Bifunctional Thiourea-tertiary Amine Research Articles

Asymmetric Organocatalytic Access to Spiro-fused Heterocyclic Compounds: E1cB Elimination Mediates Formal [4 + 2] Annulation.

Based on the intramolecular E1cB elimination, a novel [4 + 2] cyclization was designed and successfully applied to the asymmetric synthesis of polycyclic compounds which contained both chromane and spirooxindole moieties. In the reaction, regardless of the competitive pathways resulting from multireactive sites of starting materials, products could be obtained in good yields (up to 84%) and with excellent enantioselectivities (most 98 to >99% ee) under the catalysis of a chiral bifunctional thiourea-tertiary amine (1-5 mol %).

Construction of Enantioenriched 9H-Fluorene Frameworks via a Cascade Reaction Involving Remote Vinylogous Dynamic Kinetic Resolution.

The benzylic C-H group of α,α-dicyanoolefins from 3-substituted 1-indanones could be significantly activated via transmission along the aromatic system, thus enabling dynamic kinetic resolution via a traditional reversible deprotonation-protonation process. Enantioenriched 9-substituted 9H-fluorene frameworks were finally constructed through an asymmetric vinylogous Michael addition to nitroolefins, followed by a cascade cyclization and oxidative aromatization process, under the catalysis of a chiral bifunctional thiourea-tertiary amine.

Synthesis of Chiral Tertiary Amine–Thioureas Based on Spirobi­indane and Application in Catalytic Asymmetric Michael Addition Reaction

A series of novel chiral bifunctional tertiary amine–thioureas based on spirobiindane were designed and synthesized as organo­catalysts. One of these catalysts was shown to promote the asymmetric Michael addition reaction of 1,3-diphenylpropane-1,3-dione to nitro­olefins, affording the desired products in good yields (up to 95%) and enantioselectivities (up to 98% ee).

The Quinary Catalyst-Substrate Complex Induced Construction of Spiro-Bridged or Cagelike Polyheterocyclic Compounds via a Substrate-Controlled Cascade Process.

The asymmetric organocatalytic cascade reaction of cyclic β-oxo aldehydes to 2-hydroxycinnamaldehydes is developed. The bifunctional tertiary amine-thiourea catalyst was used in a rationally designed multiple catalysis where the asymmetric iminium catalysis and thiourea anion-binding catalysis were combined by carboxylate anion as a ternary catalytic system to form a quinary catalyst-substrate complex, providing an efficient protocol for the construction of enantioenriched spiro-bridged or cagelike polyheterocyclic compounds. The reuse of catalysts was also successfully realized.

Enantioselective Arylation of 3-Carboxamide Oxindoles with Quinone Monoimines and Synthesis of Chiral Spirooxindole-benzofuranones

A highly enantioselective arylation of 3-carboxamide oxoindoles with quinone monoimines is described. Various 3-aryl-3-carboxamide oxindoles with an all-carbon quaternary center were obtained in moderate to good yields (up to 99%) with moderate to good enantioselectivities (up to 98%) in the presence of a bifunctional thiourea-tertiary amine catalyst. The absolute configuration of one product was determined by an X-ray crystal structural analysis and the absolute configurations of the other products can be assigned by analogy. Moreover, several chiral spirooxindole-benzofuranones were synthesized from the 3-aryl-3-carboxamide oxindoles in moderate yields with moderate to good enantioselectivities.

Highly enantioselective aza-henry reaction of ketimines catalyzed by a chiral bifunctional thiourea-tertiary amine derived from quinine

We have developed a highly enantioselective aza-Henry reaction of aryl α-ketoester-derived N-Ts ketimines with a wide range of substrate scope by a simpler bifunctional thiourea-tertiary amine catalyst derived from quinine. A variety of ketimines were investigated and corresponding products were obtained in excellent yields (up to 99% yield) with excellent enatioselectivities (up to 99% ee).

Organocatalytic asymmetric Michael addition of pyrazoleamides to β-phthalimidonitroethene

A highly organocatalyzed asymmetric Michael addition reaction of pyrazoleamides to β-phthalimidonitroethene has been developed with a chiral bifunctional thiourea-tertiary amine as the catalyst. A wide range of γ-nitro β-amino amides were readily obtained in good to excellent yields with high diastereo- and enantioselectivities (up to 99% yield, 99% ee and >20:1 dr). The large scale experiment and transformation of the product have also been demonstrated.

Direct Asymmetric Aza-Vinylogous-Type Michael Additions of Nitrones from Isatins to Nitroalkenes.

Nitrones commonly act as 1,3-dipoles and electrophiles to furnish valuable isoxazolidine and N-hydroxyl products, respectively. They also can be converted to nitrone ylide species and undergo [3+2] formal cycloadditions to access N-hydroxyl pyrrolidines. Here, asymmetric direct aza-vinylogous-type additions of nitrones from isatins to nitroalkenes are presented, catalyzed by a bifunctional thiourea-tertiary amine, affording highly functionalized nitrones with extended carbon skeletons in excellent stereoselectivity. Notably, the nitrone moiety can be easily removed, thus furnishing the formal asymmetric α-functionalization of alkylamine-type substances. Moreover, the remaining electrophilic nitrone motif enables the subsequent annulations to construct spirocyclic products in high molecular complexity and diversity, which might have potential applications for drug discovery.

ChemInform Abstract: Organocatalytic Tandem Enantioselective Michael—Cyclization of Isatin‐Derived β,γ‐Unsaturated α‐Ketoesters with 3‐Hydroxy‐4H‐chromen‐4‐one or 2‐Hydroxy‐1,4‐naphthoquinone Derivatives.

The enantioselective formal [3 + 3] annulation reaction of isatin-derived β,γ-unsaturated α-ketoesters with 3-hydroxy-4H-chromen-4-ones or 2-hydroxy-1,4-naphthoquinone was successfully implemented under catalysis of quinine-derived bifunctional tertiary amine-thiourea catalysts. The efficient tandem Michael-cyclization has provided facile access to optically active spiro[oxindole-pyrano[3,2-b]chromenone] and spiro[oxindole-benzo[g]chromene-dione] derivatives in high yields with excellent diastereo- and enantioselectivities.

ChemInform Abstract: Organocatalytic Asymmetric Michael Addition of 3‐Pyrrolyloxindoles to β‐Phthalimidonitroethene for the Synthesis of 3,3′‐Disubstituted Oxindoles Bearing Contiguous 3,α,β‐Triamino Functionality.

An organocatalytic asymmetric Michael addition reaction of 3-pyrrolyloxindoles to β-phthalimidonitroethene has been developed with a bifunctional thiourea–tertiary amine as the catalyst. A range of 3,3′-disubstituted oxindoles bearing contiguous 3,α,β-triamino functionality could be obtained in high yields with good diastereoselectivities and high enantioselectivities (up to 99% yield, 99:1 dr, and 98% ee). The higher reactivity of β-phthalimidonitroethene compared to the reactivity of ordinary nitroalkenes in the reaction with 3-pyrrolyloxindoles was demonstrated by contrast experiments.

A Modular Strategy for the Direct Catalytic Asymmetric α-Amination of Carbonyl Compounds

Summary Direct catalytic methods for the stereoselective introduction of various non-protected amines at the carbon atom adjacent to a carbonyl group remain elusive in synthetic chemistry, even though they offer the most straightforward entry to chiral α-aminocarbonyl compounds. Here, we demonstrate that the in situ activation of hydroxylamines with trichloroacetonitrile enables direct transfer of their amine moieties to the C-3 position of oxindoles with rigorous enantiocontrol under the catalysis of chiral 1,2,3-triazolium salts. This protocol provides a powerful and practical means of accessing optically active 3-aminooxindoles with a wide array of alkyl and aryl substituents on nitrogen. Other carbonyl compounds, such as β-ketoesters and α-cyanoesters, can also be directly transformed into the corresponding α-aminocarbonyls with high enantioselectivity.

Enantioselective Nitroso Aldol Intramolecular Transesterification Cyclization Domino Reaction for Highly Effective Construction of Chiral Spirooxindoles

A catalytic asymmetric nitroso aldol intramolecular transesterification cyclization domino reaction between a C3 alkyl ester substituted oxindole and nitrosobenzene for the construction of chiral spirooxindoles was achieved in the presence of a chiral bifunctional tertiary amine thiourea catalyst and water. Optically active spirooxindoles were obtained in moderate yields (up to 76 %) and excellent enantioselectivities (up to 95 % ee).

ChemInform Abstract: Organocatalytic Asymmetric Mannich Reaction of 3‐Hydroxyoxindoles/3‐Aminooxindoles with in situ Generated N‐Boc‐Protected Aldimines for the Synthesis of Vicinal Oxindole—Diamines/Amino Alcohols.

A highly efficient asymmetric Mannich reaction of 3-monosubstituted 3-aminooxindoles/3-hydroxyoxindoles with in situ generated N-Boc-protected aldimines catalyzed by the chiral bifunctional thiourea–tertiary amine catalyst has been developed. Under mild reaction conditions, a series of structurally diverse vicinal oxindole–diamines/amino alcohols were smoothly obtained in moderate to high yields (up to 99%) with good to excellent diastereoselectivities and enantioselectivities (up to 95:5 dr and 96% ee). The synthetic application of this protocol was also demonstrated by the versatile transformation of chiral vicinal oxindole–diamine/amino alcohol into spirocyclic oxindoles.

Michael Addition-Lactonization of Arylacetyl Phosphonate to β,γ-Unsaturated α-Keto Esters for the Synthesis of Chiral syn-3,4-Dihydropyranones and 5,6-Dihydropyranones.

Catalytic asymmetric Michael addition-lactonization of arylacetyl phosphonates to β,γ-unsaturated α-keto esters by a chiral bifunctional thiourea-tertiary amine was established. Using the developed protocol, a range of optically pure syn-3,4-dihydropyranones were generated in good yields with good to excellent stereoselectivities (up to >20:1 dr and 99% ee). Meanwhile, when stoichiometric diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene were used as the base for the same reaction, a series of 5,6-dihydropyranones could be obtained in moderate to good yields (53-75% yield).

Organocatalytic Asymmetric Mannich Reaction of 3-Hydroxyoxindoles/3-Aminooxindoles with in Situ Generated N-Boc-Protected Aldimines for the Synthesis of Vicinal Oxindole-Diamines/Amino Alcohols.

A highly efficient asymmetric Mannich reaction of 3-monosubstituted 3-aminooxindoles/3-hydroxyoxindoles with in situ generated N-Boc-protected aldimines catalyzed by the chiral bifunctional thiourea-tertiary amine catalyst has been developed. Under mild reaction conditions, a series of structurally diverse vicinal oxindole-diamines/amino alcohols were smoothly obtained in moderate to high yields (up to 99%) with good to excellent diastereoselectivities and enantioselectivities (up to 95:5 dr and 96% ee). The synthetic application of this protocol was also demonstrated by the versatile transformation of chiral vicinal oxindole-diamine/amino alcohol into spirocyclic oxindoles.

Organocatalytic Asymmetric Michael Addition of 3-Pyrrolyloxindoles to β-Phthalimidonitroethene for the Synthesis of 3,3'-Disubstituted Oxindoles Bearing Contiguous 3,α,β-Triamino Functionality.

An organocatalytic asymmetric Michael addition reaction of 3-pyrrolyloxindoles to β-phthalimidonitroethene has been developed with a bifunctional thiourea-tertiary amine as the catalyst. A range of 3,3'-disubstituted oxindoles bearing contiguous 3,α,β-triamino functionality could be obtained in high yields with good diastereoselectivities and high enantioselectivities (up to 99% yield, 99:1 dr, and 98% ee). The higher reactivity of β-phthalimidonitroethene compared to the reactivity of ordinary nitroalkenes in the reaction with 3-pyrrolyloxindoles was demonstrated by contrast experiments.

ChemInform Abstract: A Quadruple Cascade Protocol for the One‐Pot Synthesis of Fully‐Substituted Hexahydroisoindolinones from Simple Substrates.

A new and efficient synthetic method to obtain fully-substituted hexahydroisoindolinones was developed by using bifunctional tertiary amine-thioureas as powerful catalysts. As far as we know, there is no efficient synthetic method developed toward fully-substituted hexahydroisoindolinones. The products were obtained in good yield and diastereoselectivity. The one-pot cascade quadruple protocol features readily available starting materials, simple manipulation, mild conditions and good atom economy.

A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates.

A new and efficient synthetic method to obtain fully-substituted hexahydroisoindolinones was developed by using bifunctional tertiary amine-thioureas as powerful catalysts. As far as we know, there is no efficient synthetic method developed toward fully-substituted hexahydroisoindolinones. The products were obtained in good yield and diastereoselectivity. The one-pot cascade quadruple protocol features readily available starting materials, simple manipulation, mild conditions and good atom economy.

Enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofurans using a Brønsted base/thiourea bifunctional catalyst.

The diastereo- and enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofuran derivatives (15 examples, up to 96 : 4 dr, 95 : 5 er) via intramolecular Michael addition has been developed using keto-enone substrates and a bifunctional tertiary amine-thiourea catalyst. This methodology was extended to include non-activated ketone pro-nucleophiles for the synthesis of 2,3-disubstituted indane and 3,4-disubstituted tetrahydrofuran derivatives.

ChemInform Abstract: Organocatalytic Regioselective Asymmetric Michael Addition of Azlactones to O‐Hydroxy Chalcone Derivatives.

AbstractThe regioselective asymmetric Michael addition of azlactones to o‐hydroxy chalcone derivatives proceeds with complete C‐2 regioselectivity by using quinine derived bifunctional thiourea tertiary amine as a catalyst.