Those of you on LinkedIn may have seen my daily #Reactionoftheday post. The purpose is to highlight reactions that I think are interesting and relevant to the synthetic organic chemistry and process chemistry communities. Please feel free to link to me and to Scientific Update on the LinkedIn platform and like or re-share my posts. This weekly blog is to summarise the proceeding weeks highlights, and to add a few supplementary references and review articles.
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Homologation of carboxylic acids using a radical polar conjunctive reagent
J. Am. Chem. Soc .2024, 146, 32919–32924
https://doi.org/10.1021/jacs.4c13687
Carbon homologation is a useful structural editing tool, however direct homologation of carboxylic acids was hitherto unrealised. The Alexanian group have developed a novel, stable, phophoryl vinyl sulfone radical-polar conjunctive reagent (phew) capable of one step conversion of aliphatic acids to their chain extended homologues.
- Iterative one-carbon homologation of unmodified carboxylic acids: Am. Chem. Soc. 2024, 146, 34285–34291
- Direct C1 homologation of carboxylic acids: free radical approach enabled by acridine catalysis: Chem. Front., 2025, 12, 2255-2259
- Carbenoid-mediated homologation tactics for assembling (fluorinated) epoxides and aziridines: Synlett 2021, 6, 551-560
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Cobalt-catalysed desymmetrization of malonitrile via enatioselective borohydride reduction
Nat. Chem. 2024, 16, 1845–1854
https://doi.org/10.1038/s41557-024-01592-z
A remarkable study by Huang et al describes the desymmetrization of readily available bulk feedstock chemicals—malonitriles—to access functionally rich β-chiral quaternary amines. In this transformation, a bisoxazoline-ligated cobalt catalyst, in the presence of sodium borohydride, generates a cobalt-hydride species that initiates the enantioselective reduction.
- Chemistry of malononitrile: Chem.Rev. 1969, 69, 591–624
- Acyclic quaternary carbon stereocenters via enantioselective transition metal catalysis. Chem. Rev. 2017, 117, 12564–12580
- Recent progress in applications of cobalt catalysts in organic reactions: Tetrahedron 2023, 89, 1446
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Sandmeyer chlorosulfonylation of (hetero) aromatic amines using DABSO as an SO2 surrogate
Org. Lett. 2024, 26, 5951–5955
https://doi.org/10.1021/acs.orglett.4c01908
This paper by Schafer and Willis presents an alternative approach to accessing valuable aryl and heteroaryl sulfonyl chloride intermediates from anilines, bypassing the traditional oxidative chlorination of thiols. The method employs a Sandmeyer-type reaction using DABSO as a stable sulfur dioxide surrogate, along with HCl and CuCl, to generate the sulfonyl chloride in situ. This intermediate can either be isolated or directly trapped with an amine to afford the corresponding sulfonamide.
- Development of a scalable electrophilic amination protocol for the multi-kg production of 5-methyl-2-pyridinesulfonamide: a regulatory starting material of endothelin receptor antagonist clazosentan. Org. Process Res. Dev. 2023, 27,1377– 1383
- DABSO – A reagent to revolutionize organosulfur chemistry. Synthesis 2022, 54, 1695–1707, DOI: 10.1055/s-0040-1719864
- Recent trends in the chemistry of Sandmeyer reaction: a review: Mol Divers 2022, 26, 1837–1873
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Enantioselective Cobalt(III)-catalyzed [4+1] annulation of benzamides: cyclopropenes as one-carbon synthons
J. Am. Chem. Soc. 2025, 147, 15041–15049
https://doi.org/10.1021/jacs.4c16953
High-valent cobalt catalysts are emerging as sustainable alternatives that complement the reactivity demonstrated by Rh(III) and Ir(III) systems. In this study, Cramer et al. report an enantioselective [4+1] annulation of N-chloroamides via C–H activation and C–C bond cleavage of a cyclopropene, showcasing reactivity that is orthogonal to the [4+2] annulation observed with rhodium catalysis. The cyclopropene substrates serve as a functional C1 synthon in this transformation.
- Recent developments in cyclopropene chemistry: Chem. Commun., 2020, 56, 5457-5471
- Rhodium catalyzed asymmetric C–H functionalization reactions. Chem. Rev. 2023, 123, 10079– 10134
- Heptamethyl indenyl (Ind*) enables diastereoselective benzamidation of cyclopropenes via Rh(iii)-catalyzed C-H activation: Sci. 2017, 8, 1015– 1020
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Regioselective synthesis of 2,3,5-trisubstituted pyridines via 5-chloro-3-fluoro-2-(methylsulfonyl)pyridine
J. Org. Chem.2024, 89, 8299–8304
https://doi.org/10.1021/acs.joc.4c00753
While numerous procedures exist for the synthesis of pyridines—as any graduate student can attest—selective functionalization of a fully assembled pyridine ring remains a significant challenge. A particularly valuable contribution from Brusoe and his team at Boehringer Ingelheim describes a one-step, large-scale (multi-kilogram) synthesis of two key building blocks. These intermediates can be orthogonally derivatized to access 2,3,5-trisubstituted pyridines, offering practical and versatile methodology.
- Halogenation of the 3-position of pyridines through Zincke imine intermediates: Science 2022, 773-779
- Synthesis of 3-Fluoropyridines via photoredox-mediated coupling of α,α-difluoro-β-iodoketones with silyl enol ethers: J. Org. Chem. 2017, 24, 12967-12974
- A mini review on the multicomponent synthesis of pyridine derivatives: ChemSelect 2022, 47, e202203668
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Synthesis of multisubstituted napthalenes through consecutive aryne reactions
Bull. Chem. Soc. Jpn. 2025, 98, uoaf001
https://doi.org/10.1093/bulcsj/uoaf001
Naphthalenes are among the most important aryl hydrocarbons and are produced on a multi-million-ton scale. In this interesting paper, Yoshida et al. describe the synthesis of substituted naphthalene derivatives via orthogonal aryne generation and directed functionalization. Selective, reagent-controlled activation of silyl or iodo precursors provides a versatile handle for diversification, enabling the synthesis of potentially valuable pharmacophores and advanced materials. Simple, yet potentially very powerful.
- Synthesis of naphthalenes and 2-naphthols by the electrophilic cyclization of alkynes: J. Org. Chem. 2006, 71, 236–243
- A comprehensive history of arynes in natural product total synthesis: Chem. Rev. 2012, 112, 3550-3577
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Green synthesis of morpholines via selective monoalkylation of amines
J. Am. Chem. Soc .2024, 146, 29847–29856
https://doi.org/10.1021/jacs.4c11708
Morpholines are important heterocycles with broad utility in drug and agrochemical design, owing in part to possible substitution vectors useful for probing structure–activity relationships. A useful paper by Brusoe et al. describes a green synthesis of morpholines via alkylation of substituted amino alcohols using ethylene sulfate as a two-carbon electrophile. The method enables access to a wide array of structurally complex morpholines, with intriguing indications that piperazines may also fall within the scope.
- A mini review on the morpholine ring containing UDFDA approved drugs: A medicinal chemistry-based analysis from 2013-23: Synlett 2025, DOI: 10.1055/a-2547-8990
- Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the structure-activity relationship (SAR): Bioorg. Chem. 2020, 103578
- Practical synthesis of chiral 2-morpholine: (4-Benzylmorpholin-2-(s)-yl)- (tetrahydropyran-4-yl) methanone mesylate, a useful pharmaceutical intermediate: Org. Process Res. Dev. 2009, 13, 209-224
