Heteroaromatic activators

Electrophilic substitution of five-membered heteroaromatics, activity and selectivity in 80KGS1587. 

A useful approach to the substitution of ring C—H positions lies in the activation of the heteroaromatic system by an A-oxide group, initiating a formal intramolecular redox reaction. 1-Methyllumazine 5-oxide reacts with acetic anhydride in a Katada rearrangement... 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

A quantitative study has been made on the effect of a methyl group in the 2-position of five-membered heteroaromatic compounds on the reactivity of position 5 in the formylation and trifluoroacetylation reaction. The order of sensitivity to the activating effect of the substituent is furan > tellurophene >selenophene = thiophene (77AHC(2l)ll9). 

Scheme 10.3. Activation Hardness for Aromatic and Heteroaromatic Compounds ...

In the second method, which can be applied to compounds with an optically active center near the potentially tautomeric portion of the molecule, the effect of the isomerization on the optical activity is measured. In favorable cases both the rate of racemization and the equilibrium position can be determined. This method has been used extensively to study the isomerization of sugars and their derivatives (cf. reference 75). It has not been used much to study heteroaromatic compounds, although the very fact that certain compounds have been obtained optically active determines their tautomeric form. For example, oxazol-5-ones have thus been shown to exist in the CH form (see Volume 2, Section II,D,1, of article IV by Katritzky and Lagowski). 

All the reactions discussed in this review are aromatic nucleophilic substitutions in the ordinary sense. These reactions are briefiy described in the following sections with respect to their general kinetic features and mainly involve aza-activated six-membered ring systems, although a few studies of other heteroaromatic compounds are also available. 

In accordance with the observed behavior of nitro-activated aromatic compounds, in all cases tested the displacement of halogens from A -heteroaromatic carbon by such reagents as sodium meth-oxide and sodium ethoxide in their respective alcohols [Eq. (2),... 

One of the merits of the above treatment, which justifies its inclusion in this review, is that it allows a quantitative comparison of the selectivity of nucleophilic heteroaromatic substitution (expressed by the reaction constant) with that for the analogous reaction with nitro-activated systems. Values for the latter are in the range 3.6 to 6.0. The fact that in both cases high p-values of similar magnitude are found is consistent with the hypothesis of similar mechanisms for both classes of compounds. 

Compounds of the type HC=C—CH=CHXR are not involved in a primary reaction with weak nucleophiles such as CH acids meanwhile, a final (secondary) cyclization with participation of active methylene groups happens to be feasible. Evidently, in most cases the energy gain in the heteroaromatic system realization is the decisive factor (81UK1252). 

Papers dealing with this topic are exhaustively reviewed in Comprehensive Heterocyclic Chemistry I (84CHEC-I(6)235) and II (96CHEC-II(3)373). Nevertheless, little information is available on the 5-oxides. Recently, the heteroaromaticity of thiazole compared with isothiazole and thiadiazole 5,5-dioxide systems was studied (97MI1). Quantum-chemical calculations and X-ray studies were performed on 3,3 -di[l,3-thiazolidin-4-one] derivatives (95JCC(25)589) studied for their potential biological activity (97FA(52)43). 

Various 1.4-benzodiazepines with a five-membered heteroaromatic ring fused to the 1,2-bond, such as 17, where A represents a heteroaromatic ring, have been prepared by such methods and tested for activity on the central nervous system, as cholecystokinin antagonists and as antagonists of platelet activating factors.245... 

C-coupling is of outstanding importance in the azo coupling reaction for the synthesis of azo dyes and pigments. An aromatic or heteroaromatic diazonium ion reacts with the so-called coupling component, which can be an aromatic primary, secondary, or tertiary amine, a phenol, an enol of an open-chain, aromatic, or heteroaromatic carbonyl compound, or an activated methylene compound. These reactions at an sp2-hybridized carbon atom will be discussed in Chapter 12. In the... 

In spite of the large amount of scientific and industrial activity on diazo compounds and azo coupling reactions since the 19th century, heteroaromatic diazo components have been studied intensively only since the 1950s. 

Recently, the required heteroaromatic organozinc halides for the Negishi reaction have also been prepared using microwave irradiation [23]. Suna reported that a Zn - Cu couple (activated Zn), prepared using a slightly modified LeGoff procedure from Zn dust and cupric acetate monohydrate, allowed the smooth preparation of (3-pyridinyl)zinc iodide and (2-thienyl)zinc iodide... 

Debnath AK, Lopez de Compadre RL, Debnath G, Shusterman AJ, Hansch C. Structure-activity relationship of mutagenic aromatic and heteroaromatic nitrocompounds—correlation with molecular orbital energies and hydrophobicity. I Med Chem 1991 34 786-97. 

Paluchowska MH et al. (1996) Structure-activity relationship studies of CNS agents, part 31 Analogs of MP 3022 with a different number of nitrogen atoms in the heteroaromatic fragment—new 5-HTlA receptor ligands. Arch Pharm (Weinheim) 329(10) 451-456... 

The pyridine family of heteroaromatic nitrogen compounds is reactive toward nucleophilic substitution at the C(2) and C(4) positions. The nitrogen atom serves to activate the ring toward nucleophilic attack by stabilizing the addition intermediate. This kind of substitution reaction is especially important in the chemistry of pyrimidines. 

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