Nitration of heterocycles

There is available a large amount of qualitative information about the nitration of heterocyclic compounds, but quantitative information is still not very extensive, being limited to nitrogen systems. 

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

The basic procedure of the preparation of nitroazoles is the nitration reaction. The nitration of organic compounds, known for a century and a half, is still very enigmatic and attracts the attention of many researchers due to the interest in the nitration of heterocyclic compounds, in particular, of azoles. The reaction mechanism is the subject of heated discussions the methods of nitration are being constantly developed and modified, and the range of nitrating agents is ever expanding. 

Some recent investigations of the nitration of heterocyclic aromatic systems such as derivatives of pyrrol should be mentioned, as they seem to support the idea of the additional mechanism of Uot in the sense of fpso-reaction. Thus, Sonnet 45] described the reaction ... 

Nitronium salts axe the most effective electrophilic nitrating agents for nitration of aromatic compounds under very mild conditions. They are also widely applied in the nitration of heterocyclic aromatic compounds. The nitration of heterocyclic compounds by nitronium salts was first studied in the case of pyridine [16,19,70). N-nitration giving N-nitropyridinium ion is followed by ring opening, if excess pyridine is present, yielding glutaconic... 

The nitration of phenylpyridines and related compounds has attracted attention for a long time, and measurements of isomer proportions have been made for several compounds of this type. Nitration occurs in the phenyl ring. For 2-phenylpyridine and 2-phenylpyridine i-oxide measurements of the dependence of rate of nitration upon acidity in 75-81 % sulphuric acid at 25 °C show that both compounds are nitrated as their cations (table 8.1). The isomer distribution did not depend significantly upon the acidity, and by comparison with the kinetic data for quinolinium ( 10.4.2) the partial rate factors illustrated below were obtained.They should be compared with those for the nitration of 2-nitrobiphenyl ( 10.1). The protonated heterocyclic groups are much... 

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

When activating substituents are present in the benzenoid ring, substitution usually becomes more facile and occurs in accordance with predictions based on simple valence bond theory. When activating substituents are present in the heterocyclic ring the situation varies depending upon reaction conditions thus, nitration of 2(177)-quinoxalinone in acetic acid yields 7-nitro-2(177)-quinoxalinone (21) whereas nitration with mixed acid yields the 6-nitro derivative (22). The difference in products probably reflects a difference in the species being nitrated neutral 2(177)-quinoxalinone in acetic acid and the diprotonated species (23) in mixed acids. 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions the former show some relation to the opioids while the latter can be recognized as NSAlD s. The triamino pyridine 17 is an analgesic which does not seem to belong stmcturally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chlorofor-mate produces flupirtine (17) [4]. 

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. 

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-... 

Cha and co-workers reported that the silver nitrate-mediated heterocyclization of the diastereomerically pure aminoallene 192 gave the desired quinolizidine 193 and 194, both possessing the E double bond geometry, as a 7 1 mixture of diastereomers (Scheme 19.36) [43]. Diastereomeric transition states 197 and 198 were proposed. The quinolizidine 201 was expected to form predominantly from 199. They pointed out that interestingly, the cyclization of a 1 1 mixture of diastereomers of 192 gave a 1 2 mixture of 193 and 194. Compound 193 was successfully converted to the target clavepictine A (195) and B (196). 

Nitration with tetranitromethane proceeds along the ion-radical ronte. Tetranitromethane is a smooth nitrating agent and mild oxidizer. It is convenient for nitration of highly activated snbstrates snch as phenols, azulene, and heterocycles in the presence of pyridine, N,iV-dialkylaniline, etc. As shown (Morkovnik 1988), these reactions inclnde one-electron transfer ... 

An unsuccessful attempt to repeat this reaction was made by Bird however, he was able to show that dibenzothiophene 5-oxide did, in fact, react with either thionyl chloride or phosphorus oxychloride to yield 2-chlorodibenzothiophene in good yield. Since all methods of nitration of dibenzothiophene yield a mixture of 2-nitrodibenzothio-phene and dibenzothiophene 5-oxide, which have identical melting points, it was concluded that the earlier workers had in fact been working with the sulfoxide and not the nitro compound. The reaction was rationalized as being a deoxygenative halogenation of a heterocyclic 5-oxide akin to the Meisenheimer reaction of A-oxides, which already had precedents in the sulfoxide field. Unfortunately the 2-chlorodibenzothiophene prepared by this route is contaminated with 2,8-dichlorodibenzothiophene which cannot be removed by crystallization. The best method of preparation of this compound is therefore via a Sandmeyer reaction on 2-aminodibenzothiophene. ... 

Olah and co-workers ° conducted a comprehensive study into the use of N-nitropyridinium salts for nitration. Such salts are easily prepared from the slow addition of the appropriate heterocyclic base to an equimolar suspension of nitronium tetrafluoroborate in acetonitrile. Olah studied the effect on nitration of changing both the structure of the heterocyclic base and the counter ion. Three of these salts (20, 21, 22) illustrated above have been synthesized and used for the 0-nitration of alcohols with success. Transfer nitrations with Al-nitropyridinium salts are particularly useful for the preparation of nitrate esters from acid-sensitive alcohols and polyols because conditions are essentially neutral. 

A mixture of anhydrous lithium nitrate and trifluoroacetic anhydride in acetonitrile in the presence of sodium carbonate has been used to convert alcohols to nitrate esters for a range of peptide, carbohydrate and steroid substrates. Yields are good to high but products need puritication to remove trifluoroacetate ester impurities, which can be signiflcant in the absence of the carbonate. A similar system used for the nitration of electron-rich aromatic heterocycles employs trifluoroacetic anhydride with ammonium or potassium nitrate. ... 

The direct A -nitration of the amino groups of the hexahydrotriazine (23) is only possible due to the inherent low basicity of the methylenediamine functionality. The methylenediamine unit is present in many cyclic and bicyclic polyamines and these are potential precursors to energetic polynitramines. Unfortunately, this route to polynitramines is rarely possible because such polyamines are usually intrinsically unstable and will readily equilibrate to a lower energy, less strained system. For the same reason, polyamines containing the methylenediamine functionality are difficult to prepare and isolate, often rapidly decomposing in both aqueous and acidic solution. A far more common route involves the preparation of iV-protected versions of the polyamine followed by nitrolysis (Section 5.6). Even so, examples of heterocyclic methylenediamine iV-nitration exist. 

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. ... 

As previously discussed, heterocyclic polyamines containing methylenediamine functionality are usually unstable if unprotected. In contrast, the presence of a urea group stabilizes this functionality and allows the isolation of a number of heterocyclic amines. These are usually synthesized via a condensation reaction and isolated as the hydrochloride salt. The A-nitration of the 2,5,7,9-tetraazabicyclo[4.3.0]nonan-8-one and 2,4,6,8-tetraazabicyclo[3.3.0]octan-3-one ° ring systems has been investigated and serve as valuable examples. 

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. 

A reagent composed of tetra-n-butylammonium nitrate and TFAA in methylene chloride has been used to nitrate a series of A-alkyl and A-aryl amides (40-90 %). The formation of significant amounts of A-nitrosamides was noted. Tetra-n-butylammonium nitrate and triflic anhydride in methylene chloride has been used to successfully nitrate a variety of heterocyclic amides, imides and ureas (66). ... 

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