One-Pot Synthesis of Polysubstituted Indolizines by an Addition/Cycloaromatization Sequence

Indolizines carrying various substituents in positions 5–8 were obtained from readily available 2-(1<i>H</i>-pyrrol-1-yl)­nitriles and α,β-unsaturated ketones or aldehydes in a one-pot procedure. Michael addition of the deprotonated aminonitriles to the acceptors followed by acid-catalyzed electrophilic cyclization produces 5,6-dihydroindolizine-5-carbonitriles. From these stable intermediates, substituted indolizines were obtained via base-induced dehydrocyanation

Enantioselective Synthesis of (−)-Dihydrocodeine and Formal Synthesis of (−)-Thebaine, (−)-Codeine, and (−)-Morphine from a Deprotonated α‑Aminonitrile

The α-benzylation of a deprotonated bicyclic α-aminonitrile, followed by Noyori’s asymmetric transfer hydrogenation combined with the Grewe cyclization onto a symmetrical A-ring precursor, are the key steps of a short and high-yielding enantioselective synthesis of the morphinan (−)-dihydrocodeine. This compound can be converted to (−)-thebaine in high yield by known transformations, while (−)-codeine and (−)-morphine are available from an advanced intermediate

Unique Regioselectivity in the C(sp³)–H α‑Alkylation of Amines: The Benzoxazole Moiety as a Removable Directing Group

The benzoxazol-2-yl- substituent was found to act as a removable activating and directing group in the Ir-catalyzed alkylation of C­(sp³)–H bonds adjacent to nitrogen in secondary amines. It can be easily introduced by oxidative coupling or by an S_NAr reaction, and it can be removed by hydroxide or by hydride reduction. For 1,2,3,4-tetra­hydroiso­quinolines, activation exclusively takes place in the 3-position. A variety of activated as well as unactivated terminal olefins are suitable reaction partners

Selective C–H Activation of Methoxy Groups in a Three-Component Photoreaction

Surprisingly, the photocatalytic activation of ethers by H-abstraction and addition of the generated radicals to iminium ions formed in situ from aldehydes and anilines predominantly yielded the products of methoxy activation for dimethoxymethane and 1,2-dimethoxyethane. Various anilines and aromatic as well as aliphatic aldehydes are suitable reaction partners for this three-component photoreaction (Porta-type process) which also provides a simple access to 1,2-aminoalcohols

A Photochemical One-Pot Three-Component Synthesis of Tetrasubstituted Imidazoles

Tetrasubstituted imidazoles can be formed in a photochemical one-pot synthesis from aldehydes, α-aminonitriles, and isoxazoles. Condensation of the first two components produces α-(alkylideneamino)­nitriles which react under basic conditions with the acylazirines formed in situ by photochemical ring transformation of the isoxazole component. This process includes an unusual cleavage of the C²–C³ bond of the acylazirine. The reaction mechanism was studied by DFT calculations

Synthesis of 1,2-Disubstituted Indoles from α‑Aminonitriles and 2‑Halobenzyl Halides

The α-alkylation of deprotonated Strecker products derived from primary amines and aromatic aldehydes with 2-halobenzyl halides furnishes intermediates that can be cyclized to 1,2-disubstituted indoles in moderate to high yields (up to 94% over two steps) by microwave-assisted copper- or palladium-catalyzed intramolecular cross-coupling

A Light-Induced Vinylogous Nazarov-Type Cyclization

The first examples of a photochemically induced vinylogous Nazarov-type cyclization forming a cycloheptadienone core are described. The reaction can be included in a three-step cascade consisting of a photochemical isoxazole–azirine ring contraction, cobalt­(II)-catalyzed ring expansion, and the photochemical cyclization. Furthermore, the first representative of the hitherto unknown 1-azatricyclo­[2.2.0.0^2,6]­hexanes has been identified as a side product of the azirine formation

Ring Expansion of 1,2,3,4-Tetra­hydro­iso­quino­lines to Dibenzo[<i>c,f</i>]azonines. An Unexpected [1,4]-Sigmatropic Rearrangement of Nitrile-Stabilized Ammonium Ylides

When the products of a Strecker reaction of 1,2,­3,4-tetra­hydro­iso­quino­lines with aromatic aldehydes are quaternized with alkyl triflates and subsequently treated with base, a ring expansion to 6,7,­8,13-tetra­hydro-5<i>H</i>-dibenzo­[<i>c,f</i>]­azonine-5-carbo­nitriles takes place. The nine-membered cyclic products can be obtained in good yields (78–89%) in a process involving the [1,4]-sigmatropic rearrangement of a nitrile-stabilized ammonium ylide. The reaction sequence provides a new, simple, and efficient method for the synthesis of these unusual N<i>-</i>heterocycles

A Light-Induced Vinylogous Nazarov-Type Cyclization

The first examples of a photochemically induced vinylogous Nazarov-type cyclization forming a cycloheptadienone core are described. The reaction can be included in a three-step cascade consisting of a photochemical isoxazole–azirine ring contraction, cobalt­(II)-catalyzed ring expansion, and the photochemical cyclization. Furthermore, the first representative of the hitherto unknown 1-azatricyclo­[2.2.0.0^2,6]­hexanes has been identified as a side product of the azirine formation

A Photoinduced Cobalt-Catalyzed Synthesis of Pyrroles through <i>in Situ</i>-Generated Acylazirines

Tetrasubstituted pyrroles can be synthesized in a one-pot procedure from isoxazoles. The process includes the photoinduced <i>in situ</i> formation of acylazirines combined with a subsequent cobalt­(II)-catalyzed ring expansion with 1,3-diketones