Elimination reactions imine-forming

More O Ferrall diagram for base-promoted, imine forming 1,2-elimination reactions. 

In Section 7.7.2 we met enamines as products from addition-elimination reactions of secondary amines with aldehydes or ketones. Enamines are formed instead of imines because no protons are available on nitrogen for the final deprotonation step, and the nearest proton that can be lost from the iminium ion is that at the P-position. 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

Electron-poor nitriles react with compound 87 and its derivatives to form the 5-amino-l,2,4-thiadiazole derivatives 104 <1985JOC1295>. Therefore, the formation of product 94 (see Scheme 21) may be explained alternatively by the addition of amidonitrile 93 to compound 90. The mechanism of the formation of product 104 was discussed in detail in CHEC-II(1996) <1996CHEC-II(4)691> but most probably the steps involved are (1) reaction of the electrophilic nitrile with the exocyclic nitrogen of compound 87 or its derivatives (2) loss of nitrogen similarly to the previous reactions and formation of an imine 103 (3) masked 1,3-dipolar cycloaddition/elimination reaction of the nitrile to the imine 103. Since the same nitrile is expelled in the elimination step, only 1 equiv of reagent is needed (Scheme 24). 

The actual cyclisation stage is not as imponderable as it appears. The first step is the acid-catalysed equilibration between hydrazone 7.8 and ene hydrazine 7.10. The next step, which is irreversible, is a concerted electrocyclic reaction, forming a strong carbon-carbon bond, and breaking a weak nitrogen-nitrogen bond. The resulting imine 7.11 immediately re-aromatises by tautomerisation to aniline 7.12. Finally, acid-catalysed elimination of ammonia forms indole 7.9, reminiscent of the last step of the Knorr pyrrole synthesis (Chapter 2). 

Reactions were studied under the pseudo first-order condition of [substrate] much greater than [initial dihydroflavin]. Under these conditions, the reactions are characterized by a burst in the production of Flox followed by a much slower rate of Flox formation until completion of reaction. The initial burst is provided by the competition between parallel pseudo first-order Reactions a and b of Scheme 3. These convert dihydroflavin and carbonyl compound to an equilibrium mixture of carbinolamine and imine (Reaction a), and to Flox and alcohol (Reaction b), respectively. The slower production of Flox, following the initial burst, occurs by the conversion of carbinolamine back to reduced flavin and substrate and, more importantly, by the disproportionation of product Flox with carbinolamine (Reaction c followed by d). Reactions c and d constitute an autocatalysis by oxidized flavin of the conversion of carbinolamine back to starting dihydroflavin and substrate. In the course of these studies, the contribution of acid-base catalysis to the reactions of Scheme 3 were determined. The significant feature to be pointed out here is that carbinolamine does not undergo an elimination reaction to yield Flox and lactic acid (Equation 25). The carbinolamine (N(5)-covalent adduct) is formed in a... 

Notice that an acid catalyst is normally added for imine formation. Without an acid catalyst, the reaction is veiy slow, though in some cases it may still take place (oximes, for example, will form without acid catalysis, but form much faster with it). It s important to notice that acid is not needed for the addition step in the mechanism (indeed, protonation of the amine means that this step is very slow in strong acid), but is needed for the elimination of water later on in the reaction. Imine formation is in fact fastest at about pH 4-6 at lower pH, too much amine is protonated and the rate of the first step is slow above this pH the proton concentration is too low to allow protonation of the OH leaving group in the dehydration step, Imine formation is like a biological reaction it is fastest near neutrality. 

A second issue is that catalytic aminations are plagued by several notable side reactions. Most prevalent among these is jS-hydride elimination (see -Hydride Elimination) of imine from the intermediate Pd-amido complex (equation 31). This reaction also produces a Pd H species, which can then reduce the substrate to form arene, the generation of which can be considered a second side reaction. Furthermore, aryl-aryl exchange has also been noted in amination reactions, and, for the monoarylation of primary amines, by-products caused by overarylation (equation 32) to form tertiary amines pose an additional difficulty. 

J.M. Sayer and W.P. Jencks, Imine-Forming Elimination Reactions. 2. 

Overall, the addition of a nitrogen nucleophile to an aldehyde or a ketone is a nucleophilic addition-elimination reaction nucleophilic addition of an amine to form an unstable tetrahedral intermediate, followed by elimination of water. The tetrahedral intermediates are unstable because the newly formed sp carbon is bonded to an oxygen and to a nitrogen—another electronegative atom. Water is eliminated, and loss of a proton from the resulting protonated imine forms a stable imine. 

A -Substituted bornyl- and isobornylamines 17-19 are best obtained by reduction of the imines formed from camphor and a suitable amine4, either by isolation of the imine or in situ formation. The substituted amines were used as the lithium salt for enantioselective deprotonation and elimination reactions (Section C ). In almost all cases, the exo-amines (isobornylamines) are formed however, using (S)-l-phenylethylamine as the starting amine, the selectivity is reversed and the enob-amine (bornylamine) is obtained. 

Reductions. Nitrones and N-oxides are deoxygenated by (BnNEtjljMoS. Acyl azides give amides. Alkyl azides undergo a homocoupling reaction to form imines, whereas stabilized azides, such as acyl, sulfonyl, and aryl azides, undergo reductive elimination of... 

The tetrahedral addition product that is formed first is similar to a hemiacetal, but with an NH group in place of one of the oxygens. These addition products are normally not stable. They eliminate water to form a product with a carbon-nitrogen double bond. With primary amines, the products are called imines. Imines are like carbonyl compounds, except that the O is replaced by NR. They are important intermediates in some biochemical reactions, particularly in binding carbonyl compounds to the free amino groups that are present in most enzymes. 

Many addition-elimination reactions at carbonyl centers involve a nucleophilic attack on the carbonyl carbon, followed by an elimination that restores the double bond. We first explore addition followed by 1,2-elimination, one of many types of reactions referred to as condensations. Strictly speaking, a condensation occurs when two large molecules combine to create a more complex molecule with the loss of a small molecule, such as water or an alcohol. Therefore, a condensation is a form of substitution. We will also examine condensation reactions that form polymers (see Chapter 13). One of the more complex condensations is the formation of an imine or enamine from a carbonyl and an amine. In both of these cases an oxygen is replaced by a nitrogen with loss of water (Eq 10.105 and 10.106). 

Elimination reactions following a hydroformylation step are quite common. In particular, in sequential reactions the condensation of aldehydes with amines plays a crucial role for the production of imines (see Section 5.4). Here only those reactions will be considered in which, immediately after the hydroformylation reaction, parts of the newly formed aldehyde are split off. 

A Hammett investigation of imine-forming radical elimination reactions of O-(l-naphthoyl)-A,A-bis(p-substituted benzyl)hydroxylamines, activated by triplet ben-zophenone, has been reported. ... 

Triazoles also serve as a precursor of metal carbene complexes. For instance, Murakami and Fokin independently reported a denitrogenative rearrangement reaction of triazolyl alcohol 69 (Scheme 7.27) [41]. The ring-chain tautomeriza-tion of 69 generates its diazo imine form, which reacts with Rh2(Oct)4 to produce a rhodium carbene complex. The following 1,2-alkyl migration and elimination of rhodium produce enaminone 70. 

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