Enamine salts, structure

In the case of enamines protonation on nitrogen or carbon is possible and gives the conjugate acids 4 and 5, respectively. Whereas the final isolated product has the iminium salt structure (5), recent work 10-12) has shown... 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

For an immonium structure of the enamine salt, protonation of the polarized mesomeric form on the j3-carbon atom is necessary. The behavior of dienamines shows59-61 that primary formation of an... 

Indole and alkyl-indoles (38) are protonated in position 3 by the action of strong mineral acids.198,197 The tendency of the enamine salts to assume the immonium structure is very general the salts of ethyl j3-aminoerotonate are derived from the imino form at the expense of the conjugation between the carbonyl group and the double bond.12,198... 

The E-isomer is generally more stable than the Z-isomer due to diminished steric hindrance, so it is assumed that the E-isomer is the major product (shown for 83). Water, a reaction by-product, may be removed to give a better yield of product and azeotropic distillation is used as well as molecular sieves (see Section 18.6.3). Enamines are structurally related to an end (HO—C=C) in that the heteroatom is directly attached to the alkene unit. Enamines are often isolable compounds, whereas enols tautomerize spontaneously to the carbonyl form. Note that when imine 76 is formed from iminium salt 80, there is no enamine product. In fact, the C-H in 80 is much less acidic that the N-H unit, so the product is the imine rather than the enamine. It is noted that there is an equilibrium between an imine and an enamine, known as imine-enamine tautomerism, but it will be ignored in this book. Many different secondary amines can be used in this reaction, including cyclic amines (see Chapter 26, Section 26.4.1) such as pyrrolidine (90), piperidine (91), and morpholine (92). It is important to note that it is generally easier to form an enamine from a ketone than from an aldehyde. 

The close agreement of the three methods supports the contention that protonation at low temperatures first occurs at nitrogen and is followed by a proton shift to give the iminium salt (M). The rate of this rearrangement is dependent on temperature, the nature of the amine, and the nature of the carbonyl compound from which the enamine was made. Even with this complication the availability of iminium salts is not impaired since the protonation reaction is usually carried out at higher temperatures than —70°. Structurally complicated enamines such as trichlorovinyl amine can be readily protonated (17,18). 

A recent adaptation of the procedure employing perchlorate and fluoro-borate salts has been reported by Leonard and Paukstelis (J5). This report includes proof of structure by direct comparison to iminium salts prepared by protonation of enamines. The general reaction reported was that of a ketone or aldehyde with a secondary amine perchlorate to give iminium salts. A large structural variety of carbonyl compounds and several amine... 

Physicochemical investigations of enamines and their salts have shown that the addition of a proton occurs almost exclusively at the /3-carbon atom of the enamine grouping. This means that salts of pyrrolines (82), piperideines (83), and enamines of 1-azabicycloalkanes (84) possess immon-ium structures. 

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). 

The stereochemical course of reduction of imonium salts by Grignard reagents was found to depend on the structure of the reagent 714). Hydro-boration of enamines and oxidation with hydrogen peroxide led to amino-alcohols (7/5). While aluminum hydrogen dichloride reacted with enamines to yield mostly saturated amines and some olefins on hydrolysis, aluminum hydride gave predominantly the unsaturated products 716). 

Phenylmercury derivatives of 3-aminomethylene-l-methyloxindols have also been investigated (79KGS65). For studies of the effect of substituents on the electronic structure of silver and potassium salts of 3-(aryl)imi-nooxindole see 76MI2. The keto-enol and imino-enamine tautomerism of compounds of type 127 (with 128 and 129) has been investigated (85KGS921). 

The isomerization of an allylic amine to an enamine by means of a formal 1,3-hydrogen shift constitutes a relatively small structural change. However, this transformation could be extremely valuable if it could be rendered stereoselective. In important early studies, Otsuka and Tani showed that a chiral cobalt catalyst, prepared in situ from a Co(ii) salt, a chiral phosphine, and diisobutylaluminum hydride (Dibal-H), can bring about the conversion of certain pro-chiral olefins to chiral, isomeric olefins by double bond migra-... 

Hydrogenation of 1,4-dimethyl-l//-2-benzothiopyran produces, as expected, cis-1,4-dimethylisothiochroman, the S, 5-dioxide of which exists in the boat conformation.260 As with 2H-l-benzothiopyran, the anion formed from the 5,5-dioxide of 6 shows considerable delocalization and potential aromaticity.286 Treatment of 1-substituted lH- 2-benzothiopyrans with thionyl chloride followed by perchloric acid yields 1-substituted 2-benzothiopyrylium salts,287 and Raney nickel desulfurization produces indane structures.288,289 Finally, the enamine... 

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

The study of the enamine structure may be associated, to a certain degree, with the problem of the so-called pseudobases an instructive, but somewhat specialized, review of these compounds was contributed by the late Professor Beke 47 to the first volume of this series. The name pseudobases was given by Hantzsch,48 towards the end of the last century, to those a-aminocarbinols which undergo a structural change during salt formation and yield salts with the loss of one molecule of water. The liberation of pseudobases from their salts is accompanied by rehydration. This behavior has been observed with a,/3-unsaturated heterocyclic compounds and, to a certain degree, with aromatic heterocyclic pyridine derivatives. As formulated by Gadamer,49 the pseudobases represent a potential tautomeric system of three components, the quaternary hydroxide A, the carbinolamine B, and the open-chain amino-carbonyl derivative C, in which all three components exist in a mobile equilibrium ... 

In the formation of salts, addition of a proton occurs at the free electron pair of one of the mesomerie forms of the enamine. The salts are usually derived from the immonium structure. With tertiary enamines, there is a substantial difference between the free bases which possess a fixed vinylamine structure and their immonium salts. 

Lactams with larger rings, e.g. seven-,143,144 eight-,145 nine-,148 eleven-, and thirteen-membered lactams,147 yield acyclic amino-ketones as the sole products, as is to be expected. With the seven- and thirteen-membered rings, the existence of both forms might be expected, and the salts of 1-methyl-2-a-naphthyl-l-aza-2-cycloheptene and l-methyl-2-a-naphthyl-l-aza-2-cyclotridecene have been prepared in both the cyclic enamine and the acyclic amino-ketone forms.148 The structure of the products also depends upon the Grignard reagent used. 

On treatment with acids the enamines undergo a structural change (as stated above, e.g. in Section II, B) provided conjugation of the double bond between the carbon atoms with the electron pair on the nitrogen atom is not precluded by steric or other factors.37,44 Thus A 1(9)-dehydroquinolizidine (36) and some more complicated compounds containing this system form immonium salts. Also the salts of... 

Treatment of perhydro-4-azaazulene (3) with mercuric acetate produces a mixture of dehydro derivatives 31a and 31b, which, with acids, yields homogeneous salts of structure 32 (56JOC344). The enamine 34, which was obtained by the same route from 33, served as a model compound in a study of the synthesis of cephalotaxine (72JOC3691). A reaction with ethyl y-bromo-acetoacetate surprisingly yielded the quinolizidine 36, which was formed by rearrangement of the intermediate annellation product 35 (Scheme 3) Phthalimides 38 were obtained from a Baeyer-Villiger oxidation of 4-azaazulen-3-ones 37 (77JOC1093). 

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