Donald A. Watson

A Highly Active Catalyst for Pd-Catalyzed Amination Reactions: Cross-Coupling Reactions Using Aryl Mesylates and the Highly Selective Monoarylation of Primary Amines Using Aryl Chlorides

A catalyst system based on a new biarylmonophosphine ligand (BrettPhos) that shows excellent reactivity for C-N cross-coupling reactions is reported. This catalyst system enables the use of aryl mesylates as a coupling partner in C-N bond-forming reactions. Additionally, the use of BrettPhos permits the highly selective monoarylation of an array of primary aliphatic amines and anilines at low catalyst loadings and with fast reaction times, including the first monoarylation of methylamine. Lastly, oxidative addition complexes of BrettPhos are included, which provide insight into the origin of reactivity for this system.

Palladium-Catalyzed Carbonylation Reactions of Aryl Bromides at Atmospheric Pressure : A General System Based on Xantphos

A method for the Pd-catalyzed carbonylation of aryl bromides has been developed using Xantphos as the ligand. This method is effective for the direct synthesis of Weinreb amides, primary and secondary benzamides, and methyl esters from the corresponding aryl bromides at atmospheric pressure. In addition, a putative catalytic intermediate, (Xanphos)Pd(Br)benzoyl, was prepared and an X-ray crystal structure was obtained revealing an unusual cis-coordination mode of Xantphos in this palladium-acyl complex.

Enantioselective Synthesis of Axially Chiral Biaryls by the Pd- Catalyzed Suzuki-Miyaura Reaction: Substrate Scope and Quantum Mechanical Investigations

We report efficient syntheses of axially chiral biaryl amides in yields ranging from 80-92%, and with enantioselectivity in the range 88-94% ee employing an asymmetric Suzuki-Miyaura process with Pd(OAc)(2) and KenPhos as ligand. These studies demonstrate that electron-rich and electron-deficient o-halobenzamides can be efficiently coupled with 2-methyl-1-naphthylboronic acid and 2-ethoxy-1-naphthylboronic acid. The yields and selectivities of the reactions are independent of the nature of halogen substituent on the benzamide coupling partner. Our investigations demonstrate that axially chiral heterocyclic and biphenyl compounds can also be synthesized with this methodology. We also report computational studies used to determine the origin of stereoselectivity during the selectivity-determining reductive elimination step of the related coupling of tolyl boronic acid with naphthylphosphonate bromide that was reported in a previous publication (J. Am. Chem. Soc. 2000, 122, 12051-12052). These studies indicate that the stereoselectivity arises from a combination of weak -(C)H..O interactions as well as steric interactions between the tolyl and naphthylphosphonate addends in the transition state for C-C coupling.

Carbonylation of Aryl Chlorides with Oxygen Nucleophiles at Atmospheric Pressure. Preparation of Phenyl Esters as Acyl Transfer Agents and the Direct Preparation of Alkyl Esters and Carboxylic Acids

A mild, functional group tolerant method of the preparation of phenyl esters from aryl chlorides via palladium-catalyzed carbonylation is described using atmospheric pressure of carbon monoxide. Phenyl esters are shown to be useful acylating agents, delivering libraries of carbonyl derivatives, including alkyl, allyl and thioesters, under very mild conditions. Direct preparation of alkyl esters and carboxylic acids is also demonstrated, providing the first method for the preparation of methyl and ethyl esters from aryl chlorides without pressured reactors.

Preparation of Allyl and Vinyl Silanes by the Palladium‐Catalyzed Silylation of Terminal Olefins: A Silyl‐Heck Reaction

A high-yielding protocol for the palladium-catalyzed silylation of terminal alkenes using silyl halides is reported. This method allows facile conversion of styrenes to E-β-silyl styrenes using either TMSI or TMSCl/LiI. Terminal allyl silanes with good E:Z ratios are also readily accessed from α-olefins by this method. When combined with existing technology, this transformation provides a powerful strategy to selectively functionalize the vinyl or allylic position of terminal alkenes.

Renewable production of phthalic anhydride from biomass-derived furan and maleic anhydride

A route to renewable phthalic anhydride (2-benzofuran-1,3-dione) from biomass-derived furan and maleic anhydride (furan-2,5-dione) is investigated. Furan and maleic anhydride were converted to phthalic anhydride in two reaction steps: Diels–Alder cycloaddition followed by dehydration. Excellent yields for the Diels–Alder reaction between furan and maleic-anhydride were obtained at room temperature and solvent-free conditions (SFC) yielding 96% exo-4,10-dioxa-tricyclo[5.2.1.0]dec-8-ene-3,5-dione (oxanorbornene dicarboxylic anhydride) after 4 h of reaction. It is shown that this reaction is resistant to thermal runaway because of its reversibility and exothermicity. The dehydration of the oxanorbornene was investigated using mixed-sulfonic carboxylic anhydrides in methanesulfonic acid (MSA). An 80% selectivity to phthalic anhydride (87% selectivity to phthalic anhydride and phthalic acid) was obtained after running the reaction for 2 h at 298 K to form a stable intermediate followed by 4 h at 353 K to drive the reaction to completion. The structure of the intermediate was determined. This result is much better than the 11% selectivity obtained in neat MSA using similar reaction conditions.

Selective Formation of Secondary Amides via the Copper-Catalyzed Cross-Coupling of Alkylboronic Acids with Primary Amides

For the first time, a general catalytic procedure for the cross-coupling of primary amides and alkylboronic acids is demonstrated. The key to the success of this reaction was the identification of a mild base (NaOSiMe3) and oxidant (di-tert-butyl peroxide) to promote the copper-catalyzed reaction in high yield. This transformation provides a facile, high-yielding method for the monoalkylation of amides.

Rational Design of a Second Generation Catalyst for Preparation of Allylsilanes Using the Silyl-Heck Reaction

Using rational ligand design, we have developed of a second-generation ligand, bis(3,5-di-tert-butylphenyl)(tert-butyl)phosphine, for the preparation of allylsilanes using the palladium-catalyzed silyl-Heck reaction. This new ligand provides nearly complete suppression of starting material alkene isomerization that was observed with our first-generation catalyst, providing vastly improved yields of allylsilanes from simple alkene starting materials. The studies quantifying the electronic and steric properties of the new ligand are described. Finally, we report an X-ray crystal structure of a palladium complex resulting from the oxidative addition of Me3SiI using an analogous ligand that provides significant insight into the nature of the catalytic system.

Benzylation of Nitroalkanes Using Copper-Catalyzed Thermal Redox Catalysis: Toward the Facile C-Alkylation of Nitroalkanes

The C-alkylation of nitroalkanes under mild conditions has been a significant challenge in organic synthesis for more than a century. Herein we report a simple Cu(I) catalyst, generated in situ, that is highly effective for C-benzylation of nitroalkanes using abundant benzyl bromides and related heteroaromatic compounds. This process, which we believe proceeds via a thermal redox mechanism, allows access to a variety of complex nitroalkanes under mild reaction conditions and represents the first step toward the development of a general catalytic system for the alkylation of nitroalkanes.

Preparation of vinyl silyl ethers and disiloxanes via the silyl-Heck reaction of silyl ditriflates.

Vinyl silyl ethers and disiloxanes can now be prepared from aryl-substituted alkenes and related substrates using a silyl-Heck reaction. The reaction employs a commercially available catalyst system and mild conditions. This work represents a highly practical means of accessing diverse classes of vinyl silyl ether substrates in an efficient and direct manner with complete regiomeric and geometric selectivity.