Iminium-enamine conversion

ReaxFF, a reactive force-field approach, has been used to model the iminium-enamine conversion in the proline-catalysed self-aldol of propanol. " " Quantum mechanical methods have been used to study the same step in the proline-catalysed aldol. " ... 

Hubin PO, Jacquemin D, Leherte L, Andre JM, van Duin ACT, Vercauteren DP (2012) Ab initio quantum chemical and ReaxFF-based study of the intramolecular iminium-enamine conversion in a proline-catalyzed reaction. Theor Chem Acc 131 1261... 

Ab initio quantum chemical and ReaxFF-based study of the intramolecular iminium-enamine conversion in a proline-catalyzed reaction... 

As mentioned in the introduction, there is an alternative mechanistic pathway supporting that the iminium-enamine conversion occurs through an oxazolidinone intermediate. We tested the possibility to form oxazolidinone from the E endo s-trans isomer of the iminium. It turns out that the energy barrier for this conversion is very low, 0.20 kcal/ mol. Moreover, this oxazolidinone species is more stable than the other considered intermediates, the difference being 7.44 kcal/mol regarding the enamine E endo s-trans. These results are not particularly surprising since, on the one hand, it is known from experimental observations that oxazolidinones are easily isolated in the reaction mixture, although it is nearly never the case for enamines, and, as on the other hand, similar theoretical results were already... 

Our theoretical investigation regarding the understanding of the conversion of iminium into enamine in the framework of a proline-catalyzed aldol reaction emphasizes that the reactive force field (FF), ReaxFF, used in combination with molecular dynamics (MD) simulations is a relevant method to investigate the mechanism of proton transfers in iminium-enamine conversions. This approach should be extended to model other steps of proline-catalyzed... 

First, we showed that similar conclusions regarding the relative stability of intermediates and energy barriers could be drawn either from ReaxFF MD simulations or from DFT calculations at the M06-2X/6-31 -I- G(d,p) level. Regarding the particular studied step of the reaction, one showed that the iminium-enamine conversion is more likely to yield an E enamine and that the energy barrier for the reaction is also smaller starting from the s-cis isomer of iminium relatively to the s-trans one. 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

Conversely, in 2(X)7, Jprgensen disclosed a sequential imiitium-iminium-enamine catalysis as an alternative to... 

Iminium ions (2) would be expected to undergo hydrolysis quite readily, since there is a contributing form with a positive charge on the carbon. Indeed, they react with water at room temperature." Acid-catalyzed hydrolysis of enamines (the last step of the Stork reaction, 12-18) involves conversion to iminium ions " ... 

Conversion of Carbonyl Croups into Schiff Bases, Iminium Salts, and Enamines... 

For the biosynthetic conversion of cathenamine (76) to the 19- and 20-epi derivatives, an equilibrium should exist between the enamine and imi-nium forms of cathenamine (i.e., 76 and 97) (767). This was examined (209) with deuterium labeling studies of incorporation into tetrahydro-alstonine (75), whereupon C-21 was labeled from both the enamine and iminium forms. When the enamine form was present, a second deuterium was incorporated (presumably at C-20) on reduction with NaBD DjO. Sulfate was effective in pushing the equilibrium toward the iminium species (209). 

The dual nature of enamine-iminium pairs allows unique possibilities for domino processes. Reactions of enamines with electrophiles afford electrophilic iminium ions that are ready to react with another (internal or external) nucleophile. Conversely, reactions of unsaturated imininm ions with nucleophiles afford enamines. Examples of intramolecular enamtne-catalyzed domino processes are depicted in Scheme 35. In all of these reactions, both enamine and iminium mediated steps can be distinguished. 

Hydrolytic conditions are tolerated by dihydrobenzoxazines, and this allows the selective hydrolysis of the ester group of 243 into the free acid with 10% sodium hydroxide <1983JHC45>. The nitrile of 244 was converted into the iminium salt followed by hydrolysis to give the ester 70 <1987M273>. Conversion of 245 into an iminium salt followed by base treatment to give the a-ethoxy enamine then allows cyclization with an aldehyde to give product 246 as shown in Scheme 27 <1986H(24)3483>. 

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

Enamines can be obtained as the products of the Polonovski reaction of amine oxides and, in particular, by reaction of piperidine A -oxides with acetic anhydride. This is primarily due to the fact that when acetate is the counterion the intermediate iminium ions are labile and readily tautomerize. The formation of enamines during the Polonovski reaction is also favored by the presence of a base. In fact, enamines are often obtained in high yield from the reaction of an IV-oxide with trifluoroacetic anhydride in the presence of triethylamine or pyridine. Conversion of intermediate iminium ions, generated under modi-fred Polonovski conditions, to enamine products can also occur during hydrolytic work-up. 

When the pre-existing stereocenter is adjacent to the iminium ion carbon atom, Pictet-Spengler cyclization most commonly occurs from the face opposite the substituent, as in the conversion of (42) to (43) (Scheme 20). A related example is the cyclization of the disubstituted A -tetrahydropyridine (44), which was treated with hydrogen chloride gas in anhydrous methanol to produce three of the four possible diastereomeric products in the indicated abundances (Scheme 21). The relative stereochemistry at C-1 is set by protonation of the enamine, while that at C-12b is determined in the cyclization step. The authors argue that protonation is kinetically controlled and occurs preferentially from the... 

An iminium ion-alkene cyclization has been employed to assemble the phenylmorphan ring system (Scheme 26). The conversion of enamine (64) to (66) was suggested to arise by 1,5-hydride migration of an initially formed bicyclic cation (65). Direct intramolecular ene cyclization of the iminium ion (67) produced by protonation of (64) provides an alternative rationale for the net cis addition to the terminal alkene that occurs in this transformation, and avoids postulating the intervention of a relatively unstable fully formed secondary carbocation. 

Formic acid has been used in a variety of rather specific reductions. Heating triphenylcarbinol (580) in formic acid, for example, led to triphenylmethane (581). 92 most common application of formic acid reduction involves enamines, presumably via conversion to an iminium salt, which is the actual species reduced... 

Stille and co-worker developed an attractive route to aza-Claisen precursors. Allylamine reacted with 2-methylpropanal (isobutyraldehyde), for example, to give allylimine 658. When this reacted with 2-methylpropanoyl chloride, N-acyl derivative 659 was produced (94% overall yield from allylamine) and reduction with LiAlH4 give a 98% yield of the tertiary amine, 660. Stille found that conversion of the amine to the ammonium salt by treatment with HCl led to clean conversion to 661 in 82% yield via a [3,3]-sigmatropic rearrangement (an aza-Claisen rearrangement). Reduction of the iminium salt led to an 81% yield of 662 from 661. Stille and co-workers also found that Lewis acids as well as HCl react with the allyl enamine precursor to facilitate the aza-Claisen rearrangement. 2... 

Also under acidic conditions, enamines are reduced to amines via iminium ions by NaBHsCN (eq 15). This type of conversion is also effected with NaBH3CN/ZnCl2. Pyridines and related nitrogen heterocycles are reduced by NaBH3CN/H+ to di-or tetrahydro derivatives (eq 16)4 Likewise, pyridinium and related salts (e.g. quinolinium, isoquinolinium) are reduced. With 4-substituted derivahves, 1,2,5,6-tetrahydropyridine products are produced (eq ll) ... 

The diflferent reactivity of aldehydes and ketones toward condensation with amines is also a differentiating element when using enals or enones as Michael donors under iminium activation. As in the enamine activation case, working with a,p-unsaturated aldehydes usually leads to faster reactions or better conversions but the same reaction with enones in many cases turns out to be a very slow or even non-existent reaction. Stereochemical control is also more problematic when a,p-unsaturated ketones are employed because the presence... 

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