Approach to Fully Substituted Cyclic Nitrones from N‐Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

An approach to cyclic nitrones from N‐hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N‐OSEM [SEM=2‐(trimethylsilyl)ethoxymethyl] lactam forms a five‐membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one‐pot process. When combined with the N‐oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio‐pure form, enabling the concise total synthesis of cylindricine C.     

Copper‐Mediated Late‐Stage Functionalization of Heterocycle‐Containing Molecules

One long‐standing issue in directed C−H functionalization is that either nitrogen or sulfur atoms present in heterocyclic substrates may bind preferentially to a transition‐metal catalyst rather than to the desired directing group. This competitive binding has largely hindered the application of C−H functionalization in late‐stage heterocycle drug discovery. Reported here is the use of an oxazoline‐based directing group capable of overriding the poisoning effect of a wide range of heterocycle substrates. The potential use of this directing group in pharmaceutical drug discovery is illustrated by diversification of Telmisartan (an antagonist for the angiotensin II receptor) through copper‐mediated C−H amination, hydroxylation, thiolation, arylation, and trifluoromethylation.     

Catalytic Enantioselective γ‐Selective Additions of 2‐Allylazaarenes to Activated Ketones

Reported herein is the first example of 2‐allylazaarenes in asymmetric catalysis. Highly γ‐selective allylation was demonstrated for activated ketones, including isatins and trifluoromethyl ketones. In the presence of either an amino‐acid‐based tertiary amine or quaternary ammonium salt catalyst, two series of tertiary hydroxy‐containing moieties were installed at the remote δ‐position of azaarenes in good chemical yields, excellent enantioselectivities, and E /Z ratios. The success of current γ‐selective reactions should provide inspiration for expansion to other allylazaarene derivatives and would open up new paradigms for the synthesis of chiral γ‐ and/or δ‐functionalized azaarenes.     

Mechanistic Insight Leads to a Ligand Which Facilitates the Palladium‐Catalyzed Formation of 2‐(Hetero)Arylaminooxazoles and 4‐(Hetero)Arylaminothiazoles

By using mechanistic insight, a new ligand (EPhos) for the palladium‐catalyzed C−N cross‐coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3‐position favors the C‐bound isomer of the ligand‐supported palladium(II) complexes and leads to significantly improved reactivity. The use of a catalyst system based on EPhos with NaOPh as a mild homogeneous base proved to be very effective in the formation of 4‐arylaminothiazoles and highly functionalized 2‐arylaminooxazoles. Previously, these were not readily accessible using palladium catalysis.     

Photoredox‐Catalyzed Site‐Selective α‐C(sp3)−H Alkylation of Primary Amine Derivatives

The synthetic utility of tertiary amines to oxidatively generate α‐amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site‐selective α‐functionalization of primary amine derivatives through the generation of α‐amino radical intermediates. Employing visible‐light photoredox catalysis, primary sulfonamides are coupled with electron‐deficient alkenes to efficiently and mildly construct C?C bonds. Interestingly, a divergence between intermolecular hydrogen‐atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site‐selectivity.     

Iridium‐Catalyzed Reductive Strecker Reaction for Late‐Stage Amide and Lactam Cyanation

A new iridium‐catalyzed reductive Strecker reaction for the direct and efficient formation of α‐amino nitrile products from a broad range of (hetero)aromatic and aliphatic tertiary amides, and N‐alkyl lactams is reported. The protocol exploits the mild and highly chemoselective reduction of the amide and lactam functionalities using IrCl(CO)[P(C₆H₅)₃]₂ (Vaska's complex) in the presence of tetramethyldisiloxane, as a reductant, to directly generate hemiaminal species able to undergo substitution by cyanide upon treatment with TMSCN (TMS=trimethylsilyl). The protocol is simple to perform, broad in scope, efficient (up to 99 % yield), and has been successfully applied to the late‐stage functionalization of amide‐ and lactam‐containing drugs, and naturally occurring alkaloids, as well as for the selective cyanation of the carbonyl carbon atom linked to the N atom of proline residues within di‐ and tripeptides.     

Divergent Late‐Stage (Hetero)aryl C−H Amination by the Pyridinium Radical Cation

(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late‐stage aryl C?H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.     

Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench‐Stable Precursor (Me4N)SCF3

Reported herein is the one‐pot synthesis of trifluoromethylated amines at room temperature using the bench‐stable (Me₄N)SCF₃ reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF₃ with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N‐CF₃. The mildness and high functional group tolerance render the method highly attractive for the late‐stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules.     

Enantioselective Phosphine‐Catalyzed Formal [4+4] Annulation of α,β‐Unsaturated Imines and Allene Ketones: Construction of Eight‐Membered Rings

The first highly enantioselective phosphine‐catalyzed formal [4+4] annulation has been developed. In the presence of amino‐acid‐derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole‐derived α,β‐unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (≥98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight‐membered rings by phosphine catalysis.