent, an organic base, and high temperature. By employing continuous flow technology, these high temperature conditions could be scaled up to produce 540 g of the desired intermediate. The continuous flow reactor allowed for rapid thermal equilibration, which minimized problematic product decomposition by reducing the time that the product was exposed to high temperature.

Although highly effective for most amide syntheses, the activation of carboxylic acids requires the use of problematic coupling reagents and is often poorly suited for challenging cases such asN-methyl amino acids. As an alternative to both secondary and tertiary amides, we report their convenient synthesis by the rapid oxidation of trifluoroborate iminiums (TIMs). TIMs are easily prepared by acid-promoted condensation of potassium acyltrifluoroborates (KATs) and amines and are cleanly and rapidly oxidized to amides with hydrogen peroxide. The overall transformation can be conducted either as a one-pot procedure orviaisolation of the TIM. The unique nature of the neutral, zwitterionic TIMs makes possible the preparation of tertiary amidesviaan iminium species that would not be accessible from other carbonyl derivatives and can be conducted in the presence of unprotected functional groups including acids, alcohols and thioethers. In preliminary studies, this approach was applied to the late-stage modifications of long peptides and the iterative synthesis of short,N-methylated peptides without the need for coupling agents.

We report the synthesis of potassium acyltrifluoroborates (KATs) by a palladium-catalyzed cross-coupling of boronic acids and the thioimidate KAT transfer reagent. The combination of widely available aryl- and vinylboronic acids with commercially available thioimidate 1 using catalytic PdII and a CuII additive enables the preparation of KATs in high yields and with good functional group tolerance. This formal insertion of CO into organoboronic acids can also be applied to boronic acid pinacol esters and potassium organotrifluoroborates using a slightly modified procedure. The cross-coupling can be telescoped into the one-pot synthesis of amides and α-aminotrifluoroborates by exploiting the unique chemistry of KATs and their trifluoroborate iminium (TIM) derivatives.

A scalable synthesis of a pyrimidine fungicide lead was developed. The pyrimidine head, 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol, was prepared by metal-halogen exchange of 2-iodo-5-bromopyridine with i-PrMgl followed by treatment with pivaloyl chloride (PivCl) in the presence of CuCN center dot 2LiCl and subsequent addition of 5-lithiopyrimidine. The boronic acid tail, (4-(1-cyanocyclobutyl)-2-fluorophenyl)boronic acid, was prepared via treatment of 1-(4-bromo-3-fluorophenyl)cyclobutane-1-carbonitrile with i-PrMgCl and trimethylborate. The o-fluoro Grignard reagent formed during this reaction sequence was analyzed by two-drop calorimetry and accelerating rate calorimetry, which revealed minimal safety concerns for scale-up. Finally, the boronic acid tail was coupled with the pyrimidine head in the presence of catalytic palladium acetate [Pd(OAc)(2)]/triphenylphosphine (PPh3) to deliver the final product in >95% yield after crystallization.

[Extract] Australia’s multi-level system for the governance of natural resources has changed significantly in the last 40 years. In this context, we refer to multiple levels of governance across spatial scales (as per Cash et al.2006). We also refer to the ‘governance system’ to describe the complex array of multiple players (from organisations to individuals) and the decision-making and influence they exert within and across different spatial levels from the site to the global level. While Parker and Braithwaite (2003) refer to governance as the ‘intentional shaping of the flow of events so as to realise desired public good’, we consider that the shaping is done in both the public and private sectors, and that both public and private outcomes might be achieved through our nation’s governance system.

This article focuses on the development of practical approaches to the in situ generation of anhydrous fluoride salts for applications in nucleophilic aromatic substitution (SNAr) reactions. We report herein that a variety of combinations of inexpensive nucleophiles (e.g., tetraalkylammonium cyanide and phenoxide salts) and fluorine-containing electrophiles (e.g., acid fluoride, fluoroformate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives) are effective for this transformation. Ultimately, we demonstrate that the combination of tetramethylammonium 2,6-dimethylphenoxide and sulfuryl fluoride (SO2F2) serves as a particularly practical route to anhydrous tetramethylammonium fluoride. This procedure is applied to the SNAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as nitroarenes.

Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120-240°C and 15-40min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity.

The 1H and 13C NMR chemical shifts of 48 industrially preferred solvents in six commonly used deuterated NMR solvents (CDCl3, acetone-d6, DMSO-d6, acetonitrile-d3, methanol-d4, and D2O) are reported. This work supplements the compilation of NMR data published by Gottlieb, Kotlyar, and Nudelman (J. Org. Chem. 1997, 62, 7512) by providing spectral parameters for solvents that were not commonly utilized at the time of their original report. Data are specifically included for solvents, such as 2-Me-THF, n-heptane, and iso-propyl acetate, which are being used more frequently as the chemical industry aims to adopt greener, safer, and more sustainable solvents. These spectral tables simplify the identification of these solvents as impurities in NMR spectra following their use in synthesis and workup protocols.

The reaction of acid fluorides with N-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluorides. With appropriate selection of acid fluoride and NHC, these salts can be used for the room temperature SNAr fluorination of a variety of aryl chlorides and nitroarenes.

This paper describes the room-temperature S(N)Ar fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe4F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO2, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO2 or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe4F is generally more cost-effective than fluorination with CsF.

AbstractThe 1,3‐dipolar cycloaddition of unstabilized azomethine ylides with electron‐poor olefins is achieved using Lewis base catalysis.