1,2‐Oxazine N‐Oxides as Catalyst Resting States in Michael Additions of Aldehydes to Nitro Olefins Organocatalyzed by α,α‐Diphenylprolinol Trimethylsilyl Ether

By combining enamines, derived from aldehydes and diphenylprolinol trimethylsilyl ether (the Hayashi catalyst), with nitroethenes ((D₆)benzene, 4‐Å molecular sieves, room temperature) intermediates of the corresponding catalytic Michael‐addition cycles were formed and characterized (IR, NMR, X‐ray analysis; Schemes 3–6 and Fig. 1–3). Besides cyclobutanes 2 , 1,2‐oxazine N‐oxide derivatives 3 – 6 and 8 have been identified for the first time, some of which are very stable compounds. It may not be a lack of reactivity (between the intermediate enamines and nitro olefins) that leads to failure of the catalytic reactions (Schemes 3–5) but the high stability of catalyst resting states. The central role zwitterions play in these processes is discussed (Schemes 1 and 2).     

Formation and stability of prolinol and prolinol ether enamines by NMR: delicate selectivity and reactivity balances and parasitic equilibria

Enamine key intermediates in organocatalysis, derived from aldehydes and prolinol or J?rgensen-Hayashi-type prolinol ether catalysts, were generated in different solvents and investigated by NMR spectroscopy. Depending on the catalyst structure, trends for their formation and amounts are elucidated. For prolinol catalysts, the first enamine detection in situ is presented and the rapid cyclization of the enamine to the oxazolidine ("parasitic equilibrium") is monitored. In the case of diphenylprolinol, this equilibrium is fully shifted to the endo-oxazolidine ("dead end") by the two geminal phenyl rings, most probably because of the Thorpe-Ingold effect. With bulkier and electron-withdrawing aryl rings, however, the enamine is stabilized relative to the oxazolidine, allowing for the parallel detection of the enamine and the oxazolidine. In the case of prolinol ethers, the enamine amounts decrease with increasing sizes of the aryl meta-substituents and the O-protecting group. In addition, for small aldehyde alkyl chains, Z-configured enamines are observed for the first time in solution. Prolinol silyl ether enamines are evidenced to undergo slow desilylation and subsequent rapid oxazolidine formation in DMSO. For unfortunate combinations of aldehydes, catalysts, solvents, and additives, the enamine formation is drastically decelerated but can be screened for by a rapid and facile NMR approach. Altogether, especially by clarifying the delicate balances of catalyst selectivity and reactivity, our NMR spectroscopic findings can be expected to substantially aid synthetically working organic chemists in the optimization of organocatalytic reaction conditions and of prolinol (ether) substitution patterns for enamine catalysis.     

Organocatalytic Asymmetric Conjugate Additions to Cyclopent‐1‐enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α‐amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent‐1‐enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona‐derived phase‐transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol % in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost‐effective preparation of pharmaceuticals.     

Secondary Amine‐Catalyzed Asymmetric γ‐Alkylation of α‐Branched Enals via Dienamine Activation

The direct and enantioselective γ‐alkylation of α‐substituted α,β‐unsaturated aldehydes proceeding under dienamine catalysis is described. We have found that the Seebach modification of the diphenyl‐prolinol silyl ether catalyst in combination with saccharin as an acidic additive promotes an S_N1 alkylation pathway, while ensuring complete γ‐site selectivity and a high stereocontrol. Theoretical and spectroscopic investigations have provided insights into the conformational behavior of the covalent dienamine intermediate derived from the condensation of 2‐methylpent‐2‐enal and the chiral amine. Implications for the mechanism of stereoinduction are discussed.     

Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.     

Organocatalyzed Michael Addition of Aldehydes to Nitro Alkenes – Generally Accepted Mechanism Revisited and Revised

The amine‐catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid‐catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4‐NO₂? C₆H₄OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol‐% (Tables 2–5). Fast formation of an amino‐nitro‐cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all‐trans‐isomers of cyclobutanes (Fig. 3) in a [2+2] cycloaddition. This reaction was shown, in one case, to be acid‐catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated amino‐nitro‐cyclobutanes with H₂O led to mixtures of 4‐nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6–9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C‐bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6 , which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13 . While the enantioselectivity of the reaction is generally very high (>97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Tables 1–5). Various acid‐catalyzed steps have been identified. The cyclobutanes 12 may be considered an off‐cycle ‘reservoir’ of catalyst, and the zwitterions 5 the ‘key players’ of the process (bottom part of Scheme 2 and Scheme 3).     

Amine‐Catalyzed Enantioselective 1,3‐Dipolar Cycloadditions of Aldehydes to C,N‐Cyclic Azomethine Imines

Amine‐catalyzed enantioselective 1,3‐dipolar cycloadditions of aldehydes to C,N‐cyclic azomethine imines were developed. The reactions between diversely substituted C,N‐cyclic azomethine imines and aldehydes proceeded smoothly in the presence of chiral prolinol silyl ether catalyst and gave the C‐1‐substituted tetrahydroisoquinolines in a highly stereoselective manner. These tetrahydroisoquinolines could be efficiently transformed to several other useful polycyclic frameworks.     

A general organocatalyzed Michael-Michael cascade reaction generates functionalized cyclohexenes

Although β-dicarbonyl compounds are regularly employed as Michael donors, intermediates arising from the Michael addition of unsaturated β-ketoesters to α,β-unsaturated aldehydes are susceptible to multiple subsequent reaction pathways. We designed cyclic unsaturated β-ketoester substrates that enabled the development of the first diphenyl prolinol silyl ether catalyzed Michael-Michael cascade reaction initiated by a β-dicarbonyl Michael donor to form cyclohexene products. The reaction conditions we developed for this Michael-Michael cascade reaction were also amenable to a variety of linear unsaturated β-ketoester substrates, including some of the same linear unsaturated β-ketoester substrates that were previously ineffective in Michael-Michael cascade reactions. These studies thus revealed that a change in simple reaction conditions, such as solvent and additives, enables the same substrate to undergo different cascade reactions, thereby accessing different molecular scaffolds. These studies also culminated in the development of a general organocatalyzed Michael-Michael cascade reaction that generates highly functionalized cyclohexenes with up to four stereocenters, in up to 97% yield, 32:1 dr, and 99% ee, in a single step from a variety of unsaturated β-ketoesters.     

An organocascade kinetic resolution

Products of a novel iminium-catalyzed oxa-Michael addition undergo a kinetic resolution by a subsequent enamine-catalyzed intermolecular reaction. This is a rare example of kinetic resolution by enamine catalysis and the first organocascade kinetic resolution. This resolution produces enantioenriched 2,6-cis-tetrahydropyrans and, notably, cascade products with absolute and relative configurations normally not observed using this diphenyl prolinol silyl ether. This resolution thus provides new insight into asymmetric induction in reactions employing this catalyst.     

Direct Access to Multifunctionalized Norcamphor Scaffolds by Asymmetric Organocatalytic Diels–Alder Reactions

A general organocatalytic cross‐dienamine activation strategy to produce chiral multifunctionalized norcamphor compounds having a large diversity in substitution pattern is presented. The strategy is based on a Diels–Alder reaction of an amino‐activated cyclopentenone reacting with most common classes of electron‐deficient olefins, such as nitro‐, ester‐, amide‐, and cyano‐substituted olefins, chalcones, conjugated malononitriles, CF₃‐substituted enones, and fumarates. The corresponding norcamphor derivatives are formed in good yield, excellent enantioselectivities, and with complete diastereoselectivity. Furthermore, it is demonstrated that quaternary stereocenters and spiro norcamphor compounds can be formed with high stereoselectivity. The present development provides a simple, direct, and efficient approach for the preparation of important norcamphor scaffolds.     

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

Reaction of 2‐phenylacetaldehyde with the Me₃Si ether of diphenyl‐prolinol, with removal of H₂O, gives a crystalline enamine ( 1 ). The HBF₄ salts of the MePh₂Si ether of diphenyl‐prolinol and of 2‐(tert‐butyl)‐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?HBF₄ 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‐of‐theory DFT calculations (Figs. 5 and 8, and Table 2). Delicate details including pyramidalization of trigonal N‐atoms, distortions around iminium C?N bonds, shielding of diastereotopic faces, and the π‐interaction 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.     

Cyclization vs. Elimination Reactions of 5‐Aryl‐5‐hydroxy 1,3‐Diones: One‐Pot Synthesis of 2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones

2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones were prepared in one step by cyclocondensation of 1,3‐diketone dianions with aldehydes. The use of HCl (10%) for the aqueous workup proved to be very important to avoid elimination reactions of the 5‐aryl‐5‐hydroxy 1,3‐diones formed as intermediates. The TiCl₄‐mediated cyclization of a 2‐aryl‐2,3‐dihydro‐4H‐pyran‐4‐one with 1,3‐silyloxybuta‐1,3‐diene resulted in cleavage of the pyranone moiety and formation of a highly functionalized benzene derivative.     

Catalytic Asymmetric Formation of δ‐Lactones from Unsaturated Acyl Halides

Previously unexplored enantiopure zwitterionic ammonium dienolates have been utilized in this work as reactive intermediates that act as diene components in hetero‐Diels–Alder reactions (HDAs) with aldehydes to produce optically active δ‐lactones, subunits of numerous bioactive products. The dienolates were generated in situ from E/Z mixtures of α,β‐unsaturated acid chlorides by use of a nucleophilic quinidine derivative and Sn(OTf)₂ as co‐catalyst. The latter component was not directly involved in the cycloaddition step with aldehydes and simply facilitated the formation of the reactive dienolate species. The scope of the cycloaddition was considerably improved by use of a complex formed from Er(OTf)₃ and a simple commercially available norephedrine‐derived ligand that tolerated a broad range of aromatic and heteroaromatic aldehydes for a cooperative bifunctional Lewis‐acid‐/Lewis‐base‐catalyzed reaction, providing α,β‐unsaturated δ‐lactones with excellent enantioselectivities. Mechanistic studies confirmed the formation of the dienolate intermediates for both catalytic systems. The active Er^III complex is most likely a monomeric species. Interestingly, all lanthanides can catalyze the title reaction, but the efficiency in terms of yield and enantioselectivity depends directly on the radius of the Ln^III ion. Similarly, use of the pseudolanthanides Sc^III and Y^III also resulted in product formation, whereas the larger La^III and other transition metal salts, as well as main group metal salts, proved to be inefficient. In addition, various synthetic transformations of 6‐CCl₃‐ or 4‐silyl‐substituted α,β‐unsaturated δ‐lactones, giving access to a number of valuable δ‐lactone building blocks, were investigated.     

Relative tendency of carbonyl compounds to form enamines

Equilibria between carbonyl compounds and their enamines (from O-TBDPS-derived prolinol) have been examined by NMR spectroscopy in DMSO-d(6). By comparing the exchange reactions between pairs (enamine A + carbonyl B → carbonyl A + enamine B), a quite general scale of the tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1,3-dioxan-5-one and 2,2-dimethyl-1,3-dioxan-5-one) show a greater tendency to afford enamines than many α-substituted aldehydes.     

Preparation of 5‐Aryl‐3‐Oxo‐δ‐Lactones by the Potassium Carbonate–Promoted Condensation of Aromatic Aldehydes and Ethyl Acetoacetate in Ethanol

5‐Aryl‐3‐oxo‐δ‐lactones (6‐aryl‐dihydro‐2H‐pyran‐2,4(3H)‐diones) were prepared by the potassium carbonate–promoted condensation of aromatic aldehydes and ethyl acetoacetate in absolute ethanol. Benzaldehyde and substituted benzaldehydes bearing an alkoxy group (2 or 3 position), a chlorine atom (2, 3, or 4 position), a nitro group (3 or 4 position), a cyano group (4 position), or an acetyl group (4 position) react in high yields under these conditions.     

Heteroatom‐Guided Torquoselective Olefination of α‐Oxy and α‐Amino Ketones via Ynolates

Ynolates were found to react with α‐alkoxy‐, α‐siloxy‐, and α‐aryloxyketones at room temperature to afford tetrasubstituted olefins with high Z selectivity. Since the geometrical selectivity was determined in the ring opening of the β‐lactone enolate intermediates, the torquoselectivity was controlled by the ethereal oxygen atoms. From experimental and theoretical studies, the high Z selectivity is induced by orbital and steric interactions rather than by chelation. In a similar manner, α‐dialkylamino ketones provided olefins with excellent Z selectivity. These products can be easily converted into multisubstituted butenolides and γ‐butyrolactams in good yield.     

Short communication: An alternative and effective catalyst for the silastannation of arylacetylenes with Me3SiSnBu3 at room temperature

The palladium‐catalyzed silastannation of acetylenes with tributyl(trimethylsilyl)stannane in the presence of triethylphosphite is reported for the first time. The reaction occurs at room temperature to give (Z)‐silyl(stannyl)ethenes in high yields. The protodemetallation of the resulting adducts with HCl–tetraethylammonium chloride is described first, which demonstrates that the reaction is governed only by the stability of a carbonium ion arising from the protonation to (Z)‐silyl(stannyl)ethenes rather than the hard and soft acid and base principle, i.e. the β‐cation stabilization effect (σ–π stabilization one) of a stannyl group in the carbonium ion is rather significant. Copyright © 2004 John Wiley & Sons, Ltd.     

Pd(0)‐Catalyzed Tandem One‐Pot Reaction of Biphenyl Ketones/Aldehydes to the Corresponding Di‐substituted Aryl Olefins

Synthesis of di‐substituted aryl olefins via a Pd(0)‐catalyzed cross‐coupling reaction of biphenyl ketones/aldehydes, tosylhydrazide, and aryl bromides (or benzyl halides) was developed. This methodology was achieved by one‐pot two‐step reactions involving the preparation of N ‐tosylhydrazones by reacting tosylhydrazide with biphenyl ketones/aldehydes, followed by coupling with aryl bromides (or benzyl halides) in the presence of Pd(PPh₃ )₄ and lithium t ‐butoxide to produce various di‐substituted aryl olefins in moderate to good yields.     

Light‐Driven Enantioselective Organocatalytic β‐Benzylation of Enals

A photochemical organocatalytic strategy for the direct enantioselective β‐benzylation of α,β‐unsaturated aldehydes is reported. The chemistry capitalizes upon the light‐triggered enolization of 2‐alkyl‐benzophenones to afford hydroxy‐o ‐quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael‐type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring‐opening.     

Asymmetric Synthesis of Tetrahydroquinolines through a [3+2] Cycloaddition Controlled by Dienamine Catalysis

A dienamine‐mediated enantioselective 1,3‐dipolar cycloaddition catalyzed by a chiral prolinol silyl ether catalyst has been developed. Removal of the benzamide group of the intermediates could furnish chiral C‐1 substituted tetrahydroisoquinolines (see scheme) in high yields and excellent stereoselectivities.