Six-membered ring heterocyclics

4-Hydroxy-6-methyl-2-pyrone (Triacetic Acid Lactone) 

The reversibility of O-allylation and the stereochemistry of the Pd(0)-catalyzed allylations have been studied in triacetic acid lactone 129, a natural polyketide. Thus, efficient and controlled C-allylations of 129 take place under Pd(0) catalysis to afford monoallylation products 130 (in toluene) 

Farina has shown that the reaction of 129 with cinnamyl chloride in THF with Pd2(dba)3 and tri-(2-furyl)phosphine as precatalytic system, results in incomplete formation of the C-allylated 130a, the isomeric cinnamyl ether of 129 being also isolated (91JA9585). 

Nitrogen-Containing Rings 1. 2-Pyridone and Pyridine-2-thione 

Benneche and Undheim have published extensive studies on the allyla-tion of pyrimidin-2-ones. A summary of their results is given below. 

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This interesting conversion of a five- into a six-membered heterocyclic ring was proven by the isolation of the enzyme GTP-cyclohydrolase from E. coli (71MI21600) and a similar one from Lactobacillus platarum (B-71MI21601) which catalyzes the reaction (300)(303). Dephosphorylation leads to 7,8-dihydro-D-neopterin (304), which is then cleaved in the side-chain to 6-hydroxymethyl-7,8-dihydropterin (305), the direct precursor of 7,8-dihy-dropteroic acid and 7,8-dihydrofolic acid (224). The alcohol (305) requires ATP and Mg " for the condensation with p-aminobenzoic and p-aminobenzoylglutamic acid, indicating pyrophosphate formation to (306) prior to the substitution step. 

Diels-Alder reactions, 4, 842 flash vapour phase pyrolysis, 4, 846 reactions with 6-dimethylaminofuKenov, 4, 844 reactions with JV,n-diphenylnitrone, 4, 841 reactions with mesitonitrile oxide, 4, 841 structure, 4, 715, 725 synthesis, 4, 725, 767-769, 930 theoretical methods, 4, 3 tricarbonyl iron complexes, 4, 847 dipole moments, 4, 716 n-directing effect, 4, 44 2,5-disubstituted synthesis, 4, 116-117 from l,3-dithiolylium-4-olates, 6, 826 electrocyclization, 4, 748-750 electron bombardment, 4, 739 electronic deformation, 4, 722-723 electronic structure, 4, 715 electrophilic substitution, 4, 43, 44, 717-719, 751 directing effects, 4, 752-753 fluorescence spectra, 4, 735-736 fluorinated derivatives, 4, 679 H NMR, 4, 731 Friedel-Crafts acylation, 4, 777 with fused six-membered heterocyclic rings, 4, 973-1036 fused small rings structure, 4, 720-721 gas phase UV spectrum, 4, 734 H NMR, 4, 7, 728-731, 939 solvent effects, 4, 730 substituent constants, 4, 731 halo... 

Part 2 (Volumes 2 and 3) deals with mono- and poly-cyclic compounds with one or more six-membered heterocyclic ring, with nitrogen, oxygen and sulfur as the heteroatoms. Volume 2 contains the six-membered rings with one nitrogen atom (Part 2A) and Volume... 

Our survey of heteroaromatic tautomerism will be completed in three further chapters, two of which will appear in Volume 77 of our series covering the tautomerism of (i) rings with three, four, and seven or more members and (ii) two or more fused five- or six-membered heterocyclic rings. The final chapter dealing with the tautomerism of six-membered monocyclic ring systems will appear in a subsequent volume. 

Tire second chapter deals with rings systems which comprise two or more fused five- or six-membered heterocyclic rings. It is authored by Dr. I. Shcherbakova of NFS Pharmaceuticals, Salt Lake City, U.S.A., together with Drs. Elguero and Katritzky. 

E. Compounds with Two Fused Six-Membered Heterocyclic Rings. 330... 

Ethylene disulfonyl-1,3-butadiene (43) is an example of an outer-ring diene with a non-aromatic six-membered heterocyclic ring containing sulfur. It is prepared by thermolysis of sulfolenes in the presence of a basic catalyst. It is very reactive [43] and even though it is electron-deficient, it readily reacted with both electron-rich and electron-poor dienophiles (Equation 2.15). 

While free radical attack in step (i) is by no means confined to carbon atom 4, the products obtained in the reactions involving the lower polyisoprenes indicate that this process is the dominant one. Likewise in step (ii) sulfur may frequently add at carbon atom 4 rather than at atom 2. Addition in the manner shown is indicated, however, by infrared spectra, which reveal the formation of —CH=CH— groups during vulcanization. The scheme accounts also for the observed constancy of the C/H ratio during vulcanization and for the relatively low efficiency of utilization of sulfur in the formation of cross-linkages in the absence of accelerators. A preponderance of the sulfur is involved in addition without formation of cross-linkages a considerable fraction of the thus-combined sulfur may occur in five- and six-membered heterocyclic rings formed by the mechanisms indicated. 

This class of tricyclic compound is dominated by the 377-pyrrolizines (systematically named 3//-pyrrolo[l,2- ]-pyrroles) and related systems, which are fused to another six-membered heterocyclic ring (Figure 1). 

Two molecules with comparable geometry in an asymmetric unit were found for 3,4-bis(4-fluorophenyl)-l,2,5-oxadiazole 2-oxide. The bond length of the dipolar N-O bond is 1.107 (7) A <2006AXEo4827>. In the molecule of 5-(6,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-2-yl)-4-phenyl-l,2,5-oxadiazole Ar-oxide, the six-membered heterocyclic ring has a flattened boat form. Intermolecular C-H- O hydrogen bonds link the molecules into dimers, which may be effective in the stabilization of the crystal structure <2006AXEo3130>. 

The six-membered heterocyclic ring has twisted boat conformation for Y = S and is nearly planar for Y = O. 

N-Methyl-2-phenyl-A2-tetraJiydropyridine and similar compounds have previously been prepared by the hydrolysis and decarboxylation of a-benzoyl-N-methyl-2-piperidone3 and by the addition of phenyl Grignard reagents to N-methyl-2-piperidone followed by dehydration.4 Both of these methods require that a heterocyclic ring already be present in the system. In contrast, this procedure offers a new flexible route to the construction of five- or six-membered heterocyclic rings which may easily be incorporated into a larger polycyclic product. Several examples of this process that can be cited to demonstrate this utility are... 

The best method used in the conformational analysis of saturated six-membered heterocyclic rings in the solid state is single-crystal X-ray structural analysis. The conformation in solution is not always identical. For solutions, H NMR spectroscopic analysis has been employed widely in the field of conformational analysis. The following methods deserve special mention. 

Mn and Re complexes of vp have also been prepared by Bennett and Watt 40) by reaction of HM(CO) 5 (M = Mn, Re) with vp in hydrocarbons. The initial product, HM(CO)4(vp), rearranges to a pair of isomers of the hydride (Fig. 32) having five- and six-membered heterocyclic rings respectively. The ratio five-membered (Markownikoff) product six-membered (anti-Markownikoff) product is ca. 6 1 for Mn but almost exclusively anti-Markownikoff for Re. 

In general, the syntheses described in this section start with those suitable for saturated six-membered heterocyclic rings and proceed through increasing degrees of unsaturation to the fully aromatic pyridines. 

Pyridine and Piperidine. These are six-membered heterocyclic rings containing one nitrogen. Piperidine (azine) is aromatic and undergoes aromatic hydroxylation. Piperidine functions as a secondary amine and undergoes hydroxylation with either glucuronic acid or sulfuric acid. 

Six-membered heterocyclic rings play much the same diverse roles on biological activity as their hve-membered counterparts. In many cases these serve as simple platforms for functional groups or in other instances provide a basic function. Those moieties can alternatively form a part of a pharmacophore. 

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