Fully Substituted Pyrazoles Assisted Palladium-Catalyzed Late-Stage Arylation of C(sp<sup>2</sup>)

Citation: Fu Xiaopan, Wang Yangyang, Yang Jinyue, Wu Gaorong, Xia Chengcai, Ji Yafei. Fully Substituted Pyrazoles Assisted Palladium-Catalyzed Late-Stage Arylation of C(sp²)—H Bond[J]. Chinese Journal of Organic Chemistry, 2020, 40(12): 4305-4314. doi: 10.6023/cjoc202005080 shu

钯催化全取代吡唑导向的C(sp²)—H键后期芳基化反应

付小盼 ^a, ,
王杨阳 ^a, ,
杨金月 ^a, ,
吴高荣 ^a, ,
夏成才 ^{b,
,} ,
冀亚飞 ^{a,
,}

a.
华东理工大学药学院制药工程与过程化学教育部研究中心上海 200237
b.
山东第一医科大学(山东省医学科学院)药学院山东泰安 271016

通讯作者: 夏成才, xiachc@163.com
冀亚飞, jyf@ecust.edu.cn

基金项目:
国家自然科学基金（No.21676088）资助项目

国家自然科学基金 21676088

摘要: 发展了一种钯催化全取代吡唑类化合物的邻位C（sp²）—H键后期芳基化的反应体系.通过对反应条件的优化，得到了最高效的芳基化反应条件.该催化体系表现出广泛的底物适用性、良好的官能团耐受性以及优良的分离收率.进行了控制实验，如分子间的竞争实验和放大克级实验，氘代动力学实验证明了C-H键的断裂是决速步骤.最后，通过制备双核二聚体环钯化中间体，提出了合理的钯催化循环反应机理.

关键词:

English

Fully Substituted Pyrazoles Assisted Palladium-Catalyzed Late-Stage Arylation of C(sp²)—H Bond

a.
Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science & Technology, Shanghai 200237
b.
Pharmacy College, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271016

Corresponding author: Xia Chengcai, xiachc@163.com Ji Yafei, jyf@ecust.edu.cn

Received Date: 28 May 2020
Revised Date: 28 June 2020
Available Online: 25 December 2020
Fund Project:
Project supported by the National Natural Science Foundation of China (No. 21676088)

Abstract: A successful protocol has been developed for palladium-catalyzed late-stage arylation of fully substituted pyrazoles. Through screening of optimazation of reaction parameters, the most efficient reaction conditions for mono-ortho-position arylation were obtained. This reaction features a broad substrate scope, good functional group tolerance as well as good to excellent yield. Moreover, the intermolecular competition experiments and gram scale reaction were also performed. The kinetic isotopic effect (KIE) result reveled C-H bond cleavage was involved in the rate-limiting step and a plausible mechanism was proposed based on the dual-core dimeric palladacycle.

Key words:

1. Introduction

Over the past few decades, the field of C—H bond functionalization has gained considerable attention, mainly because it is an efficient and powerful synthetic method for C—C or C—X bond formation.^[1] The biaryl scaffolds play an indispensable role in numerous medicinal chemistry, natural products and organic materials.^[2] Therefore, searching simple and efficient methods for construction of these structures is becoming more attractive. The oxidative coupling reaction with fewer reaction step has emerged as the most elegant method to construct biaryl scaffolds.^[3] However, poor regioselectivity hinders its development.^[4] Increasingly, directing group (DG) assisted C—H arylation has been extensively investigated with highly-site- selectivity in atom- and step-economic mode.^[5] In these reactions, diverse DGs have exhibited a superior ability to assist C(sp²)—H arylation, such as pyridine, ^[6] 8-amino- quinoline, ^[7] oxime-ester, ^[8] cyano, ^[9] amide^[10] and PIP-amine.^[11]

Recently, late-stage functionalization has become a valuable strategy, which can directly transform complicated structures into new bioactive compounds.^[12] Pyrazoles are widely distributed in drug molecules.^[13] In previous works, transition metal-catalyzed diverse C—H bond functionalizations have been realized using pyrazole as DG through reactions such as arylation, ^{[14a-14b, 14h-14i, 14k, 14m-14n]} alkenylation, ^[14c-14d] amidation, ^[14e] aroylation^{[14g, 14j, 14l]} and others.^[14f]

We recently reported Pd-catalyzed C(sp²)—H late-stage mono-acetoxylation, ^[15a] iodination^[15a] and aroylation^[15b] of pyrazoles (Scheme 1, A). Despite so many advances, efforts are still in high demand to develop late-stage functionalization containing a pharmacophore. Herein, we disclose the first C(sp²)—H bond late-stage mono-arylation using fully substituted pyrazole as auxiliary. This protocol shows a broad substrate scope and wide functional group tolerance, which provides a potential tool for the screening of potential natural products and medicines.

Scheme 1

Scheme 1. Previous related works and our present work

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2. Results and discussion

As an initial experiment, the reaction of the model substrate 1a and 2a (2.0 equiv.) was performed in the presence of Pd(OAc)₂ (10 mol%), AgTFA (2.0 equiv.) in AcOH at 120 ℃ (Table 1), and 3a was isolated in the yield of 45%. Firstly, different solvents including 1, 1, 1, 3, 3, 3-hexafluoro- 2-propanol (HFIP), toluene, N, N-dimethylformamide (DMF) and the mixture solvents of HFIP/AcOH were screened, HFIP/AcOH (V:V＝3:1) was suitable for the reaction (Entries 1~7). Subsequently, it was found that Pd(OAc)₂ was the best catalyst compared with other Pd salts (Entry 6 vs. 8~12). Furthermore, AgTFA was considered as the ideal additive (Entry 6 vs. 13~15). On the other hand, the yield was obviously improved when increased the loading of 2a from 2.0 equiv. to 3.0 equiv. (Entry 16). However, when the amount of AgTFA or the reaction temperatures were changed, the results were unsatisfactory (Entries 16~17). Therefore, the standard conditions were as followed: 1a (0.3 mmol), 2a (0.9 mmol), AgTFA (2.0 equiv.), HFIP/AcOH (V:V＝3:1, 3.0 mL), 120 ℃, 20 h.

Table 1

Table 1. Optimization of the reaction conditions^a

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Entry	Catalyst	Solvent (V:V)	Yield^b/%
1	Pd(OAc)₂	AcOH	45
2	Pd(OAc)₂	HFIP	43
3	Pd(OAc)₂	Toluene	0
4	Pd(OAc)₂	DMF	0
5	Pd(OAc)₂	HFIP/AcOH (1:1)	42
6	Pd(OAc)₂	HFIP/AcOH (3:1)	70
7	Pd(OAc)₂	HFIP/AcOH (5:1)	43
8	Pd(CH₃CN)₂Cl₂	HFIP/AcOH (3:1)	47
9	PdCl₂	HFIP/AcOH (3:1)	45
10	Pd(PPh₃)₂Cl₂	HFIP/AcOH (3:1)	42
11	Pd(TFA)₂	HFIP/AcOH (3:1)	33
12	Pd(PPh)₃	HFIP/AcOH (3:1)	32
13	Pd(OAc)₂	HFIP/AcOH (3:1)	31^c (28^d)
14	Pd(OAc)₂	HFIP/AcOH (3:1)	30^e (0^f)
15	Pd(OAc)₂	HFIP/AcOH (3:1)	47^g (38^h)
16	Pd(OAc)₂	HFIP/AcOH (3:1)	81ⁱ (70^j)
17	Pd(OAc)₂	HFIP/AcOH (3:1)	64^k (69^l)
^a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (10 mol%), AgTFA (2.0 equiv.), solvent (3.0 mL), 120 ℃, 20 h. ^b Isolated yield. ^c Ag₃PO₄ as the additive. ^d Ag₂CO₃ as the additive. ^e AgOAc as the additive. ^f K₂S₂O₈ as the additive. ^g CsOAc as the additive. ^h Cs₂CO₃ as the additive. ⁱ 2a (0.9 mmol). ^j AgTFA (3.0 equiv.). ^k110 ℃. ^l 130 ℃.

With the established conditions in hand, the scope of functionalized pyrazoles was explored and the representative products are shown in Table 2. Different functional groups including Me, OMe, F, Cl, Br, I, NO₂ and 2-naphthyl groups were tolerated and can be transformed into the desired products (3a~3q). Electron-donating groups such as methyl and methoxy are substituted at the para of 1-phenyl could favorably deliver the desired products in good yields (3a, 3b). In comparison, the substrates containing electron-withdrawing groups were less reactive (3d~3h). Especially, the strongly electron-withdrawing group NO₂ was also provided the arylation product in 48% yield (3h). It was found that the meta-substituted of 1-phenyl pyrazoles reacted in the less hindered positions with 2a giving the corresponding products (3i~3m). To our disappointment, the ortho-position substituted substrates were not suitable for this reaction, which possibly due to the fact that steric constraints toward the formation of the complex intermediate (3n~3p).^[15b] In addition, 1-(2-naphthyl) substrates could also be applied in the transformation to deliver the desired product in good yield (3q). Furthermore, the yield was decreased when alkyl group instead of the aryl at the 5-site (3r), which means the aryl group was important for the reaction. Moreover, 5-aryl bearing electron- donating group (R²＝p-Me) and electron-withdrawing group (R²＝p-Cl) were well tolerated (3s, 3t). Meanwhile, the alkyl substituted substrates could also be applied to the transformation to deliver the desired products in the moderate yield (3u, 3v).

Table 2

Table 2. Substrate scope of functionalized pyrazoles^{a, b}

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In the next stage, various of aryl iodides were examined. A range of electronically biased aryl iodides such as OMe, Me, COOEt, F, Cl, Br, CF₃, COCH₃ and COOCH₃ were tolerated in this protocol (Table 3). In general, the electron-rich partners gave higher yield than those bearing electron- withdrawing groups in the para-positions and meta- positions (4b~4l), but the ethyl 4-iodobenzoate could furnish the corresponding product in 81% yield (4g). Importantly, the reactive groups like F, Cl, Br, COOEt and COCH₃ can be easily transformed into another functional molecular. Steric effect plays a critical role in the transformation, no products were obtained for the ortho- substituted aryl iodides (4m, 4n), maybe due to the fact that the larger steric could block the formation of the complex palladacyclic intermediate. Then, the electron-rich 6-iodo-1, 4-benzodioxane also showed the excellent reactivity and gave the good yield (4o). To our surprise, the 3, 5-substituted aryl iodides also afforded the moderate yield (4p). Unfortunately, 2-substituted 6-iodopyridine and 2-iodothiophene as the coupling partners independently reacted with 1c, no desired products were obtained (4q, 4r).

Table 3

Table 3. Substrate scope of aryl iodide^{a, b}

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To gain insight into the reaction mechanism, a few control experiments were conducted. The intermolecular competition experiments revealed the donating-group was more active than those withdrawing-group (Scheme 2). Meanwhile, the kinetic isotopic effect experiment was performed between 1c and 1c' with 2a under the standard conditions, the result (k_H/k_D＝3.5) implicated the C—H bond cleavage as the rate-limiting step (Scheme 3). Besides, gram scale reaction was also performed (Scheme 4). According to the literature, the key palladacycle intermediate I was successfully obtained ^{[15b, 16]} (Scheme 5). When the intermediate II was exposed to the standard conditions in the absence of substrate 1c and Pd(OAc)₂, the target product 3c was obtained in the yield of 67%.

Scheme 2

Scheme 2. Intermolecular competition experiment

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Scheme 3

Scheme 3. Kinetic isotope effect study

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Scheme 4

Scheme 4. Gram scale reaction

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Scheme 5

Scheme 5. Preparation and functionlization of the dual-core dimeric cyclopalladated intermediate II

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Based on the experiments and the relevant documented reports, ^{[6-8, 15b, 16]} a plausible reaction pathway is proposed in Scheme 6. First, Pd(OAc)₂ coordinates with the substrate I to form the key dual-core dimeric cyclopalladated intermediate II through the C—H bond activation, the oxidative addition with aryl iodide and the key intermediate II will generate the Pd(Ⅳ) intermediate III. Finally, the product is obtained by reductive elimination and regenerating the Pd(Ⅱ) catalyst. The role of the Ag salt may facilitate oxidative addition of aryl iodides to Pd(Ⅱ) centers and be used as the iodide scavengers.^[5f]

Scheme 6

Scheme 6. Plausible mechanism

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3. Conclusions

In summary, an easily method for late-stage arylation of fully substituted pyrazoles via palladium-catalyzed have been developed. A variety of pyrazoles and aryl iodides were tolerated in this protocol. Importantly, the arylation reaction of the highly functionalized substrates can be transformed into the complex bioactive molecules in a mono-site- selectivity and simple operation way. This protocol will facilitate the potential development of the medicine and material chemistry.

4. Experimental section

4.1 General methods

All reactions were carried out in oven-dried glassware and monitored by thin layer chromatography (TLC, pre-coated silica gel plates containing HF254). NMR spectra were determined on Bruker AV400 in CDCl₃ with TMS as internal standard for ¹H NMR (400 MHz) and ¹³C NMR (100 MHz), respectively. HRMS were measured on a QSTAR Pulsar I LC/TOF MS mass spectrometer or Micromass GCTTM gas chromatograph-mass spectrometer.

4.2 General procedure for arylation reaction

A mixture of substrate 1 (0.3 mmol), 4-iodoanisole 2 (0.9 mmol), Pd(OAc)₂ (10 mol%, 6.7 mg), AgTFA (2.0 equiv., 132.6 mg) in HFIP/AcOH (V:V＝3:1, 3.0 mL) was charged in a glass sealed-tube and stirred under air atmosphere at 120 ℃ for 20 h. Upon completion of the reaction, the solution was concentrated in vacuo for 30 min, then saturated sodium bicarbonate (30 mL) and dichloromethane (15 mL) were added into the mixture, then the aqueous layer was extracted with dichloromethane (15 mL×2). The combined organic layer was dried over anhydrous MgSO₄. Finally, the solution was concentrated in vacuo to provide a crude product, which was further purified via a column chromatography on silica gel [eluents: V(petroleum ether):V(ethyl acetate)＝5:1] to supply the desired product.

Ethyl 1-(4'-methoxy-5-methyl-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carboxylate (3a): Yellow solid, 103.6 mg (81% yield). m.p. 131~133 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.55 (d, J＝8.0 Hz, 1H), 7.21 (dd, J＝8.0, 1.6 Hz, 1H), 7.12 (t, J＝7.2 Hz, 1H), 7.03 (t, J＝8.0 Hz, 2H), 6.94 (s, 2H), 6.59 (d, J＝8.8 Hz, 2H), 6.45 (d, J＝7.2 Hz, 2H), 6.41 (d, J＝8.8 Hz, 2H), 4.47 (q, J＝7.2 Hz, 2H), 3.76 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.5, 158.8, 143.5, 141.6, 139.2, 137.8, 134.9, 130.7, 130.5, 129.23 (2C), 129.17 (2C), 128.8, 128.5, 128.4, 127.69 (2C), 127.6, 118.7, 113.49 (2C), 60.7, 55.3, 21.2, 14.5, 9.7; HRMS (EI) calcd for C₂₇H₂₆N₂O₃ 426.1942, found 426.1944.

Ethyl 1-(4', 5-dimethoxy-[1, 1'-biphenyl]-2-yl)-4-methyl- 5-phenyl-1H-pyrazole-3-carboxylate (3b): Yellow solid, 96.8 mg (73% yield). m.p. 158~160 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (d, J＝8.8 Hz, 1H), 7.13 (t, J＝7.6 Hz, 1H), 7.04 (t, J＝8.0 Hz, 2H), 6.93 (dd, J＝8.8, 2.8 Hz, 3H), 6.65 (d, J＝2.8 Hz, 1H), 6.60 (d, J＝8.8 Hz, 2H), 6.47~6.43 (m, 4H), 4.47 (q, J＝7.2 Hz, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 2.16 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.5, 159.8, 159.0, 143.6, 141.5, 139.5, 130.5, 130.4, 129.9, 129.21 (2C), 129.20 (2C), 128.8, 127.7 (2C), 127.6, 118.6, 114.9, 113.5 (2C), 112.9, 60.7, 55.5, 55.3, 14.5, 9.7; HRMS (EI) calcd for C₂₇H₂₆N₂O₄ 442.1987, found 442.1990.

Ethyl 1-(4'-methoxy-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (3c): Yellow solid, 81.6 mg (66% yield). m.p. 130~132 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.68 (d, J＝7.6 Hz, 1H), 7.44~7.36 (m, 2H), 7.15 (d, J＝6.8 Hz, 1H), 7.12 (d, J＝7.2 Hz, 1H), 7.03 (t, J＝7.6 Hz, 2H), 6.60 (d, J＝8.8 Hz, 2H), 6.45 (d, J＝8.0 Hz, 2H), 6.42 (d, J＝8.8 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.18 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 158.9, 143.5, 141.8, 138.2, 137.3, 130.4, 130.1, 129.3, 129.3 (2C), 129.1 (2C), 128.83, 128.7, 127.8, 127.7 (2C), 127.7, 118.8, 113.6 (2C), 60.8, 55.3, 14.6, 9.7; HRMS (EI) calcd for C₂₆H₂₄N₂O₃ 412.1816, found 412.1817.

Ethyl 1-(5-fluoro-4'-methoxy-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carboxylate (3d): Yellow solid, 74.8 mg (58% yield). m.p. 105~107 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.60 (dd, J＝8.8, 5.6 Hz, 1H), 7.15 (t, J＝7.2 Hz, 1H), 7.11 (m, 1H), 7.05 (t, J＝7.6 Hz, 2H), 6.86 (dd, J＝9.6, 3.2 Hz, 1H), 6.61 (d, J＝8.8 Hz, 2H), 6.44 (d, J＝6.8 Hz, 2H), 6.41 (d, J＝8.8 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 3.78 (s, 3H), 2.17 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.5 (d, ¹J_CF＝247.5 Hz), 163.3, 159.3, 143.7, 141.9, 140.5 (d, ³J_CF＝8.6 Hz), 133.4 (d, ⁴J_CF＝2.9 Hz), 130.7 (d, ³J_CF＝9.2 Hz), 129.3, 129.3, 129.2 (2C), 129.1 (2C), 128.5, 127.8 (2C), 118.9, 116.6 (d, ²J_CF＝22.9 Hz), 114.66 (d, ³J_CF＝26.0 Hz), 113.7 (2C), 60.8, 55.3, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₃N₂O₃F 430.1736, found 430.1737.

Ethyl 1-(5-chloro-4'-methoxy-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carboxylate (3e): Yellow solid, 97.7 mg (73% yield). m.p. 138~140 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.63 (d, J＝8.4 Hz, 1H), 7.40 (dd, J＝8.4, 2.4 Hz, 1H), 7.18~7.14 (m, 2H), 7.06 (t, J＝8.0 Hz, 2H), 6.61 (d, J＝8.8 Hz, 2H), 6.44 (d, J＝7.2 Hz, 2H), 6.40 (d, J＝8.4 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 3.78 (s, 3H), 2.17 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 159.3, 143.5, 142.1, 139.8, 135.9, 134.9, 130.2, 130.0, 129.2 (2C), 129.1 (2C), 128.4, 127.9 (2C), 127.9 (2C), 127.7, 119.0, 113.7 (2C), 60.9, 55.3, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₃N₂O₃Cl 446.1497, found 446.1498.

Ethyl 1-(5-bromo-4'-methoxy-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carboxylate (3f): Yellow solid, 81.0 mg (55% yield). m.p. 136~138 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.58~7.53 (m, 2H), 7.31 (s, 1H), 7.15 (t, J＝7.6 Hz, 1H), 7.05 (t, J＝7.6 Hz, 2H), 6.60 (d, J＝8.8 Hz, 2H), 6.43 (d, J＝7.2 Hz, 2H), 6.39 (d, J＝8.8 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.16 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 159.3, 143.5, 142.2, 140.0, 136.4, 132.9, 130.7, 130.4, 129.2 (2C), 129.0 (2C), 129.0, 128.4, 127.9, 127.9, 123.0, 119.0, 113.7 (2C), 60.9, 55.3, 55.3, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₃N₂O₃Br 490.0981, found 490.0979.

Ethyl 1-(5-iodo-4'-methoxy-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carboxylate (3g): Yellow solid, 114.6 mg (71% yield). m.p. 157~159 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (dd, J＝8.4, 2.0 Hz, 1H), 7.50 (d, J＝2.0 Hz, 1H), 7.41 (d, J＝8.0 Hz, 1H), 7.15 (t, J＝7.6 Hz, 1H), 7.05 (t, J＝7.6 Hz, 2H), 6.59 (t, J＝8.8 Hz, 2H), 6.43 (d, J＝7.2 Hz, 2H), 6.37 (d, J＝7.2 Hz, 2H), 6.37 (d, J＝8.4 Hz, 2H), 4.47 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.16 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.3, 159.3, 143.5, 142.2, 140.1, 138.9, 137.1, 136.7, 130.4, 129.2 (2C), 129.0 (2C), 128.8, 128.4, 127.9, 127.9 (2C), 119.0, 113.7 (2C), 94.8, 60.9, 55.3, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₃N₂O₃I 538.0836, found 538.0838.

Ethyl 1-(4'-methoxy-5-nitro-[1, 1'-biphenyl]-2-yl)-4-me- thyl-5-phenyl-1H-pyrazole-3-carboxylate (3h): Yellow solid, 65.8 mg (48% yield). m.p. 170~172 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.28 (dd, J＝8.8, 2.8 Hz, 1H), 8.05 (d, J＝2.4 Hz, 1H), 7.90 (d, J＝8.8 Hz, 1H), 7.18 (t, J＝7.6 Hz, 1H), 7.06 (t, J＝7.6 Hz, 2H), 6.64 (d, J＝8.8 Hz, 2H), 6.43 (d, J＝8.8 Hz, 4H), 4.49 (q, J＝7.2 Hz, 2H), 3.80 (s, 3H), 2.19 (s, 3H), 1.47 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.0, 159.7, 147.8, 143.6, 143.0, 142.2, 139.6, 130.1, 129.2 (2C), 128.9 (2C), 128.2, 128.2, 128.1 (2C), 128.0, 125.4, 122.5, 119.5, 114.0 (2C), 61.1, 55.4, 14.5, 9.6; HRMS (EI) calcd for C₂₆H₂₃N₃O₅ 457.1687, found 457.1688.

Ethyl 1-(4, 4'-dimethoxy-[1, 1'-biphenyl]-2-yl)-4-methyl- 5-phenyl-1H-pyrazole-3-carboxylate (3i): Yellow solid, 70.3 mg (53% yield). m.p. 108~110 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.23 (d, J＝2.8 Hz, 1H), 7.14 (t, J＝7.6 Hz, 1H), 7.06~7.02 (m, 3H), 6.95 (dd, J＝8.8, 2.8 Hz, 1H), 6.58 (d, J＝8.8 Hz, 2H), 6.47 (d, J＝7.2 Hz, 2H), 6.35 (d, J＝8.8 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 2.18 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 159.0, 158.5, 143.5, 141.8, 137.9, 131.0, 130.8, 130.2, 129.1 (2C), 129.1 (2C), 128.7, 127.7 (2C), 127.7, 118.8, 116.0, 113.5 (2C), 113.3, 60.8, 55.7, 55.32 14.5, 9.7; HRMS (EI) calcd for C₂₇H₂₆N₂O₄ 442.1941, found 442.1937.

Ethyl 1-(4'-methoxy-4-methyl-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carbox ylate (3j): Yellow solid, 93.3 mg (73% yield). m.p. 113~115 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.51 (d, J＝0.8 Hz, 1H), 7.17 (dd, J＝7.6, 0.8 Hz, 1H), 7.11 (t, J＝7.2 Hz, 1H), 7.03~7.00 (m, 3H), 6.58 (d, J＝8.8 Hz, 2H), 6.44 (d, J＝7.2 Hz, 2H), 6.36 (d, J＝8.8 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 3.75 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 158.7, 143.4, 141.7, 137.8, 137.0, 135.2, 130.4, 130.1, 129.9, 129.1 (2C), 129.1, 129.1 (2C), 128.7, 127.7 (2C), 127.6, 118.7, 113.5 (2C), 60.8, 55.3, 20.9, 14.6, 9.7; HRMS (EI) calcd for C₂₇H₂₆N₂O₃ 426.1936, found 426.1938.

Ethyl 1-(4-fluoro-4'-methoxy-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carbox ylate (3k): Yellow solid, 68.4 mg (53% yield). m.p. 155~157 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.46 (d, J＝8.8 Hz, 1H), 7.17~7.11 (m, 3H), 7.05 (t, J＝7.6 Hz, 2H), 6.60 (d, J＝8.8 Hz, 2H), 6.46 (d, J＝7.2 Hz, 2H), 6.36 (d, J＝8.8 Hz, 2H), 4.49 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.17 (s, 3H), 1.47 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 162.6 (d, ¹J_CF＝247.0 Hz), 158.9, 143.5, 142.2, 138.2 (d, ³J_CF＝9.8 Hz), 134.5 (d, ⁴J_CF＝3.5 Hz), 131.5 (d, ³J_CF＝8.5 Hz), 129.4, 129.2 (2C), 129.0 (2C), 128.4, 127.8 (2C), 119.0, 116.5 (d, ²J_CF＝20.8 Hz), 116.0 (d, ²J_CF＝23.5 Hz), 113.6 (2C), 60.9, 55.3, 14.5, 9.6; HRMS (EI) calcd for C₂₆H₂₃- N₂O₃F 430.1736, found 430.1735.

Ethyl 1-(4-chloro-4'-methoxy-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carbox ylate (3l): Yellow solid, 84.3 mg (63% yield). m.p. 98~100 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (d, J＝2.0 Hz, 2H), 7.37 (dd, J＝8.4, 2.0 Hz, 1H), 7.15 (t, J＝7.2 Hz, 2H), 7.08 (d, J＝8.4 Hz, 1H), 7.05 (t, J＝8.0 Hz, 2H), 6.60 (d, J＝8.4 Hz, 2H), 6.45 (d, J＝7.2 Hz, 2H), 6.36 (d, J＝8.8 Hz, 2H), 4.49 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.17 (s, 3H), 1.47 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 159.1, 143.5, 142.2, 138.0, 136.7, 133.1, 131.2, 129.5, 129.2, 129.1 (2C), 129.0 (2C), 128.9, 128.3, 127.9 (3C), 119.0, 113.7 (2C), 60.9, 55.3, 14.5, 9.6; HRMS (EI) calcd for C₂₆H₂₃N₂O₃Cl 446.1436, found 446.1437.

Ethyl 1-(4-bromo-4'-methoxy-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carbox ylate (3m): Yellow solid, 95.6 mg (65% yield). m.p. 103~105 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.89 (d, J＝2.0 Hz, 1H), 7.51 (dd, J＝8.4, 2.0 Hz, 1H), 7.15 (t, J＝7.6 Hz, 1H), 7.07~7.00 (m, 3H), 6.59 (d, J＝8.8 Hz, 2H), 6.44 (d, J＝7.2 Hz, 2H), 6.36 (d, J＝8.8 Hz, 2H), 4.49 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.17 (s, 3H), 1.47 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 159.1, 143.5, 142.2, 138.2, 137.2, 132.4, 131.7, 131.4, 129.3, 129.1 (2C), 129.0 (2C), 128.3, 127.9 (3C), 120.8, 119.0, 113.7 (2C), 60.9, 55.3, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₃N₂O₃Br 490.0936, found 490.0937.

Ethyl 1-(3-(4-methoxyphenyl)naphthalen-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carboxylate (3q): Yellow oil, 117.9 mg (85% yield). ¹H NMR (400 MHz, CDCl₃) δ: 8.25 (s, 1H), 7.94~7.91 (m, 1H), 7.81~7.79 (m, 1H), 7.61 (s, 1H), 7.54~7.52 (m, 2H), 7.11 (t, J＝7.2 Hz, 1H), 6.99 (t, J＝7.6 Hz, 2H), 6.64 (d, J＝8.8 Hz, 2H), 6.50 (d, J＝8.8 Hz, 2H), 6.47 (d, J＝7.2 Hz, 2H), 4.51 (q, J＝7.2 Hz, 2H), 3.79 (s, 3H), 2.22 (s, 3H), 1.48 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 159.0, 143.7, 141.9, 136.1, 136.0, 133.4, 132.3, 130.5, 129.4 (2C), 129.2, 129.1 (2C), 128.6, 128.0, 127.9, 127.8 (2C), 127.8, 127.7, 127.2, 126.6, 118.9, 113.6 (2C), 60.9, 55.3, 14.6, 9.8; HRMS (EI) calcd for C₃₀H₂₆N₂O₃ 462.1943, found 462.1942.

Ethyl 5-ethyl-1-(4'-methoxy-[1, 1'-biphenyl]-2-yl)-4-me- thyl-1H-pyrazole-3-carboxylate (3r): Yellow solid, 68.8 mg (63% yield). m.p. 104~106 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.51~7.47 (m, 2H), 7.42~7.40 (m, 2H), 7.00 (d, J＝8.8 Hz, 2H), 6.76 (d, J＝8.8 Hz, 2H), 4.43 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.16 (s, 3H), 2.05~1.99 (m, 2H), 1.42 (t, J＝7.2 Hz, 3H), 0.64 (t, J＝7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.6, 159.1, 144.7, 141.2, 138.8, 137.0, 130.2, 130.2, 129.8, 129.7 (2C), 129.2, 127.7, 117.3, 113.9 (2C), 60.6, 55.2, 17.3, 14.5, 12.6, 9.1; HRMS (EI) calcd for C₂₂H₂₄N₂O₃ 364.1887, found 364.1888.

Ethyl 1-(4'-methoxy-[1, 1'-biphenyl]-2-yl)-4-methyl-5- (p-tolyl)-1H-pyrazole-3-carboxylate (3s): Yellow solid, 113.8 mg (89% yield). m.p. 143~145 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.65 (dd, J＝7.6, 2.0 Hz, 1H), 7.43~7.35 (m, 2H), 7.16 (dd, J＝7.2, 1.6 Hz, 1H), 6.83 (d, J＝8.0 Hz, 2H), 6.61 (d, J＝8.8 Hz, 2H), 6.45 (d, J＝8.8 Hz, 2H), 6.34 (d, J＝8.0 Hz, 2H), 4.47 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 158.9, 143.6, 141.7, 138.3, 137.5, 137.4, 130.4, 130.1, 129.3, 129.3 (2C), 129.0 (2C), 128.8, 128.4 (2C), 127.7, 125.7, 118.6, 113.5 (2C), 60.7, 55.3, 21.2, 14.5, 9.7. HRMS (EI) calcd for C₂₇H₂₆- N₂O₃ 426.1987, found 426.1992.

Ethyl 5-(4-chlorophenyl)-1-(4'-methoxy-[1, 1'-biphenyl]- 2-yl)-4-methyl-1H-pyrazole-3-carbox ylate (3t): White solid, 97.7 mg (73% yield). m.p. 103~105 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.67 (dd, J＝6.8, 1.2 Hz, 1H), 7.44~7.37 (m, 2H), 7.17 (dd, J＝7.2, 1.6 Hz, 1H), 6.73 (t, J＝8.8 Hz, 2H), 6.63 (d, J＝8.8 Hz, 2H), 6.45 (d, J＝8.4 Hz, 2H), 6.42~6.38 (m, 2H), 4.48 (q, J＝7.2 Hz, 2H), 3.77 (s, 3H), 2.15 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 163.3, 160.9, 159.0, 142.5, 141.8, 138.0, 137.0, 131.0, 130.9, 130.3, 130.2, 129.5, 129.2, 128.8, 127.9, 124.8, 118.8, 115.0, 114.7, 113.6 (2C), 60.8, 55.3, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₃N₂O₃Cl 446.1436, found 446.1438.

1-(4'-Methoxy-[1, 1'-biphenyl]-2-yl)-3, 4, 5-trimethyl-1H-pyrazole (3u): Clourless oil, 55.2 mg (63% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.47~7.37 (m, 4H), 6.98 (d, J＝8.0 Hz, 2H), 6.77 (d, J＝8.0 Hz, 2H), 3.77 (s, 3H), 2.24 (s, 3H), 1.81 (s, 3H), 1.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.9, 147.4, 138.7, 137.5, 137.4, 131.0, 130.2, 129.6 (2C), 128.9, 128.9, 127.7, 113.7 (2C), 111.9, 55.2, 11.9, 9.7, 8.1; HRMS (EI) calcd for C₁₉H₂₀N₂O 292.1618, found 292.1617.

1-(4'-Methoxy-[1, 1'-biphenyl]-2-yl)-3-methyl-5-phenyl-1H-pyrazole (3v): White solid, 62.2 mg (61% yield). m.p. 146~148 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (dd, J＝8.0, 4.0 Hz, 1H), 7.47~7.38 (m, 2H), 7.22 (dd, J＝8.0, 4.0 Hz, 1H), 7.09 (t, J＝8.0 Hz, 1H), 7.00 (t, J＝8.0 Hz, 2H), 6.63 (d, J＝8.0 Hz, 2H), 6.57 (d, J＝8.0 Hz, 2H), 6.45 (d, J＝8.0 Hz, 2H), 6.08 (s, 1H), 3.75 (s, 3H), 2.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.7, 148.9, 145.3, 138.6, 138.0, 130.8, 130.4, 130.3, 129.2 (2C), 128.7 (2C), 128.4 (2C), 127.9, 127.7, 127.5, 127.3, 113.4 (2C), 106.1, 55.3, 13.7; HRMS (EI) calcd for C₂₃H₂₀N₂O 340.1617, found 340.1619.

Ethyl 1-([1, 1'-biphenyl]-2-yl)-4-methyl-5-phenyl-1H- pyrazole-3-carboxylate (4a): Yellow oil, 71.1 mg (62% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (d, J＝7.6 Hz, 1H), 7.46 (t, J＝7.6 Hz, 1H), 7.40 (t, J＝7.6 Hz, 1H), 7.19~7.10 (m, 3H), 7.06~6.98 (m, 4H), 6.50 (d, J＝7.2 Hz, 2H), 6.40 (d, J＝7.2 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 2.17 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 143.5, 141.8, 138.5, 137.8, 137.4, 130.3, 129.4, 129.2 (2C), 128.8, 128.6, 128.2, 128.1 (2C), 128.1 (2C), 127.7 (2C), 127.7, 127.0, 118.8, 60.8, 14.6, 9.7; HRMS (EI) calcd for C₂₅H₂₂N₂O₂ 382.1793, found 382.1791.

Ethyl 4-methyl-1-(4'-methyl-[1, 1'-biphenyl]-2-yl)-5- phenyl-1H-pyrazole-3-carboxylate (4b): Yellow oil, 83.2 mg (70% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.68 (d, J＝7.2 Hz, 1H), 7.45~7.39 (m, 2H), 7.17 (dd, J＝7.2, 1.2 Hz, 1H), 7.13 (t, J＝7.6 Hz, 1H), 7.05 (t, J＝8.0 Hz, 2H), 6.87 (d, J＝8.0 Hz, 2H), 6.41 (t, J＝6.8 Hz, 4H), 4.48 (q, J＝7.2 Hz, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 143.5, 141.7, 138.6, 137.4, 136.8, 134.9, 130.2, 130.1, 129.3, 129.2 (2C), 128.8, 128.8 (2C), 128.7, 128.0, 127.9, 127.7, 127.6, 125.4, 118.8, 60.8, 21.1, 14.6, 9.7; HRMS (EI) calcd for C₂₆H₂₄N₂O₂ 396.1842, found 396.1845.

Ethyl 1-(4'-fluoro-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (4c): Yellow oil, 72.0 mg (60% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.70 (d, J＝8.0 Hz, 1H), 7.46 (td, J＝7.6, 1.2 Hz, 1H), 7.40 (td, J＝7.6, 1.2 Hz, 1H), 7.15~7.12 (m, 2H), 7.04 (t, J＝7.6 Hz, 2H), 6.45 (d, J＝8.0 Hz, 4H), 4.47 (q, J＝7.2 Hz, 2H), 2.18 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.3, 162.2 (d, ¹J_CF＝245.4 Hz), 143.4, 142.0, 137.5, 137.4, 133.9 (d, ³J_CF＝3.3 Hz, 2C), 130.2, 129.8, 129.7, 129.4, 129.1 (2C), 128.9, 128.6, 128.4, 127.9 (2C), 127.8, 118.8, 115.1 (d, ²J_CF＝21.3 Hz, 2C), 60.8, 14.5, 9.7; HRMS (EI) calcd for C₂₅H₂₁N₂O₂F 400.1642, found 400.1641.

Ethyl 1-(4'-chloro-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (4d): Yellow solid, 59.9 mg (48% yield), m.p. 110~112 ℃. ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (d, J＝8.0 Hz, 1H), 7.49 (t, J＝7.6 Hz, 1H), 7.42 (t, J＝7.6 Hz, 1H), 7.16~7.14 (m, 2H), 7.07~7.03 (m, 4H), 6.46 (d, J＝7.2 Hz, 2H), 6.42 (d, J＝8.4 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 2.20 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.3, 143.4, 142.1, 137.4, 137.2, 136.3, 133.3, 130.1, 129.5, 129.4 (2C), 129.2 (2C), 129.0, 128.6, 128.5, 128.2 (2C), 127.9 (2C), 127.8, 118.9, 60.9, 14.5, 9.7; HRMS (EI) calcd for C₂₅H₂₁N₂O₂Cl 416.1346, found 416.1349.

Ethyl 4-methyl-5-phenyl-1-(4'-(trifluoromethyl)-[1, 1'-biphenyl]-2-yl)-1H-pyrazole-3-carboxylate (4e): Yellow solid, 51.3 mg (38% yield). m.p. 103~105 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.75 (d, J＝7.6 Hz, 1H), 7.53 (t, J＝7.6 Hz, 1H), 7.45 (t, J＝7.6 Hz, 1H), 7.31 (d, J＝8.4 Hz, 2H), 7.19 (d, J＝7.6 Hz, 1H), 7.15 (t, J＝7.6 Hz, 1H), 7.02 (t, J＝7.6 Hz, 2H), 6.60 (d, J＝8.0 Hz, 2H), 6.38 (d, J＝7.2 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 2.18 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 143.3, 142.3, 141.5, 137.5, 136.8, 130.1, 129.5, 129.2, 129.1 (q, ²J_CF＝32.2 Hz, 2C), 129.1, 129.0 (2C), 128.4, 128.4, 128.0, 127.8, 125.49, 125.0 (q, ³J_CF＝3.5 Hz, 2C), 124.1 (q, ¹J_CF＝270.3 Hz), 118.9, 60.9, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₁N₂O₂F₃ 450.1693, found 450.1694.

Ethyl 1-(4'-acetyl-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (4f): Yellow solid, 49.6 mg (39% yield). m.p. 169~171 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J＝8.0 Hz, 1H), 7.65 (d, J＝8.4 Hz, 2H), 7.52 (t, J＝7.6 Hz, 1H), 7.44 (t, J＝7.6 Hz, 1H), 7.19 (d, J＝6.8 Hz, 2H), 7.14 (t, J＝7.6 Hz, 1H), 7.01 (t, J＝8.0 Hz, 2H), 6.60 (d, J＝8.4 Hz, 2H), 6.38 (d, J＝7.2 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 2.57 (s, 3H), 2.16 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 197.9, 163.2, 143.4, 142.7, 142.2, 137.5, 137.3, 135.5, 130.1, 129.5, 129.2 (2C), 129.1, 129.1, 128.4, 128.3 (2C), 128.1 (2C), 127.9 (2C), 127.9, 118.9, 60.9, 26.7, 14.5, 9.7; HRMS (EI) calcd for C₂₇H₂₄N₂O₃ 424.1898, found 424.1896.

Ethyl 1-(4'-(ethoxycarbonyl)-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carboxylate (4g): Yellow solid, 110.4 mg (81% yield). m.p. 105~107 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.72 (d, J＝8.0 Hz, 3H), 7.49 (t, J＝7.6 Hz, 1H), 7.41 (t, J＝7.6 Hz, 1H), 7.17 (d, J＝7.6 Hz, 1H), 7.12 (t, J＝7.2 Hz, 1H), 6.99 (t, J＝7.6 Hz, 2H), 6.55 (d, J＝8.0 Hz, 2H), 6.38 (d, J＝8.0 Hz, 2H), 4.46 (q, J＝7.2 Hz, 2H), 4.35 (q, J＝7.2 Hz, 2H), 2.15 (s, 3H), 1.44 (t, J＝7.2 Hz, 3H), 1.38 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.4, 163.2, 143.4, 142.4, 142.1, 137.4, 137.4, 130.1, 129.5, 129.3 (2C), 129.2 (2C), 129.0 (2C), 128.9, 128.4, 128.1 (2C), 127.9 (2C), 127.8, 118.9, 61.0, 60.8, 14.5, 14.3, 9.7; HRMS (EI) calcd for C₂₈H₂₆N₂O₄ 454.1903, found 454.1901.

Ethyl 1-(3'-methoxy-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (4h): Brown oil, 87.8 mg (71% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (d, J＝7.6 Hz, 1H), 7.46 (t, J＝7.2 Hz, 1H), 7.41 (t, J＝7.2 Hz, 1H), 7.21 (d, J＝7.2 Hz, 1H), 7.14 (t, J＝7.6 Hz, 1H), 7.03 (t, J＝7.6 Hz, 2H), 6.97 (t, J＝8.0 Hz, 1H), 6.72 (dd, J＝8.4, 1.8 Hz, 1H), 6.45 (d, J＝7.2 Hz, 2H), 6.13 (d, J＝7.6 Hz, 1H), 6.03 (s, 1H), 4.47 (q, J＝7.2 Hz, 2H), 3.57 (s, 3H), 2.18 (s, 3H), 1.44 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 1163.3, 159.4, 143.7, 141.8, 139.0, 138.4, 137.5, 130.2, 129.4, 129.2 (2C), 129.0, 128.8, 128.6, 128.3, 127.7 (2C), 127.7, 120.6, 118.7, 114.2, 112.3, 60.8, 54.9, 14.5, 9.7; HRMS (EI) calcd for C₂₆H₂₄N₂O₃ 412.1891, found 412.1890.

Ethyl 1-(3'-bromo-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (4i): Yellow solid, 85.6 mg (62% yield). m.p. 134~136 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (d, J＝8.0 Hz, 1H), 7.50 (t, J＝7.6 Hz, 1H), 7.42 (t, J＝7.6 Hz, 1H), 7.29 (d, J＝8.0 Hz, 1H), 7.18 (t, J＝7.6 Hz, 1H), 7.14 (d, J＝7.6 Hz, 1H), 7.08 (t, J＝7.6 Hz, 2H), 6.93 (t, J＝7.6 Hz, 1H), 6.51 (s, 1H), 6.47 (d, J＝8.0 Hz, 1H), 6.43 (d, J＝7.2 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 2.19 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 143.5, 142.1, 139.8, 137.5, 137.0, 131.2, 130.0, 130.0, 129.5, 129.4, 129.0 (2C), 128.9, 128.9, 128.3, 128.0 (2C), 127.9, 126.5, 122.3, 118.8, 60.8, 14.5, 9.7; HRMS (EI) calcd for C₂₅H₂₁N₂O₂Br 460.0806, found 460.0808.

Ethyl 4-methyl-5-phenyl-1-(3'-(trifluoromethyl)-[1, 1'-biphenyl]-2-yl)-1H-pyrazole-3-carboxylate (4j): Yellow solid, 56.7 mg (42% yield). m.p. 103~105 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.77 (d, J＝7.6 Hz, 1H), 7.53 (td, J＝7.6, 1.2 Hz, 1H), 7.46 (d, J＝7.6 Hz, 1H), 7.43 (d, J＝6.4 Hz, 1H), 7.21~7.12 (m, 3H), 7.02 (t, J＝7.6 Hz, 2H), 6.71 (d, J＝8.0 Hz, 1H), 6.68 (s, 1H), 6.38 (d, J＝7.2 Hz, 2H), 4.48 (q, J＝7.2 Hz, 2H), 2.17 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 143.4, 142.2, 138.5, 137.6, 136.9, 131.3, 130.68 (q, ²J_CF＝32.0 Hz), 130.0, 129.6, 129.1, 129.0, 128.9 (2C), 128.5, 128.3, 128.0 (2C), 127.9, 125.2 (q, ¹J_CF＝270.8 Hz), 125.1 (q, ³J_CF＝3.6 Hz), 123.8 (q, ³J_CF＝3.7 Hz), 119.0, 60.9, 14.5, 9.6; HRMS (EI) calcd for C₂₆H₂₁N₂O₂F₃ 450.1642, found 450.1641.

Ethyl 1-(3'-acetyl-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (4k): White solid, 61.1 mg (48% yield). m.p. 119~121 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (d, J＝7.6 Hz, 1H), 7.75 (d, J＝7.6 Hz, 1H), 7.52 (t, J＝7.6 Hz, 1H), 7.45 (t, J＝7.6 Hz, 1H), 7.22~7.10 (m, 3H), 7.01~6.97 (m, 3H), 6.73 (d, J＝7.6 Hz, 1H), 6.38 (d, J＝7.6 Hz, 2H), 4.47 (q, J＝7.2 Hz, 2H), 2.38 (s, 3H), 2.14 (s, 3H), 1.44 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 197.7, 163.1, 143.5, 142.1, 138.2, 137.5, 137.4, 137.0, 132.7, 130.1, 129.6, 129.0 (2C), 128.9, 128.9, 128.7, 128.4, 128.3, 127.9 (2C), 127.8, 126.6, 118.8, 60.9, 26.4, 14.5, 9.7; HRMS (EI) calcd for C₂₇H₂₄N₂O₃ 424.1841, found 424.1837.

Ethyl 1-(3'-(methoxycarbonyl)-[1, 1'-biphenyl]-2-yl)-4- methyl-5-phenyl-1H-pyrazole-3-carbo xylate (4l): Colorless oil, 91.1 mg (69% yield). ¹H NMR (400 MHz, CDCl₃) δ: 8.43 (d, J＝8.0 Hz, 1H), 7.73 (d, J＝7.6 Hz, 1H), 7.49 (td, J＝7.6, 1.2 Hz, 1H), 7.42 (t, J＝7.6 Hz, 1H), 7.20 (dd, J＝7.6, 0.8 Hz, 1H), 7.15~7.08 (m, 2H), 7.05 (s, 1H), 6.97 (t, J＝7.6 Hz, 2H), 6.71 (d, J＝7.6 Hz, 1H), 6.36 (d, J＝7.2 Hz, 2H), 4.47 (q, J＝7.2 Hz, 2H), 3.84 (s, 3H), 2.14 (s, 3H), 1.44 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 166.6, 163.2, 143.4, 142.1, 138.0, 137.5, 137.4, 132.4, 130.2, 130.1, 129.5 (2C), 129.0 (2C), 128.9, 128.80, 128.3, 128.2, 128.1, 127.8, 127.8 (2C), 118.9, 60.8, 52.0, 14.5, 9.7; HRMS (EI) calcd for C₂₇H₂₄N₂O₄ 440.1749, found 440.1750.

Ethyl 1-(2-(2, 3-dihydrobenzo[b]^{[1, 4]}dioxin-6-yl)- phenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylate (4o): Yellow solid, 108.3 mg (82% yield). m.p. 128~130 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.67 (d, J＝6.8 Hz, 1H), 7.42 (t, J＝7.2 Hz, 1H), 7.37 (t, J＝7.2 Hz, 1H), 7.14 (t, J＝7.3 Hz, 2H), 7.05 (t, J＝7.6 Hz, 2H), 6.55 (d, J＝8.4 Hz, 1H), 6.51 (d, J＝7.6 Hz, 2H), 5.97 (s, 2H), 4.47 (q, J＝7.2 Hz, 2H), 4.20 (dd, J＝13.2, 4.4 Hz, 4H), 2.21 (s, 3H), 1.45 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 143.4, 143.3, 142.9, 141.8, 137.8, 137.3, 131.2, 130.1, 129.3, 129.1 (2C), 128.8, 128.6, 127.9, 127.7 (3C), 121.2, 118.7, 117.2, 116.7, 64.5, 64.2, 60.8, 14.5, 9.7; HRMS (EI) calcd for C₂₇H₂₄N₂O₄ 440.1787, found 440.1788.

Ethyl 1-(3', 5'-dichloro-[1, 1'-biphenyl]-2-yl)-4-methyl-5- phenyl-1H-pyrazole-3-carboxylate (4p): White solid, 59.4 mg (44% yield). m.p. 163~165 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.76 (d, J＝8.0 Hz, 1H), 7.54 (t, J＝7.2 Hz, 1H), 7.44 (t, J＝7.6 Hz, 1H), 7.21 (t, J＝7.2 Hz, 1H), 7.17 (s, 1H), 7.15~7.09 (m, 3H), 6.50 (d, J＝7.6 Hz, 2H), 6.33 (s, 2H), 4.49 (q, J＝7.2 Hz, 2H), 2.24 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.1, 143.4, 142.3, 140.6, 137.6, 135.9, 134.6 (2C), 129.8, 129.6, 129.5, 129.0 (3C), 128.2, 128.1 (2C), 128.0, 127.1, 126.6 (2C), 119.0, 60.9, 14.5, 9.7; HRMS (EI) calcd for C₂₅H₂₀- N₂O₂Cl₂ 450.0910, found 450.0909.

4.3 Porcedures for derivatizations of preparation and functionlization of the dual-core dimeric cyclopalladated intermediate II

A mixture of PdCl₂ (35.4 mg, 0.2 mmol, 1.0 equiv.), NaOAc (49.2 mg, 0.6 mmol, 3.0 equiv.) and substrate 1c (61.3 mg, 0.2 mmol, 1.0 equiv.) in AcOH (1.0 mL) was charged in a glass sealed-tube and stirred under N₂ atmosphere at 100 ℃ for 4 h. Upon completion of the reaction, the reaction was diluted with dichloromethane and sequentially washed with water and brine. The crude mixture was purified by column chromatography to give the title complex II as a yellow solid (54.4 mg, 61%). A mixture of intermediate II (44.6 mg, 0.05 mmol), 4-iodoanisole (2a, 35.1 mg, 3.0 equiv.), AgTFA (22.1 mg, 2.0 equiv.) in HFIP/AcOH (V:V＝3:1, 0.5 mL) was charged in a glass sealed-tube and stirred under air atmosphere at 120 ℃ for 20 h. Upon completion of the reaction, saturated brine (15 mL) and dichloromethane (15 mL) were added to the mixture, then the aqueous layer was extracted with dichloromethane (15 mL×2). The combined organic layer was dried over anhydrous MgSO₄. Finally, the solution was concentrated in vacuo to provide a crude product, which was further purified via a column chromatography on silica gel [eluents: V(petroleum ether):V(ethyl acetate)＝5:1] to supply the product 3c (20.6 mg, 67% yield).

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Scheme 1 Previous related works and our present work

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Scheme 2 Intermolecular competition experiment

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Scheme 3 Kinetic isotope effect study

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Scheme 4 Gram scale reaction

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Scheme 5 Preparation and functionlization of the dual-core dimeric cyclopalladated intermediate II

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Scheme 6 Plausible mechanism

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Table 1. Optimization of the reaction conditions^a


Entry	Catalyst	Solvent (V:V)	Yield^b/%
1	Pd(OAc)₂	AcOH	45
2	Pd(OAc)₂	HFIP	43
3	Pd(OAc)₂	Toluene	0
4	Pd(OAc)₂	DMF	0
5	Pd(OAc)₂	HFIP/AcOH (1:1)	42
6	Pd(OAc)₂	HFIP/AcOH (3:1)	70
7	Pd(OAc)₂	HFIP/AcOH (5:1)	43
8	Pd(CH₃CN)₂Cl₂	HFIP/AcOH (3:1)	47
9	PdCl₂	HFIP/AcOH (3:1)	45
10	Pd(PPh₃)₂Cl₂	HFIP/AcOH (3:1)	42
11	Pd(TFA)₂	HFIP/AcOH (3:1)	33
12	Pd(PPh)₃	HFIP/AcOH (3:1)	32
13	Pd(OAc)₂	HFIP/AcOH (3:1)	31^c (28^d)
14	Pd(OAc)₂	HFIP/AcOH (3:1)	30^e (0^f)
15	Pd(OAc)₂	HFIP/AcOH (3:1)	47^g (38^h)
16	Pd(OAc)₂	HFIP/AcOH (3:1)	81ⁱ (70^j)
17	Pd(OAc)₂	HFIP/AcOH (3:1)	64^k (69^l)
^a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (10 mol%), AgTFA (2.0 equiv.), solvent (3.0 mL), 120 ℃, 20 h. ^b Isolated yield. ^c Ag₃PO₄ as the additive. ^d Ag₂CO₃ as the additive. ^e AgOAc as the additive. ^f K₂S₂O₈ as the additive. ^g CsOAc as the additive. ^h Cs₂CO₃ as the additive. ⁱ 2a (0.9 mmol). ^j AgTFA (3.0 equiv.). ^k110 ℃. ^l 130 ℃.

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Table 2. Substrate scope of functionalized pyrazoles^{a, b}

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Table 3. Substrate scope of aryl iodide^{a, b}

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