El-Awaad, Samar Mohamed Hilmy

El-Taweel, Fathy Mohamed Abdel Aziz

Elagamey, Abdel Ghani Ali

Osman, Ahmed Ibrahim

NOPR

Indian Journal of ChemistryVol. 37B, April 1998, pp.399 - 403Synthesis of functionaly substitutedpyridine and thiophene derivativesAhmed Ibrahim Osman, Fathy Mohamed Abdel Aziz El-Taweel*, Samar Mohamed Hilmy El-Awaad &Abdel Ghani Ali ElagameyDepartment of Chemistry, Faculty of Science,New Damiatta, A R EgyptReceived 18 April 1996; revised and accepted2 December 1997Acetoacetanilides 1 react with the ylidenenitriles 2 to givethe substituted pyridines 4,5,10 and 11 respectively.Reactionof 1 with ethyl cyanoacetate and elemental sulphur inethanolic-triethylamine yield 2-aminothiophenes 14. Conden-sation of phenyl hydrazone 15 with malononitrile affordspyridine 19.Diverse biological activities have been described forfunctionally substituted pyridines and fusedpyridines. For example, pyridoxal phosphate playsan important role in metabolism as a coenzyme for avariety of biological transformations I. Nalidixic acidis bactericidal to most of common gram negativebacteria that cause urinary tract infectiorr",Moreover, several condensed pyridines have beenused as antimalarials and antibactrials'".In the present note we report the new routes forthe synthesis of substituted pyridines and thiophenesusing (3-ketoanilides 1 and the nitriles" 2 as startingcomponents, Reaction of la,b with arylidene-malononitriles 2a-c in ethanolic-piperidine solutionhas been reported to give 3-acetylpyridones8 4, Also1 reacts with 2 in ethanolic-sodium ethoxide to giveo °II IICH3-C-CH2-C-YCN/RCH=C~2 XY 2 R x• C6HS CNb C6H4Cl( p) CNc 4H4OCH3(P) CNd CoHs C02yHse 4H4CI( p) co.c.n,r 4H4OCH3(P) C02C2HsNote6-aminopyridones 5. It is assumed to be formed bythe addition of an active methylene in la,b to thearylidenes 2a-c to give the adduct 3, which iscyclized to yield 4 (Scheme I), Compound 4 finallyeliminates its acetyl group to form 5. Elimination ofacetyl group under similar conditions has alreadybeen reported".Compounds 5a,b were also obtained by reactingl-arylethylidenemalononitriles 6 with phenylisocyanate in dry dioxane containing catalyticamount of sodium metal 10. The reactivity of acetylgroup in 4 was studied. Thus, 4a reacted withmalononitrile in dry benzene containing catalyticamount of ammonium acetate and acetic acid to give8 (cf. Scheme I), the structure of which wasconfirmed from its elemental analysis and IRspectra. .The behaviour of 1 towards ethyl aryli-denecyanoacetates was investigated. Thus 1 reactedwith 2d,e to yield products, the type of whichdepends on the utilized reaction conditions. 3-Acetylpyridone 10 was obtained directly from thereaction of 1 with 2d,e in ethanolic-piperidine(Scheme II).On the other hand products with higher molecularweights were obtained from the same reactants onheating in ethanolic-sodium ethoxide. Structure 11has been suggested for the reaction product, basedon IH NMR spectra which clearly indicate theabsence of acetyl function and the presence ofolefinic protons in the product formed. Structure of11 was also confirmed by its formation from thereaction of 10 with aromatic aldehydes in ethanolic-sodium ethoxide solution. One may assume areaction pathway for the formation of 11 from 1 and2d,e that 1 reacts with 2 to yield a 1:1 adduct 9followed by cyclization to 10. Intermediate 10 thencondenses with another molecule of aldehyde,which exists in equilibrium with 1 specially inaqueous basic medium II to give the chalcones 11(Scheme II).A mixture of la,b, ethyl cyanoacetate andelemental sulphur when heated in ethanolic-triethylamine solution afforded 2-aminothiophenes14a,b. IR spectra of 14a,b indicate clearly that the·400 INDIAN J CHEM, SEC. B, APRIL 1998o 0II /ICH3-C-CH2-C-Yla, b2a-c 2a-c~H~H/PiperidineR <ifNCtiCCH3H2N N 0Ar4I AcOH / AcONH4• CH2( CN)2NcMCNH2N N' 0 0IAr8 R= C6HS4 RtINClrCN llA,LcoNHPh7Ara Ct;H5b Ct;H.Cl( p )e C6H.OCH3(P)d c, H4Cl( p )e c, H40CH3 ( P )RCt;H5yH5C6H5C6H40CH3( P )C6H40CH3( P )Ara C6H5b C6H.Cl(p)c C6H4OCH3( P )d Ct;H5e YH.Cl(p)Ct;H5Ct;H5C6H5C6H•OCH3( P )C6H.OCH3( p )Schemenla2 d-e r ? CONHPh ]HM02~COCH3~H OH / H3CC---{ CN . Jl. ..1.. 5 . . >---< H2N N 0Piperidine R C~~H IPh9 10R=yH5jRi:io"'H.CI(P)- H2R2 d-f H2~~DCOCH=CHR~H50Na / ~H50H H2N N 0- H20; - H2 ~h21111., R = Q;H5lib, R = Q;H.Cl (P)lie , R = Q;H.OCH3 (P)CN/CI-i2"XScheme IIcyano functions are involved in the cyclizationprocess and revealed the presence of amino groups.'H NMR spectrum of 14a exhibits in addition to thearomatic protons, signals corresponding to NH, NH2and ester groups which is in good agreement withthe proposed structures (cf. Scheme Ill). Formationof 14 is assumed to proceed via condensation ofethyl cyanoacetate with 1 to give an intermediate 12which reacts with elemental sulphur to affordmercapto derivative 13. Compound 13 then cyclizesto give product 14.Phenylhydrazone 15 when heated with malono-nitrile in dry benzene containing catalytic amount ofammonium acetate and acetic acid gave 3-cyano-2,6-dioxo-4-methyl-l, 2, 5, 6-tetrahydropyridine-5-phenylhydrazone 19 and not the anticipated 3-cyano-2, 6-dioxo-4-methyl-l, 2, 5, 6-tetrahydro-l-pheriylpyridine-5-phenylhydrazone 18. The forma-tion of 19 was established on the basis of its spectral(IR, 'H NMR and mass) data. 'H NMR spectrum of19 exhibited a multiplet showing the presence oftwo NH groups. If this product was 1812a singlet forNH would be expected. Further, the compound 19was not identical with an authentic sample of 18(m.p. and mixed m.p. and fmger print region in theIR spectrum). A sequence of reaction of theformation of 19 is shown in Scheme ill. SeveralNOTES 401Y=NH4HSY + NH4H4OCH3 (p11 13H3C ~~HsAfNHOC.Ji......"---)- NH21414 • , Ar = C1;Hs14 b , Ar = 4~OCH3 (P)o NNHPhPh N2CI II II CH2 (CNhL---=-----l~ H3C-C-C-CONHPhY = NH4HS AcOH / NH4 OAc1 S - H2018alkylheterocycles, such as 4-methylcoumarin13, 4-methylpyridazines and 4-methyl-3-cyanopyridine-thione", reacted readily with cinnamonitriles 2 toyield fused heterocyclic systems, whereas thecompound 19 failed to reach with the same reagentsunder a variety of drastic conditions.Experimental SectionAll melting points are uncorrected.IR spectrawere recorded on a pye-unicam SP 1000 instrument;'H NMR spectra on EM 90-MHz spectrometer inDMSO-d6 solution using lMS as internal standard(chemical shifts in 0, ppm), mass spectra on MS30NC CNVY CONHPh. VH3C IINNHPh16Scheme IIIor MS9, (AEI) mass spectrometers operating at 70i eV. Microanalyses were carried out by the.Microanalytical Data Unit at Cairo University.3-Acetyl-6-amino-1, 4-diaryl-1, 2,3, 4-tetrahy-dropyridine-S-carhonitriles (4a-e). A mixture ofacetoacetanilides 1a or 1h-(O.OI mole) and 2a-c in50 mL of ethanol containing few drops of piperidirjewas refluxed for 5 hr. The mixture was thehconcentrated and cooled. The solid that separatedwas filtered off, dried and crystallized from ethanolto give 4a-e. Compounds 4a-c were previouslyobtained according to the literature procedure".,402 INDIAN J CHEM, SEC. B, APRIL 19984b: Yield 2.2 g (60%), m.p. 1950 (Found: C,66.15; H, 3.53; N, 11.54. C2J!\3CIN302 requiresC, 66.21; H, 3.61; N, 11.58%); IR: 3459, 3326, 3243(NH2)IS-IS,2184 (CN), P15, 1708 (CO), 1645(8NH2)'4d: Yield 2.6 g (66%), m.p. 2280 (Found: C,63.81; H, 4.33; N, 10.36. C21HlsCIN303requires C,63.72; H, 4.85; N, 10.62%); IR: 3450,3320,3310(NH2), 2195 (CN), 1725, 1700 (CO), 1665 (8NH2)'4e: Yield 2.5 g (65%), m.p. 2200 (Found: C,67.62; H, 5.60; N, 10.53. CnH21N304 requires C,67.51; H, 5.41; N, 10.74%); IR: 3450, 3350, 3255(NH2), 2198 (CN), 1718, 1700 (CO), 1638 (8NH2)'6-Amino-l, 4-diaryl-2-oxo-l, 2-dihydropyri-dine S-carbonitrile S. Method A: A solution of laor lb (0.01 mole) in abs. ethanol (50 mL) containing0.23 g (0.01 mole) of finely divided sodium metaland 0.01 mole of the arylidenes 2a-c was refluxedfor 6 hr and then left to cool. The solution was thenneutralized with dil. HCI. The products so formedwere collected by filtration, crystallized fromethanol to give Sa-c.Method B: A mixture of 6a or 6b (0.01 mole),fmelydivided sodium metal (0.23 g, 0.01 mole),phenyl isocyanate (1 mL, 0.01 mole) in dry dioxane(40 mL) was refluxed for 4 hr. It was cooled andpoured onto cold water and neutralized with dil.HC!. The precipitate was filtered off and crystallizedfrom ethanol to give Sa-e which were identified bycomparison with authentic samples".Sc: Yield 1.9 g (60%), m.p. 2050 (Found: C,71.80; H, 4.82; N, 31.21. C1JilSN302 requires C,71.91; H, 4.76; N, 13.24%); IR: 3350,3200 (NH2),2195 (CN), 1710 (CO), IH NMR: 3.65 (s, 3H,OCH3), 6.75-7.80 (m, 9H, ArH and IH, CH), 9.85(s, 2H, NH2)IO;MS: mlz 317 (M+).Sd: Yield 2.0 g (63%), m.p. 1800 (Found: C,72.11; H, 4.38; N, 13.51. C1JilSN302 requires C,71.91"; H, 4.76; N, 13.24%); IR: 3350, 3250, 3200(NH2), 2210 (CN), 1710 (CO); IH NMR: 3.68 (s,3H, OCH3), 6.76-7.82 (m, 9H, ArH and IH, CR),10.2 (s, 2H, NH2); MS: mlz 317 ~).Se: Yield 2.2 g (62%), m.p. 1750 (Found: C,64.52; H, 4.33; N, 12.00. ClJil4CIN302 requires C,64.87; H, 4.01; N, 11.94%); IR: 3425-3230 (NH2),3195 (CN), 1695 (CO), 1640 (8NH2)'7-AminD-4-methyl-2(H)-oxo-S, 8-diphenyl-S,6-dibydropyrano [2,3-b ]pyridine-3, 6-dicarbonitrile8. To a mixture of 4a (0.01 mole), ammoniumacetate (OJ g) and acetic acid (0.5 mL) in drybenzene (50 mL), malononitrile (0.01 mole) wasadded. The reaction mixture was refluxed for 6 hr.The resulting solid product was filtered andcrystallized from ethanol-DMF to give 8, yield 2.3 g(60%), m.p. >3000 (Found: C, 72.70; H, 4.43; N,14.64. C23H16N402requires C, 72.62; H, 4.24; N,14.73%); IR: 3458, 3410, 3326 (NH2), 2203 (CN),1685 (CO), 1663 (8NH2)'Ethyl 3-acetyl-6-amino-2-oxo-l-phenyl-l,2,3,4-tetrahydropyridine-S-carboxylates 10a,b. To asolution of la (0.01 mole) in abs. ethanol (50 mL)containing 0.5 mL of piperidine 2d or 2e (0.01mole) were added. The reaction mixture wasrefluxed for 1 hr, and cooled. The precipitate thusseparated was filtered and crystallized from ethanolto give 10a,b.lOa: Yield 2.5 (66%),m.p. 1430 (Found: C, 69.65;H, 5.91; N, 7.35. CnHnN204 requires C, 69.83; H,5.86; N, 7.40%); IR: 3450, 3330 (NH2), 1730, 1720,1650 (CO).lOb: Yield 3.3 g (80%), m.p. 1300 (Found: C,63.90; H, 5.01; N, 6.52. C22H21CIN204requires C,64.00; H, 5 ~3; N, 6.79%); IR: 3465, 3269 (NH2),1737, 1720, 1649 (CO); IH NMR: 1.2 (t, 3H, CH3),2.32 (s, 3H, CH3), 4.2 (q, 2H, CH2), 4.3 (s, IH,pyridine H-4), ·5.85 (s, IH, pyridine H-3), 7.10-7.52(m, IIH, 9H, ArH and 2H, NH2).3-Aryl-l-(6-amino-4-aryl-l, 2-dihydro-S-etho-xycarbonyl- 2 -oxo-l-phenylpyridine-3-yl)prop _2-enone 11a-c. Method A: A suspension of la(0.01 (mole) and 2d-f(0.1 mole) in ethanol (50 mL)containing 0.01 mole of sodium metal were refluxed. for 10 hr and then cooled. The reaction mixture wasneutralized with HCI and the solid precipitated wasfiltered off, recrystallized from ethanol to give 11a-c.Method B: Compounds 11a,b could also beprepared from 10a,b and aromatic aldehydes and byusual work-up as reported in Method A.11a: Yield 3.2 g (70%), m.p. 2350 (Found: C,74.66; H, 5.11; N, 6.34. C~24N204 requires C,74.98; H, 5.21; N, 6.03%); IR: 3400, 3350, 3200(NH2), 1725, 1685, 1675 (CO), 1665 (NH2); MS:mlz 464 (M+).11b: Yield 3.2 g (60%), m.p. 2520 (Found: C,65.11; H, 4.45; N, 5.36. C2JinCl2N204 requires C,65.30; H, 4.16: N, 5.25%); IR: 3350, 3200 (NH2),1680, 1670, 1665 (CO), 1655 (8NH2); IH NMR:1.13 (t, 3H, CH3), 2.0 (s, 3H, CH3), 4.16 (q, 2H,CH2), 7.10 (d, J=9 Hz, IH, CR), 7.40-7.76 (m, 13H,ArH), 8.20 (d, J=9 Hz, IH, CR), 10.32 (s, 2H, NH2).He: Yield 3.1 g (60%), m.p. 2250 (Found: C,71.23; H, 5.40; N, 5.12. C31H2SN206requires C,70.98; H, 5.38; N, 5.34%); IR: 3360, 3330, 3250(NH2), 1700, 1685, 1675 (CO), 1660 (oNH2), 1610(C=C).Ethyl 2-amino-5-arylcarboxyanilid0-4-methyl-thiophene-3-earboxylates 14a-e. Equimolecularamounts of the anilide la or Ib (0.01 mole), ethylcyanoacetate and elemental sulphur (0.01 mole) inethanol (50 mL) were refluxed together withtriethylamine (1 mL) for 1 hr. The solid obtained oncooling was filtered off and crystallized fromethanol to yield 14a,b.14a: Yield 2.1 g (70%) m.p. 1720 (Found: C,59.15; H, 5.47; N, 9.08. CI5HI6N203S requires C,59.19; H, 5.30; N, 9.20%); IR: 3480, 3350, 3275(NH2' NH), 1678 (CO), 1640 (oNH2); IH NMR.:1.10-1.40 (t, 3H, CH3), 2.48 (s, 3H, CH3), 3.56-4.16(q, 2H, CH2), 6.8-7.04 (m, 7H, 5H, ArH and 2H,NH2), 9.60 (s, IH, NH); MS: m/z 305 (M+).14b:Yield 2.4 g (73%), m.p. 1550 (Found: C,57.21; H, 5.68; N, 8.54. CI6HISN20.S requires C,57.47; H, 5.43; N, 8.38%); IR: 3475, 332~ (NH2'NH), 1675 (CO), 1660 (oNH2); MS: m/z 334 ~).3-Cyano-2, 6-dioxo-4-methyl-l, 2, 5, 6-tetrahy-dropyridine-5-phenylhydrazone 19. To a mixtureof 2-acetyl-N-phenylethanamide-2-phenylhydrazone15 (0.01 mole) in dry benzene (50 mL), 0.5 g ofammonium acetate and glacial acetic acid (8 mL)was added malononitrile (0.01 mole). The reactionmixture was refluxed for 6 hr. Evaporation ofbenzene left a solid product which was crystallizedfrom DMF to give 19, yield 1.6 g (63%), m.p. 2650(Found: C, 61.13; H, 4.24; N, 21.76. C\3H1oN.02requires C, 61.41; H, 3.96; N, 22.04%); IR: 3470,NOTES 4033350 (NH), 2200 (eN), 1685, 1660 (CO), 1650(C=N); IH NMR.: 2.6 (s, 3H, CH3), 7.36-7.52 (m,5H, ArR), 7.6-7.8 (m, 2H, 2NH); MS: m/z 254 (M+).ReferencesI Henderson L M & Hulse J D, Vitamin B6: Relationship intryptopha metabolism in Hamam vitamin B6requirements, (National Academic of Sciences,Washington DC), 1978, 2J.2 Brumfit W & Puvsell R, Observations on bactericidessensitivities to nalidixic acid and critical comment on the6-centre survey, postgrad, J Med,47, 1941, 16.3 Domagala J M & Peterson P, J Heterocycl Chem, 26,1989, 1147 and references cited therein.4 Chydi D F, McCarthy V C, Miller R M & Hornick R B,Antimicrob Agents Chemother, 9, 1976,384.5 Miyamoto H, Ueda H, Otsuka T, Aki S, Tamaoka H,Tominaga M & Nakagawak, Chem Pharm Bull, 38,1990,2472.6 Radl S, Bartomoa M & Kova L, Cesk Farm, 40, 1991,145.7 Freeman F, Chem Rev, 80, 1980,329.8 Hammouda H A, EI-Reedy A M & Hussein S M, JHeterocycl Chem, 23,1986, 1203.9 Conde S, Corral C & Madronero Alvarez-Insva, Synthesis,1976,412.o EI-Taweel F M A,Jprakt Chem, 332,1990,762.II EI-Taweel F M A, Khodeir M N & Elagamey A A, AnQuim, 88, 1992,379.12 Mohareb R M & Ibrahim N S, J prakt Chem, 331, 1989,387.13 Hafez E A, Elnagdi M H, Elagamey A A & EI-Taweel FM A, Heterocycles, 26, 1987,903.14 Elnagdi M H, Abdel-Razek I & Erian A v.i, Tetrahedron,45,1989,3597.15 Elagamey A A & EI-Taweel F M A, Indian J Chem, 29B,1990,885.16 Elagamey A A, Sowellim S Z, EI-Taweel F M A &Elnagdi M H, Colin Czech Chem Commun, 53, 1988,1534.17 Elagamey A A, EI-Taweel F M A, Khodeir M N M &Elnagdi M H, Bull Chem Sac Jpn 66, 1993,464.18 Sowellim S Z A, EI-Taweel F M A & Elagamey A A, BullSac Chim r-, 133, 1996,229.

Synthesis of functionaly substituted pyridine and thiophene derivatives

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Synthesis of functionaly substituted pyridine and thiophene derivatives

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