Toward Customized Tetrahydropyran Derivatives through Regioselective α‐Lithiation and Functionalization of 2‐Phenyltetrahydropyran

Abstract

In this contribution, the first direct and efficient functionalization of the preformed 2-phenyltetrahydropyran (2-PhTHP) nucleus by electrophilic interception of the corresponding α-lithiated derivative by employing sBuLi as the base and THF as the solvent at –78 °C was explored. The presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) proved to be critical to governing reaction feasibility both in polar and apolar solvents and for improving the yield of the reaction. Both carbon- and heteroatom-based halides were found to be competent electrophiles for this transformation, as well as aliphatic and aromatic aldehydes and ketones, isocyanates, and carboxylic acid derivatives. The combination of hexane/TMEDA lowered the rate of racemization of α-lithiated optically active 2-PhTHP, which thereby enabled calculation of its barrier to inversion at –78 °C

2-Diphenylphosphinomethyl-3-methylpyrazine

“…Further characterization of 2 came by allowing it to react at RT with chalcogens like selenium (2 equiv) directly in an NMR tube, and subsequently monitoring the appearance of phosphine selenide 3, which formed with >98% conversion within a few minutes (Scheme 2c). The structure and the connectivity of 3 were unambiguously assigned by means of mono-( 1 H, 13 C, 31 P and 77 Se) and two-dimensional (( 1 H-1 H)-COSY, ( 1 H-13 C)-HMBC and HMQC)) NMR techniques (Supplementary Materials), and by X-ray analysis (Figure 1 and Supplementary Materials). The major resonance displayed in the 31 P NMR spectrum at δ 32.4 (C 6 D 6 ) is that typical of phosphine selenides [43].…”

“…The structure and the connectivity of 3 were unambiguously assigned by means of mono-( 1 H, 13 C, 31 P and 77 Se) and two-dimensional (( 1 H-1 H)-COSY, ( 1 H-13 C)-HMBC and HMQC)) NMR techniques (Supplementary Materials), and by X-ray analysis (Figure 1 and Supplementary Materials). The major resonance displayed in the 31 P NMR spectrum at δ 32.4 (C 6 D 6 ) is that typical of phosphine selenides [43]. 31 P-77 Se NMR coupling could be seen either in 31 P NMR spectrum as satellites ( 1 J P-Se = 756.3 Hz) or directly in the 77 Se NMR spectrum (Supplementary Materials).…”

“…The major resonance displayed in the 31 P NMR spectrum at δ 32.4 (C 6 D 6 ) is that typical of phosphine selenides [43]. 31 P-77 Se NMR coupling could be seen either in 31 P NMR spectrum as satellites ( 1 J P-Se = 756.3 Hz) or directly in the 77 Se NMR spectrum (Supplementary Materials).…”

“…The following are available online at: copies of 1 H-, 13 C-and 31 P-NMR spectra of compound 2; copies of 1 H-, 13 C-, 31 P-and 77 Se-NMR spectra of compound 3; copies of 2D 1 H-1 H-COSY, 2D 1 H-13 C HMQC, 2D 1 H- 13 C HMBC spectra of compound 3; crystallographic data, geometric parameters and bond angles for compound 3 • C 6 D 6 ; X-ray ellipsoid plot of compound 3 • C 6 D 6 showing interactions between selenium and the neighbouring protons.…”

“…Based on our long lasting interest in the functionalization of heterocycles by direct [26][27][28][29][30][31][32][33], ortho- [34,35], and lateral [36,37] lithiation reactions, we became interested in synthesizing a pyrazine derivative incorporating a phosphine unit into its scaffold as transition metalphosphine complexes are known to be powerful catalytic tools for numerous C-C bondforming reactions in modern organic synthesis [38][39][40][41].…”