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. 2023 May 12:137:133390.
doi: 10.1016/j.tet.2023.133390. Epub 2023 Mar 31.

Ring-Opening Reactions of Phosphoramidate Heterocycles

Annu Anna Thomas  1 , Frederick J Seidl  2 , Joel T Mague  3 , Shyam Sathyamoorthi  1
Affiliations

Ring-Opening Reactions of Phosphoramidate Heterocycles

Annu Anna Thomas et al. Tetrahedron. .

Abstract

We present protocols for the conversion of phosphoramidate heterocycles into 1,3-chloroamines and 1,3-aminoalcohols. For the formation of chloroamines, our optimized protocol involves heating the phosphoramidate starting material with 4 equivalents of HCl in a dioxane/toluene solvent mixture. The substituents on the phosphoramidate starting material have a profound influence on product formation. Phosphoramidates with a variety of aza-heterocyclic substituents engage, but those containing a 5-chloro-8-quinolinol arm are most competent for 1,3-chloroamine formation. Furthermore, only the phosphoramidate cis diastereomers allow for 1,3-chloroamine formation. X-ray crystallography studies coupled with DFT analysis provide a basis for the stark difference in reactivity between the cis and trans diastereomers. Amino-alcohol products form by heating phosphoramidate heterocycles with aqueous HF in toluene. Here, there is no diastereomeric preference or a requirement for an aza-heterocyclic arm. Based on a substrate survey, both reactions tolerate a broad range of substitution patterns and functional groups. This work establishes that phosphoramidates are competent synthons for interesting amine products and further increases the prominence of tethered aza-Wacker technology.

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Figures

Figure 1.
Figure 1.
Relative DFT energies of cis and trans substrates as neutral protonated species.
Figure 2.
Figure 2.
Protonated cis substrates (computational structure). The cis substrates adopt a destabilized boat conformation. Protonation of the quinoline nitrogen leads to an intramolecular hydrogen bond to the phosphoramidate oxygen. Pi-pi stacking is observed between the quinolone and m-xylene rings.
Scheme 1.
Scheme 1.
Cyclic phosphoramidates are hidden 1,3-amino alcohols, but are they practical substrates for the formation of such products?
Scheme 2.
Scheme 2.
Upon heating with HCl/dioxane, formation of 1,3-chloroamines occurs unexpectedly.
Scheme 3.
Scheme 3.
Substrate scope for 1,3-chloroamines formation.
Scheme 4.
Scheme 4.
Effect of the phosphoramidate “third arm” substituent on 1,3-chloroamines formation.
Scheme 5.
Scheme 5.
A. The trans diastereomer is completely resistant to transformation while the cis diastereomer reacts smoothy. Note that #41 exists almost as a perfect chair, but #27 is closer to a boat B. Postulated mechanism for product formation.
Scheme 6.
Scheme 6.
A. Upon the addition of aqueous HF, clean formation of 1,3-aminoalcohols occurs. B. Postulated mechanism for product formation.
Scheme 7.
Scheme 7.
Substrates scope for 1,3-aminoalcohols formation.
Scheme 8.
Scheme 8.
Deprotection has no diastereomeric preference and the “third arm” need not be an aza-heterocycle.
See this image and copyright information in PMC

References

    1. Thomas AA; Nagamalla S; Sathyamoorthi S, Salient features of the aza-Wacker cyclization reaction. Chem. Sci 2020, 11, 8073–8088. - PMC - PubMed
    1. Kotov V; Scarborough CC; Stahl SS, Palladium-Catalyzed Aerobic Oxidative Amination of Alkenes: Development of Intra- and Intermolecular Aza-Wacker Reactions. Inorg. Chem 2007, 46, 1910–1923. - PubMed
    1. Wang D; Weinstein AB; White PB; Stahl SS, Ligand-Promoted Palladium-Catalyzed Aerobic Oxidation Reactions. Chem. Rev 2018, 118, 2636–2679. - PubMed
    1. Beccalli EM; Broggini G; Martinelli M; Sottocornola S, C−C, C−O, C−N Bond Formation on sp2 Carbon by Pd(II)-Catalyzed Reactions Involving Oxidant Agents. Chem. Rev 2007, 107, 5318–5365. - PubMed
    1. Zeni G; Larock RC, Synthesis of Heterocycles via Palladium π-Olefin and π-Alkyne Chemistry. Chem. Rev 2004, 104, 2285–2310. - PubMed