Hemiaminal intermediate

Barbier conditions have been used to carry out a silicon-induced addition of perfluoroalkyl iodides to DMF to give stable hemiaminal intermediates, which give the perfluonnated aldehydes upon heating with sulfuric acid [47 (equation 38)... 

Recently an oxidative amidation protocol, employing copper (I) as a catalyst, was developed by C.-J. Li [14]. The proposed mechanism, shown in Scheme 14.1, involves nucleophilic addition of the amine free base 8 to aldehyde 7 to afford hemiaminal intermediate 9, which is then oxidized by copper(I)/t-butyl hydrogen-peroxide (Cu(l)/TBHP) to generate the desired amide products 10 [15, 16]. 

N-Methylnitrones. The reagent converts aldehydes and aliphatic ketones into N-methylnitrones in high yield via a hemiaminal intermediate (a), which can be isolated in some cases. 

Fig. 3 (a) General reaction of reversible amine exchange between a 9-amino substituted acridine and a large excess of free amine, (b) Proposed mechanism of the amine exchange reaction via formation of a 9,9-diaminoacridine hemiaminal intermediate... 

Even though the Paal-Knorr pyrrole synthesis has been around for 120 years, its precise mechanism was the subject of debate. In 1991, V. Amarnath et al. investigated the intermediates of the reaction and determined the most likely mechanistic pathway. The formation of pyrroles was studied on various racemic and meso-3,4-diethyl-2,5-hexanediones. The authors found that the rate of cyclization was different for the racemic and meso compounds and the racemic isomers reacted considerably faster than the meso isomers. There were two crucial observations 1) the stereoisomers did not interconvert under the reaction conditions and 2) there was no primary kinetic isotope effect for the hydrogen atoms at the C3 and C4 positions. These observations led to the conclusion that the cyclization of the hemiaminal intermediate is the rate-determining (slow) step. 

The effect of sodium sulfate is not fully understood it can either act as a dehydrating agent to increase the formation of the hemiaminal intermediate or as a catalyst poison to limit carbonyl reduction. 

To a stirred solution of 23.3 mg tosyl oxime (0.0236 mmol) in 3.5 mL EtOH at 0" C was added 450 /xL 50% aqueous KOH dropwise over 1 min. The reaction mixture was stirred at 0°C for 3 h then 5 mL 6 N aqueous HCl was added. The reaction mixture was heated to 60°C for 10 h, cooled to 23°C, and purified by loading to a reversed-phase Sep-Pak column with water containing 0.1% TEA (w/v) and by washing with 15% acetonitrile in water containing 0.1% TEA (w/v) to remove salts and then in 70% acetonitrile in water containing 0.1% TEA (w/v) to collect the crude product. The solvents were removed under reduced pressure to afford the hemiaminal intermediate, which was immediately mixed with 60 mg K2CO3 (0.434 mmol) in 2 mL THE 200 /xL H2O was added at 23°C. The reaction mixture was stirred for 10 min and purified by a similar procedure for the hemiaminal intermediate to afford the crude product. After the solvents were removed under reduced pressure, the crude material was further purified by reversed-phased HPLC. Concentration under reduced pressure provided 15.0 mg amino ketone as an orange/red oil, in a yield of 96%. 

This is a fundamentally new chemical transformation. The reaction mechanism likely involves metal-hgand cooperation that operates in complex 8. The reaction plausibly proceeds via a hemiaminal intermediate (Scheme 1.11) formed by the nucleophilic attack of the amine on an intermediate aldehyde that is either coordinated to the metal or free in solution [7, 32, 50]. 

Notably, the potentially competing polyester formation [19] by dehydrogenative selfcoupling of diols was not observed under these conditions. This is probably because the intermediate aldehyde reacts preferentially with the amine, which is a better nucleophile than the alcohol, forming a hemiaminal intermediate [14] (rather than a hemiacetal [11]) followed hy its dehydrogenation to the amide (Schemes 1.6 and 1.11). In addition, it should he noted that complex 8 also catalyzes the formation of amides by coupling of esters with amines (Section 1.4.2) [15] hence, even if some ester (or oligoester) were to be initially formed, it would be converted to the polyamide. 

Two main families of histone demethylases have been identified. The LSD family (EC number 1.14.1 l.Bl) employs a monoamine oxidase mechanism to oxidise methyllysine to an imine (with concomitant reduction of FAD to FADH2), followed by addition of water to give a hemiaminal intermediate, which fragments to achieve demethylation. The JmjC family (EC number... 

The (reversible) transformation of an a-ketocarboxyhc acid in presence of ammonia and one equivalent of NAD(P)H furnishes the corresponding a-amino acid and is catalyzed by amino acid dehydrogenases [EC 1.4.1.X] [962]. Despite major differences in its mechanism, this reaction bears a strong resemblance to carbonyl group reduction and it formally respresents a reductive amination (Scheme 2.133). As deduced for L-Leu-dehydrogenase [963], the a-ketoacid substrate is positioned in the active site between two Lys-residues. Nucleophihc attack by NH3 leads to a hemiaminal intermediate, which eliminates H2O to form an iminium species. The latter is reduced by a hydride from nicotinamide forming the L-amino acid. Since this mechanism is highly tuned for a-keto/a-amino acids, it is clear that a neutral Schiff base cannot be accepted as substrate. 

In 2012, Fristrup and Madsen studied the mechanism of the same Af-alkylation reaction as above by combining experimental and theoretical methods [58]. In contrast to Eisenstein s proposal [57], Fristrup and Madsen s results suggested that both aldehyde and hemiaminal intermediates stay coordinated to the iridium catalyst... 

Write the structure of the aminal or hemiaminal intermediate and the imine product formed in the reaction of each of the following ... 

Isolated product is an imine, formed by dehydration of a hemiaminal intermediate. 

Reaction of primary amines with aldehydes and ketones (see Section 17.10) Imines are formed by nucleophilic addition of a primary amine to the carbonyi group of an aldehyde or a ketone. The key step is formation of a hemiaminal intermediate, which then dehydrates to the imine. 

A-Methyl Nitrone Formation. Aldehydes or ketones react with a stoichiometric amount of Me3SiN(Me)OSiMe3 (1) in benzene at 50 °C for 24 h to give A-methyl nitrones in good to excellent yields (eq 1). For deactivated carbonyl corrpounds, such as p-nitrobenzaldehyde, p-(dimethylamino)benzaldehyde, and 2-furaldehyde, addition of trimethylsilyl trifluoromethanesulfonate (0.03-0.04 equiv) as a catalyst is necessary for the formation of A-methyl nitrones otherwise accumulation of hemiaminal intermediates (2) occur. Sequential intra- and intermolecular [3 + 2]... 

On the other hand, the dehydrogenative amidation proved to be also sensitive to the electronic properties of the amines. Thus, with electron-poor amines, which display a low nucleophilic character, the formation of the hemiaminal intermediate is disfavored. As a consequence, substrates like anilines usually lead to low or moderate conversions, even at elevated temperatures or after long reaction periods, and large amounts of the corresponding esters by-products are formed. In this context, the ruthenium catalysts have conduced, in general, to quite disappointing results [114, 115, 117, 124], In fact, only gold nanoparticles have proven to be useful with this type of amines [132]. 

More recently, the same authors have extended their studies to the synthesis of amides from alcohols and nitriles, via formation of a transient hemiaminal intermediate (Scheme 27) [135]. Among the different catalysts tested, the best... 

Milstein modified this pathway with a catalyst that dehydrogenates the hemiaminal intermediate shown in Fig. 12.8 (right) to give the... 

However, the observed remarkable selectivity for amide formation suggests that free hemiaminal intermediate in solution is not involved, since the latter would likely liberate water faster than H2. We believe that the amine reacts with the intermediate aldehyde while it is still coordinated to the metal center, leading to formation of the quaternary salt 12 (Fig. 6), which may transfer a proton to the dearomatized phosphine arm (to give intermediate 10). Subsequent (3-hydride elimination and ring closure by the amine arm would lead to the tra/is-dihydride complex 6 and product amide. Liberation of dihydrogen from 6 would complete the catalytic cycle with regeneration of catalyst 5. 

The striking difference in the catalytic activity of the PNN complex 5, which leads to amide formation [52], and PNP 2 or 2- Bu complexes, which catalyze imine formation under similar conditions, can be rationalized as follows. In the case of the PNN complex, which bears a hemUabile amine arm, the aldehyde stays coordinated to the metal center long enough to be attacked by the amine (Fig. 6), while in the case of the PNP complex closure of the phosphine arm occurs more rapidly, resulting in liberation of the aldehyde and its attack by the amine takes place in solution, generating a hemiaminal intermediate which liberates water (Fig. 8). 

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