Pyridine 2-methylimidazo pyridines

Figure 13.8 Mutagenic and carcinogenic heterocyclic amines (a) IQ (2-amino-3-methylimidazo[4,5-/ quinoline), (b) IQx (2-amino-3-methylimidazo[4,5-/ quinoxaline), (c) PhIP, (2-amino-l-methyl-6-phenylimidazo[4,5- ] pyridine), (d) 1,5,6-TMIP (2-amino-l,5,6-trimethylimidazo[4,5-6] p5ridine).

The replacement of the polar head group of a range of piperazines by a 2-methylimidazo[4,5-f]pyridine group provided efficient orally active platelet-activating factor antagonists, for example, compounds 191-193 <1996JME487>. 

Amino-2-methylanthraquinone 2-Amino-3-methylimidazo[4,5-/]quinoline (see IQ) 2-Amino-6-methyldipyrido[l,2-a 3, 2 -fil]imidazole (see Glu-P-1) 2-Amino-l-methyl-6-phenylimidazo[4,5-6]pyridine (see PhIP)... 

Several 3-aryl-2-methylimidazo[4,5-b]pyridines (36 X = H, R = H, 4-F, 4-Et X = Cl, R = H, 4-F, 3-CF3, 2,4-Me2, 2,4-Ch, 2-Me-6-Et, 3-CF3-4-C1) with pesticidal activity have been prepared in moderate yields by the reaction of /V-(2-chloro-3-pyridyl)acetamides (37) with aromatic amines in the presence of P2O5 and Et3N-HCl at 150 C.140 With X = H the cyclized products were isolated directly, whereas with X = Cl treatment of the intermediate amidines (38) with K2CO3 in DMF was required to arrive at the final cyclized product. 

On being heated with 5" aqueous alkali, 3-bromo-2-phenyl-4-oxo-4//-pyrido[l,2-a]pyrimidine was transformed to 2-phenylimidazo[l,2-u]pyri-dine, whereas the 2-methyl analog in 7"0 aqueous potassium hydroxide yielded a mixture of the 3-unsubstituted- and 3-carboxy-2-methylimidazo-[l,2-u]pyridines. Under similar conditions, 3-bromo-2-chloro- and 3-bromo-4-oxo-4ff-pyrido[l,2-a]pyrimidines decomposed to 2-aminopyridine.294... 

Note FAP familial adenomatous polyposis ACF aberrant crypt foci FAD focal areas of dysplasia B[a]P benzo[a]pyrene DMBA 7,I2-dimethylbenz[a]nthracene TPA 12-O-tetradecanoyl-phorbol-13-acetate NNK 4-(methyl-nitrosamino)-I-(3-pyridyl)-l-butanone NQO 4-mtroquinoline 1-oxidase DMAB 3,2 -dimethyl-4-aminobiphenol PhIP 2-amino-l-methylimidazo[4,5-b]pyridine DHPN 2,2 -dihydroxy-di-n-propylnitrosamine EHEN jV-ethyl-jV-hydroxyethylnitrosamine. 

Halogenation of the imidazo[4,5-6]pyridine 4-oxides has provided some interesting results. Treatment of compound (123 R = H) with phosphorus oxychloride gave, with loss of the /v-oxide group, a mixture of the 5-chloro (124) and 7-chloro (125) isomers in comparable amounts in an overall 74% yield (Equation 3) <82JHC513>. The reaction of 3-methylimidazo[4,5-6]pyridine 4-oxide (123 R = CH3) with phosphorus oxychloride also gave a mixture of products but the yields were different, i.e. 5-chloro (124) (20%) and 7-chloro (125) (41%). However, with l-methylimidazo[4,5-6]pyridine 4-oxide (126), the chlorine atom was introduced exclusively into the more sterically hindered 7 position to give the 7-isomer (127). None of the 5-isomer was detected in this reaction (Equation (4)). 

The position of methylation of 2-methylimidazo[l,2-a]pyridine (2) has been established as N-1 by an ambiguous synthesis of l,2-dimethylimidazo[l,2-o]pyridine (3) from (4) (65JHC331). This work was extended by others to protonation and to methylation of other imidazo[l,2-o]pyridines <66JOCl29S), and it verified earlier conjectures concerning the position of quaternatization (55CB1093,26CB2048, 64JCS4226). 

Metalation of the parent heterocycle with phenyllithium produced (71a) or (71b) after quenching with cyclohexane or DMF (72JHC1157,75JHC379), respectively, indicating metalation at C-3. Treatment of (71c) with n-butyllithium followed by methyl iodide produced the C-4 substituted compound (71d). The anion was also quenched with various carbonyl compounds (80TL2195). Treatment with Raney nickel afforded 4-methylimidazo[l,5-fl]pyridine (71e). 

Alkylation of 3-methylimidazo[4,5-h]pyridine (88) with alkyl halides occurred at N-1 to give the quaternary salts (89) (68KGS954, 73KGS570, 73KGS1686), whereas methylation of the 1-methyl isomer (90) gave the l,4-dimethylimidazo[4,5-h]pyridinium chloride (91) or iodide... 

Nitration or bromination of 1- or 3-methylimidazo[4,5-fc]pyridines (102) occurs at C-6 giving (101) (68KGS953, 71KGS279), but nitration of imidazo[4,5-fe]pyridine 4-oxide (104) takes place at C-7 to give (105) (66UC403), indicating the effect of the iV-oxide on the... 

Radical methylation of 3-methylimidazo[4,5-h]pyridine (106) gave in 71% yield a mixture of 2,3,5,7-tetramethylimidazo[4,5-Z>]pyridine, 2,3,7-trimethylimidazo[4,5-h]pyridine and 2,3-dimethylimidazo[4,5-6]pyridine (107) in a ratio of 1 9.3 14.7. Similar methylation of the dimethyl compound gave a 57% yield of the tetra- and tri-methyl compounds in a 1 5 ratio. l,2-Dimethylimidazo[4,5-h]pyridine (108) was methylated simultaneously in the 5-and 7-positions (109), with the 7-position being more reactive than the 5-positions (78MI41004). 

Reaction of l-methylimidazo[4,5-c]pyridine-2(3Jf )-thlone (177) with nitric acid, or that of l-methylimidazo[4,5-c]pyridine and its 2-methyl derivative with a mixture of nitrous... 

Figure 11.4. Structures of various heterocyclic amines. IQ is 2-amino-3-methylimidazo-quinoline. MelQx is 2-amino-3,8-dimethylLtnidazo-quinoxalme. 4,8-DiMelQx is 2-amino-3,4,8-trimethylimidazo-quinoxaline. PhIP is 2-amino-l-methyl-6-phenylimidazo-pyridine. These and other related compounds can be found in fried or broil beef, fish, and chicken, but can also be created by cooking mixtures of creatinine, amino acids, and glucose. Microwave cooking, or cooking in aluminum foil, reduces the formation of heterocyclic amines. (From Sugimura, 1997.)...

IQ 2-amino-3-methylimidazo[4,5-/]quinoline MelQx 2-amino-3,8-dimethylimizado[4,5-/]quinoline PhIP 2-amino-l-methyl-6-phenylimizado[4,5-h]pyridine... 

Numerous l,3,4-oxadiazin-5(6//)-ones can be prepared by this type of cyclization. Examples arc 2-(l-ethyl-l-hydroxypropyl)-4-phenyl-4//-l,3,4-oxadiazin-5(6//)-one (6),40 4-phenyl-2-(4-tolyl)-4//-1,3,4-oxadiazin-5(6//)-one (7) (which is claimed to be useful as a miticide and nerna-tocide),41 4-cyanomethyl-, 4-(2-cyanoethyl)-, 4-(3-cyanopropyl)- and 4-(4-cyanobutyl)-6-methyl-2-phenyl-4//-l,3,4-oxadiazin-5(6//)-onc (8, n = 1, 2, 3 and 4, respectively) (which inhibit monoamine oxidase Type A and Type B),42 various 2,4-diaryl-4//-l,3,4-oxadiazin-5(6//)-ones 9 (which possess acaricidal activity),43 cardiotonic 2-aryl derivatives 10,44 and some heteroaryl-substituted compounds, such as 2-[4-(imida/.ol-l-yl)phenyl]-4f/-l,3,4-oxadiazin-5(6//)-one (11) (which is claimed to be cardiotonic and antihypertensive)45 and 2-(2-methylimidazo[l,2-a]pyridin-3-yl)-4//-l,3,4-oxadiazin-5(6//)-one (12) (which inhibits blood platelet aggrega-... 

Kinae et al. (2095a) reported that A-heterocyclic amines [2-amino-3-methylimidazo[4,5-/ quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-/ quinoline (MelQ), l-methyl-6-phenyl-l//-imidazo[4,5-/7]pyridin-2-amine (PhIP)] were produced in an incubated solution of D-glucose and several amino acids at much lower temperatures and longer time periods than those encountered in the cooking of various foodstuffs (beef, poultry, fish). Several A-heterocyclic amines not found in CSC were also generated. The generation of the A-heterocyclic amines, as measured by the Ames test (Salmonella typhimurium TA 98), increased in proportion to the conditions imposed 37°C (90 d), 50°C (30 d), 128°C (2 h)... 

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