Construction of azaheterocycles via Pd-catalyzed migratory cycloannulation reaction of unactivated alkenes

Abstract

Azahetereocycles constitute important structural components in many biologically active natural compounds and marketed drugs, and represent the most promising scaffolds in drug discovery. Accordingly, the development of efficient and general synthetic methods for the construction of diverse azaheterocycles is the major goal in synthetic chemistry. Herein, we report the efficient construction of a wide range of azaheterocycles via a Pd-catalyzed migratory cycloannulation strategy with unactivated alkenes. This strategy enables the rapid synthesis of a series of 6-, 7- and 8-membered azaheterocycles in high efficiency, and features a broad substrate scope, excellent functional group tolerance under redox-neutral conditions. The significance of this finding is demonstrated by the efficient synthesis of drug-like molecules with high step-economy. Preliminary mechanistic investigations reveal that this reaction underwent a sequentially migratory insertion to alkenes, metal migration process, and the aza-Michael addition to a quinone methide intermediate.

3-Chloropropylbis(catecholato)silicate as a Bifunctional Reagent for the One-Pot Synthesis of Tetrahydroquinolines from o-Bromosulfonamides

“…A general limitation of most of these methods is the need to prepare pre-alkylated aniline precursors. Although more recent strategies , obviate this necessity, the use of elevated temperatures or otherwise harsh conditions to accomplish the cyclization step can limit functional group compatibility in the preparation of tetrahydroquinolines. In contrast, photoredox-based cross-coupling methods have allowed chemists to reimagine classical cross-coupling approaches, including those in the service of heterocycle formation, in a way that is much more functional group tolerant .…”

“… 6 Intramolecular C–N bond formation through cross-coupling with tethered amines has also been demonstrated. 7 More recent work has built upon these precedents by developing direct approaches for the synthesis of tetrahydroquinolines from anilines and readily obtained reactants such as allylphenols 8 or 1,3-diols 9 ( Scheme 1 ).…”

Palladium Catalysis Enabled Sequential C(sp3)–H/C–C Activation: Access to Vinyl γ-Lactams

“…Furthermore, in light of the conventional reactivity of VCPs, it was anticipated that the presence of palladium would result in an initial C–C bond cleavage, followed by alkene migration and aminopalladation (disfavored path, Scheme S4, SI). However, alkene migration is difficult in unactivated nonconjugated alkenes . Moreover, the control experiment involving 1e and 2a in the presence of CD 3 CO 2 D under standard reaction conditions revealed an absence of deuterium incorporation in the allyl and vinyl positions of 3ea (Scheme S3e, SI).…”

Unlocking the Chain-Walking Process in Gold Catalysis

“…For instance, Zhu, 2 He, 3 Engle, 4 Yuan/Zhang, 5 and others 6 utilized the chainwalking process for the remote C-H functionalization reactions (Scheme 1b). Advancing forward, Kochi, 7 Yin, 8 Lin/Yao, 9 Wang, 10 Zhou, 11 and Giri 12 group eloquently showcased its applicability in achieving the non-classical and challenging remote 1,n-difunctionalization of alkenes (Scheme 1c). Based on the aforementioned reactivities, recent developments extended the scope of the chainwalking process to olefin polymerization and copolymerization reactions thus emphasizing its importance in materials chemistry.…”