Nitro-amines acyl derivatives

The resulting acetyl compound is usually hydrolyzed with aqueous alkaU to give the free amine. Other A/-acyl derivatives may be used, particularly for the less soluble succinyl and phthaloyl products. The use of -nitrobenzenesulfonyl chloride, followed by reduction of the nitro to an amino function, is much more expensive and is rarely used. A/-Acetylsulfanilyl chloride [121 -60-8] is obtained by the chlorosulfonation of acetanilide [103-84-4] which is the basic material for most of the sulfonamides. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Substituents on thiocoumarins behave in predictable fashion for example, 3-nitro compounds afford the 3-amines on reduction, while 3-acyl derivatives readily form normal carbonyl derivatives such as phenylhydrazones, or enoic acids with malonates. These derivatives may frequently be cyclized on to position 4 of a 4-hydroxythiocoumarin to give products such as (119) (equation 59). 

This method has been used chiefly for the preparation of acyl derivatives of aromatic primary and secondary amines. The anhydride and amine are heated together, sometimes with a small amount of sulfuric acid as in the preparation of o-nitro-N-methylacetanilide (73%). ° Catalytic hydrogenation of nitriles in acetic anhydride solvent leads to high yields of... 

Here again, these thiophene derivatives are much less stable than their benzenoid counterparts, unless the ring is provided with other substitution. " The unsubstituted amino-thiophenes (thiophenamines) can be obtained by reduction of the nitro-thiophenes, "" but in such a way as to isolate them as salts - usually hexachlorostannates - or via Beckmann rearrangements " or Hofmann degradation, " as acyl-derivatives, which are stable. 3,4-Dinitration of 2,5-dibromothiophene, then reduction, produces 3,4-diaminothio-phene. " " Many substituted amines have been prepared by nucleophilic displacement of halogen in nitro-halo-thiophenes. In so far as it can be studied, in simple cases, and certainly in substituted amino-thiophenes the amino form is the only detectable tautomer. " ... 

Aromatic amines, like phenols, are very easily nitrated. However, primary and secondary amines in particular readily undergo oxidative side reactions, so that it is advisable to protect the amino group by acylation or by conversion by an aldehyde into the Schiff base. Even using a large excess of sulfuric acid protects the amino group to a considerable extent, owing to formation of the ammonium salt, but then entry of the nitro group is directed to a considerable extent into the meta-position. The usual A-acyl derivative is the acetyl compound, but benzoyl, /7-toluenesulfonyl, oxalyl, ethoxycarbonyl (from chloro-formic ester), and phthaloyl derivatives are also used. 

Amine salts acyl derivatives of primary or secondary amines aromatic amino-acids sul-phanilates naphthionates hydrazine derivatives some substituted ureas and thioureas (nitro-compoiinds may give the corresponding amine, when strongly heated). 

The addition-elimination reaction of hetero-atom-substituted nitroalkenes provides functionalized derivatives of unsaturated nitro compounds.26 Nitroenamines are generally prepared from a-nitro ketones and amines (see Chapter 5 regarding acylation of nitro compounds).26... 

Further substitution on this compound leads to a somewhat more potent antinema-todal drug. Nitration of (53-6) under the usual conditions leads to the corresponding nitro derivative (54-1). The nitro group is then reduced to the corresponding amine (54-2). Acylation with isopropyl chloroformate forms the corresponding carbamate and thus cambendazole (54-3) [57]. 

Amino groups can also be derivatized using acyl chlorides that form amides. A number of suitable acyl chlorides including p-chloro-, p-methoxy-, p-nitroben-zoyl-, p-tolyl-, and p-nitro-benzenesulfonyl chloride have been successfully used for sensitive UV-Vis derivatization of nonabsorbing amine compounds (231). Among all those amide derivatives, p-methoxybenzamides appear more attractive because they exhibit high molar absorptivity at the convenient analytical wavelength of 254 nm. After derivatization in tetrahydrofuran-sodium hydroxide solu-... 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

Aliphatic and alicyclic carbamates are nitrated smoothly and in excellent yields by a nitric acid-acetic anhydride mixture (4). Similarity, we have found that treating an acyl aliphatic amine and a urethane with one equivalent of nitronium tetrafluoroborate in acetonitrile at —30° C. gave the corresponding N-nitro derivatives in good to excellent yields. However, diacylamines are more difficult to nitrate, and Kauffman and Burger (9) have reported that nitrating succinimide required 13 hours... 

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