Indian Journal of Chemistry Vol. 438, March 2004, pp. 667-669

Note

Synthesis of triazolo-pyrimidine, tetrazolo­pyrimidine and pyrimido-triazepine

C S Andotra* & Sukhbinder Kaur

Department of Chemistry, University of Jammu , Jammu 180006

Received 13 March 2002; accepted (revised) 24 Jun e 2003

Some 4-substituted aryl-6-(2,4-dialkoxypheyl) 1,2,4-triazolo­[4,3-aJ-pyrimidine, 4-substitutedaryl-6-(2,4-dialkoxyphenyl)-tet­razolo-[I ,S-aJ-pyrimidine and 4-substitutedaryl-6-(2 ,4-dialkoxy­phenyl) pyrimido-[2, l-cJ-[ I ,2,4J-triazepine have been synthesized from 4-substi tu tedary 1-6-(2,4-d i al kox y phen y 1)-2-h ydrozi nopyri­midine.

IPC: InLCL7 C 07 0253/00

Numerous pyrimidine derivatives are well known drugs for variety of diseases. Some pyrimidines are physiologically as well as pharmacologically impor­tant. Literature survey reveals that compounds having 1,2, 4-triazole, tetrazole nucleus and seven membered ring with one or more hetero atoms in them have at­tracted considerable attention as they are endowed with wide range of pharmaceutical activities like anti-b . 112 . 34 ·f 15-7 h b· ·d 189 actena· anticancer·, anti unga , er ICI a .,

. HIY IO II·h . 121 3 d .. fl antl- . , anti ypertenslve . , an antl-1I1 am-matory 14 etc. Because of the importance of 1, 2, 4-triazole nucleus and in continuation of our earlier work 15·20 on the synthesis of 1, 2, 4-triazole nucleus

and our search for biologically active new heterocy­cles, we report herein the synthesis of some tria­zolopyrimidine, tetrazolo pyrimidine and pyrimido­triazepine.

It has been reported that hydrazino pyrimidimes can be considered as key starting materials for the synthesis of diverse nitrogen bridgehead compounds. Thus the hydrazino pyrimidine reacted with formic acid and acetic acid giving triazolo [4, 3-a] pyrimidine derivative 1. Also when reacted with ni­trous acid and acetyl acetone gave the tetrazolo [1, S­a] pyrimidine derivative 2 and pyrimido [2, I-c] [1 , 2, 4] triazepine derivative 3 respectively . The IH NMR spectra of triazolo-pyrimidine showed signal at 1.2-lA as singlet for IH, 3-methyl triazo·lopyrimidine showed a signal at 1.3-1.4 as singlet for 3H which confirmed the triazole ring proton . In tetrazolo­pyrimidine no signal was recorded as there is no pro­ton in the tetrazole ring. Primido-triazepine spectra showed two singlet at lA-I.5 for 2CH3 present at po­sitions 3 and 5 which are interchangeable with CH3 of the OCH2CH3 group and C-H at positions 4 appeared as singlet at 3.5 for 1 H which confirmed primido­triazepine ring proton .

Experimental Section All the melting points were determined in Bucchi

melting point apparatus and are uncorrected. IR spec-

2

668 INDIAN J. CHEM., SEC B, MARCH 2004

tra were recorded using KBr disc on Pye unicam SP-2000, 'H NMR spectra in CDCb DPX-200 (200 MHz) (chemical shi fts in 8ppm) and mass spectra on Ion trap Brker-3000 Ms spectrometer.

4-Substituted aryl-6-(2, 4-dialkoxyphenyl)-I, 2, 4-triazolo[4, 3-a]pyrimidine 1. A solution of 4-substituted aryl-6-(2, 4-dialkoxyphenyl)-2-hydrazi no­pyrimidine (0.01 mole) in 25 mL formic ac id or 25 mL acetic acid was allowed to stand at 25°C for 24 hr. To this mixture were added few drops of PPA and it was refluxed for 3 hr. The product was decom­posed on crushed ice and the resultant precipitates were filtered off, washed with cold water and crysta l-

li zed from proper solvents. The IR spectra showed peaks at 3216 (N-H), 3000 (C-H), 1672 (N=N), 1356 (C-N). The 'H NMR spectra of Ie showed signals at 81.28 (lH, s, H-3) 1.47 (3H, t, 1=7.02 Hz, -OCH2 CHr 4" ). 1.67 (3H, t, 1=6.9 Hz, -OCH2 CH3-2"), 4. 15 (2H, g, 1=7.02 Hz, -OCH2-4") 4.28 (2H, g, 1=6.9 Hz, -OCHz-2") 6.64 (2H, dd, 1=8.85, 2.2 Hz, H-6' H-6"), 7.48 (lH, s, H-5), 7.S3 (3H, unresolved dd, 1=7. 12, 4.33 Hz, H-3' HA' H-5 '), 7.8 1 (lH, d 1=8.8Hz, B-2') 8.18 (2H, dd, 1=1.59 Hz, H-3"-H-S"). MS: mlz 360 (M+), 330 (100%), 301, 287, 272, 245, 204. The melt­ing points and yields of con.pounds prepared are given in Table I.

Table 1- Characteri za tion data of compounds la-p, 2a-h and 3a-'1

Compd R RI R2 m.p. Yield (OC) (%)

la ' C6HJ(OCH3)2 C6Hs H 148 80

l b C6H)(OCH)h C6H4(OCH) H 168 79

Ie C6H)(OCH.lh C6H3(OCHJh H 190 80

Id C6H3(OCH)h Cr,H)(OCH3)(OC2Hs) H 140 82

Ie C6H)(OC2Hsh C6Hs H 188 82

If C6H~(OC2Hs)2 C6H4(OCH) H 140 84

Ig C6H3(OC2Hs)2 C6H4(OCH3h H 170 83

Ih C6HJ (OC2Hs)2 C6H4(OCH3)(OC2Hs) H 125 80

Ii C6H3(OCH1h C6Hs CH) 130 74 l' .J C6H,(OCH1h C6H4(OCH) CH) 120 73

Ik C6H,(OCH)h C6H)(OCH)2 CH) 190 76

II C6H)(OCHJh C6HJ(OCH)(OC2Hs) CH) 210 72

1m C6H1(C'C2Hs)2 C6HS CHJ 238 76

In C6HJ(OC2Hs)2 C6H4(OCH3) CH) 168 78

10 C6HJ (OC2Hsh C6H4(OCH3)2 CHJ 155 74

Ip C6H1(OC2Hsh C6H)(OCH) (OC2Hs) CH) 190 73

2a C6H)(OCH)2 C6HS 65 63

2b C6H 1(OCH3)2 C6H4(OCH) 125 70

2e C6 i-1 3(OCH)h C6H)(OCH)2 95 64

2d C6H)(OCH)h C6H)(OCH) (OC2Hs) 85 69

2e C6H3(OC2Hs)2 C6HS Low melting 63

21" C6H)(OC2Hs)2 C6H4(OCH3) Low melting 65

2g C6H)(OC2Hs)2 C6H4(OCH)h Low melting 68

2h C6H)(OC2Hs)2 C6H4(OCH)(OC2Hs) Low melting 62

3a C6H)(OCH)2 C6HS 163 64

3b C6H)(OCH3h C6H4(OCH) 128 62

3c C6H3(OCH)2 C6H)(OCH)h 108 64

3d C6H)(OCH)2 C6H)(OCH) (OC2Hs) 98 66

3e C6HiOC2Hsh C6HS 102 63

31" C6H)(OC2Hs)2 C6H4(OCH) 160 73 3g C6H3(OC2Hsh C6H4(OCH3h Low melting 61 3h C6H)(OC2Hs)2 C6H4(OCH)(OC2Hs) 50 61

-,

NOTES 669

4-Substituted aryl-6-(2, 4-dialkoxyphenyl)-tetra­zolo[I,5-a]pyrimidine 2. The solution of 4-substi­tuted aryl-6-(2,4-dialkoxyphenyl)-2-hydrazinopyrimi­dine (0.01 mole) in cold cone. HCI «30%, 5 mL) was treated gradually with cold cone. solution of sodium nitrite (0.015 mole in IS mL water) at 0.-5°C with stirring. The reaction mixture was left aside at room temperature for 1 hr. The precipitated solid was filtered, washed with cold water and was subjected to column chromatography, over silica gel (100-200 mesh), using petr. ether (60-80°), benzene and ethyl acetate mixture as eluants. The IR spectra showed peaks at 3160 (N-H), 1660 (N=N), 1604 (C=N) , 1304 (C-N). The I H NMR spectra of 2e showed signals at ~1.34 (3H, t, J=7 .12 Hz, CH2CH3-4") 1.52(3H, t, J=6.52Hz, CH2CH3-2"), 4.03 (2H, dd, J= 7.12 Hz, CH2 CH3-4") , 4.06 (2H, dd , J=6.52 Hz, CH2CHr 2"), 6.45 (2H unresolved dd J=8.7 , um'z, H-6', H-6"), 7.37 (3H unresolved J=5.5, 1.95Hz, H-2', HA', H-5"), 7.6 1 (2H, d, J=4.19 Hz H-3' , H-5') 7.67 (I H, s, H-5) 7.8 (I H, s, H-3"); MS: mlz 360(M+) 274(l00%)255, 163, 133, 103,66. The melting points and yields of compounds prepared are given in Table I.

4-Substituted aryl-6-(2, 4-dialkoxyphenyl)-pyri­mido[2, l-e][l, 2, 4]triazepine 3. A solution of 4-substituted aryl-6-(2, 4-dialkoxyphenyl)-2-hydrazino­pyrimidine (O.ot mole) in acetylacetone (20 mL), was refluxed in presence of few drops of PPA for 6 hr. The product was decomposed in cold water and extracted with ethyl acetate. The extract was dried on anhyd. Na2S04. It was then filtered off and ethyl acetate dis­tilled off. The desired product was obtained after col­umn chromatography using pet. ether (60-800), ben­zene and ethyl acetate mixtures as eluant. The IR spec­tra showed peaks at 3316 (N-H), 1552 (N-N), 1360 (C­N). The 'H NMR spectra of 3f showed signals at ~1.20 (3H, S, CH3-3), t.41 (3H, s, CHr 5), 1.46(3H, t, J=5Hz, OCH2CHr 4,), 1.52 (3H, t, J=7.02 Hz, OCH2CHr 2"). 3.51 (I H, s, H-4), 3.85 (3H, S, -OCHr 3') 4.08 (2H, dd, )=5 , 5Hz, OCH2CH3A"), 4.12 (2H, dd, )=7.02, 7.02 Hz, -OCH2 CHr 2"), 6.4 (2H, dd, J=7 .1, 2.24, Hz H-3', H-5'), 6.91 (lH, s H-5), 8.05 (4H, br, dd, J=2.24,

4.86 Hz, H-2', 5', 6', 6"), 8.12 (lH, s H-3"). MS: mlz 444(M+), 416,398,382(100%) 365, 326. The melting points and yields of compounds prepared are given in Table I.

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