An Efficient Copper-mediated 1,3-Dipolar Cycloaddition of Pyrazolidinone-based Dipoles to Terminal Alkynes to Produce N,N-Bicyclic Pyrazolidinone Derivatives Takamichi Oishi, Kazuaki Yoshimura, Kazuya Yamaguchi, and Noritaka Mizuno* Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Received July 28, 2010; CL-100659; E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp) Asimpledinuclear copper complex [Cu(®-OH)(tmen)] 2 Cl 2 (tmen = N,N,N¤,N¤-tetramethylethylenediamine) could act as an effective precatalyst for the 1,3-dipolar cycloaddition of pyrazolidinone-based dipoles to terminal alkynes to produce the corresponding N,N-bicyclic pyrazolidinone derivatives. 1,3-Dipolar cycloaddition reactions are one of the most powerful procedures for the synthesisof a variety offive- membered heterocycles in a convergent manner. 1 For example, the groups of Sharpless 2a and Meldal 2b have independently reported that the 1,3-dipolar cycloaddition of organic azides (as dipoles) to alkynes (as dipolarophiles) can dramatically be accelerated by the presence of copper (pre)catalysts and is totally regioselective, affording the corresponding 1,4-disubstituted- 1,2,3-triazole derivatives (so-called “click reaction”). To date, many efficient copper-based (pre)catalysts have been reported for the click reaction. 25 Very recently, we have also reported that the copper- substituted silicotungstate with the diazido-bridged dicopper core TBA 4 [£-H 2 SiW 10 O 36 {Cu 2 (®-1,1-N 3 ) 2 }] (TBA = tetra-n- butylammonium) could act as an efficient homogeneous pre- catalyst with extremelyhigh turnover frequency (TOF) and turnover number (TON). 5 The dicopper core plays an important role for the click reaction: Initially, the alkyne homocoupling efficiently proceeds via the Cu(II)alkynylintermediate {Cu 2 (®- C¸CR) 2 }, followed by the formation of the corresponding diyne (as a co-product) and truly active Cu(I) species. 6 This means that an alkyne itself can act as an efficient reducing reagent to generate the catalytically active Cu(I) species insitu and no additional reducing reagents are necessary in the case of “dicopper complexes”. On the basisof the above-mentioned results, we found that a dinuclear copper complex [Cu(®-OH)(tmen)] 2 Cl 2 could act as an effective precatalyst for the click reaction (Figure S1). 7 In addition, we now found that the 1,3-dipolar cycloaddition of pyrazolidinone-based dipoles (azomethine imides) to terminal alkynes was efficiently promoted by [Cu(®-OH)(tmen)] 2 Cl 2 and the catalytic activity was superior to that of TBA 4 [£-H 2 - SiW 10 O 36 {Cu 2 (®-1,1-N 3 ) 2 }]. 8 In this paper, we mainly focused on the synthetic scope of the [Cu(®-OH)(tmen)] 2 Cl 2 -mediated 1,3-dipolar cycloaddition of pyrazolidinone-based dipoles to terminal alkynes. The N,N- bicyclic pyrazolidinone derivatives produced by this reaction have a variety of applications. 9 However, onlya few catalytic systems, for example, CuI/Cy 2 NMe 10a,10b and Cu(I)-exchanged zeolites, 10c have been reported until now. Although [Cu(®- OH)(tmen)] 2 Cl 2 has been utilized as a catalyst for various functional group transformations, 11 the [Cu(®-OH)(tmen)] 2 Cl 2 - mediated 1,3-dipolar cycloaddition reactions have never been reported. Initially, the [Cu(®-OH)(tmen)] 2 Cl 2 -mediated 1,3-dipolar cycloaddition of 1-benzylidene-3-oxo-1-pyrazolidinium-2-ide (1a) to ethyl propiolate (2a) was carried out in various solvents under Ar atmosphere (Table S1). 7 A typical procedure for the 1,3-dipolar cycloaddition is as follows: Into a glass vial were successivelyplaced catalyst (typically 1 mol% Cu with respect to adipole), a pyrazolidinone-based dipole (0.5 mmol), an alkyne (0.55 mmol), and a solvent (3 mL). Then, the resulting solution was stirred at 60 °C under Ar atmosphere. The yields were determined by 1 H NMR analyses. The products could be isolated by column chromatography on silica gel. Among the solvents examined, non- and low-polar solvents such as chloroform and toluene gave the corresponding N,N-bicyclic pyrazolidinone 3aa inhigh yields. Polar tetrahydrofuran and acetonitrile gave 3aa in moderate yields. On the other hand, protic and highly polar solvents such as methanol and N,N-dimethylformamide were poor likely because of the strong coordination to the active site(s). The hydrolytic decomposition of 1a proceeded to some extent (ca. 4%) when the reaction was carried out in water. Under the conditions described in Table 1, 12 the 1,3-dipolar cycloaddition of 1a to 2a efficiently proceeded to give the corresponding N,N-bicyclic pyrazolidinone 3aa in the presence of [Cu(®-OH)(tmen)] 2 Cl 2 (Entry 1). 8 In this case, only the single regioisomer 3aa could be obtained. The reaction hardly proceeded in the absence of catalysts (Entry 9). The catalytic activities of simple copper salts and complexes alone were lower than that of [Cu(®-OH)(tmen)] 2 Cl 2 (Entries 28). 13 Therefore, the dicopper core in [Cu(®-OH)(tmen)] 2 Cl 2 plays an important role in the present transformation. Table 1. 1,3-Dipolar cycloaddition of 1a to 2a with various copper-based catalysts a N Ph N O COOEt COOEt N N O Ph + 1a 2a catalyst 3aa Entry Catalyst Yield b /% 1 [Cu(®-OH)(tmen)] 2 Cl 2 49(98) c 2 CuSO 4 ¢5H 2 O 2 3 CuCl 2 ¢2H 2 O 4 4 Cu(ClO 4 ) 2 ¢6H 2 O 3 5 Cu(OTf) 2 3 6 CuCl 4 7 CuI 11 8 [Cu(CH 3 CN) 4 ]PF 6 19 9 None 3 a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), catalyst (Cu: 1 mol% with respect to 1a), CD 3 CN (3 mL), 60 °C, 1.0 h, Ar (1 atm). b Determined by 1 H NMR analysis. c The result obtained with CDCl 3 . Published on the web September 4, 2010 1086 doi:10.1246/cl.2010.1086 © 2010 The Chemical Society of Japan Chem. Lett. 2010, 39, 10861087 www.csj.jp/journals/chem-lett/