Imines mechanistic proposal

Fig. 41 Mechanistic proposal for highly electron-poor imines...

In the initial screening of various Cinchona alkaloids, the addition of diethyl phosphate 41 to IV-Boc imine 40 in toluene revealed the key role of the free hydroxyl group of the catalyst. Replacing the C(9)-OH group with esters or amides only results in poor selectivity. Quinine (Q) was identified as an ideal catalyst. A mechanistic proposal for the role of quinine is presented. Hydrogen-bonding by the free C(9)-hydroxyl group and quinuclidine base activation of the phosphonate into a nucleophilic phosphite species are key to the reactivity of this transformation (Scheme 9). 

Scheme 6.87 Mechanistic proposal for the asymmetric [3 -r 2] cycloaddition between buta-2,3-dienoic acid ethyl ester and various DPP-protected imines catalyzed by phosphinothiourea 75...

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... 

This mechanistic proposal has extensive experimental support Imine 16 has been trapped and localized, and enzyme-catalyzed hydrogen/deuterium (H/D) exchange at C3 and C4 of DXP as well as carbonyl oxygen exchange has been detected. Acyl transfer to the C4 hydroxyl (18 to 19) as well as transfer of oxygen from DXP to nascent ThiS-COOH (21 to 22) has been demonstrated. Intermediate 22 has been trapped and detected by mass spectrometric analysis and the reaction product 14 has been fully characterized. Thiazole synthase complexed with ThiS-COOH has been structurally characterized and the DXP imine 16 has been modeled into the active site revealing key catalytic residues. ... 

Ishii reported the Sm(III)-catalyzed route to various tri- and tetra-substituted pyrroles 347 employing 3 + 2 cydocondensation between imines 345 and ni-troalkenes 346. (Scheme 8.121) [315]. Theuseofaldimines andketemines with steric congestion at the imine functionality led to formation of the corresponding pyrrole products in diminished yields. According to the mechanistic proposal, the samarium... 

In this example, water was nsed as a nucleophile instead of an organic acid. The yields of the obtained a-amino amides 2 ranged from moderate to good (Scheme 7.3). In order to explain the resnlts, a mechanistic proposal was envisaged by the anthors where the phenyl phosphinic acid (6) was proposed to have a dnal role, as Brpnsted acid by protonation of the imine intermediate and as a Lewis base by trapping the nitrilium ion intermediate formed between the aldehyde, the amine, and the isonitrile, forming intermediate 7. In the last step, the water released from the imine formation reacts with intermediate 7 to give 8, which was transformed into the componnd 2 and catalyst 6. 

Over the past 5 years Cu(I)-catalyzed addition of terminal acetylenes to imines has been an intense area of research for the synthesis of chiral propargyl amines. Two mechanistic proposals have been put forth which utilize Cu(I) complexes as Lewis acids in these additions. Benaglia and coworkers reported a mechanism for reactions utilizing preformed imines (Scheme 17.37). The chiral Cu(I) salt (171) initially coordinates imine (172) to generate complex (173). Subsequent coordination of the terminal acetylene (174) affords complex (175). Formation of requisite copper acetylide results in the formation of complex (176), which facilitates intramolecular addition of the acetylide to the imine. Decomplexation of the resulting propargyl imine from (177) regenerates the catalytic Cu(I) species. 

An economical mechanistic proposal assumes initial coordination of the carbene to the amide carbonyl. Intramolecular transfer of a proton from the positively charged nitrogen to the negatively charged carbon of the zwitterion constitutes the second step. The final step is base catalyzed removal of the imine proton with concurrent... 

The a-methylene-p-hydroxy esters were obtained in the (R) configuration and the dioxanone in the (S) configuration, whereas the reaction with aromatic imines led to (S)-enriched N-protected-a-methylene-P-amino acid esters [44]. The mechanistic proposal for the reaction with imines, as shown in Figure 6.7, indicates more steric interaction in intermediate B than in intermediate A. As a result, intermediate A reacts to form the Morita-Baylis-Hillman product, whereas intermediate B prefers to redissociate into reactants. The difference in the rate of the elimination step of the two intermediates leads to the preference for the (S) configuration through equilibration between intermediates A and B. 

SCHEME 39.38. Mechanistic proposal for origin of stereoselectivity reversal for suUinyl imine reduction. 

A mechanistic rationale for the observed cw-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 253, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat transition state delivers the observed cw-stereochemistry of the product (Scheme 12.57). Related work by Nair and co-workers (using enones 42 in place of a,P-unsaturated sulfonylimines 251, see Section 12.2.2) generates P-lactones 43 with fran -ring substituents, while the P-lactam products 252 possess a cw-stereo-chemical relationship. 

Mechanistically the reaction is proposed to proceed via a nine-membered transition state with the chiral phosphoric acid simultaneously activating the imine by protonation and the phosphite by coordinating to the hydroxyl group (Fig. 9). 

Yang and Lenz proposed two possible mechanistic explanations for this result (Scheme 35). Attack of the enamine on the amide carbonyl would lead to the formation of a four-membered ring iminium-alkoxide intermediate that could collapse to form the imine... 

Little precise mechanistic studies have been undertaken with these inhibitors with the exception of the time-dependent inhibition of SAH hydrolase by 176. Stoichiometric loss of fluoride was observed by 19F-NMR during the inactivation process. However, there is only circumstantial evidence to support the addition-elimination mechanism proposed in Figure 1 all attempts to isolate an enzyme fragment covalently bound to an inhibitor have so far been unsuccessful. If the rate-determining step in the enzyme inhibition process is an attack of an enzyme nucleophilic residue on a 0-fluoro-a, 0-unsaturated imine or ketone, kinetic analysis of addition-elimination reactions to similar systems indicate that the ( )-isomer is the more active isomer (73) this could explain in part the isomeric preference seen with MAO and SAH hydrolase inhibitors. 

All the results show that the methylations of primary and secondary amines are favoured by the presence on the surface of mixed phases of a CuCi02 type stabilized by a promotor such as barium. Furthermore the increase in the total acidity of the catalyst by using an alumina support favours the production of the secondary amine (didodecylamine) resulting from the condensation of a primary amine with the corresponding imine. However the formation of tridodecylamine (not desirable) which can be favoured by the increase in acidity of the catalyst is also much increased, and rather unexpectedly, by the presence of metallic copper on the surface area of the catalyst, be it alumina or graphite supported. From a mechanistics point of view the reaction scheme proposed by VON BRAUN (6) and taken up by VOLF and PASEK (7) allows to account for the main results. However in the case of methylation reactions (Leuckart type reaction) in particular the methylation of the secondary amine, as well as for the formation of tridodecylamine it is apparently necessary to propose new reaction steps (8). 

A mechanistically interesting method for the formation of diazomethane was found by Staudinger and Kupfer (1912). They obtained diazomethane from hydrazine and chloroform in 25% yield. In spite of the ready availability of the reagents, the method is not attractive for the synthesis of diazomethane, even after Sepp et al. (1974) were able to increase the yield to 48% by adding small amounts of 18-crown-6. The mechanism (2-44), which was tentatively proposed by Hegarty (1978, p. 579), is, however, interesting because of the hydrazonyl chloride 2.97 formed primarily elimination of HCl gives the zwitterionic nitrile imine 2.98, which is an isomer of diazomethane (for a discussion of diazomethane isomers, see Sect. 5.4). 

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