aza-Henry Reaction Research Articles

H-Bond Donor-Directed Switch of Diastereoselectivity in the Enantioselective Intramolecular Aza-Henry Reaction of Ketimines.

We report an H-bond donor controlled diastereoselective switchable intramolecular aza-Henry reaction of ketimines derived from α-ketoesters and 2-(2-nitroethyl)anilines, allowing facile access to chiral tetrahydroquinolines bearing an aza-quaternary carbon stereocenter, which are privileged scaffold for medicinal researches. While newly developed cinchona alkaloid derived phosphoramide-bearing quaternary ammonium salt C2 selectively give cis-adducts in up to 20 : 1 dr and 99 % ee, the corresponding urea-bearing analogue C8 preferentially give trans-adducts in up to 20 : 1 dr and 99 % ee.

Catalytic asymmetric synthesis of 1,2-diamines.

The asymmetric catalytic synthesis of 1,2-diamines has received considerable interest, especially in the last ten years, due to their presence in biologically active compounds and their applications for the development of synthetic building blocks, chiral ligands and organocatalysts. Synthetic strategies based on C-N bond-forming reactions involve mainly (a) ring opening of aziridines and azabenzonorbornadienes, (b) hydroamination of allylic amines, (c) hydroamination of enamines and (d) diamination of olefins. In the case of C-C bond-forming reactions are included (a) the aza-Mannich reaction of imino esters, imino nitriles, azlactones, isocyano acetates, and isothiocyanates with imines, (b) the aza-Henry reaction of nitroalkanes with imines, (c) imine-imine coupling reactions, and (d) reductive coupling of enamines with imines, and (e) [3+2] cycloaddition with imines. C-H bond forming reactions include hydrogenation of CN bonds and C-H amination reactions. Other catalytic methods include desymmetrization reactions of meso-diamines.

Asymmetric aza-Henry reaction toward trifluoromethyl β-nitroamines and biological investigation of their adamantane-type derivatives.

Amino acid-derived quaternary ammonium salts were successfully applied in the asymmetric aza-Henry reaction of nitromethane to N-Boc trifluoromethyl ketimines. α-Trifluoromethyl β-nitroamines were synthesized in good to excellent yields with moderate to good enantioselectivities. This reaction is distinguished by its mild conditions, low catalyst loading (1mol%), and catalytic base. It also proceeded on a gram scale without loss of enantioselectivity. The products were transformed to a series of adamantane-type compounds containing chiral trifluoromethylamine fragments. The potent anticancer activities of these compounds against liver cancer HepG2 and melanoma B16F10 were evaluated. Six promising compounds with notable efficacy have potential for further development.

Towards Chemoenzymatic Syntheses of Both Enantiomers of Phosphoemeriamine.

An enzyme-promoted addition of nitromethane to the appropriate phosphorylated imine (aza-Henry reaction) intended to be used in the synthesis of the title phosphoemeriamine, a phospha-analog of emeriamine (aminocarnitine), failed due to the tautomerization of the imine to the corresponding enamine. Nevertheless, both enantiomers of phosphoemeriamine were synthesized in high yield and enantiomeric purity using another chemoenzymatic approach, starting with a crucial step involving a CAL-B-mediated acetylation of the appropriate racemic precursor-diethyl 2-amino-3-dimethylaminopropylphosphonate-under kinetic resolution conditions. The enzymatic reaction was very efficient and provided each enantiomeric product in acceptable yield and with enantiomeric excess of 91 and 92%. The following appropriate chemical transformations led to the desired enantiomers of phosphoemeriamine in the form of phosphoemeriamine sesquichloride with enantiomeric excess up to 90%.

Cage escape governs photoredox reaction rates and quantum yields

Photoredox catalysis relies on light-induced electron transfer leading to a radical pair comprising an oxidized donor and a reduced acceptor in a solvent cage. For productive onward reaction to occur, the oxidized donor and the reduced acceptor must escape from that solvent cage before they undergo spontaneous reverse electron transfer. Here we show the decisive role that cage escape plays in three benchmark photocatalytic reactions, namely, an aerobic hydroxylation, a reductive debromination and an aza-Henry reaction. Using ruthenium(II)- and chromium(III)-based photocatalysts, which provide inherently different cage escape quantum yields, we determined quantitative correlations between the rates of photoredox product formation and the cage escape quantum yields. These findings can be largely rationalized within the framework of Marcus theory for electron transfer.

Asymmetric aza-Henry reaction of BOC-protected imines with zinc-FAM catalyst

Derivatives of ferrocenyl-substituted aziridinyl methanol (FAM) ligands were used with zinc metal for asymmetric aza-Henry (nitro-aldol) reaction of N-Boc protected imines with nitroalkanes. At optimized reaction conditions Zn-PFAM1 catalyst system with a variety of aromatic imines provided products in up to 77% ee and 88% yield. In addition, the reaction of N-Boc substituted imines with nitroethane also proceeded smoothly with moderate enantioselectivities and diastereoselectivities.

Aerobic oxidative C-C bond formation through C-H bond activation catalysed by flavin and iodine.

We report a metal/light-free aerobic oxidative C-C bond formation using sp3 C-H bond activation of tetrahydroisoquinolines catalyzed by flavin and iodine. The dual catalytic system enabled the oxidative Mannich and aza-Henry reactions by the cross-dehydrogenative coupling between two sp3 C-H bonds. Furthermore, the flavin-iodine-coupled catalysis was applied to the synthesis of pyrrolo[2,1-a]isoquinolines through the sequential oxidative 1,3-dipolar cycloaddition and dehydrogenative aromatization. The biomimetic flavin catalysis efficiently activates molecular oxygen; thus the non-metal dual catalytic system enables green oxidative transformation using molecular oxygen as an environmentally friendly terminal oxidant which generates benign water.

Molybdenum trioxide-decorated carbon nanotubes: An efficient and reusable catalyst for cross-dehydrogenative coupling-type aza-Henry reaction in aqueous media

Highly efficient and reusable heterogeneous molybdenum trioxide (MoO3) catalysts were prepared by anchoring MoO3 nanoparticles onto thiolated carbon nanotubes (CNTs). Transmission electron microscopy and X-ray diffraction analyses showed that the orthorhombic-structured MoO3 nanoparticles were successfully anchored onto the surface of the CNTs, and the average particle size was approximately 2.6 nm. We evaluated the applicability of the prepared catalyst in the cross-dehydrogenative coupling-type aza-Henry reaction of N-phenyl-1,2,3,4-tetrahydroisoquinoline with nitromethane. The catalyst showed very good reactivity in water; the used catalyst could be readily recovered by simple filtration and reused eight times with almost unchanged activity. The high reactivity and good reusability can be attributed to the high surface area of the nanosized catalysts and the strong adhesion between MoO3 and thiolated CNTs.

Second Generation of Near-Infrared Cyanine-Based Photocatalysts for Faster Organic Transformations.

A second generation of cyanine-based near-infrared photocatalysts has been developed to accelerate organic transformations. Cyanines were prepared and fully characterized prior to evaluation of their photocatalytic activities. Catalyst efficiency was determined by using two model oxidation and reduction reactions. For the aza-Henry reaction, cyanines bearing an amino group on the heptamethine chain led to the best results. For trifluoromethylation, the stability of the photocatalyst was found to be the key parameter for efficient and rapid conversion.

Hyper-Cross-Linked Porous Polymer Featuring B-N Covalent Bonds (HCP-BNs): A Stable and Efficient Metal-Free Heterogeneous Photocatalyst.

The first example of a porous polymer containing B-N covalent bonds, prepared from a tetraphene B-N monomer and biphenyl as a comonomer, is reported. It was prepared using the solvent knitting strategy, which allows the connection between the aromatic rings of the two monomers through methylene groups provided by an external cross-linking agent. The new polymer exhibited micromeso porosity with an SBET of 612 m2/g, high thermal stability, and potential properties as a heterogeneous photocatalyst, since it is very active in the aza-Henry coupling reaction (>98% of conversion and selectivity). After the first run, the catalyst improves its photocatalytic activity, shortening the reaction time to only 2 h and maintaining this activity in successive runs. The presence of a radical in this structure that remains stable with successive runs makes it a new type of material with potential applications as a highly stable and efficient photocatalyst.

Metal-Free Triazine-Based Polymeric Network for Solar-to-Chemical Conversion: An Insight into the Aza-Henry Reaction

Solar light-assisted chemical transformation is one of the most amicable pathways to achieving sustainability. With this aim, herein, we have developed a metal-free triazine-based donor–acceptor polymeric network (TMP-TAPA) as a photocatalyst for cross-dehydrogenative coupling reaction with an insight toward the aza-Henry reaction. Various characterization techniques including N2 physisorption, PXRD, FTIR, and solid-state NMR spectroscopy have been adopted to characterize the synthesized TMP-TAPA photocatalyst. The BET method demonstrated the existence of microporosity with a surface area of 296 m2/g in TMP-TAPA. Photocatalytic experiments have been performed under a 15 W table lamp, showing a conversion rate of 70% with >99% selectivity in the cross-dehydrogenative coupling reaction. The mechanistic pathway of the reaction has been thoroughly investigated, which was further corroborated by controlled studies in addition to scavenger and substrate studies. The proposed mechanistic pathway showed the importance of singlet oxygen species in the photocatalyzed cross-dehydrogenative aza-Henry reaction.

Secondary Orbital Effect Involving Fluorine is Responsible for Substrate-Controlled Diastereodivergence in the Catalyzed syn-aza-Henry Reaction of α-Fluoronitroalkanes.

The fluorine atom is a powerful, yet enigmatic influence on chemical reactions. True to form, fluorine was recently discovered to effect diastereodivergence in an enantioselective aza-Henry reaction, resulting in a very rare case of syn-β-amino nitroalkane products. More bewildering was the observation of an apparent hierarchy of substituents within this substrate-controlled behavior: Ph>F>alkyl. These cases have now been examined comprehensively by computational methods, including both non-fluorinated and α-fluoro nitronate additions to aldimines catalyzed by a chiral bis(amidine) [BAM] proton complex. This study revealed the network of non-covalent interactions that dictate anti- (α-aryl) versus syn-selectivity (α-alkyl) using α-fluoronitronate nucleophiles, and an underlying secondary orbital interaction between fluorine and the activated azomethine.

Enantioselective Synthesis of cis- and trans-Cycloheptyl β-Fluoro Amines by Sequential aza-Henry Addition/Ring-Closing Metathesis.

The synthesis of 7-membered carbocyclic β-fluoroamines is accomplished by a combination of the enantioselective aza-Henry reaction of aliphatic N-Boc imines and ring-closing metathesis. Use of reductive denitration gives both diastereomers of the β-fluoro amine carbocycle, each with high enantiomeric excess.

Unleashing the photocatalytic potential of a noble-metal-free heteroleptic copper complex-based nanomaterial for an enhanced aza-Henry reaction.

In this work, we fabricated a versatile and noble metal free copper-based heterogeneous photocatalyst, representing a green shift away from precious group metals such as Ir, Ru, Pt, which have been widely utilized as photocatalysts. The successfully synthesized and characterized copper photocatalyst was employed to establish a cross dehydrogenative coupling via C-H activation between tertiary amines and carbon nucleophiles. The highly efficient copper-based photocatalyst was characterized by numerous physico-chemical techniques, which confirmed its successful formation as well as its high activity. Inductively coupled plasma (ICP-OES) analysis revealed that the composite Cu@Xantphos@ASMNPs had a very high loading of 0.423 mmol g-1 of copper. The magnetic Cu@Xantphos@ASMNPs were utilized as a potential heterogeneous photocatalyst for the very facile and regioselective conversion of aryl tetrahydroqinoline to the respective nitroalkyl aryl tetrahydroisoquinoline in high yield using air as an oxidant and methanol as a green solvent with irradiation with visible light under mild reaction conditions. Additionally, the catalyst shows exceptional chemical stability and reusability without any agglomeration even after several cycles of use, which is one of the key features of this material, rendering it a potential candidate from economic and environmental perspectives.

Organocatalyst-mediated five-pot synthesis of (–)-quinine

In this work, the enantioselective total synthesis of (–)-quinine has been accomplished in a pot-economical manner using five reaction vessels. In the first pot, reactions involve the diphenylprolinol silyl ether-mediated Michael reaction, aza-Henry reaction, hemiaminalization, and elimination of HNO2 (five reactions), affording a chiral tetrahydropyridine with excellent enantioselectivity. In the second pot, five reactions proceed with excellent diastereoselectivity to afford a trisubstituted piperidine with the desired stereochemistry. A further five reactions are carried out in the last one-pot sequence.

Aza-Henry Reaction and Oxidation of 1,2,3,4-Tetrahydroisoquinolines on a Copper Nanocatalyst

Key words copper catalysis - oxidative coupling - aza-Henry reaction - tetrahydroiso-quinolines - quinolinones - nitromethylation

Oxidative α-Functionalization of 1,2,3,4-Tetrahydroisoquinolines Catalyzed by a Magnetically Recoverable Copper Nanocatalyst. Application in the Aza-Henry Reaction and the Synthesis of 3,4-Dihydroisoquinolones.

The oxidative α-functionalization of 2-aryl-1,2,3,4-tetrahydroisoquinolines (THIQs) promoted by a versatile heterogeneous nanocatalyst consisting of copper nanoparticles immobilized on silica-coated maghemite (CuNPs/MagSilica) has been accomplished. The methodology was successfully applied in the cross-dehydrogenative coupling (CDC) reaction of N-aryl THIQs and other tertiary amines with nitromethane as a pro-nucleophile (aza-Henry reaction) and the α-oxidation of THIQs with O2 as a green oxidant. Phosphite, alkyne, or indole derivatives were also shown to be suitable candidates for their use as pro-nucleophiles in the CDC reaction with THIQs. The catalyst, with very low copper loading (0.4-1.0 mol % Cu), could be easily recovered by means of an external magnet and reused in four cycles without significant loss of activity.

Zwitterionic imidazolium salt: an effective green organocatalyst in synthetic chemistry

Abstract An environmentally benign, stable yet efficient organocatalyst is highly desirable from the viewpoint of green chemistry and catalysis. Imidazole-based zwitterionic-type molten salts are a new type of organocatalysts with high catalytic application in various organic transformations with added advantage of room temperature ionic liquid (RTIL) property. Most importantly, these ionic-liquid catalysts are easily recyclable and subsequently reusable for multiple times without loss of significant catalytic efficiency. It has also been evident that C2–H of the imidazole has a vital role in catalyzing the reaction via electrophilic activation. Moreover, by changing the cations and/or anions, the properties of ILs can be tuned in many ways. In this article, the role of imidazolium zwitterionic molten salts as an organocatalyst for selective organic transformations including syn-selective aza-Henry reaction, Erlenmeyer reaction, synthesis of different heterocycles and their functionalization and regioselective ring-opening reactions has been elaborated chronically which will definitely be helping to the readers to explore this new class of organocatalyst for further applications.

Enhanced synergistic catalysis by a light-harvesting binary organic dyes system based on FRET for cross-dehydrogenative-coupling reaction

Rose bengal (RB) showed photocatalytic performance for cross dehydrogenative-coupling (CDC) reaction. However, single organic dye only absorbs light of specific wavelength which results a lower light utilization efficiency. In this paper, we proposed a simple and effective approach based on Förster resonance energy transfer (FRET), to improve the performance of RB through the incorporation of rhodamine 6G (Rh6G) into RB solution and constructing a binary dyes system rhodamine 6G-rose bengal (Rh6G-RB). The energy transfer efficiency and antenna effect of Rh6G-RB were up to 58% and 10.8, respectively. The synergistic effect of RB and Rh6G exhibited excellent catalytic performance under low concentration (10−5 M). The catalytic rate constant (kd) for Rh6G-RB reached 0.026 mol/(L·min) at 35 °C for aza-Henry reaction of tertiary amines with nitromethane, which was 2.03 and 5.52 times higher than that of single RB and Rh6G respectively. Moreover, the synergy of Rh6G and RB was also observed in Mannich reaction of N-tertiary amine derivatives with acetone, which all afforded the coupling products with good to excellent conversions. Finally, the Rh6G-RB system was also demonstrated an efficient visible light photoredox catalyst in continuous flow fashion. The research opened a new avenue and convenient for developing of binary or ternary organic dyes systems based on FRET and advance the application of these dye systems in photocatalytic organic synthesis.

Fluorine-induced diastereodivergence discovered in an equally rare enantioselective syn-aza-Henry reaction.

Attention to the aza-Henry reaction, particularly over the past two decades, has resulted in a wide range of effective catalysts for the enantio- and diastereoselective versions, driven by the versatility of the β-amino nitroalkane products as precursors to secondary amines and vic-diamines. Despite this broad effort, syn-diastereoselective variants are exceedingly rare. We have discovered a subset of α-fluoro nitroalkane additions that are characterized by an unusual crossover in diastereoselection, often delivering the products with high selectivities. We report here a rigorous comparative analysis of non-fluorinated and α-fluoro nitroalkanes in their additions to azomethines. Both homogeneous and heterogeneous catalysis were applied to probe the possibility that this phenomenon might be more widely operative in the enantioselective additions of fluorine-substituted carbon nucleophiles. A complete correlation within four categories is described that uncovered a clear trend, while revealing a dramatic and distinct reversal of diastereoselection that would normally go undetected.