Enamines as intermediates

The first examples of mechanism must be divided into two principal classes the chemistry of enzymes that require coenzymes, and that of enzymes without cofactors. The first class includes the enzymes of amino-acid metabolism that use pyridoxal phosphate, the oxidation-reduction enzymes that require nicotinamide adenine dinucleotides for activity, and enzymes that require thiamin or biotin. The second class includes the serine esterases and peptidases, some enzymes of sugar metabolism, enzymes that function by way of enamines as intermediates, and ribonuclease. An understanding of the mechanisms for all of these was well underway, although not completed, before 1963. 

Enzymologists have freely proposed enolate anions, enols, and enamines as intermediates for many years. Such intermediates have been demonstrated for some nonenzymatic acid- or base-catalyzed reactions, but how can enzymes form enolates at pH 7 without the use of strong acids or bases The microscopic pRa value of an a-hydrogen in a ketone or aldehyde is about 17-20.72 98"... 

ENAMINES AS INTERMEDIATES IN ISOTOPE EXCHANGE AND HALOGENATION REACTIONS... 

Catalytic reactions proceeding via enamines as intermediates. An unusual annu-... 

Catalytic reactions proceeding via enamines as intermediates. A DFT study at the B3LYP/6-31H-G(2df,p)//B3LYP/6-31G(d) level of the proline-catalysed Michael addition of ketones (via enamines) to nitroalkenes has revealed that the added benzoic acids play two major roles, namely assisting the proton transfer and activating the nitro group. °... 

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

The reaction of the enamines of cyclic ketones with alkyl isocyanates, acyl isocyanates, phenyl isothiocyanates, and acyl isothiocyanates has also been reported 112). The products are the corresponding carboxamides. The products from the isothiocyanates have been utilized as intermediates in the preparation of various heterocyclic compounds 113). 

Dihydro- and 1,4-dihydro derivatives are formed as intermediates in the reduction of quaternary pyridine salts and their homologues with sodium borohydride or formic acid. A proton is added to the present enamine grouping and the formed immonium salts are reduced to the l-methyl-l,2,5,6-tetrahydropyridine derivatives (157) and to completely saturated compounds (158) (254) (Scheme 14). 

One of the most actively investigated aspects of enamine chemistry has been the acylation process (i). Initial intensive studies by Hiinig (373-375) showed the ease of preparing a variety of 9-diketones and particularly the synthetic potential of acylated cyclic ketones as intermediates in the preparation of aliphatic keto acids, keto dicarboxylic acids and diketo dicarboxylic acids (376-378). 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

XIX. Rearrangements of Enamines and Reactions where Enamines Occur as Intermediates... 

Mechanishc studies indicated the possibihty of alkynylmercury chlorides as intermediates. They would react with amines to give 2-aminovinyhnercury chlorides which could be protonated to give enamines (or imines in the case of primary amines) (Scheme 4-13) [260]. 

Since most of the fundamental chemical transformations of the tropane alkaloids were discovered during the pioneering elucidation of the structures, the most important reactions have been described in earlier chapters in this treatise (7-5). Two developments will be discussed here the recent progress in the demethylation of tropane derivatives and the use of tropinone enamines as synthetic intermediates. 

Caubere et al. [63, 64] treated 32a with sodium amide-sodium tert-butoxide (NaNH2-NaOtBu) in tetrahydrofuran (THF) in the presence of secondary amines and obtained enamines. Analogously, the corresponding thioenol ethers were formed from 32a and sodium amide-sodium thiolate in the presence or absence of NaOtBu. It was shown, however, that cyclohexyne rather than 6 is the decisive intermediate en route to the enamines as well as the thioenol ethers [63b, 64], As already mentioned above, the enol ether 41 arises inter alia from 32b and KOtBu in DMSO. The best yield (47%) was obtained in refluxing THF (Scheme 6.11) [60],... 

The 1,2-dihydropyridines are also known to undergo [2 + 2] cycloadditions of the enamine double bond with alkynes (74JCS(P1)2496). The products of these reactions are azocine derivatives such as (259), which, after removal of the A-protecting group, have been used as intermediates in pyrrolizine synthesis (Scheme 47) (77JOC2903). 

Other oxidative methods have recently been reported whereby amines yield enamines either as intermediates [130] or as isolatable chloranil [131], 2,3-dichloronaphtha-l,4-quinone [131], or 2,5-dichloro-3,6-dimethoxybenzo-quinone [132, 133] adducts. Benzoyl peroxide [131] and active manganese dioxide [134] have been reported as effective oxidizing agents in the reactions above. (See Eqs. 49, 50.)... 

An unusual course of thermolysis occurs in 5-amino- and 5-alkoxytri-azolines, which are formed only as intermediates in the reaction of enamines and enol ethers with azides bearing electron-withdrawing groups it involves cleavage of the N-l/N-2 as well as the C-4/C-5 bonds of the triazoline ring to yield diazoalkanes and imines with one fewer carbon than in the triazolines (amidines and imino ethers) (Scheme 144)233.250 272 431-433 in a cycloelimination reaction, the reverse of diazoalkane-imine cycloaddition. The intermediate formation of a diazonium zwitterion is suggested,233,247 but whether the thermolysis occurs in a one- or two-step reaction is not established. 

Earlier attempts to effect carbonyl homologation in this way have met with little successP) The necessary presence of additional stabilizing substituents at the a-carbon atom lowered the reactivity of the anions to a level where only reactions with aromatic aldehydes gave reasonable yields. Recently, Martin and coworker have obtained interesting results with diethyl dialkylaminomethyl phosphonates. In their reaction sequences enamines, although not isolated, appeared to act as intermediates. 

Pyridoxal is the reagent in other reactions of amino acids, all involving the inline as intermediate. The simplest is the racemization of amino acids by loss of a proton and its replacement on the other face of the enamine. The enamine, in the middle of the diagram below, can be reprotonated on either face of the prochiral inline (shown in green). Protonation on the bottom face would take us back to the natural amino acid from which the enamine was made in the first place. Protonation on the top face leads to the unnatural amino acid after hydrolysis of the inline (really transfer of pyridoxal to a lysine residue of the enzyme). 

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