Prasad, K J Rajendra

Shanmugasundaram, K

NOPR

Indian Journal of ChemistryVol. 37B, November 1998, pp. 1133 - 1136Synthesis and biological activity of pyrazino[3,2, I-j,k]carbazolesK Shanmugasundaram & K J Rajendra Prasad*Department of Chemistry, Bharathiar UniversityCoimbatore 641046, IndiaReceived 14May 1996; accepted (revised) 20 December 19981-0xo-l,2,3.4-tetrahydrocarbazole derivatives la-d have been reacted with ethanolamine to yield therespective ketimines 2a-d which on reduction with sodium borohydride furnish the corresponding aminoderivatives 3a-d. The pyrazino[3,2,I-j,k]carbazole derivatives 4a-d are obtained by the cyclisation of 3a-d usingammonium chloride in diphenyl ether. Compounds 4a-d have been tested for their antimicrobial activity usingchloramphenicol as a reference compound.Studies on the synthesis of 3H-pyrazino[3,2,I-j,k]carbazoleshave served as a fertile field of research in the perusalfor psychotropic agents'". 8-Methylhexahydro-1H-pyrazinocarbazole has displayed characteristics of amonoamine oxidase inhibitor and when administeredrepeatedly, increases the binding of u-adrencceptors inthe cerebral cortex I. According to Verevkina et al.' theantidepressant effect of pyrazidole was due to itsselective blockade of MAO (monoamine oxidase),deaminating physiological concentrations of neurotransmitters such as serotonin and norepinephrine inhuman brain.In a recent communication', we have demonstratedthe utility of l-oxo-l,2,3,4-tetrahydrocarbazoles for thesynthesis of pyrazinocarbazoles. The- present paper isconcerned with the synthesis and antimicrobial activityof a variety of hitherto unknown pyrazino[3,2,I-j,k]-carbazole derivatives.In our strategy the nitorgen atom of pyrazino ring wasintroduced at C-l position of the l-oxo-I ,2,3,4-tetrahydrocarbazole. The carbonyl group of 6-chloro-l-oxo-l,2,3,4-tetrahydrocarbazole la was condensed withmonoethanolamine to form an imine (Schiff base) in aquantitative yield, mp 165-167 'c. In its IR spectrum theabsorbtion at 3250 cm'l revealed the presence of NHgroup. the absence of carbonyl absorbtion (1640 ern")and the emergence of a strong band at 1600 cm'lindicated the formation of a C-N double bond,The 'n NMR spectrum showed a two-protonmultiplet at 0 1.50-1.70 corresponding to 3-H2 and twomore multiples at 0 2.45-2.58 and 2.60-2.88corresponding to 4-H2 and 2-H2 protons respectively.Two triplets at 0 3.58 and 3.88 were indicative of 2-methylene protons with 1 = 5,2 Hz. A three-protonmultiplet at 0 7.40 was assigned to the aromatic protons,H-5, H-7 and H-8 and a broad singlet at 0 8.12 was dueto NH proton.It analysed for the molecular formula CI4HI5N20Cland was assigned the structure, 1-(2' -hydroxyethyl-imino )-8-chloro-l ,2,3,4-tetrahydrocarbazole 2a.The iminocarbazole 2a, on treatment with NaB~ inmethanol gave a single product, mp 120-121 'c. in 92%yield. It's IR spectrum showed in addition to the band at3275 em", a shoulder at 3250 cm,l revealing thepresence of two types of NH groups. The IH NMRspectrum showed a six-p'roton multiplet at 0 1.61-4.05which was assigned to three sets of methylene protons.A multiplet at 0 3.74 was observed due to 2'-H2 and H-I. A triplet at 0 3.99 was assigned to 1'-H2 with 1=5.2Hz and a doublet at 0 6.96 for H-8 with 1=5.6 Hz.Another doublet observed at 07.11 was due to H-7 with1=5.6 Hz. Two singlets at 0 7.35 and 11.00 wereassigned to H-5 and NH protons respectively.The elemental analysis too supported the structure ofcompound 3a as 1-(2' -hydroxyethylamino )-8-chloro-1,2,3,4-tetrahydrocarbazole.The- amino derivative 3a was cyc1ised usingammonium chloride in diphenyl ether. The productshowed in its IR spectrum, the presence of NH groupingat 3400 cm'. lH NMR spectrum showed a six-protonmultiplet at 0 7.20-7.41. Proton H-7 appeared as a1134 INDIAN J CHEM, SEC.B, NOVEMBER 1998singlet at 0 7.46. The two-proton multiplet appearing ato 7.98-8.17 was assigned to NH and H-2. Elementalanalysis agreed well with the molecular formulaCI4H~2Cl. Hence, the structure of the product wasproved to be 8-chloro-3H-pyrazino[3,2,I-j,k]carbazole4a.The synthetic sequence leading to the formation of thetitle compounds 4a-d is outlined in Scheme I. The keyintermediate for the synthesis of pyrazino[3,2,I-j,k]-carbazole, l-oxo-l,2,3,4-tetrahydrocarbazole la-d, wasprepared by the reaction of the diazotised anilinederivative with 2-hydroxymethylenecyclohexanonefollowed by acid catalysed cyclisation'r'.The structures of the compounds 2a-d, 3a-d and 4a-dwere confirmed from their elemental analyses andspectral data «cf. Table I),Biological activity. Compounds 4a-d were testedagainst different strains of pathogenic bacteria, namelyBacillus subtilis (gram +ve), Escherichia coli,Salmonella typhi and Pseudomonas aurogenosa (gram -ve). The bacteria were maintained on nutrient agar slantsand testing was carried out by disc diffusion method,using 30 ug/ml, concentration of test compounds for theabove strains. The chloro and bromo derivatives 4a and4b, exhibited more activity against the above gram (+ve)~~N~RHO~RH N""""-OH2a - d(i)---..1a - d1(ii)0yQR ~NH~~R H NH _'~OH3a - d48 - d(1) H2NCH2CH20HlMethanol(ii) NaBH4 / Methanol(iii) NH4CI-diphenyl ether1,2,3 a: R=6-CIb: R=6-Brc: R=8-COOCH3d : R=6-0CH34 a: R=8-CIb : R=8-Brc: R=JO-COOCH3d : R=8-0CH3Scheme ICompd mp·CYield Mol.(%) formulaFound (Calcd) %Table I-Physical and IR data of new carbazole derivatiyes 2-4.'H NMR (o)(CDClyTMS) J in Hz2a 165-67C H63.72 5.68(63.99 5.75592b 158-59 54.42 4.86(54.73 4.92552c 180-81 67.16 6.40. (67..11 6.33512d 150-51 69.5:2 7.32(69.14 7.0277N10.4210.66)8.989.12)10.159.78)10.5310.84)•1.50-1.70(m,2H, H2-3), 2.45-2.58(m,2H, H2-4),2.60-2.88(m, 2H, Hr2), 3.58(t, 2H, H2-2', 1=5.2),3.88(t, 2H, Hrl', 1=5.2), 7.00-7.76(m, 3H, H-5,H-7 and H-8) and 8.l2(broad s, lH, NH, ~Oexchangeable).2.29(m, 2H, Hr3, 1=5.2), 2.58(m,2H, H2-4,1=5.3), 2.88(m, 2H, H2-2, 1=5.2), 3.52(t, 2H, Hr2',1=7.9), 3.88(t, 2H, Hrl', 1=7.9), 7.10-7.20(m,3H, H-5, H-7 and H-8) and 11.4(broad s, 1H, NH,D20 exchangeable).1.96(m, 2H, H2-3, 1=5.4), 3.63(m, 2H, H2-4,1=6.3), 3.75(m, 2H, H2-2, 1=6.3), 4.0l(s, 3H, 8-COOCH3), 4.26(t, 2H, Hr2', 1=6.3), 4.77(t, 2H,Hrl', 1=6.3), 7.04-8.02(m, 3H, H-5, H-6 and H-7)and 8.11 (broad s, lH, NH, D20 exchangeable).1.65(m, 2H, Hr3, 1=6.1), 2.l7(m, 2H, H2-4,1=5.2), 2.55(m, 2H, Hr2, 1=5.9), 3.85(s, 3H, 6-OCH3), 3.61(t, 2H, Hr2', 1=4.5), 4.09(t, 2H, Hr1', 1=4.5), 6.89-7.28(m, 3H, H-5, H-7 and H-8)and 8.55(broad s, ur, NH, D20 exchangeable).Table I - ContdRAJENDRA PRASAD et al.: PYRAZINO[3,2,I-j,k]CARBAZOLES 1135Compd mp'c3a 120-213b 111-123c 115-163d 125-264a 188-894b 165-664c 105-064d 110-11Table I-Physical and IR data of new carbazole derivatives 2-4 - ContdYield(%)Mol.formulaFound (Calcd) %C63.46(63.5154.22(54.3866.50(66.6468.96(69.2069.61(69.8658.59(58.9672.32(72.4476.11(76.25H6.526.47N10.4210.58)IH NMR (o)(CDCI:lfMS) J in Hz1.61-3.05(m, 6H, Hr2, H2-3 and H2-4), 3.74(m,3H, Hr2' and H-l), 3.99(t, 2H, H2-1', 1=5.2),6.96(d, IH, H-8, 1=5.3), 7.II(d, lH, H-7, 1=5.6),7.35(s, IH, H-5) and 11.00(broad s, lH, NH, D20exchangeable).1.95-2.58(m, 6H, Hr2, H2-3 and Hz-4), 3.50-3.76(m, 3H, H2-2' and H-I), 4.16(t, 2H, H2-1',1=5.0), 6.90-8.00(m, 3H, H-5, H-7 and H-8) and8.29(broad s, IH, NH, D20 exchangeable).1.99-2.70(m, 6H, Hr2, Hz-3 and H2-4), 3.95(s,3H, 8-COOCH3), 2.75-2.85(m, 3H, H2-2' and H-I), 3.71(1, 2H, H2-1', 1=4.5), 7.08(1, lH, H-6,1=7.2), 7.25(d, IH, H-7, 1=7.2), 7.63(d, lH, H-5,1=8.1) and 9.84(broad s, IH, NH, D20exchangeable).1.25-2.16(m, 6H, HT2, H2-3 and H2-4), 3.50-3.87(m, 3H, H2-2' and H-l), 3.92(t, 2H, H2-1,1=6.1), 4.02(s, 3H, 6-0CH3), 7.07(d, IH, H-8,1=8.7), 7.30(d, IH, H-7, 1=8.7), 7.40(s, lH, H-5),and 8.04(broad s, IH, NH, D20 exchangeable).7.20-7.4I(m, 6H, H-I, H-4, H-5, H-6, H-9 and H-10), 7.46(s, IH, H-7), 7.98-8.17(m, 2H, NH andH-2).7.00-7.25(m, 6H, H-I, H-4, H-5, H-6, H-9 and H-10), 7.46(s, IH, H-7), 7.98(broad s, lH, NH, D20exchangeable) and 8.07(d, lH, H-2, 1=8.1).4.02(s, 3H, IO-COOCH3), 6.89-7.16(m,3H, H-I,H-8 and H-9), 7.24-7.50(m, 3H, H-4, H-5, H-6),7.85(d, IH, H-7, 1=7.2), 8.02 (d, IH, H-2, 1=7.2),9.92(broad s, IH, NH, D20 exchangeable).3.91(s, 3H, 8-0CHi), 6.91-7.11«m, 3H, H-I, H-9and H-IO), 7.24-7.34(m, 3H, H-4, H-5 and H-6),7.56(s, IH, H-7), 7.99(broad s, IH, NH, D20exchangeable), 8.03(d, IH, H-2, 1=7.2).92and gram (-ve) bacteria, whereas the other derivatives,4c and 4d, exhibited moderate activity against them(Table II).95Experimental SectionGeneral. Melting points were taken in capillary tubeson a Boetius microheating table or on Mettler FP5apparatus and are uncorrected. IR specta were recordedon a Perkin-Elmer 597 spectrometer using KBr disk andIH NMR spectra on a Varian EM 390 (90 MHz)9996205253525.365.548.969.06)6.856.999.609.71)7.627.7410.5810.76)3.553.7611.5611.64)3.263.189.569.82)4.604.5710.5410.60)5.015.1111.0211.05)spectrometer using tetramethylsilane as internal stan-dard. Microanalyses were performed on a Perkin-Elmer240 CHN analyser. Each analytical sample exhibitedspectral data compatible with it's assigned structure andmoved as a single spot on TLC glass plates coated withsilica gel-G containing 13% calcium sulphate as binder.A chamber containing iodine vapour was used to locatethe spots.Synthesis of 1-(2' -hyroxyethylimino )-1,2,3,4-tetra-hydrocarbazole derivatives 2: General procedure.1136 INDIAN J CHEM, SEC.B, NOVEMBER 1998The respective l-oxo-l 'f,3,4-tetrahydrocarbazole 1Table Il=-Biologtcal screening results of pyrazino[3,2,1-j,k]-carbazole derivatives 4a-d.Compd Zone of inhibition*B. subtilis E. coli S. typhi P. aurogenosa4a 25 26 22 244b 28 27 24 264c 18 18 16 154d 17 18 17 18* Zone of inhibition with the standard reference compoundchloramphenicol was 18 mm.(0.01 mole) was dissolved in methanol (40 mL),monoethanolamine (5 mL) was added to it and thecontents were warmed on a water-bath for 1 hr. At theend of the period, the solution was filtered and washedwith water until the washings were neutral to litmus. Thecompound thus obtained was purified by crystallisationfrom methanol.Synthesis of 1-(2' -hydroxyethylamino )-1,2,3,4-tetra-hydrocarbazole derivatives 3: Generalprocedure: The Schiff base 2 (0.002 mole) wasdissolved in methanol (20 mL) and the mixture wascooled to 10·oC in an ice-bath. Sodium borohydride(0.003 mole) was added in portions to the cooledsolution with stirring. The contents were stirred at roomtemperature for 2 hr and poured into ice-cold water. Thesolid formed was filtered, washed well with water andcrystallised from methanol.Synthesis of pyrazino[3,2,l-:i,k]carbazole deriva-tives 4. To a mixture of hydroxyethylamino-l,2,3,4-tetrahydro-carbazole 3 (0.005 mole) and ammoniumchloride (0.11 g. 0.002 mole), diphenylether (15 mL) wasadded and the reaction mixture refluxed for 2 hr on aflame. Excess of diphenyl ether (15 mL) was thenremoved, and the contents were taken in ethyl acetate,dried and excess solvent was distilled off. The residualmass obtained was purified by passing through a columnof silica gel and eluting with petroleum ether-ethylacetate (2:1).ReferencesMaj J, Michaluk J, Rawlow R, Rogoz Z & Skuza G,Arzeim Forsch, 36, 1986, 1198; Chern Abstr, 105, 1986,146069n.2 Verevkina I V, Asnina V V, Gorkin V Z & MashkovskiiM D, Neirokhirniya, 6, 1987,332; Chern Abstr, 108, 1988,106361g.3 Rejendra Prasad K J, Vijayalakshmi C S & SowmithranD, Organic Preparations Procedures International, 27,1995,686.4 Sowmithran D & Rajendra Prasad K J, Heterocycles, 24,1986,71l.5 Rajendra Prasad K J & Vijayalakshmi C S, Indian JChern, 33B, 1994,481.

Synthesis and biological activity of pyrazino[3,2,1-j,k]carbazoles

http://nopr.niscair.res.in/bitstream/123456789/56981/1/IJCB%2037B%2811%29%201133-1136.pdf

Synthesis and biological activity of pyrazino[3,2,1-j,k]carbazoles

Abstract

Similar works

Full text

Available Versions

NOPR