aza-Henry Reaction Research Articles

Importance of Singlet Oxygen in Photocatalytic Reactions of 2-Aryl-1,2,3,4-tetrahydroisoquinolines Using Chalcogenorosamine Photocatalysts

Aerobic oxidation of 2-aryl-1,2,3,4-tetrahydroisoquinolines was achieved photocatalytically using chalcogenorosamine photocatalysts and LED irradiation. The photocatalytic aza-Henry reaction betwee...

Crystallization Does It All: An Alternative Strategy for Stereoselective Aza-Henry Reaction.

An efficient and experimentally straightforward method for the stereoselective synthesis of a variety of β-nitro-α-amino carboxylic acids via aza-Henry (nitro-Mannich) reaction of aldimines is disclosed, yielding either anti- or a rarely reported syn-configuration. The reaction operates directly on free glyoxylic acid and generates imine species in situ. Crystallization-controlled diastereoselectivity enables isolation of the target compounds in high enantio- and diastereomeric purities by a simple filtration.

L-tert-Leucine derived urea-ammonium salts: Efficient bifunctional phase transfer catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-derived N-Boc ketimines with α-aryl nitromethanes

An efficient way of aza-Henry reaction between isatin-derived N-Boc ketimines and α-aryl nitromethanes catalyzed by bifunctional phase transfer catalysts with a quaternary ammonium center derived from L-tert-Leucine has been developed. A series of 3-substituted 3-amino-oxindoles were constructed by this catalytic protocol in excellent yields (90–99%), with high enantioselectivities (83–95%) and diastereoselectivities (79:21–97:3). The asymmetric aza-Henry reaction of N-Boc amidosulfones and α-aryl nitromethanes were also investigated and gave the corresponding products in high to excellent yields (72–97%) with high enantioselectivities (up to 99%) and diastereoselectivities (up to >99:1).

Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions

The asymmetric aza-Henry reaction of N-Boc imines and nitroalkanes was realized in the presence of 10 mol % dinuclear zinc-AzePhenol catalysts under ambient conditions. A variety of nitroamines were obtained in good yields (up to 97%) with excellent enantioselectivities (up to 99% ee) and high diasteroselectivity (up to 14:1 dr). Our protocol combined the operational simplicity and mild reaction conditions, thus making the process amenable for technical applications.

Tuning the Ionicity of Stable Metal-Organic Frameworks through Ionic Linker Installation.

The predictable topologies and designable structures of metal-organic frameworks (MOFs) are the most important advantages for this emerging crystalline material compared to traditional porous materials. However, pore-environment engineering in MOF materials is still a huge challenge when it comes to the growing requirements of expanded applications. A useful method for the regulation of pore-environments, linker installation, has been developed and applied to a series of microporous MOFs. Herein, employing PCN-700 and PCN-608 as platforms, ionic linker installation was successfully implemented in both microporous and mesoporous Zr-based MOFs to afford a series of ionic frameworks. Selective ionic dye capture results support the ionic nature of these MOFs. The mesopores in PCN-608 are able to survive after installation of the ionic linkers, which is useful for ion exchange and further catalysis. To illustrate this, Ru(bpy)32+, a commonly used photoactive cation, was encapsulated into the anionic mesoporous PCN-608-SBDC via ion exchange. Photocatalytic activity of Ru(bpy)3@PCN-608-SBDC was examined by aza-Henry reactions, which show good catalytic performance over three catalytic cycles.

Enantiomeric O,O-dimenthyl α-iminotrifluoroethylphosphonates: Novel chiral building blocks in asymmetric synthesis of α-trifluoromethylated α-aminophosphonic acid derivatives

Based on reaction of (+)- or (-)-dimenthyl phosphite with trifluoroacetonitrile the synthesis of optically active O,O-dimenthyl α-iminotrifluoroethylphosphonates was developed. The synthetic potential of these novel chiral synthons was demonstrated by their easy diastereoselective functionalization (hydrogenation, proline-catalyzed Mannich reaction with acetone, aza-Henry reaction, aminoalkylation of electron-rich heterocycles) to afford optically active compounds bearing biorelevant (α-trifluoromethyl-α-amino)methylphosphonic residue.

Phosphorus corrole complexes: from property tuning to applications in photocatalysis and triplet-triplet annihilation upconversion.

Efficient triplet photosensitizers are important for fundamental photochemical studies and applications such as triplet-triplet annihilation upconversion (TTA UC), photoredox catalytic organic reactions and photovoltaics. We now report a series of phosphorus corrole compounds as efficient visible light-harvesting metal-free triplet photosensitizers. While the heavy-atom-free phosphorus corroles show absorption in the visible spectral region (centered at 573 nm) and have a decent triplet state quantum yield (Φ Δ = 49%), iodo-substitution on the corrole core induces red-shifted absorption (589 nm) and improves intersystem crossing significantly (Φ Δ = 67%). Nanosecond transient absorption spectra confirm triplet state formation upon photoexcitation (τ T = 312 μs) and the iodinated derivatives also display near IR phosphorescence in fluid solution at room temperature (λ em = 796 nm, τ p = 412 μs). Both singlet oxygen (1O2) and superoxide radical anions (O2 -˙) may be produced with the phosphorus corroles, which are competent photocatalysts for the oxidative coupling of benzylamine (the Aza Henry reaction). Very efficient TTA UC was observed with the phosphorus corroles as triplet photosensitizers and perylene as the triplet acceptor, with upconversion quantum yields of up to Φ UC = 38.9% (a factor of 2 was used in the equation) and a very large anti-Stokes effect of 0.5 eV.

An enantioselective aza-Henry reaction of trifluoromethyl ketimines catalyzed by phase-transfer catalysts

An enantioselective aza-Henry reaction of acyclic trifluoromethyl ketimines was performed using a bifunctional catalyst. The products were converted to diamines and imidazolidine-2-ones.

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.

Fluorine-Phenanthroimidazole Porous Organic Polymer: Efficient Microwave Synthesis and Photocatalytic Activity.

A porous polymer containing a fluorophenylphenanthroimidazole core was easily prepared via one-pot Suzuki-Miyaura cross-coupling reactions under microwave heating. These new metal-free polymers have demonstrated heterogeneous photocatalytic activity toward aza-Henry reaction with reasonable recyclability. Their preparation require a minimal workup to build porous networks with control over the apparent surface area and pore volume from suitable molecular building blocks containing 2-(1 H-phenanthro[9,10- d]imidazol-2-yl)-3,5-difluorophenol (PhIm-2F), as rigid and multitopic node, which afforded a conjugated porous polymer (CPP-PhIm-2F). A series of fluorinated ligands have shown their capability in the preparation of soluble and supported cationic Ru(bpy)2(F-phenanthroimidazole) complexes by reaction with Ru(bpy)2Cl2 and demonstrating a beneficial effect of two fluorine atoms on the photocatalytic effect.

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).

Isatin N-protected ketimines with nitromethane catalyzed by chiral binol linked monomeric macrocyclic Cu(II)–salen complex

Chiral Cu-1B generated in situ was used as an efficient catalyst for the synthesis of β-nitroamines in high yield (88%) with excellent enantioselectivity (ee up to 99%) at RT in absence of co-catalyst via asymmetric aza-Henry reaction of various isatin derived N-Boc ketimines with nitromethane. This catalytic system did not work well with other nitroalkanes under the above optimized reaction conditions. To examine this catalytic behaviour, quantum chemical DFT calculations were performed with the nucleophiles (CH2NO2− and CH3CHNO2−) for the conversion of 1a to 2a using macrocyclic Cu-1B complex. The DFT calculated results have shown that the reaction with CH2NO2− is more favourable than the corresponding CH3CHNO2−. The calculated activation barriers suggest that the reaction with CH2NO2− is ∼8.0 kcal/mol energetically favoured than CH3CHNO2−. This catalytic protocol was further used to obtain chiral β-diamines (a building block for pharmaceuticals) at gram scale. In order to elucidate the reaction mechanism of asymmetric aza Henry reaction kinetic experiments were performed with different concentrations of the catalyst Cu-1B, nitromethane and 1g as the representative substrate. The reaction of isatin N-Boc ketimine was first order with respect to the concentration of the catalyst and the nitromethane but did not depend on the initial concentration of the substrate. A possible mechanism for the aza Henry reaction was proposed.

Continuous Platform to Generate Nitroalkanes On-Demand (in situ) using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor.

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates, and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand is reported, using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction. A uniquely designed pipes-in-series plug flow tube reactor addresses a range of process challenges including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors in high selectivity, thus, completely avoiding isolation of potentially unsafe low molecular weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.

Hierarchical photocatalyst of In2S3 on exfoliated MoS2 nanosheets for enhanced visible-light-driven Aza-Henry reaction

Exploration of appropriate photocatalysts for visible-light-driven organic synthesis is of great importance. Here we design and construct a two-dimensional hierarchical In2S3/MoS2 composite as an excellent and reusable photocatalyst for Aza-Henry reaction. The dahlia-flower-like In2S3 nanostructures are homogeneously grown on both sides of the two-dimensional MoS2 nanosheets via a hydrothermal reaction. The as-prepared two-dimensional hierarchical In2S3/MoS2 composite exhibits higher photocatalytic performance than pure In2S3. The hierarchical heterostructure can enhance the light absorption in the visible region, facilitate the separation of the photo-induced electron–hole pairs, offer rich active sites for photoredox reactions and promote the generation and migration of the O2‐ and h+. Profiting from these compositional and structural features, the two-dimensional hierarchical In2S3/MoS2 composite shows remarkably enhanced photocatalytic performance and good stability.

Aza-Henry reaction with trifluoropiruvate ketimines

The aza-Henry addition of nitroalkanes at ketimines derived from trifluoropiruvate affords the corresponding α-nitro amines in up to 98% yields.

Copper-Mediated Reactions of Nitriles with Nitromethanes: Aza-Henry Reactions and Nitrile Hydrations.

In this study, the first aza-Henry reaction of nitriles with nitromethane in a CuI/Cs2CO3/DBU system is described. The process was conveniently and directly used for the synthesis of β-aminonitroalkenes 2a-x and tolerated aryl-, alkyl-, hetaryl-, alkenyl-, and alkynylnitriles. The resulting aminonitroalkenes 2 could be successfully transformed to the corresponding 2-nitroacetophenones, 2-amino-1-halonitroalkenes, 2-alkylaminonitroalkenes, or 3-nitropyridines. In the presence of H2O, the aza-Henry reaction turned the reaction path to the nitrile hydration to exclusively yield the amides 3a-s.

Pd-Catalyzed Three-Component Reaction of Anilines, Ethyl Vinyl Ether, and Nitro-Paraffin: Assembly of β-Nitroamines.

A novel palladium-catalyzed amination and nitration of ethyl vinyl ether for the construction of β-nitroamine derivatives under mild conditions has been developed. This transformation provides a new strategy for the installation of amino and nitro from aromatic amines and nitro-paraffin into alkenes. Morpholine resulted in the aza-Henry reaction, while DABCO led to the unexpected rearrangement.

Bifunctional Thiourea-Ammonium Salt Catalysts Derived from Cinchona Alkaloids: Cooperative Phase-Transfer Catalysts in the Enantioselective Aza-Henry Reaction of Ketimines.

An efficient enantioselective aza-Henry reaction of aryl α-ketoester-derived ketimines has been realized by using bifunctional thiourea-ammonium salt phase-transfer catalysts, which were derived from quinine. A variety of aryl α-ketoester-derived N-Ts ketimines were investigated, and the corresponding products were obtained in high to excellent yields (up to 99%) with good to high enantioselectivities (up to >99% ee).

Aza-Henry reaction with perfluoroalkylated cyclic ketimines

Aza-Henry reaction of 5-, 6- and 7-membered cyclic imines bearing perfluorinated group with nitroalkanes affords the corresponding nitro amines in up to 95% yield. Subsequent reduction of nitro group gives perfluoroalkyl-equipped vicinal diamines.

Journey Heading towards Enantioselective Synthesis Assisted by Organocatalysis.

This personal account summarizes the design of various organocatalysts derived from amino acids and Cinchona alkaloids and their applications in enantioselective carbon-carbon and carbon-nitrogen bond formation reactions. This account begins with the short description of the background of asymmetric organocatalysis. Various types of reactions like aldol reaction, Michael reaction, aza-Henry reaction, Morita-Baylis-Hillman reaction are described in this account.