Direct organocatalytic enantioselective α-aminomethylation of ketones

The scope and limitations of the direct organocatalytic asymmetric α-aminomethylation of ketones are disclosed. The proline-catalyzed classical Mannich reactions between unmodified ketones, aqueous formaldehyde and aromatic amines furnished the desired Mannich bases in high yield with up to >99% ee. Moreover, methyl alkyl ketones were regioselectively α-aminomethylated at the methylene carbon affording the corresponding Mannich products with up to >99% ee. In addition, the proline-catalyzed one-pot three-component reaction between p-anisidine, aqueous formaldehyde and 4,4-dimethyl-2-cycloxehen-1-one furnished the corresponding bicyclic aza-Diels–Alder adduct with >99% ee.     

Direct catalytic asymmetric mannich reactions of malonates and beta-keto esters

The first catalytic asymmetric direct Mannich reaction of malonates and beta-keto esters has been developed. Malonates react with an activated N-tosyl-alpha-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)(2) to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active beta-carboxylic ester alpha-amino acid derivatives. A series of different beta-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of beta-keto esters were used as the substrate. The reaction of different beta-keto tert-butyl esters with the N-tosyl-alpha-imino ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)(2) as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active beta-keto alpha-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-alpha-imino ester to the chiral bisoxazoline/Cu(II)-substrate intermediate are discussed.     

A convenient route to enantiopure 3-aryl-2,3-diaminopropanoic acids by diastereoselective Mannich reaction of camphor-based tricyclic iminolactone with imines

A novel and convenient route to the asymmetric synthesis of 2,3-diamino acids via Mannich reaction of iminolactones 1a and 1b with N-protected imines has been achieved in good yields (up to 95%) and high diastereoselectivity (dr: >99:1). Hydrolysis of the Mannich adducts under acidic conditions furnished the desired 3-aryl-2,3-diaminopropanoic acids in good yields (up to 85%) with excellent enantiomeric excesses (99% ee).     

三烯胺催化2,5-二烯酮的远端不对称Mannich反应

利用三烯胺机制活化环状2,5-二烯酮,对远端的不对称Mannich反应进行研究。用手性伯胺催化环状2,5-二烯酮原位生成三烯胺中间体,与苯甲醛和苯胺经三组分一锅法反应获得了7个新型的远端不对称Mannich加成产物,其结构经¹H NMR, ¹³C NMR和HR-MS(ESI)表征。在最佳反应条件下,收率达87%,对映选择性达78%。     

Acyclic chiral amines and amino acids as inexpensive and readily tunable catalysts for the direct asymmetric three-component Mannich reaction

The direct three-component asymmetric Mannich reaction catalyzed by acyclic chiral amines or amino acids is presented. Simple acyclic chiral amines and amino acids--such as alanine-tetrazole (9), alanine, valine, and serine-catalyzed the three-component asymmetric Mannich reactions between unmodified ketones, p-anisidine, and aldehydes with high chemo- and stereoselectivity, furnishing the corresponding Mannich bases with up to >99 % ee. This study demonstrates that the whole range of amino acids in nature, as well as nonproteogenic amino acid derivatives, can be considered in the design and tuning of novel, inexpensive organocatalysts for the direct asymmetric Mannich reaction.     

anti-Selective, catalytic asymmetric vinylogous Mukaiyama Mannich reactions of pyrrole-based silyl dienolates with N-aryl aldimines

Pyrrole-based silyl dienolates undergo asymmetric vinylogous Mukaiyama Mannich reactions with a series of N-aryl aldimines in the presence of the Hoveyda-Snapper amino acid-derived silver(I) catalysts. The Mannich products-α,β-unsaturated δ-amino-γ-butyrolactams-are typically obtained in high yields, excellent γ-site selectivities and anti-diastereoselectivities, and up to 80% enantioselectivity.     

Direct asymmetric three-component organocatalytic anti-selective Mannich reactions in a purely aqueous system

The direct three-component Mannich reactions of O-benzyl hydroxyacetone with p-anisidine and aromatic or aliphatic aldehydes in the presence of an L-threonine-derived catalyst afforded anti-1,2-amino alcohols in good-to-excellent yields and with enantioselectivities of up to 97%. This study is the first demonstration that direct three-component Mannich reactions can be promoted by a primary amino acid in water.     

Organocatalytic stereoselective mannich reaction of 3-substituted oxindoles

The asymmetric Mannich reaction of 3-substituted oxindoles and N-Boc imines was investigated for the first time, employing bifunctional thiourea-tertiary amine organocatalysts based on DPEN scaffold. The novel transformations exhibited high diastereoselectivities, and the Mannich adducts bearing adjacent quaternary and tertiary chiral centers were generally obtained in good to excellent enantioselectivities (up to 95% ee).     

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)‐Sitagliptin

In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona‐based‐squaramide‐catalyzed enantioselective Mannich reactions of diverse imines or α‐amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α‐amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling‐reagent‐free synthesis of the antidiabetic drug (?)‐(R)‐sitagliptin.     

Manipulation of Spiroindolenine Intermediates for Enantioselective Synthesis of 3‐(Indol‐3‐yl)‐Pyrrolidines

By manipulating the reactivity of spiroindolenine species, a sequential Michael/retro‐Mannich/Mannich reaction of ω‐indol‐3‐yl α,β‐unsaturated ketones was developed. In the presence of 10 mol % of a chiral phosphoric acid as the catalyst, a series of 3‐(indol‐3‐yl)‐pyrrolidines were synthesized in high yields (up to 91 %) with excellent stereoselectivities (up to 92 % ee, >19:1 d.r.). The products obtained here undergo diverse functional‐group transformations. The mechanistic proposal of this reaction is supported by DFT calculations.     

Highly enantioselective Mannich reactions of imines with tert-butyl acetoacetate catalyzed by squaramide organocatalyst

Highly enantioselective Mannich reactions of imines bearing a benzothiazole moiety with tert-butyl acetoacetate, catalyzed by a cinchona-based squaramide organocatalyst have been developed. The corresponding benzothiazole β-keto ester derivatives were obtained in high yields (up to 99%) and with excellent enantioselectivities (up to 98% ee).     

芳香胺参加的Mannich反应(Ⅱ)——用芳胺盐酸盐合成β-芳胺基酮

室温时芳香胺盐酸盐与甲醛、烷基芳基酮在HCl(气)-C₂H₅OH溶液中可以直接发生Mannich反应,生成β-芳胺基芳酮。这是继文献[1]之后,通过Mannich反应直接合成β-芳胺基芳酮的一个新方法。产率与文献[1]相近或略高。脂肪酮如丙酮、丁酮、甲基异丙基甲酮、甲基异丁基甲酮;环酮如环己酮、环庚酮,同样能发生上述反应。用HNMR谱测定了不对称酮与芳胺及甲醛进行Mannich反应所得到的β-芳胺基脂酮的结构。这一事实说明在室温及酸性条件下,可以用芳胺一步直接合成β-芳胺基酮,其反应机理仍符合一般公认的Mannich反应机理。     

An organocatalytic direct Mannich-cyclization cascade as [3+2] annulation: asymmetric synthesis of 2,3-substituted pyrrolidines

A new method for asymmetric synthesis of 2,3-substituted pyrrolidines from N-PMP aldimines and succinaldehyde via formal [3+2] cycloaddition is reported. This reaction involves proline catalyzed direct Mannich reaction and acid catalyzed reductive cyclization with high yields (up to 78%) and excellent enantioselectivities (up to >99%).     

Highly diastereoselective asymmetric Mannich reactions of 1,3-dicarbonyls with acyl imines

[reaction: see text] The cinchona alkaloids catalyze direct asymmetric Mannich reactions of cyclic 1,3-dicarbonyl compounds with acyl imines to afford alpha-quaternary carbon-bearing reaction products in yields of up to 98%, a diastereomeric excess of 90% or greater, and enantioselectivities up to 99% ee. A model is proposed that accounts for both the observed diastereoselectivities and the enantioselectivities for the reactions.     

Enantioselective organocatalytic Mannich reactions of ferrocenecarbaldehyde

The first examples of highly enantioselective organocatalytic Mannich reactions of ferrocenecarbaldehyde are disclosed. The reaction is catalyzed by simple amino acids and gives access to β-arylamino-β-ferrocenylketones in high yields and with up to 99% ee.     

Chiral-Directing-Group-Assisted Rhodium(III)-Catalyzed Asymmetric Addition of Inert Arene C−H Bond to Aldimines with Subsequent Intramolecular Cyclization

By using a chiral directing group, an asymmetric rhodium(III)-catalyzed C−H bond addition to aldimines followed by intramolecular cyclization to form chiral isoindolinones has been achieved (up to 68 % yield, up to 93 % ee). A three-component variant that resembles Mannich reaction was also realized (41 % yield, 83 % ee). Product elaborations and preliminary mechanistic studies were described.     

Ag-catalyzed asymmetric mannich reactions of enol ethers with aryl, alkyl, alkenyl, and alkynyl imines

An efficient catalytic and enantioselective method (up to >98% ee) for Mannich reactions between trimethylsilyl enol ethers derived from acetone and acetophenone and aryl, alkenyl, alkynyl, and alkyl imines is disclosed. A large variety of beta-amino ketones can be synthesized in the presence of 1-5 mol % AgOAc and an inexpensive and readily available amino acid-derived phosphine. All Ag-catalyzed asymmetric Mannich reactions can be run in undistilled THF and air. The o-anisyl activating groups of product amines can be removed in >70% isolated yield through a single vessel operation. The synthetic utility of the catalytic asymmetric method is illustrated by a four-pot synthesis of optically pure alkaloid (-)-sedamine.     

Brønsted acid-catalyzed, enantioselective, vinylogous Mannich reaction of vinylketene silyl N,O-acetals

Vinylketene silyl N, O-acetals undergo chiral phosphoric acid-catalyzed, vinylogous Mukaiyama-Mannich reactions with imines and afford delta-amino-alpha,beta-unsaturated amides in typically good yields, complete gamma-regioselectivity, and up to 92% ee with catalyst loadings of as low as 1 mol %. The Mannich products can be readily manipulated to furnish valuable synthetic intermediates.     

Anti-selective direct asymmetric Mannich reaction catalyzed by protease

The anti-selective direct asymmetric Mannich reaction of (hetero) aromatic aldehydes, 4-anisidine and O-protected hydroxyacetones for the synthesis of stereodefined anti-β-amino-α-hydroxycarbonyl compounds was developed. Protease type XIV from Streptomyces griseus (SGP) was used as a biocatalyst in 1,4-dioxane/phosphate buffer under mild reaction conditions. The excellent diastereoselectivities of up to >99:1 (anti/syn) and good enantioselectivities of up to 90% ee were achieved. This method provides a more sustainable complement to chemically catalyzed anti-selective direct asymmetric Mannich reactions.     

The asymmetric vinylogous Mannich reaction of dicyanoalkylidenes with alpha-amido sulfones under phase-transfer conditions

The stereoselective vinylogous Mannich reaction of dicyanoalkylidenes under phase-transfer catalytic conditions utilizing stable alpha-amido sulfones as imine precursors is presented; a rigid pyrrolidinium salt acts as the phase-transfer catalyst, giving access to the amino alkylated products in generally good yield and up to 95% ee.