Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones

Dedicated to Professor Emeritus Volker Jäger, Institut für Organische Chemie, Universität Stuttgart, on the occasion of his 70th birthday.

Abstract

A series of tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 3a–h as the first representatives of the so far unexplored saturated heterocyclic system have been synthesized, formally in 12 steps from methyl acrylate (4). The synthesis comprises a four-step preparation of methyl N-Cbz-5-alkylamino-3-oxopentanoates 9a–c, their three-step transformation into 5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a–c, three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 16b–h, followed by hydrogenolytic Cbz-deprotection and subsequent cyclization of the intermediate 1,4-diamine with CDI to furnish the title compounds 3. Most of the synthetic steps were performed as a one-pot transformation.

Key words

pyrazolo[1,5-c]pyrimidines - cyclization - saturated heterocycles - 3-pyrazolidinones

• References

• 1a Patrick GL. An Introduction to Medicinal Chemistry. 4th ed. Oxford University Press; Oxford: 2009
• 1b Pernerstorfer J. Molecular Design and Combinatorial Compound Libraries. In Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 2. Nicolaou KC, Hanko R, Hartwig W. Wiley-VCH; Weinheim: 2002: 725
• 1c Dolle RE. Solid-phase Synthesis of Heterocyclic Systems (Heterocycles Containing One Heteroatom). In Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 2. Nicolaou KC, Hanko R, Hartwig W. Wiley-VCH; Weinheim: 2002: 643
• 2a Hajos G, Riedl Z. Aza Analogues of Pyrazolo[1,5-a]pyridines Containing Additional Nitrogen Atoms in the Six-Membered Ring. In Science of Synthesis. Vol. 12. Neier R. Thieme; Stuttgart: 2006: 667 ; and references cited therein
• 2b Regan AC. Pyrazolo[1,5-c]pyrimidine. In Comprehensive Heterocyclic Chemistry III. Vol. 11. Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K, Cossy J. Elsevier Science Ltd; Oxford: 2008: 577 ; and references cited therein
• 2c Sliskovic DR. Pyrazolo[1,5-c]pyrimidine. In Comprehensive Heterocyclic Chemistry III. Vol. 8. Katritzky AR, Rees CV, Scriven EF. V. Elsevier Science Ltd; Oxford: 1996: 362 ; and references cited therein
• 3a Maier T, Baer T, Lindenmaier A, Vennemann M, Braunger J, Boehm M, Gekeler V, Zimmermann A. PCT Int. Appl. WO 2007144384, 2007 ; Chem. Abstr. 2007, 148, 79077.
• 3b Mallams AK, Madison V, Paruch K. PCT Int. Appl. WO 2007032936, 2007 ; Chem. Abstr. 2007, 146, 358880.
• 3c Maier T, Zuelch A, Ciossek T, Baer T, Beckers T. PCT Int. Appl. WO 2006027346, 2006 ; Chem. Abstr. 2006, 144, 350709.
• 4a Gudmundsson K, Johns BA. PCT Int. Appl. WO 2003076441, 2003 ; Chem. Abstr. 2003, 139, 261327.
• 4b Gudmundsson KS, Johns BA, Waterhead J. Bioorg. Med. Chem. Lett. 2009; 19: 5689
• 5 Casebier D. PCT Int. Appl. WO 2010091303, 2010 ; Chem. Abstr. 2010, 153, 260549.
• 6a Kahraman M, Smith ND, Bonnefous C, Noble SA, Payne JE. PCT Int. Appl. WO 2010088518, 2010 ; Chem. Abstr. 2010, 153, 260364.
• 6b Smith ND, Bonnefous C, Kahraman M, Noble SA, Payne JE, Govek SP. PCT Int. Appl. WO 2010048149, 2010 ; Chem. Abstr. 2010, 152, 501397.
• 7 Lee W.-C, Carter MB, Sun L, Lyne P, Chuaqui C, Zheng Z, Singh J, Boriack-Sjodin P. PCT Int. Appl. WO 2004022054, 2004 ; Chem. Abstr. 2004, 140, 270867.
• 8 Mahgoub FM, Abdel-Nabey BA, El-Samadisy YA. Mater. Chem. Phys. 2010; 120: 104
• 9a Kaneko Y, Kita H, Ikesu S. Jpn Kokai Tokkyo Koho JP 04283272, 1992 ; Chem. Abstr. 1992, 119, 74607.
• 9b Kaneko Y, Kita H, Ikesu S. Jpn Kokai Tokkyo Koho JP 04204441, 1992 ; Chem. Abstr. 1992, 118, 90726.
• 9c Yamakawa K, Ishii Y. Jpn Kokai Tokkyo Koho JP 04191736, 1992 ; Chem. Abstr. 1992, 117, 261569.
• 9d Kaneko Y. Jpn Kokai Tokkyo Koho JP 02236545, 1990 ; Chem. Abstr. 1990, 115, 18490.
• 10a Svete J. (4R*,5R*)-4-Benzoylamino-5-phenyl-3-pyrazolidinone – A Useful Building Block in the Synthesis of Functionalized Pyrazoles. Horvat MA, Golob JH. Nova Science Publishers; New York: 2008: 129 (open-access item, the pdf is available at https://www.novapublishers.com/catalog/product_info.php?products_id=16416); and references cited therein
• 10b Novak A, Bezenšek J, Pezdirc L, Grošelj U, Kasunič M, Podlipnik Č, Stanovnik B, Šimůnek P, Svete J. Tetrahedron 2011; 67: 9729 ; and references cited therein
• 11a Grošelj U, Kralj D, Wagger J, Dahmann G, Stanovnik B, Svete J. ARKIVOC 2012; (iii): 49 ; and references cited therein
• 11b Perdih P, Baškovč J, Dahmann G, Grošelj U, Kočar D, Stanovnik B, Svete J. Synthesis 2011; 2822
• 11c Žerovnik D, Grošelj U, Kralj D, Malavašič Č, Bezenšek J, Dahmann G, Stare K, Meden A, Stanovnik B, Svete J. Synthesis 2010; 3363
• 12 Xue C.-B, He X, Roderick J, Corbett RL, Decicco CP. J. Org. Chem. 2002; 67: 865
• 13 Hashiguchi S, Kawada A, Natsugari H. Synthesis 1992; 403
• 14 Farrugia LJ. J. Appl. Crystallogr. 1997; 30: 565
• 15 Structural and other crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 910129, CCDC 910351, and CCDC 910352 for compounds 3h, 3a, and 3c, respectively. A copy of the data can be obtained, free of charge, by applying to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: [phone] or e-mail: [e-mail]).