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Convergent Synthesis of 2-Oxazolone-4-carboxylates Esters by Reac- tion of Aldehydes with Ambivalent N-Cbz-α-Tosylglycinate Ester

Abstract : N-Cbz-α-tosylglycinate ester was combined with aldehydes in a redox-neutral sequence leading to 2-oxazolone-4-carboxylates with high functional groups tolerance. While the scope of the method was delineated to primary and secondary ali-phatic aldehydes as well as aromatics, no racemization occurred with chiral aldehydes such as Garner's. Hitherto unknown, this process relies on the ambivalent role of N-Cbz-α-tosylglycinate ester acting as pronucleophile. Combining nitrogen and oxygen in a 5-membered aromatic ring, 2-(3H)oxazolones (2-oxo-2,3-dihydrooxazoles) are pertinent molecules in the fields of medicinal chemistry and agrochemistry, 1 as illustrated with I and II (Scheme 1A) with respectively antibacterial 1a and herbicidal activities. 1b,2 As planar and aromatic derivatives of amino acids such as serine and threonine, electron-poor 2-(3H)oxazolone-4-carboxylates esters have much promise in the aforementioned fields (Scheme 1B). However, the known strategy toward 5-substituted-2-(3H)oxazolone-4-carboxylates requires two limiting steps. Scheme 1. First, α-ketoesters are oxidized into α-nosyloxy or α-bromo-β-ketoesters, then the nitrogen nucleus is introduced with methyl carbamate by nucleophilic addition in harsh conditions, upon activation with p-toluenesulfonic acid or silver triflate, in refluxing toluene. 3 Within this strategy, alternative routes were described by combining either α-amino-β-ketoesters with triphosgene 1b or α-diazo-β-ketoesters with methyl carbamate. 1c Beside the limited functional group tolerance displayed by these methods, the assemblage and/or oxidation of the acyclic compounds remain impediments to broader molecular diversity. At the inception of this study was an attempt to promote the Mannich coupling between dihydrocinamaldehyde 1a and N-Cbz-α-tosylglycinate ester 2 which inadvertently led to 2-(3H)oxazolone 3a in 25% yield (Eq. 1). Simply promoted by nBu 4 NF, the redox-neutral and conver-gent domino sequence gave 5-alkyl and 5-aryl-2-(3H)oxazolone-4-carboxylates from 2 and functionalized, aliphatic and aromatic, aldehydes (Scheme 1C). The role of 2 in this sequence was puzzling, reacting usually as a proelectrophile. 4,5 Interestingly, this study illustrates the ambivalent reactivity of 2 as a pronucleophile.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-03006839
Contributor : Michael de Paolis <>
Submitted on : Monday, November 16, 2020 - 10:13:02 AM
Last modification on : Saturday, November 28, 2020 - 3:29:25 AM

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Masahiro Abe, Baptiste Picard, Michaël de Paolis. Convergent Synthesis of 2-Oxazolone-4-carboxylates Esters by Reac- tion of Aldehydes with Ambivalent N-Cbz-α-Tosylglycinate Ester. Organic Letters, American Chemical Society, 2020. ⟨hal-03006839⟩

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