Trifluoroacetic anhydride-mediated solid-phase version of the Robinson-Gabriel synthesis of oxazoles.
A traceless solid-phase synthesis of oxazoles 4 via Robinson-Gabriel reaction of solid-supported alpha-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield alpha-methoxyphenyl (MAMP) resin with an alpha-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with alpha-keto aldehydes; reaction of MAMP resin with alpha-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.
Pulici
Maurizio
M
Department of Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy. maurizio.pulici@nervianoms.com
Quartieri
Francesca
F
Felder
Eduard R
ER
D000089:Acetic Anhydrides; D000215:Acylation; D000577:Amides / Q000737:chemistry; D000586:Amination; D000588:Amines / Q000737:chemistry; D000605:Amino Alcohols / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D005463:Fluoroacetates; D007659:Ketones / Q000737:chemistry; D008956:Models, Chemical; D010080:Oxazoles / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D012117:Resins, Synthetic / Q000737:chemistry; D013678:Technology, Pharmaceutical; D013997:Time Factors; D014269:Trifluoroacetic Acid / Q000737:chemistry*
D000089:Acetic Anhydrides; D000577:Amides; D000588:Amines; D000605:Amino Alcohols; D005463:Fluoroacetates; D007659:Ketones; D010080:Oxazoles; D012117:Resins, Synthetic; C017958:trifluoroacetic anhydride; D014269:Trifluoroacetic Acid