Heterocyclic annulated pyridines

Groebke, K., Weber, L. and Mehlin, E, Synthesis ofimidazo[l,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation, Synlett, 1998, 661 Blackburn, C., Guan, B., Shiosaki, K. and Tsai, S., Parallel synthesis of 3-aminoimidazo[l,2-a] pyridines and pyrazines by a new three-component condensation, Tetrahedron, 1998, 3635-3638 Bienayme, H. and Bouzid, K., A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles, Angew. Chem., Int. Ed. Engl, 1998, 37, 2234-2237. 

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. 

The acyclic version of Larock s heteroannulation was successfully applied to the synthesis of highly substituted pyridines [166]. The annulation of rert-butylimine 210 with phenyl propargyl alcohol produced pyridine 211 regioselectively in excellent yield. The regiochemistry obtained was governed by steric effects. Furthermore, the choice of imines was crucial to the success of the heteroannulations. terr-Butylimine was the substrate of choice, since all other imines including methyl, isopropyl, allyl and benzyl imines failed completely to produce the desired heterocyclic products. 

Employing ynamines, the cycloaddition-extrusion reaction can be extended to heterocondensed 1,3-oxazinones, resulting in a smooth, simple annulation of a pyridine ring to an existing heterocyclic system (87CB1427). 

Pyrimidine-annulated methanooxepene 35a is formed via regioselective heterocyclization of 6-cyclopent-2-enyl-5-hydroxy-l,3-dimethylpyrimidine-2,4(1/7,3//)-dione in the presence of concentrated sulfuric acid. The above-mentioned pyrimidinedione and 5-cyclopent-2-enyl-6-hydroxy-l,3-dimethylpyrimidine-2,4(1/7,3/7)-dione give similar annulated bromomethanooxepenes 35b and 36, respectively, when cyclization is performed with pyridine hydrotribromide or hexamethylenetetramine hydrotribromide <2003M1137>. 

In some cases the reaction is accompanied by a five-membered heterocyclic ring closure. For example, l-nitro-4-methoxynaphthalene 265 reacts with p-tolylpro-penylsulfone to give benzo[/z]quinoline 266 (35%) together with A-hydroxybenzo-pyrrole derivative 267 (14%) (Scheme 77) (00EJO521). Annulation of the pyridine ring may proceed via anion 268, whereas the formation of benzoindole 267 occurs via neutral alkene 269. 

Examples of nitrogen-containing heterocycle syntheses based on condensation reactions continue to be forthcoming. Examples include a tandem oxidation-annulation of propargyl alcohols in a one-pot synthesis of pyridines (Equation 148) <2003SL1443>, trifluoromethyl-substituted pyridines (Scheme 94) <2003S1531>, and standard malononitrile additions to a,/3-unsaturated ketones <1995JCM392>. 

Our interest in expanding the acylative pyrrole annulation approach to additional heterocyclic systems has led to an efficient synthesis of pyrrolo[3,2-c]pyridin-2-ones and pyrido[3,4-6]pyrrolizidin-l-ones starting from 4-chloro-N-benzyl-2(l//)-pyridinone and amino acid salts.811 Over the years pyrrolo[3,2-c]pyridines (5-azaindoles)41 have been of interest for applications as elements in new drug design, nucleotide analogues,42 and biochemical tools. However, available synthetic routes to multifunctionalized members from this class of heterocyclic structures are limited.41 43... 

In addition condensed heterocyclic systems formed by annulation can serve as valuable sources of polyfunctional 1,2,3-triazoles. Triazolo[l,5-a]pyridines (360) are transformed ( trans-cyclization ) into the 4-(pyrid-2-yl)-l,2,3-triazoles (361) upon heating with aniline... 

Vinamidinium salts are important intermediates in the synthesis of heterocycles. The 2-chloro-l,3-bis(dimethylamino)trimethinium hexafluorophosphate salt has been used in the preparation of the highly selective Cox-2 inhibitor etoricoxib (Scheme 1). This method describes a straight-forward preparation of the hexafluorophosphate salt which is a crystalline, thermally and shock-stable, non-hygroscopic solid. The submitters have extensively studied the preparation of vinamidinium salts and demonstrated that the method is applicable to substituted acetic acids that contain an electron-withdrawing group (Table 1)." The annulation reaction is also general and useful for the preparation of pyridines, pyridones and pyridine N-oxides. ... 

One Nitrogen Atom (it is self-subdivided into Pyridines, Pyridinium Compounds, Ylides, Pyridine N-Oxides, Applications of Pyridines, Bipyridines and Related Systems, Hydropyridines, Biologically Active Pyridines and Hydropyridines, Pyridines Annulated with Carbocycles, Pyridines Annulated with Heterocycles). 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

In conclusion, we have employed a novel, regiospecific pyridine annulation procedure to prepare a series of l,X-naphthyridinyloxy-phenox rpropanoic acids as potential herbicides. The wide variation in herbicidal activity among this seemingly very similar group of acids clearly demonstrates the importance of the nature of the heterocycle in this area of chemistry. 

Rodinovskaya LA, Shestopalov AM, Gromova AV, Shestopalov AA (2008) One-Pot synthesis of diverse 4-Di(tri)fluoromethyl-3-cyanopyridine-2(lH)-thiones and their utilities in the cascade synthesis of annulated heterocycles. J Comb Chem 10(2) 313-322 Suzuki H, Sakai N, Jwahara R, Fujiwa T, Satoh M, Kakehi A, Konakahara T (2007) Novel synthesis of 7-fluoro-8-(trifluoromethyl)-lH-l,6-naphthyridin-4-one derivatives intermo-lecular cyclization of an N-silyl-l-azaallyl anion with perfluoroalkene and subsequent intramolecular skeletal transformation of the resulting pentasubstituted pyridines. J Org Chem 72(15) 5878-5881... 

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