Timothy F. Jamison

Recent advances in homogeneous nickel catalysis

Tremendous advances have been made in nickel catalysis over the past decade. Several key properties of nickel, such as facile oxidative addition and ready access to multiple oxidation states, have allowed the development of a broad range of innovative reactions. In recent years, these properties have been increasingly understood and used to perform transformations long considered exceptionally challenging. Here we discuss some of the most recent and significant developments in homogeneous nickel catalysis, with an emphasis on both synthetic outcome and mechanism.

Continuous flow multi-step organic synthesis

Using continuous flow techniques for multi-step synthesis enables multiple reaction steps to be combined into a single continuous operation. In this mini-review we discuss the current state of the art in this field and highlight recent progress and current challenges facing this emerging area.

End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation†

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

Drug manufacturing in a fridge-sized box Commodity chemicals tend to be manufactured in a continuous fashion. However, the preparation of pharmaceuticals still proceeds batch by batch, partly on account of the complexity of their molecular structures. Adamo et al. now present an apparatus roughly the size of a household refrigerator that can synthesize and purify pharmaceuticals under continuous-flow conditions (see the Perspective by Martin). The integrated set of modules can produce hundreds to thousands of accumulated doses in a day, delivered in aqueous solution. Science, this issue p. 61; see also p. 44 Preparation of four common pharmaceuticals shows the versatility of an integrated system the size of a household refrigerator. Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

Highly Enantio‐ and Diastereoselective Hetero‐Diels–Alder Reactions Catalyzed by New Chiral Tridentate Chromium(III) Catalysts

Even moderately nucleophilic dienes react with simple aldehydes in the presence of a new Cr(III) catalyst in a hetero-Diels-Alder reaction [Eq. (1)]. Tetrahydropyranyl products with up to three stereogenic centers are generated in near-perfect diastereoselectivities and with greater than 90 % ee (99 % ee for the example shown). TBAF=tetrabutylammonium fluoride; TBS=tert-butyldimethylsilyl; TES=triethylsilyl.

Visible‐Light Photoredox Catalysis in Flow

Photoredox catalysts have recently been utilized as powerful tools for synthetic chemists to exploit the energy gained by the absorption of low-energy light within the visible spectrum to initiate a variety of organic transformations.[1] The development of methods based on the single electron transfer properties of photoredox catalysts, particularly in the last several years, has represented a paradigm shift with respect to the way synthetic chemists consider both photochemistry and redox manipulations of organic molecules.[2-4]In addition, the advent of new technologies has enabled chemists to conduct reactions with greater efficiency than ever before. Among these new technologies is the development and wide implementation of flow reactors.[5-6] Conducting transformations in flow has many advantages compared to the more traditional batch reactions, in particular: more predictable reaction scale-up, decreased safety hazards, and improved reproducibility. In addition, for photochemical transformations, the high surface area to volume ratios typical of flow reactors allow for more efficient irradiation of a reaction mixture.[7] Due to this feature, we reasoned that a mesofluidic photochemical flow reactor would be amenable to our group’s ongoing study of visible light induced organic transformations mediated by photoredox catalysts (Figure 1).[8] Figure 1 Photoredox Catalysis in Flow: Enabling Increased Efficiency by Reactor Technology. Our group has studied the utilization of both the oxidative and reductive quenching cycles of photoredox catalysts to initiate synthetically useful manipulations of organic molecules such as intra- and intermolecular radical reactions,[8] formal C-H oxidations,[9] and the halogenation of alcohols.[10] During these studies, it was commonly observed that large scale reactions were often slower than those conducted on smaller scale.[11] As a consequence of the Beer-Lambert law, the penetration of visible light through a reaction medium decreases exponentially with increasing path length. We hypothesized that this may be one reason for the observed loss of reaction efficiency. To potentially circumvent this problem we sought to design a reactor having a considerably smaller path length through which the light must travel. In addition, a reactor having a greater surface area to volume ratio would result is an increased photon flux density, potentially accelerating the reaction.[12] Commercially available PFA (perfluoro alkoxy alkane) tubing having an internal diameter of 0.762 mm was identified as a viable choice due to its chemical resistance and optical transparency. Furthermore, a photoreactor of this size will allow for optimal absorbance at typical catalyst concentrations (~1.0 mM) For instance, the molar extinction coefficient of Ru(bpy)3Cl2 has been measured to be 13000 M−1cm−1,[13] as such the thickest portion of the tubing allows for the absorption of 90% of the incident radiation. Likewise, when carried out in batch reactors, 99% of the incident radiation is absorbed by the reaction medium residing within 1.5 mm of the reactor surface while the remaining internal volume receives little productive radiation.[14] In designing our reactor, we sought to make it as simple as possible without using specialized equipment in the hopes that a similar design could be readily implemented in other laboratories. Our optimized reactor involved wrapping 105 cm (corresponding to a 479 μL reactor volume) of PFA tubing in figure-eights around a pair of glass test tubes. We then utilized a peristaltic pump to pump the reaction mixture through the tubing with irradiation from a commercially available assembly of 7 blue LEDs.[15] Finally a silver mirrored Erlenmeyer flask was positioned above the reactor to reflect any incident light back onto the tubing. [16] Our initial experiments focused on the oxidative generation of iminium ions from N-aryl tetrahydroisoquinolines, utilizing reaction conditions similar to those we recently reported.[8c] Employing BrCCl3 as the terminal oxidant, we observed rapid formation of the iminium ion, 2, from the corresponding tetrahydroisoquinoline, 1. Optimization studies revealed that subjecting a solution of 1, BrCCl3, and Ru(bpy)3Cl2 (0.05 mol%) in DMF to irradiation in our newly designed flow photoreactor, required only a very short residence time (tR) for complete consumption of 1. In particular, pumping this mixture through the photoreactor at a rate corresponding to a tR of 0.5 min and collecting the mixture in a flask containing 5.0 equiv of a diverse set of nucleophiles allowed for the efficient and rapid generation of a variety of α-functionalized amines, in yields comparable to those observed in the batch reactions (Figure 2). As expected with the flow reactor, reaction scale up was trivial and allowed for the oxidative aza-Henry reaction of 1 with MeNO2 to be conducted on a 1.0 g scale with none of the issues observed for scaling up batch reactions. Furthermore, when conducted in batch, a reaction time of 3 h was required for complete oxidation of 1 on a 0.24 mmol scale. This corresponds to a material throughput of 0.081 mmol/h. However, utilizing the flow apparatus (with a reactor volume of 479 μL) enables a much higher rate of substrate conversion, 5.75 mmol/h. In addition, this rate can be increased by utilizing a photoreactor having a greater internal volume which would require only the use of a longer section of tubing. Figure 2 Oxidation of tetrahydroisoquinolines in flow. Having validated our hypothesis of increased reaction efficiency of photoredox mediated transformations performed in a photochemical flow setup, we examined a number of other reactions developed by our group. Firstly, a number of intramolecular radical cyclization reactions were evaluated, including: intramolecular heterocycle functionalization,[8b] hexenyl radical cyclization[8c] and a tandem radical cyclization/Cope rearrangement sequence (Figure 3).[8g] We were delighted to find that both radical cyclizations onto heteroaromatics and terminal olefins catalyzed by Ru(bpy)3Cl2 proceeded efficiently with short residence times, 1.0 min, affording the products in yields comparable to those observed in batch reactions. Notably, the intermolecular pyrrole functionalization, when preformed on large scale in batch (>2.0 g, 6.2 mmol), failed to afford complete conversion of starting material even after prolonged reaction time (>2 days). However, the use of the flow reactor could allow for the transformation of large quantities of substrate without the need to perform multiple smaller scale reactions to achieve the desired conversion. Figure 3 Intramolecular radical reactions in flow. Likewise, the Ir(ppy)2(dtbbpy)PF6 catalyzed radical cyclization/rearrangement afforded the product in good yield, but required a slightly longer residence time, tR = 3.0 min. Again, performing these reactions in flow afforded a much higher rate of material throughput when compared to the transformation conducted in batch. Notably, for the cyclization/rearrangement cascade catalyzed by Ir(ppy)2(dtbbpy)PF6, the batch reaction only afforded a substrate conversion rate of 0.048 mmol/h (cf. tR = 4.0 min corresponds to a material throughput of 0.96 mmol/h with our photoreactor). Intermolecular radical reactions are also feasible in this flow setup (Figure 4). It was found that intermolecular malonation of indoles, utilizing the triarylamine reductive quencher, 4-MeO-C6H4-NPh2, proceeded smoothly with a tR = 1.0 min.[8d] Furthermore, the bromopyrroloindoline coupling with 1-methyl-indole-2- carboxaldehyde, similar to the key transformation utilized in the recent synthesis of gliocladin C from our group, proceeded efficiently with a residence time of 4.0 min.[8f] This result is particularly promising since scale up of this reaction required prolonged reaction times, up to several days for a 10 g scale reaction.[17] Figure 4 Intermolecular radical reactions in flow. Finally, we applied this new reaction technology to our reported protocol for the intermolecular atom transfer radical addition (ATRA) utilizing the oxidative quenching pathway of the photocatalyst, Ir(dF(CF3)ppy)2(dtbbpy)PF6 (Figure 5).[8e] While requiring slightly longer residence times than those observed for the transformations utilizing the reductive quenching cycle of Ru and Ir based catalysts, this transformation proceeded efficiently and cleanly to give the corresponding ATRA products in good yields. Again, a greater rate of material throughput was observed using the flow reactor. On average, the ATRA of diethyl bromomalonate in batch allowed for the conversion of 0.200 mmol of alkene per hour. Figure 5 Intermolecular ATRA reactions in flow. In summary, we have designed a readily prepared and easily implemented photochemical flow reactor which enables the marked acceleration of a variety of transformations mediated by photoredox catalysis. The entire set up has a sufficiently small footprint to easily fit in a standard fume hood and can be assembled quickly and inexpensively. In all cases the reactor employed in this work has shown an increased efficiency in terms of material throughput for all the transformations studied. It is worth noting that even higher rates of substrate conversion (in terms of mmol of material per hour) is possible simply by employing a photoreactor with a greater internal volume. Further studies into applying this technology to a greater range of photoredox methods is underway.

Epoxide-Opening Cascades Promoted by Water

Selectivity rules in organic chemistry have been inferred largely from nonaqueous environments. In contrast, enzymes operate in water, and the chemical effect of the medium change remains only partially understood. Structural characterization of the “ladder” polyether marine natural products raised a puzzle that persisted for 20 years: Although the stereochemistry of adjacent tetrahydropyran (THP) cycles would seem to arise from a biosynthetic cascade of epoxide-opening reactions, experience in organic solvents argued consistently that such a pathway would be kinetically disfavored. We report that neutral water acts as an optimal promoter for the requisite ring-opening selectivity, once a single templating THP is appended to a chain of epoxides. This strategy offers a high-yielding route to the naturally occurring ladder core and highlights the likely importance of aqueous-medium effects in underpinning certain noteworthy enzymatic selectivities.

Epoxide-Opening Cascades in the Synthesis of Polycyclic Polyether Natural Products

The structural features of polycyclic polyether natural products can, in some cases, be traced to their biosynthetic origin. However in case that are less well understood, only biosynthetic pathways that feature dramatic, yet speculative, epoxide-opening cascades are proposed. We summarize how such epoxide-opening cascade reactions have been used in the synthesis of polycyclic polyethers (see scheme) and related natural products.The group of polycyclic polyether natural products is of special interest owing to the fascinating structure and biological effects displayed by its members. The latter includes potentially therapeutic antibiotic, antifungal, and anticancer properties, and extreme lethality. The polycyclic structural features of this class of compounds can, in some cases, be traced to their biosynthetic origin, but in others that are less well understood, only to proposed biosynthetic pathways that feature dramatic, yet speculative, epoxide-opening cascades. In this review we summarize how such epoxide-opening cascade reactions have been used in the synthesis of polycyclic polyethers and related natural products.

Safe and Efficient Tetrazole Synthesis in a Continuous‐Flow Microreactor

Tetrazoles are an important class of heterocycles in a wide range of applications, such as, organocatalysis and transition metal catalysis, propellants, explosives, and perhaps most commonly, as nonclassical isosteres of carboxylic acids in medicinal chemistry. This broad utility has prompted significant effort toward tetrazole synthesis, and notable among these is that of Sharpless, in which aqueous zinc bromide (ZnBr2) facilitates the assembly of tetrazoles from nitriles and sodium azide (NaN3). [3e] Nevertheless, the majority of reported methods are generally not suited for large scale synthesis; they require explosive and/or expensive reagents, toxic metal-containing compounds, or excess azide. The most significant hazard is the generation of hydrazoic acid (HN3), particularly in reactions conducted in the presence of even trace amounts of Brønsted acids. Continuous flow synthesis is emerging as a powerful technology complementary in several contexts to batch synthesis in flasks or vessel reactors. As only small quantities of reagents and products are exposed to the reaction conditions at a given time, the risks associated with hazardous materials are minimized, and transformations using them are thus rendered much safer. Flow would thus appear to be an appropriate reaction format for the synthesis of tetrazoles from nitriles and an azide source. During the preparation of this manuscript a collaborative effort between Kappe and Lonza reported an exquisitely engineered system for the continuous flow synthesis of tetrazoles using HN3. [6] Generated in situ from NaN3 and acetic acid, HN3 (approx. 2.5 equiv at 1.6 M) may be used at elevated temperatures and pressures to prepare a range of tetrazoles from the corresponding nitriles. Figure 1. (A) Photographs of flow reactor for tetrazole synthesis. See Supporting Information for parts list and instructions for assembly and operation (video). (B) Summary of the function of each reactor feature.

Nickel-catalyzed Heck-type reactions of benzyl chlorides and simple olefins.

Nickel-catalyzed intermolecular benzylation and heterobenzylation of unactivated alkenes to provide functionalized allylbenzene derivatives are described. A wide range of both the benzyl chloride and alkene coupling partners are tolerated. In contrast to analogous palladium-catalyzed variants of this process, all reactions described herein employ electronically unbiased aliphatic olefins (including ethylene), proceed at room temperature, and provide 1,1-disubstituted olefins over the more commonly observed 1,2-disubstituted olefins with very high selectivity.