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 Bohórquez^1*, 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

Abstract

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

Resumen

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.

Resumo

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.

Introduction

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 MoK_a 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'-H_Ar), 7.10 (2H, d, J = 8.6 Hz, 3'-H_Ar), 7.35-7.40 (7H, m, all-H_Ar 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-H_Ar); 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.

Results

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: deposit@ccdc.cam.ac.uk or www.ccdc.cam. ac.uk].

Discussion

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 J_2a,3a and J_{3a, 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 MoK_a 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).

Conclusion

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.

Acknowledgments

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.

References

Bendale P, Olepu S, Kumar SP, Buldule V, Rivas K. Nallan L, et al. (2007) Second Generation Tetrahydroquinoline-Based Protein Farnesyltransferase Inhibitors as Antimalarials. Journal of Medicinal Chemistry 50: 4585-4605

Bermudez JH, Pinto JL, Meléndez CM, Henao JA. Kouznetsov VV (2011) Simple preparation of new N-(6-methyl-2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl) pyrrolidin-2-ones and their spectroscopic analysis. Universitas Scientiarum 16 (2): 160-167

Buonora P, Olsen JC, Oh T (2001) Recent developments in imino Diels-Alder reactions. Tetrahedron 57: 6099-6138

Calhoun W, Carlson RP, Crossley R, Datko LJ, Dietrich S, Heatherington K, et al. (1995) Synthesis and antiinflammatory activity of certain 5,6,7,8-tetrahydroquinolines and related compounds. Journal ofMedicinal Chemistry 38: 1473-1481

Chen W, Lin Z, Ning M, Yang C, Yan X, Xie Y, et al. (2007) Aza analogues of equol: novel ligands for estrogen receptor beta. Bioorganic & Medicinal Chemistry 15: 5828-5836

Crystal Clear 1.3.6. (2005) RigakulMSC, Inc. 9009 New Trails Drive, The Woodlands, TX 77381. USA

Crystallographic software package SHELXTL-NT V5.1. PC version (1998) Bruker Analytical X-Ray Systems, Madison, WI, USA

Farrugia LJ (1997) ORTEP-3 for Windows - a version of ORTEP-III with a Graphical User Interface (GUI). Journal of Applied Crystallography 30: 565

Glushkov VA, Tolstikov AG (2008) Synthesis of substituted 1,2,3,4-tetrahydroquinones by the Povarov reaction. New potentials of the classical reaction. Russian Chemical Reviews (Engl. Transl.) 77: 137-159

He L, Bekkaye M, Retailleau P, Masson G (2012) Chiral phosphoric acid catalyzed inverse electron-demand aza-Diels-Alder reaction of isoeugenol derivatives. Organic Letters 14: 3158-3161

Henao JA, Palma A, Kouznetsov VV, Aguirre HG, Ortega, FC, Soriano, GM (1999) 6-Chloro-1-(a-chloroacetyl)-1,2,3,4-tetrahydro-4-methylquinoline-2-spirocyclohexane. Acta Crystallographica C55: 1181-1183

KatrizkyAR, Rachwal S, Rachwal B (1996) Recent Progress in the Synthesis of 1,2,3,4,-Tetrahydroquinolines. Tetrahedron 52: 15031-15070

Kouznetsov VV; Palma A; Ewert C; Varlamov A (1998). Some aspects of reduced quinoline chemistry. Journal of Heterocyclic Chemistry 35: 761-785

Kouznetsov VV, Romero Bohórquez AR, Stashenko EE (2007) Three-component imino Diels-Alder reaction with essential oil and seeds of anise: generation of new tetrahydroquinolines. Tetrahedron Letters 48/88558860

Kouznetsov, V. V.; Merchan Arenas, D. R.; Romero Bohórquez, AR (2008) PEG-400 as green reaction medium for Lewis acid-promoted cycloaddition reactions with isoeugenol and anethole Tetrahedron Letters 49: 3097-3100

Kouznetsov VV (2009) Recent Synthetic Developments in a Powerful Imino Diels-Alder Reaction (Povarov Reaction): Application to the Synthesis of N-polyheterocycles and Related Alkaloids. Tetrahedron 65: 2721-2750

Meléndez CM, Kouznetsov VV, Sortino MA, Alvarez SL, Zacchino SA (2008) In vitro antifungal activity of polyfunctionalized 2-(hetero) arylquinolines prepared through imino Diels-Alder reactions. Bioorganic & Medicinal Chemistry 16: 7908-7920

Romero Bohórquez AR, Kouznetsov VV, Doyle MP (2011) Cu(OTf)2-Catalyzed Three-component imino Diels-Alder reaction using propenylbenzenes: Synthesis of 2,4-diaryl tetrahydroquinoline derivatives. Letters in Organic Chemistry 8: 5-11

Romero Bohórquez AR, Escobar P, Leal SM, Kouznetsov VV (2012) In vitro Activity against Trypanosoma cruzi and Leishmania chagasi Parasites of 2,4-Diaryl 1,2,3,4-Tetrahydroquinoline Derivatives. Letters in Drug Design & Discovery 9: 802-808

Sheldrick GM (2008) SHELXS97. Acta Crystallographica A64: 112-122

Singer JM, Barr BM, Coughenour LL, Walters MA (2005) 8-Substituted 3,4-dihydroquinolinones as a novel scaffold for atypical antipsychotic activity. Bioorganic & Medicinal Chemistry Letters 15: 4560-4563

Sridharan V, Suryavanshi PA, Menéndez JC (2011) Advances in the chemistry of tetrahydroquinolines. Chemical Reviews 111: 7157-7259

Uchida M, Chihiro M, Morita S, Kanbe T, Yamashita H, Yamasaki K, et al. (1989) Studies on proton pump inhibitors. II. Synthesis and antiulcer activity of 8-(2-benzimidazolyl) sulfinylmethyl-1,2,3,4-tetrahydroquinolines and related compounds. Chemical & Pharmaceutical Bulletin (Tokyo) 37: 2109-2116

Vargas-Méndez LY, Kouznetsov VV , Leal SM, Mora U, Coronado CA, Meléndez CM, Romero Bohórquez AR, Rivero, P (2007) Target-oriented synthesis of antiparasitic 2-hetaryl substituted quinolines based on imino Diels-Alder reactions. Letters in Drug Design & Discovery 4: 293-296

Wallace OB, Lauwers KS, Jones SA, Dodge JA (2003) Tetrahydroquinoline-based selective estrogen receptor modulators (SERMs). Bioorganic & Medicinal Chemistry Letters 13: 1907-1910