Enantioselective synthesis of β-amino esters bearing a quinazoline moiety via a Mannich-type reaction catalyzed by a cinchona alkaloid derivative

The cinchona alkaloids catalyzed the direct asymmetric Mannich reactions of 1,3-dicarbonyl compounds with acyl imines to produce novel β-amino ester derivatives containing a quinazoline moiety.The adducts were isolated with high enantiomeric excess(up to 99%).     

Controlling Stereoselectivity in the Aminocatalytic Enantioselective Mannich Reaction of Aldehydes with In Situ Generated N‐Carbamoyl Imines

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N‐carbamoyl imines has been developed. Both α‐imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N‐tert‐butoxycarbonyl (Boc) or N‐carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configuration and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N‐carbamate‐protected imines are generated in situ from stable and easily handled α‐amido sulfones.     

Asymmetric aza-Henry reaction of fluoromethylated imines catalyzed by cinchona-derived bifunctional thiourea

The asymmetric aza-Henry reaction of fluoromethyl imines derived from 4-methoxyaniline with nitromethane was achieved under mild conditions using cinchona-derived bifunctional thiourea as catalyst. A series of chiral fluoromethylated β-nitroamines were synthesized and their transformation to optically pure 4-fluoromethyl-2-imidazolidones was illustrated.     

3-苯基异香豆冉酮衍生物的不对称Mannich反应研究

研究了双功能手性硫脲-叔胺催化剂催化的3-苯基异香豆冉酮衍生物与N-保护亚胺的不对称Mannich反应,高收率、高对映选择性(88%~98%)地合成了一系列具有连续季碳叔碳手性中心的新化合物,其结构经1HNMR和13C NMR表征。     

Novel bifunctional chiral thiourea catalyzed highly enantioselective aza-Henry reaction

A novel bifunctional chiral thiourea organocatalyst bearing a glycosyl scaffold and a tertiary amino group was synthesized starting from readily available alpha-D-glucose. This thiourea was proven to be an effective organocatalyst for the asymmetric aza-Henry reaction between N-Boc imines and nitromethane. The corresponding adducts were obtained in good to excellent yields with excellent enantioselectivities (up to 99.8% ee). In addition, the reaction of nitroethane also proceeded smoothly with excellent enantioselectivity, albeit with low to good diastereoselectivities.     

ZrCl4-catalyzed X-C/C-C bond formation for the geometric selective synthesis of (E)-β-iodo aza Morita-Baylis-Hillman (MBH) adducts

A geometric selective synthesis of (E)-β-iodo and β-alkyl vinyl ketones (MBH amino adducts) has been developed through a three-component Mannich-type reaction. The reaction was conveniently conducted by generating 3-iodo allenolate intermediates via the α,β-unsaturated addition of TMS-I to 3-butyn-2-one followed by a carbonyl addition onto N-aryl imines in the presence of ZrCl₄ catalyst. The resulting β-iodo allylic amines can be readily converted into β-alkyl Morita-Baylis-Hillman adducts by performing Suzuki and Kumada cross-couplings.     

Base-promoted diastereoselective addition of nitromethane and nitroethane to N-tert-butylsulfinyl imines: synthesis of N-protected α-amino acids and amino ketones

The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO₃ under solvent-free reaction conditions gave β-nitro amine derivatives with reasonable levels of diastereoselectivity. Enantioenriched N-tert-butylsulfinyl protected α-amino acids or α-amino ketones are accessible upon oxidation of the adducts derived from nitromethane or nitroethane, respectively.     

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).     

Bifunctional‐Thiourea‐Catalyzed Diastereo‐ and Enantioselective Aza‐Henry Reaction

Bifunctional thiourea 1 a catalyzes aza‐Henry reaction of nitroalkanes with N‐Boc‐imines to give syn‐β‐nitroamines with good to high diastereo‐ and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N‐protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N‐Boc‐imines gives R adducts as major products, whereas the same reaction of N‐phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP‐99,994.     

β-羰基酸与N-Boc靛红亚胺的脱羧Mannich反应合成3-氨基-3,3'-二取代氧化吲哚衍生物

以5 mol%辛克宁衍生的手性双功能硫脲叔胺为催化剂,β-羰基酸和N-Boc靛红亚胺为原料,经脱羧Mannich反应合成了14个3-氨基-3,3'-二取代氧化吲哚衍生物,收率73%~99%,其结构经1H NMR,13C NMR和HR-MS(ESI)确证。     

Facile synthetic pathway to β-hydroxy-β-trifluoromethyl imines and their derivatives

Synthetic approach based on mediated addition of different trifluoromethylated building blocks to selected acyclic imines giving access to a variety of β-hydroxy-β-trifluoromethyl imines are elaborated. A reaction between fluorinated adducts and imines proceed easily giving the condensation products in good to excellent yields. β-Hydroxy-β-trifluoromethyl imines possessing trifluoromethyl group and exhibiting strong intramolecular hydrogen bonding are great precursors to different β-hydroxy-β-trifluoromethyl ketones and alcohols.     

Enantioselective aza-Henry reaction using cinchona organocatalysts

The aza-Henry reaction of imines with nitromethane was promoted by cinchona alkaloids and modified cinchona bases to give optically active β-nitroamines. Various N-protected imines were examined as substrates. N-Boc, N-Cbz, and N-Fmoc protected imines gave the best results in terms of chemical yields and enantioselectivities. After a careful screening of a series of chiral bases, very good enantioselectivities up to 94% ee were obtained using a cinchona-based thiourea organocatalyst under the optimized reaction conditions.     

Nucleophilic phosphine-catalyzed [3+2] cycloaddition of allenes with N-(thio)phosphoryl imines and acidic methanolysis of adducts N-(thio)phosphoryl 3-pyrrolines: a facile synthesis of free amine 3-pyrrolines

In this report, the dipolarophile imines with easily removable activating group O,O-diethyl(thio)phosphoryl have been investigated in the nucleophilic phosphine-catalyzed [3+2] cycloaddition reaction of electron-deficient allenes. Under the catalysis of a tertiary phosphine, N-(thio)phosphorylimines readily undergo the [3+2] cycloaddition reaction with ethyl 2,3-butadienoate or ethyl 2,3-pentadienoate, affording the corresponding N-(thio)phosphoryl 3-pyrrolines in moderate to high yields with good diastereoselectivity. Removal of the (thio)phosphoryl group from the adducts has been successfully achieved via the acidic methanolysis of the P-N bond, giving the free amine 3-pyrrolines in fair to good yields without severe aromatization. Thus, a facile synthesis of N-unsubstituted 3-pyrrolines is established from the phosphine-catalyzed [3+2] cycloaddition reaction of allenes with imines.     

Bifunctional-thiourea-catalyzed diastereo- and enantioselective aza-Henry reaction

Bifunctional thiourea 1a catalyzes aza-Henry reaction of nitroalkanes with N-Boc-imines to give syn-beta-nitroamines with good to high diastereo- and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N-protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N-Boc-imines gives R adducts as major products, whereas the same reaction of N-phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP-99,994.     

Do reaction conditions affect the stereoselectivity in the Staudinger reaction?

The stereochemistry is one of the critical issues in the Staudinger reaction. We have proposed the origin of the stereoselectivity recently. The effects of solvents, additives, and pathways of ketene generation on the stereoselectivity were investigated by using a clean Staudinger reaction, which is a sensitive reaction system to the stereoselectivity. The results indicate that the additives, usually existed and generated in the Staudinger reaction, and the pathways of the ketene generation do not generally affect the stereoselectivity. The solvent affects the stereoselectivity. The polar solvent is favorable to the formation of trans-beta-lactams. The addition orders of the reagents affect the stereoselectivity in the Staudinger reaction between acyl chlorides and imines. The addition of a tertiary amine into a solution of the acyl chloride and the imine generally decreases the stereoselectivity, which is affected by the interval between additions of the acyl chloride and the tertiary amine, and the imine substituents. Our current results provide further understanding on the stereochemistry of the Staudinger reaction between acyl chlorides and imines and on the factors affecting the stereochemistry and also provide a method to prepare beta-lactams with the desired relative configuration via rationally tuning the stereoselectivity-controlling factors in the Staudinger reaction.     

α-Amido sulfones: novel substrates for the practical and efficient aza-Morita-Baylis-Hillman reaction under neat conditions

α-Amido sulfones undergo aza-Morita-Baylis-Hillman reaction efficiently with alkyl acrylates under neat conditions in the presence of DABCO at room temperature. These sulfones generate aryl imines in the presence of DABCO and form the corresponding adducts in high yields (85-94%) within 9-12 h.     

Enantioselective Michael addition of alpha-substituted cyanoacetates to vinyl ketones catalyzed by bifunctional organocatalysts

A highly enantioselective Michael addition of alpha-substituted cyanoacetates to vinyl ketones was accomplished in the presence of simple bifunctional thiourea/tertiary amine organocatalysts. A number of alpha-aryl or alkyl cyanoacetates have been successfully applied to give multifunctional compounds with an all-carbon-substituted quaternary stereocenter in excellent enantioselectivities (82-97 % ee) and yields (61-99 %). The optical pure adducts could be smoothly converted to variously structured beta(2,2)-amino acid esters. Moreover, an interesting reaction model involving multiple hydrogen-bonding interactions amongst the thiourea/tertiary amine catalyst and the reactants has been proposed based on the absolute configuration of the adduct and computational studies.     

Novel β-hydroxy-β-bis(trifluoromethyl) imines

Selected imines reacted with hexafluoroacetone non-catalyzed at ambient temperature to give β-hydroxy-β-bis(trifluoromethyl) imines in good to excellent yields. For the imines of acetone, pentan-3-one, and of cyclohexanone a 1:2 reaction was observed giving iminodiols; for N,N′-bis(propylidene)ethylene diamine an iminotetrol was formed. The diol derivative of N-isopropyl-propylidene amine could be deprotonated and O-methylated furnishing the respective ethers. Hexafluoropropylidene amine reacted with N-isopropyl-propylidene amine, unlike hexafluoroacetone, in a 1:1 manner to form an amino-imino alcohol which in its turn is able to add hexafluoroacetone. The imines of acetophenone, trifluoroacetone, 2,4-dimethyl-pentan-3-one, 2,6-dimethyl-cyclohexanone and of acetaldehyde added hexafluoroacetone to furnish β-iminoalcohols. A multifunctional β-hydroxy enaminone was obtained from 4-isopropylamino-pent-3-en-2-one. The molecular structures of the novel β-hydroxy-β-bis(trifluoromethyl) imines exhibit strong (R)N?HO hydrogen bonds.     

Direct Asymmetric α-Selective Mannich Reaction of β,γ-Unsaturated Ketones with Cyclic α-Imino Ester: Divergent Synthesis of Cyclocanaline and Tetrahydro Pyridazinone Derivatives

The first regio-, diastereo-, and enantioselective direct Mannich reaction of β,γ,-unsaturated ketones with benzoxazinone cyclic imines was enabled by Lewis acid/Brønsted base cooperative catalysis. The dinuclear zinc complex catalyzed the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, leading to corresponding adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–99 % ee range. These products were used as general intermediates in the synthesis of multisubstituted cyclocanalines, tetrahydro pyridazinones, and 4H-furo[2,3-b][1,4]benzoxazine derivatives.     

Highly Z/E stereoselective approach to β-iodo aza Morita-Baylis-Hillman adducts

A multicomponent reaction between sulfonyl-protected imines, magnesium iodide, and acetylenic esters or ketones is described. The resulting β-iodo aza Morita-Baylis-Hillman adducts were obtained in good yields and excellent Z/E stereoselectivities. The reaction showed good tolerance for sulfonyl protecting groups, as well as for acetylenic ketones and esters. This work presents the first synthetic approach to β-iodo aza Morita-Baylis-Hillman adducts.