Compounds Containing Three Heteroatoms

The reaction used for the construction of the starting material for a pyrrolo-pyridine involves the standard pyrimidine chemistry discussed in Chapter 9. Thus condensation of the substituted cyanoacetate (16-1) with acetamidine leads to the 

In a sequence reminiscent of the scheme used to build the heterocyclic ring in quinolones (Chapter 11), condensation of aminopyrrazole (19-2) with ethyl 

An analogous scheme is used to prepare a more highly nitrogenated compound. Thus, reaction of acylpyridine (22-1) with dimethylformamide acetal gives enamide (22-2). Condensation of that with the somewhat more complex pyrrazole (22-3) leads to the soporihc agent ocinaplon (22-4) [23]. 

The synthesis of yet another example begins with the allylation of the enamide (21-2) with methyl iodide. Reaction of this intermediate (23-1) as above with the ami-nopyrrazole (23-2) leads to the formation of the fused pyrimidinopyrrazole (23-3). This last productis is next acylated with thiazole-carboxillic acid (23-4) in the presence of aluminum chloride. There is thus obtained the sleep inducing agent indiplon (23-5) [24]. 

Benzene and thiophene rings can of course often be interchanged in biologically active agents. The very broad structural latitude consistent with NSAID activity is by now a familiar theme as well. Preparation of the fused thiophene counterpart of the NSAID piroxicam (Chapter 11) starts with the reaction of thiophene (25-1), itself the product of a multistep sequence, with ethyl A-methylglycinate to give the sulfonamide (25-2). Treatment of that intermediate with a base leads to intramolecular Claisen condensation and thus the formation of the 3-ketoester (25-3). An amide-ester interchange with 2-aminopyridme (25-4) completes the synthesis of tenoxicam (25-5) [25]. 

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A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

Many strained four-membered heterocycles, containing three heteroatoms, with at least one heavier group 14 element, are moisture, thermo- or light-sensitive compounds. For example, separation from the reaction mixture of 1,3,2-oxathiasiletane 63 furnished not the expected compound, but the hydrolyzed product, a thiocarbamate (Scheme 3) <2000CL244>. The adduct 64 is moisture stable and can be chromatographically purified. However, it is sensitive to gradual hydrolysis with the liberation of phenyl isothiocyanate <2002CL34>. 

Though you have only seen a couple of examples of the latter, it is clear that organosulfur and organoselenium chemistry are closely related. In the next chapter we will look at the quite different type of chemistry exhibited by organic compounds containing three other heteroatoms—silicon, tin, and boron. 

Miscellaneous other Systems containing Three Heteroatoms. - Catechol is converted into the 1,3,2-benzodioxathiolan (503) by the action of EtNSFj. The cyclic iminodiacyl peroxide (504) is obtained from the imino-compound MeN(COCl)2 and hydrogen peroxide. The hydroxamic acid HOCPh2-CONHOH reacts with carbonyldi-imidazole to yield the dioxazolone (505). The i.r. and Raman spectra of l,3-dimethyl-l,3-diaza-2-boracyclopentanes (506 R = Cl, Br, or NMc2) have been reported. The zwitterionic salt... 

The majority of the compounds under discussion here have pyrrolidine as one of the 5-membered rings. The other ring, containing three heteroatoms, is sometimes a 6n aromatic system as in the tetrahydropyrrolotriazole (45), for example, but most of the bicyclic systems covered in this chapter, for example, (27), (31)-(33) have no aromatic character. 

Such compounds contain two or three pyridine-like heteroatoms. For the symmetrical systems (73) and (74), no ambiguity occurs, but for systems (75)-(78) there are at least two alternative reaction sites. It appears that reaction takes place at the nitrogen atom furthest away from the pyrrole-like heteroatom, as shown in (75)-(77) where evidence is available from reactions with alkylating reagents (Section 4.02.1.3.8). 

If the CH balance given by the CH multiplicities differs from the number of H atoms in the molecular formula, then the additional H atoms are bonded to heteroatoms. The C NMR spectra in Fig. 2.5 show, for example, for isopinocampheol (2), Cio// 0, a quaternary C atom (C), four CH units (C4//4), two CH2 units C2H4) and three CH3 groups (C3//5). In the C//balance, Cvfln, one H is missing when compared with the molecular formula, Cio// 0 to conclude, the compound contains one OH group. 

In using the tables, it would be best to survey the list of tables included in each chapter to determine how many categories might possibly contain the compound of interest. It should be noted that a large number of cyclophanes which contain fewer than three heteroatoms are not included in this book since they are not generally useful as cation binders. 

Topics in Heterocyclic Chemistry presents critical accounts of heterocyclic compounds (cyclic compounds containing at least one heteroatom other than carbon in the ring) ranging from three members to supramolecules. More than half of the more than 10000 compounds hsted in Chemical Abstracts are hete-rocychc compounds. The branch of chemistry deahng with these heterocyclic compounds is called heterocyclic chemistry, which is the largest branch of chemistry and as such the chemical hterature appearing every year as research papers and review articles is vast and can not be covered in a single volume. 

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