Heterocyclics imidazo pyridines

A ten Jt electron heterocycle, imidazo [7,2-a] Pyridine was studied by Paudler and Blewitt 115>. The protonation occurred at Ni, which was calculated to have a total n electron density less than N4 (Fig. 

Aminopyridines are useful substrates for the preparation of fused heterocycles. Imidazo[ 1,2- ]pyridines may be prepared in moderate to good yield by three-component coupling of 2-aminopyridine, aldehydes and isocyanides <1998S661>. The reaction proceeds by nucleophilic attack of the isocyanide onto an iminium species formed by condensation of 2-aminopyridine with the aldehyde component followed by 1,3-FI shift. For example, 2-aminopyridine reacts with benzylisocyanide and 2-hydroxyacetaldehyde in the presence of 2equiv of glacial acetic acid in methanol to give iiuidazo[2- ]pyridine 84 in 44% yield (Equation 57). 

Fig. 6.13 Detectors arranged in series. (Reproduced with permission from G. A. Gross and A. Gruter, J. Chromatogr., 592, 271 (1992).) Condition sample, heterocyclic aromatic amines column, 25cmx4.6mm i.d. stationary phase, TSK gel ODS80, 5iam mobile phase, 1 ml min water with 0.01 M triethyla-mine, pH 3.2 or 3.6, and acetonitrile, gradient UV 263 nm and fluorescence detectors. Peaks 1 and 5 = pyrido-imidazoles 2 and 4 = imidazo-chinolines 3, 6, 7, 8 = imidazo-chinoxalines 9, 10, 11, 13, 14 = pyrido-indoles 12 = an imidazo-pyridine.

Paudler and Helmick515 have measured half-lives for deuteration of some heterocycles by deuterated sulphuric acid at 100 °C. The equivalent first-order rate coefficients (lO ) are as follows imidazo[l, 2-a]pyridine, 427(3-H) imidazo[l,2-a]pyridine-N-methiodide, 62(3-H) imidazo[l,2-a]pyrimidine, 123-(3-H) imidazo[l,2-a]pyrimidine-N-methiodide, < 6.4 (3-H, 5-H) 1,2,4-tri-azolo [1,5-a]pyridimidine, 128(5-H) 1,2,4-triazolo [1,5-a]pyrimidine-N-methiodide, 11.7 (5-H). The lower reactivity in each case of the corresponding methiodides shows that the bases react as such and not as the conjugate acids. 

Kinetic studies of base-catalysed hydrogen exchange of heterocyclic compounds have been carried out. Paudler and Helmick515 measured second-order rate coefficients for deuteration of derivatives of imidazo[l,2-a]pyridine(XXXIII), imidazo[l,2-a]pyrimidine(XXXIV), and 1,2,4-triazolo[1,5-a]pyrimidine(XXXV)... 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

Reaction of pyrido[ 1,2- pyrazin-4-one 304 with methyl cyanoacetate, cyanamide, and JI-oxo nitriles in AcOH at 70 °C gave imidazo[ l,2- ] pyridine 331, imidazo[l,2- ]-pyrimidine 332, and tetracyclic heterocycles 333, respectively <1996JHC639>. 

Recent studies have demonstrated the synthetic potential of 5-aminoim-idazoles (96) as intermediates for heterocyclic synthesis, particularly for the synthesis of bicyclic systems, including imidazo[4,5-6]pyridines... 

Irnidazo[ 1,2-tf ]py ridines were covered in CHEC(1984) <1984CHEC(6)613> along with others imidazoles fused to six-membered rings and they were reviewed together with imidazo[l,5- ]pyridines in CHEC-II(1996) <1996CHEC-II(8)249>. The chemical literature on this heterocycle is very abundant, due to its easy synthesis (most of the preparations use readily available 2-aminopyridines) and to the very broad spectrum of bioactivities displayed by many derivatives. A simple Beilstein search on the fully conjugated heterocycle (free sites everywhere) disclosed ca. 3000 hits for the past decade. Therefore, this chapter cannot be exhaustive in view of space limitations, but will mainly focus on the original synthetic methods that have appeared in the last decade. 

Due to the importance of this heterocycle in medicinal chemistry, solid-phase synthesis of derivatives based on this condensation reaction have been investigated. The first report in this area uses a sodium benzenesulfinate resin 247 and gives access in five steps and good overall yields to a library of imidazo[l,2- ]pyridines 248 functionalized at C-2 with an enone moiety <2002OL3935>. Later on, the preparation of libraries of compounds related to 250 or 251 from Rink amide resin 249 have been published (Scheme 68) <2003TL6265>. 

Some other ten rr-electron N-heterocycles, but with a nitrogen atom shared by two rings, also present two or more conjugated nitrogen protonation sites. One such system is imidazo[l,2-a] pyridine (1-azaindolizine, [98]), which may be viewed as an... 

A number of other five-membered ring nitrogen heterocycles have been prepared by cyclative cleavage. The illustrative examples (Fig. 4) depict the synthesis of pyrazolones,12 succinimides and phthalimides,13 pyrrolo[3,4-h] pyridines,14 2-aminoimidazolones,15 imidazo[4,5-fr]pyridin-2-ones,16 and l,2,4-triazoline-3,5-diones.17... 

Heterocyclic chemistry was facilitated by microwave-expedited solvent-free chemistry utilizing mineral supported reagents [65]. The scope now includes parallel synthesis [66]. A representative multi-component condensation to create a library of imidazo[l,2-a]pyridines, imidazo[l,2-a]pyrazines and imidazo[ 1,2-a]pyrimidines is depicted in Scheme 12 [67]. 

Reaction of pyrido[l,2-a]pyrazin-4-one 145 with methyl cyanoacetate, cyanamide, and /3-oxo nitriles in AcOH at 70°C gave imidazo[l,2-a]pyridine 147, imidazo[l,2-u]pyrimidine 148, and tetracyclic heterocycles 149, respectively (96JHC639). 

A related intramolecular N-alkylation leading to saturated nitrogen heterocycles 99 can proceed via dehydration of intermediates 98 (Eq. 39) [96]. Unsaturated nitrogen heterocycles such as pyrroles [97], indoles [98], benzo-azoles [99], 2,3-dihydroimidazol-2-ones [100], and imidazo[l,2-a]pyridines [101] were obtained through similar cyclocondensation reactions. Interesting ruthenium-catalyzed syntheses of quinolines have been achieved by means of cyclocondensations of aniline derivatives with propanediols, aminoalcohols, or... 

---