Ligand-free Heck–Mizoroki reaction for 1,3,5-Trisubstituted Pyrazoles

Tetrahedron 71 (2015) 2833e2838

Contents lists available at ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Ligand-free HeckeMizoroki reaction for 1,3,5-Trisubstituted Pyrazoles Misayo Sera *, Hideya Mizufune *, Hiroyuki Tawada Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 December 2014 Received in revised form 19 March 2015 Accepted 22 March 2015 Available online 25 March 2015

A ligand-free HeckeMizoroki reaction with 5-trifluoromethanesulfonates of pyrazoles in high yield under mild conditions is described. The reaction conditions have been established through extensive studies on the palladium catalyst system (palladium sources, ligands, additives, base, and solvents) by considering how to avoid the Michael adduct of acrylic ester at the 4-position of the substrate pyrazole. The optimum conditions (palladium(II) chloride, lithium chloride, and triethylamine in N,N-dimethylacetamide) have provided various types of Heck products as 1,3,5-substituted pyrazoles. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: HeckeMizoroki reaction Palladium-catalyzed cross-coupling reaction Pyrazole Triflates

1. Introduction Pyrazoles are very valuable skeletons to search for biologically active compounds in the pharmaceutical industries, and several types of drug candidates with a pyrazole moiety have been reported. Among the class of compounds, 1,3,5-substituted pyrazoles have recently received much attention. For example, 1 as an allosteric inhibitor of West Nile Virus NS2B-NS3,1 2 as a CCR2 receptor antagonist for the treatment of inflammatory diseases,2 3 as a glucagon receptor antagonist for the treatment of diabetes,3 and 4 as a selective matrix metalloprotease (MMP) 13 inhibitor for the treatment of arthritic diseases4 have all been researched (Fig. 1). In order to prepare 1,3,5-substituted pyrazole derivatives, recently transition metal catalyzed cross-coupling reactions have been used for an efficient synthetic strategy, by considering regiospecific introduction of substituents to a pyrazole core via CeC bond forming reactions. For example, cross-coupling reactions of pyrazoles at the 3 or 5-positions have been reported as versatile methods to construct 1,3,5-substituted pyrazole derivatives, generally by employing 3- or 5-halogenopyrazoles as the substrates for Sonogashira,2,5 Stille,5b,6 SuzukieMiyaura,4,5b,7 and Negishi7a,8 reactions. Compound 4 was generated by SuzukieMiyaura coupling with a 5-bromopyrazole derivative. Although HeckeMizoroki7a

* Corresponding authors. Tel.: þ81 6 6300 6552; fax: þ81 6 6300 6251; e-mail addresses: [email protected] (M. Sera), [email protected] (H. Mizufune). http://dx.doi.org/10.1016/j.tet.2015.03.079 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

cross-coupling reactions of 3- or 5-halopyrazoles have already been reported, the application was for tetrasubstituted compounds and not for a regiospecific synthesis of 1,3,5-substituted pyrazoles. While the trifluoromethanesulfonate (triflate) group has also been utilized as a leaving group for the cross-coupling reaction of 1,3,5-pyrazoles, such as Stille9 and SuzukieMiyaura3,10 reactions, a synthesis of 1,3,5-substituted pyrazole derivatives using HeckeMizoroki cross-coupling reaction of pyrazole triflates has not been reported. Only one research group has reported a HeckeMizoroki reaction of a 3-triflate on the pyrazole ring, but it was not applied to a synthesis of 1,3,5-substituted pyrazoles via CeC bond formation.11

Fig. 1. 1,3,5-Substituted pyrazoles as drug candidates.

2834

M. Sera et al. / Tetrahedron 71 (2015) 2833e2838

In this paper we describe development of an efficient HeckeMizoroki reaction with a pyrazole bearing a 5-triflate for a regiospecific synthesis of 1,3,5-substituted pyrazoles as shown in the following synthetic strategy (Scheme 1).

Scheme 1. The synthetic strategy of 1,3,5-substituted pyrazole.

2. Results and discussion First, synthesis of a 5-pyrazolyl triflate was investigated utilizing the pyrazole-3-ones 7, which were easily derived from b-ketoesters 9 and benzylhydrazine. While introduction of bromide as a leaving group by reaction of PBr3 or POBr35b,12 with 7a failed, the triflate was successfully prepared using Tf2O/iPr2NEt/toluene13 or Tf2O/ aq K3PO4/toluene14 (Scheme 2).

Table 1 HeckeMizoroki reaction between ethyl acrylate and triflate 6a; catalyst and ligand investigationa

Run

Catalyst/ligand

Base

Additive

118 2 3 4 5 6 7 811,19 9 10 1120 12 13 1421

Pd(OAc)2/PPh3 Pd(OAc)2/P(o-Tol)3 Pd(OAc)2/dppfb Pd(OAc)2/rac. BINAP Pd(PPh3)4 Pd2(dba)3c Pd(dba)2d [PPh3]2PdCl2 (C6H5CN)PdCl2 [DPPF]PdCl2e Pd(OAc)2 Pd(OAc)2 PdCl2 [PPh3]2PdCl2

Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N i Pr2NEt i Pr2NEt Et3N

None None None None None None None None None None LiCl LiCl LiCl LiCl

a b c d e

Scheme 2. Preliminary studies on the HeckeMizoroki reaction of pyrazole-5-triflate.

Subsequently, the HeckeMizoroki reaction of triflate 6a with methyl acrylate was investigated under a modified Jeffry’s condichloride tion of Pd(OAc)2/PPh3/benzyltriethylammonium (BnNEt3Cl)/AcOK/NMP, which we previously reported for the HeckeMizoroki reaction of 4-iodopyrazole derivatives.15 However, the reaction did not provide the desired Heck product and surprisingly the main product was 11, which came from the Michael addition of methyl acrylate at the 4-position. The interesting result suggested to us that palladium-catalyzed acetyloxylation on the triflate and subsequent Michael addition on the electron-rich pyrazole derivative could be achievable. A thorough literature survey also supported the hypothesis by indicating an example of a Michael reaction on the kind of pyrazole.16 Therefore, we considered that an inorganic base might facilitate a palladium-catalyzed substitution reaction with an anion or hydrolysis of the triflate to give 5-oxypyrazoles or 5-pyrazolones,17 which would accelerate the Michael addition. Indeed, a classical HeckeMizoroki reaction condition employing a tertiary amine, Pd(OAc)2/PPh3/Et3N/NMP,18 provided the target compound 5a in low yield (Scheme 2). Based on the preliminary results, we started further studies on the reaction condition utilizing a tertiary amine as shown in Table 1. Although a screening of various palladium sources and ligands did not provide significant improvement (runs 1e10), interestingly, addition of LiCl to the palladium catalyst system without any phosphine ligand was very effective for improving yield (runs 11e13). Especially, a ligand-free palladium catalyst system of PdCl2/iPr2NEt/LiCl gave a remarkable improvement with 91%

Conversion (%) 6a

12a

2 9 51 4 0 20 26 2 37 21 2 6 0 3

27 6 2 14 3 8 9 39 2 23 38 58 91 1

All reactions were conducted under a nitrogen atmosphere in NMP at 100  C. 1,10 -Bis(diphenylphosphino)ferrocene. Tris(dibenzylideneacetnone)dipalladium(0). Bis(dibenzylideneacetnone)palladium(0). [1,10 -Bisdiphenylphosphino]-ferrocene palladium(II) dichloride CH2Cl2.

conversion and an efficient reaction condition (100  C, 2 h) (run 13), which was a better result than that obtained using the corresponding catalytic system with PdCl2 instead of Pd(OAc)2 (run 12 vs 13). To confirm the ligand-free effect, [PPh3]2PdCl2 was also tested in place of PdCl2 and the yield of 12a was found to greatly decreased (run 14), although the combination of [PPh3]2PdCl2 and LiCl was reported as effective for the HeckeMizoroki reaction between 3pyridyl triflates and ethyl acrylate.21 Encouraged by the ligand-free condition using PdCl2/LiCl/tertiary amine, our next focus was on optimization of the additive, base, and solvent for the catalytic system in order to identify factors proceeding the reaction (Table 2). Table 2 HeckeMizoroki reaction between ethyl acrylate and triflate 6a; additive, base, and solvent effectsa Run

Additive (equiv)

Base

Solvent

Conversionb (%) 6a

12a

1 2 3 4 5 6 7 8 9

None LiCl (2.0) Li2CO3 (2.0) LiF (2.0) LiI (2.0) LiBr (2.0) CsF (2.0) NaBr (2.0) LiCl (2.0)

i

NMP NMP NMP NMP NMP NMP NMP NMP NMP

81 0 70 69 35 2 0 24 0

3 91 5 2 5 74 1 56 88

10

LiCl (2.0)

NMP

0

53

11 12 13 14 15 16 17 18 19 20 21

LiCl LiCl LiCl LiCl LiCl LiCl LiCl LiCl LiCl LiCl LiCl

0.3 2 0 9 95 80 56 14 0 4 11

0 84 91 12 0 0 1 4 91 86 56

(2.0) (2.0) (2.0) (2.0) (2.0) (2.0) (2.0) (2.0) (3.0) (1.0) (0.5)

Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt i Pr2NEt Et3N

NaHCO3 Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N Et3N

NMP DMF DMAC DMSO Toluene DME CH3CN n-BuOH DMAC DMAC DMAC

a All reactions were conducted under a nitrogen atmosphere using 5 mol % of PdCl2, 2.0 equiv of base, and additive at 100  C. b Determined by HPLC analysis.

M. Sera et al. / Tetrahedron 71 (2015) 2833e2838

First, an inorganic salt as an additive was reinvestigated in combination with iPr2NEt as a tertiary amine base and NMP as solvent (runs 1e8). Though many kinds of additives were investigated, LiCl was identified as the most effective for giving conversion over 90% (run 2). Then, the tertiary amine base was reevaluated. Both Et3N and iPr2NEt were found to be effective for the reaction (runs 2 and 9), while a more bulky tertiary amine, 1,2,2,6,6-pentamethylpiperidine, gave only moderate yield (run 10). It was also confirmed that an inorganic base, such as NaHCO3, completely inhibited the desired reaction even in the presence of LiCl (run 11). Based on the results obtained for the additives and tertiary amines, the solvent effect was subsequently studied using LiCl and the inexpensive Et3N (runs 12e18). When the reaction was carried out in amide solvents, such as NMP, DMF, and DMAC, similar excellent yields were obtained (runs 9, 12, 13). In contrast, other solvents, e.g., toluene, 1,2-dimethoxyethane (DME), acetonitrile, and n-BuOH did not provide good results (runs 15e18). In DMSO the triflate was unfortunately decomposed (run 14). With Et3N/DMAC as the optimized base and solvent, finally, the amount of LiCl was investigated. Remarkably, more than 1 equiv of LiCl was required for an effective conversion (runs 13, 19e21). On the basis of these results, PdCl2 (5 mol %), LiCl (2.0 equiv), and Et3N (2.0 equiv) in DMAC was adopted as the best condition (run 13). With the optimized sequence of triflate preparation (Tf2O/K3PO4 aq/toluene) and the subsequent HeckeMizoroki reaction (PdCl2 (5 mol %)/LiCl (2 equiv)/Et3N (2 equiv)/DMAC at 100  C), in hand the substituent effect on the pyrazole was examined (Table 3). Various pyrazole-5-triflates with alkyl substituents at the 1- and 3positions, including the bulky tert-butyl group, provided the corresponding Heck products in good yield (runs 1e5). However, introduction of aryl substituents at the 1- or 3-positions gave reduced yield (runs 6, 7). Furthermore, introduction of a trifluoromethyl group to the 3-position did not provide the desired product (run 8). These results suggested to us that the electron density on the pyrazole ring has a great influence on the reaction. In addition, a 2pyridyl group at the 1-position also inhibited the palladiumcatalyzed reaction (run 9).

2835

Table 3 (continued) Run

Product

Yieldb (%)

6

27

7

15

8

0

9

0

a All reactions were conducted under a nitrogen atmosphere using 5 mol % of PdCl2, 2.0 equiv of LiCl, and 2.0 equiv of Et3N in DMAC at 100  C for 2 h. b Isolated yield.

Then, our next interest was to extend the ligand-free HeckeMizoroki reaction with various kinds of alkenes (Scheme 3). First, the reactions with other conjugated olefins were studied; acrylamide and styrene provided the desired products (13 and 14a) in relatively good yield, while a styrene bearing a carboxyl moiety on the phenyl ring gave the corresponding product 14b in lower yield. Next, unconjugated alkenes were examined for the reaction. Although HeckeMizoroki reaction of triflate 6a and allyl alcohol22 did not give the desired propionaldehyde 15, the reaction of 6a and acrolein acetal23 successfully provided the corresponding a, b-saturated ester 16, in much better yield than with Cacchi’s original reaction condition (Pd(OAc)2, n-Bu4NCl, n-Bu3N, DMF).

Table 3 Substituted effect on the pyrazole triflate reactivitya

Run

Product

Yieldb (%)

1

94

2

63 Scheme 3. HeckeMizoroki reaction with various kinds of alkenes.

3

82

4

91

5

82

By considering all the results of our various studies on the palladium catalytic system and the substituent effects of the substrate, we have considered that the reaction mechanism might be associated with coordinative effect of the pyrazole moiety as follows. As Stille and co-workers proposed for their palladium-catalyzed coupling with an aryl triflate in the presence of LiCl,24 after oxidative addition of a Pd(0) species to the carboneOTf bond of the pyrazole5-triflate 6, in the presence of LiCl an exchange can occur between  CF3 SO in an oxidative addition complex, which is 3 and Cl

2836

M. Sera et al. / Tetrahedron 71 (2015) 2833e2838

supported by the results of our studies on the effect of the amount of added LiCl (Table 2, run 13 vs 19e21). The generated ArePd(II)e Cl complex may coordinate with the pyrazole nitrogen of the substrate itself, which is supported by the study of the phosphine ligand (Table 1), the coordinative solvent (Table 2, DME and CH3CN), and the inhibition of reaction observed for the bidentate 2-pyridylpyrazole substrate (Table 3, run 9). The complex will react with ethyl acrylate in the same manner as described for usual olefin insertion in the HeckeMizoroki reaction. In addition, we considered that the inhibitory effects of nucleophiles, such as inorganic anions (e.g., NaHCO3) and alcohol solvents (n-BuOH) or allyl alcohol, might be due to their interference with the generation of the ArePd(II)eCl complex. 3. Conclusion In summary, we have investigated a ligand-free HeckeMizoroki reaction with 5-trifluoromethanesulfonates of pyrazoles in high yield under mild reaction conditions. The reaction conditions have been established through extensive studies on the palladium catalyst system (palladium sources, ligands, additives, solvents) by considering how to avoid the Michael adduct of acrylic ester at the 4-position of the substrate pyrazole. The optimum conditions (palladium(II) chloride, lithium chloride, and triethylamine in N,Ndimethylacetamide) provide various types of Heck products as 1,3,5-substituted pyrazoles. 4. Experimental section 4.1. General All chemicals were obtained from commercial suppliers and used without further purification. Melting points were determined € chi 535 apparatus and were by using the capillary method on a Bu uncorrected. 1H NMR and 13C NMR spectra were determined in CDCl3 or DMSO-d6 on Bruker DPX-300 or Bruker Avance 500 and reported in d ppm using tetramethylsilanes as the internal standard. The following abbreviations were used: s¼singlet, d¼doublet, t¼triplet, m¼multiplet, dd¼doublets of doublet, br¼broad. The IR spectra were obtained on a Thermo Electron Nicolet 4700 FT-IR in the range of 4000e400 cm1. Elemental analyses were carried out by Takeda Analytical Laboratories Ltd. Mass spectra EI were obtained at 70 eV with JEOL JMS-700T or ESI were obtained at 4.5 kV with LCMS-IT-TOF.

Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.19; H, 6.23; N, 14.91. 4.2.1.3. 2-Benzyl-5-ethyl-2,4-dihydro-3H-pyrazole-3-one (7c). Yield 80%; colorless solid; mp 114e115  C; 1H NMR (300 MHz, CDCl3) d 1.15 (t, J¼7.5 Hz, 3H), 2.40 (q, J¼7.5 Hz, 2H), 3.21 (s, 2H), 4.81 (s, 2H), 7.24e7.36 (m, 5H). Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85. Found: C, 71.27; H, 6.94; N, 13.98. 4.2.1.4. 2-Benzyl-5-(tert-butyl)-2,4-dihydro-3H-pyrazole-3-one (7d). Yield 59%; pale yellow-white solid; mp 166e169  C; 1H NMR (300 MHz, CDCl3) d 1.18 (s, 9H), 3.24 (s, 2H), 4.82 (s, 2H), 7.25e7.37 (m, 5H). Anal. Calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.73; H, 7.71; N, 12.18. 4.2.1.5. 5-Isopropyl-2-methyl-2,4-dihydro-3H-pyrazole-3-one (7e). Yield 89%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.19 (s, 3H), 1.20 (s, 3H), 2.65e2.74 (m, 1H), 3.19 (s, 2H), 3.29 (s, 3H); ESI-HRMS m/z [MþH]þ calcd for C7H12N2O: 141.1022. Found: 141.1029. 4.2.1.6. 1-Benzyl-3-phenyl-1H-pyrazole-5-ol (7f). Yield 75%; colorless solid; mp 207e209  C; 1H NMR (300 MHz, DMSO-d6) d 5.14 (s, 2H), 5.86 (s, 1H), 7.21e7.39 (m, 8H), 7.70e7.73 (m, 2H). Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.71; H, 5.60; N, 11.34. 4.2.1.7. 5-Isopropyl-2-phenyl-2,4-dihydro-3H-pyrazole-3-one (7g). Yield 91%; orange white solid; mp 80e82  C; 1H NMR (300 MHz, CDCl3) d 1.25 (s, 3H), 1.27 (s, 3H), 2.75e2.85 (m, 1H), 3.43 (s, 2H), 7.15e7.21 (m, 1H), 7.37e7.42 (m, 2H), 7.88e7.91 (m, 2H). Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85. Found: C, 71.19; H, 6.93; N, 13.95. 4 . 2 .1. 8 . 1- B e n z yl - 3 - ( t r i flu orom e t hyl) - 1H - p y ra z ol e - 5 - ol (7h). Yield 20%; pale orange white solid; mp 224e226  C; 1H NMR (300 MHz, DMSO-d6) d 5.16 (s, 2H), 5.78 (s, 1H), 7.18e7.21 (m, 2H), 7.26e7.38 (m, 3H),11.92 (br,1H). Anal. Calcd for C11H9N2OF3: C, 54.55; H, 3.75; N, 11.57; F, 23.53. Found: C, 54.83; H, 3.72; N, 11.56; F, 23.27. 4.2.1.9. 3-Isopropyl-1-(pyridine-2-yl)-1H-pyrazole-5-ol (7i). Yield 100%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.27 (s, 3H), 1.29 (s, 3H), 2.85e2.98 (m, 1H), 5.45 (s, 1H), 7.04e7.08 (m, 1H), 7.76e7.82 (m, 1H), 7.89e7.91 (m, 1H), 8.18e8.20 (m, 1H). Anal. Calcd for C11H13N3O: C, 65.01; H, 6.45; N, 20.68. Found: C, 64.69; H, 6.40; N, 20.72.

4.2. Synthesis of pyrazole-3-ones

4.3. Synthesis of trifluoromethanesulfonates

4.2.1. General procedure: pyrazole-3-ones. To a mixture of bketoester 9 (34.68 mmol, 1.0 equiv) in ethanol (10 mL) was added hydrazine 8 (34.68 mmol, 1.0 equiv). The mixture was stirred at room temperature for 1 h. Water (40 mL) was added to the resulting mixture, and stirring was continued at room temperature for 1 h. The resulting precipitate was collected by filtration, washed with ethanol/water (1:2, 7.5 mL2), and dried in vacuo at 50  C to give the title compound.

4.3.1. General procedure: trifluoromethanesulfonates. To a mixture of K3PO4 (129.46 mmol, 2.0 equiv) in water (70 mL) was added pyrazole-3-one 7 (64.73 mmol, 1.0 equiv) in toluene (210 mL). After cooling to 5  C, Tf2O (77.68 mmol, 1.2 equiv) was added to the mixture dropwise for 30 min, followed by stirring the mixture at 5  C for 15 min. The organic layer was separated and washed with water (70 mL2) and aq 20% sodium chloride (70 mL), successively. After the organic layer was dried with Na2SO4, activated carbon Shirasagi A (0.7 g) was added to the solution, and the mixture was stirred for 10 min. Activated carbon was filtered off and washed with toluene (28 mL). The resulting solution was concentrated in vacuo. Toluene (7 mL) and n-heptane (70 mL) were added to the resulting mixture. The precipitate was filtered off and washed with n-heptane (52 mL). The filtrate was concentrated in vacuo. The residue was used in the next reaction without further purification.

4.2.1.1. 2-Benzyl-5-isopropyl-2,4-dihydro-3H-pyrazole-3-one (7a). Yield 93%; pale yellow-white solid; mp 148e150  C; 1H NMR (300 MHz, CDCl3) d 1.14 (s, 3H), 1.16 (s, 3H), 2.63e2.72 (m, 1H), 3.20 (s, 2H), 4.80 (s, 2H), 7.24e7.36 (m, 5H). Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.21; H, 7.38; N, 13.08. 4.2.1.2. 2-Benzyl-5-methyl-2,4-dihydro-3H-pyrazole-3-one (7b). Yield 92%; colorless solid; mp 177e179  C; 1H NMR (300 MHz, CDCl3) d 2.07 (s, 3H), 3.22 (s, 2H), 4.80 (s, 2H), 7.25e7.34 (m, 5H).

4.3.1.1. 1-Benzyl-3-isopropyl-1H-pyrazol-5-yl trifluoromethanesulfonate (6a). Yield 98%; orange oil; 1H NMR (300 MHz, CDCl3)

M. Sera et al. / Tetrahedron 71 (2015) 2833e2838

d 1.24 (s, 3H), 1.26 (s, 3H), 2.89e2.98 (m, 1H), 5.21 (s, 2H), 5.97 (s, 1H), 7.15e7.35 (m, 5H). 4.3.1.2. 1-Benzyl-3-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate (6b). Yield 68%; yellow oil; 1H NMR (300 MHz, CDCl3) d 2.24 (s, 3H), 5.17 (s, 2H), 5.94 (s, 1H), 7.11e7.35 (m, 5H). 4.3.1.3. 1-Benzyl-3-ethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (6c). Yield 76%; colorless oil; 1H NMR (300 MHz, CDCl3) d 1.23 (t, J¼7.6 Hz, 3H), 2.62 (q, J¼7.6 Hz, 2H), 5.20 (s, 2H), 5.98 (s, 1H), 7.19e7.36 (m, 5H). 4.3.1.4. 1-Benzyl-3-(tert-butyl)-1H-pyrazol-5-yl trifluoromethanesulfonate (6d). Yield 100%; yellow oil; 1H NMR (300 MHz, CDCl3) d 1.29 (s, 9H), 5.21 (s, 2H), 6.01 (s, 1H), 7.16e7.19 (m, 2H), 7.27e7.34 (m, 3H). 4.3.1.5. 3-Isopropyl-1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate (6e). Yield 36%; yellow oil; 1H NMR (300 MHz, CDCl3) d 1.23 (s, 3H), 1.25 (s, 3H), 2.85e2.94 (m, 1H), 3.75 (s, 3H), 5.94 (s, 1H). 4.3.1.6. 1-Benzyl-3-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (6f). Yield 98%; colorless oil; 1H NMR (300 MHz, CDCl3) d 5.32 (s, 2H), 6.43 (s, 1H), 7.24e7.28 (m, 2H), 7.33e7.39 (m, 3H). 4.3.1.7. 3-Isopropyl-1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (6g). Yield 87%; yellow oil; 1H NMR (300 MHz, CDCl3) d 1.30 (s, 3H), 1.32 (s, 3H), 2.96e3.06 (m, 1H), 6.16 (s, 1H), 7.38e7.41 (m, 1H), 7.45e7.56 (m, 4H). 4.3.1.8. 1-Benzyl-3-(trifluoromethyl)-1H-pyrazol-5-yl trifluoromethanesulfonate (6h). Yield 89%; yellow oil; 1H NMR (300 MHz, CDCl3) d 5.32 (s, 2H), 6.43 (s, 1H), 7.24e7.28 (m, 2H), 7.33e7.39 (m, 3H). 4.3.1.9. 3-Isopropyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl trifluoromethanesulfonate (6i). Yield 99%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.27 (s, 3H), 1.29 (s, 3H), 2.93e3.02 (m, 1H), 6.13 (s, 1H), 7.19e7.24 (m, 1H), 7.70e7.82 (m, 2H), 8.41e8.43 (m, 1H). 4.4. Synthesis of Heck products 4.4.1. General procedure: Heck reaction. A mixture of PdCl2 (0.29 mmol, 5 mol %) and LiCl (11.48 mmol, 2.0 equiv) in DMAC (14 mL) was stirred at room temperature for 10 min under a nitrogen atmosphere. To the mixture were added trifluoromethanesulfonate 6 (5.74 mmol, 1.0 equiv), a vinyl compound (11.48 mmol, 2.0 equiv), Et3N (11.48 mmol, 2.0 equiv), and DMAC (2 mL). The mixture was stirred at 100  C for 2.5 h under a nitrogen atmosphere. After cooling to 25  C, to the mixture were added ethyl acetate (40 mL) and water (24 mL). The organic layer was separated, washed with water (24 mL) and aq 20 % sodium chloride (24 mL) successively, and concentrated in vacuo. The crude material was purified by column chromatography {eluant: ethyl acetate/n-hexane (1:8)} and concentrated in vacuo to give the title compound. 4.4.1.1. Ethyl (2E)-3-(1-benzyl-3-isopropyl-1H-pyrazol-5-yl)prop2-enoate (12a). Yield 94%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.22e1.31 (m, 3H), 1.27 (s, 3H), 1.29 (s, 3H), 2.95e3.02 (m, 1H), 4.21 (q, J¼7.1 Hz, 2H), 5.40 (s, 2H), 6.27 (d, J¼15.7 Hz, 1H), 6.44 (s, 1H), 7.08e7.11 (m, 2H), 7.23e7.33 (m, 3H), 7.48 (d, J¼15.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 14.26, 22.85, 27.77, 53.26, 60.64, 102.52, 119.96, 126.61, 127.23, 128.79, 129.82, 136.95, 138.43, 159.20, 166.49; IR (ATR, cm1) 2962, 2869, 1708, 1635, 1477, 1280, 1171, 966, 722,

2837

698; ESI-HRMS m/z [MþH]þ calcd for C18H22N2O2: 299.1754. Found: 299.1761. 4.4.1.2. Ethyl (2E)-3-(1-benzyl-3-methyl-1H-pyrazol-5-yl)prop-2enoate (12b). Yield 63%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.30 (t, J¼7.1 Hz, 3H), 2.30 (s, 3H), 4.22 (q, J¼7.1 Hz, 2H), 5.38 (s, 2H), 6.27 (d, J¼15.7 Hz, 1H), 6.40 (s, 1H), 7.11e7.13 (m, 2H), 7.23e7.34 (m, 3H), 7.50 (d, J¼15.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 13.43, 14.23, 53.11, 60.61, 105.39, 120.08, 126.67, 127.78, 128.78, 129.63, 136.85, 138.72, 148.48, 166.33; IR (ATR, cm1) 2980, 1708, 1635, 1455, 1291, 1174, 1023, 966, 729, 702; EIMS (rel intensity) m/z 270 (Mþ, 66), 197 (49), 104 (21), 91 (100), 65 (16); EI-HRMS m/z [Mþ] calcd for C16H18N2O2: 270.1368. Found: 270.1365. 4.4.1.3. Ethyl (2E)-3-(1-benzyl-3-ethyl-1H-pyrazol-5-yl)prop-2enoate (12c). Yield 82%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.24e1.33 (m, 6H), 2.67 (q, J¼7.6 Hz, 2H), 4.21 (q, J¼7.1 Hz, 2H), 5.39 (s, 2H), 6.27 (d, J¼15.8 Hz, 1H), 6.43 (s, 1H), 7.09e7.12 (m, 2H), 7.24e7.33 (m, 3H), 7.50 (d, J¼15.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 13.79, 14.20, 21.33, 53.14, 60.56, 103.91, 119.97, 126.63, 127.73, 128.75, 129.71, 136.90, 138.56, 154.55, 166.34; IR (ATR, cm1) 2970, 1708, 1635, 1454, 1309, 1289, 1173, 1030, 964, 725, 701; EIMS m/z 284 (Mþ, 70), 211 (62), 104 (27), 91 (100), 65 (12); EI-HRMS m/z [Mþ] Calcd for C17H20N2O2: 284.1525. Found: 284.1523. 4.4.1.4. Ethyl (2E)-3-(1-benzyl-3-tert-butyl-1H-pyrazol-5-yl) prop-2-enoate (12d). Yield 90%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.26e1.33 (m, 3H), 1.34 (s, 9H), 4.21 (q, J¼7.1 Hz, 2H), 5.42 (s, 2H), 6.26 (d, J¼15.7 Hz, 1H), 6.47 (s, 1H), 7.07e7.10 (m, 2H), 7.25e7.33 (m, 3H), 7.48 (d, J¼15.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 14.27, 30.56, 32.07, 53.26, 60.54, 102.28, 119.71, 126.56, 127.68, 128.74, 129.93, 137.15, 138.13, 161.77, 166.44; IR (ATR, cm1) 2958, 1709, 1634, 1482, 1455, 1292, 1172, 966, 723, 697; EIMS m/z 312 (Mþ, 44), 297 (33), 239 (23), 104 (8), 91 (100), 65 (7); EI-HRMS m/z [Mþ] calcd for C19H24N2O2: 312.1838. Found: 312.1824. 4.4.1.5. (2E)-3-(3-Isopropyl-1-methyl-1H-pyrazol-5-yl)prop-2enoate (12e). Yield 82%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.25 (s, 3H), 1.27 (s, 3H), 1.33 (t, J¼7.1 Hz, 3H), 2.90e2.99 (m, 1H), 3.90 (s, 3H), 4.26 (q, J¼7.1 Hz, 2H), 6.30 (d, J¼15.8 Hz, 1H), 6.38 (s, 1H), 7.53 (d, J¼15.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 14.17, 22.66, 27.58, 36.42, 60.51, 102.04, 119.51, 129.75, 138.29, 158.46, 166.42; IR (ATR, cm1) 2962, 1708, 1634, 1461, 1281, 1167, 997, 966; EIMS m/z 222 (Mþ, 52), 207 (100), 194 (16), 179 (22), 177 (15), 161 (15); EI-HRMS m/z [Mþ] calcd for C12H18N2O2: 222.1368. Found: 222.1371. 4.4.1.6. (2E)-3-(1-Benzyl-3-phenyl-1H-pyrazol-5-yl)prop-2enoate (12f). Yield 26%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.31 (t, J¼7.1 Hz, 3H), 4.24 (q, J¼7.1 Hz, 2H), 5.50 (s, 2H), 6.37 (d, J¼15.7 Hz, 1H), 6.91 (s, 1H), 7.17e7.20 (m, 2H), 7.26e7.42 (m, 6H), 7.55 (d, J¼15.8 Hz, 1H), 7.82e7.85 (m, 2H); 13C NMR (126 MHz, CDCl3) d 14.30, 53.73, 60.80, 102.85, 120.68, 125.72, 126.83, 127.98, 128.08, 128.76, 128.92, 129.54, 132.88, 136.65, 139.50, 151.26, 166.37; IR (ATR, cm1) 1719, 1633, 1290, 1157, 958, 755, 720, 690; EIMS m/z 332 (Mþ, 100), 259 (46), 104 (30), 91 (75), 65 (8); EI-HRMS m/z [Mþ] calcd for C21H20N2O2: 332.1525. Found: 332.1522. 4.4.1.7. Ethyl (2E)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl) prop-2-enoate (12g). Yield 15%; yellow oil; 1H NMR (300 MHz, CDCl3) d 1.24e1.37 (m, 9H), 2.96e3.10 (m, 1H), 4.03e4.25 (m, 2H), 6.36 (d, J¼16.0 Hz, 1H), 6.59 (s, 1H), 7.30e7.52 (m, 6H); 13C NMR (126 MHz, CDCl3) d 14.26, 22.76, 27.85, 60.61, 103.49, 118.57, 125.51, 128.81, 129.31, 131.02, 138.68, 139.08, 160.12, 166.40; IR (ATR, cm1)

2838

M. Sera et al. / Tetrahedron 71 (2015) 2833e2838

2966, 1708, 1633, 1500, 1310, 1173, 757, 653; ESI-HRMS m/z [MþH]þ calcd for C17H20N2O2: 285.1598. Found: 285.1590. 4.4.1.8. (E)-3-(1-Benzyl-3-isopropyl-1H-pyrazol-5-yl)acrylamide (13). Yield 62%; pale purple solid; mp 150e152  C; 1H NMR (500 MHz, CDCl3) d 1.25 (s, 3H), 1.27 (s, 3H), 2.91e3.06 (m, 1H), 5.37 (s, 2H), 6.20 (br s, 1H), 6.25 (br s, 1H), 6.30 (d, J¼15.5 Hz, 1H), 6.37 (s, 1H), 7.06 (d, J¼7.3 Hz, 2H), 7.17e7.32 (m, 3H), 7.47 (d, J¼15.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 22.87, 27.75, 53.05, 102.02, 121.62, 126.56, 127.71, 127.82, 128.76, 136.95, 138.63, 159.16, 167.34; IR (ATR, cm1) 3363, 3189, 2957, 1668, 1611, 1476, 1178, 960, 719, 698; ESIHRMS m/z [MþH]þ calcd for C16H19N3O: 270.1601. Found: 270.1601. 4. 4.1. 9. (E) -1-B en zyl-3 -iso propyl-5-styryl-1H-pyraz ole (14a). Yield 80%; orange oil; 1H NMR (500 MHz, CDCl3) d 1.30e1.32 (m, 6H), 2.94e3.12 (m, 1H), 5.38 (s, 2H), 6.38 (s, 1H), 6.81 (d, J¼15.9 Hz, 1H), 6.97 (d, J¼16.4 Hz, 1H), 7.11 (d, J¼7.3 Hz, 2H), 7.19e7.25 (m, 2H), 7.26e7.43 (m, 6H); 13C NMR (126 MHz, CDCl3) d 23.02, 27.88, 53.05, 99.79, 114.85, 126.51, 127.52, 128.08, 128.27, 128.71, 128.73, 131.60, 136.63, 137.52, 141.25, 158.86; IR (ATR, cm1) 2960, 2926, 1537, 1474, 1176, 999, 953, 715, 691; ESI-HRMS m/z [MþH]þ calcd for C21H22N2: 303.1856. Found: 303.1856. 4.4.1.10. (E)-4-(2-(1-Benzyl-3-isopropyl-1H-pyrazol-5-yl)vinyl) benzoic acid (14b). Yield 38%; yellow oil; 1H NMR (500 MHz, CDCl3) d 1.29 (s, 3H), 1.30 (s, 3H), 2.90e3.07 (m, 1H), 5.29 (s, 2H), 5.40e5.47 (m, 1H), 5.87e5.96 (m, 1H), 6.18 (s, 1H), 6.70e6.79 (m, 1H), 7.17e7.31 (m, 4H), 7.47 (d, J¼8.2 Hz, 2H), 7.93 (d, J¼8.5 Hz, 2H), 8.06 (d, J¼7.4 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 22.74, 28.63, 51.88, 91.44, 117.52, 126.14, 126.48, 127.12, 127.69, 128.69, 130.56, 135.73, 136.69, 143.25, 144.85, 158.21, 161.38; IR (ATR, cm1) 2963, 1749, 1606, 1540, 1496, 1253, 1177, 990, 702; ESI-HRMS m/z [MþH]þ calcd for C22H22N2O2: 347.1754. Found: 347.1754. 4.4.1.11. Ethyl 3-(1-benzyl-3-isopropyl-1H-pyrazol-5-yl)propanoate (16). Yield 68%; orange oil; 1H NMR (300 MHz, CDCl3) d 1.20e1.31 (m, 3H), 1.25 (s, 3H), 1.27 (s, 3H), 2.53 (t, J¼7.1, 8.2 Hz, 2H), 2.79 (t, J¼7.0, 8.3 Hz, 2H), 2.92e3.02 (m, 1H), 4.11 (q, J¼7.1 Hz, 2H), 5.28 (s, 2H), 5.90 (s, 1H), 7.03e7.06 (m, 2H), 7.21e7.33 (m, 3H); 13C NMR (126 MHz, CDCl3) d 14.19, 21.03, 23.01, 27.89, 32.99, 52.74, 60.61, 101.14, 126.53, 127.44, 128.67, 137.49, 141.73, 158.38, 172.22; IR (ATR, cm1) 2961, 2927, 2868, 1732, 1473, 1455, 1175, 727, 697; ESIHRMS m/z [MþH]þ calcd for C18H24N2O2: 301.1911. Found: 301.1909. Acknowledgements We thank Mr. Kokichi Yoshida, Dr. Kiminori Tomimatsu, and Dr. David Cork for helpful discussions.

References and notes 1. Sidique, S.; Shiryaev, S. A.; Ratnikov, B. I.; Herath, A.; Su, Y.; Strongin, A. Y.; Cosford, N. D. P. Bioorg. Med. Chem. Lett. 2009, 19, 5773 1,3,5-Trisubstituted pyrazole ring for compound 1 was constructed by employing an Aldol reaction between 3,5-dimethylisoxazole and 2,6-diflurobenzaldehyde, followed by Raney Ni catalyzed hydrogenation and the subsequent cyclization with 4methoxybenzylhydrazine. 2. Pinkerton, A. B.; Huang, D.; Cube, R. V.; Hutchinson, J. H.; Struthers, M.; Ayala, J. M.; Vicario, P. P.; Patel, S. R.; Wisniewski, T.; DeMartino, J. A.; Vernier, J.-H. Bioorg. Med. Chem. Lett. 2007, 17, 807. 3. Xiong, Y.; Guo, J.; Candelore, M. R.; Liang, R.; Miller, C.; Dallas-Yang, Q.; Jiang, G.; McCann, P. E.; Qureshi, S. A.; Tong, X.; Xu, S. S.; Shang, J.; Vincent, S. H.; Tota, L. M.; Wright, M. J.; Yang, X.; Zhang, B. B.; Tata, J. R.; Parmee, E. R. J. Med. Chem. 2012, 55, 6137. 4. Taylor, S. J.; Abeywardane, A.; Liang, S.; Muegge, I.; Padyana, A. K.; Xiong, Z.; Hill-Drzewi, M.; Farmer, B.; Li, X.; Collins, B.; Li, J. X.; Heim-Riether, A.; Proudfoot, J.; Zhang, Q.; Goldberg, D.; Zuvela-Jelaska, L.; Zaher, H.; Li, J.; Farrow, N. A. J. Med. Chem. 2011, 54, 8174. 5. (a) Tretyakov, E. V.; Knight, D. W.; Vasilevsky, S. F. J. Chem. Soc., Perkin Trans. 1 1999, 3713; (b) Wang, X. ej.; Tan, J.; Grozinger, K. Tetrahedron Lett. 2000, 41, 4713. 6. Muehlebach, M.; Fisera, R.; Karvas, M.; Rempfler, H.; Brunner, H. -G. WO 2003076409 A1, 2003. 7. (a) Cottineau, B.; Chenault, J. Synlett 2002, 769; (b) Organ, M. G.; Mayer, S. J. Comb. Chem. 2003, 5, 118; (c) Beltr an-Rodil, S.; Edwards, M. G.; Pugh, D. S.; Reid, M.; Taylor, R. J. K. Synlett 2010, 602. 8. Paulson, A. S.; Eskildsen, J.; Vedsø, P.; Begtrup, M. J. Org. Chem. 2002, 67, 3904. 9. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. J. Med. Chem. 2002, 45, 2994. 10. (a) Raimundo, B.; Oslob, J. D.; Braisted, A. C.; Hyde, J.; McDowell, R. S.; Randal, M.; Waal, N. D.; Wilkinson, J.; Yu, C. H.; Arkin, M. R. J. Med. Chem. 2004, 47, 3111; (b) Dvorak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I. J. Org. Chem. 2005, 70, 4188; (c) Dirat, O.; Clipson, A.; Elliott, J. M.; Garrett, S.; Jones, A. B.; Reader, M.; Shaw, D. Tetrahedron Lett. 2006, 47, 1729.   _ E.; Vilkauskaite, _ G.; Eller, G. A.; Holzer, W.; Sa 11. (a) Arba ciauskiene, ckus, A. Tet_ E.; Martynaitis, V.; Krikstolaityte, _ rahedron 2009, 65, 7817; (b) Arba ciauskiene,  S.; Holzer, W.; Sa ckus, A. Arkivoc 2011, xi, 1. 12. Hullar, T. L.; Frexch, W. C. J. Med. Chem. 1969, 12, 424. 13. Ellingboe, J. W.; Antane, M.; Nguyen, T. T.; Collini, M. D.; Antane, S.; Bender, R.; Hartupee, D.; White, V.; MaCllum, J.; Park, C. H.; Russo, A.; Osler, M. B.; Wojdan, A.; Dinish, J.; Ho, D. M.; Bagli, J. F. J. Med. Chem. 1994, 37, 542. 14. Frantz, D. E.; Weaver, D. G.; Carey, J. P.; Kress, M. H.; Dolling, U. H. Org. Lett. 2002, 4, 4717. 15. Maekawa, T.; Hara, R.; Odaka, H.; Kimura, H.; Mizufune, H.; Fukatsu, K. WO 200399793. 16. Xie, C.; Lu, Z.; Zhou, W.; Han, J.; Pan, Y. Tetrahedron Lett. 2012, 53, 6650. 17. 5-Pyrazolone has been also reported as a Michael acceptor Chande, M. S.; Barve, P. A.; Suryanarayan, V. J. Heterocycl. Chem. 2007, 44, 49. 18. Holzapfel, C. W.; Dwyer, C. Heterocycles 1998, 48, 215. 19. (a) Fretz, H. Tetrahedron Lett. 1996, 37, 8475; (b) Musso, D. L.; Orr, G. F.; Cochran, F. R.; Kelley, J. L.; Selph, J. L.; Rigdon, G. C.; Cooper, B. R.; Jons, M. L. J. Med. Chem. 2003, 46, 409. 20. Andersson, C.-M.; Hallberg, A. J. Org. Chem. 1988, 54, 2112. 21. (a) Inouye, M.; Miyake, T.; Furusyo, M.; Nakazumi, H. J. Am. Chem. Soc. 1995, 117, 12416; (b) Draper, T. L.; Bailey, T. R. Synlett 1995, 157. 22. (a) Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265; (b) Barnett, C. J.; Wilson, T. M. Heterocycles 1983, 35, 925. 23. (a) Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Bernimi, R. Synlett 2003, 1133; (b) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Org. Lett. 2003, 5, 777. 24. Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.