Sigmatropic [1,5] Carbon Shift of Transient C3 Ammonium Enolates

Abstract

The stereospecific sigmatropic [1,5] carbon shift of C3 ammonium enolates is discovered. According to mechanistic, kinetic and computational experiments, this new rearrangement proceeds via the catalytic generation of a transient C3 ammonium enolate by intramolecular aza-Michael addition. This intermediate rapidly undergoes [1,5] sigmatropic carbon migration to furnish the respective tetrahydroquinoline-4-ones with excellent diastereoselectivities of d.r. > 99 : 1 and in 61-98 % yield.Rearrangement reactions are one of the most useful tools for construction of organic scaffolds. [1] In fact, [1,2] [2] and [3,3] [3] sigmatropic rearrangements are typical reactions used to achieve molecular complexity with high stereocontrol. Observations of sigmatropic shifts of hydrogen, silicon or acyl groups across extended π-systems, such as cyclopentadiene, indenyl [4] or quinone [4d, 5] structures, have provided a basis for in-depth understanding of organic chemistry [6] in addition to the synthetic benefits. Electrophilic nitrogenylide rearrangements, like the [1,2] and [2,3] Stevens [7] and Sommelet-Hauser [8] rearrangements, offer stereoselective access to synthetically useful amino building blocks through nitrogen to carbon chirality transfer. [9] The [1,2] Stevens progresses by homolytic CÀ N bond dissociation with formation of a caged radical pair, while the [2,3] Stevens and the Sommelet-Hauser rearrangements proceed by a concerted mechanism (Scheme 1a and b).Both rearrangements require, first, quaternization of the nitrogen atom and, as a second step, formation of the ylide by deprotonation. There have been only a few reported examples of catalytic creation of the ylide intermediate. [10] And although C3 ammonium enolates [11] are well-known intermediates in aza-Michael and Morita-Baylis-Hillman reactions, [12] cyclic C3 ammonium enolates have yet to be considerd as precursors for sigmatropic [1,5] rearrangements (Scheme 1c).

Structure–Reactivity Relationships in Borane-Based FLP-Catalyzed Hydrogenations, Dehydrogenations, and Cycloisomerizations

“…However, during our mechanistic studies, we found that the enantiopure N-methyl-N-phenylethyl derivative 52a was converted to the product 53a with stereospecific migration of the phenylethyl moiety (Scheme 15a). 64 We concluded that the exceptional enantio-and diastereoselectivity must arise from a concerted [1,5] carbon shift. Kinetic experiments and quantum chemical calculations fully support this picture of a sigmatropic [1,5] carbon shift via transiently formed C3 ammonium enolates.…”

“…The quinolinones 51a – o were obtained in good to high yields, mostly as cis diastereomers. However, during our mechanistic studies, we found that the enantiopure N -methyl- N -phenylethyl derivative 52a was converted to the product 53a with stereospecific migration of the phenylethyl moiety (Scheme a) …”

Difluorocarbene-induced [1,2]- and [2,3]-Stevens rearrangement of tertiary amines

“…The Stevens rearrangement is typically applied to construct complex nitrogen/sulfur-containing compounds through [1,2]- or [2,3]-sigmatropic rearrangement, starting from ammonium or sulfonium salts. However, harsh conditions, such as the presence of a strong base, are usually necessary and unavoidable, and the key intermediate is nitrogen 6 – 14 or sulfur 15 – 19 ylide. Therefore, Stevens rearrangement is often considered a commonly used molecular editing method for prevalent tertiary amines.…”

“…In 2021, Zhang and coworkers demonstrated a 5-endo-dig cyclization of tertiary amines with intramolecular alkynes activated by π-Lewis-acid to form quaternary ammonium salts, then render nitrogen ylides 41 . However, the universalities of the known Stevens rearrangements are quite poor, usually it is difficult for them to be compatible with all allyl, propargyl, and benzyl groups in one reaction under the same conditions 6 – 14 , which thus restricts the derivation of product diversity. Consequently, studies toward the efficient and versatile methods for both [1,2]- and [2,3]-Stevens rearrangements are highly desirable.…”

Controllable construction of pharmaceutically significant scaffolds of 2,3-dihydroquinolin-4-one and benzoazepine-5-oneviaredox-neutral cascade hydride transfer/cyclization

“…Until now, the cascade [1, n ]-hydride transfer/cyclization strategy, 4 namely a “redox-neutral process”, has distinguished itself from other C–H bond functionalization approaches in amines 5 due to its fascinating advantages for the straightforward construction of various heterocycles, which feature redox-neutrality and inherent high step- and atom-economy. Remarkably, some intolerable disadvantages of this protocol still persist, e.g.…”