Direct decarboxylative Giese amidations: photocatalytic vs. metal- and light-free.

A direct intermolecular decarboxylative Giese amidation reaction from bench stable, non-toxic and environmentally benign oxamic acids has been developed, which allows for easy access to 1,4-difunctionalised compounds which are not otherwise readily accessible. Crucially, a more general acceptor substrate scope is now possible, which renders the Giese amidation applicable to more complex substrates such as natural products and chiral building blocks. Two different photocatalytic methods (one via oxidative and the other via reductive quenching cycles) and one metal- and light-free method were developed and the flexibility provided by different conditions proved to be crucial for enabling a more general substrate scope.

Direct decarboxylative Giese reactions.

The quest to find milder and more sustainable methods to generate highly reactive, carbon-centred intermediates has led to a resurgence of interest in radical chemistry. In particular, carboxylic acids are seen as attractive radical precursors due their availability, low cost, diversity, and sustainability. Moreover, the corresponding nucleophilic carbon-radical can be easily accessed through a favourable radical decarboxylation process, extruding CO2 as a traceless by-product. This review summarizes the recent progress on using carboxylic acids directly as convenient radical precursors for the formation of carbon-carbon bonds via the 1,4-radical conjugate addition (Giese) reaction.

Diazophosphonates: Effective Surrogates for Diazoalkanes in Pyrazole Synthesis.

Diazophosphonates, readily prepared from α-ketophosphonates by oxidation of the corresponding hydrazones in batch or in flow, are useful partners in 1,3-dipolar cycloaddition reactions to alkynes to give N-H pyrazoles, including the first intramolecular examples of such a process. The phosphoryl group imbues a number of desirable properties into the diazo 1,3-dipole. The electron-withdrawing nature of the phosphoryl stabilizes the diazo compound making it easier to handle, whilst the ability of the phosphoryl group to migrate readily in a [1,5]-sigmatropic rearrangement enables its transfer from C to N to aromatize the initial cycloadduct, and hence its facile removal from the final pyrazole product. Overall, the diazophosphonate acts as a surrogate for the much less stable diazoalkane in cycloadditions, with the phosphoryl group playing a vital, but traceless, role. The cycloaddition proceeds more readily with alkynes bearing electron-withdrawing groups, and is regiospecific with asymmetrical alkynes. The potential of diazophosphonates for use in bioorthogonal cycloadditions is demonstrated by their facile addition to strained alkynes.

C-H Insertion as a Key Step to Spiro-Oxetanes, Scaffolds for Drug Discovery.

A new route to spiro-oxetanes, potential scaffolds for drug discovery, is described. The route is based on the selective 1,4-C-H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-ß-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead-like properties of spiro-oxetanes are illustrated by the conversion of the 1-oxa-7-azaspiro[3,5]nonane scaffold into a range of functionalized derivatives.

Stereoselective Synthesis of Functionalized Pyrrolidines by the Diverted N-H Insertion Reaction of Metallocarbenes with ß-Aminoketone Derivatives.

A highly stereoselective route to functionalized pyrrolidines by the metal-catalyzed diverted N-H insertion of a range of diazocarbonyl compounds with ß-aminoketone derivatives is described. A number of catalysts (rhodium(II) carboxylate dimers, copper(I) triflate, and an iron(III) porphyrin) are shown to promote the process under mild conditions to give a wide range of highly substituted proline derivatives. The reaction starts as a metallocarbene N-H insertion but is diverted by an intermolecular aldol reaction.

Stereoselective Synthesis of Highly Substituted Tetrahydrofurans through Diverted Carbene O-H Insertion Reaction.

Copper- or rhodium-catalyzed reactions of diazocarbonyl compounds with ß-hydroxyketones give highly substituted tetrahydrofurans with excellent diastereoselectivity. Under mild conditions, the single-step process starts as a carbene O-H insertion reaction, but is diverted by an intramolecular aldol reaction.

Alkyl halide-free heteroatom alkylation and epoxidation facilitated by a recyclable polymer-supported oxidant for the in-flow preparation of diazo compounds.

Highly reactive metal carbenes, generated from simple ketones via diazo compounds, including diazo-amides and -phosphonates, using a recyclable reagent in-flow, are transient but versatile electrophiles for heteroatom alkylation reactions and for epoxide formation. The method produces no organic waste, with the only by-products being water, KI and nitrogen, without the attendant hazards of isolation of intermediate diazo compounds.

Potassium N-iodo p-toluenesulfonamide (TsNIK, Iodamine-T): a new reagent for the oxidation of hydrazones to diazo compounds.

A new reagent for the oxidation of hydrazones to diazo compounds is described. N-Iodo p-toluenesulfonamide (TsNIK, iodamine-T) allows the preparation of α-diazoesters, α-diazoamides, α-diazoketones and α-diazophosphonates in good yield and in high purity after a simple extractive work-up. α-Diazoesters were also obtained in high yield from the corresponding ketones through a one-pot process of hydrazone formation/oxidation.