a one-pot approach to ,-dihydropyrazoles from ketones, arylacetylenes, and hydrazines

1、A one-pot approach to 4,5-dihydropyrazoles from ketones, arylacetylenes, and hydrazinesA one-pot approach to 4,5-dihydropyrazoles from ketones,arylacetylenes, and hydrazinesYing-Chun Wanga,b, Heng-Shan Wanga,*, Guo-Bao Huanga, Fu-Ping Huanga, Kun Hua,Ying-Ming Pana,*aKey Laboratory for the Chemistry

2、 and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry & ChemicalEngineering of Guangxi Normal University, Guilin 541004, Peoples Republic of ChinabCollege of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, Peoples Republic of Ch

3、inaa r t i c l e i n f oArticle history:Received 3 September 2013Received in revised form 3 January 2014Accepted 14 January 2014Available online 18 January 2014Keywords:4,5-DihydropyrazolesKetonesArylacetylenesHydrazinesTandem reactionsa b s t r a c tAn efficient and straightforward one-pot strategy

4、 for the synthesis of 4,5-dihydropyrazole derivativesfrom ketones, arylacetylenes, and hydrazines in the presence of KOtBu/DMSO is described. This strategyprovides a flexible and rapid route to polysubstituted 4,5-dihydropyrazoles.? 2014 Elsevier Ltd. All rights reserved.1. IntroductionDihydropyrazo

5、le is a useful scaffold known for a wide variety ofpharmaceutical (antifungal, antibacterial, anti-inflammatory, anti-tumor, and antiviral) and agrochemical activities.1Recently, moreand more chemical compounds bearing dihydropyrazole moiety aspotential anticancer agents have been confirmed.2For exa

6、mple, Liuet al. have disclosed a series of 4,5-dihydropyrazole derivatives aspotential V600E mutant BRAF kinase (BRAFV600E) inhibitors, whichare aimed to treat human cancer with good potency, pharmacoki-netics, and water solubility.2dMore recently, Luo et al. reportedsome aryl-2H-pyrazole derivative

7、s as potential telomerase in-hibitors, which exhibit high activities against human gastric cancercell SGC-7901 and human melanoma cell B16-F10.2eMoreover,dihydropyrazoles are also of great importance in the preparation ofnatural products and applications in asymmetric synthesis.3It is nowonder that

8、the building up of a dihydropyrazole moiety invokesever growing synthetic efforts.Commonly, dihydropyrazole derivatives are constructed by thereaction of chalcones with hydrazine hydrate,4semicarbazide hy-drochloride or thiosemicarbazide.5They are also formed viacatalytic enantioselective 1,3-dipola

9、r cycloadditions of diazo-alkanes,6diazoacetates,7and catalytic asymmetric 3t2 cycload-ditions of azomethine imines,8nitrile imine dipole precursors,9andhydrazones.10Recently, Bri? ere et al. reported a powerful dominoaza-Michael addition/cyclocondensation reaction for the enantio-selective synthesi

10、s of 3,5-diaryldihydropyrazoles by phase-transfercatalysis.11Furthermore, Bolm et al. described an unprecedentedstrategy to access highly enantioenriched dihydropyrazoles byformal 4t1 cycloadditions of in situ-derived azoalkenes and sul-fur ylides catalyzed by a chiral copper/ToleBINAP complex.12Des

11、pite numerous diverse approaches toward the synthesis ofdihydropyrazole have been developed so far, the development ofmore convenient methodologies, especially one-pot multicompo-nent reactions, from readily available starting materials is stillhighly desirable. Herein, we report a new one-pot strat

12、egy for thesynthesis of 5-benzyl-4,5-dihydropyrazoles 4 from ketones 1, ary-lacetylenes 2, and hydrazines 3 in the presence of KOtBu/DMSO(Scheme 1).2. Results and discussionTo identify the suitable conditions for the three-componenttandem process, a series of bases and solvents were screened us-ing

13、acetophenone 1a, phenylacetylene 2a, and phenylhydrazine 3aas a model reaction (Table 1). As shown in Table 1, the base/DMSO* Corresponding authors. E-mail addresses: wang_(H.-S. Wang), (Y.-M. Pan).Contents lists available at ScienceDirectTetrahedronjournal h

14、omepage: /locate/tet0040-4020/$ e see front matter ? 2014 Elsevier Ltd. All rights reserved./10.1016/j.tet.2014.01.021Tetrahedron 70 (2014) 1621e1628system(exceptfor NaOC2H5, Cs2CO3, LiOH) promoted the formationof the expected product 4aaa (trace to 25% yield) (Table

15、1, entries1e6), and the system of KOtBu/DMSO proved to be the most ef-fective (yield of 4aaa being 78%) (Table 1, entries 7 and 8). Otherpotentially promoting base systems, such as KOtBu/DMF, KOtBu/THF, KOtBu/dioxane, and KOtBu/toluene pairs appeared to be in-efficient in the reaction studied (Table

16、 1, entries 9e12). These re-sults suggest that the solvent plays a crucial role for the successformation of 5-benzyl-4,5-dihydropyrazole. Notably, the reactantmolar ratio of KOtBu also has a key effect on the reaction results:with 10 mol % of KOtBu no product 4aaa was detected (Table 1,entry 13), wh

17、ereas with 1 equiv of KOtBu, only a 48% yield of 4aaawas obtained (Table 1, entry 14).With the optimal conditions in hand, we examined the KOtBu/DMSOsystemforone-potdihydropyrazoles from various ketones 1, arylacetylenes 2, andhydrazines 3. Table 2 illustrates the wide generality and substratescope

18、of this tandem reaction. As follows from Table 2, this strategysynthesisof5-benzyl-4,5-Scheme 1. One-pot synthesis of 5-benzyl-4,5-dihydropyrazoles 4 from ketones 1, arylacetylenes 2, and Hydrazines 3.Table 1Optimization of the formation of 5-benzyl-4, 5-dihydropyrazoleaEntryBaseSolventTemp (?C)Time

19、 (h)Yieldb(%)1234567891011121314NaOC2H5Cs2CO3LiOHNaOHKOHKOH/ButOHKOtBuKOtBuKOtBuKOtBuKOtBuKOtBuKOtBuKOtBuDMSODMSODMSODMSODMSODMSODMSODMSODMFTHFDioxaneTolueneDMSODMSO70e10070e10070e1001001001007010010010010010010010088888884888888000Trace1525567800000c48daReaction conditions: 1.2 equiv of acetophenon

20、e 1a (1.2 mmol), and 1.0 equiv of phenylacetylene 2a (1.0 mmol), 1.5 equiv of base (1.5 mmol), solvent (4 mL), at 70e100?Cfor 30 min, 1.2 equiv of phenylhydrazine 3a (1.2 mmol) then added for the period of time indicated at the same temperature.bIsolated yield of pure product based on phenylacetylen

21、e 2a.cKOtBu (10 mol %).dKOtBu (1.0 equiv).Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e16281622Table 2One-pot synthesis of 5-benzyl-4,5-dihydropyrazoles 4 from ketones 1, arylacetylenes 2, and hydrazines 3aEntryKetoneAcetyleneHydrazineProductYieldb(%)14aaa7824baa8334caa8044daa8854eaa8264faa5274gaa

22、2884haa8194iaa78104jaa58114kaa56124lab51134mab73144nab70154oaa54164paa65174bba83(continued on next page)Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e16281623is effective for a great diversity of ketones such as aromatic (Table 2,entries 1e11), heteroaromatic (Table 2, entries 12e15), and ali-phati

23、c (Table 2, entry 16), and as well as for a variety of arylacety-lenes (Table 2, entries 17e19) and aromatic hydrazines (Table 2,entries 20 and 21).Amongtheketones,whichyacetophenone 1d gave the most desirable result, providing the 5-benzyl-4,5-dihydropyrazole 4daa in 88% isolated yield (Table 2,ent

24、ry 4). The crystallization of compound 4daa from ethanol gave asingle crystal suitable for X-ray analysis. Fig. 1 illustrates the mo-lecular structure of the substituted 5-benzyl-4,5-dihydropyrazole4daa.wereexamined,p-methox-Gratifyingly, acylated condensed aromatics (2-acetonaphthone1h) and dipheny

25、l derivatives (4-acetylbiphenyl 1i) fairly toleratedthe reaction conditions and afforded the desired products in goodyields (81% and 78%, respectively) (Table 2, entries 8 and 9).Noteworthy, fluorine derivatives (both ketone 1f and arylacetylene2d) could participate in the reaction in moderate yield

26、s (52% and65%, respectively) (Table 2, entries 6 and 19), and p-chlor-oacetophenone 1g was also suitable for the reaction to give 4gaaalbeit in a low yield (28%) (Table 2, entry 7). Obviously, electron-rich aromatic ketones provided the desired products in higheryields than electron-poor aromatic ke

27、tones. When heteroaromaticketone (1le1o) and aliphatic ketone (1p) were used as the sub-strates, good yields (51%, 73%, 70%, 54% and 65%, respectively) of 5-benzyl-4,5-dihydropyrazoles 4lab, 4mab, 4nab, 4oaa, and 4paawere obtained (Table 2, entries 12e16). Arylacetylene 2c with anelectron-donating g

28、roup (eOCH3) at the benzene ring gave thecorresponding products in higher yield than 2d, which possessedan electron-withdrawing group (eF) on the benzene ring (Table 2,Table 2 (continued)EntryKetoneAcetyleneHydrazineProductYieldb(%)184bca85194bda65204aab8321HNNH2Cl4aac78aReaction conditions: 1.2 equ

29、iv of ketone 1 (1.2 mmol), and 1.0 equiv of arylacetylene 2 (1.0 mmol), 1.5 equiv of KOtBu (1.5 mmol), DMSO (4 mL), at 100?C for 30 min,1.2 equiv of hydrazine 3 (1.2 mmol) then added, kept at 100?C for an additional 3e6 h.bIsolated yield after column chromatography or recrystallization based on aryl

30、acetylene 2.Fig. 1. X-ray crystal structure of 5-benzyl-4,5-dihydropyrazole 4daa.Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e16281624entries 18 and 19). However, aliphatic alkynes did not give thedesired 5-benzyl-4,5-dihydropyrazoles under the present reactionconditions. In case of hydrazines, th

31、e substituent effect on benzenerings was not apparent, either with an electron-donating or anelectron-withdrawing group on the benzene ring, hydrazines 3gave the corresponding 5-benzyl-4,5-dihydropyrazoles in highyields (Table 2, entries 20 and 21).To our delight, the thiosemicarbazide was also tole

32、rated un-der these reaction conditions. The corresponding compound4aad was synthesized successfully with moderate yield (52%)(Scheme 2).The proposed mechanism for the formation of 5-benzyl-4,5-dihydropyrazoles 4 was depicted in Scheme 3. The reactionmechanism evidently represented the nucleophilic a

33、ttack of theenolate A at an acetylene to deliver the adduct 5 of E configu-ration, subsequently, the (E)-b,g-unsaturated ketones 5 didreadily react with aromatic hydrazines giving the hydrazones 6.Then followed by prototropic rearrangement of b,g-unsaturatedhydrazones 6 to a,b-unsaturated hydrazones

34、 7, which finallyunderwent cyclization to afford 4,5-dihydropyrazoles 4. This ra-tionale has been proven by the intermediates 5ia and 6jaa iso-lated from the reaction mixture under the same conditions(Fig. 2), and the E configuration of b,g-ethylenic ketone 5ia andhydrazone 6jaa was confirmed by3J v

35、alue (16.3 Hz and 16.0 Hz,respectively) between protons at the double bond. Furthermore,in the presence of KOtBu/DMSO, compound 6jaa can convert to5-benzyl-4,5-dihydropyrazole 4jaa in high yield (95%) at 100?Cafter 4 h.3. ConclusionIn summary, we have developed a mild, general, and efficientstrategy

36、 for the synthesis of polysubstituted 4,5-dihydropyrazolesdirectly from ketones, arylacetylenes, and hydrazines in a single-pot. This strategy is effective for a great diversity of ketones suchas aromatic, heteroaromatic, and aliphatic and as well as for a va-riety of arylacetylenes and aromatic hyd

37、razines, and it providesa flexible and rapid route to the preparation of 5-benzyl-4,5-dihydropyrazoles with both aliphatic and aromatic substituents atC-3 of the dihydropyrazole ring.4. Experimental section4.1. General methods and materialsMelting points were uncorrected. NMR spectra were in CDCl3(1

38、H at 500 MHz and13C at 125 MHz). Column chromatography wasScheme 2. Synthesis of 5-benzyl-4,5-dihydropyrazole 4aad.Scheme 3. Proposed mechanism for the formation of 5-benzyl-4,5-dihydropyrazoles.Fig. 2. Structure of the isolated intermediates 5ia and 6jaa.Y.-C. Wang et al. / Tetrahedron 70 (2014) 16

39、21e16281625performed on silica gel (300e400 mesh). Unless otherwise noted,all reagents were obtained commercially and used without furtherpurification.4.2. General procedure for the synthesis of 5-benzyl-4,5-dihydropyrazolesTo a 15-mL flask, ketones 1 (1.2 mmol), arylacetylenes 2(1.0 mmol), DMSO (4.

40、0 mL), and KOtBu (1.5 mmol) were succes-sively added. The reaction mixture was heated (100?C) and stirredat 100?C for 30 min, followed by the addition of hydrazines 3(1.2 mmol). The reaction mixturewas kept at the same temperature(100?C) for an additional 3e6 h until completion (monitored byTLC). Up

41、on cooling to room temperature, the reaction mixture wasdiluted with H2O (10 mL), neutralized with NH4Cl. When pre-cipitated, the residue was filtered off, washed with water, andrecrystallized. If the residue did not precipitate, the reaction mix-ture was extracted with ethyl acetate (3?10 mL). The

42、organic ex-tract was washed with H2O (3?5 mL) and dried over magnesiumsulfate. After filtration, the solvent was evaporated to dryness un-der reduced pressure and the residue was purified by flash columnchromatography (petroleum ether/ethyl acetate 20:1) to afford 5-benzyl-4,5-dihydropyrazoles 4.4.3

43、. Characterization of the compounds4.3.1. 5-Benzyl-1,3-diphenyl-4,5-dihydro-1H-pyrazoleyellow powder; mp 150e151?C;1H NMR (500 MHz, CDCl3): d 7.72(d, J?7.6 Hz, 2H), 7.41e7.31 (m, 7H), 7.29e7.26 (m, 5H), 6.91e6.89(m, 1H), 4.72e4.68 (m, 1H), 3.34 (dd, J?13.8, 3.3 Hz, 1H), 3.26 (dd,J?16.8, 10.8 Hz, 1H)

44、, 3.07 (dd, J?16.9, 4.1 Hz, 1H), 2.61 (dd, J?13.8,10.1 Hz, 1H) ppm;13C NMR (125 MHz, CDCl3): d 147.5, 144.2, 137.5,133.5,129.4,129.3,128.7,128.6,128.5,126.7,125.7,119.1,113.5, 61.0,37.3 (2) ppm; HRMS (m/z) (ESI): calcd for C22H21N2 313.1705MtHt; found 313.1688.(4aaa). Pale4.3.2. 5-Benzyl-3-(4-methyl

45、phenyl)-1-phenyl-4,5-dihydro-1H-pyr-azole (4baa). Pale yellow powder; mp 154e155(500 MHz, CDCl3): d 7.62 (d, J?8.1 Hz, 2H), 7.38e7.33 (m, 4H),7.32e7.27 (m, 5H), 7.22 (d, J?8.1 Hz, 2H), 6.91e6.88 (m, 1H),4.70e4.65 (m, 1H), 3.34 (dd, J?13.8, 3.3 Hz, 1H), 3.24 (dd, J?16.8,10.8 Hz, 1H), 3.05 (dd, J?16.8

46、, 4.1 Hz, 1H), 2.61 (dd, J?13.8, 10.1 Hz,1H), 2.41 (s, 3H) ppm;13C NMR (125 MHz, CDCl3): d 147.1, 143.6,137.8, 136.8, 129.5, 128.6, 128.5, 128.4, 127.9, 125.9, 124.9, 118.2,112.8, 60.2, 36.7, 36.6, 20.6 ppm; HRMS (m/z) (APCI): calcd forC23H23N2327.1861 MtHt; found 327.1853.?C;1H NMR4.3.3. 5-Benzyl-3

47、-(2-methylphenyl)-1-phenyl-4,5-dihydro-1H-pyr-azole (4caa). Pale yellow powder; mp 158e160(500 MHz, CDCl3): d 7.42e7.35 (m, 4H), 7.33e7.30 (m, 4H), 7.28 (m,3H), 7.27e7.24 (m, 2H), 6.92 (m, 1H), 4.71e4.64 (m, 1H), 3.37 (dd,J?16.7, 10.8 Hz, 1H), 3.31 (dd, J?13.8, 3.2 Hz, 1H), 3.14 (dd, J?16.7,3.8 Hz,1

48、H), 2.73 (s, 3H), 2.66 (dd, J?13.8, 9.9 Hz,1H) ppm;13C NMR(125 MHz, CDCl3): d 148.4, 144.3, 137.5, 137.4, 131.6, 131.5, 129.5,129.3, 128.7, 127.9, 127.8, 126.7, 125.7, 118.9, 113.5, 59.9, 39.5, 37.1,23.7 ppm; HRMS (m/z) (APCI): calcd for C23H23N2 327.1861MtHt; found 327.1851.?C;1H NMR4.3.4. 4-(5-Ben

49、zyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenylmethyl ether (4daa). Pale yellow crystals; mp 107e109?C;1H NMR(500 MHz, CDCl3): d 7.67 (d, J?8.5 Hz, 2H), 7.39e7.34 (m, 4H),7.30e7.26 (m, 6H), 6.94 (d, J?8.7 Hz, 2H), 4.68e4.62 (m,1H), 3.87 (s,3H), 3.34 (dd, J?13.8, 3.2 Hz,1H), 3.24 (dd, J?16.7,10.7 Hz,

50、1H), 3.04(dd, J?16.9, 4.0 Hz,1H), 2.61 (dd, J?13.7,10.2 Hz,1H) ppm;13C NMR(125 MHz, CDCl3): d 147.2, 143.7, 137.9, 136.9, 129.6, 128.7, 128.6,128.5, 128.0, 126.0, 125.0, 118.3, 112.9, 60.3, 36.8, 36.7, 20.7 ppm;HRMS (m/z) (APCI): calcd for C23H23N2O 343.1810 MtHt; found343.17. 2-(5-Benzyl-1-

51、phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenylmethyl ether (4eaa). Pale yellow crystals; mp 96e97?C;1H NMR(500 MHz, CDCl3): d 7.48 (d, J?4.3 Hz, 1H), 7.39e7.32 (m, 6H),7.29e7.27 (m, 5H), 7.03e7.00 (m,1H), 6.91e6.87 (m,1H), 4.66e4.61(m, 1H), 3.86 (s, 3H), 3.39 (dd, J?17.6, 10.5 Hz, 1H), 3.30e3.23 (m,2H),

52、2.65 (dd, J?13.7,10.0 Hz,1H) ppm;13C NMR (125 MHz, CDCl3):d 157.5, 147.9, 144.3, 137.8, 129.8, 129.4, 129.1, 128.7, 128.5, 126.4,122.4,120.7,118.7,113.4,111.3, 61.0, 55.4, 40.4, 36.9 ppm; HRMS (m/z) (APCI): calcd for C23H23N2O 343.1810 MtHt; found 343.160. 5-Benzyl-3-(4-fluorophenyl)-1-phenyl

53、-4,5-dihydro-1H-pyr-azole(4faa). Pale yellow oil;d 7.72e7.67 (m, 2H), 7.40e7.35 (m, 4H), 7.32e7.27 (m, 5H),7.12e7.07 (m, 2H), 6.94e6.90 (m, 1H), 4.74e4.67 (m, 1H), 3.34 (dd,J?13.8, 2.9 Hz, 1H), 3.24 (dd, J?16.8, 10.9 Hz, 1H), 3.04 (dd, J?16.8,4.2 Hz,1H), 2.63 (dd, J?13.8,10.1 Hz,1H) ppm;13C NMR (125

54、 MHz,CDCl3): d 162.9 (d,1JCF?244.9 Hz), 146.6, 144.2, 137.4, 129.4, 129.3,128.7, 128.6, 127.4 (d,2JCF?21.8 Hz),113.5, 61.1, 37.5, 37.4 ppm; HRMS (m/z) (ESI): calcd forC22H20FN2331.1611 MtHt; found 331.1600.1H NMR (500 MHz, CDCl3):3JCF?7.9 Hz), 126.7, 119.9, 115.5 (d,4.3.7. 5-Benzyl-3-(4-chlorophenyl

55、)-1-phenyl-4,5-dihydro-1H-pyr-azole (4gaa). Red oil;1H NMR (500 MHz, CDCl3): d 7.72e7.67 (m,2H), 7.40e7.35 (m, 4H), 7.32e7.27 (m, 5H), 7.12e7.07 (m, 2H),6.94e6.89 (m,1H), 4.74e4.67 (m,1H), 3.34 (dd, J?13.9, 3.4 Hz,1H),3.26 (dd, J?16.9,10.9 Hz,1H), 3.07 (dd, J?16.9, 4.1 Hz,1H), 2.62 (dd,J?13.7,10.0 H

56、z,1H) ppm;13C NMR (125 MHz, CDCl3): d 147.8,144.3,138.5, 137.6, 130.2, 129.4, 129.2, 129.2, 128.7, 126.6, 125.6, 118.9,113.5, 60.9, 37.5, 37.4 ppm; HRMS (m/z) (ESI): calcd for C22H20ClN2347.1315 MtHt; found 347.12. 5-Benzyl-3-(2-naphthyl)-1-phenyl-4,5-dihydro-1H-pyrazole(4haa). Yellowcrystal

57、s; mp 122e124?C;1H NMR (500 MHz, CDCl3):d 8.14 (dd, J?8.7, 1.6 Hz, 1H), 7.84e7.79 (m, 4H), 7.51e7.46 (m, 2H),7.41e7.32(m,6H),7.30e7.26(m,3H),6.94e6.90(m,1H),4.74(m,1H),3.38e3.31 (m, 2H), 3.17 (dd, J?16.7, 4.2 Hz, 1H), 2.65 (dd, J?13.9,10.1 Hz, 1H) ppm;13C NMR (125 MHz, CDCl3): d 147.6, 144.0, 137.5,

58、133.4,133.3,130.7,129.4,129.3,128.7,128.1,128.0,127.8,126.7,126.4,126.2,124.9,123.4,119.2,113.6,61.0,37.5,37.3ppm;HRMS(m/z)(ESI):calcd for C26H23N2363.1861 MtHt; found 363.18. 5-Benzyl-3-(biphenyl-4-yl)-1-phenyl-4,5-dihydro-1H-pyrazole(4iaa). Yellowpowder; mp 172e173?C;1H NMR (500 MHz, CDCl3

59、):d 7.76e7.72 (m, 2H), 7.68e7.65 (m, 2H), 7.54e7.49 (m, 2H),7.38e7.35 (m, 4H), 7.32e7.25 (m, 6H), 7.23e7.20 (m, 3H), 4.68 (m,1H), 3.34 (dd, J?13.8, 3.3 Hz,1H), 3.24 (dd, J?16.8,10.8 Hz,1H), 3.05(dd, J?16.8, 4.1 Hz,1H), 2.61 (dd, J?13.8,10.1 Hz,1H) ppm;13C NMR(125 MHz, CDCl3): d 147.3, 144.0, 141.1, 140.5, 137.5, 132.0, 129.4,129.3, 128.8, 128.7, 127.3, 127.1, 126.9, 126.7, 126.1, 119.4, 113.8, 61.0,39.7, 37.5 ppm; HRMS (m/z) (ESI): calcd for C28H25N2389.2018MtHt; found 389.200. 5-Benzyl-4-methyl-1,3-diphenyl-4,5-dihydro-