Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 769 [11C]Carbon Monoxide in Palladium- / Selenium-Promoted Carbonylation Reactions Synthesis of 11C-Imides, Hydrazides, Amides, Carboxylic Acids, Carboxylic Esters, Carbothioates, Ketones and Carbamoyl Compounds BY FARHAD KARIMI ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2002 Dissertation for the Degree of Doctor of Philosophy in Organic Chemistry at Uppsala University in 2002. ABSTRACT Karimi, F., 2002. [11C]Carbon Monoxide in Palladium- / Selenium-Promoted Carbonylation Reactions. Synthesis of 11C-imides, hydrazides, amides, carboxylic acids, carboxylic esters, carbothioates, ketones and carbamoyl compounds. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 769. 43 pp. Uppsala. ISBN 91-554-5452-6. [11C]Carbon monoxide in low concentrations has been used in palladium- or selenium- mediated carbonylation reactions such as the synthesis of 11C-imides, hydrazides, amides, carboxylic acids, esters, carbothioates, ketones and carbamoyl compounds. In these reactions aryl iodides have been used in most cases. However, less reactive aryl triflate, chloride and bromides were activated using tetrabutylammonium iodide. The reactivities of nucleophiles may have influence on the radiochemical yield of the 11C- labelled compounds. Carboxyamination of aryl halides using aniline derivatives yielded 10% of the corresponding 11C-amide. However, the radiochemical yields increased significantly when the aniline derivatives were treated with lithium bis(trimethylsilyl)amide. In contrast, this reagent did not improve the radiochemical yields when primary amines such as methylamine and benzylamine were used. In these cases the radiochemical yields were improved by using pempidine. 11C-Esterification usually gave low yields. However, the radiochemical yields of 11C-esters could be improved by using magnesium bromide and pempidine. An excess of ligand may have a significant impact on palladium-promoted carbonylation reaction. The radiochemical yields of 11C-ketones were improved when using excess amounts of tri-o-tolylphosphine. (13C)Carbon monoxide may be utilized for the synthesis of 13C-substituated compounds in order to confirm the position of 11C-labelling. Farhad Karimi, Department of Organic Chemistry, Institute of Chemistry, Uppsala University, P.O. Box 531, SE-725 21 Uppsala, Sweden. © Farhad Karimi 2002 ISSN 1104-232X ISBN 91-554-5452-6 Printed in Sweden by Kopieringshuset, Uppsala 2002. To my parents, my sister, my wife & my daughter Papers included in the thesis This thesis is based on the following papers, referred to by their Roman numerals I-X. I. [11C] / (13C)Carbon monoxide in palladium-mediated synthesis of imides. Karimi F., Kihlberg T., Långström B., J. Chem. Soc. Perkin Trans. 1, 2001, 1528-1531. II. Palladium-mediated synthesis of [carbonyl-11C]amides and hydrazides using [11C]carbon monoxide. Karimi F., Långström B., J. Chem. Soc. Perkin Trans. 1, 2002, 2111-2116. III. Synthesis of 11C-amides using [11C]carbon monoxide and in situ activated amines by palladium-mediated carboxaminations. Karimi F., Långström B., J. Chem. Soc. Perkin Trans. 1, 2002, in press. IV. Synthesis of 11 C-amides using [11C]carbon monoxide and in situ activated amines with 1,2,2,6,6-pentamethylpiperidine in palladium-mediated carboxamination. Karimi F., Långström B., submitted. V. Palladium-mediated carboxylation of aryl halides (triflates) or benzyl halides using (13C) / [11C]carbon monoxide with tetrabutylammonium hydroxide or trimethyl- phenylammonium hydroxide. Karimi F., Långström B., J. Chem. Soc. Perkin Trans. 1, 2002, 2256-2259. VI. The synthesis of [carbonyl-11C]esters using [11C]carbon monoxide in palladium- mediated reactions. Karimi F., Långström B., manuscript. VII. Appendix: Supplementary material for the synthesis of 11C-carbothioates. VIII. Palladium-mediated 11C-carbonylative cross coupling of aryl halides with organo- stannanes. An efficient synthesis of alkyl / aryl [carbonyl-11C]ketones. Karimi F., Långström B., manuscript. IX. Synthesis of 3-[(2S)-azetidin-2-ylmethoxy]-5-[11C]-methylpyridine, an analogue of A- 85380, via a Stille coupling. Karimi F., Långström B., J. Label. Compd. Radiopharm. 2002, 45, 1-12. X. [11C]Carbon monoxide in selenium-mediated synthesis of 11C-carbamoyl compounds. Kihlberg T., Karimi F., Långström B., J. Org. Chem., 2002, 67, 3687-3692. Reprints were made with permission from the publishers. Contribution report Paper I: The experimental work and writing was shared with T. Kihlberg. Paper X: The author performed the syntheses of precursors and reference compounds, the labelling of compounds 5, 6, 7, 9 and 14, NMR and MS analyses, the determination of specific radioactivity and wrote part of the experimental section. Contents ABSTRACT PAPERS INCLUDED ABBREVIATIONS 1. Introduction ............................................................................................................................7 1.1. Radionuclides..................................................................................................................7 1.2. Specific radioactivity ......................................................................................................8 1.3. Purification, analysis and identification..........................................................................9 2. Labelled precursors...............................................................................................................11 2.1. Production of [11C]carbon monoxide............................................................................11 3. Substrates used in carbonylation reactions...........................................................................12 3.1. Carbon monoxide..........................................................................................................12 3.2. Palladium ......................................................................................................................13 3.2.1. β-Hydride elimination.........................................................................................15 3.3. Selenium .......................................................................................................................16 3.4. Nucleophiles .................................................................................................................17 4. [11C]Carbon monoxide in palladium-mediated carbonylation reactions..............................18 4.1. 11C-Imides (Paper I)...........................................................................................................18 4.2. 11C-Primary amides and 11C-hydrazides (Paper II)............................................................19 4.3. 11C-Amides(Paper III, IV) ....................................................................................................21 4.4. 11C-Carboxylic acids (Paper V)..........................................................................................30 4.5. 11C-Carboxylic esters (Paper VI) ........................................................................................33 4.6. 11C-Carbothioate (Paper VII) ..............................................................................................34 4.7. 11C-Ketones (Paper VIII) .....................................................................................................35 5. [11C]Carbon monoxide in selenium-mediated carbonylation reactions ...............................37 5.1. 11C-Carbamoyl compounds (Paper X) ...............................................................................37 6. The impact of tetrabutylammonium iodide on 11C-carbonylation reactions ........................38 7. Conclusion............................................................................................................................40 8. Acknowledgments ................................................................................................................41 9. References ............................................................................................................................42 The synthesis of [carbonyl-11C]esters using [11C]carbon monoxide in palladium-mediated reactions………………………………………………………………….………………….....A Appendix: Supplementary material for the synthesis of [carbonyl-11C]carbothioates…….….F Palladium-mediated 11C-carbonylative cross coupling of aryl halides with organostannanes. An efficient synthesis of alkyl / aryl [carbonyl-11C]ketones……………………………….….G ABBREVIATIONS # 13C * 11C AsPh3 Triphenylarsine Bq Becquerel (decay per second) BuLi Butyl lithium CO Carbon monoxide DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine DMAP N,N-Dimethylpyridine-4-amine DMSO Dimethylsulfoxide GBq Giga Bequerel HPLC High Performance Liquid Chromatography L Ligand LC-MS Liquid Chromatography - Mass Spectroscopy LiM Lithium bis(trimethylsilyl)amide NMR Nuclear Magnetic Resonance OTf Trifluoromethanesulfonate P(o-tol)3 Tri-o-tolylphosphine Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) Pd2(dba)3 Tris(dibenzylideneacetone)palladium(0) PET Positron Emission Tomography PMP 1,2,2,6,6-Pentamethylpiperidine, Pempidine PQOH Trimethylphenylammonium hydroxide QI Tetrabutylammonium iodide QOH Tetramethylammonium hydroxide RCY Decay-corrected isolated radiochemical yield t½ Physical half-life of radionuclide TE Trapping efficiency. The value indicates the amount of incorporated [11C]carbon in the crude product. (Decay-corrected,