Toward a General Protocol for Catalytic Oxidative Transformations Using Electrochemically Generated Hypervalent Iodine Species.

A simple catalytic electrosynthetic protocol for oxidative transformations mediated by hypervalent iodine reagents has been developed. In this protocol, electricity drives the iodine(I)/iodine(III) catalytic cycle enabling catalysis with in situ generated hypervalent iodine species, thereby eliminating chemical oxidants and the inevitable chemical waste associated with their mode of action. In addition, no added electrolytic salts are needed in this process. The developed method has been validated using two different hypervalent iodine-mediated transformations: (i) the oxidative cyclization of N-allylic and N-homoallylic amides to the corresponding dihydrooxazole and dihydro-1,3-oxazine derivatives, respectively, and (ii) the α-tosyloxylation of ketones. Both reactions proceeded smoothly under the developed catalytic electrosynthetic conditions without reoptimization, featuring a wide substrate scope and excellent functional group tolerance. In addition, scale-up to gram-scale and catalyst recovery were easily achieved maintaining the high efficiency of the process.

Scalable electrochemical synthesis of diaryliodonium salts.

Cyclic and acyclic diaryliodonium are synthesised by anodic oxidation of iodobiaryls and iodoarene/arene mixtures, respectively, in a simple undivided electrolysis cell in MeCN-HFIP-TfOH without any added electrolyte salts. This atom efficient process does not require chemical oxidants and generates no chemical waste. More than 30 cyclic and acyclic diaryliodonium salts with different substitution patterns were prepared in very good to excellent yields. The reaction was scaled-up to 10 mmol scale giving more than four grams of dibenzo[b,d]iodol-5-ium trifluoromethanesulfonate (>95%) in less than three hours. The solvent mixture of the large-scale experiment was recovered (>97%) and recycled several times without significant reduction in yield.

Computationally Assisted Mechanistic Investigation into Hypervalent Iodine Catalysis: Cyclization of N-Allylbenzamide.

Previous experimental work identified 2-iodoanisole as the best precatalyst for the oxidative cyclization of N-alkenylamides into 2-oxazolines. Herein, we describe our investigation into the effect on the reaction rate based on the structure of the iodoarene precatalyst. We also reveal the mechanism of the cyclization based on DFT modeling and obtain a clear correlation between observed reaction rates and computationally derived activation energies for different iodoarenes. In addition, the rate-limiting step is shown to be the cyclization of the substrate that is zero order in the concentration of the iodoarene precatalyst. The rate of cyclization is found to correlate with the ease of oxidation of the iodoarene; however, the most easily oxidized iodoarenes generate iodine(III) species that decompose readily. Finally, loss of iodoarene from the cyclized intermediate can proceed by either ligand-coupling or SN2 displacement (reductive elimination), and this is shown to be substrate-dependent.

Preparation and Synthetic Utility of Stable 1,3-Enynyl- and 1,3-Dienyl(aryl)iodonium Salts.

The facile synthesis of stable enynyl- and dienyl(aryl)iodonium salts is achieved from terminal enynes. An X-ray crystal structure of an example of the latter is presented. These compounds are shown to be useful in a range of transformations.

Iodoarene-catalyzed cyclizations of N-propargylamides and ß-amidoketones: synthesis of 2-oxazolines.

Two complementary iodoarene-catalyzed methods for the preparation of 2-oxazolines are presented. The first involves the cyclization of N-propargylamides and the second involves the cyclization of ß-amidoketones. These are proposed to proceed through different mechanisms and have different substrate scopes.

Preparation of Alkyl Alkynyl Sulfones and Cyclic Vinyl Sulfones from Alkynyl(aryl)iodonium Salts.

The reaction of alkyl sulfinates with alkynyl(aryl)iodonium salts provides a facile access into otherwise difficult to obtain alkyl alkynyl sulfones and cyclic vinyl sulfones via 1,2-rearrangement or 1,5-CH insertion, respectively. In benzyl sulfinates, 1,5-CH insertion is not possible, so addition to the aromatic ring occurs, followed by ring expansion to generate novel bicyclic sulfones.

Aqueous DMSO Mediated Conversion of (2-(Arylsulfonyl)vinyl)iodonium Salts to Aldehydes and Vinyl Chlorides.

Vinyl(aryl)iodonium salts are useful compounds in organic synthesis but they are under-utilized and their chemistry is under-developed. Herein is described the solvolysis of some vinyl(phenyl)iodonium salts, bearing an arylsulfonyl group, in aqueous DMSO leading to aldehyde formation. This unusual process is selective and operates under ambient conditions. Furthermore, the addition of aqueous HCl and DMSO to these vinyl(aryl)iodonium salts allows their facile conversion to vinyl chlorides.

Improving alkynyl(aryl)iodonium salts: 2-anisyl as a superior aryl group.

The majority of alkynyl(aryl)iodonium salts reported in the literature are derived from iodobenzene. This article describes the effects of varying this iodoarene building block on the synthesis, reactivity and stability of these salts. Two procedures to synthesize a variety of known and novel alkynyl(aryl)iodonium tosylates directly from the iodoarene are reported. In the reactions of these salts, those derived from 2-iodoanisole gave superior results than the others tested in every reaction. Isothermal microcalorimetry indicated that these novel salts were significantly more stable and less prone to decomposition than all of the other derivatives.

CuI-catalyzed cycloisomerization of propargyl amides.

The synthesis of substituted dihydrooxazoles by the CuI-catalyzed cycloisomerization of terminal propargyl amides is reported. The reaction has been shown to have good substrate scope and experiments to delineate the mechanism have been performed. Substrates containing a benzylic methylene were oxidized to the ketone under the reaction conditions.

Hypoiodous acid initiated rearrangement of tertiary propargylic alcohols to α-iodoenones.

In the presence of an oxidant, sodium iodide is converted into hypoiodous acid which effects the rearrangement of tertiary propargylic alcohols to α-iodoenones in good yields.

Cyclic Vinyl(aryl)iodonium Salts: Synthesis and Reactivity.

A convenient, highly regioselective synthesis of five-membered cyclic vinyl(aryl)iodonium salts directly from ß-iodostyrenes is presented. An X-ray crystal structure confirms the identity of these heterocycles. These λ3-iodanes can be converted rapidly into functionalized arylacetylenes by treatment with mild base or undergo SNV reactions with nonbasic nucleophiles.

Rh-catalyzed enantioselective hydrogenation of vinyl boronates for the construction of secondary boronic esters.

[reaction: see text] Rh-catalyzed hydrogenation of prochiral vinyl boronates occurs in an enantioselective fashion in the presence of the chiral ligand Walphos 1. This transformation provides access to chiral secondary organoboronates that are not available from alkene hydroboration reactions. The chiral reaction products should be useful in organic synthesis, and preliminary experiments suggest that they may participate in one-pot amination and homologation reactions.

Iodoarene-catalyzed cyclizations of unsaturated amides.

The cyclization of N-alkenylamides catalyzed by iodoarenes under oxidative conditions is presented. Five-, six-, and seven-membered rings with a range of substitutions can be prepared by this route. Preliminary data from the use of chiral iodoarenes as precatalysts show that enantiocontrol is feasible.

A concise asymmetric route to Nuphar alkaloids. A formal synthesis of (-)-deoxynupharidine.

[reaction: see text] A stereocontrolled route to Nuphar alkaloids is described that employs a formal [3 + 3] cycloaddition strategy to assemble the piperidine nucleus. The addition of Pd-TMM complexes to aziridine 10 was found to be sluggish; however, the addition of a functionalized allyl Grignard reagent followed by a Mitsunobu condensation reaction provided 11 in high yield. The employment of this route in the formal synthesis of (-)-deoxynupharidine 1 is described.

Iodobenzene-catalyzed intramolecular oxidative cyclization reactions of δ-alkynyl ß-ketoesters.

Iodobenzene is shown to catalyze the 5-exo-dig cyclization of δ-alkynyl ß-ketoesters under oxidative conditions that generate hypervalent iodine species in situ. The cyclopentane products contain adjacent quaternary and tertiary stereocenters which are generated with excellent diastereoselectivity.

Synthesis of densely functionalised arenes using [2 + 2 + 2] cycloaddition reactions.

Rh(I)-catalysed [2 + 2 + 2] cycloaddition allows the synthesis of aryl ethers and diaryl methanes containing a high degree of steric hindrance from relatively simple diyne and alkyne precursors. The diarylmethanes made in this way show no evidence in their NMR spectra, however, of rotational restriction.

Development of a flexible approach to Nuphar alkaloids via two enantiospecific piperidine-forming reactions.

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (-)-deoxynupharidine ((-)-2), (-)-castoramine ((-)-3), and (-)-nupharolutine ((-)-4) via intermediate lactam 7 is delineated.