Tertiary enamines

Alkyl groups attached to aromatic rings are oxidized more readily than the ring in alkaline media. Complete oxidation to benzoic acids usually occurs with nonspecific oxidants such as KMnO, but activated tertiary carbon atoms can be oxidized to the corresponding alcohols (R. Stewart, 1965 D. Arndt, 1975). With mercury(ll) acetate, allyiic and benzylic oxidations are aJso possible. It is most widely used in the mild dehydrogenation of tertiary amines to give, enamines or heteroarenes (M. Shamma, 1970 H. Arzoumanian. 1971 A. Friedrich, 1975). 

This type of mesomerisin is much more important in enamines possessing a tertiary nitrogen atom than in those possessing a secondary nitrogen atom since the latter exist largely in the tautomeric imino form (2). 

This chapter is devoted mostly to the discussion of the structure and physical properties of the enamines with a tertiary nitrogen atom, the emphasis being on enamines of cyclic ketones. 

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

Enamines via Mercuric Acetate Oxidation of Tertiary Amines. 

The primary objectives of this chapter are to detail the methods by which enamines (a,/3-unsaturated amines) (I) can be synthesized and the mechanisms of enamine formation. The enamines discussed are those in which the nitrogen is tertiary and, with the exception of a few selected examples, Contain no other functional groups. The term simple enamines might be used to describe the majority of enamines noted in this chapter. 

The oxidation of amines by mercuric acetate is an old reaction (54) which up until recent years was employed primarily to modify alkaloid structures (55). A systemic study of the oxidizing action of mercuric acetate by Leonard and co-workers led to the development of a general method for the synthesis of enamines from cyclic tertiary amines. An observation made after a large number of compounds were oxidized, but which is worth noting at the onset, is that a tertiary hydrogen alpha to the nitrogen atom is removed preferentially to a secondary a-hydrogen. 

To return to a more historical development the mercuric acetate oxidation of substituted piperidines (77) should be discussed next. This study established that the normal order of hydrogen removal from the aW-carbon is tertiary —C—H > secondary —C—H > primary —C—H, an observation mentioned earlier in this section. The effect of substitution variations in the piperidine series can be summarized as follow s l-mcthyl-2,6-dialkyl and 1-methyl-2,2,6-trialkyl piperidines, as model systems, are oxidized to the corresponding enamines the 1,2-dialkyl and l-methyl-2,5-dialkyl piperidines are oxidized preferentially at the tertiary a-carbon the 1-methyl-2,3-dialkyl piperidines gave not only the enamines formed by oxidation at the tertiary a-carbon but also hydroxylated enamines as found for 1-methyl-decahydroquinoline (48) (62) l-methyl-2,2,6,6-tctraalkyl piperidines and piperidine are resistant to oxidation by aqueous mercuric acetate and... 

The preceding section described the preparation of enamines by mercuric acetate oxidation of tertiary amines. The initial product in these oxidations is the ternary iminium salt, which is converted to the enamine or mixture of enamines by reaetion with base. Thus iminium salts synthesized by methods other than the oxidation of tertiary amines or the protonation of enamines are potential enamine sources. 

The lithium- -propylamine reducing system has been found capable of reducing julolidine (113) to /d -tetrahydrojulolidine (114, 66% yield) and 1-methyl-1,2,3,4-tctrahydroquinoline to a mixture of enamines (87% yield), l-methyl-J -octahydroquinoline (115) and 1-methyl-al -octahydro-quinoline (116) 102). This route to enamines of bicyclic and tricyclic systems avoids hydroxylation, which occurs during mercuric acetate oxidation of certain bicyclic and tricyclic tertiary amines 62,85 see Section III.A). 

II. Kinetics and Mechanism of the Hydrolysis of Simple Tertiary Enamines 102... 

These results have led to the conclusion (11) that the formation of enammonium salts is kinetically controlled, while the protonation on the 3-carbon atom is subject to thermodynamic control, t Only tertiary enamines will be considered,... 

It might also be expected that enamines would be less basic than the corresponding saturated tertiary amines as a consequence of the delocalization of the nonbonded electron pair of the nitrogen. The older literature (/—/), which involved measurements in aqueous or partly aqueous solution, led to the opposite conclusion. This unexpected increase in basicity was rationalized in terms of an equilibrium between the enamine and the quaternary iminium hydroxide ... 

Recent work (5) using kinetic methods has shown that the enamines derived from isobutyraldehyde are indeed less basic than the corresponding saturated tertiary amines. 

The above considerations presuppose that two important conditions are fulfilled. First the nitrogen must be tertiary, as primary and secondary vinylamines are generally more stable in the imine form (5). Only in the case of enamino ketones and esters are the enamine more stable than the imine forms (7). Secondly, the atoms comprising the tt system must be able... 

H. Reaction with Formic and Trichloroacetic Acids Enamines derived from aldehydes have been treated with formic acid under the conditions of the Leuckart-Wallach reaction 141) to give saturated tertiary amines 142). The enamine (98) reacts vigorously with formic acid at room temperature to give N-isobutyl morpholine (204). 

Another convenient method for the preparation of tertiary enamines involves the dehydrogenation of saturated bases with mercuric acetate (111-116). A trans-1,2 elimination occurs, which requires an antiperi-planar position of the nitrogen-free electron pair and the eliminated atom. A preferential elimination of the hydrogen atom from the tertiary carbon atom is supposed. Overoxidation can be avoided by adding disodium ethyl-enediaminotetraacetate to the reaction mixture (117). 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

Similar behavior can be observed even in the case of substituted quinuclideines 170). Neostrychnine (68) serves as an example of more complex compounds which show spectra differing from those of other enamines. The ultraviolet spectrum of this compound exhibits no batho-chromic shift and its basicity is considerably decreased 159,171,172) (pK in methylcellosolve at 20° is 3.8, whereas the analogous saturated compound has a pK under the same conditions of 7.45, and a compound with the double bond further removed, strychnine, has a pK of 7.37). As another example, the ultraviolet spectrum of trimethyl conkurchine (69) shows the same absorption maxima as a saturated tertiary amine (A in ether, about 213 m/i). 

The study of structure and reactivity of tertiary heterocyclic enamines is associated with the problem of equilibrium of the cyclic enamine form (70) and the tautomeric hydration products 173,174) quaternary hydroxide (71), pseudo base (so-called carbinolamine) (72) and an opened form of amino aldehyde or amino ketone (73). 

Tertiary heterocyclic enamines are reduced with metals in acidic media 142) or electrolytically (237,238) and their salts are reduced with lithium aluminum hydride or sodium borohydride (239,240) to the corresponding saturated amines. 

Enamine salts react with many nucleophilic reagents. The reaction with the cyanide ion is noteworthy. l-Methyl-2-ethyl-2-cyanopyrrolidine (170) is formed on treatment of alkali cyanide with l-methyl-2-ethyl-.d -pyrrolin-ium perchlorate (242). The reduction of the tertiary nitrile (170) with... 

The most general method for synthesis of cyclic enamines is the oxidation of tertiary amines with mercuric acetate, which has been investigated primarily by Leonard 111-116) and applied in numerous examples of structural investigation and in syntheses of alkaloids 102,117-121). The requirement of a tram-coplanar arrangement of an a proton and mercury complexed on nitrogen, in the optimum transition state, confers valuable selectivity to the reaction. It may thus be used as a kinetic probe for stereochemistry as well as for the formation of specific enamine isomers. 

The stereospecific generation of enamines by -elimination reactions (187) and a vinylogous elimination, which leads to a dienamine (188), have been reported. The loss of an a substituent from a tertiary amine is seen in the generation of enamines by elimination of hydrogen cyanide from benzylic a-aminonitriles (189,190). 

The oxidation of unsymmetrical tertiary amines with mercuric acetate may also lead to isomeric enamines. In such cases, structures can often be established by NMR and IR spectra of the enamines and their corresponding imonium salts, through comparison with model systems (202-205). 

While the oxidation of tertiary amines has been used extensively for the generation of enamines, an example of overoxidation with formation of an acetoxyimonium salt has been reported (484). 

Grignard reagents do not add directly to enamines, but their reactions with the corresponding imonium salts readily furnish tertiary amines (225,526). The reductive removal of halogen has been observed in the addition of Grignard reagents to a-bromoimonium salts (527). 

Reactions of enamines with aluminum hydrogen dichloride (540,541) (UAIH4 and AICI3) or aluminum hydrogen dialkyl compounds (542) led to organoaluminum intermediates which could be hydrolyzed to tertiary amines or oxidized to aminoalcohols. The formation of olefins by elimination of the tertiary amine group has also been noted in these reactions. 

Olefins are also the products of hydroboratlon of enamines, followed by treatment of the organoborane products with hot acid (543,544). The reduction of enamines with sodium borohydride and acetic acid (545) and the selective reduction of dienamines with sodium borohydride to give homo-allylic tertiary amines (138-140,225,546,547), has been applied to the synthesis of conessine (548) and other aminosteroid analogs (545,549-552). Further examples of the reduction of imonium salts by sodium borohydride can be found in the reduction of Bischler-Napieralski products, and other cyclic imonium salts (102). 

In the acylation of enamines, the weakly basic acylated enamine does not absorb the acid formed. Consequently, one must employ 2 equivalents of the enamine or use a second tertiary amine to absorb the acid liberated. In the procedure, triethylamine is employed to absorb the hydrochloric acid. 

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