Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor GDC-1971 (migoprotafib), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by n-butyllithium, participated in umpolung reactivity via 1,2-addition to tert-butyl 4-oxopiperidine-1-carboxylate (N-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures. Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular SNAr reaction and final crystallization to generate tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971.

Syntheses of Square Planar Gallium Complexes and a Proton NMR Correlation Probing Metalloaromaticity.

Syntheses of square planar (SP) coordination complexes of gallium(III) are reported herein. Using the pyridine diimine ligand (PDI), we prepared both (PDI2-)GaH (4) and (PDI2-)GaCl (5), which were spectroscopically and structurally characterized. Reduction of PDI using Na metal afforded "Na2PDI", which reacts with in situ-prepared "GaHCl2" or GaCl3 to afford the SP 4 and 5. The planar geometry of these and previously reported SP Al(III) complexes is attributed to energetic stabilization derived from a ring-current effect, or metalloaromaticity. Typically, aromaticity in metal-containing ring systems can be difficult to characterize or confirm experimentally. An experimental approach employing proton NMR spectroscopy and described here provided an estimate of a downfield chemical shift promoted by a small ring-current associated with metalloaromaticity. Near infrared spectroscopic analyses display ligand-metal charge transfer bands which support the assignment of aromaticity. The SP complexes (PDI2-)AlH (1), (PDI2-)AlCl (2), (PDI2-)AlI (3), 4, and 5 are all discussed in this report, using aromaticity as a model for their electronic structure and reactivity properties.