Copper(I) AcetateCatalyzed Cycloaddition between

FULL PAPER DOI: 10.1002/ejoc.201300753

Copper(I) Acetate-Catalyzed Cycloaddition between Azomethine Imines and Propiolates under Additive-Free Conditions Changwei Shao,[a] Qun Zhang,[a] Guolin Cheng,[a] Chuanjie Cheng,[a] Xinyan Wang,*[a] and Yuefei Hu*[a] Keywords: Alkynes / Copper / Cycloaddition / Click chemistry Because propiolates easily undergo base-catalyzed selfMichael addition, most popular catalytic systems in CuAAC cannot be used in the cycloaddition between azomethine imines and propiolates, because such reactions usually require the use of tertiary amines as additives (as base and/or ligand). We found that this problem can be resolved simply by using copper(I) acetate as catalyst, in which the acetate

serves as a ligand and is converted into acetic acid during the reaction. Thus, copper(I) acetate catalyzed cycloaddition actually proceeds under additive-free conditions (without exogenous ligand) to efficiently give 6,7-dihydropyrazolo[1,2-a]pyrazolone derivatives, in which the side-reactions and byproducts caused by basic additives are completely avoided.

Introduction Many bicyclic polyhydropyrazolo[1,2-a]pyrazolone derivatives have important medicinal properties.[1] As shown in Figure 1, compounds LY173013 and LY186826 are antibacterial agents that are analogues of penicillin and cephalosporin.

Figure 1. The structures of LY173013 and LY186826.

In the early preparation of LY173013 and LY186826, cycloaddition[2] between azomethine imines 1 and propiolates 2 was employed to construct their molecular skeletons and introduce the ester groups in a single step. However, this thermal cycloaddition[3] was usually performed at high temperature to produce regioisomers (for example 3a and 4 in Scheme 1) when unsubstituted propiolate (as terminal alkyne) was used as dipolarophile.[4] Recently, an improved regioselective method was reported that involved Fisher carbene complexes of propiolate as dipolarophiles under thermal conditions.[5] [a] Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China E-mail: [email protected] E-mail: [email protected] Homepage: http://www.chem.tsinghua.edu.cn/publish/chemen/ 2141/2011/20110331184801309598874/ 20110331184801309598874_.html Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201300753. Eur. J. Org. Chem. 2013, 6443–6448

Scheme 1.

In the past decade, copper-catalyzed azide–alkyne cycloaddition (CuAAC)[6] has been developed as a prime example of “click chemistry”, in which high regioselectivity was achieved for many types of terminal alkynes.[7] The combinations of CuSO4·5H2O/NaAsc/aq. tBuOH and CuI/NR3 (NR3, as an additive, served as base and/or ligand, such as CuI/DIPEA and CuI/TEA) are two popular and efficient catalytic systems. However, neither approaches were used directly in the cycloaddition between 1 and 2, because the inner salt 1 decomposes in aqueous media and propiolate 2 easily undergoes self-Michael addition in the presence of common tertiary amines (Scheme 2).[8]

Scheme 2. Self-Michael addition of propiolate.

Indeed, to the best of our knowledge, only five coppercatalyzed protocols have been reported for the cycloaddition between 1 and 2 to date. In two CuI-catalyzed protocols,[9] an uncommon, highly hindered N-methyldicyclohexylamine was used as an additive. In the other three protocols,[4,10] pre-made heterogeneous catalysts were used.

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C. Shao, Q. Zhang, G. Cheng, C. Cheng, X. Wang, Y. Hu

FULL PAPER Therefore, there remains a need to develop a highly efficient homogeneous catalytic system for this cycloaddition under tertiary-amine-free conditions.

Results and Discussion In the CuAAC reaction, tertiary amines are typically used as additives (base and/or ligand) for three reasons: (a) they can promote the formation of the acetylide anion; (b) they can coordinate with copper(I) acetylide to prevent the formation of inactive polymeric structures such as [(RC⬅CCu)2]n, and (c) they can dissociate the inactive polymeric (CuI)n into active CuI, when commercial copper(I) iodide is used as CuI source. However, we recently reported a novel copper(I) acetate {as a complex [(MeCO2Cu)2]n} catalyzed CuAAC under tertiary-amine-free conditions.[11] As shown in Scheme 3, copper(I) acetate is a conjugate base of acetic acid that is strong enough to form copper(I) acetylide. Furthermore, the acetic acid that is released in situ not only activates the polymer [(RC⬅CCu)2]n, but also accelerates the protonation of the intermediate 5-cuprous 1,2,3-trizoles.[12] Because cycloaddition between 1 and 2 was proposed to proceed through a similar mechanism and involve similar intermediates to those of the CuAAC reaction,[4,9,10] we envisioned that its efficiency and regioselec-

Scheme 3.

tivity may be improved significantly by simply using copper(I) acetate as catalyst. Thus, screening experiments were made by using 1a and 2a as model substrates. As shown in Table 1, the desired product 3a could be obtained in 88 % yield by using a large amount of CuI/Cy2NMe (Entry 1),[9b] but the same product was isolated in 46 % yield from a mixture when a small amount of CuI/Cy2NMe was used (Entry 2). Not surprisingly, use of the combination of CuI/Et3N gave a mixture from which 3a was isolated in 38 % yield (Entry 3). Interestingly, use of the CuSO4·5H2O/NaOAc combination showed moderate catalytic activity in this cycloaddition. As shown in Table 1, Entry 4, when a clear solution of 1a, 2a, and CuSO4·5H2O/NaOAc in aq. tBuOH was stirred for 2 h, 3a crystallized from the solution in 56 % yield. The low yield may be caused by decomposition of the inner salt 1a in water (benzaldehyde was detected in the reaction mixture). As expected, 3a was obtained in high yield (93 %) by stirring a suspension of 1a, 2a, and [(MeCO2Cu)2]n in CH2Cl2 for 50 min (Entry 5). Other copper(I) sources, such as CuI, CuBr, CuCl, Cu2O or CuCN (Entries 6–10), showed low efficiency, possibly because they normally need to be activated by additives.[7] As shown in Table 1, Entries 11 and 12, copper(II) acetate and copper(II) benzoate also showed strong catalytic activity, because the CuI species could be generated in situ by CuII-catalyzed oxidative coupling of 2a. The effect of solvent on the reaction was then tested with [(MeCO2Cu)2]n as catalyst. As shown in Table 2, cyclohexane and toluene (Entries 1 and 2) showed low efficiency, because both substrate 1a and product 3a had poor solubility in these solvents, and it was clearly difficult to directly convert solid 1a into solid 3a. When EtOH was used as solvent, the reaction stopped within 1 h (Entry 3). To our delight, the use of MeCN, tetrahydrofuran (THF) and CH2Cl2 all gave excellent yields of 3a in short reaction times (Entries 4–6). From a practical point of view, CH2Cl2 was

Table 1. Effects of the copper(I) sources on the cycloaddition.[a]

Entry

Cu catalyst (0.01 equiv.)

Time [min]

Yield of 3a [%][b]

1[c] 2 3 4[d] 5 6[e] 7[e] 8[e] 9[e] 10[e] 11 12

CuI (0.05 equiv.)/Cy2NMe (0.5 equiv.) CuI/Cy2NMe (0.02 equiv.) CuI/Et3N (0.02 equiv.) CuSO4·H2O/NaOAc (0.02 equiv.) [(MeCO2Cu)2]n CuI CuBr CuCl Cu2O CuCN (MeCO2)2Cu (PhCO2)2Cu

20 h 180 180 120 50 60 60 60 60 60 80 90

88 46 38 56 93 10 48 40 20 15 82 84

[a] Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), Cu catalyst (0.01 mmol, 0.01 equiv.), CH2Cl2 (2 mL), r.t. [b] Isolated yield. [c] Data from ref.[9b] [d] tBuOH/H2O (1:2 v/v) was used as a solvent for the solubility of CuSO4·5H2O and NaOAc. [e] The reaction was not complete. 6444

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Cycloaddition of Azomethine Imines and Propiolates

the best solvent, because it was clear when the reaction endpoint was reached; CH2Cl2 is a poor solvent for the inner salt 1a but good solvent for the product 3a, thus the reaction endpoint was clearly indicated by the conversion of a suspension into a transparent solution. When the ratio of [(MeCO2Cu)2]n was increased, the reaction time was shortened sharply, and higher yields were obtained (Entries 7 and 8). Finally, standard conditions were established to be those detailed in Table 2, Entry 7. Table 2. Effect of solvent on the cycloaddition.[a]

Entry

Solvent

CuOAc [equiv.]

Time [min]

Yield of 3a [%][b]

1 2 3 4 5 6 7 8

cyclohexane toluene EtOH MeCN THF CH2Cl2 CH2Cl2 CH2Cl2

0.01 0.01 0.01 0.01 0.01 0.01 0.02 0.04

120 120 120 80 60 50 22 10

32 45 51 89 91 93 96 97

Scheme 5.

Table 3. Copper(I) acetate catalyzed cycloaddition.

[a] Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), [(MeCO2Cu)2]n (0.01 mmol, 0.01 equiv.), solvent (2 mL), r.t. [b] Isolated yield.

It was interesting to observe that an identical, brightyellow solid was a common intermediate for reactions performed in a number of solvents (Table 2, Entries 4–8); it had very poor solubility in all solvents and was assigned as CuC⬅CCO2Et (5a, without exogenous ligands) on the basis of IR spectra and elemental analysis data.[13] In a stoichiometric reaction of [(MeCO2Cu)2]n and HC⬅CCO2Et (2a) in MeCN, 5a was obtained in 91 % yield at room temperature after 1 h (Scheme 4). This efficient procedure is therefore a valuable new addition to the methods available for the preparation of copper propiolates.[14]

Scheme 4.

Further experiments showed that no reaction occurred between 1a and 5a by using H2O, tBuOH or aqueous solution of NaOAc as a proton source (Scheme 5). However, when DOAc was used as a source of deuterium, the expected product 3a-d1 was obtained in 94 % yield and 87 % deuterium incorporation within 15 min. Thus, two conclusions can be reached: (a) intermediate 6a exists in this cycloaddition; (b) HOAc is an excellent promoter for both cycloaddition of 5a and protonation of 6a. These conclusions are in full agreement with the hypothesis proposed in earlier studies.[4,9,10] Finally, the scope of this method was tested with a range of substrates. As shown in (Table 3), all tested samples gave excellent yields in short reaction times under the standard conditions. No significant difference was observed in the preparation of products 3a–l when C-1 was substituted by Eur. J. Org. Chem. 2013, 6443–6448

phenyl, pyridyl or alkyl groups. There was no negative effect on the preparation of 3m and 3o when C-7 bears one substituent. However, the use of substrates with two substituents on C-7 (3n) required longer reaction times and gave lower yields. Although but-3-yn-2-one (2b) proved to be an excellent dipolarophile in the preparation of 3p, phenyl-, (4fluorophenyl)- and (2-pyridyl)ethynes (i.e., which are not α,β-unsaturated carbonyl compounds) proved to be unsatisfactory dipolarophiles for this cycloaddition. These findings are in full agreement with previously reported results.[4,10]


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FULL PAPER Conclusions A novel copper(I) acetate catalyzed cycloaddition between azomethine imines 1 and propiolates 2 was developed, in which the highly efficient preparation of 5-oxo-6,7dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate derivatives 3 was achieved under extremely convenient and mild conditions. The method benefited significantly from the formation of CuC⬅CCO2Et under additive-free conditions, which meant that self-Michael addition of propiolates was avoided completely. By using DOAc in an isotopic experiment, the other promotion activities of copper(I) acetate were also described and proved.

Experimental Section General: All melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra were recorded on a Nicolet FT-IR 5DX spectrometer with KBr. The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a JEOL JNM-ECA 300 spectrometer in CDCl3. TMS was used as an internal reference and J values were given in Hz. HRMS were obtained on a Bruker micrOTOF-Q II spectrometer. PE is petroleum ether (boiling range 60–90 oC). Typical Procedure for 1a: A stirred solution of NH2NH2·H2O (1.0 g, 20 mmol) and H2C=CHCO2Me (1.9 g, 22 mmol) in EtOH (20 mL) was heated at 70–80 °C for 4 h. EtOH was then removed in vacuo, and the residue was diluted with MeOH (5 mL) and PhCHO (3.2 g, 30 mmol). The resultant mixture was stirred for 12 h, then MeOH was removed in vacuo. The residue was purified by chromatography (silica gel; MeOH/EtOAc, 20 %) to give 1a (2.2 g, 63 %) as a white solid. The same procedure was used for the preparation of 1b–o, which were used directly in the next step without further purification or characterization. Typical Procedure for 3a: To a stirred suspension of [(CuOAc)2]n (calculated based on CuOAc, 2.5 mg, 0.02 mmol, 0.02 equiv.) and 1a (174 mg, 1.0 mmol) in CH2Cl2 (2 mL), was added HC⬅CCO2Et (2a; 108 mg, 1.1 mmol) at room temperature until the suspension was converted into a transparent solution (22 min, monitored by TLC). The solvent was removed in vacuo, and the residue was purified by fast chromatography (silica gel; Et2O/PE, 50 %) to give the desired product 3a (261 mg, 96 %) as a yellow solid.

Ethyl 1-(3-Methoxyphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3c):[10b] Isolated as a yellowish solid; m.p. 88–89 °C (PE/Et2O). 1H NMR: δ = 7.54 (s, 1 H), 7.30–7.24 (m, 1 H), 6.97–6.92 (m, 2 H), 6.89–6.84 (m, 1 H), 5.13 (d, J = 1.4 Hz, 1 H), 4.15–4.01 (m, 2 H), 3.80 (s, 3 H), 3.43–3.38 (m, 1 H), 3.08–2.96 (m, 1 H), 2.92–2.81 (m, 1 H), 2.79–2.69 (m, 1 H), 1.43 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.8, 163.5, 159.9, 140.0, 129.6, 128.6, 120.7, 118.3, 113.9, 113.8, 73.3, 60.5, 55.3, 51.7, 35.8, 14.2 ppm. Ethyl 1-(4-Methylphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3d): Isolated as a white solid; m.p. 86– 88 °C (PE/Et2O). IR ν˜ = 1717, 1695, 1604, 1437, 1407, 1362 cm–1. 1 H NMR: δ = 7.53–7.52 (m, 1 H), 7.27–7.24 (m, 2 H), 7.21–7.16 (m, 2 H), 5.13 (d, J = 1.4 Hz, 1 H), 4.13–3.98 (m, 2 H), 3.39–3.32 (m, 1 H), 3.08–2.96 (m, 1 H), 2.92–2.71 (m, 2 H), 2.34 (s, 3 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.3, 163.1, 137.9, 135.0, 129.0 (2 C), 128.1, 127.8 (2 C), 118.1, 72.6, 60.0, 51.1, 35.4, 20.9, 13.8 ppm. MS: m/z (%) = 286 (51.2) [M+], 195 (100), 129 (13.2), 55 (86.3). C16H18N2O3 (286.33): calcd. C 67.12, H 6.34, N 9.78; found C 67.43, H 6.50, N 9.64. Ethyl 1-[4-(dimethylamino)phenyl]-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (3e): Isolated as a yellow solid; m.p. 102–103 °C (PE/Et2O). IR ν˜ = 1709, 1691, 1604, 1522, 1440, 1406, 1362 cm–1. 1H NMR: δ = 7.51 (s, 1 H), 7.19 (d, J = 8.3 Hz, 2 H), 6.70 (d, J = 8.3 Hz, 2 H), 5.12 (s, 1 H), 4.13–3.98 (m, 2 H), 3.32–3.24 (m, 1 H), 3.04–2.96 (m, 1 H), 2.95 (s, 6 H), 2.83–2.76 (m, 2 H), 1.16 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.1, 163.3, 150.3, 128.7 (2 C), 127.7, 124.7 (2 C), 118.7, 112.0 (2 C), 71.9, 60.0, 50.3, 40.2, 35.6, 13.9 ppm. MS: m/z (%) = 315 (100) [M+], 259 (34.8), 195 (58.3), 158 (34.9). C17H21N3O3 (315.37): calcd. C 64.74, H 6.71, N 13.32; found C 64.97, H 6.82, N 13.41. Ethyl 1-(2-Bromophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3f): Isolated as a white solid; m.p. 112– 114 °C (PE/Et2O). IR ν˜ = 1728, 1694, 1603, 1363 cm–1. 1H NMR: δ = 7.62–7.56 (m, 2 H), 7.40–7.31 (m, 2 H), 7.21–7.13 (m, 1 H), 5.81 (s, 1 H), 4.13–3.97 (m, 2 H), 3.47–3.38 (m, 1 H), 3.28–3.21 (m, 2 H), 2.91–2.70 (m, 1 H), 1.12 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR: δ = 164.7, 162.9, 137.3, 132.8, 129.6 (2 C), 129.3, 127.7, 124.3, 117.3, 71.1, 60.3, 51.9, 35.5, 13.9 ppm. MS: m/z (%) = 352 (11.9) [M + 2], 350 (12.0) [M+], 195 (96.2), 55 (100). C15H15BrN2O3 (351.20): calcd. C 51.30, H 4.31, N 7.98; found C 51.46, H 4.38, N 7.92.

Ethyl 5-Oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2carboxylate (3a):[4] Isolated as a yellow solid; m.p. 96–98 °C (PE/ Et2O). 1H NMR: δ = 7.54 (s, 1 H), 7.38–7.28 (m, 5 H), 5.15 (s, 1 H), 4.13–3.97 (m, 2 H), 3.42–3.36 (m, 1 H), 3.05–3.01 (m, 1 H), 2.96–2.84 (m, 1 H), 2.80–2.71 (m, 1 H), 1.13 (m, J = 8.6 Hz, 3 H) ppm. 13C NMR: δ = 164.4, 163.0, 138.2, 128.2, 128.12 (2 C), 128.0, 127.9 (2 C), 117.9, 73.0, 60.0, 51.4, 35.3, 13.7 ppm.

Ethyl 1-(3-Bromophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3g): Isolated as a yellow solid; m.p. 124– 125 °C (PE/Et2O). IR ν˜ = 1728, 1694, 1603, 1363 cm–1. 1H NMR: δ = 7.58–7.53 (m, 2 H), 7.50–7.43 (m, 1 H), 7.40–7.31 (m, 1 H), 7.28–7.23 (m, 1 H), 5.11 (s, 1 H), 4.11–3.97 (m, 2 H), 3.49–3.44 (m, 1 H), 3.12–2.89 (m, 2 H), 2.81–2.70 (m, 1 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.6, 163.0, 141.1, 131.2, 131.1, 129.8, 128.6, 126.9, 122.4, 117.4, 72.9, 60.3, 52.0, 35.4, 13.9 ppm. MS: m/z (%) = 352 (7.6) [M + 2], 350 (7.7) [M+], 195 (86.6), 55 (100). C15H15BrN2O3 (351.20): calcd. C 51.30, H 4.31, N 7.98; found C 51.57, H 4.51, N 7.83.

Ethyl 1-(4-Methoxyphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3b):[4] Isolated as a yellowish solid; m.p. 87–88 °C (PE/Et2O). 1H NMR: δ = 7.52 (s, 1 H), 7.28 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 5.13 (d, J = 1.1 Hz, 1 H), 4.13–4.04 (m, 2 H), 3.80 (s, 3 H), 3.36–3.33 (m, 1 H), 3.10–2.98 (m, 1 H), 2.96–2.71 (m, 2 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.2, 163.1, 159.3, 129.9, 129.0 (2 C), 127.9, 118.1, 113.5 (2 C), 72.2, 60.0, 54.9, 50.9, 35.4, 13.8 ppm.

Ethyl 1-(4-Bromophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3h): Isolated as a yellowish solid; m.p. 92–93 °C (PE/Et2O). IR ν˜ = 1725, 1692, 1592, 1431, 1364 cm–1. 1H NMR: δ = 7.53–7.48 (m, 3 H), 7.31–7.26 (m, 2 H), 5.11 (d, J = 1.7 Hz, 1 H), 4.13–4.04 (m, 2 H), 3.47–3.43 (m, 1 H), 3.10–2.89 (m, 2 H), 2.80–2.71 (m, 1 H), 1.16 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.5, 163.0, 137.7, 131.4 (2 C), 129.8 (2 C), 128.5, 122.1, 117.5, 72.8, 60.3, 51.8, 35.4, 13.9 ppm. MS: m/z (%) = 352 (12.6) [M + 2],

The same procedure was used for the preparation of products 3b– p.

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Cycloaddition of Azomethine Imines and Propiolates 350 (12.9) [M+], 195 (92.3), 55 (100). C15H15BrN2O3 (351.20): calcd. C 51.30, H 4.31, N 7.98; found C 51.54, H 4.47, N 7.90. Ethyl 1-(2-Fluorophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3i):[10b] Isolated as a yellow solid; m.p. 98–99 °C (PE/Et2O). 1H NMR: δ = 7.59 (s, 1 H), 7.36–7.26 (m, 2 H), 7.18–7.03 (m, 2 H), 5.56 (d, J = 1.0 Hz, 1 H), 4.16–4.02 (m, 2 H), 3.46–3.41 (m, 1 H), 3.20–3.10 (m, 1 H), 2.96–2.73 (m, 2 H), 1.15 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR: δ = 164.4, 162.6, 160.5 (d, J = 245.9 Hz), 129.4 (d, J = 7.9 Hz), 129.0 (d, J = 3.6 Hz), 125.4 (J = 14.4 Hz), 123.8 (d, J = 2.9 Hz), 116.0, 114.9 (d, J = 21.8 Hz), 73.0, 65.5, 59.9, 51.3, 35.0, 13.5 ppm. Ethyl 1-(4-Fluorophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3j): Isolated as a yellowish solid; m.p. 103–105 °C (PE/Et2O). IR ν˜ = 1697, 1604, 1510, 1429, 1389, 1365 cm–1. 1H NMR: δ = 7.53 (s, 1 H), 7.40–7.35 (m, 2 H), 7.08– 7.01 (m, 2 H), 5.14 (s, 1 H), 4.11–4.04 (m, 2 H), 3.44–3.40 (m, 1 H), 3.05–2.95 (m, 1 H), 2.95–2.86 (m, 1 H), 2.83–2.71 (m, 1 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.4, 163.1, 162.4 (d, J = 244.5 Hz), 134.3, 129.7 (d, J = 8.6 Hz, 2 C), 128.3, 117.8, 115.1 (d, J = 21.5 Hz, 2 C), 72.5, 60.2, 51.6, 35.4, 13.8 ppm. MS: m/z (%) = 290 (39.7) [M+], 195 (93.4), 133 (31.2), 56 (100). C15H15FN2O3 (290.29): calcd. C 62.06, H 5.21, N 9.65; found C 62.23, H 5.36, N 9.60. Ethyl 5-Oxo-1-(pyridin-2-yl)-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (3k): Isolated as a yellow oil. IR ν˜ = 1697, 1601, 1433, 1387, 1364 cm–1. 1H NMR: δ = 8.62–8.59 (m, 1 H), 7.75–7.68 (m, 1 H), 7.58 (s, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.28– 7.23 (m, 1 H), 5.29–5.28 (m, 1 H), 4.13–3.97 (m, 2 H), 3.58–3.51 (m, 1 H), 3.21–3.12 (m, 1 H), 2.98–2.87 (m, 1 H), 2.78–2.67 (m, 1 H), 1.11 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.7, 163.1, 158.0, 149.3, 136.7, 129.2, 123.1, 122.6, 116.7, 75.0, 60.2, 52.5, 35.4, 13.9 ppm. MS: m/z (%) = 273 (9.9) [M+], 184 (75.3), 78 (34.4), 55 (100). C14H15N3O3 (273.29): calcd. C 61.53, H 5.53, N 15.38; found C 61.71, H 5.64, N 15.22. Ethyl 1-Cyclohexyl-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (3l):[4] Isolated as a white solid; m.p. 101–103 °C (PE/Et2O). 1H NMR: δ = 7.39 (s, 1 H), 4.29–4.14 (m, 2 H), 4.09– 4.05 (m, 1 H), 3.63–3.54 (m, 1 H), 3.03–2.90 (m, 2 H), 2.69–2.58 (m, 1 H), 2.08–1.92 (m, 1 H), 1.85–1.10 (m, 13 H) ppm. 13C NMR: δ = 166.4, 164.0, 129.6, 115.7, 75.6, 60.2, 56.1, 39.2, 35.0, 30.1, 26.7, 26.5, 26.2, 25.9, 14.2 ppm. Ethyl 7-Methyl-5-oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3m):[4] Isolated as a yellow solid; m.p. 95– 97 °C (PE/Et2O). 1H NMR: δ = 7.48–7.41 (m, 3 H), 7.410–7.23 (m, 3 H), 5.16 (d, J = 1.7 Hz, 1 H), 4.09–4.00 (m, 2 H), 3.46–3.42 (m, 1 H), 2.69–2.60 (m, 2 H), 1.13–1.07 (m, 6 H) ppm. 13C NMR: δ = 166.0, 163.3, 140.8, 128.7, 128.2 (2 C), 128.0 (2 C), 127.9, 117.6, 73.4, 63.5, 60.2, 42.8, 17.3, 13.9 ppm. Ethyl 7,7-Dimethyl-5-oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2a]pyrazole-2-carboxylate (3n):[4] Isolated as a yellowish solid; m.p. 110–111 °C (PE/Et2O). 1H NMR: δ = 7.52–7.51 (m, 1 H), 7.47– 7.41 (m, 2 H), 7.38–7.25 (m, 3 H), 5.46 (s, 1 H), 4.13–3.98 (m, 2 H), 2.87 (d, J = 15.7 Hz, 1 H), 2.37 (d, J = 15.7 Hz, 1 H), 1.25 (s, 3 H), 1.18–1.10 (m, 6 H) ppm. 13C NMR: δ = 166.0, 163.2, 141.8, 128.9, 127.9 (2 C), 127.5 (2 C), 127.4, 116.7, 64.1, 64.0, 59.9, 48.9, 24.5, 18.6, 13.7 ppm. Ethyl 5-Oxo-1,7-diphenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (3o): Isolated as a white solid; m.p. 112–114 °C (PE/Et2O). IR ν˜ = 1717, 1692, 1603, 1498, 1432, 1405, 1361 cm–1. 1 H NMR: δ = 7.60–7.59 (m, 1 H), 7.24–7.11 (m, 10 H), 5.18 (d, J = 1.7 Hz, 1 H), 4.46–4.42 (m, 1 H), 4.09–4.01 (m, 2 H), 2.97–2.90 Eur. J. Org. Chem. 2013, 6443–6448

(m, 2 H), 1.12 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 166.0, 163.2, 140.1, 135.7, 129.4, 128.2 (3 C), 127.7 (2 C), 127.5 (2 C), 127.4, 127.2 (2 C), 116.9, 72.8, 71.4, 60.1, 44.1, 13.8 ppm. MS: m/z (%) = 348 (28.0) [M+], 271 (68.0), 131 (100). C21H20N2O3 (348.40): calcd. C 72.40, H 5.79, N 8.04; found C 72.28, H 5.64, N 8.19. 2-Acetyl-5-oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole (3p):[4] Isolated as a yellow solid; m.p. 116–118 °C (PE/Et2O). 1H NMR: δ = 7.53 (s, 1 H), 7.40–7.29 (m, 5 H), 5.21 (s, 1 H), 3.43– 3.36 (m, 1 H), 3.09–3.01 (m, 1 H), 2.97–2.85 (m, 1 H), 2.81–2.72 (m, 1 H), 2.22–2.21 (m, 3 H) ppm. 13C NMR: δ = 192.5, 165.4, 138.1, 128.4 (3 C), 128.1, 127.9 (2 C), 126.9, 72.8, 51.3, 35.4, 26.6 ppm. Supporting Information (see footnote on the first page of this article): 1H and 13C NMR spectra.

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Eur. J. Org. Chem. 2013, 6443–6448