Unconventional Method for Synthesis of 3-Carboxyethyl-4-formyl

Article pubs.acs.org/joc

Unconventional Method for Synthesis of 3‑Carboxyethyl-4formyl(hydroxy)-5-aryl‑N‑arylpyrazoles Michael J. V. da Silva,† Julia Poletto,† Andrey P. Jacomini,† Karlos E. Pianoski,† Davana S. Gonçalves,† Gessica M. Ribeiro,† Samara M. de S. Melo,† Davi F. Back,‡ Sidnei Moura,§ and Fernanda A. Rosa*,† †

Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil Departamento de Química, Universidade Federal de Santa Maria (UFSM), 97110-970 Santa Maria, RS, Brazil § Instituto de Biotecnologia, Universidade de Caxias do Sul (UCS), 295070-560 Caxias do Sul, RS, Brazil ‡

S Supporting Information *

ABSTRACT: An alternative highly regioselective synthetic method for the preparation of 3,5-disubstituted 4-formyl-Narylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the cyclocondensation reaction of β-enamino diketones with arylhydrazines. Structural modifications in the β-enamino diketone system allied to the Lewis acid carbonyl activator BF3 were strategically employed for this control. Also a one-pot method for the preparation of 3,5-disubstituted 4-hydroxymethyl-N-arylpyrazole derivatives from the β-enamino diketone and arylhydrazine substrates is described.

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INTRODUCTION 4-Formyl-N-arylpyrazole substrates occupy a prominent position in the field of organic synthesis, since they are key intermediates in obtaining a wide range of biologically active compounds.1 For instance, 4-methyl benzoate,1e 4-azomethine,1a,d and 4-N-arylaminomethyl1c,f pyrazole derivatives, which have been reported to show potent antiproliferative activity against cancer cells (I, VI),1c,e and antimalarial (II),1a antileishmanial (III),1a anti-inflammatory (IV),1d and antiviral (V)1f activities, were synthesized from 4-formyl-N-arylpyrazole substrates (Figure 1). Due to the synthetic versatility of the 4-formyl-Narylpyrazole skeleton, their synthesis has been extensively explored. Over time, numerous synthetic strategies have been employed for the preparation of these intermediates,2−6 in particular the Vilsmeier−Haack reaction, which is based on the 4-position formylation of N-arylpyrazole by DMF/POCl32 (Vilsmeier−Haack reagent7) (Scheme 1, ROUTE A). Another approach is the reaction of N-aryl hydrazones of methyl ketones or aldehydes with Vilsmeier−Haack reagent (Scheme 1, ROUTE B).1,3 Among these strategies, the reaction of N-aryl hydrazones under Vilsmeier−Haack conditions is one of the most efficient and widely used methodologies, and is performed in a reduced number of steps−formation of the pyrazole core and its formylation in a one-pot reaction (Scheme 1, ROUTE B).1,3 However, this methodology is restricted to preparation of 5© 2017 American Chemical Society

substituted 4-formyl-N-arylpyrazoles. Since combination and replacement patterns on the pyrazole core have important effects on the biological activity, the development of efficient synthetic methods to access directly multifunctionalized 3,5disubstituted 4-formyl-N-arylpyrazoles is highly desirable. In recent years, we have developed synthetic methodologies for the preparation of multifunctionalized N-arylpyrazoles from the modified Knorr reaction using β-enamino diketones and arylhydrazines (Scheme 1, ROUTE C).8 In this context, we envisage that this synthetic strategy would be an attractive onepot method to obtain 3,5-disubstituted 4-formyl-N-arylpyrazoles, via the regiochemical control of the reaction. Analyzing the reactive potential of the β-enamino diketone systems against arylhydrazine, we observed that the cyclocondensation at C1 and C2’ (carbonyl carbons) would lead to the 3,4,5trisubstituted N-aryldihydropyrazoles, which upon aromatization via water elimination and subsequent hydrolysis would afford 3,5-disubstituted 4-formyl-N-arylpyrazoles (Scheme 1, ROUTE D). However, according to the literature the cyclocondensation of β-enamino-diketones with arylhydrazines follows a different regiochemistry, where the C3 (β-carbon) and C1 or C2’ (carbonyl carbons) correspond to the 1,3dielectrophilic reactive unit, giving 4,5-disubstituted N-arylpyrazoles (Scheme 1, ROUTE C).8 Thus, we report in this letter a Received: September 18, 2017 Published: November 2, 2017 12590

DOI: 10.1021/acs.joc.7b02361 J. Org. Chem. 2017, 82, 12590−12602

Article

The Journal of Organic Chemistry

Figure 1. Bioactive molecules synthesized from 4-formyl-N-arylpyrazole substrates.1a,c−f

Scheme 1

one-pot synthetic method that enabled us to control the regiochemistry of the cyclocondensation of β-enamino

diketones with arylhydrazines to obtain 3,5-disubstituted 4formyl and 4-hydroxymethyl N-arylpyrazole derivatives. 12591


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The Journal of Organic Chemistry Scheme 2. Structural Modifications in the β-Enamino Diketone System: Synthesis of β-Enamino Diketones (2a−h)

Table 1. Evaluation of the Reactivity of β-Enamino Diketones 1a and 2a−h against Cyclocondensation Reaction with Phenylhydrazine

entry

substrate

R1/ R2

time (h)

conversion (%)a

1b 2 3 4 5 6 7 8 9

1a 2a 2b 2c 2d 2e 2f 2g 2h

Me/Me Me/H n-Bu/H Bn/H i-Pr/H t-Bu/H Ph/H 4-OMeC6H4/H 4-NO2C6H4/H

1 48 48 48 48 48 2 3 2

A(29)/B(71) A(12)/B(36)c A(10)/B(29)d A(13)/B(45)e A(6);B(24)f no reactiong A(62);B(38) A(63);B(37) A(52);B(48)

a Conversion calculated from the 1H NMR spectrum of crude product. bReported by Souza et al.8d Remnant substrate (%). c2a (52). d2b (61). e2c (42). f2d (70). g2e recovered in 98% yield.

Table 2. Optimization of Reaction Conditions

entry

precursor

i

yield (%)a

1 2 3 4 5 6 7 8

2e 2e 2e 2e 2e 2e 2d 1a, 2a−c,f−h

MeCN, BF3 (2.0 equiv), rt, 12 h MeCN, BF3 (2.0 equiv), reflux, 1 h MeCN, BF3 (1.5 equiv), reflux, 1 h MeCN, BF3 (1.0 equiv), reflux, 1 h EtOH, BF 3(1.5 equiv), reflux, 1 h CHCl3, BF3 (1.5 equiv), reflux, 1 h MeCN, BF3 (1.5 equiv), reflux, 1 h MeCN, BF3 (1.5 equiv), reflux, 1 h

82 84 83 60b 7c 59 80

a

b

d

Isolated yield, workup (H2O) and additional purification by column chromatography. 2e recovered in 31% yield. 2e recovered in 85% yield. d3a in intractable mixtures of several products.

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Article

The Journal of Organic Chemistry Scheme 3. Substrate Scope

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RESULTS AND DISCUSSION In order to control the reactivity of the β-enamino diketone system against arylhydrazines, we initially interchanged the N,N-dimethylamine group in 1a9 with different secondary amino groups (Scheme 2). Thus, through reaction of the βenamino diketone 1a with the respective primary amines, in its free or hydrochloride salt form, it was possible to obtain pure βenamino diketones 2a−h with excellent yields (90−93%). The structures of the novel precursors 2a−h were established by NMR spectral data and confirmed by X-ray crystallography analysis. The data obtained by 1H NMR of 2a−h showed a set of characteristic signals of two stereoisomeric forms, Z and E, in the ratio of approximately 80:20, respectively. On the other hand, in the solid state, the single crystal X-ray diffraction structures of 2a−g corresponded to only the Z stereoisomer (see Figures S1−7 for full details, Supporting Information).10a,b,c,d,e,f,g Next, we evaluated the reactivity of β-enamino diketones 2a−h against phenylhydrazine in MeCN at room temperature. The results are summarized in Table 1.

As observed, the substrates 2a−d,f−h (Table 1, entries 2−5, 7−9) led to the formation of the same products (pyrazoles A and B) reported by Souza et al.8d from the substrate 1a (Table 1, entry 1), but in different proportions and in a longer reaction time. On the other hand, substrate 2e was shown to be nonreactive, even after a prolonged reaction time (Table 1, entry 6). According to these results, we believe that the ketamino−iminoenol tautomeric equilibrium found in βenamino diketones with secondary amino groups,11 together with the steric demand of the R1 alkyl substituents, are the main factors responsible for the lower reactivity of substrates 2a−h against phenylhydrazine. With these results in hand, we tested strategically the reaction of the β-enamino diketone 2e with phenylhydrazine, using the Lewis acid carbonyl activator BF3 (BF3·OEt2). Gratifyingly, when 2e (1.0 equiv) and phenylhydrazine (1.0 equiv) reacted in the presence of Lewis acid BF3 (2.0 equiv) in MeCN at room temperature for 12 h, the desired product 3,5disubstituted 4-formyl-N-arylpyrazole 3a was obtained in a highly regiocontrolled fashion with 82% yield. (Table 2, entry 1). The structure of 3a was established by NMR spectral data 12593


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The Journal of Organic Chemistry Scheme 4. One-Pot Procedure for Obtaining 3,5-Disubstituted 4-Hydroxymethyl-N-arylpyrazole Derivatives

Scheme 5. Substrate Scope

hydrazine with the electrophilic centers C1 and C2’ (carbonyl carbons) in the β-enamino diketone, respectively (Table 2). Encouraged by this promising result, we investigated other reaction conditions (Table 2). First, carried out reaction at reflux we observed the total conversion of the reactants in less

and confirmed unambiguously by the single crystal X-ray analysis (see Figure S9 for full details, Supporting Information).10i According to these data, the regiochemistry of formation of 3a proceeds through the cyclocondensation of the primary (−NH2) and secondary (−NH−) nitrogens of the phenyl12594


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ESI(+)-MS/MS were acquired using a hybrid high-resolution and high accuracy microTof (Q-TOF) mass spectrometer (Bruker). For ESI(+)-MS, the energy for the collision induced dissociations (CDI) was optimized for each component. For data acquisition and processing, the Q-TOF-control data analysis software (Bruker Scientific) was used. Single crystal X-ray diffraction studies: X-ray intensity data measurements of compounds 2a (CCDC-1564288),10a 2b (CCDC-1564287),10b 2c (CCDC-1564286),10c 2d (CCDC1564285),10d 2e (CCDC-1564290),10e 2f (CCDC-1564282),10f 2g (CCDC-1564283),10g 2n (CCDC-1564291),10h and 3a (CCDC1564294)10i were collected with a Bruker APEX II CCD area-detector diffractometer and grafite-monochromatized Mo-Ka radiation. The structure was solved by direct methods using SHELXS.13 Subsequent Fourier-difference map analyses yielded the positions of the nonhydrogen atoms. Refinements were carried out the SHELXS package.13 All refinements were made by full matrix least-squares on F2 with anisotropic displacement parameters for all non-hydrogen atoms. Hydrogen atoms were included in the refinement in calculated positions but the atoms (of hydrogens) that are commenting performing special bond were located in the Fourier map. The ORTEP diagram were drawn with 50% probability displacement ellipsoids using ORTEP-3 for Windows.14 General Synthetic Procedure and Spectra Data. β-Enamino Diketone Substrates 2a−d,f−h. A mixture of compound 1a9 (0.320 g; 1.0 mmol, 1.0 equiv) and corresponding amine hydrochloride salt (MeNH2.HCl: 0.101 g; n-BuNH2.HCl: 0.164 g; BnNH2.HCl: 0.215 g; i-PrNH2.HCl: 0.143 g; PhNH2.HCl: 0.194 g; 4-OMeC6H4NH2.HCl: 0.239 g; 4-NO2C6H4NH2.HCl: 0.261 g, 1.50 mmol, 1.5 equiv) in ethanol (5 mL) was stirred under reflux for 1 h. Then, the mixture was cooled to 0 °C and the solid was filtered, washed with cold ethanol (20 mL), and dried under vacuum. (Z and E)-4-(Methylamino)-3-(4-nitrobenzoyl)-2-oxobut-3-enoic Acid Ethyl Ester (2a). Light yellow solid; yield: 0.276 g (90%); Z/E ratio in CDCl3: 80/20; mp 143.8−145.3 °C; 1H NMR (300.06 MHz, CDCl3) δ (ppm) (Z) 1.29 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 3.24 (dd, 3H, J = 5.2, 0.7 Hz, NH-CH3), 4.17 (q, 2H, J = 7.2 Hz, O−CH2CH3), 7.64 (dd, 1H, J = 14.1, 0.7 Hz, H4), 7.75 (d, 2H, J = 8.8 Hz, 4NO2C6H4), 8.28 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 10.67 (bs, 1H, NH); (E) 1.14 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 3.34 (dd, 3H, J = 5.2, 0.8 Hz, NH-CH3), 3.81 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.62 (d, 2H, J = 8.8 Hz, 4-NO2C6H4), 8.20 (dd, 1H, J = 14.3, 0.8 Hz, H4), 8.23 (d, 2H, J = 8.8 Hz, 4-NO2C6H4), 10.79 (bs, 1H, NH); 13C NMR (75.46 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 37.2 (NHCH3), 61.8 (O-CH2−CH3), 107.0 (C3), 123.7, 129.5, 144.5, 149.2 (4NO2C6H4), 163.1 (C4), 164.9 (COOEt), 186.9 (C2), 190.8 (C3′); (E) 13.7 (O−CH2−CH3), 37.1 (NH-CH3), 62.0 (O-CH2−CH3), 106.7 (C3), 123.4, 128.6, 146.4, 148.8 (4-NO2C6H4), 163.3 (C4), 164.4 (COOEt), 183.3 (C2), 193.7 (C3′); HRMS (ESI+): calcd for C14H15N2O6+, [M+H]+: 307.0925, found 307.0938. (Z and E)-4-(Butylamino)-3-(4-nitrobenzoyl)-2-oxobut-3-enoic Acid Ethyl Ester (2b). Light yellow solid; yield: 0.313 g (90%); Z/E ratio in CDCl3: 79/21; mp 123.9−124.8 °C; 1H NMR (300.06 MHz, CDCl3) δ (ppm) (Z) 0.96 (t, 3H, J = 7.3 Hz, NH-(CH2)3-CH3), 1.29 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.34−1.52 (m, 2H, NH-(CH2)2− CH2-CH3 − E/Z), 1.60−1.77 (m, 2H, NH−CH2−CH2-CH2−CH3 − E/Z), 3.41 (q, 2H, J = 6.6 Hz, NH-CH2-(CH2)2−CH3), 4.17 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.64 (d, 1H, J = 14.1 Hz, H4), 7.75 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.29 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 10.78 (bs, 1H, NH); (E) 1.00 (t, 3H, J = 7.3 Hz, NH-(CH2)3-CH3), 1.13 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.34−1.52 (m, 2H, NH-(CH2)2− CH2-CH3 − E/Z), 1.60−1.77 (m, 2H, NH−CH2−CH2-CH2−CH3 − E/Z), 3.53 (q, 2H, J = 6.6 Hz, NH-CH2-(CH2)2−CH3), 3.80 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.63 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.21 (d, 1H, J = 14.4 Hz, H4), 8.23 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 10.90 (bs, 1H, NH); 13C NMR (75.46 MHz, CDCl3) δ (ppm) (Z) 13.6 (NH-(CH2)3-CH3), 13.9 (O−CH2−CH3), 19.6 (NH-(CH2)2−CH2− CH3), 32.2 (NH−CH2−CH2−CH2−CH3), 50.8 (NH-CH2-(CH2)2− CH3), 61.9 (O-CH2−CH3), 106.8 (C3), 123.8, 129.6, 144.5, 149.3 (4NO2C6H4), 161.8 (C4), 164.9 (COOEt), 186.9 (C2), 190.8 (C3′); (E) 13.6 (NH-(CH2)3-CH3), 13.8 (O−CH2−CH3), 19.7 (NH-

time and also with high yield (Table 2, entry 2). Subsequently by lowering BF3 loading, we verified that the use of 1.5 equiv also led to obtaining the product 3a in high yield (Table 2, entry 3). On the other hand, the use of 1.0 equiv of BF3 led to a low conversion of the reactants (Table 2, entry 4). MeCN proved to be the solvent most suitable in our investigation, since the reaction in ethanol or chloroform led to low conversion of the reactants (Table 2, entries 5 and 6). The best conditions are indicated in entry 3 (Table 2). With the optimized conditions in hand, we applied them to the other βenamino diketones 1a and 2a−d,f−h. However, only the βenamino diketones 2d,e led to the formation of pure product 3a (Table 2, entries 3 and 7), whereas β-enamino diketones 1a, 2a−c,f−h led to the formation of 3a in intractable mixtures of several products (Table 2, entry 8). Thus, we evaluated the scope of the current cyclocondensation reaction by varying the electronic properties of the β-enamino diketones 2i−n and arylhydrazines. As shown in Scheme 3, a variety of substrates underwent cyclocondensation to afford 3,5-disubstituted 4-formyl-N-arylpyrazoles 3b−u with high regioselectivity and good to excellent yields (68−95%). In order to demonstrate the synthetic utility of these 4formyl-N-arylpyrazoles 3a−u, we propose a one-pot procedure for obtaining the 4-hydroxymethyl derivative 4a via reduction in situ of the 4-formyl-N-arylpyrazole 3a, by treatment of the reaction with NaBH4 (1.1 equiv) (Scheme 4). Finally, we explored this derivatization by expanding the scope of the reaction. As shown in Scheme 5, the 4-hydroxymethyl-N-arylpyrazole derivatives 4b−u were obtained with high yields from the same substrates employed in the preparation of 3b−u.

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CONCLUSION In conclusion, we have developed a simple and efficient procedure for the highly regioselective one-pot synthesis of 3,5disubstituted 4-formyl-N-arylpyrazoles by cyclocondensation of β-enamino diketones with arylhydrazines. The regiochemistry of the reaction has been reported for the first time, and was controlled by the structure of the β-enamino diketone in combination with the Lewis acid carbonyl activator BF3. According to the results, the presence of an aminoalkyl secondary group with high steric demand (i-PrNH− or tBuNH−) bound to the β-carbon of the β-enamino diketone system was determinant in this control. Furthermore, we developed an efficient protocol for the derivatization of 4formyl-N-arylpyrazoles to 4-hydroxymethyl-N-arylpyrazoles from β-enamino diketone substrates and arylhydrazine in a one-pot procedure. Further work on the mechanism of the cyclocondensation reaction with BF3 is continuing in our laboratory.

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EXPERIMENTAL SECTION

General Information. Reagents were used as obtained from comercial suppliers without further purification. The solvents were dried and purified according to recommended procedures.12 The reactions were monitored by thin-layer chromatography using Merck TLC silica gel plates and visualized with UV light. The column chromatography used was silica gel 60, with 230−400 mesh (Merck). ́ All melting points were measured with MQAPF-307 Microquimica apparatus using benzoic acid as internal standard. 1H and 13C NMR, HSQC, and HMBC experiments were run on VARIAN Mercury Plus apparatus operating at 1H 300.06 MHz and 13C 75.46 MHz, and Bruker Avance III HD apparatus operating at 1H 500.13 MHz and 13C 125.77 MHz. Chemical shifts are reported in ppm using TMS as the internal standard for CDCl3 and DMSO-d6. ESI(+)-MS and tandem 12595


Article

The Journal of Organic Chemistry (CH2)2−CH2−CH3), 32.2 (NH−CH2−CH2−CH2−CH3), 50.8 (NHCH2-(CH2)2−CH3), 62.1 (O-CH2−CH3), 106.6 (C3), 123.4, 128.7, 146.4, 148.9 (4-NO2C6H4), 162.0 (C4), 164.5 (COOEt), 183.5 (C2), 193.7 (C3′); HRMS (ESI+): calcd for C17H21N2O6+, [M+H]+: 349.1394, found 349.1388. (Z and E)-4-(Benzylamino)-3-(4-nitrobenzoyl)-2-oxobut-3-enoic Acid Ethyl Ester (2c). Light yellow solid; yield: 0.348 g (91%); Z/E ratio in CDCl3: 83/17; mp 137.7−138.3 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.28 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 4.18 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 4.58 (d, 2H, J = 5.8 Hz, NH-CH2-Ph), 7.22−7.44 (m, 5H, NH−CH2−Ph − E/Z), 7.67−7.71 (m, 3H, H4 and 4-NO2C6H4), 8.19−8.23 (m, 2H, 4-NO2C6H4 − E/Z), 10.97−11.00 (m, 1H, NH). (E) 1.12 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 3.80 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 4.69 (d, 2H, J = 6.0 Hz, NH-CH2-Ph), 7.22−7.44 (m, 5H, NH−CH2−Ph − E/Z), 7.61 (d, 2H, J = 8.9 Hz, 4NO2C6H4), 8.19−8.23 (m, 2H, 4-NO2C6H4 − E/Z), 8.29 (d, 1H, J = 14.3 Hz, H4), 11.08−11.11 (m, 1H, NH); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 54.2 (NH-CH2−Ph), 61.9 (O-CH2−CH3), 107.2 (C3), 123.7, 129.6, 144.3, 149.3 (4NO2C6H4), 127.8, 128.9, 129.4, 134.5 (NH−CH2−Ph), 161.7 (C4), 164.8 (COOEt), 187.0 (C2), 190.8 (C3′); (E) 13.7 (O−CH2−CH3), 54.5 (NH-CH2−Ph), 62.1 (O-CH2−CH3), 107.0 (C3), 123.4, 128.7 146.3, 148.9 (4-NO2C6H4), 127.8, 128.9, 129.4, 134.6 (NH−CH2− Ph), 161.8 (C4), 164.4 (COOEt), 183.5 (C2), 193.7 (C3′); HRMS (ESI+): calcd for C20H19N2O6+, [M+H]+: 383.1238, found 383.1206. (Z and E)-4-(Isopropylamino)-3-(4-nitrobenzoyl)-2-oxobut-3enoic Acid Ethyl Ester (2d). Light yellow solid; yield: 0.301 g (90%); Z/E ratio in CDCl3: 78/22; mp 133.6−134.2 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.28 (t, 3H, J = 7.2 Hz, O−CH2− CH3), 1.35 (d, 3H, J = 6.6 Hz, NH−CH(CH3)2), 3.59−3.68 (m, 1H, NH-CH(CH3)2), 4.16 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.71 (dd, 1H, J = 14.2, 0,7 Hz, H4), 7.75 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.29 (d, 2H, J = 8.8 Hz, 4-NO2C6H4), 10.78 (bs, 1H, NH); (E) 1.13 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.42 (d, 3H, J = 6.6 Hz, NH−CH(CH3)2), 3.59−3.68 (m, 3H, NH-CH(CH3)2 and O−CH2-CH3), 7.63 (d, 2H, J = 8.8 Hz, 4-NO2C6H4), 8.22−8.25 (m, 3H, H4 and 4-NO2C6H4), 10.90 (bs, 1H, NH); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 32.2 (NH−CH(CH3)2), 52.8 (NH-CH(CH3)2), 61.9 (O-CH2−CH3), 106.5 (C3), 123.7, 129.5, 144.6, 149.3 (4-NO2C6H4), 159.6 (C4), 164.9 (COOEt), 186.7 (C2), 190.9 (C3′); (E) 13.7 (O−CH2−CH3), 32.2 (NH−CH(CH3)2), 52.8 (NHCH(CH3)2), 62.0 (O-CH2−CH3), 106.4 (C3), 123.4, 128.7, 146.4, 148.9 (4-NO2C6H4), 159.8 (C4), 164.5 (COOEt), 183.5 (C2), 193.6 (C3′); HRMS (ESI+): calcd for C16H19N2O6+, [M+H]+: 335.1238, found 335.1219. (Z and E)-3-(4-Nitrobenzoyl)-2-oxo-4-(phenylamino)but-3-enoic Acid Ethyl Ester (2f). Yellow solid; yield: 0.342 g (93%); Z/E ratio in CDCl3: 79/21; mp 108.5−110.8 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.31 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 4.22 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.14−7.16 (m, 2H, Ph), 7.28−7.35 (m, 1H, Ph, E/Z), 7.41−7.45 (m, 2H, Ph), 7.85 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.12 (d, 1H, J = 13.6 Hz, H4), 8.33 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 12.38 (d, 1H, J = 13.6 Hz, NH); (E) 1.16 (t, 3H, J = 7.2 Hz, O−CH2− CH3), 3.88 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.28−7.35 (m, 3H, Ph, E/Z), 7.46−7.50 (m, 2H, Ph), 7.70 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.27 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.72 (d, 1H, J = 13.9 Hz, H4), 12.46 (d, 1H, J = 14.0 Hz, NH); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 62.2 (O-CH2−CH3), 108.7 (C3), 118.5, 127.4, 130.3, 137.8 (Ph), 123.9, 129.8, 144.0, 149.7 (4NO2C6H4), 154.4 (C4), 164.4 (COOEt), 187.3 (C2), 191.0 (C3′); (E) 13.8 (O−CH2−CH3), 62.4 (O-CH2−CH3), 108.6 (C3), 118.6, 127.4, 130.3, 137.9 (Ph), 123.6, 128.8, 145.9, 149.2 (4-NO2C6H4), 154.7 (C4), 164.0 (COOEt), 183.5 (C2), 194.1 (C3′); HRMS (ESI +): calcd for C19H17N2O6+, [M+H]+: 369.1081, found 369.1069. (Z and E)-4-[(4-Methoxyphenyl)amino]-3-(4-nitrobenzoyl)-2-oxobut-3-enoic Acid Ethyl Ester (2g). Yellow solid; yield: 0.370 g (93%); Z/E ratio in CDCl3: 80/20; mp 167.2−168.3 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.30 (t, 3H, J = 7.2 Hz, O−CH2− CH3), 3.81 (s, 3H, OCH3C6H4), 4.20 (q, 2H, J = 7.2 Hz, O−CH2CH3), 6.93 (d, 2H, J = 9.0 Hz, 4-OCH3C6H4), 7.10 (d, 2H, J = 9.0 Hz,

4-OCH3C6H4), 7.83 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.03 (d, 1H, J = 13.6 Hz, H4), 8.31 (d, 2H, J = 8.7 Hz, 4-NO2C6H4), 12.42 (d, 1H, J = 13.5 Hz, NH); (E) 1.15 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.84−3.88 (m, 3H, OCH3C6H4 and O−CH2-CH3), 6.98 (d, 2H, J = 9.0 Hz, 4OCH3C6H4), 7.26 (d, 2H, J = 9.0 Hz, 4-OCH3C6H4), 7.67 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.24 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.61 (d, 1H, J = 13.9 Hz, H4),12.54 (d, 1H, J = 13.9 Hz, NH); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 55.7 (4OCH3C6H4), 62.1 (O-CH2−CH3), 108.2 (C3), 115.4, 120.1, 131.1, 158.9 (4-OCH3C6H4), 123.9, 129.7, 144.2, 149.6 (4-NO2C6H4), 154.5 (C4), 164.5 (COOEt), 187.0 (C2), 190.9 (C3′); (E) 13.8 (O−CH2− CH3), 55.7 (4-OCH3C6H4), 62.3 (O-CH2−CH3), 108.1 (C3), 115.4, 120.2, 131.2, 159.0 (4-OCH3C6H4), 123.5, 128.8, 146.1, 149.1 (4NO2C6H4), 154.6 (C4), 164.1 (COOEt), 183.5 (C2), 193.9 (C3′); HRMS (ESI+): calcd for C20H19N2O7+, [M+H]+: 399.1187, found 399.1154. (Z and E)-3-(4-Nitrobenzoyl)-2-oxo-4-[(4-nitrophenyl)amino]but3-enoic Acid Ethyl Ester (2h). Yellow solid; yield: 0.384 g (93%); Z/E ratio in CDCl3: 74/26; mp 198.0−199.5 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.29 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.19 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.30 (d, 2H, J = 9.1 Hz, 4-NO2C6H4 B), 7.89 (d, 2H, J = 8.9 Hz, 4-NO2C6H4 - A), 8.17 (d, 1H, J = 12.9 Hz, H4), 8.27−8.38 (m, 4H, 4-NO2C6H4 - A and 4-NO2C6H4 - B − Z/E), 12.34−12.38 (m, 1H, NH − Z/E); (E) 1.16 (t, 3H, J = 7.2 Hz, O− CH2−CH3), 3.93 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.44 (d, 2H, J = 9.1 Hz, 4-NO2C6H4 - B), 7.70 (d, 2H, J = 8.9 Hz, 4-NO2C6H4 - A), 8.27−8.38 (m, 4H, 4-NO2C6H4 - A and 4-NO2C6H4 - B − Z/E), 8.75 (d, 1H, J = 13.3 Hz, H4), 12.34−12.38 (m, 1H, NH − Z/E); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 62.6 (O-CH2−CH3), 110.8 (C3), 118.2, 126.3, 143.0, 145.7 (4-NO2C6H4 B), 124.1, 130.0, 143.3, 150.1 (4-NO2C6H4 - A), 152.8 (C4), 163.6 (COOEt), 187.5 (C2), 190.9 (C3′); (E) 13.8 (O−CH2−CH3), 62.8 (O-CH2−CH3), 110.6 (C3), 118.3, 126.3, 143.2, 145.2 (4-NO2C6H4 B), 123.9, 128.8, 143.0, 149.6 (4-NO2C6H4 - A), 153.3 (C4), 163.3 (COOEt), 183.3 (C2), 194.3 (C3′); HRMS (ESI+): calcd for C19H16N3O8+, [M+H]+: 414.0932, found 414.0909. β-Enamino Diketone Substrates 2e,i−n. A mixture of compound 18a,9,15 (1a: 0.320 g; 1b: 0.293 g; 1c: 0.309 g; 1d: 0.353 g; 1e: 0.275 g; 1f: 0.289 g; 1g: 0.305 g, 1 mmol, 1 equiv) and tert-butylamine (0. 0.164 g, 1.5 mmol, 1.5 equiv) in dichloromethane (10 mL) was stirred at room temperature for 1 h. Then it was washed with distilled water (5 × 25 mL) and the organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in hot methanol (5 mL) and cooled to 0 °C which induced crystallization. The solid was filtered, washed with cold methanol (20 mL), and dried under vacuum. (Z and E)-4-(tert-Butylamino)-3-(4-nitrobenzoyl)-2-oxobut-3enoic Acid Ethyl Ester (2e). Light yellow solid; yield: 0.324 g (93%); Z/E ratio in CDCl3: 77/23; mp 146.8−147.9 °C; 1H NMR (300.06 MHz, CDCl3) δ (ppm) (Z) 1.28 (t, 3H, J = 7.1 Hz, O−CH2− CH3), 1.38 (s, 9H, t-Bu), 4.13 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.76 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 7.81 (d, 1H, J = 14.6 Hz, H4), 8.29 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 11.13 (d, 1H, J = 12.6 Hz, NH); (E) 1.12 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.47 (s, 9H, t-Bu), 3.78 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.63 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.23 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.34 (d, 1H, J = 14.8 Hz, H4), 11.28 (d, 1H, J = 12.0 Hz, NH);); 13C NMR (75.46 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 29.5 (C(CH3)3), 55.3 (C(CH3)3), 61.8 (O-CH2−CH3), 106.4 (C3), 123.7, 129.6, 144.7, 149.3 (4NO2C6H4), 157.5 (C4), 164.8 (COOEt), 186.5 (C2), 190.9 (C3′); (E) 13.7 (O−CH2−CH3), 29.6 (C(CH3)3), 55.5 (C(CH3)3), 62.0 (OCH2−CH3), 106.3 (C3), 123.4, 128.7, 146.5, 148.9 (4-NO2C6H4), 157.7 (C4), 164.6 (COOEt), 183.5 (C2), 193.5 (C3′); HRMS (ESI +): calcd for C17H21N2O6+, [M+H]+: 349.1394, found 349.1402. (Z and E)-4-(tert-Butylamino)-3-(4-fluorobenzoyl)-2-oxobut-3enoic Acid Ethyl Ester (2i). White solid; yield: 0.295 g (92%); Z/E ratio in CDCl3: 83/17; mp 109.2−111.3 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.28 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.37 (s, 9H, t-Bu), 4.15 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.12 (t, 2H, 3JH−F = 8.7 Hz, J = 8.7 Hz, 4-FC6H4), 7.65 (dd, 2H, 4JH−F = 5.4 Hz, J = 8.8 Hz, 12596


Article


(Z and E)-4-(tert-Butylamino)-3-(4-methylbenzoyl)-2-oxobut-3enoic Acid Ethyl Ester (2m). White solid; yield: 0.285 g (90%); Z/E ratio in CDCl3: 83/17; mp 105.0−106.3 °C; 1H NMR (300.06 MHz, CDCl3) δ (ppm) (Z) 1.27 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.36 (s, 9H, t-Bu), 2.40 (s, 3H, 4-CH3C6H4), 4.16 (q, 2H, J = 7.1 Hz, O−CH2CH3), 7.23 (d, 2H, J = 7.8 Hz, 4-CH3C6H4), 7.52 (d, 2H, J = 8.1 Hz, 4-CH3C6H4), 7.85 (d, 1H, J = 14.4 Hz, H4), 11.03 (d, 1H, J = 12.0 Hz, NH); (E) 1.03 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.44 (s, 9H, t-Bu), 2.37 (s, 3H, 4-CH3C6H4), 3.63 (q, 2H, J = 7,1 Hz, O−CH2-CH3), 7.18 (d, 2H, J = 7.8 Hz, 4-CH3C6H4), 7.42 (d, 2H, J = 8.1 Hz, 4-CH3C6H4), 8.30 (d, 1H, J = 14.7 Hz, H4), 11.14 (d, 1H, J = 13.0 Hz, NH); 13C NMR (75.46 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 21.6 (4-CH3C6H4), 29.6 (C(CH3)3), 54.7 (C(CH3)3), 61.6 (O-CH2− CH3), 106.9 (C3), 129.1, 129.1, 136.2, 142.2, (4-CH3C6H4), 157.7 (C4), 165.3 (COOEt), 186.9 (C2), 193.0 (C3′); (E) 13.6 (O−CH2− CH3), 21.6 (4-CH3C6H4), 29.7 (C(CH3)3), 55.0 (C(CH3)3), 61.6 (OCH2−CH3), 106.8 (C3), 128.2, 129.0, 138.4, 141.8 (4-CH3C6H4), 156.9 (C4), 164.9 (COOEt), 184.8 (C2), 195.5 (C3′); HRMS (ESI +): calcd for C18H24NO4+, [M+H]+: 318.1700, found 318.1703. (Z and E)-4-(tert-Butylamino)-3-(4-methoxybenzoyl)-2-oxobut-3enoic Acid Ethyl Ester (2n). White solid; yield: 0.300 g (90%); Z/E ratio in CDCl3: 84/16; mp 105.7−107.0 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.27 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.37 (s, 9H, t-Bu), 3.86 (s, 3H, 4-OCH3C6H4), 4.15 (q, 2H, J = 7.2 Hz, O− CH2-CH3), 6.92 (d, 2H, J = 8.8 Hz, 4-OCH3C6H4), 7.62 (d, 2H, J = 8.8 Hz, 4-OCH3C6H4), 7.85 (d, 1H, J = 14.4 Hz, H4), 11.02 (d, 1H, J = 13.6 Hz, NH − Z/E); (E) 1.05 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.44 (s, 9H, t-Bu), 3.70 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 3.83 (s, 3H, 4-OCH3C6H4), 6.88 (d, 2H, J = 8.8 Hz, 4-OCH3C6H4), 7.50 (d, 2H, J = 8.8 Hz, 4-OCH3C6H4), 8.29 (d, 1H, J = 14.7 Hz, H4), 11.02 (d, 1H, J = 13.6 Hz, NH − Z/E); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 14.0 (O−CH2−CH3), 29.7 (C(CH3)3), 54.7 (C(CH3)3), 55.5 (4OCH3C6H4), 61.6 (O-CH2−CH3), 106.9 (C3), 113.7, 131.1, 131.5, 162.5 (4-OCH3C6H4), 157.4 (C4), 165.3 (COOEt), 186.7 (C2), 192.2 (C3′); (E) 13.7 (O−CH2−CH3), 29.7 (C(CH3)3), 54.9 (C(CH3)3), 55.5 (4-OCH3C6H4), 61.7 (O-CH2−CH3), 106.7 (C3), 113.6, 130.2, 133.8, 162.3 (4-OCH3C6H4), 156.8 (C4), 165.0 (COOEt), 184.7 (C2), 194.6 (C3′); HRMS (ESI+): calcd for C18H24NO5+, [M+H]+: 334.1649, found 334.1648. Evaluation of the Reactivity of β-Enamino Diketones 2a−h against Phenylhydrazine. The reactivity of 2a−h against cyclocondensation with phenylhydrazine was evaluated according to the methodology reported by Souza et al.8d To a solution of β-enamino diketone 2 (2a: 0.153 g; 2b: 0.174 g; 2c: 0.191 g; 2d: 0.167 g; 2e: 0.174 g; 2f: 0.184 g; 2g: 0.199 g; 2h: 0.206 g, 0.5 mmol, 1 equiv) in MeCN (5 mL) was added phenylhydrazine (0.054 g, 0.5 mmol, 1 equiv). The mixture was stirred at room temperature and time showed in Table 1. Then, the solvent was evaporated under reduced pressure and the residue was washed with distilled water (20 mL), extracted with dichloromethane (3 × 10 mL), and dried with anhydrous sodium sulfate. The solvent was evaporated once again under reduced pressure to give crude pyrazoles A and B (no reaction was observed for the substrate 2e). The spectral data of pyrazoles A and B were in full accordance with the literature.8d 3,5-Disubstituted 4-Formyl-N-arylpyrazoles 3a−u. To a solution of compound 2 (2e: 0.174 g; 2i: 0.161 g; 2j: 0.169 g; 2k: 0.191 g; 2l: 0.152 g; 2m: 0.159 g; 2n: 0.167 g; 0.5 mmol, 1 equiv) in MeCN (2 mL) was added boron trifluoride diethyl etherate solution 46.5% (0.20 mL, 0.75 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 min. Next, a solution of arylhydrazine (phenylhydrazine: 0.054 g; 4-chlorophenylhydrazine: 0.071 g; 4-nitrophenylhydrazine: 0.077 g, 0.5 mmol, 1 equiv) in MeCN (2 mL) was added to the mixture, and stirred under refux for 1 h. Then, the reaction mixture was cooled to room temperature and the solvent evaporated under vacuum. The residue was washed with distilled water (25 mL), extracted with dichloromethane (3 × 20 mL), and dried over anhydrous sodium sulfate. Finally, the solvent was evaporated under reduced pressure and the product was isolated on a silica gel chromatography column using a 90:10 mixture of hexane: ethyl acetate as the eluent.

4-FC6H4), 7.83 (d, 1H, J = 14.5 Hz, H4), 11.05 (d, 1H, J = 13.3 Hz, NH); (E) 1.08 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.45 (s, 9H, t-Bu), 3.72 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.07 (t, 2H, 3JH−F = 8.7 Hz, J = 8.7 Hz, 4-FC6H4), 7.53 (dd, 2H, 4JH−F = 5.4 Hz, J = 8.8 Hz, 4-FC6H4), 8.30 (d, 1H, J = 14.8 Hz, H4), 11.12 (d, 1H, J = 13.2 Hz, NH); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 29.5 (C(CH3)3), 54.9 (C(CH3)3), 61.6 (O-CH2−CH3), 106.7 (C3), 115.5 (d, 2JC−F = 21.8 Hz, 4-FC6H4), 131.2 (d, 3JC−F = 8.8 Hz, 4-FC6H4), 135.3 (d, 4JC−F = 3.2 Hz, 4-FC6H4), 157.4 (C4), 164.7 (d, 1JC−F = 252.7 Hz, 4-FC6H4), 165.0 (COOEt), 186.6 (C2), 191.7 (C3′); (E) 13.7 (O−CH2−CH3), 29.6 (C(CH3)3), 55.1 (C(CH3)3), 61.8 (OCH2−CH3), 106.5 (C3), 115.3 (d, 2JC−F = 21.8 Hz, 4-FC6H4), 130.4 (d, 3JC−F = 8.8 Hz, 4-FC6H4), 137.3 (d, 4JC−F = 3.2 Hz, 4-FC6H4), 157.0 (C4), 164.5 (d, 1JC−F = 252.0 Hz, 4-FC6H4), 164.9 (COOEt), 184.5 (C2), 194.1 (C3′); HRMS (ESI+): calcd for C17H21FNO4+, [M +H]+: 322.1449, found 322.1439. (Z and E)-4-(tert-Butylamino)-3-(4-chlorobenzoyl)-2-oxobut-3enoic Acid Ethyl Ester (2j). White solid; yield: 0.307 g (91%); Z/E ratio in CDCl3: 83/17; mp 109.1−110.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.28 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.37 (s, 9H, t-Bu), 4.15 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.41 (d, 2H, J = 8.7 Hz, 4-ClC6H4), 7.56 (d, 2H, J = 8.7 Hz, 4-ClC6H4), 7.82 (d, 1H, J = 14.3 Hz, H4), 11.06 (d, 1H, J = 13.4 Hz, NH); (E) 1.09 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.45 (s, 9H, t-Bu), 3.72 (q, 2H, J = 7.1 Hz, O− CH2-CH3), 7.36 (d, 2H, J = 8.7 Hz, 4-ClC6H4), 7.45 (d, 2H, J = 8.7 Hz, 4-ClC6H4), 8.30 (d, 1H, J = 14.8 Hz, H4), 11.15 (d, 1H, J = 14.7 Hz, NH); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O− CH2−CH3), 29.5 (C(CH3)3), 54.9 (C(CH3)3), 61.7 (O-CH2−CH3), 106.6 (C3), 128.7, 130.2, 137.4, 137.8 (4-ClC6H4), 157.5 (C4), 165.0 (COOEt), 186.6 (C2), 191.8 (C3′); (E) 13.6 (O−CH2−CH3), 29.6 (C(CH3)3), 55.2 (C(CH3)3), 61.8 (O-CH2−CH3), 106.5 (C3), 128.5, 129.5, 137.3, 139.3 (4-ClC6H4), 157.1 (C4), 164.8 (COOEt), 184.4 (C2), 194.2 (C3′); HRMS (ESI+): calcd for C17H21ClNO4+, [M+H]+: 338.1154, found 338.1145. (Z and E)-3-(4-Bromobenzoyl)-4-(tert-butylamino)-2-oxobut-3enoic Acid Ethyl Ester (2k). White solid; yield: 0.347 g (91%); Z/E ratio in CDCl3: 82/18; mp 103.4−104.5 °C; 1H NMR (300.06 MHz, CDCl3) δ (ppm) (Z) 1.28 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.37 (s, 9H, t-Bu), 4.15 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.49 (d, 2H, J = 8.6 Hz, 4-BrC6H4), 7.58 (d, 2H, J = 8.6 Hz, 4-BrC6H4), 7.82 (d, 1H, J = 14.5 Hz, H4), 11.06 (d, 1H, J = 12.8 Hz, NH); (E) 1.09 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.45 (s, 9H, t-Bu), 3.72 (q, 2H, J = 7.1 Hz, O− CH2-CH3), 7.38 (d, 2H, J = 8.5 Hz, 4-BrC6H4), 7.52 (d, 2H, J = 8.6 Hz, 4-BrC6H4), 8.30 (d, 1H, J = 14.8 Hz, H4), 11.17 (d, 1H, J = 12.9 Hz, NH); 13C NMR (75.46 MHz, CDCl3) δ (ppm) (Z) 13.9 (O− CH2−CH3), 29.6 (C(CH3)3), 55.0 (C(CH3)3), 61.7 (O-CH2−CH3), 106.6 (C3), 126.3, 130.4, 131.7, 137.9 (4-BrC6H4), 157.5 (C4), 165.0 (COOEt), 186.7 (C2), 191.9 (C3′); (E) 13.7 (O−CH2−CH3), 29.7 (C(CH3)3), 55.2 (C(CH3)3), 61.9 (O-CH2−CH3), 106.5 (C3), 125.8, 129.7, 131.5, 139.8 (4-BrC6H4), 157.2 (C4), 164.9 (COOEt), 184.4 (C2), 194.4 (C3′); HRMS (ESI+): calcd for C17H21BrNO4+, [M+H]+: 382.0648, found 382.0667. (Z and E)-3-Benzoyl-4-(tert-butylamino)-2-oxobut-3-enoic Acid Ethyl Ester (2l). White solid; yield: 0.273 g (90%); Z/E ratio in CDCl3: 83/17; mp 111.2−113.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) (Z) 1.28 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.36 (s, 9H, t-Bu), 4.15 (q, 2H, J = 7.1 Hz, O−CH2-CH3) 7.37−7.45, 7.49−7.52, 7.60−7.63 (m, 5H, Ph − E/Z), 7.86 (d, 1H, J = 14.3 Hz, H4), 11.05 (d, 1H, J = 12.2 Hz, NH); (E) 1.04 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 1.45 (s, 9H, t-Bu), 3.60 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.37−7.45, 7.49− 7.52, 7.60−7.63 (m, 5H, Ph − E/Z), 8.32 (d, 1H, J = 14.8 Hz, H4), 11.20 (d, 1H, J = 11.6 Hz, NH); 13C NMR (125.77 MHz, CDCl3) δ (ppm) (Z) 13.9 (O−CH2−CH3), 29.6 (C(CH3)3), 54.8 (C(CH3)3), 61.6 (O-CH2−CH3), 106.8 (C3), 128.5, 128.8, 131.6, 139.0 (Ph), 157.8 (C4), 165.2 (COOEt), 186.9 (C2), 193.1 (C3′); (E) 13.6 (O− CH2−CH3), 29.7 (C(CH3)3), 55.1 (C(CH3)3), 61.6 (O-CH2−CH3), 106.7 (C3), 128.1, 128.3, 131.2, 141.0 (Ph), 157.0 (C4), 164.9 (COOEt); 184.8 (C2), 195.6 (C3′); HRMS (ESI+): calcd for C17H22NO4+, [M+H]+: 304.1543, found 304.1528. 12597


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128.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.81 (s, 3H, OCH3C6H4), 4.52 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 6.85 (d, 2H, J = 8.9 Hz, 4-OCH3C6H4), 7.21 (d, 2H, J = 8.9 Hz, 4-OCH3C6H4), 7.23−7.26 (m, 2H, Ph), 7.32−7.35 (m, 3H, Ph), 10.49 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 55.3 (4-OCH3C6H4), 62.0 (O-CH2− CH3), 113.9, 119.4 (4-OCH3C6H4), 121.1 (C4), 125.9, 128.9, 129.1 (Ph), 132.1 (4-OCH3C6H4), 138.6 (Ph), 144.8 (C3), 146.4 (C5), 160.7 (4-OCH3C6H4), 162.0 (COOEt), 186.5 (CHO); HRMS (ESI +): calcd for C20H19N2O4+, [M+H]+: 351.1339, found 351.1339. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-formy-5-(4-nitrophenyl)-1H-pyrazole (3h). Light yellow solid; yield: 0.164 g (82%); mp 162.3−163.8 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.55 (q, 2H, J = 7.1 Hz, O−CH2CH3), 7.17 (d, 2H, J = 8.7 Hz, 4-ClC6H4), 7.34 (d, 2H, J = 8.8 Hz, 4ClC6H4), 7.48 (d, 2H, J = 8.8 Hz, 4-NO2C6H4), 8.23 (d, 2H, J = 8.8 Hz, 4-NO2C6H4), 10.56 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.3 (O-CH2−CH3), 122.2 (C4), 123.7 (4-NO2C6H4), 127.0, 129.8 (4-ClC6H4), 131.8, 133.8 (4NO2C6H4), 135.7, 136.2 (4-ClC6H4), 143.6 (C5), 145.2 (C3), 148.5 (4-NO2C6H4), 161.3 (COOEt), 186.4 (CHO); HRMS (ESI+): calcd for C19H15ClN3O5+, [M+H]+: 400.0695, found 400.0693. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-5-(4-fluorophenyl)-4formyl-1H-pyrazole (3i). Light yellow solid; yield: 0.147 g (79%); mp 132.8−133.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.53 (q, 2H, J = 7.2 Hz, O−CH2CH3), 7.07 (t, 2H, 3JH−F = 8.7 Hz, J = 8.7 Hz, 4-FC6H4), 7.17 (d, 2H, J = 8.9 Hz, 4-ClC6H4), 7.27 (dd, 2H, 4JH−F = 5.2 Hz, J = 8.9 Hz, 4FC6H4), 7.31 (d, 2H, J = 8.9 Hz, 4-ClC6H4), 10.51 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.2 (OCH2−CH3), 115.9 (d, 2J = 22.2 Hz, 4-FC6H4), 121.6 (C4), 123.2 (d, 4 J = 3.6 Hz, 4-FC6H4), 127.0, 129.5 (4-ClC6H4), 132.6 (d, 3J = 8.7 Hz, 4-FC6H4), 135.1, 136.7 (4-ClC6H4), 145.0 (C3), 145.3 (C5), 161.6 (COOEt), 163.6 (d, 1J = 251.6 Hz, 4-FC6H4), 186.4 (CHO); HRMS (ESI+): calcd for C19H15ClFN2O3+, [M+H]+: 373.0750, found 373.0751. 1,5-Bis(4-chlorophenyl)-3-(ethoxycarbonyl)-4-formyl-1H-pyrazole (3j). Yellow solid; yield: 0.134 g (69%); mp 45.9−47.2 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O− CH2−CH3), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.17 (d, 2H, J = 8.9 Hz, 4-ClC6H4 - B), 7.21 (d, 2H, J = 8.7 Hz, 4-ClC6H4 - A), 7.32 (d, 2H, J = 8.9 Hz, 4-ClC6H4 - B), 7.35 (d, 2H, J = 8.7 Hz, 4-ClC6H4 - A), 10.51 (s, 1H, CHO); (500.13 MHz, DMSO-d6) δ (ppm) 1.35 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.42 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.36 (d, 2H, J = 8.8 Hz, 4-ClC6H4 - B), 7.38 (d, 2H, J = 8.6 Hz, 4-ClC6H4 A), 7.48 (d, 2H, J = 8.6 Hz, 4-ClC6H4 - A), 7.52 (d, 2H, J = 8.8 Hz, 4ClC6H4 - B), 10.28 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.2 (O-CH2−CH3), 121.7 (C4), 125.7 (4-ClC6H4 - A), 127.0 (4-ClC6H4 - B), 129.0 (4-ClC6H4 - A), 129.6 (4-ClC6H4 - B), 131.9 (4-ClC6H4 - A), 135.2 (4-ClC6H4 - B), 136.5 (4-ClC6H4 - A), 136.7 (4-ClC6H4 - B), 145.0 (C3), 145.1 (C5), 161.6 (COOEt), 186.4 (CHO); HRMS (ESI+): calcd for C19H15Cl2N2O3+, [M+H]+: 389.0454, found 389.0458. The 1H NMR (DMSO-d6) corresponded to literature.16 5-(4-Bromophenyl)-1-(4-chlorophenyl)-3-(ethoxycarbonyl)-4formyl-1H-pyrazole (3k). Light yellow solid; yield: 0.166 g (77%); mp 120.9−123.2 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.53 (q, 2H, J = 7.1 Hz, O−CH2CH3), 7.15 (d, 2H, J = 8.6 Hz, 4-BrC6H4), 7.17 (d, 2H, J = 8.9 Hz, 4ClC6H4), 7.32 (d, 2H, J = 8.8 Hz, 4-ClC6H4), 7.51 (d, 2H, J = 8.6 Hz, 4-BrC6H4), 10.51 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.2 (O-CH2−CH3), 121.6 (C4), 124.9, 126.1 (4-BrC6H4), 127.0, 129.5 (4-ClC6H4), 131.9, 132.0 (4-BrC6H4), 135.2, 136.6 (4-ClC6H4), 145.0 (C3), 145.0 (C5), 161.5 (COOEt), 186.3 (CHO); HRMS (ESI+): calcd for C19H15BrClN2O3+, [M+H]+: 432.9949, found 432.9938. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-formyl-5-phenyl-1Hpyrazole (3l). Light yellow solid; yield: 0.150 g (85%); mp 92.8−95.0 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.17 (d, 2H, J

3-(Ethoxycarbonyl)-4-formyl-5-(4-nitrophenyl)-1-phenyl-1H-pyrazole (3a). Light yellow solid; yield: 0.150 g (82%); mp 147.0−149.2 °C; 1H NMR (300.06 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.54 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.19−7.25 (m, 2H, Ph), 7.32−7.43 (m, 3H, Ph), 7.48 (d, 2H, J = 8.9 Hz, 4NO2C6H4), 8.19 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 10.57 (s, 1H, CHO); 13C NMR (75.46 MHz, CDCl3) δ (ppm) 14.4 (O−CH2− CH3), 62.3 (O-CH2−CH3), 122.0 (C4), 123.5 (4-NO2C6H4), 125.9 (Ph), 129.5 (Ph), 129.6 (Ph), 131.8 (4-NO2C6H4), 134.1 (4NO2C6H4), 137.8 (Ph), 143.5 (C5), 145.0 (C3), 148.4 (4NO2C6H4), 161.5 (COOEt), 186.6 (CHO); HRMS (ESI+): calcd for C19H16N3O5+, [M+H]+: 366.1084, found 366.1101. 3-(Ethoxycarbonyl)-5-(4-fluorophenyl)-4-formyl-1-phenyl-1Hpyrazole (3b). Light yellow solid; yield: 0.135 g (80%); mp 154.3− 157.3 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 4.53 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.03 (t, 2H, 3JH−F = 8.7 Hz, J = 8.7 Hz, 4-FC6H4), 7.21−7.24 (m, 2H, Ph), 7.27 (dd, 2H, 4JH−F = 5.2 Hz, J = 8.9 Hz, 4-FC6H4), 7.31−7.36 (m, 3H, Ph), 10.53 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 62.1 (O-CH2−CH3), 115.7 (d, 2J = 21.8 Hz, 4FC6H4), 121.5 (C4), 123.5 (d, 4J = 3.6 Hz, 4-FC6H4), 125.9, 129.2, 129.3 (Ph), 132.7 (d, 3J = 8.6 Hz, 4-FC6H4), 138.3 (Ph), 144.8 (C3), 145.3 (C5), 161.8 (COOEt), 163.5 (d, 1J = 251.1 Hz, 4-FC6H4), 186.6 (CHO); HRMS (ESI+): calcd for C19H16FN2O3+, [M+H]+: 339.1139, found 339.1127. 5-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-formyl-1-phenyl-1Hpyrazole (3c). Light yellow solid; yield: 0.126 g (71%); mp 140.1− 141.6 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.21− 7.23 (m, 4H, 4-ClC6H4 and Ph), 7.31−7.37 (m, 5H, 4-ClC6H4 and Ph), 10.53 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.1 (O-CH2−CH3), 121.5 (C4), 125.9, 125.9, 128.7, 129.2, 129.3, 131.9, 136.2, 138.1 (4-ClC6H4 and Ph), 144.8 (C3), 145.0 (C5), 161.7 (COOEt), 186.5 (CHO); HRMS (ESI+): calcd for C19H16ClN2O3+, [M+H]+: 355.0844, found 355.0834. 5-(4-Bromophenyl)-3-(ethoxycarbonyl)-4-formyl-1-phenyl-1Hpyrazole (3d). Light yellow solid; yield: 0.165 g (83%); mp 157.2− 160.2 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.15 (d, 2H, J = 8.6 Hz, 4-BrC6H4), 7.21−7.24 (m, 2H, Ph), 7.32−7.38 (m, 3H, Ph), 7.48 (d, 2H, J = 8.6 Hz, 4-BrC6H4), 10.53 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.1 (OCH2−CH3), 121.5 (C4), 124.6 (4-BrC6H4), 125.9 (Ph), 126.4 (4BrC6H4), 129.2, 129.3 (Ph), 131.7, 132.1 (4-BrC6H4), 138.1 (Ph), 144.8 (C3), 145.0 (C5), 161.7 (COOEt), 186.5 (CHO); HRMS (ESI +): calcd for C19H16BrN2O3+, [M+H]+: 399.0339, found 399.0376. 3-(Ethoxycarbonyl)-4-formyl-1,5-diphenyl-1H-pyrazole (3e). Light yellow solid; yield: 0.109 g (68%); mp 158.7−161.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.2 Hz, O− CH2−CH3), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.22−7.41 (m, 10H, Ph − A and B), 10.49 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.0 (O-CH2−CH3), 121.4 (C4), 125.9, 127.5, 128.4, 129.0, 129.1, 129.9, 130.5 (Ph − A and B) 138.4 (Ph - B), 144.7 (C3), 146.5 (C5), 161.9 (COOEt), 186.4 (CHO); HRMS (ESI+): calcd for C19H17N2O3+, [M+H]+: 321.1234, found 321.1215. 3-(Ethoxycarbonyl)-4-formyl-5-(4-methylphenyl)-1-phenyl-1Hpyrazole (3f). Light yellow solid; yield: 0.134 g (80%); mp 126.9− 128.9 °C; 1H NMR (300.06 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 2.36 (s, 3H, 4-CH3C6H4), 4.52 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.15 (sl, 4H, 4-CH3C6H4), 7.22−7.25 (m, 2H, Ph), 7.30−7.35 (m, 3H, Ph), 10.48 (s, 1H, CHO); 13C NMR (75.46 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 21.5 (4-CH3C6H4), 61.9 (O-CH2−CH3), 121.2 (C4), 124.4 (4-CH3C6H4), 125.8 (Ph), 128.8 (Ph), 129.1 (4-CH3C6H4), 129.1 (Ph), 130.3 (4-CH3C6H4), 138.5 (Ph), 140.1 (4-CH3C6H4), 144.7 (C3), 146.6 (C5), 161.9 (COOEt), 186.4 (CHO); HRMS (ESI+): calcd for C20H19N2O3+, [M +H]+: 335.1390, found 335.1360. 3-(Ethoxycarbonyl)-4-formyl-5-(4-methoxyphenyl)-1-phenyl-1Hpyrazole (3g). Light yellow solid; yield: 0.138 g (79%); mp 127.6− 12598


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5-(4-Bromophenyl)-3-(ethoxycarbonyl)-4-formyl-1-(4-nitrophenyl)-1H-pyrazole (3r). Light yellow solid; yield: 0.195 g (88%); mp 73.3−76.6 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.55 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.17 (d, 2H, J = 8.5 Hz, 4-BrC6H4), 7.45 (d, 2H, J = 9.1 Hz, 4- NO2C6H4), 7.55 (d, 2H, J = 8.5 Hz, 4-BrC6H4), 8.22 (d, 2H, J = 9.1 Hz, 4NO2C6H4), 10.51 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.4 (O-CH2−CH3), 122.1 (C4), 124.8 (4-NO2C6H4), 125.4, 125.8 (4-BrC6H4), 126.3 (4-NO2C6H4), 131.9, 132.3 (4-BrC6H4), 142.9 (4-NO2C6H4), 145.4 (C5), 145.7 (C3), 147.4 (4-NO2C6H4), 161.3 (COOEt), 186.1 (CHO); HRMS (ESI+): calcd for C19H15BrN3O5+, [M+H]+: 444.0190, found 444.0185. 3-(Ethoxycarbonyl)-4-formyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole (3s). Light yellow solid; yield: 0.139 g (76%); mp 139.3−141.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.55 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.28−7.31 (m, 2H, Ph), 7.40−7.46 (m, 4H, Ph and 4-NO2C6H4), 7.47−7.50 (m, 1H, Ph), 8.18 (d, 2H, J = 9.1 Hz, 4-NO2C6H4), 10.48 (s, 1H, CHO); 13 C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.3 (O-CH2−CH3), 122.0 (C4), 124.5, 126.1 (4-NO2C6H4), 126.9, 128.9, 130.3, 130.6 (Ph), 143.2 (4-NO2C6H4), 145.5 (C3), 146.8 (C5), 147.2 (4-NO2C6H4), 161.4 (COOEt), 186.0 (CHO); HRMS (ESI+): calcd for C19H16N3O5+, [M+H]+: 366.1084, found 366.1092. 3-(Ethoxycarbonyl)-4-formyl-5-(4-methylphenyl)-1-(4-nitrophenyl)-1H-pyrazole (3t). Light yellow solid; yield: 0.165 g (87%); mp 129.3−131.2 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 2.40 (s, 3H, 4-CH3C6H4), 4.54 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.17 (d, 2H, J = 8.3 Hz, 4-CH3C6H4), 7.21 (d, 2H, J = 8.4 Hz, 4-CH3C6H4), 7.45 (d, 2H, J = 9.1 Hz, 4NO2C6H4), 8.19 (d, 2H, J = 9.1 Hz, 4-NO2C6H4), 10.46 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2− CH3), 21.6 (4-CH3C6H4), 62.3 (O-CH2−CH3), 121.9 (C4), 123.8, (4CH3C6H4), 124.5, 126.2 (4-NO2C6H4), 129.7, 130.2, 141.0 (4CH3C6H4), 143.3 (4-NO2C6H4), 145.6 (C3), 147.0 (C5), 147.1 (4NO2C6H4), 161.5 (COOEt), 186.0 (CHO); HRMS (ESI+): calcd for C20H18N3O5+, [M+H]+: 380.1241, found 380.1250. 3-(Ethoxycarbonyl)-4-formyl-5-(4-methoxyphenyl)-1-(4-nitrophenyl)-1H-pyrazole (3u). Yellow solid; yield: 0.188 g (95%); mp 121.1−123.3 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.85 (s, 3H, OCH3C6H4), 4.54 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 6.91 (d, 2H, J = 8.9 Hz, 4OCH3C6H4), 7.22 (d, 2H, J = 8.9 Hz, 4-OCH3C6H4), 7.46 (d, 2H, J = 9.1 Hz, 4-NO2C6H4), 8.20 (d, 2H, J = 9.2 Hz, 4-NO2C6H4), 10.47 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O− CH2−CH3), 55.4 (4-OCH3C6H4), 62.3 (O-CH2−CH3), 114.4, 118.6 (4-OCH3C6H4), 121.7 (C4), 124.6, 126.2 (4-NO2C6H4), 132.0 (4OCH3C6H4), 143.4 (4-NO2C6H4), 145.6 (C3), 146.8 (C5), 147.1 (4NO2C6H4), 161.2 (4-OCH3C6H4), 161.5 (COOEt), 186.1 (CHO); HRMS (ESI+): calcd for C20H18N3O6+, [M+H]+: 396.1190, found 396.1202. 3,5-Disubstituted 4-Hydroxymethyl-N-arylpyrazoles 4a−u. To a solution of compound 2 (2e: 0.174 g; 2i: 0.161 g; 2j: 0.169 g; 2k: 0.191 g; 2l: 0.152 g; 2m: 0.159 g; 2n: 0.167 g; 0.5 mmol, 1 equiv) in MeCN (2 mL) was added boron trifluoride diethyl etherate solution 46.5% (0.20 mL, 1 mmol, 1.5 equiv). The mixture was stirred at room temperature for 2 min. Next, a solution of arylhydrazine (phenylhydrazine: 0.054 g; 4-chlorophenylhydrazine: 0.071 g; 4-nitrophenylhydrazine: 0.077 g, 0.5 mmol, 1 equiv) in MeCN (2 mL) was added to mixture and stirred under reflux for 1 h. Then, the reaction mixture was cooled to room temperature, added distilled water (0.45 mL, ∼ 25 mmol, ∼ 50 equiv), triethylamine (0.21 mL, 1.5 mmol, 3 equiv) and stirred for 30 min. After, a solution of sodium borohydride (0.021 g, 0.55 mmol, 1.1 equiv) in distilled water (1 mL) was added dropwise. The reaction was stirred at room temperature for 15 min. After completion, the reaction mixture was diluted with saturated NaCl (aq.) (25 mL) and extracted with dichloromethane (3 × 10 mL). Organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the product was isolated on a silica gel chromatography column using a 70:30 mixture of hexane: ethyl acetate as the eluent.

= 8.8 Hz, 4-ClC6H4), 7.26−7.30 (m, 4H, 4-ClC6H4 and Ph), 7.38 (t, 2H, J = 7.4 Hz, Ph), 7.43 (t, 1H, J = 7.4 Hz, Ph), 10.48 (s, 1H, CHO); 13 C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.1 (O-CH2−CH3), 121.5 (C4), 126.9 (4-ClC6H4), 127.2, 128.6 (Ph), 129.3 (4-ClC6H4), 130.1, 130.4 (Ph), 134.9, 136.9 (4-ClC6H4), 144.9 (C3), 146.4 (C5), 161.7 (COOEt), 186.2 (CHO); HRMS (ESI+): calcd for C19H16ClN2O3+, [M+H]+: 355.0844, found 355.0844. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-formyl-5-(4-methylphenyl)-1H-pyrazole (3m). Light yellow solid; yield: 0.147 g (80%); mp 129.0−132.7 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 2.38 (s, 3H, 4-CH3C6H4), 4.52 (q, 2H, J = 7.2 Hz, O−CH2-CH3), 7.14−7.20 (m, 6H) and 7.29 (d, 2H, J = 8.9 Hz) (4-ClC6H4 and 4-CH3C6H4), 10.46 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 21.6 (4CH3C6H4), 62.1 (O-CH2−CH3), 121.4 (C4), 124.2, 127.0, 129.3, 129.4, 130.3, 134.8, 137.0, 140.4 (4-ClC6H4 e 4-CH3C6H4), 144.9 (C3), 146.7 (C5), 161.8 (COOEt), 186.3 (CHO); HRMS (ESI+): calcd for C20H18ClN2O3+, [M+H]+: 369.1000, found 369.1012. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-formyl-5-(4-methoxyphenyl)-1H-pyrazole (3n). Yellow, viscous liquid; yield: 0.169 g (88%); 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.2 Hz, O−CH2−CH3), 3.83 (s, 3H, OCH3C6H4), 4.52 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 6.88 (d, 2H, J = 8.8 Hz, 4-OCH3C6H4), 7.17−7.22 (m, 4H, 4-OCH3C6H4 and 4-ClC6H4), 7.30 (d, 2H, J = 8.8 Hz, 4ClC6H4), 10.47 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 55.4 (4-OCH3C6H4), 62.1 (O-CH2− CH3), 114.1, 119.0 (4-OCH3C6H4), 121.3 (C4), 127.0, 129.4 (4ClC6H4), 132.0 (4-OCH3C6H4), 134.8, 137.1 (4-ClC6H4), 145.0 (C3), 146.4 (C5), 160.9 (4-OCH3C6H4), 161.8 (COOEt), 186.4 (CHO); HRMS (ESI+): calcd for C 20H18ClN2O4+, [M+H]+: 385.0950, found 385.0952. 3-(Ethoxycarbonyl)-4-formy-1,5-bis(4-nitrophenyl)-1H-pyrazole (3o). Light yellow solid; yield: 0.176 g (86%); mp 110.8−113.7 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.49 (t, 3H, J = 7.1 Hz, O− CH2−CH3), 4.56 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.44 (d, 2H, J = 9.1 Hz, 4- NO2C6H4 - B), 7.51 (d, 2H, J = 8.9 Hz, 4- NO2C6H4 - A), 8.23 (d, 2H, J = 9.1 Hz, 4-NO2C6H4 - B), 8.27 (d, 2H, J = 9.9 Hz, 4NO2C6H4 - A), 10.56 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.6 (O-CH2−CH3), 122.7 (C4), 124.0 (4-NO2C6H4 - A), 124.9, 126.3 (4-NO2C6H4 - B), 131.7, 133.4 (4-NO2C6H4 - A), 142.5 (4-NO2C6H4 - B), 143.9 (C5), 145.8 (C3), 147.6 (4-NO2C6H4 - B), 148.8 (4-NO2C6H4 - A), 161.1 (COOEt), 186.2 (CHO); HRMS (ESI+): calcd for C19H15N4O7+, [M +H]+: 411.0935, found 411.0934. 3-(Ethoxycarbonyl)-5-(4-fluorophenyl)-4-formyl-1-(4-nitrophenyl)-1H-pyrazole (3p). Light yellow solid; yield: 0.172 g (90%); mp 116.0−117.1 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.55 (q, 2H, J = 7.1 Hz, O−CH2CH3), 7.11 (t, 2H, 3JH−F = 8.6 Hz, J = 8.6 Hz, 4-FC6H4), 7.30 (dd, 2H, 4 JH−F = 5.2 Hz, J = 8.9 Hz, 4-FC6H4), 7.44 (d, 2H, J = 9.2 Hz, 4NO2C6H4), 8.21 (d, 2H, J = 9.2 Hz, 4-NO2C6H4), 10.51 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2− CH3), 62.4 (O-CH2−CH3), 116.3 (d, 2J = 22.2 Hz, 4-FC6H4), 122.1 (C4), 122.9 (d, 4J = 3.4 Hz, 4-FC6H4), 124.7, 126.3 (4-NO2C6H4), 132.6 (d, 3J = 8.7 Hz, 4-FC6H4), 143.0 (4-NO2C6H4), 145.6 (C5), 145.7 (C3), 147.3 (4-NO2C6H4), 161.4 (COOEt), 163.8 (d, 1J = 252.8 Hz, 4-FC 6 H 4 ), 186.1 (CHO); HRMS (ESI+): calcd for C19H15FN3O5+, [M+H]+: 384.0990, found 384.1003. 5-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-formyl-1-(4-nitrophenyl)-1H-pyrazole (3q). Light yellow solid; yield: 0.184 g (92%); mp 94.7−97.0 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 4.55 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 7.24 (d, 2H, J = 8.6 Hz, 4-ClC6H4), 7.39 (d, 2H, J = 8.6 Hz, 4-ClC6H4), 7.45 (d, 2H, J = 9.1 Hz, 4-NO2C6H4), 8.22 (d, 2H, J = 9.1 Hz, 4NO2C6H4), 10.51 (s, 1H, CHO); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 62.4 (O-CH2−CH3), 122.2 (C4), 124.8 (4-NO2C6H4), 125.3 (4-ClC6H4), 126.3 (4-NO2C6H4), 129.3, 131.8, 137.1 (4-ClC6H4), 143.0 (4-NO2C6H4), 145.4 (C5), 145.8 (C3), 147.4 (4-NO2C6H4), 161.4 (COOEt), 186.2 (CHO); HRMS (ESI+): calcd for C19H15ClN3O5+, [M+H]+: 400.0695, found 400.0690. 12599


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The Journal of Organic Chemistry 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-5-(4-nitrophenyl)-1-phenyl-1H-pyrazole (4a). Light yellow solid; yield: 0.147 g (80%); mp 143.8−145.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.80 (t, 1H, J = 7.2 Hz, OH), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.65 (d, 2H, J = 7.2 Hz, CH2OH), 7.22−7.25 (m, 2H, Ph), 7.33−7.38 (m, 3H, Ph), 7.40 (d, 2H, J = 8.9 Hz, 4-NO2C6H4), 8.22 (d, 2H, J = 8.9 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.6 (CH2OH), 62.0 (O-CH2−CH3), 123.9 (4-NO2C6H4), 124.9 (C4), 125.7, 129.0, 129.4 (Ph), 131.2, 134.8 (4-NO2C6H4), 138.7 (Ph), 140.4 (C5), 142.7 (C3), 147.9 (4-NO2C6H4), 163.7 (COOEt); HRMS (ESI+): calcd for C19H18N3O5+, [M+H]+: 368.1241, found 368.1245. 3-(Ethoxycarbonyl)-5-(4-fluorophenyl)-4-(hydroxymethyl)-1-phenyl-1H-pyrazole (4b). Yellow, viscous liquid; yield: 0.129 g (76%); 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O− CH2−CH3), 3.87 (t, 1H, J = 7.1 Hz, OH), 4.51 (q, 2H, J = 7.1 Hz, O− CH2-CH3), 4.62 (d, 2H, J = 6.7 Hz, CH2OH), 7.06 (t, 2H, 3JH−F = 8.6 Hz, J = 8.6 Hz, 4-FC6H4), 7.18 (dd, 2H, 4JH−F = 5.3 Hz, J = 8.8 Hz, 4FC6H4), 7.22−7.24 (m, 2H, Ph), 7.31−7.34 (m, 3H, Ph); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 54.9 (CH2OH), 61.8 (O-CH2−CH3), 116.0 (d, 2J = 21.8 Hz, 4-FC6H4), 124.3 (C4), 124.5 (d, 4J = 3.5 Hz, 4-FC6H4), 125.7, 128.5, 129.1 (Ph), 132.2 (d, 3J = 8.4 Hz, 4-FC6H4), 139.1 (Ph), 141.8 (C5), 142.4 (C3), 163.1 (d, 1J = 250.2 Hz, 4-FC6H4), 164.1 (COOEt); HRMS (ESI+): calcd for C19H18FN2O3+, [M+H]+: 341.1296, found 341.1327. 5-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-1phenyl-1H-pyrazole (4c). Light yellow solid; yield: 0.125 g (70%); mp 66.7−69.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.86 (bs, 1H, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.62 (bs, 2H, CH2OH), 7.13 (d, 2H, J = 8.5 Hz, 4ClC6H4), 7.22−7.25 (m, 2H, Ph), 7.33−7.35 (m, 5H, 4-ClC6H4 and Ph); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 54.9 (CH2OH), 61.9 (O-CH2−CH3), 124.4 (C4), 125.7 (Ph), 126.9 (4-ClC6H4), 128.6, 129.1 (Ph), 129.1, 131.5, 135.5 (4-ClC6H4), 139.1 (Ph), 141.6 (C5), 142.5 (C3), 164.0 (COOEt); HRMS (ESI+): calcd for C19H18ClN2O3+, [M+H]+: 357.1000, found 357.1027. 5-(4-Bromophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-1phenyl-1H-pyrazole (4d). Light yellow solid; yield: 0.138 g (69%); mp 70.4−71.8 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.86 (bs, 1H, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.62 (bs, 2H, CH2OH), 7.07 (d, 2H, J = 8.4 Hz, 4BrC6H4), 7.22−7.25 (m, 2H, Ph), 7.33−7.34 (m, 3H, Ph), 7.49 (d, 2H, J = 8.5 Hz, 4-BrC6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 54.9 (CH2OH), 61.9 (O-CH2−CH3), 123.8 (4BrC6H4), 124.4 (C4), 125.7 (Ph), 127.4 (4-BrC6H4), 128.6, 129.2 (Ph), 131.8, 132.1 (4-BrC6H4), 139.1 (Ph), 141.6 (C5), 142.6 (C3), 164.1 (COOEt); HRMS (ESI+): calcd for C19H18BrN2O3+, [M+H]+: 401.0495, found 401.0497. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-1,5-diphenyl-1H-pyrazole (4e). Yellow solid; yield: 0.130 g (81%); mp 109.0−111.7 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.2 Hz, O− CH2−CH3), 3.92 (bs, 1H, OH), 4.52 (q, 2H, J = 7.1 Hz, O−CH2CH3), 4.65 (bs, 2H, CH2OH), 7.18−7.20 (m, 2H, Ph - A), 7.23−7.25 (m, 2H, Ph - B), 7.29−7.31 (m, 3H, Ph - B), 7.33−7.39 (m, 3H, Ph A); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 55.0 (CH2OH), 61.8 (O-CH2−CH3), 124.3 (C4), 125.7, 128.3 (Ph B), 128.5 (Ph - A), 128.8 (Ph - B), 129.0, 129.2, 130.3 (Ph - A), 139.3 (Ph - B), 142.4 (C3), 142.8 (C5), 164.2 (COOEt); HRMS (ESI+): calcd for C19H19N2O3+, [M+H]+: 323.1390, found 323.1416. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-5-(4-methylphenyl)-1phenyl-1H-pyrazole (4f). Yellow, viscous liquid; yield: 0.133 g (79%); 1 H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O− CH2−CH3), 2.36 (s, 3H, 4-CH3C6H4), 3.89 (bs, 1H, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.64 (bs, 2H, CH2OH), 7.07 (d, 2H, J = 8.2 Hz, 4-CH3C6H4), 7.15 (d, 2H, J = 7.9 Hz, 4-CH3C6H4), 7.24− 7.26 (m, 2H, Ph), 7.29−7.32 (m, 3H, Ph); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 21.3 (4-CH3C6H4), 54.9 (CH2OH), 61.7 (O-CH2−CH3), 124.0 (C4), 125.3 (4-CH3C6H4), 125.6, 128.2, 128.9 (Ph), 129.4, 130.0, 139.1 (4-CH3C6H4), 139.3

(Ph), 142.3 (C3), 142.8 (C5), 164.2 (COOEt); HRMS (ESI+): calcd for C20H21N2O3+, [M+H]+: 337.1547, found 337.1574. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-5-(4-methoxyphenyl)-1phenyl-1H-pyrazole (4g). Yellow, viscous liquid; yield: 0.136 g (77%); 1 H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O− CH2−CH3), 3.81 (s, 3H, 4-CH3OC6H4), 3.89 (bs, 1H, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.63 (d, 2H, J = 5.8 Hz, CH2OH), 6.87 (d, 2H, J = 8.8 Hz, 4-CH3OC6H4), 7.11 (d, 2H, J = 8.7 Hz, 4CH3OC6H4), 7.24−7.26 (m, 2H, Ph), 7.29−7.32 (m, 3H, Ph); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 55.1 (CH2OH), 55.3 (4-CH3OC6H4), 61.8 (O-CH2−CH3), 114.2, 120.6 (4-CH3OC6H4), 124.0 (C4), 125.7, 128.2, 129.0 (Ph), 131.6 (4CH3OC6H4), 139.4 (Ph), 142.3 (C3), 142.7 (C5), 160.2 (4CH 3 OC 6 H 4 ), 164.3 (COOEt); HRMS (ESI+): calcd for C20H21N2O4+, [M+H]+: 353.1496, found 353.1529. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-5-(4nitrophenyl)-1H-pyrazole (4h). Light yellow solid; yield: 0.156 g (78%); mp 198.3−199.7 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.74 (t, 1H, J = 7.2 Hz, OH), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.63 (d, 2H, J = 7.1 Hz, CH2OH), 7.18 (d, 2H, J = 8.9 Hz, 4-ClC6H4), 7.33 (d, 2H, J = 8.8 Hz, 4-ClC6H4), 7.40 (d, 2H, J = 9.0 Hz, 4-NO2C6H4), 8.25 (d, 2H, J = 8.9 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.5 (CH2OH), 62.1 (O-CH2−CH3), 124.1 (4NO2C6H4), 125.2 (C4), 126.8, 129.6 (4-ClC6H4), 131.2, 134.5 (4NO2C6H4), 134.9, 137.2 (4-ClC6H4), 140.5 (C5), 143.1 (C3), 148.1 (4-NO 2 C 6 H 4 ), 163.5 (COOEt); HRMS (ESI+): calcd for C19H17ClN3O5+, [M+H]+: 402.0851, found 402.0824. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-(hydroxymethyl)-1H-pyrazole (4i). Light yellow solid; yield: 0.155 g (83%); mp 94.2−96.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.80 (t, 1H, J = 7.1 Hz, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.60 (d, 2H, J = 6.2 Hz, CH2OH), 7.09 (t, 2H, 3JH−F = 8.6 Hz, J = 8.6 Hz, 4-FC6H4), 7.16− 7.19 (m, 4H, 4-FC6H4 and 4-ClC6H4), 7.30 (d, 2H, J = 8.8 Hz, 4ClC6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2− CH3), 54.8 (CH2OH), 62.0 (O-CH2−CH3), 116.3 (d, 2J = 21.9 Hz, 4FC6H4), 124.2 (d, 4J = 3.6 Hz, 4-FC6H4), 124.5 (C4), 126.8, 129.3 (4ClC6H4), 132.2 (d, 3J = 8.3 Hz, 4-FC6H4), 134.4, 137.6 (4-ClC6H4), 141.8 (C5), 142.7 (C3), 163.2 (d, 1J = 250.7 Hz, 4-FC6H4), 163.9 (COOEt); HRMS (ESI+): calcd for C19H17ClFN2O3+, [M+H]+: 375.0906, found 375.0910. 1,5-Bis(4-chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)1H-pyrazole (4j). White solid; yield: 0.127 g (65%); mp 109.9−111.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.78 (t, 1H, J = 7.1 Hz, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.61 (d, 2H, J = 6.8 Hz, CH2OH), 7.13 (d, 2H, J = 8.5 Hz, 4-ClC6H4 - A), 7.18 (d, 2H, J = 8.9 Hz, 4-ClC6H4 - B), 7.31 (d, 2H, J = 8.8 Hz, 4-ClC6H4 - B), 7.37 (d, 2H, J = 8.6 Hz, 4-ClC6H4 - A); (500.13 MHz, DMSO-d6) δ (ppm) 1.33 (t, 3H, J = 7.1 Hz, O−CH2− CH3), 4.35 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.49 (d, 2H, J = 5.1 Hz, CH2OH), 4.89 (t, 1H, J = 5.1 Hz, OH), 7.29 (d, 2H, J = 8.8 Hz, 4ClC6H4 - B), 7.34 (d, 2H, J = 8.6 Hz, 4-ClC6H4 - A), 7.49−7,53 (m, 4H, 4-ClC6H4 − A and B); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 54.9 (CH2OH), 62.1 (O-CH2−CH3), 124.7 (C4), 126.6 (4-ClC6H4 - A), 126.8, 129.4 (4-ClC6H4 - B), 129.4, 131.6 (4-ClC6H4 - A), 134.5 (4-ClC6H4 - B), 135.8 (4-ClC6H4 - A), 137.6 (4-ClC6H4 - B), 141.7 (C5), 142.9 (C3), 163.9 (COOEt); HRMS (ESI+): calcd for C19H17Cl2N2O3+, [M+H]+: 391.0611, found 391.0617. The 1H NMR (DMSO-d6) corresponded to literature.16 5-(4-Bromophenyl)-1-(4-chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-1H-pyrazole (4k). White solid; yield: 0.154 g (71%); mp 99.1−101.2 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.79 (t, 1H, J = 7.2 Hz, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.60 (d, 2H, J = 7.1 Hz, CH2OH), 7.07 (d, 2H, J = 8.4 Hz, 4-BrC6H4), 7.18 (d, 2H, J = 8.8 Hz, 4-ClC6H4), 7.31 (d, 2H, J = 8.8 Hz, 4-ClC6H4), 7.53 (d, 2H, J = 8.5 Hz, 4BrC6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2− CH3), 54.8 (CH2OH), 62.0 (O-CH2−CH3), 124.0 (4-BrC6H4), 124.6 (C4), 126.8 (4-ClC6H4), 127.0 (4-BrC6H4), 129.4 (4-ClC6H4), 131.7, 12600


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5-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-1-(4nitrophenyl)-1H-pyrazole (4q). Light yellow solid; yield: 0.134 g (67%); mp 135.0−136.7 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.72 (t, 1H, J = 7.2 Hz, OH), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.61 (d, 2H, J = 7.2 Hz, CH2OH), 7.16 (d, 2H, J = 8.4 Hz, 4-ClC6H4), 7.41 (d, 2H, J = 8.5 Hz, 4-ClC6H4), 7.45 (d, 2H, J = 9.1 Hz, 4-NO2C6H4), 8.21 (d, 2H, J = 9.1 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.6 (CH2OH), 62.2 (O-CH2−CH3), 124.7 (4NO2C6H4), 125.4 (C4), 125.6 (4-NO2C6H4), 126.2, 129.7, 131.4, 136.3 (4-ClC6H4), 141.9 (C5), 143.8 (C3), 143.8, 146.9 (4NO 2 C 6 H 4 ), 163.5 (COOEt); HRMS (ESI+): calcd for C19H17ClN3O5+, [M+H]+: 402.0851, found 402.0841. 5-(4-Bromophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-1-(4nitrophenyl)-1H-pyrazole (4r). Light yellow solid; yield: 0.160 g (72%); mp 125.3−127.3 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.72 (t, 1H, J = 7.2 Hz, OH), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.61 (d, 2H, J = 7.2 Hz, CH2OH), 7.09 (d, 2H, J = 8.5 Hz, 4-BrC6H4), 7.45 (d, 2H, J = 9.1 Hz, 4-NO2C6H4), 7.57 (d, 2H, J = 8.5 Hz, 4-BrC6H4), 8.21 (d, 2H, J = 9.0 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.6 (CH2OH), 62.2 (O-CH2−CH3), 124.6 (4BrC6H4), 124.7 (4-NO2C6H4), 125.4 (C4), 125.7 (4-NO2C6H4), 126.7, 131.7, 132.6 (4-BrC6H4), 141.9 (C5), 143.8 (4-NO2C6H4), 143.9 (C3), 146.9 (4-NO2C6H4), 163.5 (COOEt); HRMS (ESI+): calcd for C19H17BrN3O5+, [M+H]+: 446.0346, found 446.0327. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole (4s). Light yellow solid; yield: 0.156 g (85%); mp 177.0−178.8 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.77 (t, 1H, J = 7.2 Hz, OH), 4.54 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.63 (d, 2H, J = 7.2 Hz, CH2OH), 7.20−7.23 (m, 2H, Ph), 7.41−7.48 (m, 5H, Ph and 4-NO2C6H4), 8.17 (d, 2H, J = 9.2 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.7 (CH2OH), 62.2 (O-CH2−CH3), 124.5 (4-NO2C6H4), 125.3 (C4), 125.6 (4-NO2C6H4), 127.8, 129.3, 129.9, 130.2 (Ph), 143.1 (C5), 143.7 (C3), 144.0, 146.7 (4NO 2 C 6 H 4 ), 163.7 (COOEt); HRMS (ESI+): calcd for C19H18N3O5+, [M+H]+: 368.1241, found 368.1242. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-5-(4-methylphenyl)-1-(4nitrophenyl)-1H-pyrazole (4t). Light yellow solid; yield: 0.147 g (77%); mp 122.6−124.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 2.40 (s, 3H, 4CH3C6H4), 3.77 (t, 1H, J = 7.1 Hz, OH), 4.53 (q, 2H, J = 7.1 Hz, O− CH2-CH3), 4.62 (d, 2H, J = 5.9 Hz, CH2OH), 7.09 (d, 2H, J = 8.0 Hz, 4-CH3C6H4), 7.22 (d, 2H, J = 8.3 Hz, 4-CH3C6H4), 7.45 (d, 2H, J = 9.2 Hz, 4-NO2C6H4), 8.17 (d, 2H, J = 9.1 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 21.5 (4CH 3C 6 H4 ), 54.7 (CH2 OH), 62.1 (O-CH2 −CH 3 ), 124.5 (4NO2C6H4), 124.8 (4-CH3C6H4), 125.1 (C4), 125.5 (4-NO2C6H4), 130.0, 130.0, 140.1 (4-CH3C6H4), 143.2 (C5), 143.7 (C3), 144.1, 146.7 (4-NO2C6H4), 163.7 (COOEt); HRMS (ESI+): calcd for C20H20N3O5+, [M+H]+: 382.1397, found 382.1402. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-5-(4-methoxyphenyl)-1(4-nitrophenyl)-1H-pyrazole (4u). Light yellow solid; yield: 0.141 g (72%); mp 96.7−98.3 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.76 (t, 1H, J = 7.2 Hz, OH), 3.85 (s, 3H, 4-CH3OC6H4), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.62 (d, 2H, J = 7.0 Hz, CH2OH), 6.93 (d, 2H, J = 8.7 Hz, 4CH3OC6H4), 7.13 (d, 2H, J = 8.8 Hz, 4-CH3OC6H4), 7.46 (d, 2H, J = 9.1 Hz, 4-NO2C6H4), 8.18 (d, 2H, J = 9.1 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.8 (CH2OH), 55.4 (4-CH3OC6H4), 62.1 (O-CH2−CH3), 114.7, 119.8 (4-CH3OC6H4), 124.5 (4-NO2 C6H4), 125.0 (C4), 125.5 (4NO2C6H4), 131.5 (4-CH3OC6H4), 143.0 (C5), 143.6 (C3), 144.2, 146.7 (4-NO2C6H4), 160.7 (4-CH3OC6H4), 163.7 (COOEt); HRMS (ESI+): calcd for C20H20N3O6+, [M+H]+: 398.1347, found 398.1346.

132.3 (4-BrC6H4), 134.5, 137.5 (4-ClC6H4), 141.6 (C5), 142.8 (C3), 163.8 (COOEt); HRMS (ESI+): calcd for C19H17BrClN2O3+, [M +H]+: 435.0106, found 435.0112. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-5phenyl-1H-pyrazole (4l). White solid; yield: 0.155 g (87%); mp 68.3− 71.2 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.47 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.85 (bs, 1H, OH), 4.52 (q, 2H, J = 7.1 Hz, O− CH2-CH3), 4.63 (d, 2H, J = 3.4 Hz, CH2OH), 7.18−7.20 (m, 4H, Ph and 4-ClC6H4), 7.27 (d, 2H, J = 8.8 Hz, 4-ClC6H4), 7.36−7.42 (m, 3H, Ph); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2− CH3), 55.0 (CH2OH), 62.0 (O-CH2−CH3), 124.5 (C4), 126.8 (4ClC6H4), 128.2, 129.0 (Ph), 129.2 (4-ClC6H4), 129.4, 130.3 (Ph), 134.2, 137.8 (4-ClC6H4), 142.7, 142.8 (C3 and C5), 164.1 (COOEt); HRMS (ESI+): calcd for C19H18ClN2O3+, [M+H]+: 357.1000, found 357.1020. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-5-(4methylphenyl)-1H-pyrazole (4m). White solid; yield: 0.135 g (73%); mp 121.0−122.7 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 2.37 (s, 3H, 4-CH3C6H4), 3.84 (t, 1H, J = 7.2 Hz, OH), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.62 (d, 2H, J = 7.0 Hz, CH2OH), 7.06 (d, 2H, J = 8.1 Hz, 4-CH3C6H4), 7.17− 7.21 (m, 4H, 4-CH3C6H4 and 4-ClC6H4), 7.26−7.29 (m, 2H, 4ClC6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2− CH3), 21.5 (4-CH3C6H4), 55.0 (CH2OH), 61.9 (O-CH2−CH3), 124.4 (C4), 125.1 (4-CH3C6H4), 126.7 (4-ClC6H4), 129.2 (4-ClC6H4), 129.7, 130.1 (4-CH3C6H4), 134.1, 137.9 (4-ClC6H4), 139.5 (4CH3C6H4), 142.7, 142.9 (C3 and C5), 164.1 (COOEt); HRMS (ESI +): calcd for C20H20ClN2O3+, [M+H]+: 371.1157, found 371.1171. 1-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(hydroxymethyl)-5-(4methoxyphenyl)-1H-pyrazole (4n). White solid; yield: 0.147 g (76%); mp 144.7−146.1 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.46 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.80−3.83 (m, 1H, OH), 3.83 (s, 3H, 4-CH3OC6H4), 4.51 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.61 (d, 2H, J = 7.1 Hz, CH2OH), 6.89 (d, 2H, J = 8.8 Hz, 4-CH3OC6H4), 7.10 (d, 2H, J = 8.8 Hz, 4-CH3OC6H4), 7.20 (d, 2H, J = 8.8 Hz, 4-ClC6H4), 7.28 (d, 2H, J = 8.9 Hz, 4-ClC6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.5 (O−CH2−CH3), 55.0 (CH2OH), 55.4 (4-CH3OC6H4), 61.9 (O-CH2−CH3), 114.4, 120.2 (4-CH3OC6H4), 124.2 (C4), 126.7, 129.2 (4-ClC6H4), 131.6 (4-CH3OC6H4), 134.0, 137.9 (4-ClC6H4), 142.6 (C3), 142.7 (C5), 160.3 (4-CH3OC6H4), 164.1 (COOEt); HRMS (ESI+): calcd for C20H20ClN2O4+, [M+H]+: 387.1106, found 387.1101. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-1,5-bis(4-nitrophenyl)1H-pyrazole (4o). Light yellow solid; yield: 0.142 g (69%); mp 183.7− 185.9 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.49 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.70 (t, 1H, J = 7.1 Hz, OH), 4.54 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.63 (d, 2H, J = 7.2 Hz, CH2OH), 7.44−7.47 (m, 4H, 4-NO2C6H4 − A and B), 8.23 (d, 2H, J = 9.1 Hz, 4-NO2C6H4 - B), 8.29 (d, 2H, J = 8.8 Hz, 4-NO2C6H4 - A); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.5 (CH2OH), 62.4 (O-CH2−CH3), 124.4 (4-NO2C6H4 - A), 124.9, 125.8 (4-NO2C6H4 B), 126.1 (C4), 131.2, 134.2 (4-NO2C6H4 - A), 140.7 (C5), 143.4 (4NO2C6H4 - B), 144.1 (C3), 147.2 (4-NO2C6H4 - B), 148.5 (4NO2C 6H4 - A), 163.3 (COOEt); HRMS (ESI+): calcd for C19H17N4O7+, [M+H]+: 413.1092, found 413.1088. 3-(Ethoxycarbonyl)-4-(hydroxymethyl)-5-(4-fluorophenyl)-1-(4nitrophenyl)-1H-pyrazole (4p). Light yellow solid; yield: 0.135 g (70%); mp 163.7−164.6 °C; 1H NMR (500.13 MHz, CDCl3) δ (ppm) 1.48 (t, 3H, J = 7.1 Hz, O−CH2−CH3), 3.78 (t, 1H, J = 7.0 Hz, OH), 4.53 (q, 2H, J = 7.1 Hz, O−CH2-CH3), 4.61 (d, 2H, J = 6.4 Hz, CH2OH), 7.14 (t, 2H, 3JH−F = 8.5 Hz, J = 8.5 Hz, 4-FC6H4), 7.23 (dd, 2H, 4JH−F = 5.3 Hz, J = 8.7 Hz, 4-FC6H4), 7.46 (d, 2H, J = 9.1 Hz, 4NO2C6H4), 8.20 (d, 2H, J = 9.1 Hz, 4-NO2C6H4); 13C NMR (125.77 MHz, CDCl3) δ (ppm) 14.4 (O−CH2−CH3), 54.6 (CH2OH), 62.1 (O-CH2−CH3), 116.6 (d, 2J = 21.9 Hz, 4-FC6H4), 123.8 (d, 4J = 3.5 Hz, 4-FC6H4), 124.6 (4-NO2C6H4), 125.3 (C4), 125.6 (4-NO2C6H4), 132.2 (d, 3J = 8.6 Hz, 4-FC6H4), 142.1 (C5), 143.7 (C3), 143.8, 146.8 (4-NO2C6H4), 163.4 (d, 1J = 251.6 Hz, 4-FC6H4), 163.5 (COOEt); HRMS (ESI+): calcd for C19H17FN3O5+, [M+H]+: 386.1147, found 386.1141. 12601


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(13) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112. (14) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565. (15) Rosa, F. A.; Machado, P.; Fiss, G. F.; Vargas, P. S.; Fernandes, T. S.; Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. Synthesis 2008, 2008, 3639. (16) Chaudhari, S. S.; Thomas, A.; Gudade, G. B.; Khairatkar-Joshi, N.; Karni, P. PCT Int. Appl. WO 2009/095752 A1, 2009.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02361. Copies of 1H, 13C, and HMBC (expansion) NMR spectra for all new compounds (PDF) X-ray crystallographic data for compounds 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2n, and 3a (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Fernanda A. Rosa: 0000-0003-0027-7117 Notes

The authors declare no competing financial interest.

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REFERENCES

(1) (a) Rathelot, P.; Azas, N.; El-Kashef, H.; Delmas, F.; Di Giorgio, C.; Timon-David, P.; Maldonado, J.; Vanelle, P. Eur. J. Med. Chem. 2002, 37, 671. (b) Abdel-Wahab, B. F.; Khidre, R. E.; Farahatd, A. A. ARKIVOC 2011, 1, 196. (c) Huang, X. − F.; Lu, X.; Zhang, Y.; Song, G. − Q.; He, Q. − L.; Li, Q. − S.; Yang, X. − H.; Wei, Y.; Zhu, H.-L. Bioorg. Med. Chem. 2012, 20, 4895. (d) Ragab, F. A.; Gawad, N. M. A.; Georgey, H. H.; Said, M. F. Eur. J. Med. Chem. 2013, 63, 645. (e) Qin, Y. − J.; Xing, M.; Zhang, Y. − L.; Makawana, J. A.; Jiang, A.-Q.; Zhu, H. − L. RSC Adv. 2014, 4, 52702. (f) Fioravanti, R.; Desideri, N.; Biava, M.; Droghini, P.; Atzori, E. M.; Ibba, C.; Collu, G.; Sanna, G.; Delogu, I.; Loddo, R. Bioorg. Med. Chem. Lett. 2015, 25, 2401. (2) (a) Finar, I. L.; Lord, G. H. J. Chem. Soc. 1959, 1819. (b) Finar, I. L.; Manning, M. J. Chem. Soc. 1961, 2733. (3) (a) Kira, M. A.; Abdel-Rahman, M. O.; Gadalla, K. Z. Tetrahedron Lett. 1969, 10, 109. (b) De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. Synlett 2004, 2299. (4) (a) Zoppellaro, G.; Enkelmann, V.; Geies, A.; Baumgarten, M. Org. Lett. 2004, 6, 4929. (b) Catala, L.; Wurst, K.; Amabilino, D. B.; Veciana, J. J. Mater. Chem. 2006, 16, 2736. (5) Taydakov, I. V.; Krasnoselskiy, S. S.; Dutova, T. Y. Synth. Commun. 2011, 41, 2430. (6) (6) Raw, S. A.; Turner, A. T. Tetrahedron Lett. 2009, 50, 696. (7) (7) Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. B 1927, 60, 119. (8) (a) Rosa, F. A.; Machado, P.; Vargas, P. S.; Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. Synlett 2008, 2008, 1673. (b) da Silva, M. J. V.; Silva, R. G. M.; Melo, U. Z.; Gonçalves, D. S.; Back, D. F.; Moura, S.; Pontes, R. M.; Basso, E. A.; Gauze, G. F.; Rosa, F. A. RSC Adv. 2016, 6, 290. (c) Jacomini, A. P.; Silva, M. J. V.; Silva, R. G. M.; Gonçalves, D. S.; Volpato, H.; Basso, E. A.; Paula, F. R.; Nakamura, C. V.; Sarragiotto, M. H.; Rosa, F. A. Eur. J. Med. Chem. 2016, 124, 340. (d) Souza, T. F.; Silva, M. J. V.; Silva, R. G. M.; Gonçalves, D. S.; Simon, P. A.; Jacomini, A. P.; Basso, E. A.; Moura, S.; Martins, M. A. P.; Back, D. F.; Rosa, F. A. Asian J. Org. Chem. 2017, 6, 627. (9) Rosa, F. A.; Machado, P.; Rossatto, M.; Vargas, P. S.; Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. Synlett 2007, 2007, 3165. (10) (a) CCDC-1564288 (for 2a); (b) CCDC-1564287 (for 2b); (c) CCDC-1564286 (for 2c); (d) CCDC-1564285 (for 2d); (e) CCDC-1564290 (for 2e); (f) CCDC-1564282 (for 2f); (g) CCDC-1564283 (for 2g); (h) CCDC-1564291 (for 2n); (i) CCDC-1564294 (for 3a) contains the supplementary crystallographic data for this article. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre. (11) (a) Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122, 10405. (b) Lazic, V.; Jurkovic, M.; Jednacak, T.; Hrenar, T.; Vukovic, J. P.; Novak, P. J. Mol. Struct. 2015, 1079, 243. (12) Perrin, D. D.; Armarego, L. F. In Purication of Laboratory Chemicals, 3rd ed.; Pergamon Press: New York, 1996. 12602


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