Elimination of amines

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

The Hofmann elimination route, of which many versions exist, can be carried out at much lower temperatures in conventional equipment. The PX is generated by a 1,6-Hofmaim elimination of amine from a quaternary ammonium hydroxide in the presence of a base. This route gives yields of 17—19%. Undesired polymeric products can be as high as 80% of the product. In the presence of a polymerization inhibitor, such as phenothiazine, DPXN yields can be increased to 50%. 

It is believed (54IZV47 72JPR353) that in the first stage the intermediate 282 is formed due to the addition of the CH acid to the enamine moiety with subsequent elimination of amine. The enol form of the intermediate 282 undergoes cyclization in two fashions, depending on the nature of substituent X. In the case of the ester (X = OMe) the attack is directed to the cyano group to form substituted 3-methoxycarbonyl-I//-pyridin-2-one (283) or its tautomer (2-hydroxy-3-methoxycarbonylpyridine). With the amide (X = NH2) intramolecular condensation leads to 3-cyano-l//-pyridin-2-one and its hydroxy tautomer (284). 

Because of their manifold reactivity, Mannich bases 4 are useful intermediates in organic synthesis. For example the elimination of amine leads to formation of an o ,/3-unsaturated carbonyl compound 8 ... 

Hydroxyalkyl sulphoxides 515 can be dehydrated either by treatment with phosphoric acid (equation 315) or by the alkylation with Mel in the presence of an excess of sodium hydride611 (equation 316). For other dehydration reactions see References 475 and 505 (Section IV.A.2.d). For elimination of amines see References 164 and 529 (Section IV.A.2.e). 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

In some cases the C /C2 double bond in methylene cyclopropenes and calicenes was found to show dienophilic functionality towards diene components. Thus, di-ethylamino butadiene combines with 497 to give the Diels-Alder adduct 507, whose proton-catalyzed elimination of amine interestingly did not lead to the dibenzo heptafulvalene 508, but to the methylene norcaradiene derivative 509293 ... 

Scheme 33 illustrates the difference in reactivity between triazolines obtained from cyclohexanone and cyclo-pentanone enamines. Thus, the reactions of azidophosphonates 239 with cyclohexanone enamines produce unstable aminotriazolines 240 that cannot be isolated due to their spontaneous elimination of amines to provide triazoles 241. Contrary to that, triazolines 242, derived from cyclopentanone enamines, are isolated in good yield (76-88%) and cannot be converted to the corresponding triazoles even by thermolysis <1995H(40)543>. Probably, introduction of a double bond between two five-membered rings would involve too much molecular strain. 

A large variety of metabolic cyclization reactions, counterparts to the reactions of hydrolytic ring opening discussed above, occur without any change in the degree of oxidation, and often nonenzymatically. Such reactions proceed by various mechanisms of intramolecular nucleophilic substitution, with elimination of amine, phenol, halide, or H20. 

When enamines are employed as sulfene traps, thiete 1,1-dioxides (e.g. 142) can be prepared by subsequent Hofmann elimination of amine. An alternative route to thiete 1,1-dioxides involves trapping sulfenes with ynamines, as illustrated by preparation of (144) (73S534). Certain thietes such as (145) (80LA873, 78TL3617, 78TL4839) are available directly from thioketones by 2 + 2 photocycloaddition with alkynes. 

Tetrazines (624) react also with the C=N double bond of aliphatic aldehyde dimethylhydrazones. Elimination of nitrogen from the adducts (629) affords 4-aminodihydro- 1,2,4-triazines (630). The elimination of amine from (630) to give (625) has not been reported (Scheme 20) (79AP452, 81AP376). 

The second step involves a syi elimination similar to the Cope elimination of amine oxides. 

When R1 = CN, a molecule of hydrogen cyanide is lost and the 5-amino-triazole is obtained.249 Spontaneous amine elimination also occurs when R2 is hydrogen and an aliphatic secondary amino group is present,214 which is similar to what is observed in the addition of tosyl azide to /3-enamino esters233 and nitriles.402 Thermal elimination of amine proceeds more... 

By a process similar to that described for the thioimidates, amidines give an intermediate ylid upon treatment with a triflate. The ylid is easily intercepted with a maleimide to give A1-pyrrol ine with the elimination of amine.264... 

The elimination of amines may also be accomplished by using the reactions of organotin amides and transition-metal hydrides, or transition-metal amides and tin hydrides4. Neither route has attracted much attention recently. 

Reductive Eliminations of Amines from Pd(II) Amido Complexes... 

Reductive elimination of amines is the key bond-forming step in the catalytic ami-nation processes. These reactions were unknown a couple of years ago, but several examples of this reaction now exist, and the factors that control the rates of this process are beginning to be understood. The identity of the intermediates in some of these reductive elimination reactions has recently been uncovered. 

The amination chemistry depends on the absence of irreversible P-hydrogen elimination from the amido complexes before reductive elimination of amine. At the early stages of the development of the amination chemistry, it was remarkable that the unknown reductive elimination of arylamines could be faster than the presumed rapid [57,58] P-hydrogen elimination from late metal amides. In fact, directly-observed P-hydrogen elimination from late metal amido complexes was rare, and no examples were observed to occur irreversibly from a simple monomeric amido species [69], At this point, it is clear that C-N bond-forming reductive elimination of amines and ethers can be rapid, and that P-hydrogen elimination can be slow. 

Two studies have been conducted that outline the effects of ligand steric and electronic properties on the relative rates for reductive elimination of amine and P-hydrogen elimination from amides. One study focused on the amination chemistry catalyzed by P(o-C6H4Me)3 palladium complexes [111], while the second focused on the chemistry catalyzed by complexes containing chelating ligands [88]. 

Early work on 1,2-elimination in cyclopropanes centred on the thermal elimination of amines from cyclopropyltrialkylammonium salts 1). An elegant example is a route to optically active cyclopropenes involving the resolution of the acid (8, R = C02H), conversion to the quaternary ammonium salt (8, R = + NMe3) and elimination over platinised asbestos at 360 °C 18) ... 

The transition metal catalyzed synthesis of arylamines by the reaction of aryl halides or tri-flates with primary or secondary amines has become a valuable synthetic tool for many applications. This process forms monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbamates, hydrazones, amides, and tosylamides. The mechanism of the process involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination are formed in the catalytic cycle in some cases by N-H activation. Side products are formed by / -hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before June 1, 2001. This chapter is based on a review covering the literature up to September 1, 1999. However, roughly one-hundred papers on this topic have appeared since that time, requiring an updated review. 

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