Assessing Carbazole Derivatives as Single-Electron Photoreductants.

The electron-donating capabilities of carbazoles have stimulated interest in their use as photoinduced single-electron reductants. Due to the modularity of the carbazole, a further broadening and understanding of their reactivity could be achieved by manipulating the structure. Herein, eight carbazole derivatives were synthesized, characterized, and assessed as single-electron photoreductants in the hydrodehalogenation of aryl halides and the arylation of N-methylpyrrole.

Bench-Stable Nickel Precatalysts with Heck-type Activation.

Herein, we report the synthesis and characterization of a new class of air- and moisture-stable phosphine-containing nickel(II) precatalysts, which activate through a Heck-type mechanism. The activities of the precatalysts are demonstrated with a carbonyl-ene coupling reaction.

Bench-Stable N-Heterocyclic Carbene Nickel Precatalysts for C-C and C-N Bond-Forming Reactions.

Herein, we introduce a new class of bench-stable N-heterocyclic carbene (NHC) nickel-precatalysts for homogeneous nickel-catalysis. The nickel(II) complexes are readily activated to Ni0 in situ under mild conditions, via a proposed Heck-type mechanism. The precatalysts are shown to facilitate carbonyl-ene, hydroalkenylation, and amination reactions.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

Ylidenemalononitrile enamine-coated media as fluorescent "turn-on" probes for volatile primary amines.

Two ylidenemalononitrile enamines, adsorbed to various media, undergo a cyclization reaction with primary amine vapors resulting in a fluorometric and colorimetric response. After determining the media with the fastest response rate for emission "turn-on" to be aluminum oxide activated neutral (AON), we further demonstrate the sensitivity (propylamine concentrations as low as 200 ppm are detected) and selectivity to various analytes including amines, methanol, and ethanethiol. Lastly, as an alternative means of detection, the colorimetric response dye on glass filter paper was shown to detect propylamine concentrations as low as 29 ppm.

Synthesis and Reactivity Profile of Ylidenemalononitrile Enamines and Their Ester Analogs Towards Electrophiles and Nucleophiles.

Herein, we describe the synthesis and reactivity of enamines derived from ylidenemalononitriles and ylidenecyanoacetates. The enamine scope was expanded by (1) increasing yields of aldehyde-derived ylidenemalononitriles, (2) incorporating silyl functionalities, and (3) using other amide acetals to expand the substitution patterns of pyridines resulting from enamine cyclization. In addition, methods to produce α-pyrones and polysubstituted pyridines from both ylidenemalononitriles and ylidenecyanoacetates are described.

Ylidenemalononitrile enamines as fluorescent "turn-on" indicators for primary amines.

Ylidenemalononitrile enamines undergo rapid amine exchange followed by a cyclization with primary amines to yield fluorescent products with emission intensities as high as 900 times greater than the starting materials. After identifying the fluorescent species by X-ray crystallography, we demonstrate that the rate of amine exchange is substrate dependent and that by simple structural variation the fluorescence can be tuned over the entire visible spectrum. We further demonstrate their potential application in biomolecule labeling.

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine.

2-Chloro-3-amino-4-picoline (CAPIC) is a strategic building block for the preparation of nevirapine, a widely-prescribed non-nucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo derivative of a CAPIC intermediate, 2-bromo-4-methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as well as other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process.

Improved synthesis of mono- and disubstituted 2-halonicotinonitriles from alkylidene malononitriles.

Pyridines with 2,3,4 and/or 5 substitution remain challenging to prepare. Existing strategies to form multisubstituted 2-halonicotinonitriles via enamines suffer from dimerization of the starting alkylidene malononitriles resulting in low yields. Through alteration of reaction conditions, a new high yielding method into enamines was realized by condensing DMF-DMA and alkylidene malononitriles in the presence of substoichiometric acetic anhydride. Cyclization of the resulting enamines under Pinner conditions provided 2-halonicotinonitriles in high overall yields.

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.

Continuous proline catalysis via leaching of solid proline.

Herein, we demonstrate that a homogeneous catalyst can be prepared continuously via reaction with a packed-bed of a catalyst precursor. Specifically, we perform continuous proline catalyzed α-aminoxylations using a packed-bed of L-proline. The system relies on a multistep sequence in which an aldehyde and thiourea additive are passed through a column of solid proline, presumably forming a soluble oxazolidinone intermediate. This transports a catalytic amount of proline from the packed-bed into the reactor coil for subsequent combination with a solution of nitrosobenzene, affording the desired optically active α-aminooxy alcohol after reduction. To our knowledge, this is the first example in which a homogeneous catalyst is produced continuously using a packed-bed. We predict that the method will not only be useful for other L-proline catalyzed reactions, but we also foresee that it could be used to produce other catalytic species in flow.