2017
DOI: 10.1002/hlca.201700182
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Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

Abstract: It has been suggested that the origin of regio-and stereoselectivity in Michael additions of pyrrolidine enamines is achieved by thermodynamic rather than kinetic control through distinct conformational preferences of the enamines. We assess this proposal by elaboration of a computational protocol that warrants sufficient accuracy. The small energy differences between the conformers necessitate a high accuracy of the electronic structure method which, in addition, must allow for computationally feasible calcul… Show more

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Cited by 24 publications
(17 citation statements)
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References 140 publications
(364 reference statements)
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“…DMSO, DMF, acetonitrile, CDCl 3 ). 25,[54][55][56][57][58] In contrast, a detailed conformational analysis of an enamine derived from an acidic proton-containing catalyst in a protic solvent has so far remained elusive. 59,23 Thus, analysis of the conformation of 1-En was expected to be challenging.…”
Section: Residual Dipolar Couplings (Rdcs) and Simulatedmentioning
confidence: 99%
See 1 more Smart Citation
“…DMSO, DMF, acetonitrile, CDCl 3 ). 25,[54][55][56][57][58] In contrast, a detailed conformational analysis of an enamine derived from an acidic proton-containing catalyst in a protic solvent has so far remained elusive. 59,23 Thus, analysis of the conformation of 1-En was expected to be challenging.…”
Section: Residual Dipolar Couplings (Rdcs) and Simulatedmentioning
confidence: 99%
“…Comparison of the NOE-derived H1/p-Hα and H2/p-Hδ 1 /Hδ 2 distances with pure s-cis and s-trans enamine structures that were generated computationally suggests a s-trans:s-cis conformer ratio of approximately 70:30. 27, 55,58 Backbone conformation of the enamine 1-En ' . Next we explored whether the structural features observed for 1 are still intact in enamine 1-En ' .…”
Section: Conformation Of the Enamine Moiety Of 1-en 'mentioning
confidence: 99%
“…Although the details of the mechanisms involved require full clarification, the absence of similar dioxocin products when employing other cyclic secondary amines, such as indoline, morpholine and tetrahydroquinoline, using our hydrosilylation protocol, suggests that an enamine is likely to be involved. Pyrrolidine derived enamines are known to be more reactive that other cyclic amines [46,47], and the protocol for reductive amination from 2′-hydroxyacetophenone and this amine starts with iminium formation at room temperature under neat conditions [48]. Moreover, the same amine was previously reported to promote the formation of 4-chromanones from 2′-hydroxyacetophenones and aliphatic aldehydes and ketones [49].…”
Section: Resultsmentioning
confidence: 99%
“…The activation barrier for cis‐trans isomerism for this compound was found to be Δ G 298 ‡ = 80.4 kJmol −1 in solution and Δ G 298 ‡ = 71.4 kJmol −1 in the gas phase, while the pseudorotational barrier in pyrrolidine was calculated to be 0.6 kJmol −1 ab initio taking into account that the nitrogen inversion of the pyrrolidine ring is of little importance in N ‐trifluoroacetyl pyrrolidine . On the other side, we consider the ab initio conformational analysis of Reiher and Seebach on C(2′)‐substituted pyrroldines, where the pyrrolidine nitrogen is bound to a sp 2 ‐hydridized carbon . These authors calculated that UP‐ and DOWN ring conformers of pyrrolidine are both significantly populated when a Boltzmann distribution is in equilibrium.…”
Section: Nmr Of Cdz173mentioning
confidence: 98%