Amines ynamine

The direct linking of a secondary amino nitrogen with a carbon-carbon triple bond to create yne-amines (ynamines) had sporadically been attempted since the end of the past century. 

Thiirane is more bactericidal than oxirane, and derivatives of 2-mei captomethylthiirane inhibit tuberculosis. The following pharmacological uses have been reported for compounds derived from thiirane derivatives gold complexes of the adducts of diethylphosphine and thiirane (antiarthritic), adducts of thiiranes and malononitrile (antibacterial, blood vessel dilators, muscle relaxants, sedatives), thermolysis products of thiirane 1-oxides and adducts of thiirane 1-oxides with sulfenyl chlorides (antibacterial), adducts of 2,3-diarylthiirene 1,1-dioxides with ynamines (antibacterial, parasiticidal), adducts of 2,3-diarylthiirene 1,1-dioxides with enamines (antifertility), adducts of p-aminophenylacetic esters with thiirane (immunosuppressants), adducts of amines and thiiranes (radioprotective drugs). 

In these reactions, the formation of imidazoline and oxazoline rings corresponds to the reagent orientation previously observed for ynamines (84ZOR1648) and alkenylynamines (83ZOR926), as well as in their reactions with mononucleophiles such as amines (79ZOR1824 81ZOR1807) and alcohols (80ZOR1141). 

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. 

Most ynamines are water-clear liquids with a slight amine odor. They are stable and can be vacuum-distilled without decomposition. Some have now become available commercially. ... 

Some elimination reactions which yield ynamines involve the dehalogenation or dehydrohalogenation of substituted amines or amides as shown in Eq. (21). 

The air oxidation of phenylacetylene and secondary amines in the presence of cupric acetate in benzene solution yields ynamines [22], This reaction requires only catalytic amounts of cupric salts and gives high conversions in less than 30 min when the Cu+2/phenylacetylene ratio is only 0.02. Only 1,4-diphenylbutadiyne is produced if the stoichiometric amount of cupric ion is used in the absence of oxygen. The yield of ynamine can be increased from 45 to 90 % if the stoichiometric amounts of a reducing agent such as hydrazine are continuously added during the course of the reaction. The use of primary amines under similar conditions yields the acetamide derivative. 

The different behaviour of bis(AT,N-diethylamino)propene and AT,A(-dimorpholinopropene towards methyl vinyl ketone is of interest. The latter yields some 4/f-pyran (153) identical with that obtained from the ynamine. However, the former compound gives only the Stork adduct (154) by proton transfer. The elimination of the amine moiety from the dihydropyran (152) is easier from the less basic enamine (Scheme 22). 

Such substitutions using lithium amides, secondary and in some cases tertiary amines as nucleophiles, have been introduced in early sixties as the first expedient method for this unique class of compounds. It is relevant that / ,/ -difluoro- and chlorofluorole-fins readily available through modified Wittig reaction from aldehydes constitute also good ynamine precursors. In the past decade, however, the more versatile lithium aminoacetylide method has gained more prominence. Substitution reactions are still used, among others, for phenyl, tert.-butyl, cinnamyl and cyclopropyl ynamines. 

It is important to note that tertiary amines can be sometimes advantageously used instead of metallated secondary amines I9,20>. This obviously necessitates more vigorous reaction conditions (autoclave) and longer reaction times but bulk quantities of ynamines can be obtained at lower cost (8) 20 22 ... 

Reactions with tertiary amines proceed via ethynylammonium salts which in many cases can be isolated 23 26 Their degradation to ynamines can be brought about thermally. This process becomes more easy in the presence of an excess of tertiary amine upon which an alkyl group is transfered (9, 10) 24 25>. 

A number of trichlorovinyl ynamines 2 were prepared from tetrachloroenyne 1 and secondary amines. The yields are almost quantitative but such ynamines are too fragile to allow a purification by distillation or even TLC on Alumina (16) 33,34). 

Strongly nucleophilic secondary amines may give to undesired side-reactions. Thus haloacetylenes bearing carbonyl groups react eagerly with secondary amines but the reaction cannot be arrested at the ynamine stage ketene N,N-acetals are formed instead (24) 48). 

The rather basic lithiated secondary amines may give rise to another kind of side-reactions e.g. isomerisation of ynamines into aminoallenes (see Propargylic Rearrangements)... 

Silylated amines are formed as side-products. Silylated ynamines are thermally very stable and can be distilled at normal pressure without decomposition 41 As a corollary, their reactivity is reduced as compared to 2-alkyl ynamines 59). The same procedure was applied to the synthesis of a few triorganogermyl ynamines (28) 58). 

Amide should be first transformed to its hydrochloride in order to cut down the formation of a-chloro-jf(-chlorocarbonyl enamines 72,73). The method is very general but the choice of experimental conditions and of the base is critical and yields may vary strongly depending on the case (39). There is also one side-reaction which can hardly be avoided the ynamine already formed reacts with the yet unreacted amide chloride, the a-chloroenamine 70) or even with the tert-amine hydrochloride to form the very stable cyclobutene cyanines and/or allenamidinium salts. These by-products have an interest of their own and will be discussed later. Formation of these salts may strikingly lower the yield of ynamines, but because of their salt character they are not harmfull during the work-up72). 

Groups R studied were various alkyl groups, phenyl, trimethylsilyl and phenylthio groups. The yields depend strongly upon the method by which 98 is generated and on the reaction conditions in general. Only one detailed experimental procedure (151) is available and certain yields were assayed by the NMR or by hydrolysis 170). It can be concluded that this approach is a valuable extension of electrophilic amination but thus far it is of only limited value for the preparation of ynamines. 

The addition of secondary amines 95 to ynamines 94106 leads to 1,1-enediamines107-109, while primary amines give the amidine tautomers110. Substituted A-allylenediamines 96 have been synthesized from the corresponding allylic amines by this method (equation 33)109, a- and / -amino esters also react with ynamines, but in... 

Reactions with tertiary amines proceed via ethynylammonium salts which in many cases can be isolated Their degradation to ynamines can be brought about... 

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