David J. Procter

Beyond the Pummerer Reaction: Recent Developments in Thionium Ion Chemistry

Since the early 1960s the Pummerer reaction has evolved to become an indispensable tool for synthesis, and continues to serve as a source of inspiration for organic chemists. In recent years, many exciting advances have demonstrated the broad scope and synthetic utility of Pummerer methodology and the versatility of thionium ion intermediates.

Beyond samarium diiodide: Vistas in reductive chemistry mediated by lanthanides(II)

Reactions proceeding through open-shell, single-electron pathways offer attractive alternative outcomes to those proceeding through closed-shell, two-electron mechanisms. In this context, samarium diiodide (SmI(2)) has emerged as one of the most important and convenient-to-use electron-transfer reagents available in the laboratory. Recently, significant progress has been made in the reductive chemistry of other divalent lanthanides which for many years had been considered too reactive to be of value to synthetic chemists. Herein, we illustrate how new samarium(II) complexes and nonclassical lanthanide(II) reagents are changing the landscape of modern reductive chemistry.

Highly Chemoselective Reduction of Amides (Primary, Secondary, Tertiary) to Alcohols using SmI2/Amine/H2O under Mild Conditions

Highly chemoselective direct reduction of primary, secondary, and tertiary amides to alcohols using SmI2/amine/H2O is reported. The reaction proceeds with C–N bond cleavage in the carbinolamine intermediate, shows excellent functional group tolerance, and delivers the alcohol products in very high yields. The expected C–O cleavage products are not formed under the reaction conditions. The observed reactivity is opposite to the electrophilicity of polar carbonyl groups resulting from the nX → π*C=O (X = O, N) conjugation. Mechanistic studies suggest that coordination of Sm to the carbonyl and then to Lewis basic nitrogen in the tetrahedral intermediate facilitate electron transfer and control the selectivity of the C–N/C–O cleavage. Notably, the method provides direct access to acyl-type radicals from unactivated amides under mild electron transfer conditions.

A ring size-selective reduction of lactones using SmI2 and H2O

The SmI2−H2O reducing system shows complete selectivity for six-membered lactones over other classes of lactone and esters. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl.

Nucleophilic Ortho Allylation of Aryl and Heteroaryl Sulfoxides

Aryl and heteroaryl sulfoxides undergo ortho allylation upon treatment with Tf(2)O and allylsilanes. The method complements the use of sulfoxides to direct ortho-metalation and reaction with electrophiles as it allows allylic carbon nucleophiles to be added ortho to the directing group in a metal-free process. The versatile sulfide adducts can be selectively manipulated using various methods including Kumada-Corriu cross-coupling of the organosulfanyl group.

Studies on the Mechanism, Selectivity, and Synthetic Utility of Lactone Reduction Using SmI2 and H2O

Although simple aliphatic esters and lactones have long been thought to lie outside the reducing range of SmI(2), activation of the lanthanide reagent by H(2)O allows some of these substrates to be manipulated in an unprecedented fashion. For example, the SmI(2)-H(2)O reducing system shows complete selectivity for the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical intermediates formed during lactone reduction with SmI(2)-H(2)O can be exploited in cyclizations to give cyclic ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.

Selective Reductive Transformations Using Samarium Diiodide-Water

Samarium diiodide (SmI(2)) is one of the most important reductive electron transfer reagents available in the laboratory. Key to the popularity of SmI(2) is the ability of additives and co-solvents to tune the properties of the reagent. Over the last decade water has emerged as a particularly valuable additive, opening up new chemical space and leading to the discovery of unprecedented selectivity and new reactions promoted by SmI(2). In this Feature Article we review recent progress in the application of SmI(2)-H(2)O systems, with an emphasis on mechanistic considerations and the development of new transformations.

Reductive cyclization cascades of lactones using SmI2-H2O.

Lactones bearing two alkenes or an alkene and an alkyne undergo reductive cyclization cascades upon treatment with SmI(2)-H(2)O, giving decorated azulene motifs in excellent yields with good diastereocontrol.

Nucleophilic ortho-propargylation of aryl sulfoxides: An interrupted pummerer/allenyl thio-Claisen rearrangement sequence

Selective C C bond formation to aromatic systems is one of the most important synthetic objectives as the resulting motifs form the core of many pharmaceuticals, agrochemicals, and functional materials. In this regard, products of propargylation are valuable synthetic intermediates as they are established precursors to other functional groups, and to carboand heterocycles. Unfortunately, direct propargylation of aromatics is often difficult and can lead to mixtures of propargyl and allenyl products. Although metal-catalyzed couplings are possible, many methods rely on Friedel– Crafts-type processes that can require stoichiometric metal reagents. Using activating substituents to facilitate nucleophilic substitution in aromatic systems is a relatively underexploited approach. In recent years, activation by sulfoxide substituents has been exploited in nucleophilic alkylations of electron-rich heteroaromatics that proceed through Pummerer-type reactions. Furthermore, Yorimitsu and Oshima and Maulide recently employed interrupted Pummerer reactions in approaches to targets such as benzofurans and a-aryl-b-ketoesters, while we have described an interrupted Pummerer approach for the allylation of aromatic and heteroaromatic rings. Herein we report a nucleophilic ortho-propargylation of aryl sulfoxides that proceeds by a new interrupted Pummererallenyl thio-Claisen rearrangement sequence involving allenyl sulfonium salts 4 (Scheme 1). The operationally simple, metal-free procedure is general, regiospecific with regard to the propargyl nucleophile, and shows complete selectivity for products of propargylation over allenylation. Realizing the value of a process that would allow propargyl groups to be selectively introduced to aryl rings under metal-free conditions, we sought to develop a reaction in which intermolecular delivery of a nucleophile to sulfur is followed by an intramolecular relay to carbon (Scheme 1). We began by investigating the reaction of diphenyl sulfoxide 1a with propargyl silane 2a (Table 1). Using Tf2O as an

Selective reductions of cyclic 1,3-diesters using SmI2 and H2O

SmI(2)-H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over-reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters and esters. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron transfer to the ester carbonyl and the anomeric stabilization of the resulting radical-anion intermediate. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes.