Imines proton abstraction

Rearrangement to an open chain imine (165) provides an intermediate whose acidity toward lithiomethylthiazole (162) is rather pronounced. Proton abstraction by 162 gives the dilithio intermediate (166) and regenerates 2-methylthiazole for further reaction. During the final hydrolysis, 166 affords the dimer (167) that could be isolated by molecular distillation (433). A proof in favor of this mechanism is that when a large excess of butyllithium is added to (161) at -78°C and the solution is allowed to warm to room temperature, the deuterolysis affords only dideuterated thiazole (170), with no evidence of any dimeric product. Under these conditions almost complete dianion formation results (169), and the concentration of nonmetalated thiazole is nil. (Scheme 79). This dimerization bears some similitude with the formation of 2-methylthia-zolium anhydrobase dealt with in Chapter DC. Meyers could confirm the independence of the formation of the benzyl-type (172) and the aryl-type... 

Proton abstraction from the neutral imine gives its conjugate base, which is a violet dye. 

Thus tryptophan synthetase, which catalyzes the addition of serine to indole via an QE.P-unsaturated imine derivative, is inactivated by QE-cyanoglycine (33). In this case, QE-cyanoglycine, an analogue of the substrate serine, undergoes Schiff base formation. Proton abstraction then occurs and the resultant QE-cyano carbanlon is apparently reprotonated to generate a reactive keteneimlne which can alkylate a nucleophilic active site residue. 

An elaboration of this work involves the 3CR between primary a-isocyanoa-mides 67, carbonyl components 6 and primary amines 146, which could be directed towards either 2//-2-imidazolines 153 or M-(cyanomethyl)amides 156 by Ag -catalysis vs. Brpnsted acid mediated reaction, respectively (Scheme 14) [60]. The selective formation of M-(cyanomethyl)amides 156 (also earlier mentioned in the SRR approach. Scheme 7) can be rationalized by the same criteria as the formation of trisubstituted oxazoles 152 (Scheme 13), since the use of a Brpnsted acid, prevents the formation of 2-imidazolines 153 by the decreased pH. By applying a Brpnsted acid, the reaction initially proceeds via the same mechanism as for the oxazole MCR. However, when intermediate 155 is formed, it does not tautomerize to form the 5-aminooxazole 157. Instead, proton abstraction at the exocyclic imine nitrogen and subsequent ring opening gave the corresponding M-(cyanomethyl)amides 156. 

Rearrangement to an open chain imine (165) provides an intermediate whose acidity toward lithiomethylthiazoie (162) is rather pronounced. Proton abstraction by 162 gives the dilithio intermediate (166) and regenerates 2-methyIthiazole for further reaction. During the final hydrolysis, 166 affords the dimer (167) that could be isolated by molecular distillation (433). A proof in favor of this mechanism is that when a large excess of butyllithium is added to (161) at and the solution is... 

While the abstraction of protons adjacent to the carbon-nitrogen double bond of imines/imine derivatives has been utilized for tiie regioselective generation of azaallyl anions (which are useful in asymmetric ketone synthesis), it competes with and often prevents the addition of nucleophiles to imines. For this reason, imine additions often involve azomethines (e.g. benzylidineanilines) which are not capable of enolization. Many potentially useful additions, however, involve substrates capable of proton abstraction. By avoiding in certain instances some of the structural features of imines/imine derivatives and the reaction conditions responsible for proton abstraction, products resulting from this serious side reaction can be minimized. 

Over the years there have been a number of mechanistic proposals for substrate oxidation by TMADH. An early proposal considered a carbanion mechanism in which an active site base deprotonates a substrate methyl group to form a substrate carbanion [69] reduction of the flavin was then achieved by the formation of a carbanion-flavin N5 adduct, with subsequent formation of the product imine and dihydroflavin. A number of active site residues were identified as potential bases in such a reaction mechanism. Directed mutagenesis and stopped-flow kinetic studies, however, have been used to systematically eliminate the participation of these residues in a carbanion-type mechanism [76-79], thus indicating that a proton abstraction mechanism initiated by an active site residue does not occur in TMADH. Early proposals also invoked the trimethylammonium cation as the reactive species in the enzyme-substrate complex, owing to the high (9.81) of free... 

Which electrophile is lost from the amino acid residue is, of course, controlled by the enzyme. One way this may occur is by the enzyme binding the PLP imine so that the electrophile is in close proximity to a suitable or base to aid abstraction and also so that the a orbital of the bond to be broken is periplanar with the p r acceptor system, i.e. orthogonal to the plane of the pyridine ring (XXXI). Maximal orbital overlap, stereoelectronic control, will lower the activation energy for the reaction. Aldol-type reactions can also occur with PLP as in the laboratory the key to making carbon-carbon bonds is the formation of a stabilised carbanion. Proton abstraction from the initially formed imine gives a masked carbanion which can nucleophili-... 

The direct observation of this reaction is difficult because of the small equilibrium constant for imine formation. This type of reaction is therefore commonly studied by trapping the imine as it is formed with hydroxylamine, which reacts rapidly to form an oxime. Because the equilibrium constant for formation of the imine between methyl amine and acetone is so small, the equilibrium is established very rapidly. (The observed rate constant for a reaction proceeding to an equilibrium position is larger than the first-order rate constant for the forward reaction [7].) Thus the addition of methylamine and acetone to an aqueous solution results in the establishment of an equilibrium concentration of imine (and iminium ion) in several seconds. In several studies described below wherein reactions subsequent to imine formation occur, it is common to find a presumption of rapid imine equilibria prior to the slower o-proton abstraction or decarboxylation events that occur subsequently. 

Pyridoxal 5 -phosphate is also a coenzyme for the enzyme-catalyzed racemization of amino acids. The key reaction is proton abstraction from the a carbon of the amino acid imine of PLP. This step converts the a carbon, which is a chirality center, from sp to sp. ... 

Stage 2 The electron-withdrawing effect of the pyridinium ring stabilizes the conjugate base formed by proton abstraction from the a carbon of the imine. 

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