Easy and Efficient Copper-Catalyzed
Synthesis of Bicyclic Pyrimidinones under Mild Conditions

Qi Guo; Haijun Yang; Hongxia Liu; Yuyang Jiang; Hua Fu

doi:10.1055/s-0030-1258803

LETTER

Easy and Efficient Copper-Catalyzed Synthesis of Bicyclic Pyrimidinones under Mild Conditions

Qi Guo^a, Haijun Yang^a, Hongxia Liu^b, Yuyang Jiang^b, Hua Fu*^a
^a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China
^b Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. of China
Fax: +86(10)62781695; e-Mail: fuhua@mail.tsinghua.edu.cn;

Abstract

All articles of this category

Abstract

A simple and efficient copper-catalyzed method has been developed for synthesis of bicyclic pyrimidinones containing six-, seven-, eight-membered rings under mild conditions. The protocol uses readily available 2-bromocycloalk-1-enecarboxylic acids, amidines, and guanidines as the starting materials, copper-catalyzed cascade couplings provide the corresponding bicyclic pyrimidinones without addition of any ligand or additive, and the method is of economical and practical advantages.

Key words

copper - cascade reaction - bicyclic pyrimidinone - nitrogen heterocycle - synthetic method

Full Text

References

References and Notes

For reviews, see:

<A NAME="RW11510ST-1A">1a</A> Undheim K. Benneche T. In Comprehensive Heterocyclic Chemistry II Vol. 6: Katritzky AR. Rees CW. Scriven EFV. McKillop A. Pergamon; Oxford: 1996. p.93

<A NAME="RW11510ST-1B">1b</A> Lagoja IM. Chemistry & Biodiversity 2005, 2: 1

<A NAME="RW11510ST-1C">1c</A> Michael JP. Nat. Prod. Rep. 2005, 22: 627

<A NAME="RW11510ST-1D">1d</A> Joule JA. Mills K. In Heterocyclic Chemistry 4th ed.: Blackwell Science Ltd.; Cambridge USA: 2000. p.194

<A NAME="RW11510ST-1E">1e</A> Erian AW. Chem. Rev. 1993, 93: 1991

Raltegravir has been approved by the FDA for the treatment of HIV/AIDS under the trademark ISENTRESS.

<A NAME="RW11510ST-3">3</A> Markowitz M. Morales-Ramirez JO. Nguyen BY. Kovacs CM. Steigbigel RT. Cooper DA. Liporace R. Schwartz R. Isaacs R. Gilde LR. Penning L. Zhao J. Teppler H. J. Acquir. Immune Defic. Syndr. 2006, 43: 509

<A NAME="RW11510ST-4A">4a</A> Hazuda DJ. Felock P. Witmer M. Wolfe A. Stillmock K. Grobler JA. Espeseth A. Gabryelski L. Schleif W. Blau C. Miller MD. Science 2000, 287: 646

<A NAME="RW11510ST-4B">4b</A> Hazuda DJ. Young SD. Guare JP. Anthony NJ. Gomez RP. Wai JS. Vacca JP. Handt L. Motzel SL. Klein HJ. Dornadula G. Danovich RM. Witmer MV. Wilson KA. Tussey L. Schleif WA. Gabryelski LS. Jin L. Miller MD. Casimiro DR. Emini EA. Shiver JW. Science 2004, 305: 528

<A NAME="RW11510ST-5">5</A> Muraglia E. Kinzel O. Gardelli C. Crescenzi B. Donghi M. Ferrara M. Nizi E. Orvieto F. Pescatore G. Laufer R. Gonzalez-Paz O. Marco AD. Fiore F. Monteagudo E. Fonsi M. Felock PJ. Rowley M. Summa V. J. Med. Chem. 2008, 51: 861

<A NAME="RW11510ST-6A">6a</A> Gangjee A. Vasudevan A. Kisliuk RL. J. Heterocycl. Chem. 1997, 34: 1669

<A NAME="RW11510ST-6B">6b</A> Bernáth G. Kóbor J. Lázár J. Fülöp F. J. Heterocycl. Chem. 1996, 33: 1983

<A NAME="RW11510ST-6C">6c</A> Bernáth G. Janáky T. Göndös G. Lázár J. Ecsery Z. Pharmazie 1983, 38: 270

<A NAME="RW11510ST-6D">6d</A> Nishio T. Fujisawa M. Omote Y.
J. Chem. Soc., Perkin Trans. 1 1987, 2523

<A NAME="RW11510ST-7A">7a</A> Sekiya T. Hiranuma H. Uchide M. Hata S. Yamada S. Chem. Pharm. Bull. 1981, 29: 948

<A NAME="RW11510ST-7B">7b</A> Claudi F. Giorgioni G. Scoccia L. Ciccocioppo R. Panocka I. Massi M. Eur. J. Med. Chem. 1997, 651

<A NAME="RW11510ST-8">8</A> Nair MG. Dhawan R. Ghazala M. Kalman TI. Ferone R. Gaumont Y. Kisliuk RL. J. Med. Chem. 1987, 30: 1256

<A NAME="RW11510ST-9">9</A> Rosowsky A. Forsch RA. Moran RG. J. Med. Chem. 1989, 32: 709

<A NAME="RW11510ST-10">10</A> Ishida J. Hattori K. Yamamoto H. Iwashita A. Miharab K. Matsuoka N. Bioorg. Med. Chem. Lett. 2005, 15: 4221

<A NAME="RW11510ST-11A">11a</A> Kawamura S. Sanemitsu Y. J. Org. Chem. 1993, 58: 414

<A NAME="RW11510ST-11B">11b</A> Fülöp F. Bernáth G. Synthesis 1985, 1148

<A NAME="RW11510ST-11C">11c</A> Ferrara M. Crescenzi B. Donghi M. Muraglia E. Nizi E. Pesci S. Summa V. Gardelli C. Tetrahedron Lett. 2007, 48: 8379

<A NAME="RW11510ST-12A">12a</A> Limbach M. Dalai S. de Meijere A. Adv. Synth. Catal. 2004, 346: 760

<A NAME="RW11510ST-12B">12b</A> Nötzel MW. Rauch K. Labahn T. de Meijere A. Org. Lett. 2002, 4: 839

<A NAME="RW11510ST-12C">12c</A> Dalai S. Belov VN. Nizamov S. Rauch K. Finsinger D. de Meijere A. Eur. J. Org. Chem. 2006, 2753

For recent reviews on copper-catalyzed Ullmann couplings, see:

<A NAME="RW11510ST-13A">13a</A> Ma D. Cai Q. Acc. Chem. Res. 2008, 41: 1450

<A NAME="RW11510ST-13B">13b</A> Kunz K. Scholz U. Ganzer D. Synlett 2003, 2428

<A NAME="RW11510ST-13C">13c</A> Ley SV. Thomas AW. Angew. Chem. Int. Ed. 2003, 42: 5400

<A NAME="RW11510ST-13D">13d</A> Beletskaya IP. Cheprakov AV. Coord. Chem. Rev. 2004, 248: 2337

<A NAME="RW11510ST-13E">13e</A> Evano G. Blanchard N. Toumi M. Chem. Rev. 2008, 108: 3054

<A NAME="RW11510ST-13F">13f</A> Monnier F. Taillefer M. Angew. Chem. Int. Ed. 2009, 48: 6954 ; and references cited therein

For recent studies on the synthesis of N-heterocycles through Ullmann-type couplings, see:

<A NAME="RW11510ST-14A">14a</A> Martin R. Rivero MR. Buchwald SL. Angew. Chem. Int. Ed. 2006, 45: 7079

<A NAME="RW11510ST-14B">14b</A> Evindar G. Batey RA. J. Org. Chem. 2006, 71: 1802

<A NAME="RW11510ST-14C">14c</A> Bonnaterre F. Bois-Choussy M. Zhu J. Org. Lett. 2006, 8: 4351

<A NAME="RW11510ST-14D">14d</A> Zou B. Yuan Q. Ma D. Angew. Chem. Int. Ed. 2007, 46: 2598

<A NAME="RW11510ST-14E">14e</A> Yuan X. Xu X. Zhou X. Yuan J. Mai L. Li Y. J. Org. Chem. 2007, 72: 1510

<A NAME="RW11510ST-14F">14f</A> Lu H. Li C. Org. Lett. 2006, 8: 5365

<A NAME="RW11510ST-15A">15a</A> Jiang D. Fu H. Jiang Y. Zhao Y. J. Org. Chem. 2007, 72: 672

<A NAME="RW11510ST-15B">15b</A> Jiang Q. Jiang D. Jiang Y. Fu H. Zhao Y. Synlett 2007, 1836

<A NAME="RW11510ST-16A">16a</A> Shafir A. Buchwald SL. J. Am. Chem. Soc. 2006, 128: 8742

<A NAME="RW11510ST-16B">16b</A> Wang D. Ding K. Chem. Commun. 2009, 1891

<A NAME="RW11510ST-17A">17a</A> Rao H. Fu H. Jiang Y. Zhao Y. J. Org. Chem. 2005, 70: 8107

<A NAME="RW11510ST-17B">17b</A> Rao H. Jin Y. Fu H. Jiang Y. Zhao Y. Chem. Eur. J. 2006, 12: 3636

<A NAME="RW11510ST-17C">17c</A> Jiang D. Fu H. Jiang Y. Zhao Y. J. Org. Chem. 2007, 72: 672

<A NAME="RW11510ST-17D">17d</A> Guo X. Rao H. Fu H. Jiang Y. Zhao Y. Adv. Synth. Catal. 2006, 348: 2197

<A NAME="RW11510ST-17E">17e</A> Zeng L. Fu H. Qiao R. Jiang Y. Zhao Y. Adv. Synth. Catal. 2009, 351: 1671

<A NAME="RW11510ST-17F">17f</A> Gao X. Fu H. Qiao R. Jiang Y. Zhao Y. J. Org. Chem. 2008, 73: 6864

<A NAME="RW11510ST-18A">18a</A> Huang C. Fu Y. Fu H. Jiang Y. Zhao Y. Chem. Commun. 2008, 6333

<A NAME="RW11510ST-18B">18b</A> Yang D. Fu H. Hu L. Jiang Y. Zhao Y. J. Org. Chem. 2008, 73: 7841

<A NAME="RW11510ST-18C">18c</A> Wang F. Liu H. Fu H. Jiang Y. Zhao Y. Org. Lett. 2009, 11: 2469

<A NAME="RW11510ST-18D">18d</A> Yang D. Liu H. Yang H. Fu H. Hu L. Jiang Y. Zhao Y. Adv. Synth. Catal. 2009, 351: 1999

<A NAME="RW11510ST-18E">18e</A> Gong X. Yang H. Liu H. Jiang Y. Zhao Y. Fu H. Org. Lett. 2010, 12: 3128

<A NAME="RW11510ST-18F">18f</A> Liu X. Fu H. Jiang Y. Zhao Y. Angew. Chem. Int. Ed. 2009, 48: 348

General Procedure for the Synthesis of Compounds 3a-s A two-neck round-bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Amidine hydrochloride or guanidine hydrochloride 2a-f (0.6 mmol) or bis(guanidine)sulfate (2g, 0.35 mmol), CuI (0.05 mmol, 9.5 mg), Cs₂CO₃ (1 mmol, 326 mg), and DMF (1 mL) were added under nitrogen atmosphere. After a 15 min stirring, 2-bromocycloalk-1-enecarboxylic acid (1, 0.5 mmol) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for some time (see Table [²] ). After completion of the reaction, the mixture was concentrated with the aid of a rotary evaporator. The residue was purified by column chroma-tography on silica gel using PE-EtOAc or CH₂Cl₂-MeOH as eluent to provide the desired product.

<A NAME="RW11510ST-20A">20a</A> Nicolaou KC. Boddy CNC. Natarajar S. Yue T.-Y. Li H. Bräse S. Ramanjulu JM. J. Am. Chem. Soc. 1997, 119: 3421

<A NAME="RW11510ST-20B">20b</A> Lindley J. Tetrahedron 1984, 40: 1433

<A NAME="RW11510ST-20C">20c</A> Kalinin AV. Bower JF. Riebel P. Snieckus V. J. Org. Chem. 1999, 64: 2986

<A NAME="RW11510ST-20D">20d</A> Cai Q. Zou B. Ma D. Angew. Chem. Int. Ed. 2006, 45: 1276

<A NAME="RW11510ST-21">21</A> Flanagan SP. Goddard R. Guiry PJ. Tetrahedron 2005, 61: 9808

Supplementary Material

Supporting Information (PDF)