Coumarin derivatives represent an important synthetic intermediate in the field of organic and pharmaceutical chemistry, as the resulting chiral lactones serve as building blocks for a variety of further transformations. As for the functionalization of this heterocyclic ring by nucleophilic additions, only a few examples have been reported to date using Grignard reagents (up to 2.5 eq) jointly with CuBr·SMe2 as a catalyst. However, intrinsic limitation of the proposed protocols are: ineffectiveness of some Grignard reagents (e.g., MeMgCl and PhMgCl), a long reaction time (up to 24 h) and the use of cryogenic conditions. On the other hand, when organozinc or organolithium or Grignard reagents are used in the absence of a copper source, the expected adducts did not form either and ring-opening products are alternatively observed. The applications of lithium zincates species in fundamental organic transformations and under unconventional reaction conditions are still in their infancy. This type of reagents show unique, synergistic chemical characteristics, which cannot be replicated by their monometallic (organolithium/organozinc) counterparts. In this Communication, an innovative approach of functionalising and dearomatising coumarins via regio-, chemo- and stereoselective alkylation reactions, mediated by lithium organozincates will be discussed. Characteristic features of our report are: (a) the use of stoichiometric amount of lithium zincate species, (b) the absence of any catalyst, and (c) the employment of “neat” conditions. In this way, the desired adducts are obtained within a short reaction time (up to 15 min), in very high yield (up to 99%), and with high regio-, chemo-, and stereoselectivity, and as the sole products. The isolation and characterisation of key intermediates and stereochemical aspects of the above transformations will be discussed as well.

Dearomatising Coumarins via Regio-, Chemo- and Stereoselective Nucleophilic Additions of Lithium Zincate Species

Marzia Dell’Aera;Filippo Maria Perna;Paola Vitale;Vito Capriati
2018

Abstract

Coumarin derivatives represent an important synthetic intermediate in the field of organic and pharmaceutical chemistry, as the resulting chiral lactones serve as building blocks for a variety of further transformations. As for the functionalization of this heterocyclic ring by nucleophilic additions, only a few examples have been reported to date using Grignard reagents (up to 2.5 eq) jointly with CuBr·SMe2 as a catalyst. However, intrinsic limitation of the proposed protocols are: ineffectiveness of some Grignard reagents (e.g., MeMgCl and PhMgCl), a long reaction time (up to 24 h) and the use of cryogenic conditions. On the other hand, when organozinc or organolithium or Grignard reagents are used in the absence of a copper source, the expected adducts did not form either and ring-opening products are alternatively observed. The applications of lithium zincates species in fundamental organic transformations and under unconventional reaction conditions are still in their infancy. This type of reagents show unique, synergistic chemical characteristics, which cannot be replicated by their monometallic (organolithium/organozinc) counterparts. In this Communication, an innovative approach of functionalising and dearomatising coumarins via regio-, chemo- and stereoselective alkylation reactions, mediated by lithium organozincates will be discussed. Characteristic features of our report are: (a) the use of stoichiometric amount of lithium zincate species, (b) the absence of any catalyst, and (c) the employment of “neat” conditions. In this way, the desired adducts are obtained within a short reaction time (up to 15 min), in very high yield (up to 99%), and with high regio-, chemo-, and stereoselectivity, and as the sole products. The isolation and characterisation of key intermediates and stereochemical aspects of the above transformations will be discussed as well.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/246754
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