Solvent-free synthesis of unsaturated amino esters in a ball-mill

Abstract

The ball-milling technique was used under solvent-free conditions to perform a Horner-Wadsworth-Emmons reaction in the presence of a mild carbonate base. Starting from a phosphonate-substituted glycine, this method gave access to Boc-protected unsaturated amino esters in excellent yield and selectivity in many cases. The scope of the reaction was delineated.

CHAPTER 6. Amino Acids and Peptides in Ball Milling

“…28 High yields of Boc-protected unsaturated amino-esters were obtained by grinding amino-phosphoryl acetate 22 and various aromatic or aliphatic aldehydes in a planetary ball-mill based on a Horner-Wadsworth-Emmons reaction, with a conversion close or equal to 100% (Scheme 6.7). 25 The (Z)/(E) selectivity was always very high (100 : 0) with exclusive formation of the (Z)-isomer using aromatic aldehydes and hindered ortho-substituted substrates, except in one case (with naphthaldehyde the selectivity was lower, (Z)/(E) 82 : 18). Linear aliphatic aldehydes were also tested: in most cases high yields (up to 90%) and 100% selectivity in favor of the (Z)-isomer were obtained, while branched or sterically hindered aldehydes were less suitable, with incomplete conversion of starting material, while ketones were unreactive.…”

“…Unsaturated unnatural amino acid derivatives 23 were also obtained using the ball-milling technique by performing a Horner-Wadsworth-Emmons reaction 25 or a Heck-Jeffery protocol, 26,27 and used as platform to access 2-carbonylindoles 26 (Scheme 6.7). 28 High yields of Boc-protected unsaturated amino-esters were obtained by grinding amino-phosphoryl acetate 22 and various aromatic or aliphatic aldehydes in a planetary ball-mill based on a Horner-Wadsworth-Emmons reaction, with a conversion close or equal to 100% (Scheme 6.7).…”

From Synthesis of Amino Acids and Peptides to Enzymatic Catalysis: A Bottom‐Up Approach in Mechanochemistry

“…[18] Complementary routes to access nonchiral unsaturated amino acids derivativesw ere reported as early as 2006 by Frejd and co-workers, [19] and in 2010 by the group of Lamaty. [20] In 2012, Lamaty and co-workers also reported an asymmetrics ynthesis of amino esters derivatives inside ab all mill with yields ranging from 91 to 97 %a nd with up to 75 % ee. [21] The reaction involvedt he alkylation of preformed Schiff bases in the presence of cinchonidine derivative 11.P articularly interesting was the preparation of phenylalanine imine 10 by treating glycine derivative 8 under basic conditions with benzyl bromide (9;S cheme 2).…”

CHAPTER 2. Carbon–Carbon Bond Forming by Ball Milling

“…52 A Horner-Wadsworth-Emmons reaction between aminophosphoryl acetate (1.1 equiv. ), aldehyde (1 equiv.)…”