Fused heterocycles, synthesis

Bhandari A, Li B, Gallop MA, Solid-phase synthesis of pyrrolo[3,4-6]pyridines and related pyridine-fused heterocycles, Synthesis, 11 1951-1960, 1999. 

Syntheses of thieno[2,3-d]pyrimidines including microwave activation and their utilities in fused heterocycles synthesis 13JHC451. 

Another important aspect of aryne chemistry that has found application in benzo-fused heterocycles synthesis is MCRs, which generally include the first addition of nucleophiles to arynes and subsequent interception of the aryl anion intermediate with other electrophiles. If the nucleophile and electrophile are not part of the same molecule, the overall process is a unique multicomponent coupling, where the aryne is inserted between the other two coupling partners to afford the final product 85 (Scheme 39). This highly efficient transition-metal-free methodology has been applied to the S5mthesis of valuable benzo-fused heterocycles and has foxmd application in natural product synthesis. 

Synthesis of tropones, tropolones, and tropylium salts with fused heterocyclic rings 95AHC(64)81. 

It has been shown that, on treatment with base, 1-aminopy-ridinium iodide undergoes 1,3-dipolar addition with ethyl propiolate or dimethyl acetylenedicarboxylate thus the N-aminoheterocycles may serve as convenient starting materials for the synthesis of a variety of unusual fused heterocycles.8... 

This method has been extended to include imines other than A -thia-zolines, hence enabling the synthesis of multi ring-fused 2-pyridones (28,30, and 33, Scheme 8). Thus, by reacting dihydroisoquinoUnes 27 or /1-carboUnes 29 with acyl Meldrum s acid derivatives 24, a set of new ring-fused heterocycles was prepared in moderate to excellent yields (a and b. Scheme 8). These systems were prepared by using trifluoro acetic acid (TFA) as a proton source instead of solutions saturated with HCl (g). The switch of acid proved to be advantageous since it reduced the formation of by-products and increased the isolated yields. From a practical point of view, TFA is also su-... 

As noted previously, a wide variety of aromatic systems serve as nuclei for arylacetic acid antiinflammatory agents. It is thus to be expected that fused heterocycles can also serve the same function. Synthesis of one such agent (64) begins with condensation of indole-3-ethanol (60) with ethyl 3-oxo-caproate (61) in the presence of tosic acid, leading directly to the pyranoindole 63. The reaction may be rationalized by assuming formation of hemiketal 62, as the first step. Cyclization of the carbonium ion... 

A fused heterocyclic compound (146) distantly related to the antiinflammatory agent cintazone (Chapter 12), which itself can be viewed as a cyclized derivative of phenylbutazone, retains the activity of the prototype, in the synthesis of 146, reaction of the nitroaniline 139 with phosgene gives intermediate 140, which is then reacted with ammonia to afford the substituted urea (141). Cyclization of the ortho nitrourea function by means of sodium hydroxide leads to the N-oxide (142) this last reaction represents... 

The synthesis of (5 5 5) fused heterocyclic compounds 7 <2001JOC412> has been achieved in 84% yield via annulation of internal alkynes by imines 287 derived from o-iodoaniline in the presence of palladium catalyst (Scheme 51). 

The synthesis of (5 5 5) fused heterocycle 62 has been achieved via intramolecular Diels-Alder reaction involving a series of A-alkenyl-substituted furanyl amides 494 (Scheme 112) <2006JOC5432>. 

Many versatile approaches to the construction of fused heterocyclic systems (6 5 6) with ring junction heteroatoms have been reported. More general reactions which can be used for synthesis of derivatives of several tricyclic systems, and transformations which have potential for use in the preparation of a series of substituted compounds, are discussed in this section. Formation of the five-membered ring is presented first because it is a conceptually simple approach. It should be noted, however, that the addition of a fused six-membered ring to a bicyclic component offers much more versatility in the construction of a (6 5 6) system. Each subsection below starts with intramolecular cyclization of an isolated intermediate product. Reactions which follow are one-pot intermolecular cyclizations. 

A general approach to the synthesis of (6 5 6) fused heterocyclic ring systems involves intramolecular cyclization of two substituents attached to a five-membered ring of the fused (6 5) system. A typical example is cyclization of 211 to... 

The synthesis of (6 5 6) fused heterocycles may involve one-pot double intramolecular cyclocondensations. A typical example of this reaction is the formation of amide intermediate 247 from 246, which further cyclizes to give pyridopurine derivative 248 (Scheme 13) <1995TL4249>. 

Many other nitrogen- and sulfur-containing rings are available from reactions of the Willgerodt-Kindler type. Benzo- and pyridino-fused thia-zoles, for example, are formed from anilines (benzeneamines) and amino-pyridines, respectively.25 Asinger26 has reviewed the scope of these reactions in heterocyclic synthesis. 

A further neat example of multicomponent reactions in heterocyclic synthesis was reported by Ma et al. <06AG(E)7793>. They prepared the furan-fused 1,4-thiazepine 140 in good yield using the three components 137, 138, and 139 in the one reaction. A range of other furan-fused analogues with different substituent groups in the thiazepine ring were also synthesised. 

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>. 

Synthesis of the triazolodithiazine derivative 109 has been reported by Pomarnacka and Gdaniec <2003BMC1259> (Scheme 20). Transformation of the semicarbazide 104 with phosphorus oxychloride gave the derivative of the fused heterocycle 109. Inspection of the connectivity of the heteroatoms clearly indicates that a predominant... 

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