Imidazo[2,1-b][1,3,4] thiadiazole derivatives are significant for their various pharmacological properties. This paper reports the synthesis and structure of one of them, 2-cyclohexyl-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde. The compound crystallizes in the monoclinic space group P21/c with a=17.316(3)Å, b=6.5420(9)Å, c =17.056(3)Å, β=112.909(2)°, V=1779.7(4)Å3, z=4. The, Imidazo[2,1-b][1,3,4] thiadiazole and the coumarin ring systems are each planar but inclined at an angle of 48.14(2)° towards each other. The crystal structure is stabilized by C–H … O interactions

Girija, C.R.

Hegde, V.S.

Khazi, I.M.

Kolavi, G.D.

Noor Shahina Begum, .

Vasundhara, D.E.

ePrints@Bangalore University

Journal of Chemical Crystallography, Vol. 37, No. 3, March 2007 ( C© 2007)DOI: 10.1007/s10870-006-9159-4Synthesis, spectroscopic and crystal structure analysisof a compound with pharmocophoric substituent:2-cyclohexyl-6-(2-oxo-2H-chromen-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehydeNoor Shahina Begum,(1)∗ D. E. Vasundhara,(1) C. R. Girija,(1) G. D. Kolavi,(2)V. S. Hegde,(2) and I. M. Khazi(2)Received April 4, 2006; accepted September 29, 2006Published Online February 3, 2007Imidazo[2,1-b][1,3,4] thiadiazole derivatives are significant for their various pharmacolog-ical properties. This paper reports the synthesis and structure of one of them, 2-cyclohexyl-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde. The com-pound crystallizes in the monoclinic space group P21/c with a = 17.316(3)Å,b = 6.5420(9)Å, c = 17.056(3)Å, β = 112.909(2)◦, V = 1779.7(4)Å3, z = 4. The,Imidazo[2,1-b][1,3,4] thiadiazole and the coumarin ring systems are each planar but in-clined at an angle of 48.14(2)◦ towards each other. The crystal structure is stabilized byC–H . . . O interactions.KEY WORDS: Imidazo[2,1-b][1,3,4] thiadiazole derivatives; Coumarin; Vilsmeier-Haack reaction; crystalstructure analysis.IntroductionImidazo[2,1-b][1,3,4] thiadiazole (IT) derivatives with pharmacophoric substituents havepromising biological and pharmacological activi-ties. The title compound is one of such derivatives,with a coumarin molecule linked to the IT ringsystem.The IT ring is bioisosteric with theImidazo[2,1-b]thiazole ring present in the wellknown anthelmintic drug ‘Tetramisole.’1 In thisregard, a large number of IT derivatives have been(1) Department of Studies in Chemistry, Bangalore University, CentralCollege Campus, Bangalore 560001, India.(2) Department of Chemistry, Karnatak University, Dharwad 580003,India.∗ To whom correspondence should be addressed; e-mail: noorsb@rediffmail.comreported to possess diverse pharmacological prop-erties viz., antibacterial,2 analgesic3 and an-thelmintic4 activities. Coumarin derivatives arealso found in varieties of natural products5 andmany of them display pharmacological proper-ties.6–9 Apart from this, coumarins are of consid-erable general importance and are prominent innatural products chemistry. They have been foundto possess a wide variety of uses in the perfumeindustry, as flavor enhancers, sunscreens and laserdyes. Encouraged by thesewide variety of appli-cations, we thought it might be interesting to linkcoumarin molecule with the biologically active ITmoiety expecting a molecule with enhanced bio-logical activity. These molecules were preparedas precursors during the synthesis of potential an-tidiabetic thiazolidine-2,4-dione derivatives of IT.1931074-1542/07/0300-0193/0 C© 2007 Springer Science+Business Media, LLC194 Begum et al.The title compound was synthesized usingVilsmeier-Haack reagent which was made to reactwith the prepared 3-(2-cyclohexylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2H-chromen-2-one. Thiswas followed by measurement of analytical datarelating to the compound.The compound was then subjected to spec-troscopic analysis using IR and1H NMR tech-niques to confirm the presence of the supposedring system, formylation at the appropriate posi-tion and the signals for the existence of aldehydicand other protons.A single crystal X-ray diffraction analysiswas carried out on the compound to investigatethe geometry of the coumarin moiety and alsopossible contributions like intramolecular inter-actions towards the stabilization of the molecule.The analysis revealed certain interesting featureslike the individual planarity of the two ring sys-tems despite the presence of non-planarity in theircombined structure. Also, the cyclohexyl ring isfound to be in chair conformation. No interestingintramolecular hydrogen bonding is observed, al-though there is an infinite zigzag pattern of link-age between molecules, brought about by severaldirectionally specific C–H . . . O interactions.NSNNH21BrO OO2I  Dry EtOHii Na2CO3NNSNOO3DMF/POCl3NNSNOOCHO4+Scheme 1.ExperimentalSynthesis and characterizationThe title compound was prepared in twostages as shown in Scheme 1. The reactionof 2-amino-5-cyclohexyl-1,3,4-thiadiazole10 (1)and 3-bromoacetyl coumarin11(2) in boilingethanol afforded 3-(2-cyclohexylimidazo[2,1-b]-[1,3,4]thiadiazol-6-yl)-2H-chromen-2-one (3) ashydrobromide salt, which was neutralized bysodium carbonate solution to get the free base. Itwas subjected to Vilsmeir Haack reaction to yield2-cyclohexyl-6- (2-oxo-2H-chromen-3-yl) imi-dazo [2,1-b][1,3,4] thiadiazole-5-carbaldehyde(4). The structures of the synthesized compoundswere established by analytical and spectral data.3-(2-cyclohexylimidazo[2,1-b]- [1,3,4]thia-diazol-6-yl)-2H-chromen-2-one (3). Equimolarquantities of 2-amino-5-cyclohexyl-1,3,4-thiadiazole (1.83 g, 0.01 mol) and 3-bromoacetylcoumarin (2.67 g, 0.01 mol) were refluxed inabsolute ethanol for 8 h. The resultant solid(hydrobromide) was separated by filtration. Thefree base was obtained by neutralization withsodium carbonate solution. It was washed withSynthesis, spectroscopic and crystal structure 195water and recrystallised from alcohol as anyellow amorphous solid. (Compound 3: Yield58%; mp 182–184◦C).2-cyclohexyl-6- (2-oxo-2H-chromen-3-yl)imidazo [2,1-b][1,3,4] thiadiazole-5-carbal-dehyde (4). Vilsmeier- Haack reagent wasobtained by adding POCl3 (3 ml) in DMF (20 ml)at 0◦C, with stirring. Compound 3 (3.51 g,0.01 mol) was added to the reagent and stirred at0◦C for 30 min. The mixture was further stirredat room temperature for 2 h and at 60◦C foradditional 2 h. The reaction mixture was thenpoured into sodium carbonate solution and stirredat 90◦C for 2 h. After cooling, the mixture wasdiluted with water, extracted with chloroformand the chloroform extracts were washed withwater, dried over anhydrous sodium sulphate. Thesolvent was removed under reduced pressure toyield the residual solid, which was recrystallisedfrom chloroform and hexane mixture (90:10) toget pale yellow crystalline solid. (Compound 4:Yield 66%; mp. 176–178◦C).Physical measurementsMelting points were determined in opencapillaries and are uncorrected. IR spec-tra were recorded on Nicolet FT-IR 410spectrophotometer.1H NMR spectra wererecorded on Varian RX-300 MHz spectrometerusing TMS as internal standard.The Infrared spectra of imidazo[2,1-b][1,3,4]thiadiazole derivatives does not containabsorption band due to υC=O (ketone carbonylof bromoacetyl coumarin),υNH2 and presence oflactone υC=O confirming the formation of imidazo[2,1-b]-[1,3,4]thiadiazoles. The1H NMR spectra(CDCl3) showed appropriate signals due to differ-ent protons present in the molecule. The formy-lation products showed a band due to υC=O in itsIR spectra and a singlet due to aldehyde protonin the NMR spectrum. The absence of singlet dueto C5-H was considered as the confirmation offormylation at C5.Compound 3: IR (KBr) cm−1 1734 (υC=O,lactone), 1600 (υC=N);1H NMR(CDCl3) δ,1.26–3.03 (m, 11H, cyclohexyl), 7.32–7.60 (m,4H, coumarinyl), 8.57 (s, 1H, C4H, coumarin),8.63 (s, 1H, C5H imidazole); Anal.Calcd for, C19H17 N3 O2 S; C, 64.94; H, 4.88; N, 11.96; Found;C, 64.85; H, 4.82, N, 11.90.Compound 4: IR (KBr) cm−1; 2858 (υC−Haldehyde), 1736(υC=O, lactone), 1676(υC=O,aldehyde) 1601 (υC=N);1H NMR (CDCl3) δ 1.30–3.52 (m, 11H, cyclohexyl), 6.92–7.64 (m, 4H,coumarinyl), 8.33 (s, 1H, C4-H coumarin), 10.21(s, 1H, aldehyde); Anal.Calcd for, C20 H17 N3 O3S; C, 63.31; H, 4.52; N, 11.07; found, C, 63.27;H, 4.38; N, 11.10.Crystal structure determination of (4)The X-ray diffraction data were collected ona Bruker Smart CCD Area Detector System usingTable 1. Crystal Data and Structure RefinementEmpirical formula C20 H17 N3 O3 SFormula weight 379.43Temperature (K) 293(2)Wavelength (A) 0.71073Crystal system MonoclinicSpace group P21/cCell dimensionsa (Å) 17.316(3)b (Å) 6.5420(9)c (Å) 17.056(3)ß (◦) 112.909(2)Volume (Å3) 1779.7(4)Z 4Density(Calculated)(Mg/m3) 1.416Absorption coefficient (mm−1) 0.209F(000) 792Crystal size 0.1 mm × 0.2 mm × 0.25 mm range for data collection 2.40 to 27.99◦Index ranges −22 < = h < = 22−8 < = k < = 8−22 < = l < = 22Reflections collected 14876Independent reflections 4234 [R(int) = 0.0306]Refinement method Full–matrix least–squares on F2Data/restraints/parameters 4234/0/268Goodness-of-fit on F2 1.128Final R indices [I > 2sigma(I)] R1 = 0.0601, wR2 = 0.1222R indices (all data) R1 = 0.0862, wR2 =0.1316Largest diff. peak and hole(e. A−3)0.313 and −0.218CCDC deposit no. 271066.196 Begum et al.Mo-Kα radiation (λ= 0.71073Å), to θmax of 28.00in ω–	 scan mode. The data were processed usingSAINTPLUS12 and absorption corrections wereapplied in SADABS13 A total of 14876 reflectionswas collected, resulting in 4234 (Rint = 0.031); ofthese, the number of ‘observed’ reflections (withI > 2 σ (I)) was 3218. Corrections for Lorentzand polarization effects were applied. The struc-ture was solved by direct methods and differenceFourier synthesis using SHELXS97.14 The posi-Table 2. Selected Bond Lengths [Å] and Angles [◦]S(1)–C(8) 1.721(2)S(1)–C(2) 1.762(2)N(3)–C(2) 1.295(2)N(3)–N(4) 1.375(2)O(14)–C(15) 1.378(3)O(14)–C(12) 1.383(2)N(4)–C(8) 1.349(3)N(4)–C(5) 1.388(2)O(13)–C(12) 1.197(2)O(10)–C(9) 1.211(3)C(6)–N(7) 1.376(3)C(6)–C(5) 1.384(3)C(21)–C(11) 1.338(3)N(7)–C(8) 1.322(3)C(8)–S(1)–C(2) 88.0(1)C(2)–N(3)–N(4) 108.0(2)C(15)–O(14)–C(12) 122.3(2)C(8)–N(4)–N(3) 118.5(2)C(8)–N(4)–C(5) 107.7(2)N(3)–N(4)–C(5) 133.8(2)N(7)–C(6)–C(5) 112.2(2)N(7)–C(6)–C(11) 118.6(2)C(5)–C(6)–C(11) 129.2(2)C(21)–C(11)–C(6) 121.4(2)C(12)–C(11)–C(6) 118.0(2)N(3)–C(2)–C(22) 124.7(2)N(3)–C(2)–S(1) 116.2(1)C(22)–C(2)–S(1) 119.0(1)O(13)–C(12)–O(14) 116.7(2)O(13)–C(12)–C(11) 126.4(2)O(14)–C(12)–C(11) 116.9(2)O(14)–C(15)–C(16) 117.8(2)O(14)–C(15)–C(20) 120.5(2)C(6)–C(5)–N(4) 103.4(2)N(4)–C(5)–C(9) 122.4(2)C(8)–N(7)–C(6) 103.6(2)O(10)–C(9)–C(5) 123.7(2)N(7)–C(8)–N(4) 113.0(2)N(7)–C(8)–S(1) 137.6(2)N(4)–C(8)–S(1) 109.3(1)tions of all non-hydrogen atoms were includedin the full-matrix least-square refinement usingSHELXL97.15 Anisotropic refinement using full-matrix least-square procedures was carried out fora few cycles until convergence was reached. Thehydrogen atoms were fixed geometrically; thoseon the coumarin moiety and in the aldehyde groupwere then refined freely, while the remainder wereset to ride on the parent carbon atoms. The fi-nal R factors were wR2 = 0.132 and R1 = 0.086for all 4234 reflections, and R1 = 0.060 for the‘observed’ data; the maximum and the minimumvalues of residual electron density were 0.3 and–0.2 eÅ−3. Molecular diagrams were generatedusing ORTEP.16 The details of crystal data andrefinement are given in Table 1.Results and discussionThe selected bond distances and angles aregiven in Table 2. Table 3 shows the selected tor-sion angles. The ORTEP diagram of the moleculeis shown in Fig. 1.The bond lengths and angles in 4 are withinnormal ranges.17 The angle between the IT groupand the coumarin moieties is 48.14(2)◦, showingdeviation from planarity, as observed for othercoumarin derivatives.18,19 The two ring systemsare each planar.Table 3. Selected Torsion Angles [◦]N(7)–C(6)–C(11)–C(21) −46.3(3)C(5)–C(6)–C(11)–C(21) 136.4(2)N(7)–C(6)–C(11)–C(12) 126.5(2)C(5)–C(6)–C(11)–C(12) −50.8(3)C(27)–C(22)–C(2)–N(3) −114.1(2)C(23)–C(22)–C(2)–S(1) −169.65(15)C(6)–C(11)–C(12)–O(13) 1.1(3)C(6)–C(11)–C(12)–O(14) −177.52(17)C(11)–C(6)–C(5)–N(4) 176.67(18)N(7)–C(6)–C(5)–C(9) 174.5(2)C(11)–C(6)–C(5)–C(9) −8.1(4)C(8)–N(4)–C(5)–C(9) −175.33(18)N(3)–N(4)–C(5)–C(9) 6.0(3)C(6)–C(5)–C(9)–O(10) −6.3(4)N(4)–C(5)–C(9)–O(10) 168.16(19)Synthesis, spectroscopic and crystal structure 197Fig. 1. The molecular structure and atom labeling scheme of the title compound.The coumarin skeleton geometry can becompared with that of unsubstituted coumarin.20 of coumarin-3-carboxylic acid21 and of3-(bromoacetyl) coumarin.22 The double-bondcharacter of C11 –C21 is observed in all thesecompounds. The C12–C11 and C21–C20 bonds,adjacent to the double bond, are systematicallylonger than 1.40 Å in these four molecules. Theangles C16–C15–O14 and C19–C20–C21 at thejunction of the two rings are, respectively, smallerand greater than 120◦. The angles around C12follow the same behavior in all the compounds.Compared with unsubstituted coumarin,20the decrease in the C12–C11–C21 bond angle by2◦ and increase in C11–C21–C20 by the sameamount may be due to the IT group substituted atC11.Fig. 2. View of (i) C–H . . . O interaction (ii) Intermolecularshort contacts between cyclohexyl proton and coumarin ring.The C12–O13 1.996 (3) Å, C12–C11 1.462(3) Å and C11– C21 1.337 (3) Å distances showconjugation of the C–O, C–C and C = C bonds.Carbaldehyde group is inclined at an angle of9.77(5)◦ to the IT group.No interesting intramolecular hydrogenbonding is seen in the molecule. However, inthis crystal structure, the molecule is linkedto its neighbors by several directionally spe-cific C–H. . .O interactions [C21–H21 · · · O10,C . . . O distance being 3.293(3) Å and C–H . . . O angle being 168(2)◦, Fig. 2]. Othersignificant intermolecular short contacts are be-tween H24b of cyclohexane ring and the face of aneighboring coumarin ring with C12 . . . H24band C15 . . . H24b distances being 2.881 and2.891 Å respectively [Fig. 2].Supplementary material CCDC 271066 contains the supplemen-tary crystallographic data for this paper. These data can be ob-tained free of charge at www.ccdc.com.ac.uk/conts/retrieving.htmlor from the Cambridge Crystallographic Data Centre(CCDC), 12Union Road, Cambridge CB2 1BZ. UK: fax: + 44(0)1223.336033:e-mail: deposit@ccdc.com.ac.uk.AcknowledgmentsN. S. B thanks UGC-DRS for financial sup-port D. E. V thanks UGC–FIP for the Teacherfellowship. The authors thank the Department ofScience and Technology, India, for data collectionon the CCD facility set up under the IRHPA-DSTprogram.References1. Thienopont, D.C.; Vanparijs, O.F.J.; Raeymaekers, A.H.M.;Vandenberk, J.; Demoen, P.G.A.; Allewijin, F.T.N.; Marsboom,198 Begum et al.R.P.H.; Niemegeers, C.J.E.; Shellekens, K.H.L.; Janssen, A. J.Nature. 1966, 209, 1084.2. Gadad, A.K.; Mahajanshetti, C.S.; Nimbalkara S.; Raichurkar,A. Eur. J. Med. Chem. 2000, 35, 853.3. Khazi, I.M.; Mahajanshetti, C.S.; Gadad, A.K.; Tarnalli A.D.;Sultanpur, C.M. Arzneim-Forsch./Drug Res. 1966, 46, 949.4. Eldwy, A.; Shams, S.A.; El-Dine., El.; Brembaly, K. M. Phar-mazie. 1979, 34(3), 144.5. Spath, E. Ber. 1937, 70, 83.6. Jois, S.S.; Manjunath, B.L.; Rao, S.V. J. Indian Chem. Soc. 1933,10, 41.7. Braon, S.A. Nature. 1961, 194, 372.8. Wallick, H.; Haris, D.A.; Reagan, M.A.; Ruger, M.; Woodruff,H. Antibiot. Ann. 1956, 909.9. Childress, S. Topics Med. Chem. 1967, 1, 109.10. Gadad, A.H.; Khazi, I.M.; Mahajanshetti, C.S. Ind. J. Het. Chem.1992, 2, 47.11. Koelsch, C.F. J. Am. Chem. Soc. 1950, 72, 2993.12. Bruker, SMART (V5.628).; SAINT (V6.02), Program for datareduction, Bruker Axs Inc.Madison, Wisconsin: USA, 1998.13. Sheldrick, G.M. SADABS, Program for absorption correction,University of Go¨ttingen: Germany, 1996.14. Sheldrick, G. M. SHELXS97, Program for Crystal StructureSolution, University of Go¨ttingen, Germany, 1997.15. Sheldrick, G.M. SHELXL97, Program for crystal structure re-finement, University of Go¨ttingen: Germany, 1997.16. Farrugia, L.J. ORTEP-3 for Windows-A Version of ORTEP-111with a graphical User Interface (GUI), J. Appl. Cryst. 1997, 30,565.17. Allen, F.H.; Kennard, O.; Watson, D.G.; Brammer, L.; Orpen,A.G.; Taylor, R. J. Chem. Soc. Perkin Trans. 1987, S1-19.18. Chinnakali, K.; Sivakumar, K.; Natarajan, S. Acta Cryst. 1990,C46, 405.19. Dhaneshwar, N.N.; Tavale, S.S.; Guru Row, T.N. Acta Cryst.1988, C44, 1858.20. Gavuzzo, E.; Mazza, F.; Giglio, E. Acta Cryst. 1974, B30,1351.21. Dobson, A.J.; Gerkin, R.E. Acta Cryst. 1996, C52, 3081.22. Vasudevan, K.T.; Puttaraja Kulkarni, M.V. Acta Cryst. 1991,C47, 775.

Synthesis, spectroscopic and crystal structure analysis of a compound with pharmocophoric substituent: 2-cyclohexyl-6-(2-oxo-2H-chromen-3-yl)- imidazo[2,1-b]  [1,3,4]thiadiazole-5-carbaldehyde

http://eprints-bangaloreuniversity.in/4906/1/girija.pdf

Synthesis, spectroscopic and crystal structure analysis of a compound with pharmocophoric substituent: 2-cyclohexyl-6-(2-oxo-2H-chromen-3-yl)- imidazo[2,1-b] [1,3,4]thiadiazole-5-carbaldehyde

Abstract

Similar works

Full text

Available Versions

ePrints@Bangalore University