Imidazopyridine synthesis

Imtdazo[4,5-c]pyridtne, 4,5,6,7-tetrahydro-synthesis, 5, 623, 640, 641 Imidazo[4,5-c]pyridine-6-carboxylic acid, 4,5,6,7-tetrahydro-synthesis, 5, 623, 641 Imidazopyridines as anthelmintic, 1, 202 synthesis, 5, 462 Imidazo[l,2-n]pyridines deuterium exchange, 5, 611 diazo coupling, 5, 614 Dimroth rearrangement, 5, 613 halogenation, 5, 611 hydrogenation, 5, 614 Mannich reaction, 5, 612 nitration, 5, 612 1-oxides... 

As with the reaction of pyrroles, diazoles and triazoles react with propargyl bromide to yield TV-substituted products and, depending upon the base strength, either TV-prop-2-ynylazoles or allenic derivatives are formed [30]. Generally, with potassium carbonate under soliddiquid two-phase conditions at room temperature in the absence of a solvent, the prop-2-ynyl compounds are formed as sole products, whereas with solid potassium hydroxide at elevated temperatures the allenes are obtained as the major products. Benztriazole produces a mixture of the N1- and N2-prop-2-ynyl, and N2-allenic derivatives, whereas with potassium hydroxide only the N -allenic derivative is obtained. The alkynes readily isomerize to the allenes in the presence of base and the quaternary ammonium salt, or upon treatment with methanolic sodium hydroxide. A series of l-(alk-2-ynyl)imidazoles have been prepared, as intermediates in the synthesis of imidazopyridines [31 ] and the reaction of 3-hydroxymethylpyrazoles with propargyl bromide leads to pyrazolooxazines [32]. 

The synthesis of zolpidem began with an alkylation/condensation reaction of amino-pyridine 5 and bromide 6 to give imidazopyridine 7 (Scheme 15.1). Mannich-type reaction with formaldehyde and dimethylamine provided 8. Treatment of 8 with methyliodide to form the quaternary salt 9, followed by reaction with sodium cyanide, gave 10. Acidic hydrolysis followed by reaction of the resultant acid 11 with carbonyldiimidazole (GDI) and dimethylamine afforded zolpidem (1) in 46% overall yield (George et al., 1991 Rossey and Long, 1988). 

A more efficient and convergent industrial-scale synthesis that avoids toxic methyl iodide and sodium cyanide was developed (Scheme 15.2). Condensation of N,N-dimethyl-2,2-dimethoxyacetamide with imidazopyridine 7 under acidic conditions afforded hydroxy derivative 12. Conversion of the hydroxyl group to a chloride with thionyl chloride followed by reductive removal of the chloride with sodium borohydride provided zolpidem. 

Vasella and co-workers (72) employed mtinchnone chemistry in the synthesis of several pyrrolopyridines and imidazopyridines as novel inhibitors of p-D-glucosi-dases (Scheme 10.23). Thus, treatment of the lactam glycine (119) with acetic... 

A catalytic Fe(lll)/Fe(ll) redox cycling approach to imidazopyridines has also been reported for the synthesis of imidazo[4,5-f]pyridines (Equations 41 and 42) <2000S1380>. 

Imidazolium ligands, in Rh complexes, 7, 126 Imidazolium salts iridium binding, 7, 349 in silver(I) carbene synthesis, 2, 206 Imidazol-2-ylidene carbenes, with tungsten carbonyls, 5, 678 (Imidazol-2-ylidene)gold(I) complexes, preparation, 2, 289 Imidazopyridine, in trinuclear Ru and Os clusters, 6, 727 Imidazo[l,2-a]-pyridines, iodo-substituted, in Grignard reagent preparation, 9, 37—38 Imido alkyl complexes, with tantalum, 5, 118—120 Imido-amido half-sandwich compounds, with tantalum, 5,183 /13-Imido clusters, with trinuclear Ru clusters, 6, 733 Imido complexes with bis-Gp Ti, 4, 579 with monoalkyl Ti(IV), 4, 336 with mono-Gp Ti(IV), 4, 419 with Ru half-sandwiches, 6, 519—520 with tantalum, 5, 110 with titanium(IV) dialkyls, 4, 352 with titanocenes, 4, 566 with tungsten... 

In Stark contrast, a biomimetic approach [76] that was reported shortly after Weinreb s classical synthesis gave access to 70 in three steps (Scheme 9.8) from the commercially available 4,5-dibromo-2-formylpyrrole 80 and 2-aminohistidine 81. Protection of the pyrrole 80 followed by Lewis acid-catalyzed Pictet-Spengler condensation with 81 gave tetrahydroageladine A 83. Treatment of 83 with chloranil in refluxing chloroform effected aromatization of the imidazopyridine ring system... 

DiMauro and co-workers [67] have developed a rapid and efficient synthesis of 3-amino-imidazopyridines 16 using a microwave-assisted one-pot cyclization. The intermediate 15 was further reacted with various aryl bromides in the presence of a catalytic amount of Pd(dppf)Cl2 to yield the target compounds 16. The reaction scope is quite broad with respect to the aldehyde and aryl bromide components which might be electron-rich, electron-poor, aromatic, aliphatic, or sterically encumbered (Scheme 15). 

DiMauro EF, Kennedy JM (2007) Rapid synthesis of 3-amino-imidazopyridines by a microwave-assisted four-component coupling in one pot. J Org Chem 72 1013-1016... 

Figure 11.7 Synthesis of imidazopyridine systems 21 from 3-chlorotetrafluoropyridine 22.

Table 11.5 Synthesis of pyrido[3,4-b]pyrazine and imidazopyridine scaffolds [47, 56]... 

The old Wallach synthesis, which ring closed an A, A -disubstituted oxamide, has been adapted to the synthesis of imidazopyridines. Kinetic and labeling experiments support a mechanism involving a nitrile ylide species in this transformation <93JCS(Pl)675). Chlorination and cyclization of... 

When we started our research in the late 1960s, the synthesis of various derivatives of imidazopyridines was seldom studied. 

Imidazopyridines (IPs) may be synthesized from pyridine or imidazole derivatives by building up the second ring, and also by ring transformations from the other heterocyclic compounds. However, these methods are not of equal efficiency, and the most important preparative procedures utilize amino derivatives of pyridine as initial compounds for IP s synthesis. The main IP s precursors are o-diaminopyridines (o-DAP). 

Similarity to the benzimidazole synthesis led sometimes to an erroneous assignment of an imidazopyridine structure to acyl derivatives of o-DAPs. Thus, Garmaise and Komlossy (64JOC3403) indicated that Takahashi and Yajima (46JPJ31) believed the products they had prepared by acylation of 2,3-DAP with aromatic acid anhydrydes really had the IP structure. Moreover, it was revealed that the reaction between u-DAP and anthranilic add afforded merely a salt of these compounds. 

However, the most powerful and versatile activity among all the imidazopyridine-like antimetabolites was shown by 3-DAG 178, its nucleoside 182, and nucleotides. At the start of research, the low solubility of 3-DAG and its salts, similar to that of 1-DAG, impeded the studies. Fortunately, this obstacle was circumvented by the synthesis of 3-DAG mesylate, well soluble in water (84EUP0103417, 85MI3). 

Isoelectronic replacement of a carbanionic carbon by a hetero atom gives much more stable compounds such 5,5-bicyclic aromatic systems have received considerable attention pyrrolo[2,l-b]thiazole is one such example. Although we have not had sufficient space to describe these in this short chapter, their properties and synthesis follow the general principles discussed for example, imidazothiazoles are prepared from substituted thiazoles in a way analogous to the preparation of imidazopyridines, from substituted pyridines. 

Synthesis and biological evaluation as microtubule-active agents of several tetrahydrofiiran and spiroacetal derivatives 13CMD1173. Tandem multicomponent reactions toward the des p and synthesis of novel polysubstituted imidazopyridines and imidazopyrazines as antibacterial and cytotoxic motifs 13CMD1445. 

A ramification of the DreM strategy in an unusual heteroaromatic framework is illustrated in the synthesis of the previously unknown triazadibenzo[cd,/]azulen-7(6H)-one 75 in which the imidazopyridines 70 and 71 are coupled by a Suzuki-Miyaura reaction with the DoM-derived boronic add 72 to give 73 and 74, respectively (Scheme 14.18). Compound 74 undergoes DreM cyclization on treatment with LiTMP to give the potentially bioactive 75 in modest yields [126]. 

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