Synthesis and Crystal Structure of Two Nitro-Regioisomers

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Synthesis and Crystal Structure of Two Nitro-Regioisomers
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  67   65 Synthesis and Crystal Structure o Two Nitro-Regioisomers o cis-4(4-Methoxyphenyl)-3-Methyl-2-Phenyl-1,2,3,4-Tetrahydroquinoline  Arnold R. Romero Bohórquez m 1 , Teresa González 2 and Vladimir V. Kouznetsov  1  Abstract. Here we synthesized two nitro regioisomersof cis-4-(4-methoxyphenyl)-3-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline via the “one pot” three-componentimino Diels-Alder reaction catalyzed by BF 3 .OEt 2  and completed its structural characterization using thesingle crystal X-ray diffraction technique and otherspectroscopic methods. To monitor the purity of theproducts and the composition of the reaction mixtures we used thin layer chromatography, and isolated and puried the products by column chromatography. Then using nuclear magnetic resonance (NMR) and mass spectrometry (MS) identied the substances. We collected X-ray diffraction data for crystal characterization by using a Bruker AFC7S Mercury diffractometer with Mo-K  α radiation (  λ  = 0.71073Å) at room temperature .  The structures of these regioisomers were conrmed by  1 HNMR and 13 C NMR studies and studied their crystalstructure using single crystal X-ray diffraction technique. The spectroscopy analyses (NMR, GC-MS and X-ray diffraction) provided a complete characterizationand 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 regioisomer3 is mainly due to weak intermolecular van der Waals interactions and N—H···  π . Keywords: Tetrahydroquinolines, Imino Diels-Alderreaction, nitro-regioisomers, single crystal X-ray diffraction 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. Resumen. Dos nitro-regioisómeros de la moléculacis-4-(4-metoxifenil)-3-metil-2-fenil-1,2,3,4-tetrahydroquinolina fueronpreparados vía una síntesis one-pot de tres componentes basada en lareacción de cicloadición imino Diels-Alder catalizada por BF 3 .OEt 2 . Sucompleta caracterización estructural se llevó a cabo usando la técnicade 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 na (CCD). Losproductos fueron aislados y puricados usando cromatografía encolumna. Las sustancias fueron identicadas usando resonancia magnética nuclear (RMN) y espectrometría de masas (EM). Los datos para lacaracterización por difracción de rayos-X fueron colectados usando undifractómetro Bruker AFC7S Mercury con radiación de Mo-K  α (  λ  =0.71073Å) a temperatura ambiente. Las estructuras de los regio-isómeros fueron conrmadas por 1 H RMN y  13 C RMN y la estructura cristalinafue estudiada usando la difracción de rayos-X de monocristal. El análisisespectroscópico (RMN, EM y difracción de rayos-X) mostró una completacaracterización y permitió establecer la correcta estereoquímica para elanillo tetrahidroquinolínico. El empaquetamiento molecular en el cristalpara 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 regioisómeros da molécula cis-4-(4-metoxifenil)-3-metil-2-fenil-1,2,3,4-tetrahydroquinolina foram preparados através de umasíntese de um só recipiente de três componentes com base na reacçãode imino Diels-Alder cicloadição catalisada BF 3 .OEt 2 e sua completacaracterização estrutural foi realizada usando a técnica de difracção cristalograa de raios X, e outros métodos espectroscópicos. A pureza do produto e a composição das misturas reaccionais foram monitorizadas por cromatograa em camada na (CCD). Os produtos foram isoladose puricados utilizando cromatograa em coluna. As substâncias foramidenticadaos 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 comMo-Ka radiação (  λ  = 0,71073Å) à temperatura ambiente. As estruturas dosa regioisómeros foram conrmadaos por 1 H RMN e 13 C RMN aestrutura de cristal foi investigada usando difracção de raios X de cristalúnico. As análises espectroscópicas (RMN, EM e difracção de raios-X)demonstraram uma completa caracterização e permitiramu estabelecer aestereoquímica correcta de anel tetrahidroquinolínico. O empacotamentomolecular no cristal para 5-nitro regioisómero 4 é derivado de umacombinação de ligações de hidrogénio intermoleculares e interacções de  van der Waals, e ao 7-nitro regioisómero 3 embalagens é principalmentedevido a interacções intermoleculares fracas do tipo van der Waals e N-H• • • π . Laboratorio de Química Orgánica y Biomolecular, Escuelade Química, Universidad Industrial de Santander. A.A. 678,Bucaramanga, Colombia.Laboratorio de Síntesis y Caracterización de Nuevos Materiales,Centro de Química, Instituto Venezolano de Investigaciones Cientícas (IVIC). Apartado 21827, Caracas, Venezuela.  Edited by Alberto Acosta  m & Josena Jover de la Prida    m Received: 14-12-2012 Accepted: 26-02-2013 Published on line: 26-02-2013 Universitas Scientiarum, Journal of the Faculty of Sciences, Ponticia Universidad Javeriana, is licensed under the Creative Commons 2.5 of Colombia: Attribution - Noncommercial - No Derivative Works. http://puj-portal.javeriana.edu.co/portal/page/portal/Facultad%20de%20Ciencias/publi_universitasSICI: 2027-1352(201301/04)18:1<65:SACSOTNOC>2.0.TS;2-V  Universitas Scientiarum Univ. Sci. 2013, Vol. 18 (1): 65-72 ORIGINAL PAPER  12  68   66  Nitro-tetrahidroquinolines structures  Introduction  A great number o natural and synthetictetrahydroquinoline compounds are core structuresin many important pharmaceutical agents (Katrizky et al. 1996, Kouznetsov et al. 1998). Teseheterocycle compounds play a key role in bioorganicand medicinal chemistry; they exhibit a wide rangeo biological activity, such as, antipsychotic (Singeret al. 2005), anti-inammatory (Calhoun et al.1995), anti-ulcers (Uchida et al. 1989), estrogenicreceptors (Chen et al. 2007, Wallace et al. 2007) andantimalarial activities (Bendale et al. 2007), among others.Many methods have been developed or synthesiso tetrahydroquinoline derivatives (Sridharan etal. 2011). Cycloaddition reactions have provedto be the most powerul and successul reactionsto construct these ring systems rapidly; while theacid-catalyzed imino Diels-Alder reaction (Povarov reaction) between 2-azadienes and electron-richalkenes in its three-component version is one o themost powerul synthetic tools or the constructiono nitrogen-containing six-membered heterocycliccompounds, including tetrahydroquinolines(Kouznetsov 2009, Glushkov et al. 2008, Buonora et al. 2001). Tis reaction enables the condensationo anilines, aldehydes, and electron-rich alkenesusing acidic catalysts under mild conditions toobtain new substituted tetrahydroquinolines.Recently, the use o phenylpropenoid derivatives(electron-rich alkenes, e.g. trans  -anethole) such asdienophile in this cycloaddition process has beengiven signicant attention (He et al. 2012, Romeroet al. 2011). However, little has been explored onthe crystallographic study o this type o derivativesby X-ray diraction.Our ongoing research program has ocused on thechemistry and bioactivity o tetrahydroquinolinederivatives (Romero et al. 2012) and its singlecrystal X-ray crystallographic study, to explain thestereochemistry o the imino Diels-Alder reaction andthe perormance o this material in the crystalline state(Bermudez et al. 2011). In this paper, we will show an easy and simple preparation o two constitutionalisomers o nitro-tetrahydroquinoline derivatives,compounds cis  -4-(4-methoxyphenyl)-3-methyl-7-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 3and cis  -4-(4-methoxyphenyl)-3-methyl-5-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 4 using thethree-component imino Diels-Alder cycloadditionmethodology (Kouznetsov 2009), this reaction thatenables the generation o 1,2,3,4-tetrahydroquinolinederivatives with high structural diversity. We havealso determined the crystal structure o thesecompounds using X-ray techniques, conrming their spectral characterization and obtaining detailedinormation about their molecular conormation. Materials and methods Inrared (IR) spectra were recorded on a Lumex Inralum F-02 spectrophotometer. 1 H and 13 CNMR spectra were measured on a Bruker AM-400spectrometer (400 MHz 1 H NMR and 100 MHz 13 CNMR), using CDCl 3 as the solvent. rimethylsilyl(MS) was used as an internal standard. Chemicalshits ( δ ) and  J  values are reported in ppm and Hz,respectively. A Hewlett Packard 5890a Series II GasChromatograph interaced to an HP 5972 MassSelective Detector with an HP MS ChemStationData system was used or MS identication at70eV using a 60m capillary column coated withHP-5 [5% phenylpoly (dimethylsiloxane)]. Melting points (uncorrected) were measured on a Fisher Johns melting point apparatus. X-ray diractiondata were collected using a Bruker AFC7S Mercury diractometer with graphite-monochromated Mo-K  α radiation ( λ  = 0.71073Å) 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 to25 º were integrated and the structure was solved by the direct method using the SHELXS-97 program(Sheldrick 2008), which was rened by the ull-matrix least-squares method using the SHELXS-97program. Crystal data and experimental details arelisted in tables 1, 2 and 3 respectively. All H atomswere placed in geometrically idealized positionsand constrained to ride on their parent atoms withC-H distances o 0.96Å and U  iso (H) = 1.2 U  eq (C).Te H atom bonded to N was located romFourier dierence map. Te reaction progress wasmonitored using thin layer chromatography (LC)on a Siluol UV 254 LC aluminum sheet. Column  69   67 Bohorquez et al. chromatography was carried out using Silica gel(230-400 mesh). All reagents were purchased romSigma and Aldrich Chemical Co. and used withouturther purication. Synthesis o Two Nitro-Regioisomers o  cis  -4-(4-methoxyphenyl)-3-Methyl-2-Phenyl-1,2,3,4-Tetrahydroquinoline. General procedure: Tegeneral procedure was previously described by Kouznetsov et al.   (2007) and perormed as ollows: A mixture o  m -nitroaniline (2.90mmol) andbenzaldehyde (3.19mmol) in anhydrous CH 3 CN(15mL) was stirred or 30 min. at room temperature.BF 3 .OEt 2 (2.90mmol) was then added. A solutiono commercial trans-anethole (3.48mmol) inCH 3 CN (10mL) was added dropwise over a periodo 20min. Te resulting mixture was stirred at 70 º Cor 10 hours. Once the reaction was completed,as indicated by the LC, the reaction mixture wasdiluted with water (30mL) and extracted with ethylacetate (3 times  x  15mL). Te organic layer wasseparated and dried (Na  2 SO 4 ) then concentrated invacuo .   Te crude product was puried by columnchromatography using silica gel (60-120 mesh)and eluted with petroleum ether-ethyl acetate toaord the tetrahydroquinoline products, the cis  -4-(4-methoxyphenyl)-3-methyl-7-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 3 (8% yield) and theirregioisomer, the cis  -4-(4-methoxyphenyl)-3-methyl-5-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline4 (yield 80%). Both compounds were obtainedas a yellow solid with melting point 174-175 º Cand 141-142ºC, respectively. Both compoundswere recrystallized by slow evaporation o a dichloromethane solution. Cis- 4-(4-Methoxyphenyl)-3-methyl-7-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline 3: Tiscompound was isolated as a yellow solid withMelting point (Mp) 141-142 º C (uncorrected). Temolecular characterization that was carried outwith inrared (IR) spectrometry showed the ollowing characteristic signals: 3376, 1610, 1521 and 1317cm -1 ; Mass Spectrometry (MS) gave a molecular peak    m/z  = 374 (67, M + ·); Nuclear Magnetic Resonanceon protons 1 H NMR (400 MHz, CDCl 3 Me 4 Si)showed δ (ppm) to be 0.59 (3H, d,  J  = 6.5 Hz,-CH 3 ), 2.17 (1H, m, 3-H), 3.73 (1H, d,  J  = 11.0Hz, 2-H), 3.82 (3H, s, Ar-OCH 3 ), 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 Resonanceon Carbons 13 C-NMR (100 Hz, CDCl 3 Me 4 Si), δ  (ppm), presented the ollowing 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-1,2,3,4-tetrahydroquinoline 4: Tiscompound was isolated as a yellow solid; withMelting point (Mp) 174-175 º C (Uncorrected).Te molecular characterization carried out by inrared (IR) spectrometry showed the ollowing  characteristic signals: 3395, 1609, 1527 and 1323cm -1 ;Mass Spectrometry (MS) gave a molecular peak  m/z   = 374 (30, M + ·); Nuclear Magnetic Resonance onprotons 1 H NMR (400 MHz, CDCl 3 Me 4 Si) showed δ (ppm) to be : 0.68 (3H, d,  J  = 6.6 Hz, –CH 3 ), 2.03(1H, m, 3-H), 3.75 (3H, s, Ar-OCH 3 ), 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), 7.33-7.42 (5H, m, all-H  Ar ); Nuclear Magnetic Resonanceon Carbons 13 C-NMR (100 Hz, CDCl 3 Me 4 Si), δ  (ppm), presented the ollowing 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 o a “onepot” three-component imino Diels-Alder reactionbetween in situ orming N-aryl aldimines and trans- anethole in the presence o BF 3 .OEt 2 , at70 º C in acetonitrile. Tese compounds weresynthesized by cycloaddition reaction starting rom the commercially available 3-nitroanilines 1,benzaldehyde 2, and trans  -anethole, according tothe literature procedure (Kouznetsov et al. 2007,  70   68 Kouznetsov et al. 2008). Te required products 3 and   4   were obtained in good yields ater columnchromatography purifcation on silica gel ( Figure 1 ).  Te structures o the nitro-regioisomers 3 and4   were conrmed on the basis o analytical andspectral data using  1 H NMR and 13 C NMR studiesand were supported by inverse-detected 2D NMR experiments. Teir crystal structure was studiedusing single crystal X-ray diraction technique.Crystal data, renement and experimental detailsare listed ( Tables 1 and 2 ), respectively.Te crystal packing or the 5-nitro regioisomer4 was the result o combinations o intermolecularhydrogen bonds o the N—H···O type and vander Waals interactions, which may lead to thesupramolecular structure o the molecule.Te hydrogen bonding descriptions are listed in( Table 3 ).Crystallographic data (excluding structureactors) or the structural analysis has been depositedwith the Cambridge Crystallographic Data Centre,Nos. CCDC 913850 (Comp. 3) and 913851(Comp 4). A copy o the data can be obtained ree o  Fig.1. Synthesis o nitro-regioisomers o tetrahydroquinolines using the three-component iminoDiels-Alder reaction. Table 1. Crystal data and renement o the nitro-regioisomers tetrahydroquinolines (3, 4).C 23 H 22 N 2 O 3 374.43250.71073MonoclinicP2 1  /c  (N º 14)19.203 (4)6.0446 (10)18.336 (4)116.293 (4)1908.1 (7)41.303210253716 [R  int =0.032]Full-matrix least-squareson F2R  1 = 0.055, w R  2 = 0.150C 23 H 22 N 2 O 3 374.43250.71073MonoclinicP2 1 / c (N º 14)7.2170 (12)14.026 (2)19.484 (3)98.394 (4)1951.2 (6)41.275223304056 [R  int =0.054]Full-matrix least-squareson F  2R  1 = 0.067, w R   2  = 0.166 7-nitroTHQ (3)5-nitroTHQ (4)Crystal data and renement  Data crystal  Empirical Formula Formula weightemperature (ºC) Wavelength (Å)Crystal systemSpace group Unit cell dimensions  a (Å) b (Å) c (Å)  β (º) Volume (Å3)ZDensity (calculated)(Mg/m 3 )Reections collectedIndependentreectionsRenement methodsFinal R indices[I>2 σ (I) = 2972 data] Crystal data and renement  1.366 (3)1.432 (3)1.387 (3)1.453 (3)0.85001.513 (4)1.526 (4)1.546 (4)118.6 (2)113.2117.2109.7 (2)108.1 (2)113.5 (2)108.4108.4107.7 Table 2. Selected bond lengths (Å) and bond angles ( º ) o the nitro-regioisomers HQs (3, 4).1.372 (2)1.429 (2)1.390 (2)1.460 (2)0.98441.511 (3)1.533 (3)1.542 (3)119.92 (15)117.0112.6109.52 (15)108.98 (14)113.02 (15)108.4108.4108.3 5-nitroTHQ (4) Bond lengths (Å) O1—C21O1—C24N1—C10N1—C2N1—H1C2—C11C2—C3C3—C4 Bond angle (  º   ) C10—N1—C2C10—N1—H1C2—N1—H1N1—C2—C11N1—C2—C3C11—C2—C3N1—C2—H2A C3—C2—H2A C2—C3—H3A  7-nitroTHQ (3) D—H···A D—H···A  170130 Table 3 . Hydrogen-bond geometry and Short contactdata (Å, °) o the nitro-HQ  4 . 2.362.53 H···A  3.197 (3)3.233 (4) D···A  N1—H1···O3iC24—H24B···O1ii0.850.96 D—H Symmetry codes: (i) −  x  +1,  y  +1/2, − z  +1/2; (ii) −  x  , −  y  , − z  +1.  Nitro-tetrahidroquinolines structures   71   69 charge rom the Director, CCDC, 12 Union Road,Cambridge CB2 1EZ, UK [ax: +44 1223 336-033;e-mail:deposit@ccdc.cam.ac.uk orwww.ccdc.cam. ac.uk ]. DiscussionSynthesis and Characterization: Our reportis based on our experience in the synthesis o bioactive tetrahydro (quinoline) derivatives via multi-component Povarov reaction (Meléndez etal. 2008, Vargas et al. 2007). Here, we describeour synthetic and crystallographic studies onnitro-regioisomers 2, 4-diaryl-3-methyl-1,2,3,4-tetrahydroquinoline derivatives 3 and 4, synthesizedby cycloaddition reaction, as shown ( Figure 1 ).Tese nitro tetrahydroquinoline regioisomers wereeasily prepared in good yield with almost no by-products via the protocols o a “one pot” three-component imino Diels-Alder reaction. Studiedtetrahydroquinolines were isolated and puried by column chromatography (SiO 2 ) using petroleumether/ethyl acetate as yellow solids with denedmelting points ( Table 4 ). We observed characteristic IR spectrumabsorption bands in both compounds at 3395-3376 and 1610-1609cm -1 , assignable to the aminegroups, and the nitro group signals at 1527-1521and 1323-1317cm -1 , respectively. Teir massspectrum showed a molecular ion m/z  : = 374 thatcoincided in both cases with their molecular weight(374g/mol). 1 H NMR and GC-MS analyses o the tetrahydroquinoline products showed that thestructure o the unique diastereoisomer 3 and 4   detected was a  cis  -(2e, 4e) conguration. Te largevicinal coupling constants  J  2a,3a  and  J  3a,4a  = 9.9-11.0Hz indicate an axial-axial ( trans  ) relationship, andthe aryl groups on C-2 and C-4 are both pseudo-equatorial and are in the cis  -conguration ( Figure2 ). Te X-ray crystallographic analysis showed thatthe substituents o the tetrahydroquinoline ring occupy equatorial positions, conrming that thereaction was highly diastereoselective.  X-Ray Difraction Single Crystal Study: Crystalssuitable or single crystal X-ray diraction weregrown rom slow evaporation o a dichloromethanesolution at room temperature. We collected X-ray diraction data using a Bruker AFC7S Mercury diractometer with graphite-monochromated Mo-K  α radiation ( λ  = 0.71073Å) at room temperature.In both case (compounds 3 and 4) data collection,cell renement and data reduction was achievedusing the CrystalClear program (Rigaku 2005). Andto solve and to rene the structure, SHELXLL-NV5.1 sotware (Bruker 1998) was used.Te perspectives o the analyzed molecules3 and 4 indicated that these compounds have Table 4. Physicochemical properties o the nitro-regioisomers tetrahydroquinoline (3) and (4).   a  Conrmed by MS data  b Uncorrected, c    Isolated yield ater CC. IR  υ N-H , υ NO2 (cm -1 ) 3376, 1610,3395, 16091521, 13171527, 1323141-142174-175 M.p. ( º C) b 880  Yield (%) c 34 Comp.Mol. ormula  a  C 23 H 22 N 2 O 3 C 23 H 22 N 2 O 3 374374 M.W. (g/mol)Fig. 2. Coupling between 3-H proton and 2-H and 4-Hprotons in 1H RMN spectra o  cis- 4-(4-methoxyphenyl)-3-methyl-7-nitro-2-phenyl-1,2,3,4-tetrahydroquinoline. Bohorquez et al.
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