Michael C. Willis

Transition Metal Catalyzed Alkene and Alkyne Hydroacylation

3. Intermolecular Alkene Hydroacylation 734 3.1. Rhodium Catalysis 734 3.2. Ruthenium Catalysis 738 3.3. Cobalt Catalysis 739 3.4. Stereoselective Reactions 740 4. Intramolecular Alkyne Hydroacylation 741 4.1. Catalytic Achiral Systems 741 4.2. Enantioselective Processes 742 5. Intermolecular Alkyne Hydroacylation 742 5.1. Catalytic Achiral Processes 742 6. Mechanistic Studies 743 7. Outlook 746 8. References 746

Palladium-Catalyzed Aminosulfonylation of Aryl Halides

The palladium-catalyzed three-component coupling of aryl iodides, sulfur dioxide, and hydrazines to deliver aryl N-aminosulfonamides is described. The colorless crystalline solid DABCO·(SO(2))(2) was used as a convenient source of sulfur dioxide. The reaction tolerates significant variation of both the aryl iodide and hydrazine coupling partners.

DABSO-Based, Three-Component, One-Pot Sulfone Synthesis

The addition of Grignard reagents or organolithium reagents to the SO2-surrogate DABSO generates a diverse set of metal sulfinates, suitable for direct conversion to sulfone products. The metal sulfinates can be trapped in situ with a wide range of C-electrophiles, including alkyl, allyl, and benzyl halides, epoxides, and (hetero)aryliodoniums.

Palladium‐Catalyzed Three‐Component Diaryl Sulfone Synthesis Exploiting the Sulfur Dioxide Surrogate DABSO

Aryl, heteroaryl, and alkenyl sulfones play a prominent role in organic and medicinal chemistry. Not only are they versatile intermediates in organic synthesis[1], but they are also of particular pharmaceutical relevance, and exhibit an extensive and broad range of biological activities (Scheme 1).[2] In addition, sulfone-containing polymers display novel properties as materials.[3] Although there are a variety of methods known for the preparation of sulfones, the majority of these processes feature associated limitations. For example, oxidation of the corresponding sulfide relies on functional-group compatibility with oxidizing agents and the availability of catalysts to promote selectivity for sulfone formation over sulfoxide formation; in addition, the preparation of the required sulfide substrate often involves the use of foul-smelling thiols.[4,5] Friedel–Crafts-type sulfonylation of arenes is limited not only by the generally harsh reaction conditions, but also by the inherent regioselective bias imposed by the electronic and steric properties of the arene substrate.[5,6]

DABCO-Bis(sulfur dioxide), DABSO, as a Convenient Source of Sulfur Dioxide for Organic Synthesis: Utility in Sulfonamide and Sulfamide Preparation

The charge-transfer complex generated from the combination of DABCO and sulfur dioxide, DABSO, is a bench-stable colorless solid suitable for use in organic synthesis as a replacement for gaseous sulfur dioxide. The complex can be combined with Grignard reagents to form sulfinates, which can then be converted in situ to a series of sulfonamides. Alternatively, reaction with anilines and iodine leads to the formation of a series of sulfamides. Cheletropic addition between DABSO and 2,3-dimethylbutadiene provides the corresponding sulfolene.

Palladium(II)‐Catalyzed Synthesis of Sulfinates from Boronic Acids and DABSO: A Redox‐Neutral, Phosphine‐Free Transformation

Abstract A redox‐neutral palladium(II)‐catalyzed conversion of aryl, heteroaryl, and alkenyl boronic acids into sulfinate intermediates, and onwards to sulfones and sulfonamides, has been realized. A simple Pd(OAc)2 catalyst, in combination with the sulfur dioxide surrogate 1,4‐diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO), is sufficient to achieve rapid and high‐yielding conversion of the boronic acids into the corresponding sulfinates. Addition of C‐ or N‐based electrophiles then allows conversion into sulfones and sulfonamides, respectively, in a one‐pot, two‐step process.

Palladium-Catalyzed Synthesis of Ammonium Sulfinates from Aryl Halides and a Sulfur Dioxide Surrogate: A Gas- and Reductant-Free Process†

Sulfonyl-derived functional groups populate a broad range of useful molecules and materials, and despite a variety of preparative methods being available, processes which introduce the most basic sulfonyl building block, sulfur dioxide, using catalytic methods, are rare. Described herein is a simple reaction system consisting of the sulfur dioxide surrogate DABSO, triethylamine, and a palladium(0) catalyst for effective convertion of a broad range of aryl and heteroaryl halides into the corresponding ammonium sulfinates. Key features of this gas- and reductant-free reaction include the low loadings of palladium (1 mol %) and ligand (1.5 mol %) which can be employed, and the use of isopropyl alcohol as both a solvent and formal reductant. The ammonium sulfinate products are converted in situ into a variety of sulfonyl-containing functional groups, including sulfones, sulfonyl chlorides, and sulfonamides.

Catalytic Enantioselective Intermolecular Hydroacylation : Rhodium-Catalyzed Combination of β-S-Aldehydes and 1,3.Disubstituted Allenes

A rhodium(I) catalyst incorporating the Me-DuPhos ligand promotes enantioselective intermolecular hydroacylation between beta-S-aldehydes and 1,3-disubstituted allenes. The nonconjugated enone products are obtained in good yields and with high enantioselectivities.

Aryl methyl sulfides as substrates for rhodium-catalyzed alkyne carbothiolation: arene functionalization with activating group recycling.

A Rh(I)-catalyzed method for the efficient functionalization of arenes is reported. Aryl methyl sulfides are combined with terminal alkynes to deliver products of carbothiolation. The overall process results in reincorporation of the original arene functional group, a methyl sulfide, into the products as an alkenyl sulfide. The carbothiolation process can be combined with an initial Rh(I)-catalyzed alkene or alkyne hydroacylation reaction in three-component cascade sequences. The utility of the alkenyl sulfide products is also demonstrated in simple carbo- and heterocycle-forming processes. We also provide mechanistic evidence for the course of this new process.

Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO, and Amines: A One‐Pot Preparation of Sulfonamides, Amenable to Array Synthesis

We describe a method for the synthesis of sulfonamides through the combination of an organometallic reagent, a sulfur dioxide equivalent, and an aqueous solution of an amine under oxidative conditions (bleach). This simple reaction protocol avoids the need to employ sulfonyl chloride substrates, thus removing the limitation imposed by the commercial availability of these reagents. The resultant method allows access to new chemical space, and is also tolerant of the polar functional groups needed to impart favorable physiochemical properties required for medicinal chemistry and agrochemistry. The developed chemistry is employed in the synthesis of a targeted 70 compound array, prepared using automated methods. The array achieved a 93 % success rate for compounds prepared. Calculated molecular weights, lipophilicities, and polar surface areas are presented, demonstrating the utility of the method for delivering sulfonamides with drug-like properties.