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Homolytic Aromatic Substitution, Conformational Dynamics Of Homolytic Aromatic Substitution, Conformational Dynamics of Dihydrophenanthridines, and High-Throughput Synthesis of Amides with Fluorous Technology: Methodologies in Reaction, Analysis, and Separation by Adam I. Keller B.S. Chemistry, The Ohio State University, 2002 Submitted to the Graduate Faculty of The University of Pittsburgh in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2007 UNIVERSITY OF PITTSBURGH COLLEGE OF ARTS AND SCIENCES This dissertation was presented by Adam I. Keller It was defended on March 2nd, 2007 and approved by Craig Wilcox, Professor, Chemistry Paul Floreancig, Associate Professor, Chemistry Billy Day, Professor, Pharmacuetical Science Dissertation Advisor: Dennis P. Curran, Professor, Chemistry ii Copyright © by Adam I. Keller 2007 iii Homolytic Aromatic Substitution, Conformational Dynamics of Dihydrophenanthridines, and High-Throughput Synthesis of Amides with Fluorous Technology: Methodologies in Reaction, Analysis, and Separation Adam I. Keller, PhD University of Pittsburgh, 2006 Homolytic aromatic substitution encompa sses a wide range of synthetic transformations based on inter- and intramolecular additions of radicals to arenes. Additions of radicals derived from aryl iodides to arenes are promoted by tris(trimethylsilyl)silane and occur under exceptionally mild conditions in non-degassed benzene. Experimental observations led to a proposed mechanism involving reaction of the intermediate cyclohexadienyl radical with dioxygen to generate the aromatic product and the hydroperoxy radical. This methodology was extended to the synthesis of biaryl and heterocyclic compounds. N-Acetyldihydrophenanthridines exhibit remarkable conformational dynamics that are observable on the NMR timescale. Semiempirical calculations were performed to understand their conformational preferences. The predictions derived from the calculated structures were verified by x-ray crystallography, two-dimensional exchange and variable temperature NMR spectroscopy. The rate constants for conformational switching were calculated by a matrix- based routine with data extracted from the two-dimensional exchange spectra. A fluorous equivalent of diisopropylcarbodiimide (FDIC) was synthesized to overcome the separation problems encountered when conducting solution-phase, carbodiimide mediated acyl couplings. The reactivity of the fluorous analog was not greatly affected by the presence of a fluorous domain, and was equally as effective as diisopropylcarbodiimide in facilitating amide bond formation. Coupled with a reverse F-SPE strategy, FDIC mediated couplings were conducted to provide the target amides in high-purities (95-99%). A small library of amides was prepared in a high-throughput fashion to demonstrate the utility of this approach. iv TABLE OF CONTENTS LIST OF ABBREVIATIONS ............................................................................................. XIV 1.0 HOMOLYTIC AROMATIC SUBSTITUTION IN ORGANIC SYNTHESIS ............1 1.1 Biaryl synthesis ............................................................................................................. 1 1.2 Heterocycle syntheses.................................................................................................... 3 1.3 The mechanism of HAS and the role of AIBN............................................................... 4 1.4 Other fates of cyclohexadienyl radicals.......................................................................... 8 1.5 Tris(trimethylsilyl)silane (TTMSS) as an alternative to Bu3SnH.................................... 9 2.0 INVESTIGATION INTO THE USE OF OXIDANTS IN HOMOLYTIC AROMATIC SUBSTITUTION.....................................................................................................................12 2.1 Aim of project ..............................................................................................................12 2.2 Reaction of an Aryl Halide with Bu3SnH/AIBN in Benzene – Control Experiments .....12 2.3 Diazo Compound Screening .........................................................................................16 2.4 Use of other oxidants....................................................................................................19 2.5 Experimentation with TTMSS......................................................................................24 2.6 Utility of TTMSS without AIBN or TEMPO................................................................26 2.7 The importance of dioxygen .........................................................................................30 2.8 Application of TTMSS/pyridine protocol to intramolecular HAS..................................31 2.9 Proposed role of oxygen ...............................................................................................34 2.10 29Si NMR experiments: attempts to identify silicon containing byproducts .................36 2.11 Summary....................................................................................................................39 v 2.12 Experimental ..............................................................................................................40 3.0 APPLICATION OF NMR TO THE STUDY OF CONFORMATIONAL DYNAMICS ............................................................................................................................49 3.1 Introduction..................................................................................................................49 3.2 Two dimensional exchange spectroscopy (2D EXSY) ..................................................49 3.3 Choosing an appropriate mixing time ...........................................................................51 3.4 Example of 2D EXSY applied to the study of conformational exchange .......................52 4.0 INVESTIGATION OF THE CONFORMATIONAL DYNAMICS OF ORTHO- SUBSTITUTED N-ACYL-DIHYDROPHENANTHRIDINES.............................................55 4.1 Aim of project ..............................................................................................................55 4.2 Molecular modeling of silylated benzazapine 60...........................................................56 4.3 Crystal structure of silylated dihydrophenanthridine 60 ................................................58 4.4 2D EXSY NMR of silylated hydrophenanthridine 60 ...................................................61 4.5 1H NMR of dihydrophenanthridine 60 at elevated temperatures....................................66 4.6 Conformational dynamics of hydrophenanthridine 59...................................................68 4.7 Attempted synthesis of N-alkyl analogs ........................................................................74 4.8 HPLC experiments .......................................................................................................76 4.9 Summary......................................................................................................................77 4.10 Experimental ..............................................................................................................78 5.0 APPLICATION OF FLUOROUS TECHNOLOGY TO AMIDE BOND SYNTHESIS 81 5.1 Introduction..................................................................................................................81 5.1.1 Carbodiimide-mediated amide bond synthesis ...............................................81 5.1.2 Light-fluorous reagents..................................................................................83 5.2 Discovery and synthesis of a fluorinated carbodiimide..................................................84 5.3 Model studies with FDIC..............................................................................................87 vi 5.4 Optimization of a high-throughput purification strategy................................................90 5.5 FDIC-mediated synthesis of a small amide library........................................................93 5.6 Conclusion ...................................................................................................................97 5.7 Experimental ................................................................................................................98 APPENDIX A........................................................................................................................107 APPENDIX B ........................................................................................................................115 APPENDIX C........................................................................................................................125 BIBLIOGRAPHY .................................................................................................................156 vii LIST OF TABLES Table 1. Selected examples and yields of aryl radical addition to benzene ..................................2 Table 2. Radical addition of halobenzoates 35 to benzene ........................................................13 Table 3. Model reaction in the presence of diazo compounds 40a-e..........................................17 Table 4. Model reaction in the presence of TEMPO of Galvinoxyl...........................................21 Table 5. Preliminary experiments with TTMSS........................................................................26 Table 6. HAS of benzene with iodobenzene analogs 47a-e in the presence of TTMSS and pyridine.....................................................................................................................................28
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