Amine displacement

Because neuronal uptake is necessary for the hypotensive activity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal (see Chapter 6) block its effects. These include cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine. 

The relative ease of the cyclization step from A to C may also be linked to the nucleophilic or coordinative ability of the heteroatom bound to the metal. The reaction of 7 with diphenylacetylene (Ph2C2) leads to the seven-membered derivatives 68 and 69 after prior isolation of the monoinsertion product 24, treatment with a silver salt, followed by the usual thermolytic conditions. This is another rare example of an intramolecular formation of a C-S bond within the coordination sphere of a transition metal and a novel, albeit limited to one alkyne, route to the rare family of dibenzo[bd] thiepins. With the closely related 8, which differs from 7 only by the tertiary amine unit in the metallacyclic framework instead of a thioether function, a carbocyclic product 71 is obtained (see under carbocycle reactions, next section). The formation of the seven-membered S-heterocycles is attributed to the good coordinative ability of the thioether group in 7. The S-atom remains close to the vinylic carbon function before the cyclization. With the poorly coordinating, readily displaced amine function in 8, the N-atom is detached from the metal and ultimately affords a spirocyclic product (see Scheme 18). 

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 ... 

In the reaction of aryl and alkenyl halides with 1,3-pentadiene (248), amine and alcohol capture the 7r-allylpalladium intermediate to form 249. In the reactions of o-iodoaniline (250) and o-iodobenzyl alcohol (253) with 1,3-dienes, the amine and benzyl alcohol capture the Tr-allylpalladium intermediates 251 and 254 to give 252 and 255[173-175]. The reaction of o-iodoaniline (250) with 1,4-pen tadiene (256) affords the cyclized product 260 via arylpalladiuni formation, addition to the diene 256 to form 257. palladium migration (elimination of Pd—H and readdition to give 258) to form the Tr-allylpalladium 259, and intramolecular displacement of Tr-allylpalladium with the amine to form 260[176], o-Iodophenol reacts similarly. 

The rather unreactive chlorine of vinyl chloride can be displaced with nucleophiles by the catalytic action of PdCb. The conversion of vinyl chloride to vinyl acetate (797) has been studied extensively from an industrial standpoint[665 671]. DMF is a good solvent. 1,2-Diacetoxyethylene (798) is obtained from dichloroethylene[672]. The exchange reaction suffers steric hindrance. The alkenyl chloride 799 is displaced with an acetoxy group whereas 800 and 801 cannot be displaccd[673,674]. Similarly, exchange reactions of vinyl chloride with alcohols and amines have been carried out[668]. 

Allylic amine is a less reactive leaving group[7], but the allylic ammonium salts 214 (quaternary ammonium salts) can be used for allylalion(l30,131]. Allylic sulfonium salts are also used for the allylation[130]. The allylic nitrile in the cyclic aminonitrile 215 can be displaced probably via x-allylic complex formation. The possibility of the formation of the dihydropyridinium salts 216 and subsequent conjugate addition are less likelyfl 32],... 

Simple ketones and esters are inert. On the other hand, nitroalkanes react smoothly in r-butyl alcohol as a solvent with butadiene, and their acidic hydrogens are displaced with the octadienyl group. From nitromethane, three products, 64, 65, and 66, are formed, accompanied by 3-substituted 1,7-octadiene as a minor product. Hydrogenation of 65 affords a fatty amine 67 which has a primary amino function at the center of the long linear chain[46,61]. 

A number of less hindered monoalkylboranes is available by indirect methods, eg, by treatment of a thexylborane—amine complex with an olefin (69), the reduction of monohalogenoboranes or esters of boronic acids with metal hydrides (70—72), the redistribution of dialkylboranes with borane (64) or the displacement of an alkene from a dialkylborane by the addition of a tertiary amine (73). To avoid redistribution, monoalkylboranes are best used /V situ or freshly prepared. However, they can be stored as monoalkylborohydrides or complexes with tertiary amines. The free monoalkylboranes can be hberated from these derivatives when required (69,74—76). Methylborane, a remarkably unhindered monoalkylborane, exhibits extraordinary hydroboration characteristics. It hydroborates hindered and even unhindered olefins to give sequentially alkylmethyl- and dialkylmethylboranes (77—80). 

Amines also react with diacyl peroxides by nucleophilic displacement on the oxygen—oxygen bond forming an ion pair iatermediate (187) ... 

Poly(phenylene oxide)s undergo many substitution reactions (25). Reactions involving the aromatic rings and the methyl groups of DMPPO include bromination (26), displacement of the resultant bromine with phosphoms or amines (27), lithiation (28), and maleic anhydride grafting (29). Additional reactions at the open 3-position on the ring include nitration, alkylation (30), and amidation with isocyanates (31). 

Trilialophenols can be converted to poly(dihaloph.enylene oxide)s by a reaction that resembles radical-initiated displacement polymerization. In one procedure, either a copper or silver complex of the phenol is heated to produce a branched product (50). In another procedure, a catalytic quantity of an oxidizing agent and the dry sodium salt in dimethyl sulfoxide produces linear poly(2,6-dichloro-l,4-polyphenylene oxide) (51). The polymer can also be prepared by direct oxidation with a copper—amine catalyst, although branching in the ortho positions is indicated by chlorine analyses (52). 

Sulfur Substituents. Acetylation and alkylation of pyridinethiones usually take place on sulfur (39). An exception to this is 4-pyridinethione [19829-29-9] which is acetylated on nitrogen. Displacement of thioethers can be achieved with hydroxide or amines (eq. 13) (40). Thioether functional groups can also be removed by reduction (39). 

Chemical Properties. Reactions of quaternaries can be categorized iato three types (169) Hoffman eliminations, displacements, and rearrangements. Thermal decomposition of a quaternary ammonium hydroxide to an alkene, tertiary amine, and water is known as the Hoffman elimination (eq. la) (170). This reaction has not been used extensively to prepare olefins. Some cycHc olefins, however, are best prepared this way (171). Exhaustive methylation, followed by elimination, is known as the Hoffman degradation and is important ia the stmctural determination of unknown amines, especially for alkaloids (qv) (172). 

Displacement of a tertiary amine from a quaternary (eq. lb) iavolves the attack of a nucleophile on the a-carbon of a quaternary and usually competes with the Hoffman elimination (173). The counterion greatiy iafluences the course of this reaction. For example, the reaction of propyltrimethylammonium ion with hydroxide ion yields 19% methanol and 81% propylene, whereas the reaction with phenoxide ion yields 65% methoxybenzene and 15% propylene (174). 

Halosilanes can also be produced by displacement of amines with a hydrogen hahde (173). 

Solvent for Displacement Reactions. As the most polar of the common aprotic solvents, DMSO is a favored solvent for displacement reactions because of its high dielectric constant and because anions are less solvated in it (87). Rates for these reactions are sometimes a thousand times faster in DMSO than in alcohols. Suitable nucleophiles include acetyUde ion, alkoxide ion, hydroxide ion, azide ion, carbanions, carboxylate ions, cyanide ion, hahde ions, mercaptide ions, phenoxide ions, nitrite ions, and thiocyanate ions (31). Rates of displacement by amides or amines are also greater in DMSO than in alcohol or aqueous solutions. Dimethyl sulfoxide is used as the reaction solvent in the manufacture of high performance, polyaryl ether polymers by reaction of bis(4,4 -chlorophenyl) sulfone with the disodium salts of dihydroxyphenols, eg, bisphenol A or 4,4 -sulfonylbisphenol (88). These and related reactions are made more economical by efficient recycling of DMSO (89). Nucleophilic displacement of activated aromatic nitro groups with aryloxy anion in DMSO is a versatile and useful reaction for the synthesis of aromatic ethers and polyethers (90). 

Nicotinyl alcohol (3-pyridinylcarbinol, 3-pyridinemethanol) (27) has use as an antilipemic and peripheral vasodilator. It is available from either the reductions of nicotinic acid esters or preferably, the reduction of the nitrile to the amine followed by dia2otation and nucleophilic displacement. It is frequently adininistered in the form of the tartrate (Eig. 7). Nicotinic acid is frequently used as a salt in conjunction with basic dmgs such as the peripheral vasodilator xanthinol niacinate (28). Nicotinic acid and its derivatives have widespread use as antihyperlipidemic agents and peripheral vasodilators (1). 

Methyl bromide slowly hydrolyzes in water, forming methanol and hydrobromic acid. The bromine atom of methyl bromide is an excellent leaving group in nucleophilic substitution reactions and is displaced by a variety of nucleophiles. Thus methyl bromide is useful in a variety of methylation reactions, such as the syntheses of ethers, sulfides, esters, and amines. Tertiary amines are methylated by methyl bromide to form quaternary ammonium bromides, some of which are active as microbicides. 

It resembles tetracyanoethylene in that it adds reagents such as hydrogen (31), sulfurous acid (31), and tetrahydrofuran (32) to the ends of the conjugated system of carbon atoms suffers displacement of one or two cyano groups by nucleophilic reagents such as amines (33) or sodiomalononittile (34) forms TT-complexes with aromatic compounds (35) and takes an electron from iodide ion, copper, or tertiary amines to form an anion radical (35,36). The anion radical has been isolated as salts of the formula (TCNQ) where is a metal or ammonium cation, and n = 1, 1.5, or 2. Some of these salts have... 

Hydroxyl Group. The OH group of cyanohydrins is subject to displacement with other electronegative groups. Cyanohydrins react with ammonia to yield amino nitriles. This is a step in the Strecker synthesis of amino acids. A one-step synthesis of a-amino acids involves treatment of cyanohydrins with ammonia and ammonium carbonate under pressure. Thus acetone cyanohydrin, when heated at 160°C with ammonia and ammonium carbonate for 6 h, gives a-aminoisobutyric acid [62-57-7] in 86% yield (7). Primary and secondary amines can also be used to displace the hydroxyl group to obtain A/-substituted and Ai,A/-disubstituted a-amino nitriles. The Strecker synthesis can also be appHed to aromatic ketones. Similarly, hydrazine reacts with two molecules of cyanohydrin to give the disubstituted hydrazine. 

A.mina.tlon. Amination describes the introduction of amino groups into aromatic molecules by reaction of ammonia or an amine with suitably substituted halogeno, hydroxy, or sulfonated derivatives by nucleophilic displacement. Although reaction and operational conditions vary, the process always involves the heating of the appropriate precursor with excess aqueous ammonia or amine under pressure. 

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