Nitrosoamines

N-Nitrosoamines are highly versatile substrates for a-lithiation, because while the N=0 group has activating and coordinating properties similar to the carbonyl group, it lacks the carbonyl group s electrophilicity. The nitroso group will direct lithiation even to a tertiary position (90 - 91), and can be removed by reduction with Raney nickel.60 The drawback is the toxicity of N-nitrosoamines. 

N-Nitroso pyrrolidine 92 can be lithiated just with LDA. Double benzylation gives principally the trans isomer of 93 after reduction.61 

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Fischer-Hepp rearrangement The nitros-amines of aromatic secondary amines when treated with hydrochloric acid give nuclear substituted nitrosoamines. Among the benzene derivatives, if the para position is free the -NO group displaces the hydrogen atom there in naphthalene derivatives it enters the 1-position ... 

Note on the laboratory preparation of monoethylaniline. Although the laboratory preparation of monomethyl- or monoethyl-aniline is hardly worth whUe, the following experimental details may be useful to those who wish to prepare pure monoethylaniline directly from amline. In a flask, fitted with a double surface reflux condenser, place 50 g. (49 ml.) of aniline and 65 g. of ethyl bromide, and boU gently for 2 hours or until the mixture has almost entirely sohdified. Dissolve it in water and boil off the small quantity of unreacted ethyl bromide. Render the mixture alkaUne with concentrated sodium hydroxide solution, extract the precipitated bases with three 50 ml. portions of ether, and distil off the ether. The residual oil contains anihne, mono- and di-ethylaniline. Dissolve it in excess of dilute hydrochloric acid (say, 100 ml. of concentrated acid and 400 ml. of water), cool in ice, and add with stirring a solution of 37 g. of sodium nitrite in 100 ml. of water do not allow the temperature to rise above 10°. Tnis leads to the formation of a solution of phenyl diazonium chloride, of N-nitrosoethylaniline and of p-nitrosodiethylaniline. The nitrosoethylaniline separates as a dark coloured oil. Extract the oil with ether, distil off the ether, and reduce the nitrosoamine with tin and hydrochloric acid (see above). The yield of ethylaniline is 20 g. 

All three mononuclear amines and 3-amino-2,l-benzisothiazole can be diazotized and coupled to form azo dyes (see Section 4.02.3.5), but 3-amino-1,2-benzisothiazole reacts with nitrous acid to give 3,3 -bis(l,2-benzisothiazoline) (72AHC(14)43), and 5-aminoisothiazoles bearing an electron-withdrawing group at the 4-position form iV-nitrosoamines (72AHC(14)1). 

Dinitrosopentamethylene- tetramine (II) Nitrosoamine N2 N0,H20, CH,NH2 160-200 210 Widely used in natural and synthetic rubbers. Some use in polyolefins. 

Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato-carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl-benzanthracene, and vinyl chloride.Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or... 

Meroquinenine, CgHjjOaN (meroquinene), formed by the oxidation of all four alkaloids and of cinchoninone or quininone and by the hydrolysis of quinenine or cinchenine (p. 489), crystallises from methyl alcohol in needles, m.p. 223-4° (dee.), [ajp -f- 27-5° (H2O). It gives a nitrosoamine, m.p. 67°, and a monoacetyl derivative, m.p. 110°, and can be esterified the ethyl ester hydrochloride has m.p. 165°. When oxidised by chromic acid it yields formic and cincboloiponic acids. On reduction with zinc dust and hydriodic acid, it adds on two atoms of hydrogen forming cincholoipon, CgH jOaN, and when heated with hydrochloric acid at 250-60° gives 3-ethyl-4-methylpyridine ()3-collidine). 

Tetrahydrostrychnine, CgjHggOgNg. HgO. This substance, also formed by the electrolytic reduction of strychnine, crystallises from alcohol in prisms, m.p. 202°, gives colour reactions of the strychnidine type, and yields both neutral and acid salts the hydrochloride, B. HCl, occurs in small needles readily soluble in water and the dihydriodide, B. 2HI. 2HjO, in pyramidal crystals. The base yields an amorphous nitrosoamine, the hydrochloride of which crystallises from warm water in lustrous, yellowish prisms. It also furnishes a crystalline monoacetyl derivative, and on heating with hydrochloric acid or phosphorus oxychloride is dehydrated to strychnidine. 

The condensation of aromatic o-nitrosoamines with cyanoaeetic acid or cyanoacetamide affords an unambiguous synthesis of un-... 

The cation 5 loses a proton to give the more stable nitrosoamine 6, which is in equilibrium with the tautomeric diazohydroxide 7. Protonation of the hydroxy group in 7 and subsequent loss of H2O leads to the diazonium ion 3. 

Indazoles can be considered as either azaindoles or azaisoindoles depending on the reader s prejudice. Benzydamine (54) represents a drug with this heterocyclic nucleus. Alkylation of the amine of anthranilic acid methyl ester with benzyl chloride in the presence of sodium acetate gives 52. Treatment with nitrous acid leads to the nitrosoamine, which cyclizes spontaneously to the 3-ketoindazole system, 53. This intermediate forms an ether of its enol form on heating the sodium salt with 3-dimethylaminopropyl chloride. There is thus obtained benzydamine (54), a fairly potent nonsteroidal antiinflammatory agent with significant antipyretic and analgesic properties. 

N-Nilrosoamines are reduced easily lo ihe hydrazine and, if continued, lo the amine (62). Early workers ruled out cleavage of dimeihylhydrazine as the source of dimethylamine in hydrogenation of N-nitrosodimethylamine since liule ammonia was found the letramethylietrazene was implicated in the hydrogenolysis (fSI). Palladium-on-carbon under mild conditions is used for industrial production of dialkyl hydrazines from N-nitrosoamines. 

Although chemicals in closed circulation systems do not generally come into contact with the environment - except perhaps on disposal - problems can exist with safety in handling. A particular example is the need for caution in the mixing of coolants containing nitrites with those containing amines because of the possible production of carcinogenic nitrosoamines. This caution has been expressed in other fields of use of inhibitors (see below). 

A characteristic property of most diazotizations of aminoazoles is the occurrence of a relatively stable transient intermediate (probably the A-nitrosoamine), in contrast with the diazotization of carbocyclic aromatic amines, where A-nitrosoamines have been considered to be unstable intermediates. This problem will be discussed in the context of the mechanism of diazotization in Section 3.4. 

An interesting example of how the reaction conditions can influence the structure of the product is shown in Scheme 2-10. Depending on the acidity of the reaction medium and on the reaction time, the diazotization of aminotriazoles (2.18) yields the nitrosoamines (2.19), the chloro compounds (2.20), or the azo coupling products i.e., the triazenes (2.21), as shown by Gehlen and Dost (1963). 

Research into the mechanism of diazotization was based on Bamberger s supposition (1894 b) that the reaction corresponds to the formation of A-nitroso-A-alkyl-arylamines. The TV-nitrosation of secondary amines finishes at the nitrosoamine stage (because protolysis is not possible), but primary nitrosoamines are quickly transformed into diazo compounds in a moderately to strongly acidic medium. The process probably takes place by a prototropic rearrangement to the diazohydroxide, which is then attacked by a hydroxonium ion to yield the diazonium salt (Scheme 3-1 see also Sec. 3.4). 

We mention Williams work briefly here because it may also explain Blangey s observations strongly basic primary amines unequivocally form 7V-nitrosoanilinium ions in strongly acidic media. In contrast to the rate-limiting deprotonations of the less basic aromatic and heteroaromatic nitrosoamine cations discussed in this section, the TV-nitroso cation of a strongly basic amine deprotonates extremely slowly. Therefore, the nitroso rearrangement, the Fischer-Hepp reaction, competes effectively with the 7V-deprotonation. 

In Sections 3.1 to 3.3 the discussion of the mechanism of diazotization concentrated on the rate-determining part of the reaction which, in most cases, does not include steps occurring after the formation of the A-nitrosoamine. The various pathways of nitrosation are summarized in Scheme 3-35. The transformation of the N-nitrosoamine will be discussed in Section 3.4. 

Unfortunately there have been no more recent investigations using fast kinetic methods such as stopped flow, by adding methanol or even methanol with some water to the ether solution obtained by the procedure of Muller and Haiss, so as to check whether an equilibrium mixture of nitrosoamine and diazohydroxide is formed. 

It is worth noting, however, that the prototropic equilibrium between the N-nitrosoamine (3.7) and the diazohydroxide (3.9) has been determined semiquan-titatively for the analogous diazotization of an aliphatic amine. Fishbein and coworkers (Hovinen et al., 1992) determined an upper limit for the nitrosoamine equilibrium concentration (<1.5% see also Zollinger, 1995, Sec. 7.2). 

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