Karl D. Collins

A robustness screen for the rapid assessment of chemical reactions

In contrast to the rapidity with which scientific information is published, the application of new knowledge often remains slow, and we believe this to be particularly true of newly developed synthetic organic chemistry methodology. Consequently, methods to assess and identify robust chemical reactions are desirable, and would directly facilitate the application of newly reported synthetic methodology to complex synthetic problems. Here, we describe a simple process for assessing the likely scope and limitations of a chemical reaction beyond the idealized reaction conditions initially reported. Using simple methods and common analytical techniques we demonstrate a rapid assessment of an established chemical reaction, and also propose a simplified analysis that may be reported alongside new synthetic methodology. For researchers to rapidly adopt new synthetic methodology, they need to gauge whether the reaction will work for their substrate — a point not easily conveyed by traditional screens of reaction scope. Here, a simple method is described to assess the likely scope and limitations of a chemical reaction beyond the idealized conditions initially reported.

Completely Regioselective Direct C–H Functionalization of Benzo[b]thiophenes Using a Simple Heterogeneous Catalyst

The first completely selective C3 C-H arylation of benzo[b]thiophenes is reported, demonstrating previously unexploited reactivity of palladium. Benzo[b]thiophenes are coupled with readily available aryl chlorides using a ligand-free, dual catalytic system of heterogeneous Pd/C and CuCl. The reaction is operationally simple and insensitive to air and moisture, and it provides valuable products with complete selectivity. Significant investigations into the nature of the active catalytic species and mechanistic considerations are discussed.

Pd/C as a Catalyst for Completely Regioselective CH Functionalization of Thiophenes under Mild Conditions†

The completely C3-selective arylation of thiophenes and benzo[b]thiophenes was achieved by using Pd/C as a heterogeneous catalyst without ligands or additives under mild reaction conditions. The practicability of this transformation is demonstrated by notable functional group tolerance and the insensitivity of the reaction to H2 O and air. This method is also applicable to nitrogen- and oxygen-containing heterocycles, yielding the corresponding C2-arylated products. Three-phase tests along with Hg-poisoning and hot-filtration tests suggest that the catalytically active species is heterogeneous in nature.

[3]Dendralene Synthesis: Rhodium(III)‐Catalyzed Alkenyl CH Activation and Coupling Reaction with Allenyl Carbinol Carbonate

[3]DendrAl(l)ene! A new synthesis of [3]dendralenes is based on a Rh(III) -catalyzed alkenyl CH activation and coupling reaction with allenyl carbinol carbonates (see scheme; DG=directing group). A variety of [3]dendralenes with diverse substitution patterns are accessible with good efficiency. The reaction is highly stereoselective and compatible with different directing groups and numerous functional groups.

Contemporary screening approaches to reaction discovery and development

New organic reactivity has often been discovered by happenstance. Several recent research efforts have attempted to leverage this to discover new reactions. In this Review, we attempt to unify reported approaches to reaction discovery on the basis of the practical and strategic principles applied. We concentrate on approaches to reaction discovery as opposed to reaction development, though conceptually groundbreaking approaches to identifying efficient catalyst systems are also considered. Finally, we provide a critical overview of the utility and application of the reported methods from the perspective of a synthetic chemist, and consider the future of high-throughput screening in reaction discovery.

Selective reductions of cyclic 1,3-diesters using SmI2 and H2O

SmI(2)-H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over-reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters and esters. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron transfer to the ester carbonyl and the anomeric stabilization of the resulting radical-anion intermediate. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes.

Intermolecular Reaction Screening as a Tool for Reaction Evaluation

Synthetic organic chemistry underpins many scientific disciplines. The development of new synthetic methods proceeds with the ultimate intention of providing access to novel structural motifs or providing safer, increasingly efficient, or more economical chemical reactions. To facilitate the identification and application of new methods in solving real synthetic problems, this Account will highlight the benefits of providing a fuller picture of both the scope and limitations of new reactions, with a primary focus on the evaluation of functional group tolerance and stability of a reaction using intermolecular screens. This Account will begin with a discussion on reaction evaluation, specifically considering the suitability of a given reaction for application in target-oriented synthesis. A comparison of desirable and essential criteria when choosing a reaction is given, and a short discussion on the value of negative and qualitative data is provided. The concept of intermolecular reaction screening will be introduced, and a direct comparison with a traditional substrate scope highlights the benefits and limitations of each and thus the complementary nature of these approaches. In recent years, a number of ad hoc applications of intermolecular screens to evaluate the functional group tolerance of a reaction or the stability of functional groups to a given set of reaction conditions have been reported, and will be discussed. More recently, we have developed a formal high-throughput intermolecular screening protocol that can be utilized to rapidly evaluate new chemical reactions. This simple and rapid protocol enables a much broader evaluation of a reaction in terms of functional group tolerance and the stability of chemical motifs to the reaction conditions than is feasible with a typical reaction scope. The development, evaluation, and application of this method within our group will be discussed in detail, with both the potential benefits and limitations highlighted and discussed. In addition, we will discuss more recent applications of intermolecular screens from both industrial and academic groups. Modifications in protocols and applications will be highlighted, including problem based evaluations, assessment of biomolecule compatibility, establishment of relative rate data, and the identification of new reactivity. Such screens have been applied in diverse chemistries including C-H functionalization reactions, frustrated Lewis-pair-catalyzed hydrogenations, heterogeneous catalysis, photoredox catalysis, enantioselective organocatalysis, and polymer science. We feel that the application of intermolecular screens to such a diversity of reactions highlights the practical simplicity of such screens. A summary of the applications and potential utility of intermolecular reaction evaluation is provided.

Application of a robustness screen for the evaluation of synthetic organic methodology

This protocol provides a rapid method for evaluating the tolerance of a given set of reaction conditions to a wide range of functional groups, as well as the stability of functional groups to the reaction conditions. This information is highly desirable when considering the application of a given protocol in the preparation of complex compounds, including natural products or biologically active molecules. By using a contemporary Rh(III)-catalyzed C-H activation protocol for the preparation of indole derivatives as a demonstrative example, here we describe a simple process that uses batch reaction preparation, small-scale parallel reaction techniques, simplified gas chromatography (GC) calibration techniques and GC analysis to undertake this evaluation in a rapid and cost-effective manner. This analysis provides quantitative data for a large number of functional groups and heterocycles, and it is readily adaptable to investigate structural motifs of choice, such as common moieties or functional groups within a given medicinal or agrochemical project or within a family of natural products. Twenty chosen additives plus controls can be evaluated in ∼3 d depending on the reaction time, with actual reaction setup and analysis taking 12–24 h depending on the reaction.

Selective Reductions of Cyclic 1,3-Diesters by Using SmI2 and H2O

SmI(2)/H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters, and esters. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes. The ketal unit and the reaction temperature have a marked impact on the diastereoselectivity of the cyclizations. Cyclization cascades are possible when two alkenes are present in the starting cyclic diester and lead to the formation of two rings and four stereocenters with excellent stereocontrol.

SmI2-Mediated Radical Cyclizations Directed by a C−Si Bond

The use of a silicon stereocontrol element in cyclobutanol and cyclopentanol-forming cyclizations mediated by SmI(2) results in excellent diastereocontrol. The C-Si bond in the products of cyclization provides a versatile handle for further manipulation. An asymmetric route to cyclization substrates involving copper-catalyzed silyl transfer has also been developed.