Synthesis and Crystal Structure of Two Nitro-Regioisomers of cis-4(4-Methoxyphenyl)-3-Methyl-2-Phenyl-l,2,3,4-Tetrahydroquinoline

Síntesis y estudio de la estructura cristalina de dos nitro regio-isómeros de la cis-4-(4-metoxifenil)-3-metil-2-fenil-1,2,3,4-tetrahydroquinolina

Arnold R. Romero Bohórquez1*, Teresa González2 and Vladimir V Kouznetsov1

1Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander. A.A. 678, Bucaramanga, Colombia.
2Laboratorio de Síntesis y Caracterización de Nuevos Materiales, Centro de Química, Instituto Venezolano de Investigaciones Científicas (TVIC). Apartado 21827, Caracas, Venezuela.
*Edited by Alberto Acosta & Josefina Jover de la Prida

Received: 14-12-2012 Accepted: 26-02-2013 Published on line: 26-02-2013


Here we synthesized two nitro regioisomers of cis-4-(4-methoxyphenyl)-3-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline via the "one pot" three-component imino Diels-Alder reaction catalyzed by BF3.OEt2 and completed its structural characterization using the single crystal X-ray diffraction technique and other spectroscopic methods. To monitor the purity of the products and the composition of the reaction mixtures we used thin layer chromatography, and isolated and purified the products by column chromatography. Then using nuclear magnetic resonance (NMR) and mass spectrometry (MS) identified the substances. We collected X-ray diffraction data for crystal characterization by using a Bruker AFC7S Mercury diffractometer with MoKa radiation (λ = 0.71073Å) at room temperature. The structures of these regioisomers were confirmed by 1H NMR and 13C NMR studies and studied their crystal structure using single crystal X-ray diffraction technique. The spectroscopy analyses (NMR, GC-MS and X-ray diffraction) provided a complete characterization and enabled the correct stereochemistry for the tetrahydroquinoline ring. We determined the molecular packing for the 5-nitro regioisomer 4 is the product of the combination of intermolecular hydrogen bonds and van der Waals interactions, while for 7-nitro regioisomer 3 is mainly due to weak intermolecular van der Waals interactions and N—H···π.

Keywords: Tetrahydroquinolines, Imino Diels-Alder reaction, nitro-regioisomers, single crystal X-ray diffraction


Dos nitro-regioisómeros de la molécula cis-4-(4-metoxifenil)-3-metil-2-fenil-1,2,3,4-tetrahydroquinolina fueron preparados vía una síntesis one-pot de tres componentes basada en la reacción de cicloadición imino Diels-Alder catalizada por BF3.OEt2. Su completa caracterización estructural se llevó a cabo usando la técnica de difracción de rayos-X de monocristal y métodos espectroscópicos. La pureza de los productos y la composición de las mezclas de reacción fueron monitoreadas por cromatografía en capa fina (CCD). Los productos fueron aislados y purificados usando cromatografía en columna. Las sustancias fueron identificadas usando resonancia magnética nuclear (RMN) y espectrometría de masas (EM). Los datos para la caracterización por difracción de rayos-X fueron colectados usando un difractómetro Bruker AFC7S Mercury con radiación de Mo-Κα (λ = 0.71073Å) a temperatura ambiente. Las estructuras de los regio-isómeros fueron confirmadas por 1H RMN y 13C RMN y la estructura cristalina fue estudiada usando la difracción de rayos-X de monocristal. El análisis espectroscópico (RMN, EM y difracción de rayos-X) mostró una completa caracterización y permitió establecer la correcta estereoquímica para el anillo tetrahidroquinolínico. El empaquetamiento molecular en el cristal para el regioisómero 5-nitro 4 es producto de la combinación de enlaces de hidrógeno intermoleculares e interacciones de van der Waals, mientras que en el 7-nitro regioisómero 3 el empaquetamiento se debe principalmente a interacciones intermoleculares débiles de tipo van der Waals y N—H···π.


Dois nitro regtoisómeros da molécula cis-4-(4-metoxifenil)-3-metil-2-fenil-1,2,3,4-tetrahydroquinolina foram preparados através de uma síntese de um só recipiente de três componentes com base na reacção de imino Diels-Alder cicloadição catalisada BF3.OEt2 e sua completa caracterização estrutural foi realizada usando a técnica de difracção cristalografia de raios X, e outros métodos espectroscópicos. A pureza do produto e a composição das misturas reaccionais foram monitorizadas por cromatografia em camada fina (CCD). Os produtos foram isolados e purificados utilizando cromatografia em coluna. As substâncias foram identificadaos por ressonância magnética nuclear (RMN) e espectrometria de massa (EM). Os dados para caracterização por difração de raios X foram coletados usando um Bruker AFC7S Mercury difratômetro com Mo-Ka radiação (λ = 0,71073Å) à temperatura ambiente. As estruturas dosa regioisómeros foram confirmadaos por 1H RMN e 13C RMN a estrutura de cristal foi investigada usando difracção de raios X de cristal único. As análises espectroscópicas (RMN, EM e difracção de raios-X) demonstraram uma completa caracterização e permitiramu estabelecer a estereoquímica correcta de anel tetrahidroquinolínico. O empacotamento molecular no cristal para 5-nitro regioisómero 4 é derivado de uma combinação de ligações de hidrogénio intermoleculares e interacções de van der Waals, e ao 7-nitro regioisómero 3 embalagens é principalmente devido a interacções intermoleculares fracas do tipo van der Waals e N—H···π.


A great number of natural and synthetic tetrahydroquinoline compounds are core structures in many important pharmaceutical agents (Katrizky et al. 1996, Kouznetsov et al. 1998). These heterocycle compounds play a key role in bioorganic and medicinal chemistry; they exhibit a wide range of biological activity, such as, antipsychotic (Singer et al. 2005), anti-inflammatory (Calhoun et al. 1995), anti-ulcers (Uchida et al. 1989), estrogenic receptors (Chen et al. 2007, Wallace et al. 2007) and antimalarial activities (Bendale et al. 2007), among others.

Many methods have been developed for synthesis of tetrahydroquinoline derivatives (Sridharan et al. 2011). Cycloaddition reactions have proved to be the most powerful and successful reactions to construct these ring systems rapidly; while the acid-catalyzed imino Diels-Alder reaction (Povarov reaction) between 2-azadienes and electron-rich alkenes in its three-component version is one of the most powerful synthetic tools for the construction of nitrogen-containing six-membered heterocyclic compounds, including tetrahydroquinolines (Kouznetsov 2009, Glushkov et al. 2008, Buonora et al. 2001). This reaction enables the condensation of anilines, aldehydes, and electron-rich alkenes using acidic catalysts under mild conditions to obtain new substituted tetrahydroquinolines. Recently, the use of phenylpropenoid derivatives (electron-rich alkenes, e.g. fram-anethole) such as dienophile in this cycloaddition process has been given significant attention (He et al. 2012, Romero et al. 2011). However, little has been explored on the crystallographic study of this type of derivatives by X-ray diffraction.

Our ongoing research program has focused on the chemistry and bioactivity of tetrahydroquinoline derivatives (Romero et al. 2012) and its single crystal X-ray crystallographic study, to explain the stereochemistry of the imino Diels-Alder reaction and the performance ofthis material in the crystalline state (Bermudez et al. 2011). In this paper, we will show an easy and simple preparation of two constitutional isomers of nitro-tetrahydroquinoline derivatives, compounds rá-4-(4-methoxyphenyl)-3-methyl-7-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 3 and cis-4-(4-methoxyphenyl)-3-methyl-5-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 4 using the three-component imino Diels-Alder cycloaddition methodology (Kouznetsov 2009), this reaction that enables the generation of 1,2,3,4-tetrahydroquinoline derivatives with high structural diversity. We have also determined the crystal structure of these compounds using X-ray techniques, confirming their spectral characterization and obtaining detailed information about their molecular conformation.

Materials and methods

Infrared (IR) spectra were recorded on a Lumex Infralum FT-02 spectrophotometer. 1H and 13C NMR spectra were measured on a Bruker AM-400 spectrometer (400 MHz 1H NMR and 100 MHz 13C NMR), using CDCl3 as the solvent. Trimethylsilyl (TMS) was used as an internal standard. Chemical shifts (δ) and J values are reported in ppm and Hz, respectively. A Hewlett Packard 5890a Series II Gas Chromatograph interfaced to an HP 5972 Mass Selective Detector with an HP MS ChemStation Data system was used for MS identification at 70eV using a 60m capillary column coated with HP-5 [5% phenylpoly (dimethylsiloxane)]. Melting points (uncorrected) were measured on a Fisher Johns melting point apparatus. X-ray diffraction data were collected using a Bruker AFC7S Mercury diffractometer with graphite-monochromated MoKa radiation (λ = 0.71073A) at room temperature. Crystals with dimensions 0.53 x 0.48 x 0.43mm (comp. 3) and 0.55 x 0.48 x 0.45mm (comp. 4) were used. Data having theta less than or equal to 25° were integrated and the structure was solved by the direct method using the SHELXS-97 program (Sheldrick 2008), which was refined by the full-matrix least-squares method using the SHELXS-97 program. Crystal data and experimental details are listed in tables 1, 2 and 3 respectively. All H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with C-H distances of 0.96A and U (H) = 1.2U (C). The H atom bonded to N was located from Fourier difference map. The reaction progress was monitored using thin layer chromatography (TLC) on a Silufol UV 254 TLC aluminum sheet. Column chromatography was carried out using Silica gel (230-400 mesh). All reagents were purchased from Sigma and Aldrich Chemical Co. and used without further purification.

Synthesis of Two Nitro-Regioisomers of cis-4-(4-methoxyphenyl)-3-Methyl-2-Phenyl-l,2,3, 4-Tetrahydroquinoline. General procedure: The general procedure was previously described by Kouznetsov et al. (2007) and performed as follows: A mixture of m-nitroaniline (2.90mmol) and benzaldehyde (3.19mmol) in anhydrous CH3CN (15mL) was stirred for 30 min. at room temperature. BF3.OEt2 (2.90mmol) was then added. A solution of commercial trans-anethole (3.48mmol) in CH3CN (10mL) was added dropwise over a period of 20min. The resulting mixture was stirred at 70°C for 10 hours. Once the reaction was completed, as indicated by the TLC, the reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (3 times x 15mL). The organic layer was separated and dried (Na2SO4) then concentrated in vacuo. The crude product was purified by column chromatography using silica gel (60-120 mesh) and eluted with petroleum ether-ethyl acetate to afford the tetrahydroquinoline products, the cis-4- (4-methoxyphenyl)-3-methyl-7-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 3 (8% yield) and their regioisomer, the ci's-4-(4-methoxyphenyl)-3-methyl-5- nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 4 (yield 80%). Both compounds were obtained as a yellow solid with melting point 174-175°C and 141-142°C, respectively. Both compounds were recrystallized by slow evaporation of a dichloromethane solution.

Cis-4-(4-Methoxyphenyl)-3-methyl-7-nitro-2-phenyl-l,2,3,4-tetrahydroquinoline 3: This compound was isolated as a yellow solid with Melting point (Mp) 141-142°C (uncorrected). The molecular characterization that was carried out with infrared (IR) spectrometry showed the following characteristic signals: 3376, 1610, 1521 and 1317cm-Mass Spectrometry (MS) gave a molecular peak mlz = 374 (67, M+-); Nuclear Magnetic Resonance on protons 1H NMR (400 MHz, CDCl3 Me4Si) showed δ (ppm) to be 0.59 (3H, d, J = 6.5 Hz, -CH3), 2.17 (1H, m, 3-H), 3.73 (1H, d, J = 11.0 Hz, 2-H), 3.82 (3H, s, Ar-OCH3), 4.17 (1H, d, J = 10.0 Hz, 4-H), 4.38 (1H, s, N-H), 6.66 (1H, d, J = 8.8 Hz, 8-H), 6.89 (2H, d, J = 8.6 Hz, 2'-HAr), 7.10 (2H, d, J = 8.6 Hz, 3'-HAr), 7.35-7.40 (7H, m, all-HAr and 6-H, 7-H); Nuclear Magnetic Resonance on Carbons 13C-NMR (100 Hz, CDCl3 Me4Si), δ (ppm), presented the following data: 158.5, 147.1, 145.4, 141.7, 134.8, 132.5, 131.2, 130.5, 128.8, 128.6, 127.7, 114.0, 111.7, 107.5, 64.8, 54.5, 50.8, 40.3, 16.3.

Cis-4-(4-Methoxyphenyl)-3-methyl-5-nitro-2-phenyl-l,2,3,4-tetrahydroquinoline 4: This compound was isolated as a yellow solid; with Melting point (Mp) 174-175°C (Uncorrected). The molecular characterization carried out by infrared (IR) spectrometry showed the following characteristic signals: 3395, 1609, 1527 and 1323cm-1; Mass Spectrometry (MS) gave a molecular peak mlz = 374 (30, M+-); Nuclear Magnetic Resonance on protons 1H NMR (400 MHz, CDCl3 Me4Si) showed δ (ppm) to be : 0.68 (3H, d, J = 6.6 Hz, -CH3), 2.03 (1H, m, 3-H), 3.75 (3H, s, Ar-OCH3), 4.01 (1H, d, J = 10.2 Hz, 2-H), 4.21 (1H, d, J = 10.2 Hz, 4-H), 4.36 (1H, s, N-H), 6.75 (1H, dd, J = 8.1, 1.2 Hz, 8-H), 6.76 (2H, d, J = 8.7 Hz, 2'-HAr), 6.89 (1H, dd, J = 7.8, 1.2 Hz, 6-H), 6.98 (2H, d, J = 8.7 Hz, 3'-HAr), 7.08 (1H, td, J = 8.1, 0.6 Hz, 7-H), 7.337.42 (5H, m, all-HAr); Nuclear Magnetic Resonance on Carbons 13C-NMR (100 Hz, CDCl3 Me4Si), δ (ppm), presented the following data: : 158.0, 152.3, 147.8, 141.2, 135.1, 130.4, 128.6, 128.2, 127.7, 127.1, 119.4, 118.0, 114.1, 113.4, 62.6, 55.1, 48.0, 45.0, 16.1.


Regioisomeric nitro-tetrahydroquinolines 3 and 4 were easily prepared via the protocol of a "one pot" three-component imino Diels-Alder reaction between in situ forming N-aryl aldimines and trans-anethole in the presence of BF3.OEt2, at 70°C in acetonitrile. These compounds were synthesized by cycloaddition reaction starting from the commercially available 3-nitroanilines 1, benzaldehyde 2, and frans-anethole, according to the literature procedure (Kouznetsov et al. 2007, Kouznetsov et al. 2008). The required products 3 and 4 were obtained in good yields after column chromatography purification on silica gel (Figure 1).

The structures of the nitro-regioisomers 3 and 4 were confirmed on the basis of analytical and spectral data using 1H NMR and 13C NMR studies and were supported by inverse-detected 2D NMR experiments. Their crystal structure was studied using single crystal X-ray diffraction technique.

Crystal data, refinement and experimental details are listed (Tables 1 and 2), respectively.

The crystal packing for the 5-nitro regioisomer 4 was the result of combinations of intermolecular hydrogen bonds of the N—H—O type and van der Waals interactions, which may lead to the supramolecular structure of the molecule.

The hydrogen bonding descriptions are listed in (Table 3).

Crystallographic data (excluding structure factors) for the structural analysis has been deposited with the Cambridge Crystallographic Data Centre, Nos. CCDC 913850 (Comp. 3) and 913851 (Comp 4). A copy of the data can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 1223 336-033; e-mail: or].


Synthesis and Characterization: Our report is based on our experience in the synthesis of bioactive tetrahydro (quinoline) derivatives via multi-component Povarov reaction (Meléndez et al. 2008, Vargas et al. 2007). Here, we describe our synthetic and crystallographic studies on nitro-regioisomers 2, 4-diaryl-3-methyl-1,2,3,4-tetrahydroquinoline derivatives 3 and 4, synthesized by cycloaddition reaction, as shown (Figure 1). These nitro tetrahydroquinoline regioisomers were easily prepared in good yield with almost no byproducts via the protocols of a "one pot" three-component imino Diels-Alder reaction. Studied tetrahydroquinolines were isolated and purified by column chromatography (SiO2) using petroleum ether/ethyl acetate as yellow solids with defined melting points (Table 4).

We observed characteristic IR spectrum absorption bands in both compounds at 33953376 and 1610-1609cm-1, assignable to the amine groups, and the nitro group signals at 1527-1521 and 1323-1317cm-1, respectively. Their mass spectrum showed a molecular ion m/z: = 374 that coincided in both cases with their molecular weight (374g/mol). 1H NMR and GC-MS analyses of the tetrahydroquinoline products showed that the structure of the unique diastereoisomer 3 and 4 detected was a cis-(2e, 4e) configuration. The large vicinal coupling constants J2a,3a and J3a, 4a = 9.9-11.0 Hz indicate an axial-axial (trans) relationship, and the aryl groups on C-2 and C-4 are both pseudo-equatorial and are in the cis-configuration (Figure 2). The X-ray crystallographic analysis showed that the substituents of the tetrahydroquinoline ring occupy equatorial positions, confirming that the reaction was highly diastereoselective.

X-Ray Diffraction Single Crystal Study: Crystals suitable for single crystal X-ray diffraction were grown from slow evaporation of a dichloromethane solution at room temperature. We collected X-ray diffraction data using a Bruker AFC7S Mercury diffractometer with graphite-monochromated MoKa radiation (λ = 0.71073Å) at room temperature. In both case (compounds 3 and 4) data collection, cell refinement and data reduction was achieved using the CrystalClear program (Rigaku 2005). And to solve and to refine the structure, SHELXLTL-NT V5.1 software (Bruker 1998) was used.

The perspectives of the analyzed molecules 3 and 4 indicated that these compounds have normal values of bond lengths and angles (Figure 3). We also noted also that compounds 3 and 4 are isomorphous, only with significant variations in their a and b unit-cell parameters. This difference between the two regioisomers could be due to their capability to form intermolecular hydrogen bonds through interactions between a nitro group and tetrahydroquinoline.

Analyzing the X-ray data, we found that the 7-NO2 isomer 3 could form only weak van der Waals type interactions, while their 5-NO2 regioisomer 4 was capable of organizing both van der Waals and hydrogen bond (N—H—O) interactions. It should be noted that there are three stereogenic centers in each studied compound; therefore the C2(S), C3(S), C4(R)-configuration was suggested for the structures of the obtained molecules. However, the centrosymmetric space group P21 Ic (N°14) indicates that the compounds are racemates, with configuration C2 (SR), C3 (SR), C4 (RS). The conformation for compounds 3 and 4 was imposed by the tetrahydroquinoline structural fragment, which possesses a half-chair conformation, despite some small deviations. All three substituent groups (two aryl rings and methyl) of both compounds occupy equatorial positions in the tetrahydropiperidine moiety of the quinoline core. This affirmation confirms, unequivocally, the high diastereoselectivity of the imino Diels-Alder reaction for this case.

On the other hand, the data of compounds 3 and 4 indicated that the sum of the values of angles measured between the three neighboring atoms C10—N1—H1, C2—N1—H1, and C10—N1— C2 were 349.30° and 349.00°, respectively. These values, closer to 360°, suggest that the atom N1 of the tetrahydroquinoline ring did not completely adopt sp3 hybridization and tends towards an sp2 hybridization type (Henao et al. 1999). These small deviations in N1 hybridization in the compounds are possibly due to the imminent relocation of the free electron pair in the nitrogen atom of the piperidine moiety through the aromatic ring and towards the oxygen atoms in the NO2 group present in all molecules. Moreover, regioisomers (3) and (4) differ in bond lengths between atoms C10— N1 (1.38 and 1.39Å, respectively), these values are closer to a double bond than to a typical simple C—N bond, which has a C2—N1 bond (1.45 and 1.46A, respectively).

The crystal packing of compound 4 was governed principally by hydrogen bond-like intermolecular interactions (Table 3). However, they also presented van der Waals interactions, such as the intermolecular N—H-O interaction [N1-O1 3.197A] (Figure 4) involving the N—H of the quinoline saturated part and one oxygen atom of the NO2 group and the intermolecular van der Waals interactions C—H-O [C24-O1 3.234A], and C—H-C [C15--C23 3.559Å]. In contrast, compound 3 had only intermolecular van der Waals interactions. The most significant interactions were between the N1 atom and one aromatic carbon N—H—C [N1—C13 3.469A], between C—H-O [C24-O2 3.346A] and the C—H-O [C6-O1 3.392Å] interactions (Figure 4).


An easy and efficient synthetic method was employed to prepare two nitro tetrahydroquinoline regioisomers. The spectroscopy analyses (NMR, GC-MS and X-ray diffraction) enabled a complete characterization and established the correct stereochemistry for the tetrahydroquinoline ring. The complete spectral analysis indicated an axial-axial (trans) relationship, and the aryl groups on C-2 and C-4 are both pseudo-equatorial and are in the cis-configuration. The X-ray crystallographic analysis showed that the substituents of the tetrahydroquinoline ring occupy equatorial positions, confirming that the reaction was highly diastereoselective. The molecular packing for the 5-nitro regioisomer 4 is the result of combinations of intermolecular hydrogen bonds and van der Waals interactions, while the 7-nitro regioisomer 3 maintains only intermolecular van der Waals interactions and N—H— π interactions, which also occur.


The authors appreciate the financial support by the Universidad Industrial de Santander (VIE-UIS, project 5714). ARRB thanks COLCIENCIAS for the PhD studies scholarship (2005-2010). The authors would like to acknowledge Reinaldo Atencio of the Instituto Zuliano de Investigaciones Tecnológicas, INZIT (Maracaibo-Venezuela) for the data collection.

The authors declare that no conflicts of interest exist in relation to this work.


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