Browsing by Subject "Synthetic chemistry methodology"

Now showing 1 - 3 of 3
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    A photochemical dehydrogenative strategy for aniline synthesis
    (Nature Research, 2020-08-06) Dighe, Shashikant; Juliá Hernández, Fabio; Luridiana, Alberto; Douglas, James J.; Leonori, Daniele; Química Inorgánica
    Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3,4,5,6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C–H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon–nitrogen (C–N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C–N coupling protocol by preparing commercial medicines and by the late-stage amination–aromatization of natural products, steroids and terpene feedstocks.
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    Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer
    (Nature Research, 2021-07-12) Gorski, Bartosz; Barthelemy, Anne-Laure; Douglas, James J.; Juliá Hernández, Fabio; Leonori, Daniele; Química Inorgánica
    Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature. The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues.
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    Practical and regioselective amination of arenes using alkyl amines
    (Nature Research, 2019-05) Ruffoni, Alessandro; Juliá Hernández, Fabio; Svejstrup, Thomas D.; McMillan, Alistair J.; Douglas, James J.; Leonori, Daniele; Química Inorgánica
    The formation of carbon–nitrogen bonds for the preparation of aromatic amines is among the top five reactions carried out globally for the production of high-value materials, ranging from from bulk chemicals to pharmaceuticals and polymers. As a result of this ubiquity and diversity, methods for their preparation impact the full spectrum of chemical syntheses in academia and industry. In general, these molecules are assembled through the stepwise introduction of a reactivity handle in place of an aromatic C–H bond (that is, a nitro group, halogen or boronic acid) and a subsequent functionalization or cross-coupling. Here we show that aromatic amines can be constructed by direct reaction of arenes and alkyl amines using photocatalysis, without the need for pre-functionalization. The process enables the easy preparation of advanced building blocks, tolerates a broad range of functionalities, and multigram scale can be achieved via a batch-to-flow protocol. The merit of this strategy as a late-stage functionalization platform has been demonstrated by the modification of several drugs, agrochemicals, peptides, chiral catalysts, polymers and organometallic complexes.