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Site Selective Alkoxymethylation of Imidazo[4,5-b]pyridines: Structural Analysis by High Field NMR Methods

1993; Elsevier BV; Volume: 36; Issue: 5 Linguagem: Inglês

10.3987/com-92-6224

1881-0942

J. William Lown, Malvinder P. Singh, Yadagiri Bathini,

Synthesis and Characterization of Heterocyclic Compounds

The alkylation -lions of 2-aryl-1(3)H-imidazo[4J-b]pyridines (equivalml to 1d-purines) with alkoxymuhyl chlorides and bromoacetonivilc arc desuibcd.The svuctlrral assipmenla of the p n d w wen made by rhs use of twodimsnsional I H -~H NOE (NOFSY) and sdcctive INEFl (NAPI') I3c nmr experiments utilizing polailation w n s f a from csrban-bound hydrogens in the alkyl side chains to sdsted resananca via long-range 31CH muplings.Although three isomeric N-alkyl dsrivatives d d arise fmm a single heferocycle based on mnsidaarim of lauomaic equillibaa, however, the d m exhibit marked site sclstivity evm under quite d i f f m t d o n mnditim.Thus.N-3 dkyl derivatives arc pmdud wdusively in basic (Et3N/NaH) nonpolar media following an SEZfB mshanisrn.Solvent dfsls m z evident in a loss of N-3 vs N-1 sdeetivify far akylafion whm the polar a p t i c salvmt DMFis used.Under neutral mnditim d i m dkylatim omm al the N-4 position following an SE2' &sm.The overall site selectivity aplxars to be govaned by the relative d v i t y of individual nwlmphilic sites ratha than tAe tautomrie mmpsition id solution.washed with wata, dried %SO4) and evapaated to afford a solid -due which was d y d before and after putilkation by silica gel flash chromatography (2: I E1OAc:Hexane duant).Mahod B. l l i s p d was similar lo method A in dl respeeu except for the use of anhydrous DMF in place of b c as the d o n aolvent.Method C involved ucatmcnt of rhe hererocyde derivative with dkyl halide in DMF.At the hepletion of the reaction as madtored by nmr of the diquou.Lriethylamine was added and the -tion mixture worked up as desaibed undm melhod A.3-Methoxymethyl-2-(4-mcthaxyphenyl)-5-melhyl-3H-imld.Eol4,5-b]pyridiac (4. ) was obtained in 88% isolated yield from 1 and methoxymethyl chloride using method A. mp 109-111 ' C (MeOHiHexane); ir (KBr) vm, 2980.2940.2830.IMX).1500.I460 c m l ; IH nmr (CDCl3) 6 2.64 (3H.s.C5-CH3).3.54 (3H.s, CH20CH3).3.86 (3H.n.C4*-0CH3), 5.60 (ZH.s, CH& 7.02 (2H.d, J = 8.5 Hz C3dC~n-H).7.10 (IH.d.I = 8 Hz.Cg-H).7.90 (LH.d.I = 8 Hz.C7-H).8.02 (ZH, d.I = 8.5 Hz, C21C6~-H); 13c nmr (-3) 8 24.49(C5-CH3).5537 (C4--OCH3).57.16 (OCH3), 72.87 (CH2).114.24 (C3dC5*).118.87 ( c d , 122.14 (C1n).126.86 (C7) 130.99 (C$61), 132.64 (CT~), 148.84 (C3& 153.20 (Cg) 154.45 (C;?), 16131 (C4*); fikns d c d for CI6Hl7N3% d z 283.1321, found miz 2%3.1320(M+, 113%).252 (97%).238 (21%); a. Calcd for C16H17N302: C, 67.W. H, 6.00, N. 14.84.Found: C. 67.74; H, 6.21; N, 14.%.3-Ethaxymethyl-2-(4-methoxyph~nyl)-CmelhyI-3H-lmidazo[4,5-b]pyridine (5. ) was obtained in 92% isolated yield fmm 1 and ethoxymethyl d o r i d e using method A. mp 122-124 ' C (EcoWHexane); ir (KBr) v , , 2960.