Enamines conformations

Two different models were proposed by Ley for the 2b-catalyzed reaction which should also be of application for the cases of proline 1 and proline-tetrazole catalysts 2a, both of them in good agreement with the observed absolute configuration of the final Michael adducts (Figure 2.2). One proposal involved the possibility of the tetrazole moiety acting as a bulky substituent which directed the income of the electrophile by the less hindered face of the enamine intermediate in the most stable pseudo-rrarw conformation. Alternatively, the formation of a hydrogen-bonded transition state was also proposed, in this case with the participation of the pseudo-cj5 enamine conformer. This second pathway was afterwards estimated to be the energetically most favored one by DFT calculations. ... 

Figure 11.3 Syn- versus anii-enamine conformation equilibria using (S)-proline (1) or (S )-a-2-methyl-proline (7a).

Alexakis et al. proposed in 2010 the use of aminals deriving from 4-hydroxyproline for the asymmetric addition of aliphatic aldehydes to vinyl sulfones." " The idea that a fluorine atom at the C4 position of these pyrrolidine-based organocatalysts could be used to favour one single reactive enamine conformation was further exploited by the same authors in 2011, designing a catalyst (28) able to afford excellent yields and enantioselec-tivities (Scheme 11.24). ... 

The reversal of facial selectivity was ensured by two rationally designed structural features i) the methyl substituent at C2, which imposes a fixed enamine conformation (Figure 11.4A) and ii) the distal carbo>ylic acid at C4, which successfully directs the facial-selective approach of the reagents (Figure 11.4B). 

The equilibria between bicyclic oxazolidines and enamines derived from prolinol derivatives and aldehydes have been studied spectroscopically by Schmid et al. [44] In the case of prolinol, the less stable c db-oxazolidinone is the kinetic product, which is in equilibrium with the aw/f-enamine conformer. The zwitterionic amonium alkoxide, not detected, is the key intermediate in the oxazolidine-enamine equilibrium. For diarylprolinol derivatives, minor amounts of en amine can be detected, and only the e/J[Pg.27]

First, the carboxylic acid group is moved farther to the third position and an additional trans methyl group is introduced at the fifth position. While the later substituent would steer the enamine conformation to an s-trans arrangement, the carboxyhc acid can still participate in effective proton transfer as shown in Figure 17.15b. The relative energies of transition states indicated 95 5 anti syn diastere-oselectivity and about 98% enanhomeric excess for the (2S,3R)-Mannich product. Subsequent experimental verification of these predictions yielded near quantitative agreements for the extent of both enanho- and diastereoselectivities in favor of onti-Mannich product. 

The enamine conformer (b) is of similar stability than its counterpart (a), 0.05 kcaPmol, but the corresponding... 

ZPVE corrections were not taken into account The enamine conformation considered in 1,2, and 3 is not the same than in 4 and 5... 

Because of the same preference for coplanarity in the enamine system, a alkyl substituents adopt an axial conformation to minimize steric interaction with the amino groi. ... 

That the methyl group in the pyrrolidine enamine of 2-methylcyclo-hexanone (7) is in fact axial was demonstrated by Johnson and Whitehead (8). They found that careful hydrolysis of the pyrrolidine enamine of the conformationally more stable system, i.e., 2-methyI-4-t-butylcyclohexanone (13), led to a 1 4 mixture of cis and trans isomers of the ketone (14 and 15), showing that the methyl group in the enamine is largely in the axial orientation. 

The course of alkylation is also influenced by the steric arrangement of the enamine. 1-Pyrrolidino-l-cycloheptene gave approximately equal quantities of the C- and N-alkylated products in dioxane, while 1-pyrroli-dino-l-cyclooctene, and 1-pyrrolidino-l-cyclononene afforded N-alkylated products exclusively under similar eonditions (29). The reason for N alkylation in the eight- and nine-membered ring compounds is to be found in the conformation of these rings, which prevents full interaction of the unshared electrons on nitrogen with the n eleetrons of the double bond. 

In contrast to the five-membered ring, conformational factors would be expected to influence the equilibrium between the imine and enamine forms in the case of the six-membered-ring piperideine derivatives (154). 

The conformationally locked racemic enamine, 4-(4-rOT-butyl-1-cyclohexenyl)morpholine, reacts with (l-nitroethenyl)benzene to give a mixture of diastereomeric 1,2-oxazine 2-oxides 1 and 2 (ratio 1/2 75 25). Whether these arise via an ionic or a cycloaddition mechanism is unclear. Hydrolysis of 1 and 2 with dilute acid gave a 80 20 mixture of trans- and cis-ketones, 3 and 414. 

The orbital phase theory was applied to the conformations of alkenes (a- and P-substituted enamines and vinyl ethers) [31] and alkynes [32], The conformational stabilities of acetylenic molecules are described here. 

The preparation and investigation of the thietane oxide system (5a) is largely associated with stereochemical and conformational studies . The investigation of the thietane dioxides (5b) is substantially related to the chemistry of sulfenes , the [2 -I- 2] cycloaddition of which with enamines is probably the method of choice for the synthesis of 5b . The study of the thiete dioxide system (6) evolved, at least in part, from the recognition that the unstable thiete system 183 can be uniquely stabilized when the sulfur in the system is transformed into the corresponding sulfone , and that the thiete dioxide system is very useful in cycloadditions and thermolytic reactions. The main interest in the dithietane oxides and dioxides (7) appears to lie in the synthetic challenge associated with their preparation, as well as in their unique structural features and chemical behavior under thermolytic conditions . ... 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

The electron-rich and cyclically conjugated 8 rr electron system of 1,4-dihydropyrazine can be stabilized in essentially planar conformation by organosilicon substitution at the enamine nitrogen centers [1], In addition to electron transfer [1] and triorganosilyl exchange reactions [2], we have explored the possibility of inserting heterocumulenes X=C = Y into one or both of the N-Si bonds of the compounds 1 in order to functionalize this unusual ring structure [3],... 

The NMR measurements for the Schiff bases being derivatives of (R)-l-(9-anthryl)-ethylamine and 2-(2 -pyridyl or quinolyl)acetophenone [23] have revealed the presence of the rigid conformation of the enamine form.56... 

Evidently, in the crystalline state, BENA can adopt one of two conformations (A or B) presented in Fig. 3.3. Nevertheless, the nitrogen atom is characterized by a high degree of pyramidalization in both conformations, and the C-N bond is substantially elongated compared to similar bond in classical enamines (see, e.g., (417)). It should also be noted that the C,C double bond in BENA is substantially shortened compared to the analogous bond in standard enamines. 

However, a quite different situation is observed for ene nitroso acetal (423). First, a stable conformation and, correspondingly, new transition states TSR1 and TSR1 with a low barrier (8.8 kJ/mol) appear on the rotation coordinate about the C,N bond at the place of the transition state of enamine (422). Therefore, the barrier to rotation about the C,N bond decreases so that the process is fast on the NMR time scale and cannot be detected by this method. 

Compounds in which the amino group is directly connected with another functional group like hydrazines, hydroxylamines, enamines and amides were already briefly mentioned in Section II.C. In several cases it has been shown that orbital interactions of these systems can be used for conformational analysis by PES66,67. 

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