Bicyclic heterocycles

These intramolecular IHDA pyrimidine-to-pyridine ring transformations are also successfully applied to synthesize bicyclic heterocycles, containing a... 

One of the more complex local anthetics in fact comprises a basic ether of a bicyclic heterocyclic molecule. Condensation of 1-nitropentane with acid aldehyde, 79, affords the phthalide, 81, no doubt via the hydroxy acid, 80. Reduction of the nitro group... 

Due to the instability of the seven-membered heterocyclic ring, oxepin is prone to isomerization reactions to bicyclic heterocycles such as benzene oxide. Irradiation of oxepin with UV light of/. > 310 nm gives the isomeric 2-oxabicyclo[3.2.0]heptadiene(l) in high yield.12 207 At shorter wave lengths, phenol is formed predominantly.207... 

The order of aromaticity of these compounds is benzene > thiophene > pyrrole > fiiran, as calculated by an aromaticity index based on bond-distance measurements. This index has been calculated for five- and six-membered monocyclic and bicyclic heterocycles Bird, C.W. Tetrahedron, 1985, 41, 1409 1986, 42, 89 1987, 43, 4725. 

The Boger group [64-66] has extensively studied the use of a-ketoheterocycles as FAAH inhibitors. In their initial studies, a range of a-ketoheterocycles based on oleic acid was synthesised. A range of five- and six-membered monocyclic heterocycles and three bicyclic heterocycles (benzothiazole, benzimidazole and benzoxazole) was examined. Although many of the compounds tested were found to inhibit FAAH activity with micromolar affinities, the best results were obtained with heterocycles that incorporated a weakly basic nitrogen a - to the heterocycle (Table 6.5) [64]. 

One last word on heterocycles. Very small couplings (< 1 Hz) have been found to exist between some protons on different rings of bicyclic heterocycles. For example, in indole, there is a 3-7 coupling of about 0.7 Hz. In practise however, these very small couplings may only manifest themselves as a broadening of the signals concerned. 

A series of mesoionic bicyclic heterocycles was prepared in good yield by reacting iV-alkylhetarylamines 89-92 with activated malonesters. Thus, 2-ethylaminopyridazine 89 afforded 93 (Equation 8) <2000BMC1917>. 

The infrared (IR) spectra of these compounds were mostly studied in the solid state which showed all the basic peaks characteristic of various functionalities attached to such bicyclic heterocycles with bridgehead nitrogen atoms. The difference in the frequency of carbonyl and carbon nitrogen double bond in tautomers of compound 18 (R = H) has been discussed previously in CHEC-II(1996) <1996CHEC-II(8)713>. 

The survey of possible structures was given in Chapter 8.31 of CHEC-II(1996) <1996CHEC-II(8)747>. However, a short overview could be useful here. This chapter deals with three main types of bicyclic heterocycles containing two ring junction nitrogen atoms, namely bicyclic 5-5, 5-6, and 6-6 ring fused systems which are depicted in their fully saturated forms as structures 1-3. 

A cascade reaction involving multiple C-H functionalizations has been employed for the formation of bicyclic heterocycles with palladium catalysis (Equation (160)).134... 

Highly substituted pyrrolo[l,2- ][l,2,4]triazines were synthesized from pyrrole derivatives, by closure of the triazine ring. Thus, hydrolytic cleavage of some 1,2-diaminopyrroles having a 1-NH-BOC-protected amino function 43 followed by reaction with 1,2-dicarbonyl compounds afforded a one-pot access to the corresponding bicyclic heterocycles 44 (BOC = f-butoxycarbonyl Equation 6) < 1997J(P 1)1829>. 

In Scheme 12 several ring openings are summarized that proceed via solvolysis or nucleophilic attack at the six-membered moiety. These reactions take place under relatively smooth conditions in the case of azoloazinium salts or the electron-deficient azinones, but neutral bicyclic heterocycles can also react with strong nucleophiles. 

Two transformations should be discussed in more detail (1) presence of the amino group in 275 was utilized for the synthesis of the fused isoquinolinium salt 276 bearing the bicyclic heterocycle as an A-substituent <2003JHC1041> (2) selective nucleophilic substitution of 277 with pyrrolidine was reported <2001ZOR604> to yield only substitution on the phenyl substituent without formation of an amide from the ester group 278. 

Bicyclic heterocycles (139) were reacted with EMME at 130-150°C for 1.5-5.0 hr to give condensation products (140) in good yields [82JAP(K)-203085]. 

The large literature on cyclization reactions of aminoalkylidene-malonates is surveyed in order of the various ring systems that are formed. Of particular importance are the preparations of 4-hydroxyquino-line derivatives and of the corresponding naphthyridines. But a wide variety of other bicyclic heterocycles has also been prepared by methods of this type, as have tri- and polycyclic analogs. 

The thermolysis of tetrazoles 168 may result in the formation of mono-and bicyclic heterocycles 169. 

The heteroatom-tethered enynes, If-i, were converted to the corresponding bicyclic heterocycles 2f-i without event, thereby further illustrating the scope of this transformation. The [RhCl(CO)2]2-catalyzed PK reaction with the 1,6-enynes Ij and Ij, which have a methyl group at a terminal position of the olefin moiety, furnishes the corresponding bicyclopentenone 2j and 2j in good to excellent yield. Interestingly, treatment of 1 j with a phosphine ligand-bound catalyst, such as 10, affords a mixture of the desired cyclopentenone 2j with the cycloisomerization product 2j (Eq. 1). 

This approach has been extended to cyclic 1,3-dicarbonyls for the synthesis of tetrahydrobenzopyrane derivatives, also known as tetrahydrochromenes, which have attracted much attention due to their wide range of biological properties. Thus, a mixture of an aromatic aldehyde, dimedone, and malonitrile in aqueous media catalyzed either by (5)-proline [123] or tetramethylammoniura hydroxide (TMAH) [124] gave the bicyclic heterocycle in excellent yields (Scheme 35). 

Synthesis of novel bicyclic heterocyclic systems involving aziiidine ring formation has been described. The sodium salts of tosylhydrazones 11 decomposed by heating in benzene and gave aziridinopyrroloindoles 12 in yields up to 73% (equation 5) . Intramolecular cyclization of oxime ether 13 in the presence of base (for example, DBU) in acetonitrile afforded aziridinopyrrolidine 14 in yields up to 51% (equation 6) °. 

Ph, R = NHj, with phosgene gives a novel bicyclic heterocyclic system which can be represented as a bicyclic meso-ionic l,3,4-thiadiazol-2-one (493) (Section VII,H,1). A similar reaction using A -benzoyl isocyanide dichloride (PhCO.N=(i Cl2) gives the novel meso-ionic 1,3,4-thiadiazol-2-imine (494) (Section VII,H,2). ... 

In a series of papers, Jarry and co-workers demonstrated the utility of a 2-aminooxazoline 647 (Fig. 8.26) to prepare bicyclic heterocycles. This oxazoline undergoes annulation reactions with bifunctional electrophiles to give triazinones or pyrimidinones. Selected examples are summarized in Table 8.42. ... 

This approach is used for the syntheses of fused heterocycles which have a [l,3]-heteroatom juxtaposition in one of the rings <1996CHEC-II(7)49>. The unambiguous synthesis of tetrahydro-3//-benzothieno[2,3- / imidazole 87, as a target for the potential treatment of anxiety disorders, was accomplished starting from commercially available ethyl 2-amino-4,5,6,7-tetrahydro-benzothiophene-3-carboxylate 85 the key formation of the bicyclic heterocycle occurred through a final acid-mediated cyclization of 86 (Scheme 17) <1997SC473>. 

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