Five-membered ring heterocyclics

The highly acidic tetronic acid 15 and 3-methyltetronic acid 25 (furan numbering) are efficiently allylated under Pd(0) catalysis (88T7205, 

Allylations at oxygen are the rule with alkyl halide-base systems. However, ascorbic acid 33, which is a tetronic acid derivative, has been allylated 

The cinnamyl system has frequently been adopted as the allylic system for regioselectivity studies since these derivatives are very reactive, they give solid, high-molecular-weight compounds, and moreover, they usually present a very regioselective reactivity, the attack by the nucleophile taking 

T)3-ailylpalladium cation which gives rise, regioselectively, to the same final product 70 generated from attack at the less hindered terminal of the allylic system. A similar result is exemplified by the reaction of 67 with rac-12 to afford rac-73 [91JCS(P1)2603]. 

4(5)-Methoxyimidazole 84 was also allylated under Pd(0) catalysis. However, this reaction was not useful and gave a complicated array of products 85-89 arising from attacks at N-l, N-3, and C-5. Probably the experimental conditions were too severe for a very reactive imidazole such as 84 (95JHC1325). 

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Some examples of ring opening reactions with carbanions leading to five-membered heterocyclic ring formation are shown in Scheme 85. Pyrrole syntheses from functionally substituted oxiranes and amines are often described and typical examples are shown in Scheme 86. 

A theoretical, comparative study of the tautomerism of 56 five-membered heterocyclic rings announced in (76AHC(Sl)l) has appeared (81MI40402). The stabilities of the three forms for 5-pyrazolones, 5-pyrazolethiones and 5-aminopyrazoles have been calculated by a simple Hiickel o) iterative method. The relative energies and the substituent and solvent effects are in agreement with the experimental results. 

Polymers with a backbone of five-membered heterocyclic rings have been developed in the new area of thermally stable materials during the last 10 years (B-80MI40408). The simple polypyrazole (741) is prepared by condensation of polydiethynylbenzene with hydrazine in pyridine with yields of 60-97%. 

The photocycloaddition of arylazirines with a variety of multiple bonds proceeds in high yield and provides a convenient route for the synthesis of five-membered heterocyclic rings. Some of the dipolarophiles include azodicarboxylates, acid chlorides, vinylphosphonium salts and p-quinones. 

The 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

Histidine is one of the 20 naturally occurring amino acids commonly found in proteins (see Chapter 4). It possesses as part of its structure an imidazole group, a five-membered heterocyclic ring possessing two nitrogen atoms. The pAl for dissociation of the imidazole hydrogen of histidine is 6.04. 

II. Reactions with Five-Membered Heterocyclic Rings.63... 

A five-membered heterocyclic ring packs a relatively large number of polarized bonds into a relatively small molecular space. This provides a convenient framework to which to attach necessary side chains. In some cases, the framework itself is believed to be part of the pharmacophore. 

Free amino acids can be derivatized with isothiocyanates to phenyl- or methyl-thiohydantoin derivatives. The thiohydantoins can be separated on a CSP with poly-[Af-acryloyl-L-phenylalanine ethylester] (Chiraspher ) as a chiral selector [25]. This CSP offers a known selectivity for many five-membered heterocyclic rings. 

Various ring systems in which the pentathiepin ring is fused to a five-membered heterocyclic ring have "been described. 

Tricyclic Species with One Six- and Two Five-Membered Heterocyclic Rings... 

Volume 59 consists of four chapters. The first is by M. J. Silvester (Aldrich Chemical Co. Ltd.), and deals with polyfluoroheterocycles, updating the review by Chambers and Sargent which appeared in Volume 28 of Advances in Heterocyclic Chemistry in 1981. It covers mainly six-membered ring heterocycles and complements a review by Burger that will appear in Volume 60 of our series and will cover fluorine-containing five-membered heterocyclic rings. 

While these reports are mainly concerned with an evaluation of the peculiar structure of the iminophosphenium cation, this species also reveals cycloaddition properties. The cation shows a [2-t-l] cycloaddition behaviour towards alkynes [50]. With iminophosphanes and alkylazides the cations react with the formation of four- and five-membered heterocyclic ring systems [51], as shown for example in Scheme 9. 

A fairly large number of different fused (5 5 5) systems of three five-membered heterocyclic rings are reported in Chapter 8.35 of the Comprehensive Heterocyclic Chemistry (second edition) <1996CHEC-II(8)933>. In order to understand the various properties systemically, it is important to have an unambiguous idea about the structural patterns of different representative members of this unique fused (5 5 5) system of three five-membered rings. 

All compounds reported within the review period are indolizines or their hetero-substituted derivatives, fused through the a- or -edge to a five-membered heterocyclic ring. 

This is the case for the [Fe N6]2+ derivatives of 40 [50], 41 [51], 42 [52] and is consistent with the behaviour of the pyridyl-quinoline or 6-methyl-bipyridine systems. The incorporation of five-membered heterocyclic ring systems in this way could be readily achieved but does not seem to have been exploited in the generation of the crossover situation. 

DRUGS WITH FIVE-MEMBERED HETEROCYCLIC RINGS 80... 

The new five-membered, heterocyclic ring clues you in to the fact that a 1,3-dipolar cycloaddition has occurred here to form bonds 01-C9 and C10-C13. Disconnect these bonds, putting a + charge on C13 and a - charge on 01, to see the immediate precursor to the product. 

Examples of different types of tropones and tropolones fused to a five-membered heterocyclic ring are given in Scheme 1. Different fusion with respect to the heteroatom or group (Z) leads to... 

While it is clear that 1,2,5-thiadiazoles are clearly aromatic in nature, efforts have been made to quantify the degree of aromaticity. Three detailed comparative studies of relative aromaticity in five membered heterocyclic rings have been carried out by Bird <85T1409>, Katritzky <90JPR885>, and... 

Nitrile imines have been added to 1,4-diazepines (246) (143,144), 1,2, 4-triazepines (247) (145), 1-benzazepines (248) (146), 1,4-benzodiazepines (249-251) (147-149), 1,5-benzodiazepines (252, 253) (X = NH) (143,150-153), 1,5-benzothiazepines (253) (X=S) (153). Interest in this area has been stimulated by the known pharmacological activity of many compounds with five-membered heterocyclic rings fused to a benzodiazepine skeleton. 

This chapter reviews the systems where account is taken of the size of the central carbocyclic ring, the relative orientation of the fused five-membered heterocyclic rings, the types of heteroatoms, their number, and, in rings with more than one heteroatom, their relative situations. 

In the first chapter, D. S. Donald and O. W. Webster summarize much fundamental heterocyclic chemistry dealing with the preparation of heterocycles from hydrogen cyanide and its derivatives, mostly previously available only in the patent literature. In the second, the account of the ringopening of five-membered heteroaromatic anions by T. L. Gilchrist brings together the numerous transformations that can succeed the removal of a proton from a carbon atom in a five-membered heterocyclic ring. 

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