Five-membered heterocycles nitration

Allenes can also act as the -participant in electrophilic heteroatom cyclizations. Reviews of electrophilic additions to allenes discuss early examples of this type of cyclization.ld le-202 Numerous examples of cyclizations of a-functionalized allenes, including carboxylic acids, phosphonates, sulfinates and alcohols, to form five-membered heterocycles (equation 84) are cited in these reviews. The silver nitrate-mediated conversion of ot-allenic alcohols to 2,5-dihydrofurans203 has recently been applied to trimethylsilyl-substituted systems.204... 

Nitro compounds, in particular aromatic and heterocyclic derivatives, absorb strongly in the near UV. They have properties similar to ketones in their excited state. These compounds are characterized by an unpaired electron in the n0 orbital and thus by a radical character. A typical example of this radical character is the easy intramolecular hydrogen abstraction in nifedipine and related vasodilators (Sch. 7) (18). Another manifestation of the radical character of the nitro group is the rearrangement often observed with nitrated five-membered heterocycles, as in the case of metronidazole (Sch. 8) (19). 

Since the classic papers by Ingold and his co-workers,110, 111 nitration has for a long time been considered as the standard electrophilic substitution. Many orientation and relative rate data on the nitration of both carbocyclic and heterocyclic substrates have been accumulated and the results have been generalized as valid for all electrophilic substitutions. As a matter of fact, this popularity is partially undeserved nitration is a complicated reaction, which can occur by a multiplicity of parallel mechanisms.112 In particular, in the case of the very reactive substrates that five-membered heterocycles are, two complications may make meaningless both kinetic measurements and competitive experiments.113 (i) Due to the great reactivity of both partners the encounter limiting rate may be achieved in this case, of course, all the substrates react at the same rate and the effect of structure on the reactivity cannot be studied. (ii) Nitrous acid, always present in traces, may exert an anticatalytic effect in some cases and a markedly catalytic effect in others with a very reactive substrate, nitration may proceed essentially via nitrosa-tion, followed by oxidation. For these reasons, the nitration data must be handled with much caution. 

A fundamental investigation of the kinetics and the mechanism of nitration of five-membered heterocycles containing nitrogen is due to Ridd and his co-workers.125 126 They studied the reaction of pyrazole and imidazole with nitric acid in 90-99% sulfuric acid. 

The previously described reactivity data for the five-membered heterocycles are gathered (in terms of o+ values) in Table 6.12 no data are given for nitration because the rates are encounter controlled and meaningless in terms of electronic effects. Among the other data, those for mercuriation, protiodemercuriation, and protiodeboronation are doubtful, and other qualifying aspects are noted in the table footnotes. The following main features are noteworthy. 

A great number of publications deal with the reaction of nitration [7-20], At the same time, volumes literature on nitro heterocycles has not been systematized until the present time. Direct nitration of some five-membered heterocycles such as pyrroles, furans, thiophenes, pyrazoles, imidazoles, and thiazoles has been discussed by Katritzky [21, 22], Some synthetic routes to nitrated six-membered nitrogen-containing aromatic heterocycles [23], as well as the nitration of oxo-pyrimidines and -imidazoles [24], and quantum-chemical studies of the nitration of benzazoles [25] have been reported. 

Like other aromatic compounds, these five-membered heterocycles undergJ nitration, halogenation, sulfonation, and Friedel-Crafts acylation. They are mucji more reactive than benzene, and resemble the most reactive benzene derivatives (amines and phenols) in undergoing such reactions as the Reimer-Tiemann reaction, nitrosation, and coupling with diazonium salts. 

The rates of nitration of isothiazole (and its 3- and 5-methyl derivatives) have been measured. While isothiazole and its 3- and 5-methyl derivatives are nitrated as free bases, the 3,5-dimethyl-compound is nitrated as the conjugate acid. Isothiazoles are nitrated in the 4 position 10 times slower than benzene. The order of reactivity for nitration is pyrazole > isothiazole > isoxazole, in contrast to that of five-membered heterocycles containing one heteroatom, which for trifluoroacetylation is pyrrole > furan > thiophen. ... 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

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