Five- or six-membered heterocyclic

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. 

Insertion of a C=0 or C=S group between hydroxy or amino groups and a thiol function in 1,2- or 1,3-positions leads to a five- or six-membered heterocycle ... 

The proposed catalytic cycle of the ruthenium-catalyzed intermolecular Alder-ene reaction is shown in Scheme 21 (cycle A) and proceeds via ruthenacyclopentane 100. Support for this mechanism is derived from the observation that the intermediate can be trapped intramolecularly by an alcohol or amine nucleophile to form the corresponding five-or six-membered heterocycle (Scheme 21, cycle B and Equation (66)).74,75 Four- and seven-membered rings cannot be formed via this methodology, presumably because the competing /3-hydride elimination is faster than interception of the transition state for these substrates, 101 and 102, only the formal Alder-ene product is observed (Equations (67) and (68)). 

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... 

Ring-closing metathesis is well suited for the preparation of five- or six-membered heterocycles, and has also been successfully used to prepare tetrahydropyridines on insoluble supports (Entries 1 and 2, Table 15.23). Because metathesis catalysts (ruthenium or molybdenum carbene complexes) are electrophilic, reactions should be conducted with acylated amines to avoid poisoning of the catalyst. 

A review on the ring enlargement of SCBs leading to the formation of five- or six-membered heterocycles has been published <1998J(P1)2209>. 

It is known that the reaction of trialkylboranes with polyacetylenic derivatives of group 14 elements affords five- or six-membered heterocycles depending on the nature of substituents [eq. (5)].1... 

It is also appropriate here to remind the reader that carbonyl compounds or diols can be protected via formation of cyclic acetals or thioacetals. These reactions, as we have already seen, occur under mild conditions owing to the ease of formation of five- or six-membered heterocyclic rings. 

Pyridopyrimidines and pyrimidines fused with five- or six-membered heterocycles can be prepared via the ring closure of intermediate ethynylpyrimidines, which are themselves obtained by the Pd-catalyzed cross-coupling of halopyrimidines with alkynic compounds (Scheme 34). ° ""° o-Alkynylanilines such as (51), which are made by Pd-catalyzed coupling reactions of alkynes with o-haloaniline precursors, are easily cyclized to the indoles in the presence of base (Scheme 35). " " Similar meth( s can be employed in the synthesis of isocoumarins," thienopyridines," furopy-ridines" and the marine alkaloid asptamine." ... 

R1 — R3 = alkyl, cycloalkyl, phenalkyl, phenyl, naphthyl, or R2R3N form a five or six membered heterocyclic groups). 

Thionamides are the most important class of antithyroid compounds in clinical practice used in nondestructive therapy of hyperthyroidism. These agents are potent inhibitors of TPO, which is responsible for the iodination of tyrosine residues of thyroglobulin and the coupling of iodotyrosine residues to form iodothyronines. These drugs have no effect on the iodide pump or on thyroid hormone release. The most clinically useful thionamides are thioureylenes, which are five- or six-membered heterocyclic derivatives of thiourea and include the thiouracil 6-n-propyl-2-thiouracil (PTU) and the thioimidazole 1-methyl-2-mercaptoimidazole (methimazole, Tapazole, MMI). The uptake of these drugs into the thyroid gland is stimulated by TSH and inhibited by iodide. 

This moiety is a feature of either an arylanilide (X = N log P = 2.45,3.36 80, 82, respectively), arylether (X = O log P = 4.90,5.37,4.28 83, 85, 86, respectively) or of a substituted N-methyl-enaminone structure (X = C-C bond log P = 1.87, n.d. 81, 84, respectively) in a five- or six-membered heterocycle, respectively. It is assumed that the biochemical activity of these compounds is determined by the properties of the meto-trifluoromethylphenyl group, such as high lipophilicity (for X = O) and an electron-withdrawing nature. Furthermore, there are strict requirements for substitution at the five- or six-membered heterocycle of the inhibitor, especially at the position most distant from the carbonyl group (for more details see Chapter 4.1). 

Scheme 6 exemplifies the first path. Intramolecular cyclization of sulfonamides 1 is caused by action of a base, thus resulting in the formation of nitroaromatics fused with five- or six-membered heterocycles [22-24]. It should be emphasized that in some cases the formation of isomeric products can be observed due to a nucleophilic attack at the para-position relative to the nitro group. Also it is worth noting that the cyclic sulfamides 2 and 3 can be used as precursors to obtain some other N-heterocyclic compounds, such as isoindoles 4 [25] or 1,2,3,4-tetrahydroquinolines 5 [24] (Scheme 6). 

Transition metal-catalyzed carbocyclization of nitrogen- and oxygen-tethered 1, n-enynes and diynes to give five- or six-membered heterocyclic compounds 12CC10271. 

In this chapter, the retrosynthetic analysis and proposals for the synthesis of heterocyclic compounds with one to three heteroatoms in five- or six-membered heterocyclic rings are presented. Such heterocyclic rings are constituents of thousands of biologically active compounds. Compendia on the synthesis and structural properties of all classes of heterocyclic compounds are available [1 ]. Numerous syntheses of heterocycles and descriptions of their physico-chemical properties are presented in separate chapters of organic chemistry handbooks cited in the introduction chapter of this book. 

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