Nitroaldol Products Research Articles

K2CO3/PG DES promoted transition metal free room temperature synthesis of nitroaldols and nitroolefins

In this work, we have described the use of K2CO3/Propylene Glycol (PG) deep eutectic solvent (DES) as green and efficient alternative to volatile organic solvents for the formation of a very important reaction intermediate i.e., nitroaldols via Henry Reaction. Interestingly, the DES acted both as the solvent as well as the catalyst without the assistance of external base, solvent and additive. Further, the obtained nitroaldol product was utilized for nitroolefin synthesis.

Synthesis of Nitro Alcohols by Riboflavin Promoted Tandem Nef‐Henry Reactions on Nitroalkanes

AbstractWe disclose a unprecedented riboflavin promoted Nef reaction of primary nitroalkanes coupled with a nitroaldol reaction. This tandem process allows the synthesis of functionalized nitro alcohols under mild reaction conditions. Secondary nitroalkanes fail to give the expected nitroaldol products although they are consumed under the reaction conditions.magnified image

∞3[Cu2(mand)2(hmt)]–MOF: A Synergetic Effect between Cu(II) and Hexamethylenetetramine in the Henry Reaction

∞3[Cu2(mand)2(hmt)]·H2O (where mand is totally deprotonated mandelic acid (racemic mixture) and hmt is hexamethylenetetramine) proved to be a stable metal–organic framework (MOF) structure under thermal activation and catalytic conditions, as confirmed by both the in situ PXRD (Powder X-ray diffraction) and ATR–FTIR (Attenuated total reflection-Fourier-transform infrared spectroscopy) haracterization. The non-activated MOF was completely inert as catalyst for the Henry reaction, as the accessibility of the substrates to the channels was completely blocked by H-bonded water to the mand entities and CO2 adsorbed on the Lewis basic sites of the hmt. Heating at 140 °C removed these molecules. Only an insignificant change in the relative ratios of the XRD facets due to the capillary forces associated to the removal of the guest molecules from the network has been observed. This treatment afforded the accessibility of nitromethane and various aldehydes (4-bromobenzaldehyde, 4-nitrobenzaldehyde, and p-tolualdehyde) to the active catalytic sites, leading to conversions up to 48% and selectivities up to 98% for the desired nitroaldol products. The behavior of the catalyst is solvent-sensitive. Protic solvents completely inhibited the reaction due to the above-mentioned strong H-bonds. Accordingly, very good results were obtained only with aprotic solvents such as acetonitrile and 1,4-dioxane. The synthesized MOF is completely recyclable as demonstrated for five successive cycles.

Synthesis of chiral salalen ligands and their in-situ generated Cu-complexes for asymmetric Henry reaction.

Chiral salalen ligands derived from (S)-proline and derivatives of salicyaldehydes were synthesized, and their in-situ generated Cu (II) complexes were evaluated in the asymmetric Henry reaction. Salalen ligand of different substituents on the phenyl moiety showed remarkable effect on the enantioselectivity of nitro-aldol product of 4-nitrobenzaldehyde and nitromethane. Cu (II) complex generated in situ with (S)-2-(tert-butyl)-6-((2-(((2-hydroxy-3-methylbenzylidene)amino)methyl)pyrrolidin-1-yl)methyl) phenol (10mol%) and Cu (OAc)2 .H2 O (10mol%), found to be better catalyst for nitro-aldol reaction between 4-nitrobenzaldehyde and nitromethane, gave corresponding product in 85% yield and 88% enantiomeric excess (ee) in isopropanol at 35°C after 40hours. The catalyst also used for the Henry reaction with different substituted benzaldehydes and corresponding products were obtained in 22% to 99% yields with 66% to 92% ee. Henry reaction of 4-nitrobenzaldehyde and prochiral nitroethane gave anti-selective product (dr=79/21; anti/syn) in a 91% yield with 80% ee.

Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients.

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

An indirect approach for encapsulation of chiral cobalt catalyst in microporous Zeolite-Y

Hierarchical structure in microporous zeolite-Y was introduced to overcome the diffusional restriction for direct encapsulation of chiral cobalt (II) Schiff base complexes. Mesopores with cylindrical channels of ∼5 nm dimensions were formed on post modification of zeolite-Y and was evident from the transmission electron microscopy and surface area analysis. Two different chiral cobalt (II) Schiff base complexes with minor variation in the ligand structure were constructed inside the mesoporous zeolite-Y cavity. The formation of the metal complexes was ascertained from the decrease in surface area and mesoporous pore volume. The two synthesized heterogeneous chiral cobalt Schiff base complexes were used as catalysts for asymmetric Henry reaction. At −35 °C, more than 80% ee with S-major nitro-aldol product was achieved within 3 h. Initial activation of the reaction mixture with microwave irradiation was found to have dramatic influence on the catalytic performance of the two catalysts.

Asymmetric Henry reaction catalyzed by chiral Cu(II) salalen and salan complexes derived from ( S )-proline

Single chiral center C1 symmetric salalen and salan ligands were synthesized from (S)-proline and their Cu(II) complexes were used as catalysts for the asymmetric Henry reaction between aromatic aldehydes and nitromethane/nitroethane. The reaction of 4-nitrobenzaldehyde and nitromethane using salalen ligand (10 mol%) and Cu(OAc)2·H2O (10 mol%) in isopropanol with 4-methoxyphenol (10 mol%) as an additive at room temperature, afforded the (S)-2-nitro-1-(4-nitrophenyl)ethanol in 82% yield and 81% ee. We have also generalized the catalysis of nitro-aldol reaction for a variety of substrates using nitromethane, gave 67–94% yields with 49–98% ee after 96–120 h. The absolute configuration of nitro-aldol product was governed by the use of the metal, Mn(III) complex of the ligand 2 gives (R)-enantiomer while Cu(II) complex of same ligand gives the (S)-enantiomer.

Synthesis and Characterization of Hybrid Mg(OH)2 and CeCO3OH Composite with Improved Activity Towards Henry Reaction

AbstractA new approach was developed for carbon–carbon bond formation via Henry reaction using a mixture of Mg(OH)2 and CeCO3OH (MgCe‐HDC). The MgCe‐HDC was synthesized using a co‐precipitation method and was characterized by SEM, XRD, FTIR, TGA‐DTA, and AFM. The effects of temperature, solvent, and the amount of catalyst were investigated to find the optimum reaction conditions. The highest yield of nitroaldol product, 92 %, was achieved over the reusable solid base catalyst in solvent‐free conditions at 20 °C.

Non-Hydrothermal Synthesis of Cu(I)-Microleaves from Cu(II)-Nanorods

Simultaneous transformation of structural morphology, material dimension and oxidation state of Cu (II)-nanorod was achieved with 3-(Triethoxysilyl)propylamine, (APTS) and 4-nitrobenzaldehyde (4-NB) under non-hydrothermal condition. Morphology of the modified Cu(I) material was found to resemble with the leaf of colocasea. Conversion of a Cu(II) based nono-material to a Cu(I)-based micro-material was confirmed from EPR, MAS- NMR and cyclic voltametric (CV) study. BET-surface area, Raman signal intensity and thermal stability of the Cu(I)-microleaf was greatly enhanced due to presence of Cu-O−Si linkage. Both the Cu(II) and Cu(I) material were found to be effective catalyst systems for nitro-aldol reaction as well as catalytic oxidation of methylene blue (MB) dye in presence of H2O2. High %yield (>90 %) of nitro-aldol product was obtained with both the catalyst. Catalytic reaction under microwave irradiation was found to bring substantial decrease in reaction time. Cu (II)-material was however not recyclable because of its soft nature. While the Cu(I)-microleaf was recycled upto four consecutive cycles. These materials were found to degrade methylene blue dye within 20 min in presence of H2O2 but in absence of light. Dark phase catalytic oxidation of MB was monitored both via UV-vis and cyclic voltametric study.

ChemInform Abstract: Trifunctional Squaramide Catalyst for Efficient Enantioselective Henry Reaction Activation.

A new class of trifunctional squaramide catalyst acting by means of multiple interactions has been found in a study of the Henry reaction. Enantiomerically enriched nitroaldol products were obtained in good yields and high enantioselectivities under mild conditions using one of the smallest amounts of organocatalyst reported so far for this reaction (0.25 mol%). The catalyst was able to generate hydrogen bonding and anion-π/hydrogen-π interactions with the substrates, responsible of the improvement in the reactivity and the enantioselectivity of this process. Computational calculations support a mechanistic hypothesis based on an anion-π effect, this being the first example reported in asymmetric catalysis.

Chiral Ni-Schiff Base Complexes inside Zeolite-Y and Their Application in Asymmetric Henry Reaction: Effect of Initial Activation with Microwave Irradiation

Chiral Ni(II)-Schiff base complexes synthesized inside the cavity of zeolite-Y were used as heterogeneous chiral catalyst for asymmetric Henry reaction. Synthesized catalysts were characterized using various spectrochemical and physicochemical techniques. Solid state NMR analysis has been used to confirm the internal location of the metal complexes. To the best of our knowledge MAS NMR has not been used to characterize chiral diamagnetic Ni2+-Schiff base complex inside zeolite-Y. The catalytic activities of the materials were dependent on temperature, solvent, and amount of catalyst. High catalytic transformation of aldehydes with nitromethane to nitro-aldol product (92% yield and 83% ee, S-isomer) was achieved at −10 °C. Initial activation of the reaction with microwave irradiation for 15 min leads to a substantial decrease in the reaction time in comparison to normal stirring. Heterogeneous catalysts were found to be advantageous over the homogeneous counterparts in terms of recyclability of the catalys...

Trifunctional Squaramide Catalyst for Efficient Enantioselective Henry Reaction Activation

AbstractA new class of trifunctional squaramide catalyst acting by means of multiple interactions has been found in a study of the Henry reaction. Enantiomerically enriched nitroaldol products were obtained in good yields and high enantioselectivities under mild conditions using one of the smallest amounts of organocatalyst reported so far for this reaction (0.25 mol%). The catalyst was able to generate hydrogen bonding and anion‐π/hydrogen‐π interactions with the substrates, responsible of the improvement in the reactivity and the enantioselectivity of this process. Computational calculations support a mechanistic hypothesis based on an anion‐π effect, this being the first example reported in asymmetric catalysis.magnified image

ChemInform Abstract: (S)‐Pyrrolidine‐Containing Chiral Manganese(III)—Salalen and —Salan Complexes as Catalysts for the Asymmetric Henry Reaction.

Chiral Mn(III)–salalen and –salan complexes derived from (S)-proline have been used as catalysts for the asymmetric Henry (nitro-aldol) reaction. We have also used this methodology for a variety of substrates to afford nitroaldol products in 40–94% yields with 25–92% ee.

(S)-Pyrrolidine-Containing Chiral Manganese(III)–Salalen and –Salan Complexes as Catalysts for the Asymmetric Henry Reaction

Chiral Mn(III)–salalen and –salan complexes derived from (S)-proline have been used as catalysts for the asymmetric Henry (nitro-aldol) reaction. We have also used this methodology for a variety of substrates to afford nitroaldol products in 40–94% yields with 25–92% ee.

Asymmetric Henry reaction of trifluoromethyl ketone and aldehyde using Cu(II)-complex: computational study offers the origin of enantioselectivity with varied size of catalysts

Chiral ligand 3 was synthesised from inexpensive and readily available (1R,2R)-(+)-1,2-diphenyl-1,2-diaminoethane and tert-butylbromoacetate. In situ generated complex obtained by the reaction of ligand 3 with copper triflate was used as catalyst for asymmetric Henry reaction of trifluoromethyl ketone having different substituents in the aromatic ring with nitromethane at 0 °C in presence of N,N-DIPEA as additive to give nitroaldol products in excellent enantioselectivity (ee upto 99%) with good yield (upto 80%). Ligand 3 with in situ generated complex with copper acetate was also found to be good catalyst for asymmetric nitroaldol reaction of aldehydes (ee up to 80–92%, yield up to 85%) with nitromethane at −5 °C. The DFT calculations performed with B3LYP and M06-2X functionals revealed the role of non-covalent interactions (such as π–π interaction and hydrogen bonding) and the steric factors in the catalyst play important role towards the enhancement of enantioselectivity.

ChemInform Abstract: Asymmetric Henry Reactions Catalyzed by Copper(II) Complexes of Chiral 1,2,4‐Triazine‐oxazoline Ligands: The Impact of Substitution in the Oxazoline Ring on Ligand Activity.

Abstract An enantiomerically pure 1,2,4-triazine-oxazoline ligand with an indanol-derived substituent in the oxazoline ring has been synthesized using Buchwald–Hartwig amination of 3-bromo-1,2,4-triazine. The catalytic efficiency of the ligand was estimated in the asymmetric nitroaldol (Henry) reaction of nitromethane with several aromatic and aliphatic aldehydes. The appropriate nitroaldol products were formed in good yields (up to 91%) and with up to 92% ee. In order to investigate the influence of the conformational rigidity and the additional stereocenter in the oxazoline ring on the catalytic activity of the ligand, a 1,2,4-triazine-oxazoline ligand with two phenyl substituents in the oxazoline ring was synthesized and tested in the asymmetric nitroaldol reaction.

Effect of ligand N,N-substituents on the reactivity of chiral copper(II) salalen, salan, and salalan complexes toward asymmetric nitroaldol reactions

The synthesis and effect of ligand N,N-substituents on the reactivity of chiral copper(II) salalen, salan, and salalan complexes toward nitroaldol reactions of nitromethane with various aldehydes have been described. The salan complexes exhibit superior results compared to the salalen and salalan complexes; the nature of the N,N-substituents is crucial for the enantioselectivity of the target nitroaldol products.

Asymmetric Henry reactions catalyzed by copper(II) complexes of chiral 1,2,4-triazine-oxazoline ligands: the impact of substitution in the oxazoline ring on ligand activity

An enantiomerically pure 1,2,4-triazine-oxazoline ligand with an indanol-derived substituent in the oxazoline ring has been synthesized using Buchwald–Hartwig amination of 3-bromo-1,2,4-triazine. The catalytic efficiency of the ligand was estimated in the asymmetric nitroaldol (Henry) reaction of nitromethane with several aromatic and aliphatic aldehydes. The appropriate nitroaldol products were formed in good yields (up to 91%) and with up to 92% ee. In order to investigate the influence of the conformational rigidity and the additional stereocenter in the oxazoline ring on the catalytic activity of the ligand, a 1,2,4-triazine-oxazoline ligand with two phenyl substituents in the oxazoline ring was synthesized and tested in the asymmetric nitroaldol reaction.

Effect of Nanospace Confinement on the Catalytic Activity and Stability of a Chiral Schiff Base Complex (CuL; L=C22 H24 N2 O4 ): A Combined Experimental and Theoretical Study.

Emerging trends in recyclable homogeneous chiral catalysts and their application in asymmetric synthesis are prompting a renewed interest in the field of catalysis as well as in industry. However, owing to fatal disadvantages of the homogeneous catalyst, they are not easily recoverable and recyclable. Herein, a comparison is made of the recyclability and stability of a homogeneous chiral CuII Schiff base complex of general formula CuL, in which L=C22 H24 N2 O4 , with that of a zeolite-Y-confined heterogeneous catalyst. On the basis of our experimental evidence, we demonstrate how self-decomposition and bimetallic formation disrupt the catalytic activity of a homogeneous catalyst. By exploiting the special structure of faujasite zeolite, self-decomposition of the chiral catalyst is fully controlled and efficiently used for the asymmetric nitroaldol reaction. The use of ionic liquid results in catalytic enhancement and provides a convenient way to recycle the homogeneous catalyst up to three cycles. When encapsulated in a cavity of faujasite by means of the "ship-in-a-bottle" synthesis method, it shows much better catalytic activity with enhanced enantioselectivity, recyclability, and stability. The heterogeneous catalyst is recycled up to nine cycles and retains the catalytic activity for a longer period of time relative to its homogeneous counterpart. The synthesized heterogeneous CuII complex provides the nitroaldol product with a maximum of 84 % yield and 87 % enantiomeric excess (ee; R isomer). Structural and reactivity differences between the homogeneous and heterogeneous chiral complexes are substantiated by density functional theory (DFT) calculations.

ChemInform Abstract: Asymmetric Synthesis of 1,2,3‐Trisubstituted Indanes via an Enantioselective Copper(II)‐Catalyzed Asymmetric Nitroaldol Reaction Followed by an Intramolecular Michael Cyclization.

Abstract Herein we describe a novel approach for the synthesis of a chiral 1,2,3-trisubstituted indane, a privileged substructure in medicinal chemistry, via an enantioselective nitroaldol reaction and subsequent intramolecular Michael addition. The asymmetric copper(II)-catalyzed reactions of ortho -formyl cinnamates, ortho -formyl cinnamonitrile, or ortho -formyl α-benzalketones with nitromethane were carried out using the C1-symmetric chiral secondary diamine L1 as a ligand, which afforded the nitroaldol products in high yields (up to 92%) and with good to excellent enantioselectivities (up to 97%) under mild conditions. The notable effect of the base and the dosage of nitromethane on the reaction are also discussed.