Heterocycles nitrations, nitric acid

RATE COEFFICIENTS AND ARRHENIUS PARAMETERS FOR NITRATION OF HETEROCYCLICS IN NITRIC ACID-SULPHURIC ACID50... 

Nitroimidazoles substituted by an aromatic ring at the 2-position are also active as antitrichomonal agents. Reaction of p-fluorobenzonitrile (83) with saturated ethanolic hydrogen chloride affords imino-ether 84. Condensation of that intermediate with the dimethyl acetal from 2-aminoacetaldehyde gives the imidazole 85. Nitration of that heterocycle with nitric acid in acetic anhydride gives 86. Alkylation with ethylene chlorohydrin, presumably under neutral conditions, completes the synthesis of the anti-... 

Similar results were obtained during the nitration of 2-methoxythiazole [289], Katritzky et al. proposed the use of so-called standardized rate constants (k2°), obtained during the nitration of various aromatic heterocycles by nitric acid in 75% sulfuric acid at 25°C (H0 - 6.6) [59], These constants make it possible to compare quantitatively the reactivity of various types of heterocyclic compounds in nitration. The calculated standardized rate constants for the nitration of azoles are given in Table 4. 

The sole known example of electrophilic substitution in quinazoline is nitration. Quinazoline gives 6-nitroquinazoline with fuming nitric acid in concentrated sulfuric acid. No oxidation of the heterocyclic ring can occur under these conditions because the hydrated cation (see Section IIA>4) is not present. This substitution is in agreement with theoretical calculation [see (2) and reference 36]. 

The conclusion that the nitration of quinoline in sulphuric acid takes place via the conjugate acid has been confirmed by Moodie et al.50, who measured the rates of nitration of a wide range of heterocyclic compounds in nitric acid-sulphuric acid mixtures at a range of temperatures. A summary of the second-order rate coefficients and Arrhenius parameters is given in Table 4. From an analysis of the shapes of the plots of log k2 versus sulphuric acid acidity (or some function of this), it was concluded that all of the compounds starred in Table 4... 

The nitration of some heterocyclic compounds by nitric acid in sulphuric acid has been studied by Katritzky et al.s0 d and the results are exactly as expected in that electron-supplying substituents in the ring favour reaction on the conjugate acid whereas electron-withdrawing substituents produce reaction on the free base. Rate coefficients and the kinetic parameters for nitration of pyridine derivatives (and some benzene analogues)50 are given in Table 4a. 

The A-nitration of the furazan-based heterocycle (29) has been reported. The corresponding tetranitramine (30) is an unstable substance, but obtained on treating (29) with either trifluoroacetic anhydride (TFAA) in nitric acid or dinitrogen pentoxide in nitric acid. In this case the furazan rings stabilize the 1,4,5,8-tetraazadecalin structure and further reduce the basicity of the amidine amino groups. A number of other furazan and nitrogen-rich nitramines... 

The strained A-nitroazetidine (36) has been synthesized from the nitration of the hydrochloride salt of the corresponding azetidine (35) with acetic anhydride-nitric acid. The heterocyclic guanidine (38) is synthesized from (37) in a similar way. ... 

N, iV -Dinitrourea (DNU) has been prepared by the nitration of urea with a mixture of 98 % nitric acid and 20 % oleum between -10 °C and -15 °C. N, IV -Dinitrourea is unstable at room temperature. However, the diammonium and dipotassium salts are more stable and decompose at 110 °C and 135 °C respectively. N, IV -Dinitrourea may find future use for the synthesis of bicyclic and caged heterocyclic IV.lV -dinitroureas. 

The nitrogen atoms of heterocycles like imidazoles and triazoles have been converted into IV-nitroimide groups. The A -nitroimide (164) is synthesized from 1-amino-1,3,4-triazole (162) by IV-amination of the tertiary nitrogen with 0-picrylhydroxylamine, addition of nitric acid to give the nitrate salt (163), followed by IV-nitration with nitronium tetrafluoroborate in acetonitrile. The 1,2,3-triazole (165) and the imidazole (166) ° are synthesized in a similar way. The synthesis of IV-nitroimides has been the subject of an excellent review. ... 

The furazan-based heterocycle (12) is iV-nitrated to the corresponding nitramine (13) with nitrogen pentoxide in nitric acid without chloride catalyst because of the inherent low basicity of the methylenediamine functionality." ... 

These compounds are less common than indole (benzo[ ]pyrrole). In the case of benzo[i>]furan the aromaticity of the heterocycle is weaker than in indole, and this ring is easily cleaved by reduction or oxidation. Electrophilic reagents tend to react with benzo[Z ]furan at C-2 in preference to C-3 (Scheme 7.21), reflecting the reduced ability of the heteroatom to stabilize the intermediate for 3-substitution. Attack in the heterocycle is often accompanied by substitution in the benzenoid ring. Nitration with nitric acid in acetic acid gives mainly 2-nitrobenzo[Z ]furan, plus the 4-, 6- and 7-isomers. When the reagent is in benzene maintained at 10 °C, both 3- and 2-nitro[ ]furans are formed in the ratio 4 1. Under Vilsmeier reaction conditions (see Section 6.1.2), benzo[Z ]furan gives 2-formylbenzo[6]furan in ca. 40% yield. 

The particularly good activity against protein kinases of a-aminoquinazoline derivatives is borne out by their activity against both in vitro and in vivo models of human tumors. The examples that follow are but two of a number of compounds from this structural class that have emerged from the focus that has been devoted to this stmctural class. Nitration of the benzoate (78-1) with nitric acid affords the nitro derivative. Hydrogenation converts this to the anthrandate (78-2). In one of the standard conditions for forming quinazolones, that intermediate is then treated with ammonium formate to yield the heterocycle (78-3). Reaction of this last product with phosphorus oxychloride leads to the corresponding enol chloride (78-4). Condensation of this last intermediate with meta-iodoanUine (78-5) leads to displacement of chlorine and the consequent formation of the aminoquinazoline... 

Nitration Instead of a mixture of nitric acid and sulphuric acid, nitration of these three heterocycles is carried out with acetyl nitrate (formed from nitric acid and acetic anhydride). Nitration is in place mainly at one of the carbon atoms next to the hetero-atom. 

Compounds (49) undergo nitration in the heterocyclic ring on reaction with nitric acid acetic anhydride in nitromethane at - 15°C (77JHC1021). 

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. 

Another criterion suggested [71JCS(B)2454] for identifying the nature of the reacting species was comparison of the behavior of a base on nitration in acetic anhydride with that on nitration in sulfuric acid. Applied to weak bases the method seemed to work well, but subsequent work by the same authors showed that it fails with stronger bases, such as most heterocycles, since they form salts in acetic anhydride-nitric acid solutions, as well as in sulfuric acid application of this method to some relatively weak bases may also be vitiated by side reactions [72JCS(P2)1654], The whole question of reliability of rate profile interpretation is still... 

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. 

The nitration of 2-phenylamino-4-phenylselenazole takes place in a more complicated way ([230], part 3). A very vigorous reaction with the formation of several nitration products is observed even with careful addition of this compound to the sulfuric-nitric acid mixture. It was possible to separate and partly to identify the products by column chromatography and thin-layer chromatography. The products from opening of the heterocycle were not detected (Scheme 30). 

It is not possible to introduce a nitro group into the 1,2,4-triazole ring by the action of the sulfuric-nitric acid mixture because of the disactivation of the cycle by two pyridine nitrogen atoms furthermore, their disactivation effect is aggravated by the heterocycle protonation in the acid medium. The only exception is the nitration of l,2,4-triazolon-5 [250-264], This is probably due to the specific electronic structure of the substrate (the azolone form) (Scheme 32). 

Nitronium tetrafluoroborate is often used to introduce a nitro group into the molecule of azoles. In some cases it is not even isolated in the individual form, but the azole is added to a mixture of concentrated nitric acid and boron trifluoride [334, 341-345], Nitronium tetrafluoroborate is used particularly often for the selective nitration of a heterocycle in aryl-substituted azoles [101, 102, 164, 346, 347] (Scheme 35). 

Ipso-nitration of 4-bromopyrazoles by the sulfuric-nitric acid mixture is approximately 100 times slower than normal nitration of the corresponding unsubstituted pyra-zoles [46], Substitutive nitration of 4-halogeno-l-alkylpyrazoles takes place in parallel with normal nitration at positions 3 and 5 of the heterocycle [46, 74] (Scheme 47). 

The nitration of benzazoles is usually effected using concentrated (65%) to fuming (100%) nitric acid generally at temperature between 0 and 5°C. Indazoles are usually nitrated into 5 position, benzimidazoles - as a rule - into 5- or 6-position of the phenylene fragment whereas benzotriazole into position 4 or 7. For the preparation of other nitrobenzazoles the reaction of heterocyclization is used. 

Nitration of triazolinones (possibly reacting as phenolic hydroxytriazoles) with fuming nitric acid affects the heterocyclic ring with simultaneous nitration of the benzene ring in 1- and 4-phenyl derivatives. However, 2- or 3-phenyl derivatives of l,2,4-triazolin-5-one are nitrated in the benzene ring exclusively (69cb75s). 

Dipole moment studies of the conformations of arylimidazoles have shown that the aryl ring is not always coplanar with the heterocyclic C-NMR spectroscopy of phenylimidazoles has been studied. In mixed acids 1-phenylimidazole is nitrated as the conjugate acid to give mainly the p-nitrophenyl product with nitric acid in acetic anhydride only the nitrate salt forms. With 4-(p-alkoxyphenyl) imidazoles much of the nitration occurs ortho to the alkoxy group" the alkoxynitroaryl substituents are readily oxidized to carboxyl by alkaline permanganate. ... 

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