HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 11, 2014, pp. 2572-2587
Received, 29th September, 2014, Accepted, 31st October, 2014, Published online, 5th November, 2014.
DOI: 10.3987/COM-14-13094

■ A Diversity-Oriented Approach to 1H-Pyrazole-4,5-diols, 4-Hydroxy-3H-pyrazol-3-ones, and Phenylhydrazones from Key Intermediate 4-Acetyloxy-3H-pyrazol-3-one

Eiichi Masumoto, Fumi Okabe, Toshihiro Fujioka, Kenji Yamagata, and Hiroshi Maruoka*

Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

An approach to 1H-pyrazole-4,5-diols 4a−d, 4-hydroxy-3H-pyrazol-3-ones 5a−d, and phenylhydrazones 6a−d from key intermediate 4-acetyloxy-3H-pyrazol-3-one 3a is described. 4-Alkylidene-3H-pyrazol-3-ones 1a−c were reacted with m-chloroperbenzoic acid in the presence of potassium carbonate to give the corresponding spiroepoxide-3H-pyrazol-3-ones 2a−c. Treatment of 2a with acid anhydride such as acetic, propionic, butyric, and pentanoic anhydride in the presence of boron trifluoride diethyl etherate led to the corresponding 4-acyloxy-3H-pyrazol-3-ones 3a−d. The reactions of 3a with α-chloroketones, ketones, and/or secondary amines gave the corresponding 4a−d, 5a−d, and 6a−d.

INTRODUCTION
Five-membered nitrogen-containing heterocycles have received intensive research interests due to their biological properties and their utilities as intermediates, and found a wide range of applications in pharmaceutical and agrochemistry.1 Among them, the pyrazol-3-one and pyrazole motifs make up the core structures of numerous biologically active synthetic compounds. For example, pyrazol-3-ones are an important class of aza-heterocycles in several biologically active compounds: antiviral,2a antimicrobial,2b anti-inflammatory,2c antitumor,2d antiprion,2e and CCR3 antagonist.2f Recently, a new pyrazol-3-one compound, edaravone (2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one, also known as MCI-186), has been developed as a medical drug for brain ischemia and has also been reported to be effective for myocardial ischemia.3 Compounds containing pyrazole moiety have a wide range of biological activities, such as the HIV-1 reverse transcriptase inhibitor PNU-32945,4a cyclooxygenase-2 (COX-2) inhibitor celecoxib,4b fungicide pyraclostrobin,4c insecticides fipronil,4d and phosphodiesterase inhibitor sildenafil.4e For these reasons, a large number of general methods for the preparation of pyrazol-3-one and pyrazole derivatives have recently been reported.5
On the other hand, hydrazones have also been a useful scaffold in medicinal chemistry for many years. Hydrazone-containing organic compounds have been shown to possess potent biological activity including: antitumor, analgesic, antidepressant, antiviral, antimicrobial, and antimalarial.6 Although phenylhydrazones showed various bioactivities including antioxidative,7a antiparasitic,7b and antitubercular properties,7c as far as we are aware, naturally occurring ones almost have not been reported in the literature. Farylhydrazones A and B are naturally occurring phenylhydrazones recently isolated from cultures of the Cordyceps-colonizing fungus Isaria farinosa.8 Phenylhydrazones have been used extensively for protection of the carbonyl groups in organic synthesis,9 for derivatization, resolution, and characterization of carbonyl-containing natural products,10 and for studying the hydrazone-enehydrazine tautomeric transformation in the synthesis of indole derivatives.11 In addition, Sheibani and Esfandiarpoor have discussed the synthesis of pyridazines in a one-step procedure from three-component reactions of arylhydrazones, aldehydes, and malononitrile.12

In the course of our investigation of the synthesis of novel pyrazol-3-one and pyrazole derivatives, we have shown the synthesis of spirocyclopropanepyrazoles C,13a pyrano[2,3-c]pyrazoles D,13b O-substituted pyrazoles E,13c C-cyanomethylated pyrazoles F,13d and spiroiminolactonepyrazoles G13e from 3H-pyrazol- 3-ones as versatile starting materials (Figure 1). In connection with the synthesis and reactivity of pyrazol-3-one and pyrazole derivatives, it seems to us of interest to examine the chemical properties of spiroepoxidepyrazole derivatives as the key intermediate. Epoxides, especially spiroepoxideheterocycles, are versatile building blocks for the synthesis of many bioactive natural products. They are an ideal source for diversity because they can be opened with nucleophiles. They are well-known carbon electrophiles and their ability to undergo regioselective ring-opening reactions contributes to their synthetic value.14 On the basis of the above experimental results together with some literature reports, we decided to extend the utility of spiroepoxide-3H-pyrazol-3-ones, and herein describe a divergent synthesis of 1H-pyrazole-4,5-diols, 4-hydroxy-3H-pyrazol-3-ones, and phenylhydrazones from 4-acetyloxy-3H- pyrazol-3-one, which is easily prepared by boron trifluoride-assisted ring opening of spiroepoxide-3H- pyrazol-3-ones with acid anhydride.

RESULTS AND DISCUSSION
The starting materials, 4-alkylidene-3H-pyrazol-3-ones 1a−c, were prepared by treatment of 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one with ketones such as acetone, cyclopentanone, and cycloheptanone according to the method reported in literature.15 An initial attempt to react 1a−c with m-chloroperbenzoic acid (m-CPBA) using the method of DeRuiter and co-workers15c failed and the expected spiroepoxide-3H-pyrazol-3-ones 2a−c were observed as trace level. The reaction was not clean. Therefore, to achieve an efficient synthesis of spiroepoxide-3H-pyrazol-3-ones, we examined the epoxidation of 2a−c. As a consequence, the reaction of 1a−c with m-CPBA in the presence of potassium carbonate in CHCl3 at room temperature led to the corresponding spiroepoxide-3H-pyrazol-3-ones 2a−c (Scheme 1). In this case, it seems that the substrates 1a−c were activated by deprotonation of alkylidene proton in the presence of potassium carbonate and then the epoxidation could be promoted by using activated intermediates H.

With the aim of extending the ring-opening reaction of spiroepoxide derivatives of 3H-pyrazol-3-ones, we next tried the reaction of 2a with acetic anhydride in the presence of H2SO4 as acid catalyst according to the method reported by Kirschke and Schmitz.15b In this reaction, however, our attempts were unacceptable with respect to yield (up to 22%). The reaction was not clean. After different conditions were screened, we were delighted to find that the expected 4-acetyloxy-3H-pyrazol-3-one 3a was obtained from this reaction with boron trifluoride diethyl etherate (BF3 • OEt2) as Lewis acid in CHCl3 (Scheme 2 and entry 1 in Table 1). The effect of Lewis acid was observed with BF3 • OEt2 giving the highest yield of 3a, while other Lewis acids such as zinc chloride and titanium(IV) chloride gave none of 3a (entries 4 and 5). With the optimized reaction conditions in hand, 2a was subjected to react with acetic, propionic, butyric, and pentanoic anhydride, and the representative results are summarized in Scheme 2.

These products 3b−d gave satisfactory elemental analyses and spectroscopic data (IR, 1H NMR, 13C NMR, and MS) consistent with their assigned structures (see experimental section). Further, to confirm the structure of 3a, we carried out the reaction of 2b,c with acetic anhydride. Thus, treatment of 2b,c with acetic anhydride in the presence of BF3 • OEt2 afforded the 4-acetyloxy-3H-pyrazol-3-one 3a (60% from 2b, 30% from 2c), which were identical with an authentic sample prepared from 2a and acetic anhydride according to Scheme 2 on the basis of a comparison of the melting point, IR, and NMR spectra. The formation of 4-acyloxy-3H-pyrazol-3-ones 3a−d could be explained by possible mechanism presented in Scheme 2. It is conceivable that the initial event is the formation of the ring-opening BF3 complexes I from compound 2a and acid anhydride, which underwent elimination of acyl group and acetone to result in the formation of 3a−d.
With these results in hand, we investigated a divergent method for the synthesis of pyrazole derivatives from 4-acetyloxy-3H-pyrazol-3-one 3a in detail (Scheme 3). Thus, when a mixture of 3a and α-chloroketones, such as chloroacetone, phenacyl chloride, 4-methylphenacyl chloride, and 4-chlorophenacyl chloride, in the presence of sodium hydride in DMF was stirred at room temperature for 12 h, the 1H-pyrazole-4,5-diols 4a−d were obtained with 56−79% isolated yields. While, the reaction of 3a with ketones, such as acetone, acetophenone, 4’-methylacetophenone, and 4’-chloroacetophenone, in the presence of Et3N and H2O using air as the oxidant at room temperature for 12 h led to the corresponding 4-hydroxy-3H-pyrazol-3-ones 5a−d in moderate to good yields. To simplify the reaction, the ketones were used to serve as the reagent and solvent. We carried out several experiments on 5a, testing different reaction conditions, e.g. time and substrate/base molar ratio, but no positive result was achieved (entries 3−6 in Table 2). Additive effects were observed with H2O giving the highest yield of 5a (entries 1 and 4). It makes us believe that this reaction can only be promoted by using Et3N/H2O system (entries 1 and 2).

Furthermore, we found the reaction condition under which phenylhydrazone derivatives 6a−d could be isolated. Indeed, thermal treatment of 3a with secondary amines,16 such as dimethylamine hydrochloride, morpholine, piperidine, and pyrrolidine, using air as the oxidant for 1−2 h gave the corresponding phenylhydrazones 6a−d in 48−66% yields. In this reaction, secondary amines were used to serve as the reagent and solvent in order to simplify the reaction. In general, the NH proton of E-phenylhydrazones is observed in high magnetic field (near δ 9.0), whereas that of Z-phenylhydrazones appears at lower field (near δ 12.0).9 The 1H NMR spectra of 6a−d in CDCl3 exhibit a one-proton singlet near δ 8.7 due to the hydrazone NH proton. These observations indicate that 6a−d existed as a geometrical single isomer of E configuration. In addition, for products 6a−d, a clear nuclear Overhauser effect was observed between the hydrazone NH proton and the methyl protons of E configuration. The structures of compounds 4a−d, 5a−d, and 6a−d were deduced from their elemental analyses, MS, IR, 1H NMR, and 13C NMR spectra (see experimental section).
A plausible mechanism for the formation of 5a−d and 6a−d is shown in Scheme 4. These reactions are assumed to proceed through the formation of the non-isolable intermediate 1H-pyrazole-4,5-dione J. In all cases of synthesis of compounds 5 and 6, J was not observed at all, and this could be explained by the instability structure of J under these reaction conditions. Thus, a deacetylation and subsequent aerobic oxidation17 of 4-acetyloxy-3H-pyrazol-3-one 3a easily occurs and then J would be produced. The reaction of J with ketones probably causes aldol-type addition of activated methyl group of ketones to C-4 position of J, giving the 4-hydroxy-3H-pyrazol-3-ones 5a−d. On the other hand, thermal treatment of J with secondary amines would cause nucleophilic addition of secondary amines to C-5 position of J and subsequent ring opening to afford the phenylhydrazones 6a−d. In these reactions, to check something about the reactivity of the intermediate 1H-pyrazole-4,5-dione J, we examined a ring transformation of 5b. Indeed, thermal treatment of 5b with piperidine caused a retro-aldol reaction of acetophenone and subsequent ring opening via a nucleophilic addition of piperidine to give 6c (66%), which was identical with an authentic sample prepared from 3a and piperidine according to Scheme 3 on the basis of a comparison of the melting point, IR, and NMR spectra.

In conclusion, we have demonstrated the divergent synthesis of 1H-pyrazole-4,5-diols 4a−d, 4-hydroxy-3H-pyrazol-3-ones 5a−d, and phenylhydrazones 6a−d from the key intermediate 4-acetyloxy- 3H-pyrazol-3-one 3a, which is easily prepared by BF3•OEt2-assisted ring opening of the spiroepoxide-3H- pyrazol-3-one 2a with acetic anhydride via an elimination of acetyl group and acetone. Pyrazole and phenylhydrazone derivatives are important building blocks in organic synthesis and for the preparation of biologically active compounds with interest in medicinal chemistry. Further synthesis and evaluation for biological activities of novel pyrazole and phenylhydrazone derivatives are in progress.

EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a JASCO FT/IR-4100 spectrometer. The 1H and 13C NMR spectra were measured with a JEOL JNM-A500 spectrometer at 500.00 and 125.65 MHz, respectively. The 1H and 13C chemical shifts (δ) are reported in parts per million (ppm) relative to TMS as internal standard. Positive FAB MS spectra were obtained on a JEOL JMS-700T spectrometer. Elemental analyses were performed on YANACO MT-6 CHN analyzer. The starting compounds 1a,15c 1b,15e and 1c were prepared in this laboratory according to the procedure reported in literature.15
4-Cycloheptylidene-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one (1c): Yellow scales (63%), mp 99−100 °C (Et2O/petroleum ether); IR (KBr): ν 1679 cm-1 (CO); 1H NMR (CDCl3): δ 1.58−1.61 (m, 4H, 2CH2), 1.79−1.84 (m, 4H, 2CH2), 2.42 (s, 3H, 5-Me), 2.88−2.91 (m, 2H, CH2), 3.33−3.35 (m, 2H, CH2), 7.13−7.16 (m, 1H, Ph-H), 7.36−7.39 (m, 2H, Ph-H), 7.93−7.94 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 19.2 (5-Me), 25.8, 27.0, 28.7, 28.9, 33.3, 34.8 (CH2), 119.0, 124.5 (Ph-C), 124.6 (C-4), 128.6, 138.5 (Ph-C), 147.7 (C-5), 163.6 (cycloheptane C-1), 176.5 (CO); FAB MS: m/z 269 [M+H]+. Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51; N, 10.44. Found: C, 76.07; H, 7.51; N, 10.32.
General procedure for the preparation of spiroepoxide-3H-pyrazol-3-ones 2a−c from 1a−c and m-CPBA in the presence of K2CO3. To an ice-cooled and stirred solution of 1a−c (15 mmol) and m-CPBA (3.88 g, 22.5 mmol) in CHCl3 (100 mL), K2CO3 (3.11 g, 22.5 mmol) was added. After the mixture was stirred at 0−5 °C for 1 h, the solid was removed by filtration and washed with CHCl3. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with CHCl3 as the eluent to give 2a15c (2.90 g, 84%), 2b (3.02 g, 79%), and 2c (2.14 g, 50%).
4-Methyl-11-oxa-2-phenyl-2,3-diazadispiro[4.0.4.1]undec-3-en-1-one (2b): Colorless needles (3.02 g, 79%), mp 70−72 ˚C (Et2O/petroleum ether); IR (KBr): ν 1726 cm-1 (CO); 1H NMR (CDCl3): δ 1.62−2.12 (m, 6H, 3CH2), 2.13 (s, 3H, 4-Me), 2.14−2.27 (m, 2H, CH2), 7.12−7.20 (m, 1H, Ph-H), 7.37−7.42 (m, 2H, Ph-H), 7.88−7.91 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 14.9 (4-Me), 24.4, 25.3, 29.9, 32.0 (CH2), 65.5 (C-5), 79.3 (C-6), 118.5, 125.1, 128.8, 138.3 (Ph-C), 156.7 (C-4), 167.5 (CO); FAB MS: m/z 257 [M+H]+. Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.27; H, 6.34; N, 10.88.
4-Methyl-13-oxa-2-phenyl-2,3-diazadispiro[4.0.6.1]tridec-3-en-1-one (2c): Yellow prisms (2.14 g, 50%), mp 59−61 ˚C (Et2O/petroleum ether); IR (KBr): ν 1719 cm-1 (CO); 1H NMR (CDCl3): δ 1.44−1.86 (m, 8H, 4CH2), 2.04−2.19 (m, 2H, CH2), 2.20 (s, 3H, 4-Me), 2.21−2.49 (m, 2H, CH2), 7.17−7.21 (m, 1H, Ph-H), 7.38−7.42 (m, 2H, Ph-H), 7.87−7.90 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 16.6 (4-Me), 24.1, 24.9, 28.5, 29.3, 34.8 (CH2), 66.6 (C-5), 76.3 (C-6), 118.7, 125.2, 128.8, 138.3 (Ph-C), 156.4 (C-4), 168.0 (CO); FAB MS: m/z 285 [M+H]+. Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85. Found: C, 71.89; H, 7.12; N, 9.81.
General procedure for the preparation of 4-acyloxy-3H-pyrazol-3-ones 3a−d from 2a and acid anhydride in the presence of BF3 • OEt2. To an ice-cooled and stirred solution of 2a (0.230 g, 1 mmol) and/or acetic anhydride (0.204 g, 2 mmol), propionic anhydride (0.260 g, 2 mmol), butyric anhydride (0.316 g, 2 mmol), or pentanoic anhydride (0.373 g, 2 mmol) in CHCl3 (10 mL), BF3 • OEt2 (0.284 g, 2 mmol) was added. After the mixture was stirred at rt for 12 h, cold H2O was added to the reaction mixture with stirring and ice-cooling. The resulting mixture was extracted with CHCl3 (60 mL). The extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with CHCl3 as the eluent to yield 3a−d.
4-(Acetyloxy)-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one (3a): Colorless prisms (0.153 g, 66%), mp 128−130 ˚C (acetone/petroleum ether); IR (KBr): ν 1761, 1631 cm-1 (CO); 1H NMR (CDCl3): δ 2.13 (s, 3H, pyrazole 5-Me), 2.23 (s, 3H, OCOMe), 5.57 (s, 1H, pyrazole 4-H), 7.18−7.26 (m, 1H, Ph-H), 7.36−7.41 (m, 2H, Ph-H), 7.81−7.84 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 14.7 (pyrazole 5-Me), 20.1 (OCOMe), 73.1 (pyrazole C-4), 118.8, 125.5, 128.9, 137.7 (Ph-C), 155.6 (pyrazole C-5), 167.6 (pyrazole C-3), 169.2 (OCOMe); FAB MS: m/z 233 [M+H]+. Anal. Calcd for C12H12N2O3: C, 62.06; H, 5.21; N, 12.06. Found: C, 62.05; H, 5.27; N, 11.98.
2,4-Dihydro-5-methyl-4-(1-oxopropoxy)-2-phenyl-3H-pyrazol-3-one (3b): Colorless needles (0.192 g, 78%), mp 150−152 ˚C (acetone/petroleum ether); IR (KBr): ν 1771, 1632 cm-1 (CO); 1H NMR (CDCl3): δ 1.22 (t, J = 7.3 Hz, 3H, OCOCH2Me), 2.12 (s, 3H, pyrazole 5-Me), 2.48−2.54 (m, 2H, OCOCH2Me), 5.56 (s, 1H, pyrazole 4-H), 7.17−7.26 (m, 1H, Ph-H), 7.36−7.41 (m, 2H, Ph-H), 7.82−7.85 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 9.0 (OCOCH2Me), 14.7 (pyrazole 5-Me), 26.9 (OCOCH2Me), 73.0 (pyrazole C-4), 118.8, 125.4, 128.9, 137.8 (Ph-C), 155.6 (pyrazole C-5), 167.7 (pyrazole C-3), 172.7 (OCOCH2Me); FAB MS: m/z 247 [M+H]+. Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.36; H, 5.79; N, 11.30.
2,4-Dihydro-5-methyl-4-(1-oxobutoxy)-2-phenyl-3H-pyrazol-3-one (3c): Colorless needles (0.158 g, 61%), mp 121−123 ˚C (acetone/petroleum ether); IR (KBr): ν 1766, 1631 cm-1 (CO); 1H NMR (CDCl3): δ 1.00 (t, J = 7.3 Hz, 3H, OCOCH2CH2Me), 1.69−1.78 (m, 2H, OCOCH2CH2Me), 2.12 (s, 3H, pyrazole 5-Me), 2.47 (t, J = 7.3 Hz, 2H, OCOCH2CH2Me), 5.57 (s, 1H, pyrazole 4-H), 7.17−7.26 (m, 1H, Ph-H), 7.37−7.41 (m, 2H, Ph-H), 7.82−7.84 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 13.5 (OCOCH2CH2Me), 14.7 (pyrazole 5-Me), 18.4 (OCOCH2CH2Me), 35.3 (OCOCH2CH2Me), 73.0 (pyrazole C-4), 118.8, 125.4, 128.9, 137.8 (Ph-C), 155.6 (pyrazole C-5), 167.7 (pyrazole C-3), 171.9 (OCOCH2CH2Me); FAB MS: m/z 261 [M+H]+. Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.66; H, 6.26; N, 10.75.
2,4-Dihydro-5-methyl-4-(1-oxopentyloxy)-2-phenyl-3H-pyrazol-3-one (3d): Colorless needles (0.252 g, 92%), mp 80−82 ˚C (Et2O/petroleum ether); IR (KBr): ν 1770, 1635 cm-1 (CO); 1H NMR (CDCl3): δ 0.94 (t, J = 7.3 Hz, 3H, OCOCH2CH2CH2Me), 1.35−1.45 (m, 2H, OCOCH2CH2CH2Me), 1.59−1.76 (m, 2H, OCOCH2CH2CH2Me), 2.12 (s, 3H, pyrazole 5-Me), 2.50 (t, J = 7.3 Hz, 2H, OCOCH2CH2CH2Me), 5.57 (s, 1H, pyrazole 4-H), 7.17−7.34 (m, 1H, Ph-H), 7.35−7.43 (m, 2H, Ph-H), 7.82−7.85 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 13.6 (OCOCH2CH2CH2Me), 14.7 (pyrazole 5-Me), 22.1 (OCOCH2CH2CH2Me), 26.9 (OCOCH2CH2CH2Me), 33.2 (OCOCH2CH2CH2Me), 73.0 (pyrazole C-4), 118.8, 125.4, 128.9, 137.8 (Ph-C), 155.6 (pyrazole C-5), 167.7 (pyrazole C-3), 172.0 (OCOCH2CH2CH2Me); FAB MS: m/z 275 [M+H]+. Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.65; H, 6.66; N, 10.19.
The preparation of 4-acetyloxy-3H-pyrazol-3-one 3a from 2b,c and acetic anhydride in the presence of BF3• OEt2. To an ice-cooled and stirred solution of 2b (0.256 g, 1 mmol) or 2c (0.284 g, 1 mmol) and/or acetic anhydride (0.204 g, 2 mmol) in CHCl3 (10 mL), BF3 • OEt2 (0.284 g, 2 mmol) was added. After the mixture was stirred at rt for 12 h, cold H2O was added to the reaction mixture with stirring and ice-cooling. After work-up as described above, 3a (0.142 g, 60% from 2b; 0.070 g, 30% from 2c) was obtained.
General procedure for the preparation of 1H-pyrazole-4,5-diols 4a−d from 3a and α-chloroketones in the presence of NaH. To an ice-cooled and stirred solution of 3a (0.232 g, 1 mmol) in DMF (5 mL), 60% NaH (0.040 g, 1.1 mmol) was added. The stirring was continued at rt until evolution of gas ceased. To the obtained mixture, chloroacetone (0.185 g, 2 mmol), phenacyl chloride (0.309 g, 2 mmol), 4-methylphenacyl chloride (0.337 g, 2 mmol), and 4-chlorophenacyl chloride (0.378 g, 2 mmol) were added with stirring at rt, and then the mixture was stirred at rt for 12 h. After removal of the solvent in vacuo, cold H2O was added to the residue. The resulting mixture was extracted with CHCl3 (60 mL). The extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with CHCl3 as the eluent to afford 4a−d.
1-{[4-(Acetyloxy)-3-methyl-1-phenyl-1H-pyrazol-5-yl]oxy}-2-propanone (4a): Colorless prisms (0.216 g, 75%), mp 103−105 ˚C (acetone/petroleum ether); IR (KBr): ν 1768, 1731 cm-1 (CO); 1H NMR (CDCl3): δ 2.14 (s, 3H, pyrazole 3-Me), 2.18 (s, 3H, OCH2COMe), 2.28 (s, 3H, OCOMe), 4.55 (s, 2H, OCH2COMe), 7.26−7.31 (m, 1H, Ph-H), 7.41−7.44 (m, 2H, Ph-H), 7.63−7.66 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 11.7 (pyrazole 3-Me), 20.2 (OCOMe), 26.1 (OCH2COMe), 76.2 (OCH2COMe), 118.3 (pyrazole C-4), 122.4, 126.9, 129.0, 138.4 (Ph-C), 141.7 (pyrazole C-3), 142.6 (pyrazole C-5), 168.8 (OCOMe), 203.3 (OCH2COMe); FAB MS: m/z 289 [M+H]+. Anal. Calcd for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72. Found: C, 62.53; H, 5.64; N, 9.67.
2-{[4-(Acetyloxy)-3-methyl-1-phenyl-1H-pyrazol-5-yl]oxy}-1-phenylethanone (4b): Pale red needles (0.262 g, 75%), mp 87−89 ˚C (acetone/petroleum ether); IR (KBr): ν 1771, 1763, 1753, 1700 cm-1 (CO); 1H NMR (CDCl3): δ 2.09 (s, 3H, OCOMe), 2.12 (s, 3H, pyrazole 3-Me), 5.29 (s, 2H, OCH2COPh), 7.25−7.28 (m, 1H, Ph-H), 7.38−7.47 (m, 4H, Ph-H), 7.58−7.61 (m, 1H, Ph-H), 7.69−7.72 (m, 2H, Ph-H), 7.83−7.85 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 11.8 (pyrazole 3-Me), 20.1 (OCOMe), 73.9 (OCH2COPh), 118.3 (pyrazole C-4), 122.4, 126.7, 127.8, 128.9, 129.0, 134.0, 138.5 (Ph-C), 141.7 (pyrazole C-3), 142.8 (pyrazole C-5), 168.8 (OCOMe), 192.5 (OCH2COPh); FAB MS: m/z 351 [M+H]+. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.48; H, 5.23; N, 7.99.
2-{[4-(Acetyloxy)-3-methyl-1-phenyl-1H-pyrazol-5-yl]oxy}-1-(4-methylphenyl)ethanone (4c): Colorless prisms (0.286 g, 79%), mp 105−107 ˚C (acetone/petroleum ether); IR (KBr): ν 1766, 1694 cm-1 (CO); 1H NMR (CDCl3): δ 2.09 (s, 3H, OCOMe), 2.12 (s, 3H, pyrazole 3-Me), 2.40 (s, 3H, OCH2CO-4-Me-C6H4), 5.27 (s, 2H, OCH2CO-4-Me-C6H4), 7.24−7.28 (m, 2H, Ph-H), 7.38−7.42 (m, 3H, Ph-H), 7.70−7.76 (m, 4H, Ph-H); 13C NMR (CDCl3): δ 11.8 (pyrazole 3-Me), 20.1 (OCOMe), 21.7 (OCH2CO-4-Me-C6H4), 73.8 (OCH2CO-4-Me-C6H4), 118.3 (pyrazole C-4), 122.3, 126.6, 127.9, 128.9, 129.6, 131.5, 138.6 (Ph-C), 141.6 (pyrazole C-3), 142.9 (pyrazole C-5), 145.1 (Ph-C), 168.8 (OCOMe), 192.1 (OCH2CO-4-Me-C6H4); FAB MS: m/z 365 [M+H]+. Anal. Calcd for C21H20N2O4: C, 69.22; H, 5.53; N, 7.69. Found: C, 69.29; H, 5.56; N, 7.65.
2-{[4-(Acetyloxy)-3-methyl-1-phenyl-1H-pyrazol-5-yl]oxy}-1-(4-chlorophenyl)ethanone (4d): Pale red needles (0.216 g, 56%), mp 114−116 ˚C (acetone/petroleum ether); IR (KBr): ν 1764, 1698 cm-1 (CO); 1H NMR (CDCl3): δ 2.13 (s, 3H, pyrazole 3-Me), 2.14 (s, 3H, OCOMe), 5.22 (s, 2H, OCH2CO-4-Cl-C6H4), 7.25−7.29 (m, 1H, Ph-H), 7.38−7.43 (m, 2H, Ph-H), 7.66−7.68 (m, 2H, Ph-H), 7.76-7.79 (m, 2H, Ph-H), 7.83−7.85 (m, 2H, Ph-H); 13C-NMR (CDCl3): δ 11.7 (pyrazole 3-Me), 20.2 (OCOMe), 73.9 (OCH2CO-4-Cl-C6H4), 118.5 (pyrazole C-4), 122.4, 126.8, 129.0, 129.3, 132.3, 138.5, 140.6 (Ph-C), 141.6 (pyrazole C-3), 142.7 (pyrazole C-5), 168.8 (OCOMe), 191.7 (OCH2CO-4-Cl-C6H4); FAB MS: m/z 385 [M+H]+. Anal. Calcd for C20H17ClN2O4: C, 62.42; H, 4.45; N, 7.28. Found: C, 62.17; H, 4.45; N, 7.29.
General procedure for the preparation of 4-hydroxy-3H-pyrazol-3-ones 5a−d from 3a and ketones in the presence of Et3N and H2O. A mixture of 3a (0.232 g, 1 mmol), Et3N (0.202 g, 2 mmol), H2O (1 mL), and acetone (5 mL, 68.1 mmol), acetophenone (5 mL, 42.9 mmol), 4’-methylacetophenone (5 mL, 37.4 mmol), or 4’-chloroacetophenone (5 mL, 38.6 mmol) was stirred at rt for 12 h. The reaction mixture was extracted with CHCl3 (60 mL). The extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with CHCl3 as the eluent to provide 5a−d.
2,4-Dihydro-4-hydroxy-5-methyl-4-(2-oxopropyl)-2-phenyl-3H-pyrazol-3-one (5a): Pale yellow oil (0.209 g, 85%); IR (KBr): ν 3361 (OH), 1714, 1632 cm-1 (CO); 1H NMR (CDCl3): δ 2.12 (s, 3H, pyrazole 5-Me), 2.19 (s, 3H, CH2COMe), 2.99 (s, 2H, CH2COMe), 4.85 (br, 1H, OH), 7.17−7.21 (m, 1H, Ph-H), 7.37−7.40 (m, 2H, Ph-H), 7.82−7.85 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 13.2 (pyrazole 5-Me), 31.1 (CH2COMe), 46.4 (CH2COMe), 77.2 (pyrazole C-4), 119.0, 125.4, 128.9, 137.6 (Ph-C), 160.1 (pyrazole C-5), 172.0 (pyrazole C-3), 206.1 (CH2COMe); FAB MS: m/z 247 [M+H]+. Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.22; H, 5.93; N, 11.27.
2,4-Dihydro-4-hydroxy-5-methyl-4-(2-oxo-2-phenylethyl)-2-phenyl-3H-pyrazol-3-one (5b): Colorless prisms (0.226 g, 73%), mp 106−108 ˚C (Et2O/petroleum ether); IR (KBr): ν 3436 (OH), 1726, 1665 cm-1 (CO); 1H NMR (CDCl3): δ 2.13 (s, 3H, pyrazole 5-Me), 3.60 (s, 2H, CH2COPh), 4.80 (br, 1H, OH), 7.17−7.20 (m, 1H, Ph-H), 7.36−7.46 (m, 4H, Ph-H), 7.57−7.60 (m, 1H, Ph-H), 7.86−7.89 (m, 4H, Ph-H); 13C NMR (CDCl3): δ 13.4 (pyrazole 5-Me), 42.6 (CH2COPh), 77.5 (pyrazole C-4), 119.0, 125.3, 128.2, 128.8, 128.9, 134.2, 135.7, 137.7 (Ph-C), 160.4 (pyrazole C-5), 172.1 (pyrazole C-3), 196.9 (CH2COPh); FAB MS: m/z 309 [M+H]+. Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.18; H, 5.31; N, 9.09.
2,4-Dihydro-4-hydroxy-5-methyl-4-[2-oxo-2-(4-methylphenyl)ethyl]-2-phenyl-3H-pyrazol-3-one (5c): Colorless needles (0.211 g, 66%), mp 120−122 ˚C (Et2O/petroleum ether); IR (KBr): ν 3273 (OH), 1702, 1671 cm-1 (CO); 1H NMR (CDCl3): δ 2.13 (s, 3H, pyrazole 5-Me), 2.40 (s, 3H, CH2CO-4-Me-C6H4), 3.54 (s, 2H, CH2CO-4-Me-C6H4), 4.95 (br, 1H, OH), 7.17−7.20 (m, 1H, Ph-H), 7.22−7.25 (m, 2H, Ph-H), 7.36−7.40 (m, 2H, Ph-H), 7.70−7.79 (m, 2H, Ph-H), 7.86−7.89 (m, 2H, Ph-H); 13C NMR (CDCl3): δ 13.5 (pyrazole 5-Me), 21.7 (CH2CO-4-Me-C6H4), 42.2 (CH2CO-4-Me-C6H4), 77.6 (pyrazole C-4), 118.9, 125.2, 128.4, 128.8, 129.5, 133.3, 137.7, 145.3 (Ph-C), 160.4 (pyrazole C-5), 172.0 (pyrazole C-3), 196.8 (CH2CO-4-Me-C6H4); FAB MS: m/z 323 [M+H]+. Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.80; H, 5.69; N, 8.69.
2,4-Dihydro-4-hydroxy-5-methyl-4-[2-oxo-2-(4-chlorophenyl)ethyl]-2-phenyl-3H-pyrazol-3-one (5d): Colorless needles (0.256 g, 75%), mp 122−124 ˚C (Et2O/petroleum ether); IR (KBr): ν 3457 (OH), 1714, 1681, 1672 cm-1 (CO); 1H NMR (CDCl3): δ 2.13 (s, 3H, pyrazole 5-Me), 3.55 (s, 2H, CH2CO-4-Cl-C6H4), 4.73 (br, 1H, OH), 7.18−7.21 (m, 1H, Ph-H), 7.37−7.42 (m, 4H, Ph-H), 7.79−7.86 (m, 4H, Ph-H); 13C-NMR (CDCl3): δ 13.4 (pyrazole 5-Me), 42.7 (CH2CO-4-Cl-C6H4), 77.4 (pyrazole C-4), 119.0, 125.4, 128.9, 129.2, 129.6, 134.0, 137.6, 140.8 (Ph-C), 160.2 (pyrazole C-5), 172.0 (pyrazole C-3), 195.5 (CH2CO-4-Cl-C6H4); FAB MS: m/z 343 [M+H]+. Anal. Calcd for C18H15ClN2O3: C, 63.07; H, 4.41; N, 8.17. Found: C, 63.05; H, 4.49; N, 8.18.
General procedure for the preparation of phenylhydrazones 6a−d from 3a and secondary amines.
Procedure A. A mixture of 3a (0.232 g, 1 mmol), dimethylamine hydrochloride (0.163 g, 2 mmol), and Et3N (0.202 g, 2 mmol) in THF (5 mL) was refluxed for 2 h. After removal of the solvent in vacuo, cold H2O was added to the residue. The resulting mixture was extracted with CHCl3 (60 mL). The extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with CHCl3 as the eluent to give 6a.
Procedure B. A solution of 3a (0.232 g, 1 mmol), and morpholine (5 mL, 57.2 mmol), piperidine (5 mL, 50.6 mmol), or pyrrolidine (5 mL, 59.9 mmol) was stirred at 80 °C for 1 h. After the excess amine was removed in vacuo, the residue was purified by column chromatography on silica gel with CHCl3 as the eluent to give 6b−d.
(3E)-1-(Dimethylamino)-3-(2-phenylhydrazone)-1,2,3-butanetrione (6a): Colorless needles (0.113 g, 48%), mp 170−172 ˚C (acetone/petroleum ether); IR (KBr): ν 3221 (NH), 1661, 1636 cm-1 (CO); 1H NMR (CDCl3): δ 1.99 (s, 3H, Me), 2.89, 3.10 (s, 6H, NMe2), 6.98−7.01 (m, 1H, Ph-H), 7.11−7.13 (m, 2H, Ph-H), 7.24−7.27 (m, 2H, Ph-H), 8.71 (s, 1H, NH); 13C-NMR (CDCl3): δ 33.8, 37.2 (NMe2), 7.41 (Me), 114.5, 123.1, 129.3 (Ph-C), 138.4 (C-3), 142.5 (Ph-C), 169.0 (C-1), 190.3 (C-2); FAB MS: m/z 234 [M+H]+. Anal. Calcd for C12H15N3O2: C, 61.79; H, 6.48; N, 18.01. Found: C, 61.85; H, 6.61; N, 17.93.
(3E)-1-(4-Morpholinyl)-3-(2-phenylhydrazone)-1,2,3-butanetrione (6b): Yellow needles (0.158 g, 57%), mp 173−175 ˚C (acetone/petroleum ether); IR (KBr): ν 3446 (NH), 1656, 1622 cm-1 (CO); 1H NMR (CDCl3): δ 2.00 (s, 3H, Me), 3.28−3.29 (m, 2H, CH2), 3.60−3.62 (m, 2H, CH2), 3.75−3.80 (m, 4H, 2CH2), 7.01−7.04 (m, 1H, Ph-H), 7.15−7.17 (m, 2H, Ph-H), 7.26−7.29 (m, 2H, Ph-H), 8.64 (s, 1H, NH); 13C NMR (CDCl3): δ 7.40 (Me), 41.4, 46.3, 66.5, 66.6 (CH2), 114.5, 123.3, 129.4 (Ph-C), 138.6 (C-3), 142.2 (Ph-C), 167.4 (C-1), 189.7 (C-2); FAB MS: m/z 276 [M+H]+. Anal. Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26. Found: C, 61.10; H, 6.31; N, 15.23.
(3E)-3-(2-Phenylhydrazone)-1-(1-piperidinyl)-1,2,3-butanetrione (6c): Yellow needles (0.181 g, 66%), mp 190−191 ˚C (acetone/petroleum ether); IR (KBr): ν 3274 (NH), 1659, 1623 cm-1 (CO); 1H NMR (CDCl3): δ 1.50−1.53 (m, 2H, CH2), 1.65−1.80 (m, 4H, 2CH2), 1.98 (s, 3H, Me), 3.20−3.68 (m, 4H, 2CH2), 6.97−7.00 (m, 1H, Ph-H), 7.16−7.18 (m, 2H, Ph-H), 7.22−7.27 (m, 2H, Ph-H), 8.87 (s, 1H, NH); 13C NMR (CDCl3): δ 7.49 (Me), 24.4, 25.4, 25.8, 41.9, 47.1 (CH2), 114.5, 122.9, 129.2 (Ph-C), 138.5 (C-3), 142.5 (Ph-C), 167.2 (C-1), 190.5 (C-2); FAB MS: m/z 274 [M+H]+. Anal. Calcd for C15H19N3O2: C, 65.91; H, 7.01; N, 15.37. Found: C, 65.89; H, 7.01; N, 15.35.
(3E)-3-(2-Phenylhydrazone)-1-(1-pyrrolidinyl)-1,2,3-butanetrione (6d): Yellow needles (0.160 g, 62%), mp 180−182 ˚C (acetone/petroleum ether); IR (KBr): ν 3465 (NH), 1665, 1620 cm-1 (CO); 1H NMR (CDCl3): δ 1.88−1.97 (m, 4H, 2CH2), 1.98 (s, 3H, Me), 3.33 (t, J = 6.7 Hz, 2H, CH2), 3.64 (t, J = 6.7 Hz, 2H, CH2), 6.96−7.00 (m, 1H, Ph-H), 7.12−7.14 (m, 2H, Ph-H), 7.22−7.26 (m, 2H, Ph-H), 8.87 (s, 1H, NH); 13C NMR (CDCl3): δ 7.53 (Me), 24.2, 25.7, 45.0, 46.4 (CH2), 114.5, 123.0, 129.3 (Ph-C), 138.2 (C-3), 142.6 (Ph-C), 167.4 (C-1), 190.2 (C-2); FAB MS: m/z 260 [M+H]+. Anal. Calcd for C14H17N3O2: C, 64.85; H, 6.61; N, 16.20. Found: C, 64.92; H, 6.72; N, 16.13.
The preparation of phenylhydrazone 6c from 5b and piperidine. A mixture of 5b (0.308 g, 1 mmol) and piperidine (5 mL, 50.6 mmol) was stirred at 80 °C for 1 h. After work-up as described above, 6c (0.181 g, 66%) was obtained.

ACKNOWLEDGEMENTS
The authors thank Hiroshi Hanazono and Yukiko Iwase for obtaining MS and NMR spectra and Junko Honda for her valuable help with elemental analyses.

References

1. (a) J. Elguero, 'Comprehensive Heterocyclic Chemistry II,' Vol. 3, ed. by I. Shinkai, Elsevier Science Ltd., Oxford, 1996, pp. 1−75; CrossRef (b) J. Elguero, ‘Comprehensive Heterocyclic Chemistry,’ Vol. 5, ed. by A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984, pp. 167−303; CrossRef (c) G. M. Cragg, P. G. Grothaus, and D. J. Newman, Chem. Rev., 2009, 109, 3012; CrossRef (d) N. Kaur, J. Dwivedi, and D. Kishore, Synth. Commun., 2014, 44, 1671. CrossRef
2. (a) K. Sujatha, G. Shanthi, N. P. Selvam, S. Manoharan, P. T. Perumal, and M. Rajendran, Bioorg. Med. Chem. Lett., 2009, 19, 4501; CrossRef (b) S. Bondock, R. Rabie, H. A. Etman, and A. A. Fadda, Eur. J. Med. Chem., 2008, 43, 2122; CrossRef (c) R. N. Brogden, Drugs, 1986, 32, 60; CrossRef (d) J. S. Casas, E. E. Castellano, J. Ellena, M. S. García-Tasende, M. L. Pérez-Parallé, A. Sánchez, Á. Sánchez-González, J. Sordo, and Á. Touceda, J. Inorg. Biochem., 2008, 102, 33; CrossRef (e) A. Kimata, H. Nakagawa, R. Ohyama, T. Fukuuchi, S. Ohta, T. Suzuki, and N. Miyata, J. Med. Chem., 2007, 50, 5053; CrossRef (f) C. Pégurier, P. Collart, P. Danhaive, S. Defays, M. Gillard, F. Gilson, T. Kogej, P. Pasau, N. V. Houtvin, M. V. Thuyne, and B. V. Keulen, Bioorg. Med. Chem. Lett., 2007, 17, 4228. CrossRef
3. (a) H. Kawai, H. Nakai, M. Suga, S. Yuki, T. Watanabe, and K. Saito, J. Pharmacol. Exp. Ther., 1997, 281, 921; (b) T. Watanabe, M. Tanaka, K. Watanabe, Y. Takamatsu, and A. Tobe, Yakugaku Zasshi, 2004, 124, 99; CrossRef (c) T.-W. Wu, L.-H. Zeng, J. Wu, and K.-P. Fung, Life Sci., 2002, 71, 2249. CrossRef
4. (a) M. J. Genin, C. Biles, B. J. Keiser, S. M. Poppe, S. M. Swaney, W. G. Tarpley, Y. Yagi, and D. L. Romero, J. Med. Chem., 2000, 43, 1034; CrossRef (b) T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miyashiro, R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G. Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert, A. W. Veenhuizen, Y. Y. Zhang, and P. C. Isakson, J. Med. Chem., 1997, 40, 1347; CrossRef (c) J. V. Mercader, C. Suárez-Pantaleón, C. Agulló, A. Abad-Somovilla, and A. J. Abad-Fuentes, J. Agric. Food Chem., 2008, 56, 7682; CrossRef (d) J. P. Singh, A. K. Jaiswal, and M. D. Monobrullah, Indian J. Agric. Sci., 2014, 84, 64; (e) N. K. Terrett, A. S. Bell, D. Brown, and P. Ellis, Bioorg. Med. Chem. Lett., 1996, 6, 1819. CrossRef
5. (a) G. Varvounis, Y. Fiamegos, and G. Pilidis, Adv. Heterocycl. Chem., 2001, 80, 73; CrossRef (b) G. Varvounis, Y. Fiamegos, and G. Pilidis, Adv. Heterocycl. Chem., 2004, 87, 141; CrossRef (c) G. Varvounis, Y. Fiamegos, and G. Pilidis, Adv. Heterocycl. Chem., 2008, 95, 27; CrossRef (d) G. Varvounis, Adv. Heterocycl. Chem., 2009, 98, 143; CrossRef (e) S. Fustero, M. Sánchez-Roselló, P. Barrio, and A. Simón-Fuentes, Chem. Rev., 2011, 111, 6984; CrossRef (f) S. Kumari, S. Paliwal, and R. Chauhan, Synth. Commun., 2014, 44, 1521. CrossRef
6. (a) S. Rollas and S. G. Küçükgüzel, Molecules, 2007, 12, 1910; CrossRef (b) R. Narang, B. Narasimhan, and S. Sharma, Curr. Med. Chem., 2012, 19, 569. CrossRef
7. (a) V. I. Shverov, N. B. Galstukhova, Z. A. Pankina, T. N. Zykova, N. B. Lapaeva, and G. N. Pershin, Khim.-Farm. Zh., 1978, 12, 88; (b) P. Rathelot, N. Azas, H. El-Kashef, F. Delmas, C. D. Giorgio, P. Timo-David, J. Maldonado, and P. Vanelle, Eur. J. Med. Chem., 2002, 37, 671; CrossRef (c) A. N. Mirskova, G. G. Levkovskaya, P. V. Lidina, and M. G. Voronkov, Khim.-Farm. Zh., 1977, 11, 74.
8. C. Ma, Y. Li, S. Niu, H. Zhang, X. Liu, and Y. Che, J. Nat. Prod., 2011, 74, 32. CrossRef
9. D. H. R. Barton, J. Cs. Jaszberenyi, W. Liu, and T. Shinada, Tetrahedron, 1996, 52, 14673. CrossRef
10. (a) Z. Jiang and D.-Q. Yu, J. Nat. Prod., 1997, 60, 122; CrossRef (b) P. Chomcheon, N. Sriubolmas, S. Wiyakrutta, N. Ngamrojanavanich, N. Chaichit, C. Mahidol, S. Ruchirawat, and P. Kittakoop, J. Nat. Prod., 2006, 69, 1351; CrossRef (c) T. Matsuda and Y. Tomaru, Tetrahedron Lett., 2014, 55, 3302; CrossRef (d) J. Grover, S. K. Roy, and S. M. Jachak, Synth. Commun., 2014, 44, 1914; CrossRef (e) C. M. R. Volla, A. Das, L. Atodiresei, and M. Rueping, Chem. Commun., 2014, 50, 7889. CrossRef
11. J. A. Kereselidze, Chem. Heterocycl. Compd., 1999, 35, 666. CrossRef
12. H. Sheibani and Z. Esfandiarpoor, J. Heterocycl. Chem., 2011, 48, 1122. CrossRef
13. (a) H. Maruoka, N. Kashige, T. Eishima, F. Okabe, R. Tanaka, T. Fujioka, F. Miake, and K. Yamagata, J. Heterocycl. Chem., 2008, 45, 1883; CrossRef (b) H. Maruoka, E. Masumoto, T. Eishima, F. Okabe, S. Nishida, Y. Yoshimura, T. Fujioka, and K. Yamagata, J. Heterocycl. Chem., 2009, 46, 782; CrossRef (c) E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, Y. Yoshimura, T. Fujioka, and K. Yamagata, J. Heterocycl. Chem., 2011, 48, 96; CrossRef (d) E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, R. Tomita, T. Fujioka, and K. Yamagata, J. Heterocycl. Chem., 2012, 49, 893; CrossRef (e) E. Masumoto, H. Maruoka, F. Okabe, T. Fujioka, and K. Yamagata, J. Heterocycl. Chem., in press.
14. (a) R. E. Parker and N. S. Isaacs, Chem. Rev., 1959, 59, 737; CrossRef (b) A. S. Rao, S. K. Paknikar, and J. G. Kirtane, Tetrahedron, 1983, 39, 2323; CrossRef (c) C. Bonini and G. Righi, Synthesis, 1994, 225; CrossRef (d) A.-H. Li, L.-X. Dai, and V. K. Aggarwal, Chem. Rev., 1997, 97, 2341; CrossRef (e) S. H. Krake and S. C. Bergmeier, Tetrahedron, 2010, 66, 7337; CrossRef (f) T. B. Bisol, A. J. Bortoluzzi, and M. M. Sá, J. Org. Chem., 2011, 76, 948; CrossRef (g) T. Gasperi, M. A. Loreto, A. Migliorini, and C. Ventura, Eur. J. Org. Chem., 2011, 385; CrossRef (h) S. Singhal, S. L. Jain, and B. Sain, Synth. Commun., 2011, 41, 1829; CrossRef (i) C. Wang and H. Yamamoto, J. Am. Chem. Soc., 2014, 136, 6888; CrossRef (j) T. Tomioka, R. Sankranti, A. M. James, and D. L. Mattern, Tetrahedron Lett., 2014, 55, 3443; CrossRef (k) C. Beattie and M. North, Chem. Eur. J., 2014, 20, 8182; CrossRef (l) K. B. Mishra and V. K. Tiwari, J. Org. Chem., 2014, 79, 5752; CrossRef (m) A. Reddi, M. Mujahid, M. Sasikumar, and M. Muthukrishnan, Synthesis, 2014, 46, 1751; CrossRef (n) G. Shukla, A. Nagaraju, A. Srivastava, G. K. Verma, K. Raghuvanshi, and M. S. Singh, Synthesis, 2014, 46, 1815; CrossRef (o) L.-F. Wang, Z.-F. Shi, X.-P. Cao, B.-S. Li, and P. An, Chem. Commun., 2014, 50, 8061; CrossRef (p) R. L. Davis, J. Stiller, T. Naicker, H. Jiang, and K. A. Jørgensen, Angew. Chem. Int. Ed., 2014, 53, 7406; CrossRef (q) L. Wei, L. Liu, and J. Zhang, Org. Biomol. Chem., 2014, 12, 6869; CrossRef (r) J. He, J. Ling, and P. Chiu, Chem. Rev., 2014, 114, 8037. CrossRef
15. (a) S. N. Ege, A. D. Adams, E. J. Gess, K. S. Ragone, B. J. Kober, and M. B. Lampert, J. Chem. Soc., Perkin Trans. 1, 1983, 325; CrossRef (b) K. Kirschke and E. Schmitz, J. Prakt. Chem., 1985, 327, 35; CrossRef (c) J. DeRuiter, D. A. Carter, W. S. Arledge, and P. J. Sullivan, J. Hetrocycl. Chem., 1987, 24, 149; (d) K. Kirschke, P. Hübner, G. Lutze, E. Gründemann, and M. Ramm, Liebigs Ann. Chem., 1994, 159; CrossRef (e) N. Ahmad, Acta Cien. Indica, Chem., 2011, 37, 5.
16. Although we examined the reaction of 3a with primary amine such as tert-butylamine, phenylhydrazone could not be detected at all, and the reaction was not clean. The reason for this change of behavior is not clear at present.
17. (a) T. Siu, D. Qin, and S. J. Danishefsky, Angew. Chem. Int. Ed., 2001, 40, 4713; CrossRef (b) C. Joo, S. Kang, S. M. Kim, H. Han, and J. W. Yang, Tetrahedron Lett., 2010, 51, 6006; CrossRef (c) X. Wang and D. Z. Wang, Tetrahedron, 2011, 67, 3406. CrossRef