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Facile One-Pot Synthesis of 1,3,5-Trisubstituted Pyrazoles from α,β-Enones
Facile One-Pot Synthesis of 1,3,5-Trisubstituted Pyrazoles from α,β-Enones
Bulletin of the Korean Chemical Society. 2014. Jun, 35(6): 1692-1696
Copyright © 2014, Korea Chemical Society
  • Received : January 27, 2014
  • Accepted : February 12, 2014
  • Published : June 20, 2014
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About the Authors
Jin Yu
Ko Hoon Kim
Hye Ran Moon
Jae Nyoung Kim

Abstract
A practical and efficient one-pot synthesis of 1,3,5-trisubstituted pyrazoles from α,β-enones and arylhydrazine hydrochlorides has been developed. The pyrazoles were formed via a tandem formation of the corresponding pyrazolines and an acid-catalyzed aerobic oxidation process.
Keywords
Introduction
1,3,5-Trisubstituted pyrazolines are important heterocyclic compounds which can be prepared from substituted hydra-zines and α,β-enones. The oxidation of these pyrazolines provides the corresponding pyrazoles, which are known to possess diverse biological activities. 1 Thus various oxidation methods have been reported including the use of MnO 2 , 2a-c p -chloranil, 2d Pb(OAc) 4 , 2e Zr(NO 3 ) 4 , 2f claycop, 2g PhI(OAc) 2 , 2h-j I 2 , 2k HIO 3 /I 2 O 5 , 2l HNO 2 /AcOH, 2m TBPA cation radical, 2n and 1,3-dibromo-5,5-dimethylhydantoin. 2o Hayashi and co-workers reported an effective conversion of pyrazoline to pyrazole in acetic acid with or without Pd/C catalyst. 3 An aerobic oxidation of pyrazoline to pyrazole has also been reported by using activated carbon, 4a cobalt salts, 4b,c or HAuCl 4 . 4d Very recently, Balakrishna and co-workers have reported FeCl 3 -catalyzed aerobic oxidation of 1,3,5-trisub-stituted pyrazolines to the corresponding pyrazoles. 5 A direct synthesis of 1,3,5-trisubstituted pyrazoles from α,β-enones has also been reported; however, most of them suffer from low yield and/or harsh reaction conditions. 6 Thus, an efficient and practical one-pot synthetic procedure of 1,3,5-trisubstituted pyrazoles is highly required until now.
Results and Discussion
During our recent studies on the synthesis of pyrazole and related compounds, 7 we observed that an aerobic oxidation of pyrazoline proceeded readily to afford the pyrazole in good yield in the presence of an acid catalyst. As an ex-ample, 1,3,5-triphenylpyrazoline ( 2a ) was converted quan-titatively to 1,3,5-triphenylpyrazole ( 3a ) in the presence of phenylhydrazine hydrochloride as an acid catalyst in 1,2-dichlorobenzene (ODCB, 130 °C) in short time (40 min, vide infra ). In these contexts, we decided to develop an efficient one-pot procedure of 1,3,5-trisubstituted pyrazoles from arylhydrazines and α,β-enones.
Initially, we examined an aerobic oxidation of 2a under various conditions as summarized in Table 1 . The oxidation in acetic acid at 80 °C under O 2 balloon atmosphere (entry 1) gave 3a in moderate yield (72%) even in the absence of Pd/C, as already reported by Hayashi. 3 The yield of 3a increased in AcOH at refluxing temperature (81%, entry 2). The reac-tion in ODCB (90-110 °C) did not afford an appreciable amount of 3a (entries 3 and 4). The result stated that an aerobic oxidation of 2a is effective in an acidic medium. It is interesting to note that the reaction in ODCB at elevated temperature gave 3a in moderate to good yields (entries 5 and 6). The use of p -xylene instead of ODCB was less effec-tive (entry 7) although the reaction temperature was similar. 4a The reactions at low temperature (90-110 °C) in ODCB were not effective even in the presence of NH 4 Cl (entries 8 and 9). However, the use of NH 4 Cl (entries 10-12) was certainly helpful for the oxidation when we compare the results of (i) entry 5/entry 10, (ii) entry 6/entry 11, and (iii) entry 7/entry 12. When we use phenylhydrazine hydrochloride as an acid catalyst (entry 13), 3a was obtained in high yield (91%). The reaction under N 2 balloon atmosphere (entry 14) was in-effective, and the result stated that the reaction must be an aerobic oxidation. The use of hydroxylamine hydrochloride (entry 15), p -TsOH (entry 16), acetic acid (entry 17), silica gel (entry 18) or FeCl 3 (entry 19) 5 was less effective than the use of phenylhydrazine hydrochloride. In addition, a base-mediated aerobic oxidation (entries 20 and 21) was less effective than an acid-catalyzed one.
Based on the results, we examined a one-pot synthesis of 3a from chalcone (1a) and phenylhydrazine hydrochloride (1.2 equiv) in ODCB (130 °C) under O 2 balloon atmosphere. To our delight, 3a was obtained in good yield (87%) in a one-pot reaction in short time (5 h). 8 Encouraged by the results, we prepared various pyrazoles 3b-p from the corre-sponding α,β-enones 1a-n and arylhydrazine hydrochlorides, and the results are summarized in Table 2 . The reactions of chalcone ( 1a ) with p -chlorophenylhydrazine hydrochloride and p -methoxyphenylhydrazine hydrochloride afforded 3b and 3c in good yields (80-88%). The reactions of various chalcone derivatives 1b-n and phenylhydrazine hydrochlo-ride provided the corresponding pyrazoles 3d-p in good to moderate yields (74-88%) in a one-pot reaction. It is interesting to note that the yields of 4-substituted pyrazoles 3m-o were somewhat lower (74-78%) than those of other 4-unsubstituted pyrazoles. During the preparation of 3m and 3n , the starting materials 1k and 1l were remained even after 4 days whereas the corresponding pyrazolines were not observed on TLC. The results stated that moderate yields of 3m and 3n are due to the sluggish reactivity of 1k and 1l for the formation of the corresponding pyrazolines. 2a However, the reaction of α-benzyl-α,β-enone 1m was faster than 1k and 1l presumably due to the presence of a small methyl group around the ketone as compared to the large phenyl group of 1k and 1l.
Aerobic oxidation of2ato3aaPyrazoline2a(0.3 mmol), O2balloon atmosphere.bIsolated yield.cUnder N2balloon atmosphere.dSome unidentified side products were formed.
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Aerobic oxidation of 2a to 3a aPyrazoline 2a (0.3 mmol), O2 balloon atmosphere. bIsolated yield. cUnder N2 balloon atmosphere. dSome unidentified side products were formed.
One-pot synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazolesa1a(R1=Ph, R2=Ph, R3=H);1b(R1=4-ClPh, R2=Ph, R3=H);1c(R1=4-NO2Ph, R2=Ph, R3=H);1d(R1=4-MePh, R2=Ph, R3=H);1e(R1=4-MeOPh, R2=Ph, R3=H);1f(R1=2-furyl, R2=Ph, R3=H);1g(R1=5-Me-2-thienyl, R2=Ph, R3=H);1h(R1=Ph, R2=4-ClPh, R3=H);1i(R1=Ph, R2=4-NO2Ph, R3=H);1j(R1=Ph, R2=Me, R3=H);1k(R1=Ph, R2=Ph, R3=Me);1l(R1=Ph, R2=Ph, R3=Ph);1m(R1=Ph, R2=Me, R3=benzyl);1n(R1=cinnamyl, R2=Ph, R3=H).b3jwas isolated in 7%.c1,5-diphenyl-3-(4-methoxyphenyl)pyrazole(3g')was isolated in 9%.d3dwas isolated in 8%.eReaction time is 6 days.fReaction time is 4 days.
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One-pot synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles a1a (R1=Ph, R2=Ph, R3=H); 1b (R1=4-ClPh, R2=Ph, R3=H); 1c (R1=4-NO2Ph, R2=Ph, R3=H); 1d (R1=4-MePh, R2=Ph, R3=H); 1e (R1=4-MeOPh, R2=Ph, R3=H); 1f (R1=2-furyl, R2=Ph, R3=H); 1g (R1=5-Me-2-thienyl, R2=Ph, R3=H); 1h (R1=Ph, R2=4-ClPh, R3=H); 1i (R1=Ph, R2=4-NO2Ph, R3=H); 1j (R1=Ph, R2=Me, R3=H); 1k (R1=Ph, R2=Ph, R3=Me); 1l (R1=Ph, R2=Ph, R3=Ph); 1m (R1=Ph, R2=Me, R3=benzyl); 1n (R1=cinnamyl, R2=Ph, R3=H). b3j was isolated in 7%. c1,5-diphenyl-3-(4-methoxyphenyl)pyrazole (3g') was isolated in 9%. d3d was isolated in 8%. eReaction time is 6 days. fReaction time is 4 days.
Both the formation of pyrazoline 2a and a subsequent aerobic oxidation of 2a to 3a have to occur effectively in order to produce 3a efficiently. Thus a plausible reaction mechanism is proposed in Scheme 1 . Phenylhydrazine could be generated slowly by the loss of HCl under the non-polar ODCB solvent at high temperature. The liberated phenyl-hydrazine reacted with chalcone (1a) to form the pyrazoline 2a , and a subsequent aerobic oxidation of 2a to 3a proceed-ed. The role of an acid catalyst (liberated HCl) is not fully clear at this stage; however, an acid-catalyzed isomerization of imine-form 2a to an electron-rich enamine-form I (imine-enamine tautomerization) could facilitate the aerobic oxida-tion process. 9 Aerobic oxidation at the benzylic/allylic position of I could generate 5-hydroperoxide II ; however, we could not rule out the possibility for the formation of 4-hydroperoxide III from the electron-rich enamine-form I . 10 In addition, the liberated HCl in the reaction mixture might be helpful for the effective dehydration ( vide infra ).
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The mechanism of aerobic oxidation might follow the generally known one, 11 as shown in Scheme 2 . The hydro-peroxide II , formed from I and oxygen, can be dissociated to O -centered radical IV and a hydroxide radical. This step is slow due to high activation energy barrier. 11b The reaction of IV and I produced a C -centered radical VI and 5-hydroxy-pyrazoline V , which could be converted to the product 3a by acid-catalyzed dehydration. In the propagation step, radical VI and O 2 produced a chain-carrying peroxy radical VII . The reaction of VII and I produced II and VI. 11b 12 In a termination stage, two molecules of VII might be converted to 3a and II , which was converted eventually to 3a . 11d-g
A trace amount of regioisomeric pyrazole was formed together in most of the reactions. As an example, the reac-tion of 1h produced 3j as a major product along with a low yield (8%) of 3d , as shown in Scheme 3. The minor product 3d might be produced via a conjugate addition of phenyl-hydrazine, dehydrative cyclization, and aerobic oxidation. Although the formations of regioisomeric pyrazoles were observed in most entries, albeit in a trace amount ( ca . 5-10%), we did not separate them in every cases (see, Table 2 ). In order to further increase the yield of 3j , we examined a solvent effect once again ( vide supra ). However, the ratio between 3j and 3d was not improved. In addition, the yield of 3j decreased in AcOH or 2-propanol as compared to ODCB. It is interesting to note that the ratio between 3j / 3d is dependent on the reaction conditions including solvent polarity although the difference is minute (from 10:1 to 6:1). 13
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As a last examination, we tried the synthesis of N -un-substituted pyrazole 3q , as shown in Scheme 4 . The syn-thesis of N -unsubstituted pyrazoles from α,β-enones and hydrazine afforded quite low yields of products in most cases. 6b 14 The use of an acid catalyst such as AcOH caused the formation of unwanted N -acetyl derivative. 14 Thus, the synthesis has been carried out with modified α,β-enones such as β-thioalkyl-α,β-enones 15a or chalcone epoxides. 15b When we performed the reaction of 1a and hydrazine hydrate (2.0 equiv) in the presence of hydrazine hydrochloride (0.2 equiv) as an acid catalyst in ODCB (130 °C,12 h) 3q was obtained in low yield (44%), unfortunately. The major side product was confirmed as a mixture of benzaldazine ( 4a ), acetophenone azine ( 4b ) and a mixed azine 4c . 16 The yield of azines was around 20-25% in a ratio of 4a / 4b / 4c = 3:1:3 based on 1 H NMR spectrum of the mixture. 16a The mech-anism for the formation of azines might involve a conjugate addition of hydrazine to the hydrazone VIII to form IX , retro-Mannich type decomposition of IX to X and XI (or their corresponding carbonyl compounds), and the conden-sations between them.
In summary, a practical and efficient one-pot synthesis of poly-substituted pyrazoles from α,β-enones and arylhydra-zine hydrochlorides has been disclosed. The mechanism is thought to be a tandem formation of pyrazoline and an acid-catalyzed aerobic oxidation. Various 1,3,5-trisubstituted and 1,3,4,5-tetrasubstituted pyrazoles could be synthesized in good to excellent yields; however, this protocol was not effective for the synthesis of N -unsubstituted pyrazole.
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Experimental Section
Typical Procedure for the Synthesis of 3a. A mixture of chalcone ( 1a , 208 mg, 1.0 mmol) and phenylhydrazine hydrochloride (173 mg, 1.2 mmol) in ODCB (2.0 mL) was heated to 130 °C under O 2 balloon atmosphere for 5 h. After removal of ODCB and column chromatographic purification process (hexanes/ether, 12:1) pyrazole 3a was obtained as a pale yellow solid, 258 mg (87%). Other pyrazole derivatives were synthesized similarly and identified by comparison their mp and/or 1 H NMR data with the reported. Known compounds are 3a, 3 3c , 6d 3d , 4b 3e , 3 3f , 4d 3g , 3 3g ’, 6c 3h , 4d 3j , 4d 3k , 5 3l , 4b 3m , 17a 3n , 2d 3p , 17b 3q , 6a,e and the selected spectro-scopic data of unknown compounds 3b , 3i and 3o are as follows.
Compound 3b: 88%; white solid, mp 118-120 °C; IR (KBr) 1495, 1460, 1362 cm −1 ; 1 H NMR (CDCl 3 , 300 MHz) δ 6.83 (s, 3H), 7.25-7.40 (m, 10H), 7.41-7.48 (m, 2H), 7.92 (d, J = 8.7 Hz, 2H); 13 C NMR (CDCl 3 , 75 MHz) δ 105.55, 125.86, 126.35, 128.24, 128.60, 128.65, 128.69, 128.75, 129.06, 130.16, 132.55, 133.12, 138.41, 144.51, 152.16; ESIMS m/z 331 [M + +H], 333 [M + +H+2]. Anal. Calcd for C 21 H 15 N 2 : C, 76.24; H, 4.57; N, 8.47. Found: C, 76.37; H, 4.61; N, 8.31.
Compound 3i: 84%; yellow oil; IR (film) 1596, 1499, 1457, 1363 cm −1 ; 1 H NMR (CDCl 3 , 300 MHz) δ 2.45 (d, J = 1.2 Hz, 3H), 6.61 (dq, J = 3.6 and 1.2 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 6.82 (s, 1H), 7.22-7.51 (m, 8H), 7.90 (d, J = 8.4 Hz, 2H); 13 C NMR (CDCl 3 , 75 MHz) δ 15.17, 104.50, 125.60, 125.77, 126.21, 127.22, 127.98, 128.21, 128.59, 128.84, 128.98, 132.86, 138.49, 139.95, 141.28, 151.78; ESIMS m/z 317 [M + +H]. Anal. Calcd for C 20 H 16 N 2 : C, 75.92; H, 5.10; N, 8.85. Found: C, 75.96; H, 5.32, N, 8.79.
Compound 3o: 78%; white solid, mp 88-90 °C; IR (KBr) 1599, 1505, 1365 cm −1 ; 1 H NMR (CDCl 3 , 300 MHz) δ 2.22 (s, 3H), 3.82 (s, 2H), 7.09-7.33 (m, 15H); 13 C NMR (CDCl 3 , 75 MHz) δ 12.27, 29.31, 117.60, 124.50, 125.85, 126.46, 128.07, 128.17, 128.36, 128.47, 128.63, 129.78, 130.67, 140.06, 140.71, 141.22, 149.05; ESIMS m/z 325 [M + +H]. Anal. Calcd for C 23 H 20 N 2 : C, 85.15; H, 6.21; N, 8.63. Found: C, 85.04; H, 6.15, N, 8.78.
Acknowledgements
This study was financially supported by Chonnam National University, 2013. Spectroscopic data were obtained from the Korea Basic Science Institute, Gwangju branch.
References
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