Indi an Journal o f Chemi stry Vol. 40B, March 200 1, pp. 191 - 194

Reactions of 2-chloro-4,5-diamino-6-methylpyrimidine with 1,3-diketones-Formation of new substituted purines+

K Srinivas, P Shanthan Rao·, B Narsaiah & J Madhusudana Rao

Organic Chemistry Division , Indi an In stitute o f Chemical Technology, Hyderabad 500 007 .1ndia

Received /0 November/999: accepted (revised) 16 March 2000

Condensation of 2-chloro-4,5-diamino-6-methylpyrimidine 1 with 1.3-diketones 2 results intermed iate schifrs base 3 . The latter on cycl isation yie lds purines 4a-e. The reactio n of 1 with aromatic aldehyde is also studied .

The purine based nucleotide with appropriate sugar moiety are known to possess antiviral and anticancer activity 1

-3

• This has prompted us to attempt the synthesis of pyrimidinodiazepines with a view to couple with a sugar moiety and study the ir biological activity . One of the well known and simplest route to fuse a diazepine ring system from the condensation of I ,2-diamine with a I ,3-dicarbonyl compound results in the formation of the corresponding fused diazepine4

-6

. However depending on the reaction condition the reaction of I ,2-diamines with I ,3-dicarbonyl compounds is known to give a diazepine and some imidazole ring system may also be formed as byproduct. The present investigation involves a systematic study on the condensation of 2-chloro-4,5-diamino-6-methylpyrimidine 1 and carbonyl compounds.

The reaction of 1 with 1, 1, 1-tritluoro-2,4-pentanedione in toluene under microwave irradiation conditions gave an intractable material which showed several spots in TLC along with the unreacted starting material 1. However the above reaction in glacial acetic acid at room temperature yielded a crystalline compound with mp 225°C.The absorptions in the IR spectrum (KBr) of the compound showed the presence of a carbonyl and amino functional groups . It indicates the participation of one amine function in the reaction . The 1HNMR (CDCI3 +DMSO-d6)

revealed the presence of two methyls , amino group (0 20 exchangeable) and one signal appeared as a singlet at 8 5.2-5.8 ppm attributed to vinyl proton. The mass spectrum showed the molecular ion at m/z 294 and the fragment ions at m/z 197, 183 for the loss of tritluoroacetyl and tritluoroacetonyl groups

+IICT Commun icat ion No. 4446

respectively. Based on the spectral data it may be characterized as 2-chloro-4-amino-5-( I' -tritluoro­acetonyl-1-methyl) methyleneamino-6-methylpyrimi­dine 3b (Scheme 1). This finds support from literature that of the two amino groups of pyrimidinediami ne the 5-amino group preferentially involves in the Schiff's base formation or acetylation reaction comparing to 2 or 4 positions 7 .

The uncyclised monoschiff's base 3b was dissolved in a neutral solvent like toluene and subjected to microwave irradiation for a specified period. The TLC of the mixture showed several spots and starting material. When 3b was heated alone without solvent at 200°C gave a sublimed compound with mp 235 uc. The compound 3b was heated in nitrobenzene gave a crystalline solid mp 235 °C. Both the products obtained during cyclisation of 3b have same melting point and its mixed melting point was not depressed . Their IR spectra are superimposable and showed a broad peak between 3500-2400 cm-1 characteristic absorption of benzimidazole - NH function. The 1HNMR (CDC13 +DMSO-ch) spectrum revealed two singlets for methyls and broad signal due to -NH (020 exchangeable) function. Mass spectrum showed the molecular ion at m/z 182. Based on spectral data the compound was characterized as 2-chloro-6,8-dimethyl-7/ or 9 (H)-purine 4a. The reaction of diamine 1 and acetylacetone in glacial acetic ac id gave the intermediate 3a which on cyclisation in retluxing nitrobenzene yielded 4a.

The methyl group of pentanedione was replaced by aryl group with a view to see the effect of tritluoromethyl group on cyclisation to get the diazepine ring system. The condensation of diamine 1 and 1-phenyl-4,4,4-tri tluoro-1 ,3-butanedione in acetic acid gave the uncyclised schiffs base 3d which on

192 INDIAN J. CHEM., SEC 8 , MARCH 2001

!iN~ N

ClAN CH3

+

1

J PhCHO

NH2

:xN~CHPh N

ClAN I CH3

5

PhNO,l· Ph

N=(

:1NH N

ClAN CH3

4c

R'

~ R

2

R

a, CH3 b, c~

c, CF3

d, CsHs

e, p-CICsH4

f, p- F<;;H4

gla. AcOH

rt, 3h

R'

CH3 CF3

CF3

CF3

CF3

CF3

J

b, CF3

c, CsHs

d, p-CIC6H4

e, p-FCsH4

Scheme I

retluxing in nitrobenzene gave the corresponding purine 4c. The structure of 4c has been confirmed by comparing with an authentic sample synthesised by unambiguous route. The condensation of diamine 1 with benzaldehyde in equimolar ratio using acetic acid medium gave the intermediate mono schiff's base 5. The latter on heating in nitrobenzene gave the cyclised product 4c (Table 1) .

The cyclisation of the intermediate schiff's base has been tri ed under different experimental conditions, though the corresponding imidazole formation is tak ing place. Preferential attack of the 4-amino group

on C=N fun ction rather than at the carbonyl carbon of trifluoroacetyl group may be taking place to get imidazole but not diazepine system. The carbonyl group of the tritluoroacetyl group may be in the tautomeric form, thus the nucleophilic attack may not be favoured to give diazepine ring system. The condensati on of diamine 1 with different combi­nations of I ,3-diketones was carried out.

Experimental Section

Melting points are uncorrected . 1H NMR spectra were recorded on a Varian Ge mini-200 spectrometers ,

SRINIY AS eta/. : FORMATION OF NEW SUBSTITUTED PURINES 193

Table 1- Physical and spectral data of compounds 3a-f and 4a-e

Compd R R' mp Yield 1 H NMR(8,ppm) MS oc (%) (M+)

3a CH3 CH3 205 74 1.7(s.3H,N=C-CH3),2. 1 (s,3H,6-CH3) ,2.2(s,3H, R'CH3) . 240 5.2(s, I H,-CH=),5.6(s,brd.,2H,-N H2 ), 11 .4(s, I H,-OH)

3b CH3 CF3 225 96 1.8(s,3H ,-N=C-CH3),2.2(s,3H,6-CH3),5.5(s, I H,-CH=), 294 7 .2(s,brd.,2H,-NH2) , 11.3(s, I H,-OH)

3c CF3 CF3 140 79 2.5(s,3H.-CH3).7.8(s, I H,-CH=),8.6(brs 2H,-NH2), 11 .4(s, I H, 348 -OH )

3d C6Hs CF3 228 87 2.1 (s, 3H,-CH3), 5.8(s, I H,-CH=), 6(brs 2H,-NH 2) . 7.2-7.6(m, 356 5H, Ar-H ), 11.6(s, I H,-OH )

3e p-CIC6H4 CF3 194 71 2. 1 (s,3H , -C H3),5 .6(s, I H,-CH=),7 .2(d,2 H,A r-H) 7 .4(brs 2H, 390 -NH 2),7.8(d,2 H. Ar-H), 11 .2{s, I H.-OH)

3f p-FC6H4 CF3 180 73 2(s,3H,-CH3),5.8(s, I H.-CH=),7.0-7.6(m.6H,Ar-H). 11.4(s.l H, 374 -OH)

4a CH.1 235 8 1 2.6(s,3H,8-CH3),2.8(s,3 H,6-CH3) , 12.6(brs I H,-N H) 182

4b CF3 207 85 2.9(s,3H,-CH3), 12.8(brs I H,-NH) 236

4c C6Hs 282 78 2.8(s.3 H,-C H3) , 7 .4(m.3H,Ar-H),8.2(m,2H,Ar-H), 13.6(brs, 244 IH ,-NH)

4d p-CIC6H4 267 76 2.3(s,3H.-CH3),7 .3(d,2H,Ar-H),7.7(d,2H.Ar-H), 13.4(brs I H, 278 -NH)

4e p-FC6H4 257 83 2.6(s.3 H,-CH3),7 .2(m,2H,Ar-H),8.2(m.2H.Ar-H), 13.6(brs. 262 I H,-N H)

All -NH 2 protons are 0 20 exchangeable. Sati sfactory microanalysis obtained: C ± 0.12, H ± 0.1 0, N ± 0.05

using TMS as internal standard. mass spectra on a VG micromass 7070H instrument, and IR spectra recorded on a Ff-IR Schimadzu Perkin-Elmer 1310 infrared spectrophotometer. Elemental analyses were obtai ned on a Vario-EL instrument.

2-Chloro - 4 - amino - 5-(1' -trifluoroacetonyl-1'-methyl)methyleneamino-6-methylpyrimidine (3): General procedure. 2-Chloro-4,5-diami no-6-methy l­pyrimidine 1 (0.316g,2 mmoles) was dissolved in glacial acetic acid (3 mL) and I ,3 -diketone (2 mmole) was added dropwise with stmtng at room temperature. The react ion mixture was stirred for 3hr and poured on to ice. The separated solid was filtered, washed with water till washings are neutral to p H paper. The fi ltrate was neutra li sed with am monia solution to collect add itional small quantity of the earlier obtained solid . The solids combinedly dried and purified by passing th rough a column of si lica gel using CHCI3 : EtOAc ( I : I) as eluent and isolated compound 3.The reactions of 1-(4'- flu orophenyl)-4,4,4-trifl uoro-1 ,3-butaned ione and 1-( 4'-chloro­phenyl)-4,4,4-trifluoro-1 ,3-butanedione w ith diamine 1 has taken longer periods 15 hr.

2-Chloro-6-methyl-8-alkyl/ or aryl -7/ or 9(11)­purine 4 : General procedure. The uncyclised

compound 3 (I mmole) was dissolved in nit robenzene (2 mL) and refluxed for 3hr at its boiling point. The reaction mixture was cooled and 15-20 mL of hex ane was added. The separated solid was washed with excess hexane. That product was further purified through a column of silica gel using CHCI 3 : EtOAc ( I : I) to isolate pure compound 4.

2-Chloro-4-amino-5-(phenylmethylene)amino-6-methylpyrimidine 5. A mi xture of diamine 1 (0. 158g, I mmole) and benzaldehyde (0. 1 06g, I mmole) was dissolved in g lacia l aceti c ac id (3 mL) and stirred at room te mperature for 2hr. The react ion mixture gets solidified. The mixture was diluted wi th water (5 mL), filtered and thoroughly washed with

hexane . The monoschiff's base 5 was isolated in good yield after passing through a column us ing CHCb : EtOAc ( I: I ) as an e lu ent , mp 197 °C, y ield 85 %.

2-Chloro-6-methyl-8-phenyl-7 I or 9 (H)-purine 4c. The monoschiff's base 5 was di ssolved and refluxed in nitrobenzene for 2hr. The reacti on mi xtu re was cooled, diluted with hexane and the separated product was filtered. Thoroughly washed with hexane and passed through a column of chromatography to g ive pure compound 4c.

194 INDIAN J. CHEM ., SEC B, MARCH 200 1

Acknowledgement The authors are grateful to Dr K V Raghavan,

Director, IICT, for his constant encouragement. One of the au thors (KS) is thank ful to the CSIR, New Delhi, for the award of Senior Research Fellowship.

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