An efficient protocol for accessing β-amino dicarbonyl compounds through aza-Michael reaction

SHORT REPORT

An efficient protocol for accessing β-amino dicarbonyl compounds through aza-Michael reaction

Ihssan Meskini^I; Loïc Toupet^II; Maria Daoudi^I; Abdelali Kerbal^I; Brahim Bennani^I; Pierre H. Dixneuf^III; Zahid H. Chohan^IV; Ana Cristina Lima Leite^V,*; Taibi Ben Hadda^VI,*

^ILaboratoire de Chimie Organique, Faculté des Sciences Dhar Mehraz, Fès, Morocco

^IIInstitut de Physique - IPR - UMR 6251, CNRS, Université de Rennes, 1, Rennes, France

^IIILaboratoire Catalyse et Organométalliques, Institut Sciences Chimiques de Rennes, UMR 6226, CNRS, University of Rennes, Av. Géneral Leclec, 35042 Rennes, France

^IVDepartment of Chemistry, Bahauddin Zakariya University, Multan 60800, Pakistan

^VDepartment of Pharmaceutical Science, Centre for Health Science, Federal University of Pernambuco, 50740-520 Recife-PE, Brazil

^VILaboratoire Chimie des Matériaux, Faculté des Sciences, 60000 Oujda, Morocco

ABSTRACT

β-Amino dicarbonyl compounds comprise a class of useful ligands on the coordination chemistry. In view of their importance, an efficient and facile method for the synthesis of β-amino dicarbonyl compounds has been developed, exploring the aza-Michael addition reactions in an aqueous medium. It was possible to achieve good to excellent yields, along with regioselectivity, the substituted diethyl 2-(phenylmethyl)malonates that were easily isolated without any chromatographic purification. The correct configuration of two of these β-amino dicarbonyl compounds were confirmed by X-ray crystallography. A complementary mechanism of this aza-Michael protocol is proposed to explain the results obtained.

Keywords: polydentate ligands, β-amino dicarbonyl compounds, Michael addition, aqueous medium

RESUMO

Compostos β-amino-dicarbonilados constituem uma classe de ligantes promissores para a química de coordenação. Diante desta perspectiva, um método eficiente e fácil visando à síntese de compostos β-amino-dicarbonilados foi desenvolvido, explorando a reação de adição do tipo azo-Michael em meio aquoso. Com isso, uma série de dez dietil 2-(feniletil)malonatos dissubstituídos foram obtidos de uma maneira regiosseletiva e facilmente purificados, levando à rendimentos satisfatórios. As análises cristalográficas de dois destes compostos forneceram as informações apropriadas sobre a conformação e configuração dos mesmos. Por último, uma proposta complementar do mecanismo reacional para as reações de adição de Michael em meio aquoso foi também descrito.

Introduction

The rational design of new HIV-1 Integrase (HI) inhibitors, a valid target for chemotherapeutic intervention,¹ is primarily based on intermolecular coordination between HI / chemical inhibitor / metals (Mg²⁺ and Mn²⁺, co-factors of the HI), leading to the formation of bimetallic complexes.^2,3 A number of bimetallic metal complexes, in many cases exploring the well-known polydentate ligands, appear therefore in this context to be the most promising drug candidates to HI inhibitors.^4,5 Another interesting application for such polydentate ligands involves the synergic water activation that occurs by way of the so-called 'remote metallic atoms'. Such organometallic compounds are considered in structural terms to block the intramolecular electron transfer on the HI structure.⁶ This explanation clearly demonstrates that polydentate ligands are of special interest in the field of bioorganometallic chemistry.⁷ In view of our interest in designing novel bimetallic coordinating ligands⁸ endowed with potential action to inhibit the HI enzyme, the object of this study is the synthesis of polydentate ligands with the same topology, as drawn in Figure 1.⁹

For preparation of such polydentate ligands, the aza-Michael reactions appear to be the key-step leading the expected β-amino esters adducts.¹⁰ In fact, this kind of reaction has been widely employed to generate structurally diverse β-amino dicarbonyl compounds, where the undoubted importance of the aza-Michael step can be seen from the large number of unconventional methodologies, as well as the broad range of applications.¹¹ Most of these unconventional methodologies have used Lewis acids, which although leading to satisfactory yields, require to remove the Lewis acids through tediously chromatography.¹² Moreover, the use of an aqueous medium also has been successful achieved.¹³ As a drawback, the use of substituted alkenes, such as benzylidene-malonic acid diethyl ester, is rarely reported in the literature. These substrates are expected to be less reactive or conversely more resistant to undergo the Michael condensation, resulting in low conversion of the desired adducts.¹⁴ For a synthetic point of view, this is a considerable limitation on the aza-Michael reaction process and poses a significant challenge.

To this end, we decided to investigate the feasibility of applying the aza-Michael reactions to the more challenging substituted alkene derivatives. Our plan also included the application of this key-step to the synthesis of a novel set of polydentate ligands, in order to highlight the versatility of the procedure as well as to generate some insights regarding the reaction mechanism.

Results and Discussion

Firstly, diethyl 2-benzylidenemalonates (4a-d) were prepared from the classical condensation of benzaldehydes with diethyl malonate under ethanol reflux, using piperidine and glacial acetic acid as a catalyst system. This procedure furnished the intermediates, 2-arylidene-malonic acid diethyl esters (4a-d), very quickly and in excellent yields (Scheme 1).

To understand the scope and limitations of the aza-Michael reactions, compound 6 was chosen as the model reaction because of its thermostability and also because piperidinyl is considerably less reactive when employing the traditional Michael protocols. Some of these conditions are presented in Table 1. During the investigation of experimental conditions, it was possible to observe that the acid catalyst (HOAc, 0.1 mL) accelerates such reactions. Interestingly, only a short reaction time (3 h) was required to furnish product 6 on very good yields with no detected by-products (Table 1, entries 4 and 5). In contrast, neither the presence of co-solvent (EtOH) nor the heating were crucial, the yields remaining similar to or lower than those expected when using pure water (entries 2 and 3). Boric acid also well works, but it was necessary additional purification by chromatography. Apart from the aqueous medium, the use of dichloromethane as solvent at catalyst-free condition led to low conversion (yield < 20%) of the desired product 6, in agreement with the previous results by Shou and colleagues.¹⁵

Having determined the best conditions, it was identified that precursors 4a-d reacted satisfactorily, albeit slowly, with various secondary amines under catalyst-free conditions to provide the desired adducts 6-15 in good to excellent yields, along with regioselectivity and without needs of column chromatography (Table 2). Moreover, the reactions proceeded normally even when the methoxy group was attached on aromatic ring (14 and 15), in contrast with the protocol described by Shou and colleagues.¹⁵ It is worth noting that the yields were found to be essentially the same as those obtained when the reactions were performed under either the presence or absence of the acid catalyst (HOAc). These results suggest that the acid catalyst accelerates the aza-Michael reactions under these substrates.

These products were characterized using spectroscopic and micro-analytical data. Compounds 8 and 9 were crystallized from ethanol solutions and gave single crystals suitable for X-ray analysis. These single crystals displayed centrosymmetric space groups for both compounds, indicative that each crystalline structure was composed of both enantiomers. An ORTEP view of the polydentate ligands 8 and 9 are shown in Figures 2 and 3, while the crystal data for these are reported in Table 3 and the bond lengths and angles of compound 9 are summarized in supplementary material. In the molecular structure of 9, the nitrogen (N2) and the two oxygen (O1 and O3) of the carbonyl groups are in cisoidal / transoidal conformations, with respective dihedral angles of the 0.04(1), 145.7(2) and 88.3(1) for the planes O1-C3-C6-O2, O1-C3-C1-N1 and O3-C6-C1-N1. We have note that after the trans addition around the C1=C2 double bond; the observed angles were quite different from 180º [H1-C1-C2-H2 = 176.9(2), C3-C2-C1-C9 = 56.9(1) and N1-C1-C2-C6 = 60.6(9)]. In fact, these untypical values were confirmed by the angle of atoms in trans positions, which was again different of 180º, as the example the [N1-C1-C2-H2 = -60.3(5)]. More unexpected, it was possible to observe that, in contrast with the polydentate ligand 8, the crystal structure of the ligand 9 was stabilized by one unusual intramolecular type-H bonding within the C-Cl^+δ...-δN=C, resulting in an interesting 3D network, as depicted in Figure 4.

In light of this interesting finding, we decided to apply several primary amines (arylamines, benzylamines, 1,4-phenylenediamine and unprotected amino acids) using this same synthetic protocol, but the presence of the desired products was no longer observed in all the cases using either prolonged reaction times or a large excess of amines. In contrast to secondary amines, which enabled functionalized polydentate compounds 6-15 to be obtained in good to excellent yields, the reaction of 4a-d with the primary amines (arylamines, benzylamine and para-phenylenediamine) in water did not furnish the expected polydentate ligands bearing the central RN-H group, either in the presence of the acid catalyst (HOAc) or with the addition of more than one equivalent of aniline.

Moreover, the mechanism for formation of the aza-Michael adducts should be mentioned. This is different from the Lewis acid-promoted aza-Michael reactions, in that such Lewis acids function by activating the unsaturated double bond, generating a nucleophilic attack by way of chelation of the 1,3-dicarbonyl core. More recently, Ranu and Banerjee¹³ have argued that the aqueous medium creates a dual action through the H-bonds, increasing the nucleophilic character of the nitrogen atom of the amine. This proposed mechanism would seem to present a plausible and satisfactory explanation of the formation of enol intermediates. To complement this, we would like to address the issue of why this protocol did not work well with primary amines. Since the chemical behaviour of primary and secondary amines undergoing these aza-Michael reactions is quite different, it is plausible to suggest that secondary amines in an aqueous medium probably give rise to the formation of ammonium species, which easily attacks the electrophilic alkene, thereby furnishing the unstable intermediate of addition with subsequent proton abstraction from protonated water by way of the enolate. On the other hand, using primary amines under aqueous medium probably results in the formation of ammonium salts. This implies that these ammonium salts are catalytically deactivated species or, conversely, less nucleophilic and thus less susceptible to attack from the respective alkenes (Scheme 2). Furthermore, the equilibrium steps occurring in the course of the aza-Michael reactions are probably the slowest, and are, consequently, speeded up when an acid catalyst is used. Additionally, a referee commented that the water effect in reactions with amines is more complex than dual activation. This statement is genuine and we agree with him. For instance, the nature of species generated from mixture of primary / secondary amines and water depends on the nucleophilicity of the employed amine.¹⁶ Likewise, solubilization of reactants and products in water is usually of relevancy to get desirable yields in such aza-Michael reactions.¹⁴

Conclusions

One important result of this study was a straightforward synthesis of ten novel 2-(aryl-disubstituted amino-1-yl-methyl)-malonic acid diethyl esters (6-15), which constitute a functionalized class of polydentate ligands. Despite prolonged reaction times, this aza-Michael protocol led to higher yields in an aqueous medium at room temperature, and consequently, would appear to be a simple and useful synthetic protocol. Considering their high efficiency on the gram-scale synthesis, in addition to the especially high purity of the final products, this protocol appears to be of use for synthesis and pharmacological screening of drug candidates.

Experimental

General methods

Synthesis of intermediates 4a-d

To a solution of ethyl malonate (15 g, 93 mmol) in 40 mL of ethanol, were added the respective aldehyde (100 mmol), 1.5 mL of piperidine and 1 mL of glacial acetic acid. Then, the mixture was stirred at refluxing temperature of ethanol for 12 h, until thin-layer chromatography indicated the complete consume of the starting material. After removing solvent, the crude product was washed with a saturated solution of sodium bisulfite (20 mL). The product was extracted by diethyl ether (2 × 20 mL), dried with sodium sulphate and evaporated to give the respective pure oil.

General procedure for the synthesis of compounds 6-15

To a solution of the intermediate 4a-d (8.1 mmol) in water (25 mL) was added the respective secondary amine (6 mmol) at the presence or absence of acetic acid (0.1 mL) and the mixture was stirred at room temperature until the complete consume of the starting material. After removing solvent, the crude products were dissolved in diethyl ether (2 × 40 mL) and washed with water until the pH became neutral. The organic solvent was dried with sodium sulphate and then evaporated to give the respective pure compound.

Acknowledgements

This work was funded by Project Global de Recherche de l'Université Mohamed Premier (PGR-UMP-BHT-2005, Morocco), Centre National de la Recherche Scientifique (CNRS, France), Brazilian Research National Council (CNPq, grant 479982/2008-2), National Institute of Research and Technology in Dengue (INCT-Dengue, grant 573876/2008-8, Brazil) and FACEPE PRONEX (grant APQ-0981-1.06/08). Authors acknowledge the referees and the editor of JBCS for their helpful comments and corrections.

Received: August 27, 2009

Web Release Date: February 1, 2010

Supplementary Information

Detailed experimental procedures, full set of ¹H and ¹³C NMR spectra and X-ray data are available free of charge at http://jbcs.sbq.org.br, as a PDF file.

General remarks

All common laboratory chemicals were purchased from commercial sources and used without further purification. Melting points were determined using a Thomas Hoover apparatus and are uncorrected. Infrared spectra were recorded on a Beckman 310 spectrometer as KBr pellets. The ¹H and ¹³C NMR spectra were recorded on Bruker AC 300 spectrometer and TMS as an internal standard. Coupling constants (J) are given in hertz. The FAB mass spectra were obtained on a Hewlett-Packard 5989A Mass Spectrometer (70 eV). Elemental analyses (C, N and H) were performed by the Service Central Analyses (CURI, Université Sidi Mohamed Ben Abdellah, Fès, Morocco) and the results lay within the acceptable range (±0.4%). CCD Saphire 3 Xcalibur diffractometer (Oxford Diffraction) with graphite monochromatized MoKa radiation was used to record the X-ray analysis.

General procedure

To a solution of ethyl malonate (15 g, 93 mmol) in 40 mL of ethanol, were added the respective aldehyde (100 mmol), 1.5 mL of piperidine and 1 mL of glacial acetic acid. Then the mixture was stirred at refluxing temperature of ethanol for 12 h, until thin-layer chromatography indicated the complete consume of the starting material. After removing solvent, the crude product was washed with a saturated solution of sodium bisulfite (20 mL). The product was extracted by diethyl ether (2 x 20 mL), dried with sodium sulphate and evaporated to give the respective pure oil.

Diethyl 2-benzylidenemalonate (4a): Yellow oil, 71% of yield, Rf 0.7 (ether/n-hexane, 1/1). IR (KBr): n_max/cm^-1 2875-2982 (CH), 1722 (C=O), 1629 and1497 (C=C), 1294-1254 (C-O). ¹H NMR (300 MHz, CDCl₃) δ: 1.25 (t, 3H, H₂C-CH_3, ³J 7.1 Hz), 1.31 (t, 3 H, CH₂-CH₃, ³J 7.1 Hz), 4.28 (q, H, CH₂-CH₃, ³J 7.2 Hz), 4.32 (q, 2H, CH₂-CH₃, ³J 7.2 Hz), 7.45-7.32 (m, 5H, Ph), 7.72 (s, 1H, C=CH-Ph). ¹³C NMR (75.5 MHz, CDCl₃) δ: 61.6/61.6 (2C, 2CH₂-CH₃), 14.1/13.8 (2C, 2CH₂-CH₃), 126.1 (C_quat, =C-), 128.7 (2C_tert, ortho), 129.4 (C_tert, para), 130.5 (2C_tert, meta), 132.8 (C_quat, Ph), 142.0 (Ph-CH), 166.6 and 166.2 (2C=O). MS (IE): Calc. for [M]⁺ C₁₄H₁₆O₄: 248, [M+H]⁺ (m/z) = 249 (100%).

Diethyl 2-(4-chlorobenzylidene)malonate (4b): Yellow oil, 77% yield, Rf 0.73 (ether/hexane, 1/1). IR (KBr): n_max/cm^-1 2906-2982 (CH), 1724 (CO) 1591/1631 (C=C), 1254/1308 (C-O). ¹H NMR (300 MHz, CDCl₃) δ: 1.31-1.25 (2 t, 6H, 2H₂C-CH₃, ³J 7.11 Hz), 4.31-4.4 (2 q, 4H, 2CH₂-CH₃, ³J 7.12 Hz), 7.45-7.30 (m, 4H, Ph), 7.7 (s, 1H, C=CH-ph). ¹³C NMR (75.5 MHz, CDCl₃)δ: 13.7 and 13.8 (2CH₃-CH₂), 61.4 and 61.7 (2CH₂-CH₃), 125.4 (C=C-(CO₂Et)₂), 129.0 (2C_ortho), 130.3 (2C_meta), 130.4 (C_quat, para/Cl), 132.9 (C_quat, C-Cl-Ph), 140.0 (ClPh-CH=), 166.3 and 163.8 (2C=O). MS (IE): Calc. for [M]⁺ C₁₄H₁₅ClO₄: 282.07; [M+H]^+. = 283 (100%).

Diethyl 2-(3-methoxybenzylidene)malonate (4c): Yellow oil, 70% yield, Rf 0.53 (ether/hexane, 2/1). IR (KBr): n_max/cm^-1 2906-2982 (CH), 1754 (C=O), 1254/1308 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.31-1.25 (2 t, 6H, 2H₂C-CH₃, ³J 7.11 Hz), 4.31-4.4 (m, 4H, 2CH₂-CH₃), 4.01 (s, 3H, CH₃O), 7.30 -7.45 (m, 4H, Ph), 7.4 (s, 1H, C=CH-Ph). ¹³C NMR (75.5 MHz, CDCl₃)δ: 13.7 and 14.0 (2CH₃-CH₂), 61.4 and 60.1 (2CH₂-CH₃), 125.4 (C=C-(CO₂Et)₂), 125.4 (C=C-(CO₂Et)₂), 129.0 (2C_ortho), 130.3 (2C_meta), 130.4 (C_quat, para/CH₃O), 132.9 (C_quat, Ph-OMe), 140.0 (Ph-CH=), 166.3 and 163.8 (2C=O). Elemental analysis for C₁₅H₁₈O₅ Calc. (Found): C 64.74 (65.03) H 6.52 (6.32)%.

General procedure for the synthesis of 6-15

To a solution of the intermediate 4a-d (8.1 mmol) in water (25 mL) was added the respective secondary amine (6 mmol) at the presence or absence of acetic acid (0.1 mL) and the mixture was stirred at room temperature until the complete consume of the starting materials. After removing solvent, the crude products were dissolved in diethyl ether (2 × 40 mL) and washed with water until the pH became neutral. The organic solvent was dried with sodium sulphate and then evaporated to give the respective pure compound.

Diethyl 2-(phenyl(piperidin-1-yl)methyl)malonate(6): White powder, mp 67-68 ºC. Rf = 0.72 (ether/hexane, 1/1). IR (KBr): n_max/cm^-1 2848-2974 (C-H, Ph), 2754/2800 (C-H, aliph), 1750/1740 (C=O), 1514/1450 (C=C), 1313/1257 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.00 (t, 3H, H₂C-CH₃,³J 7.1 Hz); 1.26 (m, 2H, -C^3'H₂-,piper)_, 1.35 (t, 3H, H₂C-CH₃,³J 7.1 Hz), 1.50 (m, 4H, 2C^2'H₂, piper), 2.20 (s large, 2H, C^1'H₂, piper), 2.59 (s large, 2H, C^1'H₂ , piper), 4.02 (dq, 2H_AB, O-CH₂ -CH₃, ²J_A-B 10.7 Hz, ³J 6.9 Hz), 4.23 (d, 1H, C²H-(CO₂Et)₂, ³J 12.1 Hz), 4.33 (dq, 2H, O-CH₂ -CH₃, J_A-B 0.2 Hz, ³J 7.1 Hz), 4.43 (d, 1H, ph-C³H, ³J 12 Hz), 7.15-7.34 (m, 5H, Ph). ¹³C NMR (75.5 MHz, CDCl₃)δ: 14.30/13.75 (2C, 2OCH₂CH₃), 24.40 (C, C^3'H₂, piper), 26.50 (2C, 2C^2'H₂, piper), 50.55 (2C, 2C^1'H₂, piper), 54.96 (C_tert, C²H(CO₂Et)₂), 61.30/ 61.15 (2C, 2OCH₂CH₃), 69.15 (C_tert, PhC²H), 127.53 (2C_tert, meta, Ph), 127.80 (C_tert, para,Ph), 128.69 (2C_tert, ortho, Ph), 133.93 (C_quat, Ph), 167.22/168.04 (2C=O). MS (IE): Calc. for [M]⁺ C₁₉H₂₇NO₄^: 333.19, [M+H]⁺ (m/z) = 334 (35%), 174 (100%). Elemental analysis for C₁₉H₂₇NO₄ Calc. (Found): C 68.46 (67.89), H 8.40 (7.89), N 4.20 (4.22)%.

Diethyl 2-((4-chlorophenyl)(morpholino)methyl)malonate(7): White crystals, mp 68-69 ºC. Rf = 0.55 (ether/ hexane: 1/1). IR (KBr): n_max/cm^-1 2935-2985 (C-H, 4-Cl-Ph), 2826-2887 (C-H), 1747 (C=O), 1712 (C=O), 1590-1489 (C=C), 1306-1258 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.06 (t, 3H, OCH₂CH₃, ³J 7.1 Hz), 2.30 (s, 2H, C^1'H₂), 2.53 (s, 2H, C^1'H₂), 3.93 (s, 4H, C²'H₂OC^2'H₂), 3.90-4.07 (m, 2H, OCH₂CH₃), 4.20 (d, 1H, C²H (CO₂Et)₂, ³J 10.3 Hz), 4.25-4.39 (m, 3H, OCH₂CH₃ + PhC³H), 7.12 (d, 2H, meta, ³J 8.30 Hz), 7.35 (d, 2H, ortho, ³J 8.30 Hz). ¹³C NMR (75.5 MHz, CDCl₃)δ: 13.8 (C, OCH₂CH₃, ester), 14.3 (C, OCH₂CH₃, ester), 49.5 (2C, 2 C¹'H₂N, morph), 54.6 (C_tert, C²H(CO₂Et)₂), 61.5 (C, CH₂OCH₃, ester), 61.6 (C, CH₂OCH₃, ester), 67.1 (2C, 2C^2'H₂O, morph), 68.0 (C_tert, C³H-Ph), 128.4 (C_tert, 2C-meta, Ph), 130 (C_tert, 2C-ortho, Ph), 131.8 (C_quat, Ph, para/Cl), 134.8 (C_quat, CCl, Ph), 167.6 (2 C=O). 2D NMR experiments have confirmed the signals observed and the different correlations of homo and heteronuclear. MS (IE): Calc. for [M]⁺ C₁₈H₂₄ClNO₅: 369.13, [M+H]⁺ (m/z) = 370 (15%), [M-CH(CO₂Et)₂]⁺ (m/z) = 210 (100%). Elemental analysis for C₁₈H₂₄NO₅Cl Calc. (Found): C 58.53 (58.60), H 6.50 (6.71), N 3.79 (4.03)%.

Diethyl 2-((3,5-dimethyl-pyrazol-1-yl)(phenyl)methyl)malonate (8): White powder, mp 86-88 ºC. Rf = 0.69 (ether/hexane: 1/1). IR (KBr): n_max/cm^-1 2868-2974 (C-H), 1747/1719 (C=O), 1586/1554 (C=C), 1460/1419 (C=N), 1269/1264 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 0.98 (t, 3H, CH₂CH₃, ³J 7.1 Hz), 1.17 (t, 3H, CH₂CH₃, ³J 7.1 Hz), 2.21 (s, 1H, C^3'H, pyrazol), 2.25 (s, 1H, C^1'H, pyrazol), 3.97(q, 2H, OCH₂CH₃, ³J 7.1 Hz), 4.16-3.99 (2q, 2H, OCH₂CH₃, ³J 7.3 Hz), 4.9 (d, 1H, PhC³HC²H, ³J 11.4 Hz), 5.74 (s, 1H, H^2', pyrazol), 7.45-7.25 (m, 5H, Ph), 7.78 (d, 1H, ph-C³H, ³J 11.2 Hz). ¹³C NMR (75.5 MHz, CDCl₃)δ: 13.67 (C, C^3'H₃, pyrazol), 13.64/10.06 (2C, 2CH₂CH₃), 13.87 (C, C^1'H3, pyrazol), 57.52 (C_tert, Ph-C³HC²H), 60.35 (C_tert, PhC³HC²H), 61.57 (2C, 2CH₂CH₃), 105 (C_tert, C^2'H, pyrazol), 128.50/128.3/127.93 (5C, Ph), 137.30 (C_quat, C^3', pyrazol), 139.30 (C_quat, Ph), 147.3 (C_quat, C^1', pyrazol), 166.90/166.85 (2C=O). MS (IE): Calc. for [M]⁺ C₁₉H₂₄N₂O₄: 344.17, [M+H]⁺ (m/z) = 345 (11%), 83 (100%). Elemental analysis for C₁₉H₂₄N₂O₄ Calc. (Found): C 66.27 (65.71), H 6.97 (5.80), N 8.13 (8.78)%.

Diethyl 2-((4-chlorophenyl)(3,5-dimethyl-pyrazol-1-yl)methyl)malonate (9): White powder, mp 77-79 ºC. Rf = 0.68 (ether/hexane: 1/1). IR (KBr): n_max/cm^-1 2969 (C-H , Ph), 2674/2806 (C-H), 1747/1720 (C=O), 1592/1464 (C=C), 1329/ 1256 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 7.32-7.29 (m, 2H, aromatic), 7.14-7.18 (m, 2H, Ph), 4.5 (d, 1H, PhC³H, ³J 11.40 Hz), 4.25 (q, 2H, CH₂OCH₃, ³J 7.1 Hz), 4.09 (d, 1H, C²H(CO₂Et)₂, ³J 11.40 Hz), 3.95 (m, 2H, CH₂OCH₃), 2.49 (m, 2H, N-C^1'H₂, pyrazole), 2.35 (m, 2H, NC^1'H₂, pyrazole), 1.59 (m, 4H, 2C^1'H₂C^2'H₂, pyrazole), 1.30 (t, 3H, OCH₂CH₃, ³J 7.1 Hz), 1.03 (t, 3H, OCH₂CH₃, ³J 7.1 Hz). ¹³C NMR (75.5 MHz, CDCl₃)δ: 166.97/167.88 (2C=O), 133.35 (C_quat, CCl, Ph), 133.22 (C_quat, Ph, para/Cl), 130.35 (C_tert, 2C ortho, Ph), 128.05 (C_tert, 2C meta, Ph), 64.05 (C_tert, C³HPh), 61.40 (C, OCH₂CH₃, ester), 61.30 (C, OCH₂CH₃, ester), 56.50 (C_tert, C²H(CO₂Et)₂), 48.41/46.88 (2C, 2C¹'H₂N, pyrazole), 22.84 (2C, 2C¹'H₂C^2'H₂), pyrazole), 13.91/14.12 (2C, 2OCH₂CH₃). MS (IE): Calc. for [M]⁺ C₁₈H₂₄ClNO₄: 353.14, [M+H]⁺ (m/z)=354 (18%), [M-CH(CO₂Et)₂]⁺ (m/z)=194 (100%), [M-pyrol]⁺ (m/z) = 283. Elemental analysis for C₁₈H₂₄NO₄Cl Calc. (Found): C 62.12 (62.10), H 7.08 (7.28), N 3.18 (4.04)%.

Diethyl 2-((4-chlorophenyl)(pyrazol-1-yl)methyl)malonate (10): White crystals, mp 87-89 ºC. Rf = 0.65 (ether/hexane; 1/1). IR (KBr): n_max/cm^-1 2896/2985 (CH), 1748 (C=O), 1514/1595 (C=C), 1292/1308 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 7.5 (d, 2H, C^3'H, C⁵H, pyrazol, ³J 14.27 Hz), 7.28-7.44 (m, 4H, Ph, ³J 8.68 Hz), 6.20 (t, 1H, pyrazol, ³J 2.08 Hz), 5.85 (d, 1H, PhC³H, ³J 11.33 Hz), 4.80 (d, 1 H, C²H(CO₂Et)₂, ³J 11.33 Hz), 4.10 (dq, 2H_AB, OCH₂CH_3, J_AB 14.32 Hz, ³J 7.11 Hz), 4.01 (dq, 2H_AB, OCH₂CH_3,J_AB 14.32 Hz, ³J 7.11 Hz), 2.25 (s, 3H, CH₃, pyrazol), 2.20 (s, 3H, CH₃, pyrazol), 1,13 (t, 3H, OCH₂CH₃, ³J 7.11 Hz), 1.04 (t, 3H, OCH₂CH₃, ³J 7.11 Hz). ¹³C NMR (75.5 MHz, CDCl₃)δ: 166.36 (C=O), 166.26 (C=O), 147.65 (C_quat, pyrazol), 139.3 (C_quat, pyrazol), 135.7 (C_quat, CCl, Ph), 134.62 (C_quat, Ph, para/Cl), 129.83 (C_tert, 2C meta, Ph), 128.7 (C_tert, 2C ortho, Ph), 129.27 (C_tert, C^3'C^4', pyrazol), 105.45 (C_tert, C⁴H, pyrazol), 61.75/ 61.70 (C_sec, 2CH₂, ester), 59.55 (C_tert, C³HPh), 57.45 (C_tert, C²H(CO₂Et)₂), 13.87 (C, OCH₂CH₃, ester), 13.75 (C, OCH₂CH₃, ester), 13.66 (C, CH₃, pyrazol), 10.95 (CH₃, pyrazol). MS (IE): Calc. for [M]⁺ C₁₇H₁₉N₂O₄Cl: 350.5, [M+H]⁺ (m/z) = 351 (15%), [M-CH(CO₂Et)₂]⁺ (m/z) = 191 (100%), [M-pyrol] ⁺ (m/z) = 283 (21%). Elemental analysis for C₁₈H₂₄ClNO₄ Calc. (Found): C 64.55 (64.46), H 6.32 (6.62), N 8.86 (9.06)%.

Diethyl 2-((4-chlorophenyl)(piperidin-1-yl)methyl)malonate (11): White powder, mp 63-65 ºC. Rf = 0.65 (ether/hexane: 1/1). IR (KBr): n_max/cm^-1 2973/2930 (aromatic C-H, Ph), 2797/2848 (aliphatic C-H), 1755 (C=O), 1737 (C=O), 1493/1452 (C=C), 1312/1257 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.05 (t, 3H, OCH₂CH₃, ³J 7.10 Hz), 1.26 (m, 2H, 2N(CH₂)₂C ^3'H₂, ³J 5.9 Hz), 1.35 (t, 3H, OCH₂CH₃, ³J 7.10 Hz), 1.48 (m, 4 H, NC ^1'H₂C^2'H₂), 2.16 (m, 2H, NC^1'H₂), 2.46 (m, 2H, NC ^1'H₂), 4.16* (d, H, C²H(CO₂Et)₂, ³J 12.10 Hz), 4.35* (d, H, PhC³H, ³J 12.20 Hz); 4.02 (dq, 2H_AB, OCH₂CH₃, J_AB 11.3 Hz); 4.30 (dq, 2H_AB, OCH₂CH₃, J_AB 10.7 Hz); 7.1 (d, 2H, aromatic-ortho, ³J 10.7 Hz), 7.32 (d, 2H, aromatic-meta, ³J 10.9 Hz). ¹³C NMR (75.5 MHz, CDCl₃)δ: 14.3 and 13.8 (2C, 2CH₃, esters), 24.40 (C, N(CH₂)₂C^3'H₂), 26.4 (2C, 2C²'H₂CH₂N), 50.51 (2C, 2C^1'H₂N), 54.95 (C_tert, C²H(CO₂Et), 61.4 and 61.3 (2C, 2CH₂CH₃, ester), 69.5 (C_tert, C³HPh), 129.9 (C_tert, 2C meta/Ar), 128.04 (C_tert, 2C ortho/Ar), 132.6 (C_quat, para/Cl), 133.4 (C_quat, ClC), 167.03 (C=O), 167.71 (C=O). MS (IE): Calc. for [M]⁺ C₁₉H₂₆ClNO₄: 367.16, [M+H]⁺ (m/z) = 368 (16%), [M-CH(CO₂Et)₂]⁺ (m/z) = 208 (100%), [M-PhCl]⁺ (m/z) = 256. Elemental analysis for C₁₉H₂₆NO₄Cl Calc. (Found): C 62.12 (62.10), H 7.08 (7.28), N 3.18 (3.14)%.

Diethyl 2-((benzyl(ethyl)amino)(4-chlorophenyl)methyl)malonate (12): White crystals, mp 70-72 ºC. Rf = 0.56 (ether/hexane: 1/1). IR (KBr): n_max/cm^-1 2808/2985 (CH); 1732 (C=O), 1594/1595 (C=C), 1248/1291 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.30 (t, 3H, OCH₂CH₃ , ³J 7.07 Hz); 2.1 (m, 1H, CHCH₃, ³J 12.90 Hz), 1.01 (t, 3H, OCH₂CH₃ , ³J 7.07 Hz), 2.55 (m, 1H, CHCH₃, ³J 12.90 Hz), 2.9 (d, 1H, CH-Ph, ³J 13.80 Hz ), 3.9 (d, 1H, CH-Ph, ³J 13.80 Hz), 4.01 (dq, 2H_A-B, OCH₂CH_3, J_AB 14.10 Hz, ³J 7.07 Hz), 4.24 (d, 1H, C²H(CO₂Et)₂, ³J 12.30 Hz), 4.30 (dq, 2H_AB, OCH₂CH_3, J_AB 14.10 Hz, ³J 7.07 Hz), 4.62 (d, 1H, ClPhC³H, ³J 12.30 Hz), 7.23-7.1 (m, 5H, aromatic, ³J 4.42 Hz), 7.24-7.37 (m, 4H, PhCl, ³J 8.43 Hz). ¹³C NMR (75.5 MHz, CDCl₃)δ: 13.41 (C, NCH₂CH₃), 13.79 (C, OCH₂CH₃, ester), 14.07 (C, 2OCH₂CH₃, ester), 54.21 (C_sec, NCH₂CH₃), 55.47 (C_tert, C²H(CO₂Et)₂), 61.75 (C_tert, C³HPhCl), 61.75/61.70 (C_sec, 2CH₂, ester), 126.91 (C_tert, 2C para, Ph), 167.84 (C-O), 128.15 (C_tert, 2C ortho, Ph), 128.15 (C_tert, 2C ortho, Ph-Cl), 128.28 (C_tert, 2C meta, Ph), 130.81 (C_tert, 2C meta, Ph-Cl), 133.54 (C_quat, Ph, para/Cl), 139.41 (C_quat, CCl, Ph), 166.93 (C=O). MS (IE): Calc. for [M]⁺ C₂₃H₂₈ClNO₄: 417.5, [M+H]⁺ (m/z)= 418 (12%), [M-CH(CO₂Et)₂]⁺ (m/z) = 258 (100%), [M- N(CH₂Ph,C₂H₅)]⁺ (m/z) = 283. Elemental analysis for C₂₃H₂₈ClNO₄ Calc. (Found): C 66.18 (65.53), H 6.71 (6.66), N 3.35 (3.55)%.

Diethyl 2-((4-chlorophenyl) (pyrrolidin-1-yl)methyl) malonate (13): White crystals, mp 81-83 ºC. Rf = 0.67 (ether/hexane: 1/1). IR (KBr): n_max/cm^-1 2981/2935 (CH); 1764 (C=O), 1594/1554 (C=C), 1490/1463 (C=N), 1300/1257 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.04 (t, 3H, OCH₂CH₃, ³J 7.1 Hz), 1.16 (t, 3H, OCH₂CH₃, ³J 7.1 Hz), 2.20 (s, 3H, CH₃, pyrazol), 2.25 (s, 3H, CH₃, pyrazol), 4.0 (dq, 2H_AB, OCH₂CH_3, J_AB 14.3 Hz, ³J 7.2 Hz); 4.12 (dq, 2H_AB, OCH₂CH_3, J_AB 14.3 Hz, ³J 7.2 Hz), 4.84 (d, 1H, C²H(CO₂Et)₂, ³J 11,3 Hz), 5.70 (d, 1H, PhC³H, ³J 11.3 Hz), 5.74 (s, 1H, pyrazol), 7.25-7.44 (m, 4H, Ph, ³J 8.25 Hz). ¹³C NMR (75.5 MHz, CDCl₃)δ: 10.95 (CH₃, pyrazol), 13.66 (CH₃-pyrazol), 13.75 (OCH₂CH₃, ester), 13.87 (OCH₂CH₃, ester), 57.45 (C_tert, C²H(CO₂Et)₂), 59.55 (C_tert, C³HPh), 61.75/61.70 (C_sec, 2CH₂, ester), 105.45 (C_tert, CH, pyrazol), 128.7 (C_tert,2C ortho, Ph), 129.4 (C_tert, 2C meta, Ph), 134.25 (C_quat, Ph, para/Cl), 138.9 (C_quat, CCl, Ph), 139.3 (C_quat, pyrazol), 147.65 (C_quat, pyrazol), 166.60 (C=O), 166.75 (C=O). MS (IE): Calc. for [M]⁺ C₁₉H₂₃ClN₂O₄: 378.13, [M+H]⁺ (m/z) = 379 (17%), [M-CH(CO₂Et)₂]⁺ (m/z) = 219 (100%), [M-pyrazol)]⁺ (m/z) = 283. Elemental analysis for C₁₉H₂₃N₂O₄Cl Calc. (Found): C 60.31 (60.43), H 6.08 (6.05), N 7.40 (7.69)%.

Diethyl 2-((3-methoxyphenyl)(piperidin-1-yl)methyl)malonate (14): White crystals, mp 98 ºC. Rf = 0.70 (ether/hexane: 2/1). IR (KBr): n_max/cm^-1 1760 (C=O), 1320/1277 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.30 (t, 3H, OCH₂CH₃, ³J 9.0 Hz), 1.58 (t, 3H, OCH₂CH₃, ³J 9.0 Hz), 2.45-2.30 (m, 2H, NC^1'H₂), 2.58-2.66 (m, 2H, NC^1'H₂), 4.19 (dq, 2H_AB, OCH₂CH₃, J_AB 10 Hz), 4.07 (s, 3H, CH₃OPh), 4.38 (dq, 2H_AB, OCH₂CH₃, J_AB 10 Hz); 4.73 (d, H, PhC³H, ³J 10 Hz); 7.03 (d, 2H, Ph), 7.25 (d, 2H, Ph). ¹³C NMR (75.5 MHz, CDCl₃)δ: 14.3 and 14.5 (2C, 2CH₃, ester), 22.10 (C, N(CH₂)₂C^3'H₂), 24.8 (2C, 2C²'H₂CH₂N), 50.1 (2C, 2C^1'H₂N), 54.1 (C_tert, C²H(CO₂Et), 58.3 (C_tert, C³HPh), 60.5 (CH₃OPh), 61.9 and 62.3 (2C, 2CH₂CH₃, ester), 119.6 (C_tert), 130.5 (C_tert), 159.3 (C_quat, CH₃OC), 137.2 (C_quat), 175.1 (C=O), 176.7 (C=O). MS (IE): Calc. for [M]⁺ C₂₀H₂₉NO₅: 363.56, [M+H]⁺ (m/z) = 364 (10%), [M-CH(CO₂Et)₂]⁺ (m/z) = 204 (100%). Elemental analysis for C₂₀H₂₉NO₅ Calc. (Found): C 66.09 (66.12), H 8.04 (8.14), N 3.85 (3.89)%.

Diethyl 2-((4-methoxyphenyl)(piperidin-1-yl)methyl)malonate (15): White crystals, mp 101 ºC. Rf = 0.71 (ether/hexane: 2/1). IR (KBr): n_max/cm^-1 2981/2935 (CH); 1764 (C=O), 1280/1277 (C-O). ¹H NMR (300 MHz, CDCl₃)δ: 1.35 (t, 3H, OCH₂CH₃, ³J 7.0 Hz), 1.51 (t, 3H, OCH₂CH₃, ³J 7.0 Hz), 2.45 (m, 2H, NC^1'H₂), 2.76 (m, 2H, NC^1'H₂), 4.05 (s, 1H, CH₃O), 4.35 (dq, 2H_AB, OCH₂CH₃, J_AB 10 Hz), 4.48 (dq, 2H_AB, OCH₂CH₃, J_AB 11.3 Hz), 4.81 (d, H, PhC³H, ³J 10 Hz); 7.58-7.69 (m, 4H, Ph). ¹³C NMR (75.5 MHz, CDCl₃)δ: 15.0 and 14.8 (2C, 2CH₃, ester), 22.10 (C, N(CH₂)₂C^3'H₂), 25.2 (2C, 2C²'H₂CH₂N), 48.61 (2C, 2C^1'H₂N), 56.15 (C_tert, C²H(CO₂Et), 58.3 (C_tert, C³HPh), 61.4 and 61.3 (2C, 2CH₂CH₃, ester), 113.10 (C_tert), 129.9 (C_tert), 132.6 (C_quat), 153.1 (C_quat, CH₃OC), 172.71 (C=O), 171.00 (C=O), MS (IE): Calc. for [M]⁺ C₂₀H₂₉NO₅: 363.57, [M+H]⁺ (m/z) = 364 (19%), [M-CH(CO₂Et)₂]⁺ (m/z) = 204 (100%). Elemental analysis for C₂₀H₂₉NO₅ Calc. (Found): C 66.09 (65.92), H 8.04 (8.02), N 3.85 (3.68)%.

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Publication Dates

• Publication in this collection
  19 July 2010
• Date of issue
  2010

History

• Received
  27 Aug 2009
• Accepted
  01 Feb 2010