Isolation and X‐Ray Structures of Reactive Intermediates of Organocatalysis with Diphenylprolinol Ethers and with Imidazolidinones

Abstract

In memoriam A. I. Meyers 3 ), who paved the way for the use of heterocycles in stereoselective organic synthesis 4 )Reaction of 2-phenylacetaldehyde with the Me 3 Si ether of diphenyl-prolinol, with removal of H 2 O, gives a crystalline enamine (1). The HBF 4 salts of the MePh 2 Si ether of diphenyl-prolinol and of 2-(tertbutyl)-3-methyl-and 5-benzyl-2,2,3-trimethyl-1,3-imidazolidin-4-one react with cinnamaldehyde to give crystalline iminium salts 2, 3, and 4. Single crystals of the enamine and of two iminium salts, 2 and 3, were subjected to X-ray structure analysis (Figs. 1, 2, and 6), and a 2D-NMR spectrum of the third iminium salt was recorded (Fig. 7). The crystal and NMR structures confirm the commonly accepted, general structures of the two types of reactive intermediates in organocatalysis with the five-membered heterocycles, i.e., D, E (Scheme 2). Fine details of the crystal structures are discussed in view of the observed stereoselectivities of the corresponding reactions with electrophiles and nucleophiles. The structures 1 and 2 are compared with those of other diphenyl-prolinol derivatives (from the Cambridge File CSD; Table 1) and discussed in connection with other reagents and ligands, containing geminal diaryl groups and being used in enantioselective synthesis (Fig. 4). The iminium ions 3 and 4 are compared with N-acylated imidazolidinones F and G (Figs. 9, 12, and 13, and Table 3), and common structural aspects such as minimalization of 1,5-repulsion (the A 1,3 -effect), are discussed. The crystal structures of the simple diphenyl-prolinol · HBF 4 salt ( Fig. 3) and of Boc-and benzoyl-(tert-butyl)methyl-imidazolidinone (Boc-BMI and Bz-BMI, resp.; Figs. 10 and 11) are also reported. Finally, the crystal structures are compared with previously published theoretical structures, which were obtained from high-level-oftheory DFT calculations (Figs. 5 and 8, and Table 2). Delicate details including pyramidalization of trigonal N-atoms, distortions around iminium C¼N bonds, shielding of diastereotopic faces, and the pinteraction between a benzene ring and a Me group match so well with, and were actually predicting the experimental results that the question may seem appropriate, whether one will soon start considering to carry out such calculations before going to the laboratory for experimental optimizations. 2000 5 ) In this expanding field of organic chemistry, we have to refer to selected reviews and a few seminal original articles [1], and the enumeration of reactions given here cannot be complete. 6 ) Besides proline itself, derivatives such as a-methyl-proline, proline amides, a tetrazole [1r], sulfonylimides, and (aminomethyl)-pyrrolidines [1m] have been used as catalysts. 7 ) See also the use of chiral H-bond donors [1j], of Brønsted acids [1t], and of heterocyclic carbenes [1p] as catalysts. 8 ) See summary of a 1990 review article entitled Organic Synthesis -Where now? [2]. 9 ) Cf. the title In the Golden Age of Organocatalysis [1c]; Asymmetric Organocatalysis: From Infancy to Adolescence [1u]...

Kinetics and mechanism of organocatalytic aza-Michael additions: direct observation of enamine intermediates

“…NOE analysis showed the preference of the (s-E)-conformation of the C(sp 2 )-N bond in both diastereoisomers as depicted in Scheme 2. As kinetically controlled additions of nucleophiles to 2 often proceed with high diastereoselectivity, the formation of 3c as a 1 : 1 mixture of diastereomers may either be explained by a reversible reaction of the iminium ion 2 with the imidazole 1c or by deprotonation of the imidazolidinone moiety in the intermediate iminium ion in the a-position to the carbonyl group, as suggested by Seebach et al 11 The latter mechanism can be excluded under the conditions of this work because we have recovered the enantiopure imidazolidinone 5 after hydrolysis of 3c, confirming that the configuration of the asymmetric center of the imidazolidinone 5 has not been affected.…”

Stereochemical Models for Discussing Additions to α,β‐Unsaturated Aldehydes Organocatalyzed by Diarylprolinol or Imidazolidinone Derivatives – Is There an ‘(E)/(Z)‐Dilemma’?

“…In an equilibrating mixture of (E)-and (Z)- iminium ions, which are formed at different rates, the situation becomes more complex 18 ), as outlined in Scheme 5: If the formation of the iminium ions from enals Footnotes 12 and 14)). c) Epimerization at C(5) of an iminium ion through a zwitter-ionic intermediate; the known higher stability of analogous cis-vs. trans-1-acyl-imidazolidinones suggests that the equilibrium lies on the side of the cisisomer (see the discussion in [11]). d) Epimerization at C(2) has been observed upon reaction of imidazolidinones with electrophiles (see the discussion in [11]).…”

“…c) Epimerization at C(5) of an iminium ion through a zwitter-ionic intermediate; the known higher stability of analogous cis-vs. trans-1-acyl-imidazolidinones suggests that the equilibrium lies on the side of the cisisomer (see the discussion in [11]). d) Epimerization at C(2) has been observed upon reaction of imidazolidinones with electrophiles (see the discussion in [11]). e) Incorporation of an added carbonyl compound into the heterocycle (see Scheme in [15a]).…”

“…1) [10]. Moreover, structural and theoretical investigations of reactive intermediates in catalyses with diarylprolinol ethers have revealed that the facial selectivity, with which the derived enamines and iminium ions react, is probably not caused by a benzene ring but by the ether RO group and a meta-substituent on the benzene ring [11] [12], while it is likely that the benzene ring provides shielding in the corresponding fluoro derivative [13] (see Eqn. 2).…”

“…Finally, the more electrophilic iminium ions derived from 5-benzylimidazolidinones 10 ) appear to exist as an equilibrating mixture of conformers around the exocyclic benzylic ethane bond, in which the conformer with the Ph group over the heterocyclic ring (and not, as commonly assumed, over the p-system) generally prevails (according to DFT, NMR, and X-ray investigations) (Eqn. 3)) [11] [15] [16]. Here, we…”