Tandem Organocatalytic Functionalization and Fisher Indole Synthesis: A Greener Approach for the Synthesis of Indoles (original) (raw)
Angewandte Chemie International Edition, 2006
The aldehyde is arguably the most versatile carbonyl functionality. Furthermore, it is more active than any other carbonyl functionality toward a plethora of nucleophilic reactions. This unique combination of functional versatility and activity renders chiral aldehydes highly valuable intermediates in asymmetric synthesis. The emergence of numerous catalytic enantioselective reactions that involve aldehydes as either nucleophiles or electrophiles further enhances the synthetic value of chiral aldehydes. Enantioselective transformations of the readily available prochiral aldehydes are now emerging as a fundamentally important approach toward optically active aldehydes. In particular, great strides have been made in the development of enantioselective bond formations with the a-carbon atom of prochiral aldehydes with chiral enamine catalysis, enantioselective cycloadditions and Friedel-Crafts reactions with chiral immonium catalysis, and conjugate additions of aryl boronic acids and silyl nitronates to a,b-unsaturated aldehydes by chiral transition-metal catalysis and chiral phase-transfer catalysts, respectively. Despite its synthetic importance, the highly enantioselective and general conjugate addition of carbonyl donors to a,b-unsaturated aldehydes remains elusive, even with considerable efforts. [6] Herein, we wish to report significant progress toward the development of such a reaction with cinchona-alkaloid-derived organic catalysts.
Asymmetric Organocatalytic Cascade Reactions with α-Substituted α,β-Unsaturated Aldehydes
Angewandte Chemie International Edition, 2009
In the past decade, asymmetric aminocatalysis has become a fundamental synthetic strategy for the stereoselective construction of chiral molecules. The extraordinary pace of innovation and progress in aminocatalysis has been dictated mainly by the discovery of distinct catalytic activation modes which have enabled previously inaccessible transformations. To the same extent, the design of novel structural classes of organic catalysts has also ignited the field, enabling the activation of challenging types of carbonyl substrates. Whereas chiral secondary amines have proven invaluable for the asymmetric functionalization of aldehydes, primary amine catalysis has offered the unique possibility of participating in processes between sterically demanding partners. Therefore it overcomes the inherent difficulties of chiral secondary amines in generating congested covalent intermediates. Chiral primary amine based catalysts have been successfully used for the enamine activation of challenging substrates, such as a,a-disubstituted aldehydes and ketones. In 2005, Ishihara and Nakano [6a] additionally extended the potential of chiral primary amines to include the iminium ion activation of a-acyloxy-acroleins toward a stereoselective Diels-Alder process. [6] However, the use of a,b-disubstituted unsaturated aldehydes still represents an elusive and fundamental target for asymmetric aminocatalysis. This is particularly true when considering that an alternative asymmetric metal-catalyzed strategy for the functionalization of this compound class is also lacking. Herein we show that the chiral primary amine catalyst 1 provides an efficient solution to this longstanding and sought after issue, activating a,b-disubstituted enals toward a welldefined iminium/enamine tandem sequence (Scheme 1). Specifically, we developed organocascade reactions which combine two intermolecular and stereoselective steps involving a Michael addition/amination pathway. The described olefin aryl-amination and thio-amination processes afford straightforward access to valuable precursors of a-amino acids which have two adjacent stereogenic centers, one of which is quaternary, with very high optical purity.
Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones
Beilstein Journal of Organic Chemistry, 2012
The organocatalytic Michael addition of malonates to symmetric unsaturated 1,4-diketones catalyzed by thiourea and squaramide derivatives with Cinchona alkaloids afforded the formation of a new C–C bond in high yields (up to 98%) and enantiomeric purities (up to 93%). The absolute configuration of the product was suggested from comparison of the experimental and calculated VCD spectra of the reaction product 3a.
Enantioselective Michael addition catalyzed by cinchona alkaloids
Chirality, 2001
Enantioselective Michael additions of cyclic -ketoesters to methyl vinyl ketone catalyzed by cinchona alkaloids were studied. The results revealed that the induced enantioselectivity was significantly influenced by both the structure of the catalyst and that of the substrate. Interesting differences in the effect of the structure of the alkaloid on the enantioselectivity of this reaction in the case of three -ketoesters were discovered. High enantioselectivities were obtained in the reaction of ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate (up to 83 and 80%, respectively) at a low cinchona:reactant ratio of 1:500. As the specific rotations of the product enantiomers were unknown, they were determined by optical rotation and chiral GC measurements and verified by NMR experiments. Chirality 13: 614-618, 2001.
RSC Advances, 2012
Unless otherwise stated, all commercial reagents were used as received and all reactions were carried out directly under open air except the aldehydes that were distilled before using. All flash chromatography was carried out using 60-mesh silica gel and dry-packed columns. NMR spectra were registered in a Bruker Advance 400 Ultrashield spectrometer in CDCl 3 at room temperature, operating at 400.13 MHz (1H) and 100.63 MHz (13C{1H}). TMS was used as internal standard for 1 H-NMR and CDCl 3 for 13 C-NMR. Chemical shifts are reported in ppm referred to TMS. Chemical shifts are given in δ and coupling constants in Hz. Optical rotations were measured at room temperature on a Jasco P-1030 polarimeter. Racemic standard products were prepared using DL-proline as catalyst according to reported procedures in order to establish HPLC conditions. The absolute configuration of the reaction products was confirmed by HPLC and optical rotations, by comparison with reported data. 2. General procedure of -aminoxylation of aldehydes Catalyst 3 (2 mol%, 0.005mmol) and nitrosobenzene (1 eq., 0.25 mmol, 27.6 mg) were dissolved in 0.25 mL acetonitrile in a 1 mL vial. The mixture was cooled to 0 o C in an ice-water bath and the corresponding aldehyde (3 eq., 0.75 mmol) was added with stirring. When the limiting reactant had been completely consumed, 0.5 mL of EtOH and 1 eq. of NaBH 4 were added respectively at 0 o C. After 20 minutes, the reaction mixture was treated with saturated aqueous NH 4 Cl solution (5 mL) and extracted with dichloromethane (3 x 5 mL). The organic fraction was dried over MgSO 4 and concentrated under reduced pressure at room temperature. The crude alcohol was then purified by flash chromatography on silicagel, with hexane/ethyl acetate mixtures as eluent to give the pure product. All the spectroscopic data of the products matched those reported in the literature. 1-2 3. General procedure of -aminoxylation of ketones Catalyst 3 (5 mol%, 0.0125mmol) and the corresponding ketone (1 eq., 0.25 mmol) were dissolved in 0.25 mL acetonitrile in a 1 mL vial. The nitrosobenzene (3 eq., 0.75mmol, 83 mg) was dissolved in 0.25 mL of acetonitrile and was added by a syringe pump during 30 minutes. The mixture was stirred during the corresponding time (0.5h for 6a, 1h for 6b, 3h for 6c and 1h for 6d). When the reaction is completed, the solvent is evaporated and the crude of the reaction was dissolved in CH 2 Cl 2 (1.0 mL/0.3 mmols) and was treated with 3,5-dinitrobenzoyl chloride (2.0 eq., benzoyl chloride was used in the case of 2l) and DMAP (2.0 eq.). After reaction completion, the solution mixture was treated with saturated aqueous NH 4 Cl solution (10 mL) and extracted with dichloromethane (3 x 5 mL). The organic fraction was dried over MgSO 4 and concentrated under reduced pressure at room temperature. The crude ester was then purified by flash chromatography on silica gel with hexane/ethyl acetate mixtures as eluent to give the pure product, which was analyzed by NMR and HPLC. All the spectroscopic data of the products matched those reported in the literature. 3-4
Angewandte Chemie International Edition, 2009
Asymmetric organocatalysis provides an elegant and easy procedure to introduce chiral information into a substrate. [1] Thus, the challenging problem of developing efficient organocatalytic methods for C À C bond formations has been attractive to many chemists, and within the past few years new reaction protocols have been disclosed by numerous research groups. [1, 2] Within this context, the organocatalytic asymmetric conjugate addition of carbon nucleophiles to a,b-unsaturated carbonyl compounds is a well-documented strategy, which provides a direct and simple route for the synthesis of versatile, enantiomerically enriched building blocks. [3] However, the majority of reports to date are limited to simple nucleophiles, which lead only to the bond formation between two sp 3-hybridized carbon atoms. [4] In contrast, asymmetric conjugate addition of sp 2and sp-hybridized carbonbased nucleophiles remains a challenging task. [5, 6] Nowadays, new synthetic strategies offering high diversity and operational efficiency are becoming more evident. [7] In this respect, catalytic tandem reactions in an iterative manner are an especially robust model, which enables the efficient conversion of simple starting materials into a library of small molecules. [8] The general concept involves the formation of a chiral intermediate, which can be distinctly manipulated, through different transformations, to afford products containing divergent skeletal arrays. [9] Therefore, expanding the scope of the Michael reaction with respect to the nucleophilic species would represent an important advance. Herein we report the first highly enantioselective formal alkynylation, alkenylation, and homo-ketonylation using the concept of the conjugate addition of b-keto-heterocyclic sulfones 2 to cyclic a,b-unsaturated ketones 1, catalyzed by the 9-epi-amino cinchona alkaloid salt 3. We found that applying b-ketosulfone 2 as a reaction partner leads to a privileged addition intermediate 4, [10] which can be easily transformed into the corresponding trans-3-alkenyl cyclohexanols 5, b-alkynylketones 6, or the ketone products 7, depending on the applied reaction conditions (Scheme 1). [11] We began our investigations by examining the ability of the 9-amino-9-deoxyepiquinine TFA salt (3) [12] to promote the organocatalytic asymmetric conjugate addition of either b-keto-1-phenyl-1H-tetrazol-5-yl sulfone (2 a) or b-keto-benzothiazol-2-yl sulfone (2 b) to cyclohexenone (1 a), and some representative results are presented in Table 1. To our delight, by performing the reaction in toluene we were able to isolate the desired Michael adduct 4 aa in 80 % yield and 91 % ee (Table 1, entry 1). In attempts to improve the yield and enantioselectivity, we screened several solvents and different heterocyclic-substituted nucleophiles. Whereas Scheme 1. Organocatalytic asymmetric alkynylation, alkenylation, and homo-ketonylation reactions of enones.
Tetrahedron: Asymmetry, 2013
Simple and commercially available chiral 1,2-diamines were used as organocatalysts for the enantioselective conjugate addition of aldehydes, including a,a-disubstituted, to maleimides. The reaction was carried out in the presence of hexanedioic acid as an additive in aqueous solvents at room temperature. By employing (1S,2S)-and (1R,2R)-cyclohexane-1,2-diamine as organocatalysts, the corresponding Michael adducts bearing new stereocenters were obtained in high or quantitative yields with enantioselectivities of up to 92%, whereas the use of (1S,2S)-1,2-diphenylethane-1,2-diamine gave a much lower ee. Theoretical calculations were used to justify the observed sense of the stereoinduction.
Chemistry-a European Journal, 2009
The Michael reaction is generally regarded as one of the most efficient, atom-economical and powerful carboncarbon bond-forming reactions in organic chemistry. The development of organocatalytic asymmetric Michael reactions has been a significant research focus for several years. The direct asymmetric Michael addition of carbonyl compounds with nitroalkenes to produce enantiomerically enriched nitroalkanes has been described. Among these reactions, the Michael addition of unmodified aldehydes to nitroalkenes is of particular interest because of the valuable synthetic intermediates that are generated. Betancort and Barbas originally reported the organocatalytic asymmetric Michael addition of unmodified aldehydes to nitroalkenes with moderate to good enantioselectivities. [4a] Recently 3,3'bimorpholine derivatives, [4b] a chiral primary amine/thiourea catalyst [4c] and l-prolinol [4d] organocatalysts have been developed for the Michael addition of aldehydes to nitroolefins. Highly diastereo-and enantioselective conjugate additions that involve aldehydes were independently reported by the research groups of Wang, [4e] Hayashi, [4f] and Palomo [4g] using pyrrolidine sulfonamide (1), diphenylprolinol silyl ether and trans-4-hydroxyprolylamide (3) respectively. However, some of these reactions required a large excess of donor source (up to 10 equiv of aldehyde) and high catalyst loadings (between 10 and 20 mol %). Despite the excellent results achieved from previous studies, the development of an efficient organocatalyst for direct asymmetric Michael addition of aldehydes to various aryl-and alkylnitroalkenes with low catalyst loading remains challenging in asymmetric synthesis.