Pyridine five-membered rings

Clear theoretical evidence is presented to show that the u-electron systems of benzenoid aromatic molecules are described well in terms of localized, non-orthogonal, singly-occupied orbitals. The characteristic properties of molecules such as benzene or naphthalene arise from a profoundly quantum mechanical phenomenon, namely the mode of coupling of the electron spins, rather than from any supposed delocalization of the orbitals. Other systems considered include azobenzenes, such as pyridine, five-membered rings, such as furan, and inorganic heterocycles, such as borazine ( inorganic benzene ). 

Reduction of isoindoles with dissolving metals or catalytically occurs in the pyrrole ring. Reduction of indolizine with hydrogen and a platinum catalyst gives an octahydro derivative. With a palladium catalyst in neutral solution, reduction occurs in the pyridine ring but in the presence of acid, reduction occurs in the five-membered ring (Scheme 38). Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cw-1,3-dihydro derivative (Scheme 39) (80JOC3982). 

Ring expansion of five- to six-membered rings such as oxazole —> pyridine derivatives via a Diels-Alder reaction is a well-established procedure. However, the conversion of a six-membered heterocycle into a five-membered ring system has not been exploited to any great extent, and those systems that have been studied usually involve a cationic species. 

However, five-membered rings containing two or more heteroatoms necessarily possess both a pyridine-like heteroatom and a pyrrole-like heteroatom. Thus their chemistry shows similarities to both those of the six-membered rings and of the five-membered rings with one heteroatom this is dealt with in Part 4. 

Disconnecting the five-membered ring from the six is a sensible start as it leaves a stable pyridine (50) after some adjustment of the double bonds. 

Formation of five-membered rings onto central pyridine core... 

A more widely applied approach to modifying the terpyridine system so as to reduce the field has been to replace one or more of the pyridine rings with five-membered rings. The effects of replacement are much more pronounced for the central ring, because of the steric and electronic features mentioned above, and the [Fe N6]2+ derivative of l,3-bis(pyridin-2-yl)pyra-zole 47, for example, is high spin [64]. This effect is revealed further by the drastically different properties of the [Fe N6]2+ derivatives of the isomeric tridentate ligands 2,4-bis(pyridin-2-yl)thiazole 48 (Dq(Ni2+) 1125 cm-1) and 6-(thiazol-2-yl)-2,2/-bipyridine 49 (Dq(Ni2+) 1230 cm-1). 

This contrasts with the purely high spin nature of the complex of 2,6-bis(quinolin-2-yl)pyridine [62] 46 and is consistent with the reduced steric barrier to coordination from substitution adjacent to the donor atom within five-membered rings, evident in the diimine systems. 

Hydrosilylation of 1,6-dienes accompanied by cyclization giving a five-membered ring system is emerging as a potential route to the synthesis of functionalized carbocycles.81,81a,81b 82 As its asymmetric version, diallylmalonates 86 were treated with trialkylsilane in the presence of a cationic palladium catalyst 88, which is coordinated with a chiral pyridine-oxazoline ligand. As the cyclization-hydrosilylation products, //ww-disubstituted cyclopentanes 87 were obtained with high diastereoselectivity (>95%), whose enantioselectivity ranged between 87% and 90% (Scheme 25).83 83a... 

In contrast with the conjugated system, the reactivity of hexahydro-oxazolo[3,4- ]pyridines has been the subject of considerably more attention, which can most certainly be attributed to their greater synthetic potential, as demonstrated with the synthesis of many complex natural products. However, most of the reactions reported since 1996 have been known for many years, and the last decade was in fact characterized by their use in syntheses or optimization. After a brief survey of the thermal reactions, procedures involving the opening of the five-membered ring will be surveyed and the last part of this section will be devoted to the functionalization of the C-6 and C-7 positions. 

Instead of water (or hydroxide ion), amines can be used to cleave the five-membered ring of tetrahydro-oxazolo[3,4- ]pyridine-l,3-dione 172 pipecolic acid amides 173 are usually obtained in good yields (36-93%, Scheme 50) <1998EJM23>. 

A quite simple way to form the oxazolo[3,4- ]pyridine or thiazolo[3,4- ]pyridine ring system is to build the five-membered ring, respectively, starting from a 2-hydroxymethyl-piperidine or 2-thiomethyl-piperidine. The reaction of the latter compounds with aldehydes, acetals, phosgene, carbonates, or synthetic equivalents have been known for years and will therefore not be detailed here. Representative and typical examples are summarized in Table 10. 

The recently synthesized phosphatriazolo[l,5- ]pyridines 4 can also participate in reactions involving the ring opening of the five-membered ring <1995ZNB558>. When the unsubstituted phospha-heterocycle is treated with aqueous acetonitrile, a hydrolysis occurs and the open-chained phosphenic amide 47 can be obtained in acceptable yield (Scheme 13). 

Parent heteroaromatic structures have recently been described and typical couplings in the pyridine series, as reported by Thomas et a/.<1969 122,123) are shown in 114. Data for five-membered ring heterocyclics... 

Further side-chain chemistry can be carried out either at one of the side chains attached to the five-membered ring [228-232] or at the pyrrolidine nitrogen [215, 224, 231, 233-239], For example, upon heahng 3-triphenylmethyloxazolidin-5-one (210) at reflux for 16 h with Cjq in equimolar amounts, 211 can be isolated in 39% yield [204], Subsequent treatment of 211 with trifluoromethanesulfonic acid, then with pyridine and dansyl chloride (DnsCl) yields the dansyl pyrrolidine derivative 213 in 76% yield (Scheme 4.35). The amine 212 is an intermediate in this reachon. 

---