We previously described a new organocatalytic oxidation–reduction–condensation for amide/peptide construction. The reaction system relies on triethylphosphite as the stoichiometric reductant and organocatalytic benzoisothiazolone/O2 in air as the oxidant. The reaction was assumed to generate catalytic quantities of S-acylthiosalicylamides as electrophiles, which are rapidly intercepted by amine reactants to generate amides/peptides and o-mercaptobenzamides. The latter are then gently reoxidized to the benzoisothiazolones under Cu-catalyzed aerobic conditions to complete the catalytic cycle. To gain a mechanistic understanding, we describe herein our studies of the stoichiometric generation of S-acylthiosalicylamides under oxidation–reduction–condensation conditions from a variety of benzoisothiazolones and carboxylic acids using triethylphosphite as the terminal reductant. These studies have revealed the presence of more than one reaction pathway when benzoisothiazolones react with triethylphosphite (including a rapid, direct deoxygenation of certain classes of benzoisothiazolones by triethylphosphite) and allow the identification of optimal reaction characteristics (benzoisothiazolone structure and solvent) for the generation of thioesters. These explorations will inform our efforts to develop highly effective and robust organocatalytic oxidation–reduction–condensation reactions that are based on the benzoisothiazolone and related motifs.

Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5–36 h at 50 °C using catalytic quantities of a redox-active benzoisothiazolone and a copper complex. These catalytic “oxidation–reduction condensation” reactions are carried out open to dry air using O2 as the terminal oxidant and a slight excess of triethyl phosphite as the reductant. Triethyl phosphate is the easily removed byproduct. These simple-to-run catalytic reactions provide practical and economical procedures for the acylative construction of C–N bonds.

A novel uncatalyzed reaction between TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyranyl/dihydropyridinyl) complexes and electron-rich arenes/olefins is reported. The reaction proceeds under mild reaction conditions so that a variety of functional groups are tolerated. Combined with a stereospecific annulative demetalation, the new reaction provides a rapid access to polycyclic alkaloid structures. The sequential protocol was used to prepare analogues of the antimalarial agent isofebrifugine.

The density functional theory method is used to elucidate the nature of the active species and the mechanism of the aerobic CuI-catalyzed cross-coupling of S-acyl thiosalicylamide thiol esters and boronic acids reported previously (J. Am. Chem. Soc.2007, 129, 15734–15735; Angew. Chem., Int. Ed.2009, 48, 1417–1421). The energetically lowest isomer of the proposed active species [LC(O)R1]Cu-(O2)-Cu[LC(O)R1]2+, 2a (where L = thiolatosalicylamide), is found to be I1(OO,OO), with a μ-η2:η2-peroxo Cu2O2 core, while its isomers I2(OO,OO), with a bis(μ-O) Cu2O2 core, and I3(OO,OO), with a (μ-η1:η1) Cu2O2 core, lie only a few kcal/mol higher and are separated by 4–7 kcal/mol energy barriers. In all these isomers, the thiol ester is coordinated to the Cu centers via its two O ends. Isomers with (SO,OO) and (SO,SO) coordination modes of the thiol esters lie slightly higher and are separated with moderate energy barriers. We found the latter isomers to be vital for the reported CuI-templated cross-coupling of S-acyl thiosalicylamide thiol esters and boronic acids under aerobic conditions. The presence of an anion (halide, carboxylate modeled as formate) in the reaction medium is found to be necessary. Its coordination to the active catalyst I1(SO,SO) is the first step of the proposed anion-assisted transmetalation by boronic acid. Overall the transmetalation reaction requires 34.0 kcal/mol and is 24.0 kcal/mol exergonic. This conclusion is in reasonable agreement with available experiments. The C–C bond formation in the transmetalation product requires a 6.3 kcal/mol lower energy barrier and is highly exergonic.

A series of acyclic and cyclic 1-alkoxy- and 1-arylsulfonyloxy-substituted TpMo(CO)2(η3-allyl) complexes was synthesized and characterized, and exchange of the oxygenated substituent was investigated under a variety of reaction conditions. 1-Alkoxy-substituted η3-allyl and η3-butenyl complexes participated in direct, uncatalyzed exchange of the alkoxy substituent with benzylamine, but required a Lewis acid for exchange with alcohols. The 1-alkoxy-substituted η3-cyclohexenyl complex was unreactive toward exchange under all conditions investigated. The corresponding acyclic arylsulfonyloxy-substituted complexes underwent direct, uncatalyzed exchange with both benzylamine and alcohols, while the arylsulfonyloxy-substituted cyclohexenyl compounds participated in direct substitution with benzylamine, but not alcohols. High enantiopurity acyclic and cyclic alkoxy- and arylsulfonyloxy-substituted complexes provided exchange products with predominant, but incomplete, losses in enantiomeric excess in all cases examined. Mechanisms accounting for the observed reactivity trends and for the losses in enantiomeric excess are discussed. Reactions of alkoxy-substituted complexes through an associative mechanism and of arylsulfonyloxy-substituted compounds through a dissociative mechanism are suggested.

Charge neutral TpMo(CO)2(5-acyloxy-η3-pyranyl) and TpMo(CO)2(5-acyloxy-η3-pyridinyl) scaffolds undergo a novel intermolecular “homo-SN2′-like” reaction with a variety of carbon nucleophiles. Combined with an annulative demetalation, the homo-SN2′-like substitution/annulative demetalation sequence rapidly generates 2,7-dioxabicyclo[4.3.0]nonane and 2-aza-7-oxabicyclo[4.3.0]nonane frameworks in good to excellent yields with high enantiopurity. An enantiocontrolled total synthesis of the antimalarial alkaloid (+)-isofebrifugine was achieved utilizing this reaction cascade.

TpMo(CO)2(5-oxo-η3-pyranyl) scaffolds bearing an internal alkoxide undergo a novel intramolecular nucleophilic ketalization reaction. The anionic intermediate is easily demetalated, rapidly providing the 6,8-dioxabicyclo[3.2.1]oct-3-en-2-one framework in moderate to good yields with high enantiopurity. An enantiocontrolled total synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin was accomplished utilizing the reaction sequence.

Computational studies of the mechanism of Pd-catalyzed, Cu(I) carboxylate mediated desulfitative coupling of thioorganics with boronic acids have determined that the requisite Cu(I)-carboxylate plays multiple important roles. It enhances the transmetalation process and provides a vital carboxylate, which facilitates displacement of a phosphine ligand from the Pd center and generates a catalytically competent (less hindered and more electrophilic) Pd-monophosphine intermediate, and acts as a reactive center for boronic acid activation.