Mitra Matloobi and C. Oliver Kappe* Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria Advances in Microwave-Assisted Organic Synthesis, August 26-27 2006, Budapest, Hungary email: mitra.matloobi@uni-graz.at website: http://www.maos.net Retrosynthetic Analysis o Introduction n p Displacement of the Sulfonyl Group with Nucleophiles q High Diversity Analogues (40 examples) The 2-aminopyrimidine structural subunit is contained in a growing number of both natural products and synthetic compounds with interesting biological properties [1]. Of particular interest are derivatives possessing an aryl ring at the C4 position and an electron-withdrawing substituent such as an ester or amide group at C5 [2]. Herein we describe the rapid and efficient synthesis of 2-amino-4-arylpyrimidines by taking advantage of the high diversity initially generated on the pyrimidine core through a Biginelli multicomponent (MCR) approach using thiourea as starting material N N N OH OH OOC F Me SO 2 Me Rosuvastatin (Ca-salt) N N N H N Me HN O N N Me Gleevec _ 1] Review: Lagoja, I. M. Chem. Biodiversity 2005, 2, 1. [2] (a) Sehon, C. A.; Lee, D.; Goodman, K. B.; Wang, G. Z.; Viet, A. Q. PCT Int. Appl. WO 2006009889, 2006; Chem. Abstr. 2006, 144, 150383. (b) Drewry, D. H.; Evans, B.; Goodman, K. B.; Green, D. V. S.; Jung, D. K.; Lee, D.; Stavenger, R. A.; Wad, S. N. PCT Int. Appl. WO 2004112719, 2004; Chem. Abstr. 2004, 142, 93847. The rapid and efficient synthesis of 2-amino-4-arylpyrimidines of type A is accomplished by taking advantage of the high diversity initially generated on the pyrimidine core using a Biginelli MCR. Our method allows for considerable diversity in all building blocks. Ar O H O R 2 O R 1 NH 2 H 2 N S + N H NH R 2 O R 1 Ar S Biginelli MCR N N R 2 O R 1 Ar S Me O O 1. S-Methylation 2. Aromatization 3. Sulfide Oxidation N N R 2 O R 1 Ar Nu NuH A [3] For related approaches, see (a) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K. Bioorg. Med. Chem. 1997, 5, 437. (b) Vanden Eynde, J. J.; Labuche, N.; Van Haverbeke, Y. ; Tietze, L. ARKIVOC 2003, (xv), 22. Synthesis of 2-Sulfonylpyrimidine Precursors The pyrimidine sulfone precursors of type B were synthesized via a rapid four step, all microwave synthetic sequence from readily available building blocks and inexpensive alkylation and oxidation reagents. O Me O EtO Ph O H NH 2 H 2 N S N H NH Me O EtO Ph S (87%) N H N Me O EtO Ph SMe (92%) N N Me O EtO Ph SMe (82%) N N Me O EtO Ph S Me O O B (92%) + TMSCl MeCN, DMF MW, 120 °C, 10 min 1. MeI, MeCN MW, 100 °C, 5 min 2. NaOH (1M) MnO 2 , DCM MW, 100 °C, 10 min Oxone, H 2 O, MeOH MW, 100 °C, 20 min The 2-methylsulfone group on pyrimidine B can be displaced with a variety of different nitrogen, oxygen, sulfur and carbon nucleophiles, by applying microwave irradiation in sealed vessels and, in most cases provides excellent yields of the anticipated 2-functionalized pyrimidines 1-14 in very short reaction times. N N Me O EtO Ph S Me O O B N N Me O EtO Ph Nu 1-14 nucleophile, solvent/base MW, 70-230 °C, 10-50 min 85 10 70 MeCN/Cs2CO3 malonodintrile 14 82 30 140 THF/K2CO3 p-thiocresol 13 83 15 70 MeCN/Cs2CO3 phenol 12 45 10 140 THF/ K2CO3 N-methyl-methanesulfonamide 11 73 50 230 dioxane p-anisidine 10 67 50 230 dioxane aniline 9 81 20 200 DMF dimethylaminec 8 82 15 100 DMSO ammoniab 7 80 10 140 THF 2-methoxyphenethylamine 6 45 10 140 THF 4-fluorophenethylamine 5 73 10 140 THF benzylamine 4 74 10 140 THF ethanolamine 3 68 10 140 THF piperidine 2 72 10 140 THF pyrrolidine 1 yield (%)a time (min) temp (°C) solvent/base nucleophile Comp. r Solid-Phase Synthesis of 2-Aminopyrimidines s In addition to the solution phase protocol outlined above, we also considered a microwave-assisted solid-phase method in order to be able to prepare large compound libraries using combinatorial principles in a high-speed format. Reaction conditions: Single-mode sealed vessel microwave irradiation. a Isolated yields of pure products after chromatography. b Ammonium acetate as substitute for NH3. c Dimethylamine was generated in situ by dec. of DMF. N H NH Me O EtO Ph S Cl N N Me O EtO Ph S N N Me O EtO Ph S O O N H N Me O EtO Ph S N N Me O EtO Ph N CAN, H 2 O, DCM MW, 130 °C, 30 min (or 25 °C, 10 h) + DMF, K 2 CO 3 MW, 160 °C, 30 min (or 60 °C, 20 h) Oxone, H 2 O, DMF MW, 150 °C, 45 min (or 25 °C, 16 h) piperidine , EtOH MW, 100 °C, 10 min Conclusion  Readily available 2-methylsulfonyl-pyrimidines derived via Biginelli multicomponent strategies are excellent precursors for the generation of a variety 2-substituted pyrimidines.  A variety of 2-substituted pyrimidines were synthesized via displacement of the reactive sulfonyl group with different nitrogen, oxygen, sulfur and carbon nucleophiles.  The use of high temperature sealed vessel microwave irradiation allows the preparation of the desired target structures in high yields and comparatively short reaction times.  All synthetic steps required for the synthesis of the target structures were carried out under microwave irradiation, both in solution phase and on solid phase. Acknowledgement. This work was supported by the Austrian Science Fund. M. M. thanks the University of Graz for a Gandolph Doelter Scholarship. We thank also Biotage AB (Uppsala, Sweden) for the use of the Emrys Synthesizer and Initiator Eight. Microwave-Assisted Solution- and Solid-Phase Synthesis of 2-Amino-4-arylpyrimidine Derivatives N N O O N Cl N N O O N H O N N O O N H N N O O S N N O O O N N O O CN CN N N O O N Me N N O N N F Selected examples: