Imidazo pyridine, formation

This reaction appears to be similar to the imidazo-pyridine formation mentioned above, most likely via a [5+1] insertion reaction of the isocyanide into the corresponding hydrazone. This reaction mechanism seems likely since only electron-rich aromatic hydrazines yielded cinnolines. The Ugi 4-CR reaction with phe-nylhydrazine is known and has been reported to give the expected Ugi-type 4-CR product. 

In 1998, three different research groups discovered a novel multi-component reaction almost simultaneously40. They found (partly by serendipity ) that when using 2-aminopyridines as the amine component in the Ugi four-component reaction (4CR), the formation of imidazo-pyridines was observed. The imidazo-pyridine is the product... 

Scheme 5.10 Presumed mechanism of imidazo[1,2-a]pyridine formation.

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. 

More recently, a new and straightforward one-pot approach was reported by Bu et al. <2003JOC5415>. This reaction involves the cyclocondensation of l,2-dipyridin-2-yl-ethane-l,2-dione 120 and arylaldehydes, in the presence of ammonium acetate. Imidazo[l,5- ]pyridines 121 were obtained in reasonable yields, but competitive formation of imidazoles 122 was observed. The amount of ammonium acetate used in this reaction was also shown to strongly influence the yield of the cyclization (Scheme 38). 

Table 13 Palladium-catalyzed C-C bond formation from halo derivatives of imidazo[1,2-a]pyridines...

Imidazo[4,5- ]pyridines 117 <2003BML2485>, 118 <2004BML3165>, 119 <2005BML2129>, and 120 <2003BML289> have been prepared from the corresponding diaminopyridine and the appropriate trialkyl ortho-formate or, in the case of 120, triethyl orthopropionate. However, in each case, the authors fail to report product yields. 

Fig. 13.2. Illustration of the basic concept of Basis Products, (a) The PGVL reaction scheme of VRXN-2-00051 (formation of the H-imidazo[1,2-a]pyridine ring system using aminoheterocycles and alpha-halo ketones) is used for the illustration (b) The Basis Products of A are formed by all A reactants with one constant reactant (B CAP, 1 -bromopropan-2-one). The Basis products of are formed by all reactants with a constant A reactant (A CAP, 2-amino pyridine). The blue triangle and yellow hexagon represent two such basis products. The red star represents a product molecule which is related to those two corresponding basis products.

Reactions with methylphenylcyclopropenone (154) provided an opportunity to compare the reactivities of the two different C—CO bonds. The reaction of 2-aminopyridines with methylphenylcyclopropenone (154) proceeded more slowly than with the diphenyl analog (153). In ether, formation of the ds-2-oxopyrido[l,2-a]pyrimidines (158 R1 = Me) and/or the imidazo[l,2-c<]pyridines (162) was observed, indicating that the cycloaddition proceeds via cleavage of the PhC—CO bond. The methyl-substituted trans-2-oxopyrido[l,2-a]pyrimidine (160 R1 = Me) was only detected in the reaction mixture of 2-amino-3-methylpyridine, where the H NMR spectrum exhibited signals assigned to 160 (R1 = Me, R = 9-Me). The compound was not isolated. The imidazo[l,2-a]pyridines (162) readily hydrolyzed to the acids (163), work-up therefore leading mainly to isolation of the acids. 

The reaction with pyridone (167) was interpreted as proceeding by the formation of the pyridone (168), followed by the Smiles rearrangement leading to the spiro compound (169), which by ring opening provides the pyrimidine derivative (170). In a subsequent cyclization step the pyrido-[1,2-aJpyrimidine skeleton (171) is formed, and finally hydrolysis of the imino group leads to the 6-oxo derivative (172). In the homologous imidazo-[l,2-n]pyridine series, the 5-iminoimidazo[l,2-c<]pyridine intermediate of type (171) could be isolated. 

A kinetic study of the bromination of imidazo[l,2-u]pyridine showed reaction to take place on the neutral species, at the 3-position, and 2000 times faster than at the 5-position in imidazole (74AJC2349), the formation of a stable 6ir-pyridinoid ring in the transition state for the former accounting for this reactivity difference. 

Similarly, a novel one-pot microwave-assisted reaction has been described by Hulme and co-workers that enables the selective formation of 3-iminoaryl-imidazo[l,2-a]pyridines 19 and imidazo[l,2-a]pyridyn-3-ylamino-2-acetonitriles 20, in good yields. Reactions were performed in methanol by mixing a suitable a-aminopyridine, an aldehyde and trimethylsilylcyanide (TMSCN) with polymer-bound scandium triflate, to afford either product 19 or 20 (Scheme 16). Initially, the 3-iminoaryl-imidazo[l,2-a]pyridine 19, was observed as a minor side product (0-10%) during the pseudo-Ugi reaction affording the 3-aminoimidazo[l,2-a]pyridine 18. However, by increasing the aldehyde input to 2.2 equiv the reaction could be directed to the formation of 19 in moderate yields. Interestingly, low yields of... 

In a recent article by Beifuss and co-workers [126], the synthesis of pyrido [2, l 2,3]imidazo[4,5-c]isoquinolin-5(6//)-ones 90 has been described in good yields by means of a microwave-assisted three-component reaction of a 2-amino-pyridine, an isocyanide and a 2-carboxybenzaldehyde under acidic conditions. The reactions are easy to perform, robust, and highly efficient. This process allows the formation of two heterocyclic rings and four new bonds in a single synthetic operation (Scheme 67) ... 

The 3-substituted-imidazo[l,5-a]pyridines (ix) were conveniently synthesized in a two step protocol from picolinic esters (vii) via the formation of picolinamides (viii) under microwave radiation by Aravapalli et al. [12]. Zhu et al. [13] used the ionic liquid 1,2,3-trimethyl-imidazole tetrafluroborate for the synthesis of ZnOHF nanabelts (NBs). 

Oxidation of imidazo[l,2-a]pyridin-2(3if )-one (31) results in the formation of a red dye (24CB2092, 23MI41000), which probably has the structure (57) (26CB2921). 

Alkylcobaloximes (313) with acetic anhydride in pyridine gave an imidazo[l,2-a]pyridine (314). A mechanism for the degradation of (313) involving formation of (314) prior to cleavage of the cobalt complex has been proposed (75JCS(P1)386). 

Synthetic procedures exist for both saturated and unsaturated imidazo[l,5-a]pyridines. All procedures form the five-membered ring by formation of one bond adjacent to the... 

Cleavage of perhydro-imidazo[l,2-a]pyridine (211) with diisobutyl-aluminum hydride produces 1,4-diazacyclononane (82TL4I8I). Addition of phenylmagnesium bromide to 2-phenyl-6,7,8,8a-tetrahydro-3//,5//-imi-dazo[l,2-a]pyridin-l-oxide (224) resulted in the formation of 2,2-diphenyl-perhydro-imidazo[l,2-a]pyridin-l-ol (225) (83AP47). 

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