Conjugate Addition Reactions ofN-Carbamoyl-4-pyridones and 2,3-Dihydropyridones with Grignard Reagents in the Absence of Cu(I) Salts

Abstract

N-Boc- and N-ethoxycarbonyl-4-pyridones and the resulting 2,3-dihydropyridones undergo 1,4-addition reactions with Grignard reagents in the presence of chlorotrimethylsilane (TMSCl) or BF3·Et2O in excellent yields. Copper catalysis is not required, and mechanistic considerations suggest that the reaction is proceeding by a conjugate addition pathway rather than by a pathway involving 1,2-addition to an intermediate pyridinium ion. TMSCl-mediated conjugate addition of Grignard reagents to 2-substituted-2,3-dihydropyridones gives the trans-2,6-disubstitued piperidinones stereoselectively, while cuprate reagents give either the trans or cis diastereomers or mixtures.

A Twist on Facial Selectivity of Hydride Reductions of Cyclic Ketones: Twist-Boat Conformers in Cyclohexanone, Piperidone, and Tropinone Reactions

“…As described above, previous experimental and computational studies have indicated that similar piperidones (albeit bearing bulkier 2- and 6-substituents) exist predominantly in a twist-boat conformation in solution and in the solid state. 9a , 15 , 16 …”

Diastereoselective Synthesis of Spirodihydrobenzofuran Analogues of the Natural Product Filifolinol

“…[20] Recently however, it has been shown that although the use of small nucleophiles tends to add to the axial face, some six-membered cyclic ketones suffered the hydride addition from the equatorial face even when a small hydride reagent such as sodium borohydride (NaBH 4 ) is used. [21] With this in mind, three bulky hydride reagents, -H, LiAlH(t-BuO) 3 and NaBH(OCOCH 3 ) 3 in order to favor the equatorial approach of the hydride to the carbonyl compound were used. Unfortunately, all of them failed since no reduction was observed.…”

Rhodium(I)-Complexes Catalyzed 1,4-Conjugate Addition of Arylzinc Chlorides to N-Boc-4-pyridone

“…There is also one isolated example on rhodium(I)-BINAP-catalyzed 1,4-conjugate addition to N - tert -butoxycarbonyl-4-pyridone [ 55 ]. Other approaches involving 2,3-dihydro-4-pyridones via direct conjugate addition of organocuprates and Grignard reagents have also been reported [ 56 , 57 ]. In our study, ligands such as phosphoramidite ligands (A, B) [ 12 , 13 , 14 ], 1,5-diphenyl-1,5-cyclooctadiene (C) [ 54 ], and BINAP (D) [ 18 , 19 ] were initially studied in rhodium(I)-catalyzed conjugate addition of p-tolylZnCl 6a to N -Boc 4-pyridone 3A at −5 °C.…”

“…HRMS data for compounds 5Aa , 5Ad , 5Af − Ag , 5Ai , 5Ak – Al were analyzed by TOF MS, see supplementary . Compounds 5Ab – Ac , 5Ae , 5Ah , and 5Aj have been fully characterized and reported [ 55 , 57 , 60 ].…”