Diazaphospholene-Catalyzed Radical Reactions from Aryl Halides.

Diazaphospholenes are widely used as hydride transfer catalysts, however their use in radical reactions is a recently emerging area. Here, we show prior stoichiometric radical cyclizations of aryl iodides mediated by diazaphospholene hydrides are made catalytic by the combination of phenylsilane and alkali metal salts to regenerate the diazaphospholene hydride. The scope was expanded to include aryl bromides, which benefit from visible light irradiation. Twenty one substrates underwent cyclization, including a dearomative cyclization. Extension to six intermolecular radical hydroarylations with arenes, thiophenes, and a pyridine was also accomplished.

Room-temperature reduction of sulfur hexafluoride with metal phosphides.

Upon treatment with sulfur hexafluoride, alkali metal diphenyl or dicyclohexyl phosphides are oxidized within seconds to tetraphenyl or tetracyclohexyl diphosphines. When bulky di-tert-butylphosphide is employed, fluorophosphine intermediates are detected. This is the first reported reaction of sulfur hexafluoride with metal phosphides, and a rare example of reactivity of sulfur hexafluoride at ambient temperature.

Short syntheses of 1-substituted dibenzothiophene derivatives.

The 1-substituted dibenzothiophene motif is an unusual substitution pattern that has previously been accessed via a multi-step synthesis. We demonstrate a simple one-pot preparation of 1-lithiodibenzothiophene from commercial materials via a cascade of two benzyne additions and conversion to several derivatives by addition of electrophiles. A chiral amine containing the 1-dibenzothiophene motif was also prepared. This work avoids the use of precious metals or tert-butyllithium and is much shorter and more convenient than existing routes to 1-substituted dibenzothiophenes.

Applications of diazaphospholene hydrides in chemical catalysis.

Diazaphospholenes have recently emerged as main-group hydride transfer catalysts. This review will briefly summarize the common structural variants of diazaphospholenes, and the properties that make them superb hydride transfer catalysts, followed by a critical examination of the various preparative routes toward diazaphospholenes. Finally, an in-depth examination of the reactivity of diazaphospholenes in contemporary catalysis, including asymmetric catalysis will be undertaken.

Air and water stable secondary phosphine oxides as diazaphospholene precatalysts.

Air-stable secondary phosphine oxides (SPOs) are readily formed from diazaphospholene bromides. In the presence of pinacolborane, these SPOs are transformed into catalytically active diazaphospholene hydrides. A silyl triflate transforms the SPOs into phosphenium triflates. The use of diazaphospholene SPOs as reduction reaction precatalysts was validated by imine reduction, conjugate reduction, pyridine hydroboration, and asymmetric reduction.

Enantioselective Imine Reduction Catalyzed by Phosphenium Ions.

The first use of phosphenium cations in asymmetric catalysis is reported. A diazaphosphenium triflate, prepared in two or three steps on a multigram scale from commercially available materials, catalyzes the hydroboration or hydrosilylation of cyclic imines with enantiomeric ratios of up to 97:3. Catalyst loadings are as low as 0.2 mol %. Twenty-two aryl/heteroaryl pyrrolidines and piperidines were prepared using this method. Imines containing functional groups such as thiophenes or pyridyl rings that can challenge transition-metal catalysts were reduced employing these systems.

Bis-aminocyclopropenylidene carbene borane catalyzed imine hydrogenation.

Certain borenium cations supported by carbenes can function as hydrogenation catalysts for imines. While many carbenes have been explored, variation of the other groups on boron has been less common. We have investigated several carbene-borane adducts in an attempt to understand the ability of a bis-amino cyclopropenylidene (BAC) carbene dicyclohexylborane adduct to hydrogenate relatively sterically unhindered benzyl imines. As an additional variant, a BAC carbene adduct of diphenylborane was prepared. A convenient preparation of diphenylboron fluoride via a potassium fluoroborinate salt was employed in this chemistry. Reaction of diphenylboron fluoride with a BAC carbene afforded a modest yield of a carbene-fluoroborane adduct. Reaction between the fluoroborinate salt and a lithium tetrafluoroborate adduct of the carbene provided the adduct in much improved yield and cleanliness, and the product was structurally characterized. The fluoroborate could be converted to a boron hydride through fluoride-hydride exchange with dimethylchlorosilane. The boron hydride adduct was also structurally characterized. Unlike the BAC carbene dicyclohexylborane adduct, the BAC carbene diphenylborane adduct showed essentially no activity in hydrogenation of imines or enamines.

Protic additives or impurities promote imine reduction with pinacolborane.

We report here that addition of stoichiometric amounts of alcohols or water to mixtures of imines and pinacolborane promote reduction reactions. The reactions of several imines were examined, revealing that alkyl imines were reduced, while aniline derived imines were not effectively reduced. The use of binol as an additive resulted in modest enantioinduction, however other chiral additives that were screened gave negligible enantioinduction. While the reactions described herein are not competitive in conversion with established imine reduction technologies, this work reveals that the presence of protic impurities must be considered as a promoter of side reactions in catalyzed imine hydroborations. Amines also promote imine reduction in certain cases, raising the possibility of a slow autocatalytic reaction. The ability of water or other protic impurities to promote the reduction of imines with pinacolborane represents an important identification of a potential source of background reaction in catalyzed reductions of imines.

Asymmetric Imine Hydroboration Catalyzed by Chiral Diazaphospholenes.

The first use of diazaphospholenes as chiral catalysts has been demonstrated with enantioselective imine hydroboration. A chiral diazaphospholene prepared in a simple three-step synthesis from commercial materials has been shown to achieve the highest enantioselectivity for the hydroboration of alkyl imines with pinacolborane reported to date. Enantiomer ratios of up to 88:12 were obtained with low (2 mol %) catalyst loadings. Twenty examples of asymmetric reduction employing this main-group catalysis protocol, including the synthesis of the pharmaceuticals ent-rasagiline and fendiline, are shown.

Hydroboration Catalyzed by 1,2,4,3-Triazaphospholenes.

The synthesis and study of the catalytic activity of 1,2,4,3-triazaphospholenes (TAPs) is reported. TAPs represent a more modular scaffold than previously reported diazaphospholenes. TAP halides were shown to catalyze the 1,2 hydroboration of 19 imines, and three α,ß unsaturated aldehydes with pinacolborane, including examples that did not undergo hydroboration by previously reported diazaphospholene systems. DFT calculations support a mechanism where a triazaphospholene cation interacts with the substrate, a mechanism distinct from diazaphospholene catalyzed hydroborations.

Diazaphospholene Precatalysts for Imine and Conjugate Reductions.

The first examples of 1,3,2-diazaphospholene-catalyzed imine reduction and conjugate reduction reactions are reported. This approach employs readily synthesized alkoxydiazaphospholene precatalysts that can be handled in open air. Reduction of substrates containing Lewis basic functionality, isolated unsaturation, and protic functional groups was accomplished. The synthetic utility of this approach is demonstrated by the synthesis of the important antiparkinson medicine rasagiline and the natural product zingerone.

Kinetically E-selective macrocyclic ring-closing metathesis.

Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization-a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib-a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

Catalytic Z-selective cross-metathesis in complex molecule synthesis: a convergent stereoselective route to disorazole C1.

A convergent diastereo- and enantioselective total synthesis of anticancer and antifungal macrocyclic natural product disorazole C1 is reported. The central feature of the successful route is the application of catalytic Z-selective cross-metathesis (CM). Specifically, we illustrate that catalyst-controlled stereoselective CM can be performed to afford structurally complex Z-alkenyl-B(pin) as well as Z-alkenyl iodide compounds reliably, efficiently, and with high selectivity (pin = pinacolato). The resulting intermediates are then joined in a single-step operation through catalytic inter- and intramolecular cross-coupling to furnish the desired 30-membered ring macrocycle containing the critical (Z,Z,E)-triene moieties.

Effect of counterion structure on rates and diastereoselectivities in α,ß-unsaturated iminium-ion Diels-Alder reactions.

The use of cyclic α,ß-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.

An aldol-based synthesis of (+)-peloruside a, a potent microtubule stabilizing agent.

A convergent synthesis of the marine natural product (+)-peloruside has been reported. This target has been assembled through the successive application of two methyl ketone boron aldol addition reactions to the latent C(7)-C(11) dialdehyde synthon. This approach afforded a 22-step synthesis of this natural product. The influence of resident stereocenters on aldol reaction diastereoselection has been examined in detail.