2008
DOI: 10.1021/ol7028788
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An Efficient Synthesis of Enamides from Ketones

Abstract: A new synthesis of enamides from ketones is disclosed that involves a phosphine-mediated reductive acylation of oximes. The resulting enamides are isolated in good yields (up to 89%) and excellent purity, permitting a subsequent hydrogenation to access enantiopure acetamides at catalyst loadings practical for large-scale applications.

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Cited by 77 publications
(37 citation statements)
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“…Ligands L1 a , f , g , L11 a , f , g , L12 g , L14 g and L18 f , g and complexes [Rh(cod)( L14 g )]BF 4 and [Ir(cod)( L14 g )]BAr F were synthesized as previously reported . Substrates S1 , S2 , S5 , S6 – S7 , S8 , S9 , S10 – S11 , S12 – S14 , S17 – S23 , S24 , S25 , S26 , S31 , S33 – S38 , S39 – S43 , S44 – S45 and S46 were prepared following literature procedures. All other reagents are commercially available and were used as received.…”
Section: Methodsmentioning
confidence: 99%
“…Ligands L1 a , f , g , L11 a , f , g , L12 g , L14 g and L18 f , g and complexes [Rh(cod)( L14 g )]BF 4 and [Ir(cod)( L14 g )]BAr F were synthesized as previously reported . Substrates S1 , S2 , S5 , S6 – S7 , S8 , S9 , S10 – S11 , S12 – S14 , S17 – S23 , S24 , S25 , S26 , S31 , S33 – S38 , S39 – S43 , S44 – S45 and S46 were prepared following literature procedures. All other reagents are commercially available and were used as received.…”
Section: Methodsmentioning
confidence: 99%
“…Oxime formation, the first step, is high yielding24 but the second reaction step, radical rearrangement of the in situ formed O ‐acetylated oxime to an N ‐acetylenamide, requires excess Fe in the presence of acetic anhydride at elevated temperature and provides poor to mediocre yields (30–69%) 25. Industrial chemists have recently commented that this Fe‐based “method is not amenable to scale‐up and adaptation in the pharmaceutical industry,”24a and offered an alternative enamide synthesis: toluene reflux of the oxime with approximately equal molar quantities of acetic anhydride and Et 3 P. Using this method an advanced Zoloft‐related (Figure 1) enamide was synthesized and enantioselectively hydrogenated at the 75‐kg scale. Yields for this new method are generally around 70%, but range from 58–90%.…”
Section: Enantioselective N‐acetylenamide Reductionmentioning
confidence: 99%
“…Aldehydes and ketones play a vital role as precursors and are required to be protected during the synthesis of biologically significant poly‐functional molecules and complex natural products. 1 Several methods are well established for the protection of carbonyl groups as acetal/ketal,, oximes,, hydrazones,, thioacetals,, dioxolanes,,, oxathiolanes,, or dithiolanes ,,,,. The subsequent deprotection of these moieties is of prime importance for their further use in organic synthesis.…”
Section: Introductionmentioning
confidence: 99%