In five-member heterocycles

Just as in the Diels-Alder reaction, 1,4-dipolar cycloadditions lead to six-membered rings. Their principal use in five-membered heterocycles is for ring annulations giving [5,6] ring-fused systems. 

Structures and nomenclature for the most important five-membered monocycles with one or more heteroatoms are depicted in Scheme 1. The aromaticity scale in five-membered heterocycles has been long debated.97-101 The decreasing order of aromaticity based on various criteria is (DRE values in kcal/ mol) benzene (22.6) > thiophene (6.5) > selenophene > pyrrole (5.3) > tellurophene > fur an (4.3). Pyrrole and furan have comparable ring strains (Scheme 38). The aromaticity of furan is still controversial 100 the NMR shielding by ring current estimated it at about 60% of the aromaticity of benzene, and other methods reviewed earlier102 estimated it at less than 20%. 

Scheme 38. Aromaticity Scales in Five-Membered Heterocycles...

Silicon protection is also commonly used to direct lithiation chemistry in five-membered heterocycles. For example, oxazoles , thiazoles and Ai-alkylimidazoles ° ° lithiate preferentially at C-2, where the inductive effect of the heteroatoms is greatest. If C-2 is blocked, lithiation occurs at C-5, where there is no adjacent lone pair to destabilize the organolithium. Functionalization of these heterocycles at C-5 can therefore be achieved by first silylating C-2, reacting at C-5 and then removing the silyl group. The synthesis of 666 illustrates this sort of sequence (Scheme 258) °. ... 

No nucleophilic substitution in five membered heterocycles with hydroxylamines has been reported so far, although any nucleophilic substitution reaction known for amines should be suitable for hydroxylamines as well. 

Diketo oxime 43 (Scheme 27) find extensive use in organic synthesis. These compounds are useful building blocks in five-membered heterocyclic chemistry. These oximes can be used for the synthesis of pyrroles , thiazoles , oxazoles and pyrazoles . The diketo oxime 43 was synthesized in high yield by addition of an aqueous solution of sodium nitrite to a 0°C solution of 1-benzoylacetone 42 in AcOH . ... 

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... 

In five-membered heterocycles, formally derived from benzene by the replacement of a CH=CH unit by a heteroatom, aromaticity is achieved by sharing four p-electrons, one from each ring carbon, with two electrons from the heteroatom. Thus in pyrrole, where the heteroatom is N, all the ring atoms are sp hybridized, and one sp orbital on each is bonded to hydrogen. To complete the six 7i-electron system the non-hybridized p-orbital of N contributes two electrons (Box 1.9). It follows that the nitrogen atom of pyrrole no longer possesses a lone pair of electrons, and the compound cannot function as a base without losing its aromatic character. 

The gas phase basicities at both the a- and (3-positions in five-membered heterocycles have been studied by ion cyclotron resonance equilibrium and bracketing experiments on deuteriated substrates. a-Protonation is preferred by 2.8-4.6 kcal mol-1 for both furan and thiophene as compared to 0-2.9 kcal mol 1 for pyrrole (81NJC505) and heteroatom protonation is much less favored than a-protonation. Semiempirical (MNDO) molecular orbital calculations have provided quantitative confirmation of the above conclusions. 

As in five-membered heterocycles, the introduction of a carbonyl group produces a dramatic effect on the photoreactivity. Pyran-2-ones undergo other electrocyclic processes in addition to those discussed in preceding sections.213 Photorearrangement, however, does not occur in the coumarin nucleus, although a photo-Fries rearrangement of 3-benzoyloxy-6,7-... 

Much work in the review period has concerned enantioselective substitution in five-membered heterocyclics. The enantioselective alkylation of some pyrroles by unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(in) triflate complex (31) has been reported.39 Compound (33) is formed in 98% yield and 94% ee from the 2-acylimidazole (32) and pyrrole at —40 °C. A series of enantiomer- ically pure aziridin-2-ylmethanols has been tested as catalysts in the alkylation of /V-mclhylpyrrolc and (V-methylindole by ,/l-unsalura(cd aldehydes.40 Enantiomeric excesses of up to 75% were observed for the alkylation of /V-mcthylpyrrole by ( >crotonaldehyde using (2.S ,3.S )-3-mclhylazirin-2-yl(diphenyl)methanol TFA salt as catalyst to form (34). 

The ability of thienothiophenes and selenoloselenophenes to transmit substituent effects has been determined by H and l3C NMR, and also calculated by the CNDO/2 method [82CS(20)208 83CS(22)22]. As expected, resonance effects are better transmitted between the 2- and 5-positions in 8.185 than in 8.186, since only in the former is direct conjugation between these positions possible. Both resonance and inductive/field effects were greater in the sulfur- relative to the selenium-containing compounds, but in general, replacement of sulfur by selenium caused only minor perturbations of data, which follows from the fact that the main mode of transmission of substituent effects in five-membered heterocycles must be via the carbon chain (cf. Chapter 6, Section 9.C). 

In contrast to the heteroatom in five-membered heterocycles (Chapter 6), a pyridine nitrogen atom should be able to transmit electronic effects in a manner similar to a CH group in benzene. Difficulty attends assessment of such transmission abilities by comparison of the reactivities of pyridines and benzenes because the Hammett p factor obtained will be a measure of both the transmission ability (64JCS627) and the transition-state charge. Because pyridine is less reactive, the transition state for its reactions should be nearer to the Wheland intermediate than the corresponding transition states for reactions of the corresponding benzene... 

Theoretically 3), the intensities of the three lines are equal however, the Boltzmann factor, possible anisotropy of the crystalline sample and, most of all, the relaxation times can modify them to the extent that some lines remain unobserved (cf. Ref. 77 in Five-membered heterocycles ). 

Structures and nomenclature for the most important five-membered monocycles with one or more heteroatoms are depicted in Figure 24. The aromaticity scale in five-membered heterocycles has long been debated <2001PCA5486, 1996CHEC-II(2)471, 1984CHEC(4)28, 1974AHC(17)255, B-1986MI2>. 

Figure 25 Aromaticity scaies in five-membered heterocycles.

In five-membered heterocycles, NMR signals of /3-carbons shift upfield with decrease in electronegativity of the ... 

Distibanes and dibismuthanes in which the antimony or bismuth atoms are incorporated in five-membered heterocycles are named bistiboles and bibismoles. This important class of thermochromic compounds has been studied intensively by the group of Ashe. The synthesis and X-ray structure determination of tetramethylbistibole. 

This article is organized by ring system. Thus, Claisen rearrangements in five-membered heterocyclic rings are covered in Section 11, rearrangements of A/-allyl heterocycles in Section 111, and Claisen rearrangements of six-... 

Aminoacridines 84 and 85 (R1 = H, F, Br, Cl R2 = Me, CH2Br, OMe, etc. R3 = H, OMe) exist in amino imino tautomeric equilibrium in DMSO-<76 solution at ambient temperature however, increasing the temperature to 370 K results in the complete shift toward the imino tautomers (03MRC549). The tautomeric equilibria in five-membered heterocycle-fused 9-aminoacridines are completely shifted toward the imino tautomers in CDC13 and DMSO-4, solution (01MRC225). 

Directing groups can overcome the normal tendency for a-lithiation in five-membered heterocycles, as shown in the thiophene example below, however the use of lithium diisopropylamide does allow normal a-lithiation in this case. ... 

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