Heterocycles nitric acid

The oxidative desulfurisation of 1,2,4-triazole thiones is a type of reaction common to other electron-deficient nitrogen heterocycles nitric acid is the oxidant in the example below. The process involves loss of sulfur dioxide from an intermediate sulfinic acid. ... 

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]. 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140)... 

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... 

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

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. 

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-... 

A safe method of preparing 5-nitro-2-methylbenzimidazole involves preliminaiy addition of the heterocycle to nitric acid (d 1.40) with subsequent addition of sulfuric acid, keeping the temperature below 110°C. 

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. 

This unusual process known as the W-method was discovered in Germany by Wolfram and involves the condensation of the potassium salt of sulfamic acid with formaldehyde to form the heterocycle (238) followed by treatment with nitric acid. The extreme sensitivity of (238) to hydrolysis means that nitrolysis has to be conducted under anhydrous conditions using sulfur trioxide or phosphorous pentoxide " dissolved in fuming nitric acid. The yield of RDX from the W-method is 80-90 %. 

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. 

Owing to its aromatic structure which has been compared to naphthalene, 1,2,3-benzothiadiazole survives exposure to 20% potassium hydroxide at 150 °C or 27% sulfuric acid at 200 °C. Potassium permanganate, potassium ferricyanide, chromic acid or dilute nitric acid failed to oxidize the heterocycle (B-61M142400). 

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