Five- and Six-Membered Heterocycles

SC calculations have subsequently also been carried out on many aromatic systems, such as heterocyclic five- and six-membered rings, on naphthalene and on azulene. For naphthalene and azulene, with 10 n electrons, the orbitals obtained are very similar to those of benzene, with the exception of the two orbitals localized at each of the C atoms which bridge the two rings. These orbitals display a three-way deformation, towards each of the three adjacent carbon atoms. In addition equation (12) shows that for a 10-electron system there are 42 possible spin functions which should be taken into account. But since the SC orbitals are fully optimized, it turns out that the only spin functions which play any significant role in these molecules are those corresponding to the Kekul structures (in the case of naphthalene, structures (3), (4), and (5) in Section 3) and that the contribution of the other 39 structures may be neglected. 

In this case similar patterns are found for both the heterocyclic five- and six-membered rings compared to the carbocyclic benzene system. The number of adjacent C—H oscillators effectively determines the position of the all-in-phase out-of-plane bend location in the spectral region. Thus we find that ... 

Sulfur containing heterocycles are also common Compounds m which sulfur is the heteroatom m three four five and six membered rings as well as larger rings are all well known Two interesting heterocyclic compounds that contain sulfur-sulfur bonds are hpoic acid and lenthiomne... 

The proton affinities (gas phase) of thiirane and other three-membered heterocycles have been determined azirane (902.5), thiirane (819.2), phosphirane (815.0), oxirane (793.3 kJ moF ) (80JA5151). Increasing s character in the lone electron pairs decreases proton affinities. Data derived from NMR chemical shifts in chloroform indicate the order of decreasing basicity is azirane > oxirane > thiirane (73CR(B)(276)335). The base strengths of four-, five- and six-membered cyclic sulfides are greater than that of thiirane. 

DFT calculations for other heterocycles (neutral azoles, protonated forms) have been reported (94T2405, for semiempirieal ealeulations see 93ZOR1297 see also AMI, MNDO, and PM3 ealeulations for neutral five-and six-membered nitrogen heteroeyeles). 

M. P. Groziak and F. G. Jacobs, Tricyclic Systems Central Carbo-cyclic Ring with Fused Five- and Six-membered Rings Chapter 7.22 pp. 875-919 in Katritzky A. R., Rees Ch. W., and Scriven E. F. V, Comprehensive Heterocyclic Chemistry II A review of the Literature 1982-1995, Vol. 7 Fused Five- and Six-membered Rings without Ring Junction Heteroatoms, vol. ed. Ramsden Ch. A., Elsevier Science, Oxford, 1996. 

Syntheses of five- and six-member P-heterocycles from 1,4- and 1,5-diketones 98IZV1905. 

This tendency is especially significant in compounds containing functional groups capable of addition with the formation of both five- and six-membered rings. It has been shown that for amides and hydrazides of azolecarboxylic acids, selectively, and for the acids with any arrangement of a function and triple bond, heterocyclization always leads to the closure of the six-membered ring. Similar reactions in the benzoic series mainly lead to the formation of five-membered rings. 

Thus, the reaction of 4-dialkylaminobut-3-yn-2-ones with various bifunctional reagents makes it possible to carry out a targeted synthesis of five- and six-membered nitrogen-, oxygen-, and sulfur-containing heterocycles having two heteroatoms. 

Volume 81 of Advances in Heterocyclic Chemistry consists of four chapters. G. Rauhut (University of Stuttgart, Germany) provides a contemporary overview of methods and results for the computation of heteroatom-rich five- and six-membered ring systems, covering many advances in MO theory made over the last decade. The review will be useful to a wide range of heterocyclic chemists. 

Bis(trifluoromethyl)thiobut-2-yne is a source of CF3S-substituted five-and six-membered heterocycles through pyrolysis, photolysis, and 1,3-dipolar cycloaddition (88CB1833). 

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. 

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. 

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]. 

Scheme 21 Formation of five- and six-membered ring heterocycles by lanthanocene complexes...

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

The third chapter Recent Developments in the Chemistry of N-Heterocyclic Phosphines presents a survey on five- and six-membered phosphorus-nitrogen heterocyclic compounds whose rings combine a phosphazene or phosphazane unit... 

On chlorination of dialkyl esters of 2-chloro-3-methyl-l,3-butadienephosphonic acid in non-polar media, a mixture of five- and six-membered heterocyclic compounds was obtained (Scheme 77) [153, 154],... 

Prior to the discovery of niacin receptors, medicinal chemistry efforts were mainly directed toward small heterocyclic carboxylic acids that are structurally similar to niacin. Systematic study of nitrogen-containing five- and six-membered heterocyclic carboxylic acids revealed that activity at GPR109A was significantly reduced for any of the variants of niacin shown in general structures (A and B) [45,46]. These heterocycles include pyrazole, isoxazole, thiazole, pyrazine, and pyrimidine. 

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