Enamides protonation

Analysis of 111 NMR spectra revealed that the two enamide protons resonate as doublets at 5.28-5.36 and 5.55-5.62 ppm with a 5.6 Hz coupling constant. 

An interesting mechanistic study (Scheme 31.26), supported by control experiments and density functional theory (DFT) calculation, shows a crucial function of the chiral ligand and proposes the following pathway. The authors showed the determinant role of the hydrogen atom of the enamide moiety. Based on deuterium labeling and supported by DFT calculation, a (3-hydride elimination of the enamide proton followed by a hydride transfer from the... 

Formation of A-acyliminium ions via protonation of enamides or enecarbamatcs is occasionally utilized. 

When the pyrrolo[l,2-c]oxazole 269 was treated with trimethyl orthoformate in the presence of BF3 Et20, in dichloromethane at — 78 °C, a mixture of compounds was obtained from which the expected 5-dimethoxymethyl derivative, 270, was isolated in poor yield (12%) with another dimethoxylated compound 271 (23%). The formation of 271 could be explained by the addition of the formyl cation equivalent at C-7, followed by the protonation at C-6 of the resulting enamide 272 leading to the electrophilic iV-acyliminium ion 273 (Scheme 40). The regioselectivity of this electrophilic addition of trimethylorthoformate to the silyloxypyrrole 269 at C-7, in a non-vinylogous manner, is unusual <1999TL2525>. 

Incorporation of 4-aminobut-2-enoic acids in a peptide relies on the classical procedures for peptide synthesis. A critical point might be their possible racemization under basic conditions, due to the higher acidic character of the allylic a-proton compared with the homologous a-amino acids. Substantial epimerization has been observed when incorporating ( )-but-2-enamide analogues of Met and Gin, but the step responsible for epimerization is not specified.11971... 

It is assumed that the intermediate N-acyliminium ions formed from the Lewis acid-assisted ring opening of the isomiinchnone cycloadducts undergo rapid proton loss to produce tetra-substituted enamides. In the case of 65, this process is clearly evident as witnessed by the stereochemical outcome observed... 

Pyrimidin-2-one exchanges its 5-hydrogen much faster than pyridin-2-one. However, this is due to the existence of a small proportion of the covalent hydrate 118 that undergoes rapid exchange via -protonation of the enamide unit (Scheme 20). 

The same reaction attempted on similar non-cyclic enamides gave no results. The mechanism would involve a transition state in which Mg2 + is simultaneously linked to the NADH model and the substrate, through their respective carbonyl groups. Within this ternary complex an electron migrates from the NADH model to the substrate and this migration is successively followed by a proton transfer from the NADH model radical cation to the radical anion. 

Several reactions have been examined in which the substrates, though not enamines in the strict sense, are nonetheless related to enamines in their reliance on the powerful p—7T donor ability of nitrogen to activate an unsaturated carbon toward electrophilic attack. Rate constants, and in some cases equilibrium constants, for C-protonation of these modified enamines are known. The substrates include p-amino- and/7-dimethyla-minostyrene (41, 42)", seven 1,3,5-triaminobenzenes (43-49)100-1 °2, six enamides (N-vinyl- or A-styrylamides 50-55)103 and three trialkylated/pyrroles (56104, and 57 and 58105). 

TABLE 11. Rate and equilibrium constants for C-protonation of some modified enamines aminoarenes, enamides and pyrroles (H20, 25 °C)... 

Compounds in which the donor nitrogen is separated from the carbon-protonation site by an intervening aromatic ring (aminostyrenes, aminoarenes), or in which conjugation between nitrogen and the alkene moiety is diverted by cross-conjugation (enamides), are protonated much more slowly and to a far smaller extent than are simple enamines. 

Ninomiya and Naito established an enantioselective variant of their enamide photocyclization based on chiral proton donors. The enamide photocyclization... 

In a more recent study, the enamide photocyclization with very similar photosubstrates was examined in the presence of chiral amino alcohols and chiral amines as asymmetric inductors [47]. The achieved enantioselectivities are in the same range as the ones reported by Ninomiya and Naito, but in this approach the asymmetric induction was more effective for the cis products. In cyclopentane at — 40°C, 0.1 equivalents of the most effective inductor, (— )-ephedrine (entity, gave the cis cyclization products with up to 37% ee and the trans products with only 2% ee. The role of the chiral inductor as a Br0nsted acid was supported by flash photolysis experiments. The presence of the chiral amino alcohol led to an increase in the rate of disappearance of a transient that was assigned to the primary cyclization intermediate of type 29, i.e., the chiral inductor accelerates the protonation/deprotonation sequence that reestablishes the aromatic ring. 

The third type of cyclization examined in the presence of chiral lactam hosts is the [6 7r]-cyclization of enamide 28a, the protonation step of which has been already enantioselectively directed with up to 38% ee by chiral proton donors, as described in Sec. Ill [46]. When the cyclization of enamide 28a was... 

A1 and concanamycin A—two established V-ATPase inhibitors.163 This observation was confirmed by both in vitro enzyme assays and in vivo activity studies in mutant yeast. These studies indicated that, while the benzolactone enamides were potent V-ATPase inhibitors, a profound selectivity occurred between the mammalian and fungal enzymes. Subsequent studies by De Brabander determined that salicylihalamide A binds irreversibly to the trans-membranous proton-translocating domain via A-acyliminium chemistry.164... 

Therefore, the formation of a dehydrolactam by irradiation of enamides under nonoxidative or unrestrictive conditions can be assumed to proceed via the route involving a 1,5-hydrogen shift of the Hb proton from the cyclic intermediate A to afford a thermally very unstable lactam 10 with a dihydrobenzene structure. This compound (10) would then undergo facile dehydrogenation even at room temperature to afford the dehydrolactam (9) as the final product, although the actual role of the oxidizing agent remains to be clarified. 

Enamide 11 was irradiated in benzene-methanol (10 1) in the presence of a large excess of sodium borohydride at low temperature (75). A mixture of two hydrogenated lactams, 12 and 13, was obtained. Therefore, the reaction was proved to proceed as expected by the manner of hydride attack on the immonium moiety, followed by protonation from methanol at two positions on the benzene ring. When acetonitrile was used as solvent, only the unconjugated lactam 12 was obtained in an excellent yield (75) (Scheme 17). 

Scheme 9 demonstrates the further synthetic application of the thus obtained N,0-acetals. Substitution of the alkoxy or acyloxy group by nucleophiles like enol ethers, enol esters, enamines, other electron-rich olefins, CH-acidic compounds, electron-rich aromatics, isocyanides, trimethylsilyl cyanide, organometallics, vinyl and allyl silanes, hydroxy functions, or trialkylphosphites either catalyzed by Lewis acids or proton acids leads to the product of the amidoalkylation reaction (path a). In the presence of stereocenters as control elements, diasteroselective amidoalkylation reactions can be performed as shown in a large number of examples. On the other side, as Nyberg showed for the first time [196], elimination with formation of enecarbamates [208] and enamides [196,208,209] followed by reaction with electrophiles or nucleophiles (path b) also is possible. 

Acyiiminium ions can also be created by treatment of the easily accessible enamides (63) with protic acids (Scheme 31 see also Section 4.2.2.1). Alternatively, transformation of enamides (63) to (60) can be achieved with C-electrophiles, by simultaneous formation of carbon-carbon bonds (cf. Scheme 37). In contrast, considerably less importance can be attributed to the comparable preparation of (60) from acylimines (64 Scheme 31), by protonation for example, due to their usually pronounced instability. 

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