Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• cores for these compounds in high yields (63–83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps. Keywords: arginine; Horner–Wadsworth–Emmons; integrin; phosphoramidate; tetrahydronaphthyridine

• , affording phosphoramidate 9 in low yield, indicating good leaving group ability of the stabilised tetrahydronaphthyridine anion. No formation of phosphonate 10 was detected (Scheme 3). It was proposed that a deprotonation of 7-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine (11) with two equivalents of sec-BuLi

• due to a close match of the pKa of tetrahydronaphthyridine 11 and the pKaH of the base; s-BuLi also gave reasonable conversion to the product (Table 1, entry 4) albeit contaminated with some impurities. This could likely be attributed to the thermal instability of the base and/or lithiated