Automated library synthesis of cyclopropyl boronic esters employing diazomethane in a tube-in-tube flow reactor.

The efficient synthesis of cyclopropyl boronic esters in library format using a diazomethane flow reactor has been achieved. A pivotal component of the system is a fully automated tube-in-tube reactor allowing for safe handling of hazardous diazomethane on repeated small scale and for the generation of larger quantities of product. The setup enables the repeated execution of Pd-catalyzed cyclopropanation reactions without compromising its operation over time.

[1]  M. Doyle.  Catalytic methods for metal carbene transformations , 1987 .

[2]  L. Mannina,et al.  Stereocontrolled synthesis of carbon–carbon double bond locked analogues of strobilurins which are characterized by a trans-1,2-disubstituted cyclopropane ring , 2001 .

[3]  Nicholas A. McGrath,et al.  A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives , 2010 .

[4]  A. Charette,et al.  Stereoselective cyclopropanation reactions. , 2003, Chemical reviews.

[5]  M. Baird,et al.  Biologically Active Cyclopropanes and Cyclopropenes , 1995, Current Medicinal Chemistry.

[6]  T. Poulos,et al.  Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase. , 2013, Bioorganic & medicinal chemistry.

[7]  Steven V Ley,et al.  Flow chemistry: intelligent processing of gas-liquid transformations using a tube-in-tube reactor. , 2015, Accounts of chemical research.

[8]  M. Fraaije,et al.  Exploiting the enantioselectivity of Baeyer-Villiger monooxygenases via boron oxidation , 2012 .

[9]  Jeffrey Y. Pan,et al.  An Integrated Synthesis-Purification System to Accelerate the Generation of Compounds in Pharmaceutical Discovery , 2011 .

[10]  Erick M Carreira,et al.  Iron-Catalyzed Cyclopropanation in 6 M KOH with in Situ Generation of Diazomethane , 2012, Science.

[11]  Shaodong Zhou,et al.  Efficient Suzuki-Type Cross-Coupling of Enantiomerically Pure Cyclopropylboronic Acids. , 1998, Angewandte Chemie.

[12]  M. Lautens,et al.  Transition Metal-Mediated Cycloaddition Reactions. , 1996, Chemical reviews.

[13]  Steven V. Ley,et al.  Flow ozonolysis using a semipermeable Teflon AF-2400 membrane to effect gas-liquid contact. , 2010, Organic letters.

[14]  Steven V Ley,et al.  The continuous-flow synthesis of carboxylic acids using CO2 in a tube-in-tube gas permeable membrane reactor. , 2011, Angewandte Chemie.

[15]  C. Oliver Kappe,et al.  Continuous flow generation and reactions of anhydrous diazomethane using a Teflon AF-2400 tube-in-tube reactor. , 2013, Organic letters.

[16]  P. Poechlauer,et al.  One-Pot Synthesis of α-Haloketones Employing a Membrane-Based Semibatch Diazomethane Generator , 2016, Journal of Flow Chemistry.

[17]  Jeffrey Y. Pan,et al.  An Automated Synthesis–Purification–Sample-Management Platform for the Accelerated Generation of Pharmaceutical Candidates , 2014, Journal of laboratory automation.

[18]  T. Root,et al.  PTFE-Membrane Flow Reactor for Aerobic Oxidation Reactions and Its Application to Alcohol Oxidation , 2015 .

[19]  N. Meanwell.  Synopsis of some recent tactical application of bioisosteres in drug design. , 2011, Journal of medicinal chemistry.

[20]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[21]  A. Bogdan,et al.  A high-throughput synthesis of 1,2,4-oxadiazole and 1,2,4-triazole libraries in a continuous flow reactor , 2015 .

[22]  Jeremy L. Steinbacher,et al.  Simplified Mesofluidic Systems for the Formation of Micron to Millimeter Droplets and the Synthesis of Materials , 2012, Journal of Flow Chemistry.

[23]  S. Marsden,et al.  A Novel, Stereocontrolled Synthesis of 1,2-trans-Cyclopropanes: Cyclopropyl Boronate Esters as Partners in Suzuki Couplings with Aryl Halides , 1996 .

[24]  O. Illa,et al.  Cyclopropanation of Cyclohexenone by Diazomethane Catalyzed by Palladium Diacetate: Evidence for the Formation of Palladium(0) Nanoparticles , 2007 .

[25]  L. Mario Amzel,et al.  Impact of linker strain and flexibility in the design of a fragment-based inhibitor , 2009, Nature chemical biology.

[26]  David C. Forbes,et al.  Recent Advances in Asymmetric Catalytic Metal Carbene Transformations. , 1998, Chemical reviews.