(Thio)urea-mediated benzoxazinone opening: mild approach towards synthesis of o-(substituted amido)benzamides
| Title | (Thio)urea-mediated benzoxazinone opening: mild approach towards synthesis of o-(substituted amido)benzamides |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Nair, RV, Sanjayan, GJ |
| Journal | RSC Advances |
| Volume | 4 |
| Issue | 14 |
| Pagination | 6858 to 7367 |
| Date Published | NOV |
| Type of Article | Journal Article |
| ISSN | 2046-2069 |
| Abstract | C-terminal activation of N-acylated o-aminobenzoic acids and their derivatives during coupling reactions with amines would often pose a challenge due to the formation of a benzoxazinone intermediate, which may resist reacting with amines. This communication reports a mild approach towards the installation of an amide bond via benzoxazinone ring opening utilizing Schreiner's (thio)urea organocatalyst. Peptide coupling reactions oen encounter major hurdles because of the formation of side products during carbonyl activation of various amino acids, like N-carboxyanhydride, diketopiperazine etc. 1 1,3-benzoxazinones (Fig. 1) are a class of heterocyclic side products obtained upon C-terminal activation of anthranilic acid and their derivatives due to the intra-molecular cyclization of the benzamide oxygen, resulting in trace or no coupling. 2 Strategies meant either to avert its formation in situ or to react it with amines have been attempted through heating the reactants at elevated temperatures 3 and/or in the presence of bases. 2b,c However, such drastic conditions may cause quinazoline formation as well, owing to a second cyclodehydration of the coupled product. Moreover, applying such drastic conditions to amino acids may not be advisable due to the possibility of epimerization. We have been interested for quite some time in the devel-opment of foldamers containing the Ant–Pro reverse-turn motif (Ant ¼ anthranilic acid, Pro ¼ proline), Fig. 1. 4 The striking feature of this motif is its robust 9-membered-ring intra-molecular H-bonding network. Occasionally, the formation of a benzoxazinone intermediate causes a drastic fall in the yield of coupled products. 5 Owing to the reduced reactivity of benzox-azinones towards amine nucleophiles, we attempted different conditions, such as heating the reaction mixture and under microwave conditions. Unfortunately, these procedures led to only partial conversion of the oxazinone into the product. Aer extensive effort, we were successful in developing an efficient method for coupling a range of isolated benzoxazinone inter-mediates via nucleophilic ring-opening utilizing DBU (1,8-dia-zabicycloundec-7-ene) in DMF containing A molecular sieves. 5 However, in a few cases, this method produced only meagre yields of the coupled product. One such instance was the reac-tion of 2-(2-azidopropan-2-yl)-2H-benzo[d][1,3]oxazin-4-one 1a, Table 1 (isolated as the major by-product on activation of 2-(2-azido-2-methylpropanamido)benzoic acid) with H-L Pro-OBn to obtain compound 2a. Scanty yields of the product isolated under DBU-mediated opening conditions impelled us to explore a carbonyl activation route to open the azlactone moiety. Hence, we employed some lactone activating agents, such as Sc(OTf) 3 , Ti(O i Pr) 4 etc., but none of the trials were rewarding. |
| DOI | 10.1039/c3ra45903a |
| Type of Journal (Indian or Foreign) | Foreign |
| Impact Factor (IF) | 2.936 |
Divison category:
Organic Chemistry
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