Christopher G. Frost

Selectivity in palladium catalysed allylic substitution

Palladium catalysed allylic substitution has emerged as one of the more useful synthetic methods for the construction of C-C and C-X bonds. The reaction offers the advantages of mild reaction conditions, as well as the ability to accomodate a wide range of nucleophiles and their electrophilic partners. The issues of regiocontrol, diastereocontrol and enantiocontrol have been documented by a number of researchers over the last twenty years. The levels of selectivity in many cases are very high, and current research is driving these selectivities higher still. A greater understanding of the nature of the process is occurring as more detailed mechanistic and structural studies are being undertaken. Many uses have been found for palladium catalysed allylic substitution methodology, since the strong stereocontrol allows for the selective formation of numerous products. A few other metals are also able to catalyse allylic substitution, with modified stereochemical behaviour, although these are currently less well documented than for palladium catalysed process.

Asymmetric palladium catalysed allylic substitution using phosphorus containing oxazoline ligands

Abstract A series of new phosphorus-containing oxazoline ligands has been developed. The use of these ligands for asymmetric palladium catalysed allylic substitution of 1,3-diphenylprop-2-enyl-1-acetate 12 with the sodium salt of dimethylmalonate has been achieved with 90 – 94% ee and 88 – 99% yield.

Ruthenium-catalyzed meta sulfonation of 2-phenylpyridines

A selective catalytic meta sulfonation of 2-phenylpyridines was found to occur in the presence of (arene)ruthenium(II) complexes upon reaction with sulfonyl chlorides. The 2-pyridyl group facilitates the formation of a stable Ru-C(aryl) σ bond that induces a strong para-directing effect. Electrophilic aromatic substitution proceeds with the sulfonyl chloride to furnish a sulfone at the position meta to the chelating group. This new catalytic process offers access to atypical regioselectivity for reactions involving chelation-assisted cyclometalation.

Post‐Synthetic Modification of Tagged Metal–Organic Frameworks

Metal–organic frameworks (MOFs) are currently attracting considerable attention, largely because of their potential for porosity, and their consequent use in applications as diverse as gas storage, catalysis, separations, and drug delivery. The first generation of MOFs were formed by linking together metal centers with simple, commercially available bridging ligands, such as 1,4-benzenedicarboxylate (bdc), but there has since been an increasing shift towards more complex structures and increased functionality. For example, MOFs in which the pores contain accessible hydrogenbonding groups, unsaturated metal centers, or chirality have been reported and studied, and the preparation of dynamic porous materials, capable of undergoing guestinduced transformations or reformations, has been explored. Another approach to forming functionalized networks is to undertake reactions on preformed MOFs, converting one solid state material into another. The incorporation of an additional functional group, a “tag”, into a linking ligand offers the opportunity to form structures in which this group is preserved during the MOF synthesis, allowing it to project into the pores or channels of the network structure. We define a “tag” as a group or functionality that is stable and innocent (that is, non-structure-defining) during MOF formation, but that can be transformed by a post-synthetic modification. This approach is shown schematically in Figure 1. A similar concept of tagging has also recently been applied in medicinal chemistry. Post-synthetic modification allows the pores in a preformed MOF to be tailored for a specific purpose, which offers the possibility of fine-tuning for selective adsorption and catalysis. The strategy also facilitates the incorporation into a MOF of functional groups that would not survive the conditions of the MOF synthesis (e.g., temperature and pH) and of functional groups that might compete with the donor groups on the bridging ligands. Given these advantages, it is surprising that there has been very little focus on postsynthetic modification of MOFs. Kim and co-workers showed that the pendant pyridyl groups in a chiral zinc network could be methylated and, very recently, Wang and Cohen, and Gamez and co-workers have both demonstrated that the amino groups in 2-amino-1,4-benzenedicarboxylate MOFs can be converted into amides or urethanes. Rosseinsky and co-workers have converted these amines into salicylidenes, and then used these to coordinate vanadium. Fujita and co-workers have shown that guest molecules can undergo similar transformations within the pores of a MOF. Herein, we report our endeavors to prepare tagged MOFs suitable for post-synthetic modification, starting from an aldehyde-modified dicarboxylate. Following seminal work from Yaghi and co-workers, it is now well-established that the octahedral zinc secondary building unit (SBU) Zn4O(O2CR)6 forms an isoreticular series of MOFs containing the same framework topology with linear dicarboxylates, such as bdc and 4,4’-biphenyldicarboxylate (bpdc). We have prepared the aldehyde-tagged dicarboxylic acid H2L 1 (2-formylbiphenyl-4,4’-dicarboxylic acid, Scheme 1), and used it in MOF synthesis. The coordinated L ligand is suitable for Figure 1. Schematic representation of the post-synthetic modification strategy for MOFs.

Tetrahedron: Assymetry Report Number 11Selectivity in palladium catalysed allylic substitution

Palladium catalysed allylic substitution has emerged as one of the more useful synthetic methods for the construction of C-C and C-X bonds. The reaction offers the advantages of mild reaction conditions, as well as the ability to accomodate a wide range of nucleophiles and their electrophilic partners. The issues of regiocontrol, diastereocontrol and enantiocontrol have been documented by a number of researchers over the last twenty years. The levels of selectivity in many cases are very high, and current research is driving these selectivities higher still. A greater understanding of the nature of the process is occurring as more detailed mechanistic and structural studies are being undertaken. Many uses have been found for palladium catalysed allylic substitution methodology, since the strong stereocontrol allows for the selective formation of numerous products. A few other metals are also able to catalyse allylic substitution, with modified stereochemical behaviour, although these are currently less well documented than for palladium catalysed process.

Synthetic applications of rhodium catalysed conjugate addition

The rhodium catalysed conjugate addition of organometallics to activated alkenes is a powerful synthetic tool for establishing new carbon-carbon bonds often with high stereoselectivity. The introduction of a practical, efficient method for introducing functionalised aryl and alkenyl fragments with predictable stereocontrol has caught the attention of synthetic chemists and emerging examples are growing in number and complexity. In this tutorial review, we document notable advances in the application of rhodium catalysed conjugate addition processes within the context of synthesis of complex molecules and intermediates in drug discovery. The chosen examples illustrate important issues regarding scope, selectivity and reactivity that will help guide the selection of appropriate donor and acceptor to achieve the desired carbon-carbon bond construction when planning new synthetic routes.

Heterogeneous catalytic synthesis using microreactor technology

The application of heterogeneous catalysis in conjunction with microreactor technology can facilitate a cleaner and scalable flow methodology for organic synthesis. In this tutorial review we present recent advances in the design of supported catalysts for emerging synthetic applications within microreactor technology. Specifically, transition metal catalysts such as palladium, copper, ruthenium, and nickel are described on silica, monolithic, magnetic nanoparticles and polymer supports. These catalysts have been utilised to promote a range of reactions including Heck, Sonogashira, Suzuki, Kumada, olefin metathesis, hydrogenation and benzannulation reactions.

Silver phosphanes partnered with carborane monoanions: Synthesis, structures and use as highly active lewis acid catalysts in a hetero-Diels-Alder reaction

Four Lewis acidic silver phosphane complexes partnered with [1-closo-CB(11)H(12)](-) and [1-closo-CB(11)H(6)Br(6)](-) have been synthesised and studied by solution NMR and solid-state X-ray diffraction techniques. In the complex [Ag(PPh(3))(CB(11)H(12))] (1), the silver is coordinated with the carborane by two stronger 3c-2e B-H-Ag bonds, one weaker B-H-Ag interaction and a very weak Ag.C(arene) contact in the solid state. In solution, the carborane remains closely connected with the [Ag(PPh(3))](+) fragment, as evidenced by (11)B chemical shifts. Complex 2 [Ag(PPh(3))(2)(CB(11)H(12))](2) adopts a dimeric motif in the solid state, each carborane bridging two Ag centres. In solution at low temperature, two distinct complexes are observed that are suggested to be monomeric [Ag(PPh(3))(2)][CB(11)H(12)] and dimeric [Ag(PPh(3))(2)(CB(11)H(12))](2). With the more weakly coordinating anion [CB(11)H(6)Br(6)](-) and one phosphane, complex 3 [Ag(PPh(3))(CB(11)H(6)Br(6))] is isolated. Complex 4, [Ag(PPh(3))(2)(CB(11)H(6)Br(6))], has been characterised spectroscopically. All of the complexes have been assessed as Lewis acids in the hetero-Diels-Alder reaction of N-benzylideneaniline with Danishefskys diene. Exceptionally low catalyst loadings for this Lewis acid catalysed reaction are required (0.1 mol %) coupled with turnover frequencies of 4000 h(-1) (quantitative conversion to product after 15 minutes using 3 at room temperature). Moreover, the reaction does not occur in rigorously dry solvent as addition of a substoichiometric amount of water (50 mol %) is necessary for turnover of the catalyst. It is suggested that a Lewis assisted Brønsted acid is formed between the water and the silver. The effect of changing the counterion to [BF(4)](-), [OTf](-) and [ClO(4)](-) has also been studied. Significant decreases in reaction rate and final product yield are observed on changing the anion from [CB(11)H(6)Br(6)](-), thus demonstrating the utility of weakly coordinating carborane anions in organic synthesis.

Enantioselective palladium catalysed allylic substitution with thienyl oxazoline ligands

Abstract Homochiral thienyl oxazolines have been employed as ligands for enantioselective palladium catalysed allylic substitution. The ligands are straightforw

Preparation of novel sulfur and phosphorus containing oxazolines as ligands for asymmetric catalysis

Abstract The preparation of enantiomerically pure liginds which contain both an oxazoline group and an additional sulfur or phosphorus donor atom are described. Methyithiomethyl, o -thioanisyl and thienyl oxazolines have been prepared in one step, and o -diphenylphosphinophenyl oxazolines have been prepared in two steps in good yields from commercially available starting materials.