Convenient ultrasound mediated synthesis of substituted pyrazolones under solvent-free conditions

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Ultrasonics Sonochemistry 15 (2008) 828–832 www.elsevier.com/locate/ultsonch

Convenient ultrasound mediated synthesis of substituted pyrazolones under solvent-free conditions Mohammad M. Mojtahedi *, Mashal Javadpour, M. Saeed Abaee

*

Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran Received 5 November 2007; received in revised form 17 February 2008; accepted 20 February 2008 Available online 29 February 2008

Abstract Smooth condensation of hydrazine derivatives with various ß-keto esters was performed under solvent-free conditions by using ultrasound irradiation to facilitate the formation of pyrazolone derivatives in good to excellent amounts within very short time periods. Ó 2008 Elsevier B.V. All rights reserved. Keywords: Pyrazolone; Hydrazine; Ultrasound irradiation; Solvent-free reaction

1. Introduction Pyrazolone derivatives are of particular importance in pharmaceutical chemistry [1] due to their numerous applications as analgesic, antipyretic, antiarthritic, uricosuric, antiinflammatory, and antiphlogistic properties. Particularly, the 3-methyl-1-phenyl-2-pyrazolin-5-one derivative (edaravone) [2] acts as a radical scavenger to interrupt the preoxidative chain reactions and membrane disintegrations associated with ischemia [3]. In addition, these compounds are appropriate precursors for industrial preparation of herbicides [4], liquid crystals [5], dyes [6], thermally stable polymers [7], and color photographical compounds [8]. On the other hand, chemical oxidation of pyrazolones to azo dienophiles provides suitable substrates for hetero Diels–Alder cycloadditions [9]. In recent years, synthetic applications of ultrasonic irradiation in various types of organic transformations are demonstrated widely in chemical literature [10]. Consequently, many protocols have been developed to carry out chemical processes in shorter reaction times and under milder and more environmentally friendly conditions. As

some illustrative examples, ring opening of epoxides [11], reduction of carbonyl compounds [12], Suzuki cross-coupling reaction [13], acetylation of alcohols [14], aldol reaction [15], oximes synthesis [16], reductive coupling of amines [17], and alcohols protection [18] can be pointed out. Pyrazolones are traditionally synthesized by treatment of b-keto esters with hydrazine substrates under acidic conditions at elevated temperature [19]. A number of alternative methods have been documented in the literature for the synthesis of these compounds [20]. Recent developments include solid-phase synthesis [21], a two-step reaction of benzoyl hydrazones with silyl enolates in the presence of catalytic amounts of Sc(OTf)3 [22], and microwave irradiation techniques [23]. In the framework of our investigations on the development of green chemical procedures [24], we would like to herein report a novel and environmentally safe procedure for rapid preparation of various pyrazolone derivatives using ultrasound irradiation (Scheme 1). 2. Method 2.1. Apparatus and analysis

*

Corresponding authors. Tel.: +98 21 44580720; fax: +98 21 44580762. E-mail addresses: [email protected] (M.M. Mojtahedi), abaee@ ccerci.ac.ir (M.S. Abaee). 1350-4177/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ultsonch.2008.02.010

Reactions were monitored by TLC and GC. FT-IR spectra were recorded using KBr disks on a Bruker

M.M. Mojtahedi et al. / Ultrasonics Sonochemistry 15 (2008) 828–832

O

O

O

R

O

PhNHNH2 ))))

1a-h

Ph

N N

R 2a-k

Scheme 1.

Vector-22 infrared spectrometer and absorptions were reported as wave numbers (cm 1). NMR spectra were obtained on a FT-NMR Bruker Ultra ShieldTM (500 MHz) or Bruker AC 80 MHz instrument as CDCl3, DMSO-d6, or CDCl3-DMSO-d6 solutions and the chemical shifts were expressed as d units with Me4Si as the internal standard. Mass spectra were obtained on a Finnigan Mat 8430 apparatus at ionization potential of 70 eV. Compound 1c was prepared using available methods [25]. All other chemicals and reagents were purchased from commercial sources and were used without further purification. Sonication was performed using a Sartorius Ultrasonichomogenizer LABSONICÒP 230 V/50 Hz instrument with a frequency of 24 KHz and nominal power of 460 W/cm2. The intensity level of irradiation was adjusted at 90% and 40% levels for the synthesis of 2a–h and 2i–k, respectively. In all reactions the tip of the sonotrode was located in the same position just under the liquid surface in order to obtain optimal sonication and reproducible results. 2.2. General procedure A mixture containing phenyl hydrazine or hydrazine (5 mmol) and 1 (5 mmol) was sonicated in a 10 mL test tube for appropriate length of time (as indicated in Table 1) until TLC showed complete disappearance of the starting materials. In temperature controlled experiments, reactions were performed in a water bath at 25 ± 1 °C. The reaction mixture was poured into ice–water mixture and the precipitates were collected by filtration. The pure product was obtained by recrystallization of the precipitates using ethanol and water. Products were identified based on their melting point, 1H NMR, 13C NMR, and IR data. Known structures were verified by comparison of their data with those reported in the literature [26].

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43.5, 119.3, 125.5, 129.3, 138.5, 156.7, 171.0; MS m/z (%) 174 (M+, 100), 105 (55), 91 (94), 77 (92); IR (KBr, cm 1) 2420, 1594, 1530. 2.2.3. 3-(Furan-3-yl)-1-phenyl-1H-pyrazol-5(4H)-one (2c) M.p. 182 °C; 1H NMR (DMSO-d6) d 5.92 (s, 2H), 6.80– 8.00 (m, 8H), 11.90 (br s, 1H); MS m/z (%) 226 (M+, 52), 93 (100), 77 (68); IR (KBr, cm 1) 2900, 1595, 1557. 2.2.4. 4-Ethyl-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2d) M.p. 108 °C; 1H NMR (CDCl3) d 0.85 (t, J= 7.5 Hz, 3H), 1.88–2.06 (m, 2H), 2.19 (s, 3H), 7.23 (t, J = 7.4 Hz, 1H), 7.43 (dd, J = 7.4, 7.7 Hz, 2H), 7.89 (d, J = 7.7 Hz, 2H); 13C NMR (CDCl3) d 7.3, 13.4, 29.7, 81.3, 119.3, 125.8, 129.2, 137.9, 162.4, 174.3; MS m/z (%) 202 (M+, 63), 174 (23), 91 (42), 77 (100); IR (KBr, cm 1) 2965, 1687, 1496. 2.2.5. 1,3-Diphenyl-1H-pyrazol-5(4H)-one (2e) M.p. 88 °C; 1H NMR (CDCl3) d 3.90 (s, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.45–7.52 (m, 5H), 7.81–7.84 (m, 2H), 8.02 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3) d 40.0, 119.5, 125.7, 126.5, 129.3, 129.4, 131.1, 131.3, 138.6, 155.1, 170.7; MS m/z (%) 236 (M+, 91), 194 (42), 103 (80), 91 (79), 77 (100); IR (KBr, cm 1) 2965, 1705, 1593. 2.2.6. 3-Isopropyl-1-phenyl-1H-pyrazol-5(4H)-one (2f) M.p. 78 °C; 1H NMR (CDCl3) d 1.28 (d, J = 7 Hz, 6H), 2.79 (m, 1H), 3.45 (s, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.41 (dd, J = 7.4, 8 Hz, 2H), 7.92 (d, J = 8 Hz, 2H); 13C NMR (CDCl3) d 20.5, 31.2, 40.3, 119.3, 125.4, 129.2, 138.7, 164.7, 171.1; MS m/z (%) 202 (M+, 100), 187 (42), 91 (28), 40 (97). 2.2.7. 1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5(4H)-one (2g) M.p. 170 °C; 1H NMR (CDCl3-DMSO-d6) d 5.62 (s, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 7.5, 8 Hz, 2H), 7.54 (d, J = 8 Hz, 2H); 13C NMR (CDCl3-DMSOd6) d; MS m/z (%) 228 (M+, 18), 105 (20), 95 (33), 77 (100); IR (KBr, cm 1) 2720, 1758, 1599.

2.2.1. 1-Phenyl-3-propyl-1H-pyrazol-5(4H)-one (2a) M.p. 110 °C; 1H NMR (CDCl3) d 1.06 (t, J = 7.4 Hz, 3H), 1.68–1.76 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 3.44 (s, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.43 (dd, J = 7.4, 7.7 Hz, 2H), 7.91 (d, J = 7.7 Hz, 2H); 13C NMR (CDCl3) d 14.2, 20.4, 33.5, 42.2, 119.3, 125.4, 129.2, 138.6, 160.3, 171.0; MS m/z (%) 202 (M+, 100), 173 (59), 105 (32), 91 (99), 77 (97); IR (KBr, cm 1) 2928, 1595, 1540.

2.2.8. 2-Phenyl-4,5,6,7-tetrahydro-2H-indazol-3(3aH)-one (2h) M.p. 160 °C; 1H NMR (CDCl3) d 1.46–1.57 (m, 2H), 1.74–1.82 (m, 1H), 1.98–2.01 (m, 1H), 2.17–2.21 (m, 1H), 2.39 (ddd, J = 5.7, 12.9, 13, 1H), 2.55–2.59 (m, 1H), 2.82 (dd, J = 3, 15, 1H), 3.18 (dd, J = 7.4, 11.9, 1H), 7.19–7.22 (m, 1H), 7.41–7.45 (m, 2H), 7.92–7.95 (m, 2H); 13C NMR (CDCl3) d 24.7, 27.9, 29.1, 29.8, 50.0, 119.2, 125.3, 129.2, 138.7, 163.8, 173.8; MS m/z (%) 214 (M+, 100), 185 (12), 109 (24), 77 (25), 40 (25); IR (KBr, cm 1) 2935, 1705, 1635.

2.2.2. 3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one (2b) M.p. 127 °C; 1H NMR (CDCl3) d 2.24 (s, 3H), 3.47 (s, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.44 (dd, J = 7.3, 8 Hz, 2H), 7.91 (d, J = 8 Hz, 2H); 13C NMR (CDCl3) d 17.4,

2.2.9. 3-(Furan-3-yl)-1H-pyrazol-5(4H)-one (2i) M.p. 212 °C; 1H NMR (DMSO-d6) d 5.73 (s, 1H), 6.64– 7.75 (m, 3H), 11.20 (br s, 2H); MS m/z (%) 150 (M+, 100), 121 (31), 93 (45); IR (KBr, cm 1) 2598, 1608, 954.

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M.M. Mojtahedi et al. / Ultrasonics Sonochemistry 15 (2008) 828–832

Table 1 Ultrasound promoted synthesis of pyrazolone derivatives Entry

Substrate

Hydrazine

Product

Time (min) 20

O

O

1

C6H5NHNH2

O

Yield (%)a

1a

91 O

N

2a

N

2 2b

N Ph

O

O

C6H5NHNH2

2 O

1b

O

N

15

84

2

95

Ph O

O

O

3

O

C6H5NHNH2

1c

O

O

N

2c

N

2d

20

85

N

2e

2

95

N

2f

5

94

2g

25

95

15

94

N Ph

O

4

Et

O

O

C6H5NHNH2

1d

O

N

Et

Ph Ph O

O

5 1e Ph

O

C6H5NHNH2

O

N Ph

O

6

O

O

C6H5NHNH2

1f

O

N Ph CF3

O

O

7 O

1g CF3

C6H5NHNH2

N

O

N Ph

O

Ph

O

8

N

C6H5NHNH2

O 1h

O

O

NH2NH2

1c

O

1d

a b

O

N H

O

N H

N

2j

2b

94

N

2k

2b

90

O

NH2NH2

11 O

92

N H

NH2NH2

Et

O

2b 2i

Et

O

O

N

O

O

10

2h O

O

O

9

N

1a

Isolated yields. Lower power.

2.2.10. 4-Ethyl-3-methyl-1H-pyrazol-5(4H)-one (2j) M.p. 222 °C; 1H NMR (DMSO-d6) d 1.12 (t, J = 7 Hz, 3H), 2.11 (s, 3H), 2.42 (q, J = 7 Hz, 2H), 10.30 (br, 2H); MS m/z (%), 126 (M+, 76), 111 (90), 98 (42), 42 (100); IR (KBr, cm 1) 2965, 1616, 1404.

2.2.11. 3-Propyl-1H-pyrazol-5(4H)-one (2K) M.p. 207 °C; 1H NMR (CDCl3) d 0.96 (t, J = 7.5 Hz, 3H), 1.57 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 5.32 (s, 1H), 10.50 (br s, 2H); MS m/z (%) 126 (M+, 52), 111 (25), 98 (100); IR (KBr, cm 1) 2735, 1620, 1507.

M.M. Mojtahedi et al. / Ultrasonics Sonochemistry 15 (2008) 828–832

2.2.12. Ethyl 4,4,4-trifluoro-3-(2-phenylhydrazono)butanoate (3g) M.p. 170 °C; 1H NMR (CDCl3) d 1.35 (t, J = 7.1 Hz, 3H), 3.55 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 8 Hz, 2H), 7.35 (dd, J = 7.3, 8 Hz, 2H), 9.12 (s, 1H); 13C NMR (CDCl3) d 14.4, 32.6, 62.8, 114.4, 120.0, 122.6, 123.0, 129.7, 143.8, 168.5; MS m/z (%) 274 (M+, 10), 228 (45), 105 (10), 40 (100); IR (KBr, cm 1) 2733, 1720, 1601, 1565.

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Based on these observations, a mechanistic pathway as depicted in Fig. 1 can be proposed in which an immine intermediate is formed first which subsequently undergoes intermolecular condensation to form the final product. This hypothesis was supported by isolation of the proposed immine intermediate 3g for the reaction between phenyl hydrazine and ethyl 4,4,4-trifluoro-3-oxobutanoate (entry 7). 4. Conclusion

3. Results and discussion First, an equimolar mixture of phenyl hydrazine and ethyl butrylacetate 1a (R = n-Pr) was sonicated under various sets of conditions. The best results were obtained in the presence of no solvent leading to sole formation of 1phenyl-3-propyl-1H-pyrazol-5(4H)-one 2a via elimination of water and ethanol after 15 min sonication (Table 1, entry 1). The solid product was easily separated from the reaction mixture by aqueous work up. Control experiments showed the crucial rule of the ultrasonic irradiation for the reaction to proceed and excluded the effect of a possible simultaneous thermal activation. Therefore, conduction of the reaction by maintaining the temperature at 25 ± 1 °C yielded similar results after 17 min sonicaion. Alternatively, in the absence of irradiation, the same mixture gave only 41% of 2a after several hours treatment of the mixture at elevated temperatures (140 °C). These observations suggest that the ultrasonic irradiation can significantly assist the process, as also previously proposed by Wang [27] and Entezari [28], presumably by providing the required energy for the transition state of the reaction. To examine the feasibility of a relatively large-scale synthesis, a mixture containing 50 mmol of each of the two reactants was subjected to the reaction conditions for 25 min leading to isolation of more than 90% of 2a. Other b-keto esters reacted in the same manner with phenyl hydrazine (entries 2–8) or hydrazine (entries 9–11) to obtain 84–95% of their respective pyrazolone derivatives in short time periods. In case of hydrazine, reactions could complete at lower power level of sonication within shorter time periods. All reactions proceeded cleanly and resulted easily in precipitation of single products. O

O EtO

O H2.. NNHPh

CF3

EtO

OH CF3 HN .. NHPh

CF3 CF3 N O

N N Ph

2g

O

O Et

O

OH2

NHPh 3g

EtO

CF3 HN .. NHPh

Fig. 1. Proposed mechanism for the condensation of hydrazines with acetoacetates.

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