Synthesis and Crystal Structure of Two Nitro-Regioisomers

Recursos humanos

8 pages

Please download to get full document.

View again

of 8
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Synthesis and Crystal Structure of Two Nitro-Regioisomers
  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. 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; ]. 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.
Related Documents
View more...
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks