Divergent Cascade Ring-Expansion Reactions of Acryloyl Imides.

Macrocyclic and medium-sized ring ketones, lactones and lactams can all be made from common acryloyl imide starting materials through divergent, one-pot cascade ring-expansion reactions. Following either conjugate addition with an amine or nitromethane, or osmium(VIII)-catalysed dihydoxylation, rearrangement through a four-atom ring expansion takes place spontaneously to form the ring expanded products. A second ring expansion can also be performed following a second iteration of imide formation and alkene functionalisation/ring expansion. In the dihydroxylation series, three- or four-atom ring expansion can be performed selectively, depending on whether the reaction is under kinetic or thermodynamic control.

Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides.

Two new ring expansion strategies are reported for the synthesis of medium sized ring and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with the key ring expansion step initiated by nitro reduction and amine conjugate addition respectively. Each method can be used to make diversely functionalised cyclic sulfonamides in good to excellent yields, in a range of ring sizes. The ring size dependency of the synthetic reactions is in good agreement with the outcomes modelled by Density Functional Theory calculations.

Visible-Light-Mediated Energy Transfer Enables the Synthesis of ß-Lactams via Intramolecular Hydrogen Atom Transfer.

The synthesis of 2-azetidinones (ß-lactams) from simple acrylamide starting materials by visible-light-mediated energy transfer catalysis is reported. The reaction features a C(sp3 )-H functionalization via a variation of the Norrish-Yang photocyclization involving a carbon-to-carbon 1,5-hydrogen atom transfer (supported by deuterium labelling and DFT calculations) and can be used for the construction of a diverse range of ß-lactam products.

Selectivity, Speciation, and Substrate Control in the Gold-Catalyzed Coupling of Indoles and Alkynes.

A convenient and mild protocol for the gold-catalyzed intermolecular coupling of substituted indoles with carbonyl-functionalized alkynes to give vinyl indoles is reported. This reaction affords 3-substituted indoles in high yield, and in contrast to the analogous reactions with simple alkynes which give bisindolemethanes, only a single indole is added to the alkyne. The protocol is robust and tolerates substitution at a range of positions of the indole and the use of ester-, amide-, and ketone-substituted alkynes. The use of 3-substituted indoles as substrates results in the introduction of the vinyl substituent at the 2-position of the ring. A combined experimental and computational mechanistic study has revealed that the gold catalyst has a greater affinity to the indole than the alkyne, despite the carbon-carbon bond formation step proceeding through an η2(π)-alkyne complex, which helps to explain the stark differences between the intra- and intermolecular variants of the reaction. This study also demonstrated that the addition of a second indole to the carbonyl-containing vinyl indole products is both kinetically and thermodynamically less favored than in the case of more simple alkynes, providing an explanation for the observed selectivity. Finally, a highly unusual gold-promoted alkyne dimerization reaction to form a substituted gold pyrylium salt has been identified and studied in detail.

Indole-ynones as Privileged Substrates for Radical Dearomatizing Spirocyclization Cascades.

Indole-ynones have been established as general substrates for radical dearomatizing spirocyclization cascade reactions. Five distinct and varied synthetic protocols have been developed─cyanomethylation, sulfonylation, trifluoromethylation, stannylation and borylation─using a variety of radical generation modes, ranging from photoredox catalysis to traditional AIBN methods. The simple and easily prepared indole-ynones can be used to rapidly generate diverse, densely functionalized spirocycles and have the potential to become routinely used to explore radical reactivity. Experimental and computational investigations support the proposed radical cascade mechanism and suggest that other new methods are now primed for development.

Synthesis of macrocyclic and medium-sized ring thiolactones via the ring expansion of lactams.

A side chain insertion method for the ring expansion of lactams into macrocyclic thiolactones is reported, that can also be incorporated into Successive Ring Expansion (SuRE) sequences. The reactions are less thermodynamically favourable than the analogous lactam- and lactone-forming ring expansion processes (with this notion supported by DFT data), but nonetheless, three complementary protecting group strategies have been developed to enable this challenging transformation to be achieved.

Evaluating the Viability of Successive Ring-Expansions Based on Amino Acid and Hydroxyacid Side-Chain Insertion.

The outcome of ring-expansion reactions based on amino/hydroxyacid side-chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previous work on Successive Ring Expansion (SuRE) methods, details efforts to better define the scope and limitations of these reactions on lactam and ß-ketoester ring systems with respect to ring size and additional functionality. The synthetic results provide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using a density functional theory (DFT) approach. Calculating the relative Gibbs free energies of the three isomeric species that are formed reversibly during ring expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational results are expected to support the design of new lactam- and ß-ketoester-based ring-expansion reactions.

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium-Sized Lactones and Lactams.

A strategy for the synthesis of medium-sized lactones and lactams from linear precursors is described in which an amine acts as an internal nucleophilic catalyst to facilitate a novel cyclisation/ring expansion cascade sequence. This method obviates the need for the high-dilution conditions usually associated with medium-ring cyclisation protocols, as the reactions operate exclusively via kinetically favourable "normal"-sized cyclic transition states. This same feature also enables biaryl-containing medium-sized rings to be prepared with complete atroposelectivity by point-to-axial chirality transfer.

Visible-light-induced intramolecular charge transfer in the radical spirocyclisation of indole-tethered ynones.

Indole-tethered ynones form an intramolecular electron donor-acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols. This initiates a novel radical chain sequence, based on dearomatising spirocyclisation with concomitant C-S bond formation. Sulfur-containing spirocycles are formed in high yields using this simple and mild synthetic protocol, in which neither transition metal catalysts nor photocatalysts are required. The proposed mechanism is supported by various mechanistic studies, and the unusual radical initiation mode represents only the second report of the use of an intramolecular electron donor-acceptor complex in synthesis.