D. Tyler McQuade

The Continuous‐Flow Synthesis of Ibuprofen

Organic synthesis is a powerful enterprise that continues to develop more selective and efficient chemical methods and synthetic routes. To synthesize complex molecules, whether in academic laboratories or industrial manufacturing, reactions are often performed iteratively in batch reactors. Although these stepwise methods are effective, they are also very wasteful. The pharmaceutical industry, for example, produces 25–100 kg of waste for every kilogram of a complex molecule synthesized. Though chemists are constantly striving to devise more efficient syntheses, recent reminders of a resource-limited world underscore the need for more sustainable methods and technologies to synthesize molecules of importance. The application of new technologies, such as microreactors, to organic synthesis can be used to achieve this goal. Microreactors are a developing technology used to perform safer, more efficient, and more selective chemical transformations in microchannels or narrow-bore tubing. The many advantages associated with conducting reactions in flow are attributed to large surface-area-to-volume ratios that allow precise reaction control through rapid heat transfer and mixing. The syntheses can be scaled up by running a single reactor for extended periods of time or by the addition of more identical flow reactors in parallel, a process known as numbering up. Although most applications of microreactors in organic synthesis have focused on single-step reactions, recent examples have demonstrated multistep reaction sequences in flow. 28–32] Our group has a long-standing interest in the development of new methodologies that enable the rapid and efficient synthesis of important small molecules. Specifically, we have aimed to run multistep reaction sequences in one pot (i.e. in batch reactors) or in series (i.e. in microreactors). 34] We report herein a three-step, continuous-flow synthesis of ibuprofen, a high-volume, nonsteroidal anti-inflammatory drug (NSAID), using a simplified microreactor that eliminates the need for purification and isolation steps. To achieve this continuous-flow synthesis, a careful retrosynthetic analysis of ibuprofen was performed, considering the synthesis of ibuprofen as an entity, as opposed to a series of independent reactions steps. Reactions therefore had to be designed such that byproducts and excess reagents from one reaction were compatible with downstream reactions. In this way, reactions could be performed in sequence without any breaks in the synthesis. The general three-step synthesis of ibuprofen we investigated is outlined in Scheme 1.

A Chiral 6-Membered N-Heterocyclic Carbene Copper(I) Complex That Induces High Stereoselectivity

A chiral 6-membered annulated N-heterocyclic (6-NHC) copper complex that catalyzes β-borylations with high yield and enantioselectivity was developed. The chiral 6-NHC copper complex is easy to prepare on the gram scale and is very active, showing 10,000 turnovers at 0.01 mol % of catalyst without significant decrease of enantioselectivity and with useful reaction rates.

One-pot multi-step synthesis: a challenge spawning innovation

Creating one-pot synthetic routes is a challenge that is already spawning new chemistry, enzymes, materials, and mechanistic insight. Through one-pot reactions, the chemical products that add value to our lives can be produced with less waste and greater economic benefits. Within this Emerging Area, we describe models for designing one-pot reactions as well as advanced catalysts created to facilitate their realization.

Continuous‐Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen

Primary and secondary amines can be rapidly and quantitatively oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temperature continuous-flow LED-photoreactor with a catalytic amount of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addition and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at -50 °C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.

A Concise Flow Synthesis of Efavirenz

Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45%. This streamlined proof-of-principle synthesis relies on the efficient copper-catalyzed formation of an aryl isocyanate and a subsequent intramolecular cyclization to install the carbamate core of Efavirenz in one step. The three-step method represents the shortest synthesis of this life-saving drug to date.

A biphasic oxidation of alcohols to aldehydes and ketones using a simplified packed-bed microreactor.

Summary We demonstrate the preparation and characterization of a simplified packed-bed microreactor using an immobilized TEMPO catalyst shown to oxidize primary and secondary alcohols via the biphasic Anelli-Montanari protocol. Oxidations occurred in high yields with great stability over time. We observed that plugs of aqueous oxidant and organic alcohol entered the reactor as plugs but merged into an emulsion on the packed-bed. The emulsion coalesced into larger plugs upon exiting the reactor, leaving the organic product separate from the aqueous by-products. Furthermore, the microreactor oxidized a wide range of alcohols and remained active in excess of 100 trials without showing any loss of catalytic activity.

Use of Bifunctional Ureas to Increase the Rate of Proline-Catalyzed α-Aminoxylations

The rate of the proline-catalyzed alpha-aminoxylation of aldehydes is significantly increased in the presence of a bifunctional urea. Structure-activity relationship data indicate that both an amine and a urea are crucial for rate enhancement. The evidence presented herein suggests that this rate enhancement originates from the hydrogen bonding interaction between the bifunctional urea and an oxazolidinone intermediate to increase the rate of enamine formation. Proline derivatives that are incapable of forming oxazolidinones exhibit no rate enhancement in the presence of the bifunctional urea. The rate enhancement is general for a variety of aldehydes, and the faster reactions do not reduce yields or selectivities.

Iterative Asymmetric Allylic Substitutions: syn‐ and anti‐1,2‐Diols through Catalyst Control

A copper-catalyzed asymmetric allylic boronation (AAB) gives access to syn- and anti-1,2-diols. The method facilitates an iterative strategy for the preparation of polyols, such as the fully differentiated L-ribo-tetrol and protected D-arabino-tetrol. P=protecting group.

Continuous Synthesis and Use of N-Heterocyclic Carbene Copper(I) Complexes from Insoluble Cu2O

It is demonstrated that homogeneous N-heterocyclic carbene-copper(I)-chloride complexes can be prepared continuously by flowing NHC precursors through a packed bed of solid Cu(2)O suspended in molecular sieves. The method enables the synthesis of a wide range of complexes including those that are challenging to prepare using standard approaches. Our strategy enables both sustained output of complex production for long-term catalytic reactions (greater than 5 h) and for generation of gram quantities for storage (greater than 1 g of complex in ~16 min).

Organic Reaction Systems: Using Microcapsules and Microreactors to Perform Chemical Synthesis

The appetite for complex organic molecules continues to increase worldwide, especially in rapidly developing countries such as China, India, and Brazil. At the same time, the cost of raw materials and solvent waste disposal is also growing, making sustainability an increasingly important factor in the production of synthetic life-saving/improving compounds. With these forces in mind, our group is driven by the principle that how we synthesize a molecule is as important as which molecule we choose to synthesize. We aim to define alternative strategies that will enable more efficient synthesis of complex molecules. Drawing our inspiration from nature, we attempt to mimic (1) the multicatalytic metabolic systems within cells using collections of nonenzyme catalysts in batch reactors and (2) the serial synthetic machinery of fatty acid/polyketide biosynthesis using microreactor systems. Whether we combine catalysts in batch to prepare an active pharmaceutical ingredient (API) or use microreactors to synthesize small or polymeric molecules, we strive to understand the mechanism of each reaction while also developing new methods and techniques. This Account begins by examining our early efforts in the development of novel catalytic materials and characterization of catalytic systems and how these observations helped forge our current models for developing efficient synthetic routes. The Account progresses through a focused examination of design principles needed to develop multicatalyst systems using systems recently published by our group as examples. Our systems have been successfully applied to produce APIs as well as new synthetic methods. The multicatalyst section is then juxtaposed with our work in continuous flow multistep synthesis. Here, we discuss the design principles needed to create multistep continuous processes using examples from our recent efforts. Overall, this Account illustrates how multistep organic routes can be conceived and achieved using strategies and techniques that mimic biological systems.