Synthesis of Fused Heterocycles

The synthesis of pyrido[2,3-dlpyrimidines has attracted considerable interest in heterocychc chemistry. This ring system constitutes a deaza-analogue of the pyrazino[2,3-d]pyrimidine heterocychc core of fohc acid, analogues which can exhibit a wide range of biological properties as folate antagonists. Thus, the synthesis of this motif by MCR under microwave-assisted conditions has the potential to rapidly introduce diversity into a biologically relevant scaffold. 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88] 

A related pyranopyrimidine 63 has been prepared by the irradiation of 1,3-dimethylbarbituric acid 61, a methylene active nitrile 47a and N,N-di-methylformamide dimethylacetal 45 [77]. After initial formation of the enam- 

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Diaminofurazans 156 are useful starting materials for the synthesis of fused heterocyclic compounds. For example, 3,4-diaminofurazans 156 reacted with dicarbonyl compounds (e.g., with ct-keto acids) to produce a series of 5-hydroxy[l,2,5]oxadiazolo[3,4-A pyrazines 163 (Equation 26) <2003BML3133>. 

E. A. Kaigorodova, V. K. Vasilin, and G. D. Krapivin, Amino-tieno[2,3-b]piridiny v sinteze kondensirovarmykh geterotsiklov [Aminothieno[2,3- bjpyridines in Synthesis of Fused Heterocycles] , Krasnodar (2001) Deposited in VINITI, No. 1901-V2001. 

Synthesis of fused heterocycles, general monograph 87CH(47), 92 CH(47,2)1. 

Dipolar addition reactions of suitably substituted 1,3-dipoles to dipolarophiles offer a wide range of utility in the synthesis of fused heterocyclic ring systems (63AG(E)565). The... 

An interesting new application of enaminone chemistry is ring closure involving benzyne intermediates. In this way an intramolecular arylation of enaminones is effected. The method is used for the synthesis of fused heterocyclic compounds and natural products119-121. Phenanthridone derivatives can be obtained in good yield119. 

Historically, the use of pyridine derivatives as cyclization substrates in the synthesis of fused heterocyclic systems has had great impact in pharmaceuticals, metal-chelation chemistry and other applications. Fused heterocycles incorporating different regioisomers... 

Shaaban MR (2008) Microwave-assisted synthesis of fused heterocycles incorporating trifluoromethyl moiety. J Fluorine Chem 129 1156-1161... 

Bekircan O, Kucuk M, Kahveci B et al (2005) Convenient synthesis of fused heterocyclic... 

Ellis, G. P. in Synthesis of Fused Heterocycles, Part 2 Taylor, E. C Ed. Wiley-Interscience Chichester, 1992. 

In general, three approaches are possible for the synthesis of fused heterocyclic compounds. 

There is one major review in two parts on the synthesis of fused heterocycles the approach focuses on the type of functional group(s) and/or ring atom(s) of the first ring involved in the formation of the second heterocyclic ring. 

Synthesis of fused heterocycles via Pd-catalyzed multiple aromatic C—H activation reactions 12KGS22. 

Apphcation of benzothiadiazole in organic solar cells 13CJ0288. 4-(2-R-Aryl)-l,2,3-chalcogenadiazoles in the synthesis of fused heterocycles 13ZOR497. 

Synthesis of fused heterocycles derived from 2H to 1,4-benzoxazin-3(4H)-ones 13HC387. 

Seven-membered ring closures via e do-cyclization are by far more widespread than the analogous gndo-modes for five- or six-membered cycles. There are some examples using substructure G (Figure 6.4) as substrate. Joseph and cowoikers [145] reported the synthesis of fused heterocycles bearing a benzazepinone moiety. Tetracycle 202 was obtained in excellent yield starting from indole derivative 201 in the presence of silver salt (Scheme 6.59). 

Joucla, L., Putey, A. and Joseph, B. (2005) Synthesis of fused heterocycles with a benzazepinone moiety via intramolecular Heck coupling. Tetrahedron Lett., 46, 8177-9. 

Scheme 4 Sundberg Indole Synthesis of Fused Heterocyclic Indoles...

The synthesis of fused heterocyclic systems via cycUzation of aryne intermediates has also been achieved on a solid phase (Equation 12.14) [18], An aryne intermediate generated by dehydrofluorination upon treatment with 2equiv. of LiOt-Bu was subsequently trapped by an intramolecular primary amine moiety, leading to biologically interesting quinoxaline, thiazine and oxazine analogues. 

Synthesis of Fused Heterocycles through Cascades Involving Smiles Rearrangements... 

Synthesis of Fused Heterocycles. Use of chloroacetyl chloride in the reaction with l-[(trimethylsilyl)methyl]benzotriazole opens new possibilities. Thus, the l-(benzotriazol-l-yl)-3-chloroacetone obtained in the first step is further reacted with 2-mercaptobenzothiophene to give l-(benzotriazol-l-yl)-3-[(benzothiophen-2-yl)thio]acetone in a practically quantitative yield (eq 8). Cyclization of the obtained acetone derivative with ZnCl2 readily provides 3-[(benzotriazol-l-yl)methyl][2,3-ft]benzothiophene (eq 9). The structure can be further modified by subshtufion of the benzotriazolyl moiety with other groups. Preparation of several other fused thiophene systems, starting from other aryl mercaptans, is also reported. ... 

R. Patil, P. Bhoir, P. Deshpande, T. Wattamwar, M. Shirude, P. Chaskar, Relevance of sonochemistry or ultrasormd (US) as a proficient means for the synthesis of fused heterocycles, Ultrason. Sonochem. 20 (2013) 1327-1336. 

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