Diisopropylethylamine Research Articles

A Homage to Siegfried Hünig and His Research.

Examples from different research areas of Siegfried Hünig are displayed to remind us that organic chemistry owes much more than Hünig's base to this exceptionally versatile and creative chemist. The main research lines dealing with the synthesis and physical characterization of new dyes, multistage redox systems, and organic metals will be presented as well as his contributions to enamine chemistry, the discovery of diimine as a hydrogenation agent, and nucleophilic acylation with trimethylsilyl cyanide, which are less well-known nowadays. In addition, exotic compounds with parallel C=C and N=N bonds were systematically studied in Hünig's group. Reflecting on the development of his research demonstrates both the importance of a systematic approach and how fruitful entirely unexpected results are if they meet a "well-prepared mind". During Hünig's academic career, teaching played an indisputable role. His efforts in modernizing the chemistry institute at Würzburg and his support of young researchers in the academic system in Germany are also highlighted.

Regioselective Sulfonylation/Acylation of Carbohydrates Catalyzed by FeCl3 Combined with Benzoyltrifluoroacetone and Its Mechanism Study.

A catalytic amount of FeCl3 combined with benzoyl trifluoroacetone (Hbtfa) (FeCl3/Hbtfa = 1/2) was used to catalyze sulfonylation/acylation of diols and polyols using diisopropylethylamine (DIPEA) or potassium carbonate (K2CO3) as a base. The catalytic system exhibited high catalytic activity, leading to excellent isolated yields of sulfonylation/acylation products with high regioselectivities. Mechanism studies indicated that FeCl3 initially formed [Fe(btfa)3] (btfa = benzoyl trifluoroacetonate) with twice the amount of Hbtfa under basic conditions in the solvent acetonitrile at room temperature. Then, Fe(btfa)3 and two hydroxyl groups of the substrates formed a five- or six-membered ring intermediate in the presence of the base. The subsequent reaction between the cyclic intermediate and a sulfonylation reagent led to the selective sulfonylation of the substrate. All key intermediates were captured in the high-resolution mass spectrometry assay, therefore demonstrating this mechanism for the first time.

Hunig's base catalyzed synthesis of new 1-(2,3-dihydro-1H-inden-1-yl)-3-aryl urea/thiourea derivatives as potent antioxidants and 2HCK enzyme growth inhibitors

A series of 1-(2,3-dihydro-1H-indan-1-yl)-3-aryl urea/thiourea derivatives (4a-j) have been synthesized from the reaction of 2,3-dihydro-1H-inden-1-amine (2) with various aryl isocyanates/isothiocyanates (3a-j) by using N,N-DIPEA base (Hunig's base) catalyst in THF at reflux conditions. All of them are structurally confirmed by spectral (IR, 1H &13C NMR and MASS) and elemental analysis and screened for their in-vitro antioxidant activity against DPPH and NO free radicals and found that compounds 4b, 4i, 4h &4g are potential antioxidants. The obtained in vitro results were compared with the molecular docking, ADMET, QSAR and bioactivity study results performed for them and identified that the recorded in silico binding affinities were observed in good correlation with the in vitro antioxidant results. The Molecular docking analysis had unveiled the strong hydrogen bonding interactions of synthesized ligands with ARG 160 residue of protein tyrosine kinase (2HCK) enzyme and plays an effective role in its inhibition. Toxicology studies have assessed the potential risks of 4a-j and inferred that all of them were in the limits of potential drugs. The conformational analysis of 4a-j inferred that the urea/thiourea spacer linking 2,3-dihydro-1H-inden-1-amino and substituted aryl units has facilitated all these molecules to effectively bind with ARG 160 amino acid residue present on the α-helix of the protein tyrosine kinase (2HCK) enzyme specifically on chain A of hemopoetic cell kinase. Collectively this study has established a relationship between the antioxidant potentiality and ligands binding with ARG 160 amino acid residue of chain A of 2HCK enzyme to inhibit its growth as well as proliferation of reactive oxygen species in vivo.

Unprecedented Nucleophilic Attack of Piperidine on the Electron Acceptor during the Synthesis of Push‐Pull Dyes by a Knoevenagel Reaction

AbstractAn unprecedented nucleophilic addition of piperidine on an electron acceptor, namely, 2‐(3‐oxo‐2,3‐dihydro‐1H‐cyclopenta[b]naphthalen‐1‐ylidene)malononitrile is reported. This unexpected behavior was observed during the synthesis of push‐pull dyes using the classical Knoevenagel reaction. To overcome this drawback, use of diisopropylethylamine (DIPEA) enabled to produce the expected dyes PP1 and PP2. The optical and electrochemical properties of the different dyes were examined. Theoretical calculations were also carried out to support the experimental results. To evidence the higher electron‐withdrawing ability of this electron acceptor, a comparison was established with two dyes (PP3 and PP4) comprising its shorter analogue.

Synthesis and In Vitro Antibacterial Activity of New C-3-Modified Carbapenems

New C-3 modified carbapenems have been synthesized by the AdNE-substitution of the enol phosphate group of 4-nitrobenzyl (4R)-3-[(diphenylphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylate by the corresponding thiols in acetonitrile in the presence of diisopropylethylamine (DIPEA). Mercaptoacetic acid methyl ester, furan-1-methylthiol, methyl N-(mercaptoacetyl)methioninate, and 2-(4-methylpiperazin-1-yl)-2-oxoethanethiol as thiols have been used. As a result, we have obtained the expected 4-nitrobenzyl esters of 3-[(2-methoxy-2-oxoethyl)thio]-, 3-[(2-furylmethyl)thio], 3-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]thio}, and 3-[((2-(S)-1-methoxy-4-methylthio-1-oxopropan-2-yl)amino)-2-oxoethyl]thio derivatives of (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid in yields of 67–87% after purification by column chromatography. The p-nitrobenzyl (pNb) esters of carbapenems have been converted to the corresponding acids by hydrogenolysis over 10% Pd/C in methanol. The antibacterial activity of the resulting carbapenems and their preceding pNb-esters has been studied against microorganisms of Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Streptococcus oralis. The compounds that have been found exceed in their activity the known drugs Meropenem and Cilapenem.

Facile Synthesis of α-N-Heterocyclic Carbene-Boryl Ketones from N-Heterocyclic Carbene-Boranes and Alkenyl Triflates.

Reactions of readily available alkenyl triflates with N-heterocyclic carbene (NHC)-boranes in the presence of diisopropyl ethyl amine provided about three dozen stable α-NHC-boryl ketones. Isolated yields were typically 40-56% for B-unsubstituted NHC-boranes (NHC-BH3), and somewhat lower for NHC-boranes with B-substituents (NHC-BH2R). The requisite alkenyl triflates can be made separately or prepared in situ from either ketones or alkynes. The experimental evidence supports a radical chain mechanism that involves the following: (1) addition of an NHC-boryl radical to the alkenyl triflate, (2) fragmentation to give the α-NHC-boryl ketone, SO2, and trifluoromethyl radical, and (3) hydrogen abstraction by trifluoromethyl radical from the starting NHC-borane to return the NHC-boryl radical along with trifluoromethane. Reactions 1 and 3 are both new and evidently rather fast.

Merging Visible‐Light Photoredox and Organoamine Catalysis for the C‐3 Difluoroalkylation of Quinoxalin‐2(1H)‐Ones

AbstractA mild and efficient protocol for visible‐light and organoamine cocatalyzed difluoroalkylation of quinoxalin‐2(1H)‐ones with functionalized difluoromethyl bromides has been developed. The transformation could be carried out at room temperature and gave a variety of C‐3 difluoroalkylated quinoxaline‐2(1H)‐ones in moderate to excellent yields. Moreover, mechanistic studies revealed that this transformation proceeded through a radical‐type debrominative coupling process with only need of catalytic amount of diisopropylethylamine (DIPEA). This strategy featured wide functional group tolerance, excellent regioselectivity, mild conditions, and operational simplicity.

Heptazine-based porous polymer for selective CO2 sorption and visible light photocatalytic oxidation of benzyl alcohol

Heptazine units with highly rich nitrogen sites were employed to fabricate a new porous organic polymer (POP-HE) via direct coupling of 2,5,8-trichloro-s-heptazine and 4,4′,4″,4‴-(ethene-1,1,2,2-tetrayl)tetraaniline with the mild base N, N′-diisopropylethylamine (DIPEA) in tetrahydrofuran (THF) solution. POP-HE displays good CO2 uptake capacity (50.6 cm3 g−1, 10 wt%, 1 bar/273 K) and highly selectively adsorptive separation of CO2 over CH4 under ambient conditions. Impressively, at 273 K, the predicted IAST selectivity of POP-HE is 47.0-13.4 for the natural gas mixture (CO2/CH4 = 5:95) at pressures varying from 0 to 1 atm. Meanwhile, the result of calculated band gap value based on Tauc plot motivated us to investigate its photocatalytic activity. POP-HE was applied as heterogeneous photocatalyst for visible light-induced selective oxidation of benzyl alcohol to benzaldehyde, and exhibited great conversion of 33.6% under irradiation of white LED light, which is much higher than that of g-C3N4. Moreover, POP-HE can be recycled up to three times without significant decrease in catalytic activity.

Catalytic Enantioselective Synthesis of 3,4,5‐Trisubstituted Isoxazoline N‐Oxides and Regioselective Synthesis of 3,4,5‐Trisubstituted Isoxazoles

An efficient catalytic asymmetric synthesis of 3,4,5‐trisubstituted isoxazoline N‐oxides and regioselective synthesis of 3,4,5‐trisubstituted isoxazoles has been described. α‐Nitrocinnamates and α‐nitrobenzophenones were utilized as Michael acceptors respectively. Hydroquinine derived thiourea in combination with cesium carbonate was effective for the synthesis of isoxazoline N‐oxides whereas stoichiometric di‐isopropylethylamine (DIPEA) was the best choice for isoxazole synthesis. In both cases a range of aryl and heteroaromatic groups was tolerated.

Regio/Site-Selective Benzoylation of Carbohydrates by Catalytic Amounts of FeCl3.

This work uncovered the regio/site-selective benzoylation of 1,2- and 1,3-diols and glycosides containing a cis-vicinal diol using a catalytic amount of FeCl3 with the assistance of acetylacetone. FeCl3 may initially form [Fe(acac)3] (acac = acetylacetonate) with excess acetylacetone in the presence of diisopropylethylamine (DIPEA) in acetonitrile at room temperature. Then, benzoylation was catalyzed by Fe(acac)3 with added benzoyl chloride in the presence of DIPEA under mild conditions as reported. This reaction produced selectivities and isolated yields similar to or slightly lower than the reaction using Fe(acac)3 as a catalyst in most cases. The result provides not only the green and convenient selective benzoylation method associated with the most inexpensive catalysts but also the possibility that the effects of various metal salts and ligands on the regioselective protection can be extensively investigated in future study to obtain the optimized catalytic system.

Synthesis and photophysical properties of azuleno[1′,2′:4,5]pyrrolo[2,1-b]quinazoline-6,14-diones: Azulene analogs of tryptanthrin

Azulene analog of tryptanthrin, azuleno[1′,2′:4,5]pyrrolo[2,1-b]quinazoline-6,14-dione, was successfully prepared by the condensation reaction of azuleno[2,1-b]pyrrole-2,3-dione with isatoic anhydride in the presence of sodium hydride or diisopropylethylamine (DIPEA). Its 2-halo derivatives were also obtained in high yields by the condensation reaction with 5-haloisatoic anhydrides in the presence of DIPEA. Reactivity toward electrophilic reagents was revealed by halogenation with N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) to afford 12-halo derivatives in high yields. Among the halo derivatives, 2-iodo and 12-iodo derivatives were reactive enough to afford phenylethynyl derivatives under Pd-catalyzed Sonogashira cross-coupling conditions. Within the phenylethynyl derivatives, only 12-phenylethynyl derivative was transformed into its 1,1,4,4-tetracyanobutadiene (TCBD) derivative by the reaction with TCNE. Amphoteric redox properties of the novel azulene analogs of tryptanthrin were characterized by spectroscopic and voltammetric analyses.

Synthesis of 4‐Substituted Pyrrolo[2, 3‐c]quinolines via Microwave‐Assisted C‐N Bond Formation

AbstractA metal‐free approach for the synthesis of 4‐substituted pyrolo[2, 3‐c]quinoline is reported in this paper. Synthesis of the target molecule started from easily available quinoline and was carried out in five steps. The fused pyrrolo‐quinoline unit was assembled using Bartoli indolization and the crucial final step involving microwave assisted C−N bond formation was carried out by reaction of 4‐chloro‐3H‐pyrrolo[2, 3‐c]quinolines and diverse aliphatic amines, in the presence of N, N’‐diisopropylethylamine (DIPEA). Final molecules were obtained in good yields even in the presence of additional bromine functionality on the quinolines, thus demonstrating the selectivity of the developed coupling procedure and possibility of increasing the product diversity.

Photo-induced reductive cross-coupling of aldehydes, ketones and imines with electron-deficient arenes to construct aryl substituted alcohols and amines

Umpolung reactions of C=X bonds (X = O, N) are valuable ways of constructing new C–C bonds, which are sometimes difficult to be constructed using traditional synthetic pathways. Classical polarity inversion of C=X bonds (X = O, N) usually requires air or moisture-sensitive and strong reducing agents, which limit the feasibility of substrate scope. Herein we describe a photo-induced reductive cross-coupling reaction of aldehydes, ketones and imines with electron-deficient arenes (aromatic nitriles) using fac-Ir(ppy)3 as a photocatalyst and diisopropylethylamine (DIPEA) as a terminal reductant under visible light irradiation. Mild conditions and high yields mean that this new polarity inversion strategy can be used with aryl-substituted alcohols and amines. Spectroscopic studies and control experiments have demonstrated the oxidative quenching of Ir(ppy)3* by electron-deficient arenes involved in the key step for the C–C bond formation.

Base‐Catalyzed Formal [3+2] Cycloaddition of Diazooxindoles with Oxazol‐5‐(4H)‐ones

In the presence of DIPEA (diisopropylethylamine), a formal [3+2] cycloaddition reaction between diazooxindoles and oxazol‐5‐(4H)‐ones takes place easily to give new 3‐(1H‐1,2,4‐triazol‐1‐yl)indolin‐2‐ones in 61–98 % yield. The structure of the target molecules was confirmed by single‐crystal X‐ray structure analysis.

Diisopropylethylamine-triggered, highly efficient, self-catalyzed regioselective acylation of carbohydrates and diols.

A diisopropylethylamine (DIPEA)-triggered, self-catalyzed, regioselective acylation of carbohydrates and diols is presented. The hydroxyl groups can be acylated by the corresponding anhydride in MeCN in the presence of a catalytic amount of DIPEA. This method is comparatively green and mild as it uses less organic base compared with other selective acylation methods. Mechanistic studies indicate that DIPEA reacts with the anhydride to form a carboxylate ion, and then the carboxylate ion could catalyze the selective acylation through a dual H-bonding interaction.

Synthesis of AEI/CHA intergrowth zeolites by dual templates and their catalytic performance for dimethyl ether to olefins

A series of SAPO molecular sieves were hydrothermally synthesized by employing mixture template of diethylamine (DEA) and N, N′-diisopropylethylamine (DIEA). The influences of template composition and crystallization time were investigated systematically. The results revealed that the crystalline products switched from SAPO-34/5 to SAPO-18/34 and finally to SAPO-18, the crystal size and acidity decreased with the increasing of DIEA ratio in the mixed template. Furthermore, crystallization time was also found to play a significant role in the particulate properties of the zeolites, the metastable AEI phase converted into more stable CHA phase, the Si content and acidity increased with the prolonged crystallization time. Dimethyl ether (DME) to olefins (DTO) reactions showed that the extending of the crystallization time was against the formation of light olefins, but favorable for the formation of light alkanes, due to the increase in CHA/AEI ratio, particle size and acidity may increase the probability of unfavorable hydrogenation of the target light olefins.

α-Azido Esters in Depsipeptide Synthesis: C–O Bond Cleavage during Azido Group Reduction

α-Azido esters, when treated with dithiothreitol (DTT)/diisopropylethylamine (DIPEA), undergo both azido group reduction to give α-amino esters and C-O bond cleavage to give triazoles. The extent of triazole formation depends upon leaving group ability. Some C-O bond cleavage via triazole formation was also found to occur when a resin-bound peptide, which contained a terminal α-azido ester group, was treated with DTT/DIPEA. C-O bond cleavage also took place when this peptide was treated with PPh3, PBu3, or PMe3; however, in these cases, C-O bond cleavage occurred via either triazole formation and/or hydrolysis of the ester bond in the iminophosphorane intermediate to give betaines. The mechanism that dominated for C-O bond cleavage depended upon the phosphine that was used for azido group reduction. C-O bond cleavage during reduction of the azido group in the peptide was minimized by performing the reduction with PBu3 in the presence of a symmetric anhydride derived from an amino acid in dry THF followed by the addition of water. Surprisingly, these conditions provided the amine as the major product, while the expected amide was formed as a minor product. These conditions were employed in an improved synthesis of an analogue of the cyclic lipodepsipeptide antibiotic daptomycin.

A Reinvestigation of the Ionic Liquid Diisopropylethylammonium Formate by NMR and DFT Methods.

The complex between diisopropylethylamine (DIPEA) and formic acid has been reinvestigated. Mixing the compounds in the ratio 1:1 leads to a phase separation in which the upper phase is DIPEA and the lower phase is the "ionic liquid" named DIPEF. A combined NMR and DFT study shows that the lower phase primarily is formic acid:formate and diisopropylammonium ions in the ratio 2:1 (acid:base) plus the formic acid dimer. Addition of more acid leads to more and more of the acid dimer. The proton transfer in the system is 65-80%. The structural picture presented in this paper is very different from that presented elsewhere. However, the present picture should be considered using acids and bases with a pKa difference less than 8. The formic acid content in the DIPEF ionic liquid causes desorption of the dye-sensitized solar cell (DSC) dye N719 from the photo anode, and DIPEF is therefore not a suitable electrolyte for DSCs.

ChemInform Abstract: An Unexpected Diastereoselective Synthesis of Novel Substituted Pyridines via One‐Pot, Four‐Component Reaction.

An efficient diastereoselective approach for the preparation of novel substituted pyridines has been developed through a one-pot, four-component reaction of easily available aromatic aldehydes, malononitrile, and 6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidine-4-one, in appropriate alcohols at reflux in the presence of diisopropylethylamine (DIPEA) as organic base catalyst. Unexpected products were obtained in high to excellent yields using a simple workup procedure. The products synthesized showed high diastereoselectivity, and the stereochemistry was confirmed by X-ray diffraction analysis.

A Novel Preparation of SAPO-18 Molecular Sieve with Enhanced Stability for Dimethyl Ether to Olefins

SAPO-18 molecular sieve is an important catalyst for dimethylether-to-olefins (DTO) reaction. Although the conventional synthesized SAPO-18 using N,N′-diisopropylethylamine (DIEA) alone exhibits nanoparticles and better catalytic performance due to the weaker diffusion resistance, its high cost of preparation and difficult separation of the powder limit the industrial process of this type of molecular sieve. Therefore, reducing the cost and increasing the particle size appropriately become the key issues for its practical application. In this study, SAPO-18 catalysts were synthesized hydrothermally using mixture of triethylamine (TEA) and a small amount of DIEA as templates. The results revealed that fairly pure SAPO-18 molecular sieve with particle size of approximately 1.0 μm could be synthesized under the initial gel composition as: xDIEA:(1.4−x)TEA: 1.0 Al2O3: 0.9 P2O5:0.6SiO2:50H2O, where x varies from 0.2 to 0.6. Furthermore, the catalytic performance for DTO reaction over the novel synthesized SAPO-18 catalysts showed higher selectivities to light olefins and much lower coke deposition than the conventional synthesized SAPO-18 using DIEA alone.