Szabolcs Makai


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Makai

First Name

Szabolcs

ORCID

0000-0003-1546-5145

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2020 - 20226
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Publications 1 - 6 of 6
  • The advent of electrophilic hydroxylamine-derived reagents for the direct preparation of unprotected amines
    Item type: Journal Article
    Gasser, Valentina C.M.; Makai, Szabolcs; Morandi, Bill (2022)
    Chemical Communications
    Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on their reactivity, several noble and non-noble transition metal catalysed amination reactions have been developed. These include the aziridination and difunctionalisation of alkenes, the amination of arenes as well as the synthesis of aminated sulfur compounds. In particular, the use of hydroxylamine-derived (N–O) reagents, such as PONT (PivONH3OTf), has enabled the introduction of unprotected amino groups on various different feedstock compounds, such as alkenes, arenes and thiols. This strategy obviates undesired protecting-group manipulations and thus improves step efficiency and atom economy. Overall, this feature article gives a recent update on several reactions that have been unlocked by employing versatile hydroxylamine-derived aminating reagents, which facilitate the generation of unprotected primary, secondary and tertiary amino groups.
  • Preparation of O-Pivaloyl Hydroxylamine Triflic Acid
    Item type: Journal Article
    Makai, Szabolcs; Falk, Eric; Morandi, Bill (2020)
    Organic Syntheses
  • Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction
    Item type: Journal Article
    Makai, Szabolcs; Falk, Eric; Morandi, Bill (2020)
    Journal of the American Chemical Society
    Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simple synthesis through an iron-catalyzed difunctionalization of alkenes. A wide array of alkene substrates are tolerated, including complex drug-like molecules and a tripeptide. Facile derivatizations of the azidoamine group demonstrate the versatility of this masked diamine motif in chemoselective, orthogonal transformations. Applications of the methodology in the concise synthesis of RO 20-1724 as well as in the formal total syntheses of both (±)-hamacanthin B and (±)-quinagolide further demonstrate the broad synthetic potential of this highly functional-group-tolerant reaction.
  • Direct Access to Unprotected Primary Amines via Iron Catalysis
    Item type: Doctoral Thesis
    Makai, Szabolcs (2022)
    Nitrogen-containing molecules, particularly amines, play crucial roles within the molecular sciences. Despite their significance throughout the scientific community, the synthesis of these target molecules is often hampered by the challenging installation of the amino group. The majority of synthetic strategies consisted of the use of pre-functionalised building blocks and tedious protecting-group manipulations. To increase synthetic simplicity and versatility, the use of abundant feedstock chemicals such as unsaturated hydrocarbons and sulfur compounds, and the installation of unprotected amino groups are highly desired. Moreover, the development of difunctionalisation reactions that install a useful functional group in the proximity of the amine would accelerate the transformation of simple building blocks into densely functionalised molecules, thus reducing synthetic steps and resources. Within this thesis, these concepts were followed and resulted in the discovery of novel amination reactions using benign iron-catalysts. First, an aminoazidation reaction was established which functioned as an unsymmetrical diamination strategy to access unprotected 2-azidoamines from alkenes in a single step. Applying this methodology, a broad range of aliphatic alkenes and vinyl arenes were successfully converted with excellent regio- and chemoselectivity. Moreover, this reaction displayed immense functional group tolerance allowing for the specific transformation of highly complex alkenyl substrates, including a tripeptide. Simultaneously, it demonstrated high tolerance towards air and moisture and good scalability, making it a practical synthetic tool. Owing to the unprotected nature of the primary amino group, these synthesised azidoamines are ideally masked, unsymmetrical vicinal diamines which allowed for sequential functionalisation of both amino groups. This behaviour could be harnessed in the (formal) synthesis of three different bioactive compounds. Mechanistically, the stereoconvergent transformation of internal alkenes, as well as radical clock experiments and the results of a Hammett-plot support a radical pathway. Furthermore, the same hydroxylamine-derived reagent was employed in an iron catalysed aminooxygenation reaction of thiols to afford unprotected, primary sulfinamides. A dual role was played by the reagent as it acted both as aminating reagent and oxidant in this transformation. This enabled the facile conversion of several aliphatic and aromatic thiols, resulting in a broad substrate scope and good functional group tolerance. Further investigations led to a proposed mechanism which featured an uncommon sulfinimidate-ester. This intermediate would result from a reaction with methanol, thus identifying the solvent as the source for the incorporated oxygen
  • Hydroxylamine‐derived Reagent as a Dual Oxidant and Amino Group Donor for the Iron Catalyzed Preparation of Unprotected Sulfinamides from Thiols
    Item type: Journal Article
    Chatterjee, Sayanti; Makai, Szabolcs; Morandi, Bill (2021)
    Angewandte Chemie. International Edition
    An iron catalyzed reaction for the selective transformation of thiols (‐SH) to sulfinamides (‐SONH 2 ) by a direct transfer of ‐ O and free ‐ NH 2 groups has been developed. The reaction operates under mild conditions using a bench stable hydroxylamine derived reagent, exhibits broad functional group tolerance, is scalable and proceeds without the use of any precious metal catalyst or additional oxidant. This novel, practical reaction leads to the formation of two distinct new bonds (S=O and S–N) in a single step to chemoselectively form valuable, unprotected sulfinamide products. Preliminary mechanistic studies implicate the role of the alcoholic solvent as an oxygen atom donor.
  • Design and scalable synthesis of novel N‐alkyl‐hydroxylamine reagents for the direct, Fe‐catalyzed installation of medicinally relevant amines
    Item type: Journal Article
    Falk, Eric; Makai, Szabolcs; Delcaillau, Tristan; et al. (2020)
    Angewandte Chemie. International Edition
    Secondary and tertiary alkylamines are privileged substance classes which are often found in pharmaceuticals and other biologically active small molecules. Herein, we report their direct synthesis from alkenes through an aminative difunctionalization reaction enabled by iron catalysis. A family of ten novel hydroxylamine‐derived aminating reagents were designed for the installation of several medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination of alkenes. The methodology displays an excellent functional group tolerance, and a broad scope of alkenes was converted to the corresponding products, including several drug‐like molecules. Besides aminochlorination, the installation of other functionalities through aminoazidation, aminohydroxylation and even intramolecular carboamination reactions, is demonstrated, further highlighting the broad potential of these new reagents for the discovery of novel amination reactions.
Publications 1 - 6 of 6