Title: Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates
Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C–C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C–H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.
Zhang, Xuan; Nottingham, Kyle G.; Patel, Chirag; Alegre-Requena, Juan V.; Levy, Jeffrey N.; Paton, Robert S.; McNally, Andrew(
, Nature)
null
(Ed.)
Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence virtually all metrics associated with their pharmacokinetic and pharmacodynamic profiles. Drug candidates increasingly contain CF3 and CF2H groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect, and plant life. New fluoroalkylation reactions have undoubtedly stimulated this uptake; however, methods that directly convert C–H bonds into C–CF2X (X = F or H) groups in complex drug-like molecules are rare. For pyridine, the most common aromatic heterocycle in pharmaceuticals, only one approach, via fluoroalkyl radicals, is viable for pyridyl C–H fluoroalkylation in the elaborate structures encountered during drug development. Here, we have developed a set of bench-stable fluoroalkylphosphines that directly convert the C–H bonds in pyridine building blocks, drug-like fragments, and pharmaceuticals into fluoroalkyl derivatives. No pre-installed functional groups or directing groups are required; the reaction tolerates a variety of sterically and electronically distinct pyridines and is exclusively selective for the 4-position in most cases. The reaction proceeds via initial phosphonium salt formation followed by sp2-sp3 phosphorus ligand-coupling, an underdeveloped manifold for C–C bond formation.
Metal-mediated cross-coupling reactions offer organic chemists a wide array of stereo- and chemically-selective reactions with broad applications in fine chemical and pharmaceutical synthesis.1 Current batch-based synthesis methods are beginning to be replaced with flow chemistry strategies to take advantage of the improved consistency and process control methods offered by continuous flow systems.2,3 Most cross-coupling chemistries still encounter several issues in flow using homogeneous catalysis, including expensive catalyst recovery and air sensitivity due to the chemical nature of the catalyst ligands.1 To mitigate some of these issues, a ligand-free heterogeneous catalysis reaction was developed using palladium (Pd) loaded into a polymeric network of a silicone elastomer, poly(hydromethylsiloxane) (PHMS), that is not air sensitive and can be used with mild reaction solvents (ethanol and water).4
In this work we present a novel method of producing soft catalytic microparticles using a multiphase flow-focusing microreactor and demonstrate their application for continuous Suzuki-Miyaura cross-coupling reactions. The catalytic microparticles are produced in a coaxial glass capillary-based 3D flow-focusing microreactor. The microreactor consists of two precursors, a cross-linking catalyst in toluene and a mixture of the PHMS polymer and a divinyl cross-linker. The dispersed phase containing the polymer, cross-linker, and cross-linking catalyst is continuously mixed and then formed into microdroplets by the continuous phase of water and surfactant (sodium dodecyl sulfate) introduced in a counter-flow configuration. Elastomeric microdroplets with a diameter ranging between 50 to 300 micron are produced at 25 to 250 Hz with a size polydispersity less than 3% in single stream production. The physicochemical properties of the elastomeric microparticles such as particle swelling/softness can be tuned using the ratio of cross-linker to polymer as well as the ratio of polymer mixture to solvent during the particle formation. Swelling in toluene can be tuned up to 400% of the initial particle volume by reducing the concentration of cross-linker in the mixture and increasing the ratio of polymer to solvent during production.5
After the particles are produced and collected, they are transferred into toluene containing palladium acetate, allowing the particles to incorporate the palladium into the polymer network and then reduce the palladium to Pd0 with the Si-H functionality present on the PHMS backbones. After the reduction, the Pd-loaded particles can be washed and dried for storage or switched into an ethanol/water solution for loading into a micro-packed bed reactor (µ-PBR) for continuous organic synthesis. The in-situ reduction of Pd within the PHMS microparticles was confirmed using energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS) and focused ion beam-SEM, and TEM techniques.
In the next step, we used the developed µ-PBR to conduct continuous organic synthesis of 4-phenyltoluene by Suzuki-Miyaura cross-coupling of 4-iodotoluene and phenylboronic acid using potassium carbonate as the base. Catalyst leaching was determined to only occur at sub ppm concentrations even at high solvent flow rates after 24 h of continuous run using inductively coupled plasma mass spectrometry (ICP-MS).
The developed µ-PBR using the elastomeric microparticles is an important initial step towards the development of highly-efficient and green continuous manufacturing technologies in the pharma industry. In addition, the developed elastomeric microparticle synthesis technique can be utilized for the development of a library of other chemically cross-linkable polymer/cross-linker pairs for applications in organic synthesis, targeted drug delivery, cell encapsulation, or biomedical imaging.
References
1. Ruiz-Castillo P, Buchwald SL. Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem Rev. 2016;116(19):12564-12649.
2. Adamo A, Beingessner RL, Behnam M, et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science. 2016;352(6281):61 LP-67.
3. Jensen KF. Flow Chemistry — Microreaction Technology Comes of Age. 2017;63(3).
4. Stibingerova I, Voltrova S, Kocova S, Lindale M, Srogl J. Modular Approach to Heterogenous Catalysis. Manipulation of Cross-Coupling Catalyst Activity. Org Lett. 2016;18(2):312-315.
5. Bennett JA, Kristof AJ, Vasudevan V, Genzer J, Srogl J, Abolhasani M. Microfluidic synthesis of elastomeric microparticles: A case study in catalysis of palladium-mediated cross-coupling. AIChE J. 2018;0(0):1-10.
Wang, Fei; Stahl, Shannon S.(
, Angewandte Chemie International Edition)
Abstract
Direct amination of C(sp3)−H bonds is of broad interest in the realm of C−H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp3)−H/N−H coupling that exhibits good reactivity with both sp2and sp3N−H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N−I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C−H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.
Direct amination of C(sp3)−H bonds is of broad interest in the realm of C−H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp3)−H/N−H coupling that exhibits good reactivity with both sp2and sp3N−H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N−I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C−H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.
Direct preparation of alkylated amide‐derivatives by cross‐coupling chemistry using sustainable protocols is challenging due to sensitivity of the amide functional group to reaction conditions. Herein, we report the synthesis of alkyl‐substituted amides by iron‐catalyzed C(sp2)−C(sp3) cross‐coupling of Grignard reagents with aryl chlorides. The products of these reactions are broadly used in the synthesis of pharmaceuticals, agrochemicals and other biologically‐active molecules. Furthermore, amides are used as versatile intermediates that can participate in the synthesis of valuable ketones and amines, providing access to motifs of broad synthetic interest. The reaction is characterized by its good substrate scope, tolerating a range of amide substitution, including sterically‐bulky, sensitive and readily modifiable amides. The reaction is compatible with challenging organometallics possessing β‐hydrogens, and proceeds under very mild, operationally‐simple conditions. Optimization of the catalyst system demonstrated the beneficial effect of O‐coordinating ligands on the cross‐coupling. The reaction was found to be fully chemoselective for the mono‐substitution at the less sterically‐hindered position. Mechanistic studies establish the order of reactivity and provide insight into the role of amide to control mono‐selectivity of the alkylation. The protocol provides the possibility for convenient access to alkyl‐amide structural building blocks using sustainable cross‐coupling conditions with high efficiency.
Hilton, Michael C., Zhang, Xuan, Boyle, Benjamin T., Alegre-Requena, Juan V., Paton, Robert S., and McNally, Andrew. Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates. Science 362.6416 Web. doi:10.1126/science.aas8961.
Hilton, Michael C., Zhang, Xuan, Boyle, Benjamin T., Alegre-Requena, Juan V., Paton, Robert S., & McNally, Andrew. Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates. Science, 362 (6416). https://doi.org/10.1126/science.aas8961
Hilton, Michael C., Zhang, Xuan, Boyle, Benjamin T., Alegre-Requena, Juan V., Paton, Robert S., and McNally, Andrew.
"Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates". Science 362 (6416). Japan: American Association for the Advancement of Science (AAAS). https://doi.org/10.1126/science.aas8961.https://par.nsf.gov/biblio/10079630.
@article{osti_10079630,
place = {Japan},
title = {Heterobiaryl synthesis by contractive C–C coupling via P(V) intermediates},
url = {https://par.nsf.gov/biblio/10079630},
DOI = {10.1126/science.aas8961},
abstractNote = {Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C–C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C–H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.},
journal = {Science},
volume = {362},
number = {6416},
publisher = {American Association for the Advancement of Science (AAAS)},
author = {Hilton, Michael C. and Zhang, Xuan and Boyle, Benjamin T. and Alegre-Requena, Juan V. and Paton, Robert S. and McNally, Andrew},
}
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