Article Type: Full Paper Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis Tamara Husch,† Dieter Seebach,∗,‡ Albert K. Beck,‡ and Markus Reiher∗,† †ETH Zürich, Laboratorium für Physikalische Chemie, Vladimir-Prelog-Weg 3, 8093 Article Zürich, Switzerland ‡ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland E-mail: [email protected]; [email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as Accepted doi: 10.1002/hlca.201700182 This article is protected by copyright. All rights reserved. Abstract It has been suggested that the origin of regio- and stereoselectivity in Michael addi- tions 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 calcula- tions of a large number of conformers. Our protocol is based on density functional theory which we validated against explicitly correlated coupled cluster theory. The results are in agreement with the available experimental data, but illustrate that conformational preferences determined for one enamine are not readily transferable to other types of enamines. We found that an appropriate conformational sampling is inevitable to arrive Article at meaningful conclusions. Most prominently, s-cis and s-trans conformers are similarly stable for aldehyde- and ketone-derived enamines. The regio- and stereoselectivity in Michael additions of pyrrolidine-derived enamines can, however, not be explained by pronounced stability differences of the enamine isomers and conformers in general, dis- proving the thermodynamic-control hypothesis. The elucidation of the origin of regio- and stereoselectivity requires further theoretical investigations of the elementary steps of Michael additions. Introduction The reaction of aldehydes and ketones with nitroolefins to form γ-nitro-carbonyl compounds has become a playground in enantioselective organocatalytic chemistry involving enamine intermediates. The preferred chiral secondary amines are substituted pyrrolidines 1 with a myriad of substituents in the 2-position. A by no means complete or chronological collec- tion 2–36 is presented in Scheme 1 for illustration purposes. Catalytic reactions require conditions that favor enamine formation from the precursor carbonyl compounds and the pyrrolidine derivatives and/or cause cleavage of intermediates Accepted This article is protected by copyright. All rights reserved. Article Scheme 1: List of pyrrolidine derivatives that have been used successfully for enantioselective Michael additions to nitroolefins in catalytic or stoichiometric applications. Some formulae of selected pyrrolidine derivatives with peculiar structures, containing additional functional groups and/or stereogenic centers are shown, and acceptors other than nitroolefins are pre- sented. The examples are from a personal randomly collected pile of references in a folder of one of the authors (DS). In many cases, the authors used pyrrolidine derivatives with an absolute configuration opposite to the one shown throughout this paper. For a most recent collection of further examples see the first sixteen pages in Ref. [36]. Accepted This article is protected by copyright. All rights reserved. in the catalytic cycle (cf. acid additives). Stoichiometric reactions of preformed pyrrolidine enamines with nitroolefins occur upon mixing and lead to cyclobutanes 37 and/or dihydro- oxazines, 38 i.e (2+2)- and (4+2)-cycloadducts. The hydrolysis of these cycloadducts leads 16,22,37,38 to γ-nitro-carbonyl compounds upon acidic aqueous workup. There is a remarkable difference between the reactions of aldehydes and of ketones: no matter whether the Michael addition occurs in a catalytic or in a stoichiometric fashion, with a polymer-bound pyrrolidine-type catalyst, 39,40 in a ball mill, 41 microwave-assisted, 42 in the presence of an ionic liquid, 43 in protic, aprotic, polar or non-polar solvents, with acidic, basic or hydrocarbon side chains on the pyrrolidine moiety (see Scheme 1), as an inter- or intramolecular step of so-called domino sequences of reactions, 34,44 or with acceptors other than nitroolefins (see lower part of Scheme 1), a reversal of enantioselectivity between Article aldehydes and ketones has been observed. In the overall process the trigonal centers of the aldehyde or ketone α-carbonyl carbon and of the β-nitroolefin carbon couple with relative topicity lk in both cases, but the 1.4-induction by the stereogenic center in the 2-position of the pyrrolidine ring reverses: it is a [lk, lk -1.4]- process with aldehydes and a [lk, ul -1.4]- 45,46 process with ketones (see Scheme 2 ). Scheme 2: (Si /Si )-Coupling of nitroolefins with aldehydes and (Re /Re )-coupling 45 with ketones is induced by the same (S )-form 45 of 2-substituted pyrrolidines, to give rise to enantiomeric structural units of γ-nitro-aldehydes and γ-nitro-ketones, respectively, of so- 46 called syn -configuration. This reversal was first reported by Yamada et al. in 1969 in stoichiometric reactions of Accepted This article is protected by copyright. All rights reserved. proline-ester and -amide-derived enamines with acrylonitrile, acrylic esters, and methyl-vinyl 5 ketone without interpretation. Besides the reversal of enantioselectivity between aldehydes and ketones, there is another notable effect observed in additions of unsymmetrical ketones, such as 2-butanone, to ni- troolefins under catalysis by 2-substituted pyrrolidines: the higher substituted α-carbonyl carbon reacts regioselectively (see Scheme 3). Most of the numerous authors who have reported topicity reversals for aldehydes versus ketones in nitroolefin additions or regioselec- tivities (for the higher substituted α-carbonyl carbon atom of ketones) did not comment on possible reasons. According to the Curtin –Hammett principle, a fast equilibrium of intermediates that can eventually lead to different stereoisomers would not affect the product ratio. Instead, the Article product ratio is then entirely determined by the activation free energies of the reactions leading to the products. For the present case, however, it was argued that equilibration is too slow to allow for Curtin –Hammett kinetics14b and that thermodynamic control by pre- equilibrium conditions should be considered. 19 Note that the latter term does not refer to thermodynamic control of product formation, but instead implies a predominant role of stable intermediates. Hence, both, the enantioselectivity reversal and the regioselectivity, have been interpreted as resulting from preferred conformations (s-cis /s-trans ), configurations (E/Z), 10,14,19 or constitutions (di-/trisubstituted double bond) of the enamines involved. Due to repulsion by the R-group on the pyrrolidine ring the s-trans conformation of the aldehyde-derived enamine is more stable than the s- cis form (see Scheme 2), so that the Si -face is open for coupling with the nitroolefin. Barbas 10 and Alexakis 14 argued that the more stable arrangement of a ketone-derived enamine is s-cis because an sp2-CH-group is supposed to be sterically smaller (“flat”) than an sp3-hybridized carbon atom with its sub- stituents (cf. a freely rotating CH3-group), so that the Re -face would become the preferred topical face for the approach by a nitroolefin. It is speculated that “the equilibrium be- tween the enamine rotamers must be well displaced to one side”.14a The regioselectivity has Accepted This article is protected by copyright. All rights reserved. been discussed in terms of higher stability of the corresponding enamine with a trisubsti- tuted double bond14b,19 (Scheme 3). Besides the explicit discussions of these remarkable phenomena, a difference in the stability of the enamines is often assumed implicitly when suggesting transition state models in which the enamines adopt an s-trans or s-cis confor- mation. 2–4,6,9,11–13,15,17–20,24,25,27–32 Before turning back to the structures of enamines, the relative topicity of their reactions with nitroolefins, i.e. the coupling of the trigonal centers of these two reactants, must be briefly discussed in view of Alexakis ’ and Barbas ’ proposals. If we make the assumptions that (i ) the s-trans enamine from an aldehyde and a 2-substituted pyrrolidine and the corre- sponding s-cis enamine from a ketone are the most stable and the most reactive isomers, 10,14 (ii ) the electrophilic attack of the nitroolefin occurs from the less hindered anti -face with re- Article spect to the substituent on the pyrrolidine ring, and (iii ) the coupling of the trigonal centers follows the general topological rule, which one of our groups has put forward in 1981, 47 then the resulting approach trajectories A and B (Scheme 4) lead to the observed products (see also Scheme 2 and 3). With the observed identical stereochemical outcome of the numerous reactions involving so many different substituents R on the heterocycle (Scheme 1), 50,51 it is tempting to propose