Nitrogen containing heterocycles are known subunits in many natural products and biological active compounds ^[1]. Among those,pyrazole is one of the important heterocycles and attracts much attention in recent years owing to its wide application in chemistry,biology,and material science as well ^{[2, 3, 4, 5]}. The synthesis of pyrazole derivatives generally involves the Knorr condensation of hydrazines with 1,3-diketones ^[6],multi component coupling and Claisen rearrangement ^{[7, 8, 9, 10, 11]} (Scheme 1). Recently,Wu et al. developed the copper-catalyzed tandem reaction of 2-alkynylbromobenzenes and pyrazoles that forms fused pyrazole derivatives in good yields ^[12]. Shortly after,Ma and coworkers developed the copper catalyzed three-component reaction of 2-alkynoates,amines and nitriles affording fully substituted pyrazoles ^[13]. In 2014,Yu et al. reported the regioselective pyrazole synthesis through I₂-mediated oxidative C-N bond formation ^[14]. More recently,Allwood group found that cyclic pyrazoles can be convenient prepared from tosylhydrazones and alkynes ^[15]. To the best of our knowledge,the direct synthesis of pyrazole derivatives via one-step cyclization of o-alkynylchalcones and hydrazine has never been fully explored.

Scheme 1

	Download: JPG larger image
Scheme 1. The representative procedure for synthesis of pyrazole derivatives.

In a program of developing highly efficient methodology for nitrogen-containing heterocycles ^[16],we recently reported the new pathway for synthesis of fused pyrazoles via cyclization of ortho-alkynylaldehydes with ketones and hydrazine under metalfree conditions ^[17]. As part of our continuing research,we decided to pursue the preparation of pyrazole derivatives from the easily available o-alkynylchalcones and hydrazine. Herein,we present the first efficient synthesis of fused pyrazoles via simple cyclization of o-alkynylchalcones and hydrazine under mild condition. 2. Experimental

Analytical-grade solvents were purchased,and used as received. NMR spectra were measured at 400 MHz for ¹H NMR and 100 MHz for ¹³C NMR and calibrated from residual solvent signal. Analytical thin-layer chromatography (TLC) was performed on silica gel aluminum sheets with F-254 indicator. Visualization was accomplished by UV light. Mass spectra (MS) were measured on IonSpec 4.7 T FTMS using DART Positive. Purification by chromatography was performed using 230-400 mesh SiO₂ with compressed air as a source of positive pressure (Eluent: petroleum ether/ethyl acetate = 6:1,v/v,except for compounds 2q,2r,2s and 2t,which were purified by petroleum ether/ethyl acetate = 1:1, v/v). The starting materials o-phenylethynylchalcones were prepared according to the literatures ^{[18, 19, 20]}. The purity of all final compounds was determined by HPLC analysis,confirming >95% purity. 2.1. Representative procedure for the synthesis of 2a

The mixture of o-alkynylchalcone 1a (0.2 mmol),hydrazine dihydrochloride (1.0 mmol,5 equiv.),and TEA (2.0 mmol, 10 equiv.) in methanol (2 mL) was refluxed for 12 h. Then,5 mL of water was added,extracted with ethyl acetate (3× 20 mL). Then the organic layer was dried with anhydrous sodium sulfate. Evaporation of ethyl acetate gave a yellow residue,which was further purified by gel column chromatography to afford the pure product. Some selected data were list below and others were available in Supporting information.

2a: ¹H NMR (400 MHz,CDCl₃): δ 7.42 (d,1H,J = 7.5 Hz),7.28 (t, 1H,J = 7.5 Hz),7.19 (dd,3H,J = 5.1,1.7 Hz),7.16-7.11 (m,1H),7.03 (dd,2H,J = 6.8,2.4 Hz),6.88 (d,1H,J = 4.0 Hz),6.08 (s,1H),5.31 (dd, 1H,J = 4.0,4.0 Hz),3.73 (dd,1H,J = 4.0,4.0 Hz),3.08 (dd,1H,J = 8.0, 8.5 Hz),2.41 (s,3H). ¹³C NMR (100 MHz,CDCl₃): δ 153.07,145.81, 143.98,135.66,130.73,129.78,128.23,128.16,126.79,126.57, 123.87,120.23,95.90,63.32,40.07,14.50. MS ESI [M]⁺ m/z,260.

2b: ¹H NMR (400 MHz,CDCl₃): δ 7.38 (d,1H,J = 7.5 Hz),7.30- 7.24 (m,1H),7.17 (dd,3H,J = 5.0,1.8 Hz),7.13 (td,1H,J = 7.6, 1.1 Hz),7.01 (dd,2H,J = 6.5,2.9 Hz),6.88 (d,1H,J = 7.6 Hz),5.95 (s, 1H),5.30 (dd,1H,J = 4.0,4.0 Hz),3.71 (dd,1H,J = 4.0,4.0 Hz),3.08 (dd,1H,J = 8.0,8.4 Hz),2.09-2.00 (m,1H),1.00-0.93 (m,2H),0.81 (dt,2H,J = 6.2,5.0,3.7 Hz). ¹³C NMR (100 MHz,CDCl₃): δ 159.82, 145.59,144.00,135.64,130.73,129.77,128.17,128.13,126.75, 126.54,123.82,120.12,92.58,63.33,40.04,9.99,8.12,8.07. MS ESI [M]⁺ m/z,286.

2c: ¹H NMR (400 MHz,CDCl₃): δ 7.31 (dd,1H,J = 4.0,4.6 Hz), 7.18 (t,1H,J = 7.5 Hz),7.11-7.00 (m,4H),6.98-6.86 (m,3H),6.02 (d,1H,J = 4.0 Hz),5.28 (dd,1H,J = 4.0,4.0 Hz),3.60 (td,1H,J = 16.0, 3.7 Hz),3.19 (dt,1H,J = 8.0,16.0,20.0 Hz),2.87 (m,1H),1.80-1.61 (m,2H),1.33 (dd,3H,J = 7.0,5.0 Hz),0.95 (td,3H,J = 7.4,2.3 Hz). ¹³C NMR (100 MHz,CDCl₃): δ 162.87,145.56,143.91,135.37, 130.96,128.10,127.94,126.66,126.46,123.69,120.07,93.40, 63.21,39.80,30.60,21.08,12.17. MS ESI [M]⁺ m/z,289.

2d: ¹H NMR (400 MHz,CDCl₃): δ 8.05 (d,2H,J = 7.6 Hz),7.54 (dd,3H,J = 8.0,7.7 Hz),7.48-7.33 (m,3H),7.27 (m,4H),7.13 (s, 2H),7.05 (d,1H,J = 7.5 Hz),6.67 (s,1H),5.51 (dd,1H,J = 4.0, 3.8 Hz),3.84 (dd,1H,J = 4.0,3.4 Hz),3.33 (dd,1H,J = 8.0,8.0 Hz). ¹³C NMR (100 MHz,CDCl₃): δ 155.97,146.50,143.97,135.53, 134.38,130.54,128.86,128.41,128.32,127.84,127.00,126.94, 125.83,123.94,120.54,93.66,63.40,40.04. MS ESI [M]⁺ m/z,322.

2e: ¹H NMR (400 MHz,CDCl₃): δ 7.92 (d,2H,J = 8.5 Hz),7.48 (d,1H,J = 7.5 Hz),7.34 (t,1H,J = 7.5 Hz),7.27-7.20 (m,4H),7.10 (dd,2H,J = 6.4,2.7 Hz),7.03 (dd,3H,J = 8.0,8.2 Hz),6.56 (s,1H), 5.47 (dd,1H,J = 4.0,4.0 Hz),3.87 (s,3H),3.81 (dd,1H,J = 4.0, 4.0 Hz),3.28 (dd,1H,J = 8.0,8.0 Hz). ¹³C NMR (100 MHz,CDCl₃): d 159.43,155.82,146.36,143.96,135.56,130.60,129.87,128.31, 128.25,127.17,126.98,126.85,123.88,120.41,114.17,93.02, 63.66,55.35,40.03. MS ESI [M]⁺ m/z,352.

2f: ¹H NMR (400 MHz,CDCl₃): δ 8.65-8.55 (m,1H),7.99-7.91 (m,1H),7.66 (td,1H,J = 7.8,1.7 Hz),7.43 (d,1H,J = 7.5 Hz),7.24 (t, 1H,J = 7.5 Hz),7.16-7.07 (m,5H),6.97 (dd,2H,J = 6.5,2.8 Hz),6.87 (t,2H,J = 3.7 Hz),5.38 (dd,1H,J = 4.1,4.1 Hz),3.71 (dd,1H,J = 4.0, 4.2 Hz),3.13 (dd,1H,J = 8.0,8.2 Hz). ¹³C NMR (100 MHz,CDCl₃): d 155.92,152.73,149.42,146.50,143.75,136.64,135.40,130.35, 129.77,128.38,128.27,127.01,126.86,123.87,122.39,120.59, 120.08,95.07,63.84,40.04. MS ESI [M]⁺ m/z,323. 3. Results and discussion

At first,we treated 2-phenylethynyl chalcone 1a with hydrazine dihydrochloride in methanol using TEA as the base at reflux for 12 h,the desired product 2a was formed in 50% yield (Table 1, entry 1). The yield was improved to 74% when 10 equiv. hydrazine was used (entry 3). Further study on the effect of base led to the observation that TEA provided the best result (entries 3-6). Solvent screening revealed that methanol was the best choice of solvent in the cyclization reaction. When ethanol was used as solvent in this reaction under same reaction condition,the desired product was obtained in 65% yield (entry 15). No reaction occurred when toluene,acetic acid and TEA were used (entries 12-14). Thus,we concluded the reaction of o-alkynyl chalcone 1a with 5 equiv. hydrazine and 10 equiv. TEA in methanol refluxing for 12 h as the standard reaction conditions.

Table 1

Table 1 Optimization of reaction conditions.a

Table 1 Optimization of reaction conditions.a

Following optimization,the scope of o-alkynylchalcones was investigated under the standard conditions and the results were summarized in Table 2. As shown in Table 2,the reaction of hydrazine with different o-alkynylchalcones in methanol afforded the corresponding pyrazoles in moderate to good yields,the substituents R1 had obvious influence on the yield of the products. For instance,the reaction of 1n having fluoro group in the phenyl ring,proceeded well and gave the product 2n in yield of 84% (entry 14). While,when 1o was used in this reaction,the product 2o was obtained in only 48% yield (entry 15). It seems that all substituents at R² are tolerated. When alkyl and electron-rich aromatic substitutes were used as R²,reactions proceeded well and pyrazoles were obtained in 54%-84% yields (entries 1-4,5,10). In the case of heteroaromatic group was used as R²,the products were formed in lower yields (entries 6-9,11). It is worth noting that the highest yield (84%) was achieved when 3-(5-fluoro-2-((4- methoxyphenyl)ethynyl)phenyl)-1-(4-hydroxyphenyl)prop-2-en- 1-one 1n was used in this reaction (entry 14). While,the p-hydroxyphenyl substituted o-alkynyl chalcone 1m gave the 63% of 2m(entry 13). In all case,the reaction was clean,and there is no side-product was detected in this reaction.

Table 2

Table 2 Reaction of o-alkynylchalcones 1 with hydrazine in methanol.a

Table 2 Reaction of o-alkynylchalcones 1 with hydrazine in methanol.a

The reaction was also extended to the cyclic o-alkynylchalcones. As shown in Scheme 2,low yields of polycyclic pyrazole derivatives were observed. The 2-(2-(phenylethynyl)benzylidene) cycloheptanone 1t underwent the cyclization to afford the 2t in 47% yield. The 2-(2-(phenylethynyl)benzylidene)-cyclopentanone 1q was recovered in 50% yield along with 11% of polycyclic pyrazole 2q.

Scheme 2

	Download: JPG larger image
Scheme 2. Reaction of cyclic o-alkynylchalcone with hydrazine in methanol,the reaction condition is same to that in Table 2.

In conclusion,we have developed the facile synthesis of pyrazole derivatives by a simple cyclization of easily accessed o-alkynylchalcones and hydrazine under mild condition. This greener synthetic methodology provides a straightforward approach to the synthesis of a variety of pyrazole derivatives under mild reaction condition.

We are grateful to the Fundamental Research Funds for the Central Universities (No. 2042014kf0248) for support of this research.

Supplementary data associated with this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2015.01.002.