Catalyst-free aza-Michael Addition Research Articles

Catalyst-free aza-Michael addition of azoles to 3-hydroxypyridine-based quinone methides

We have studied the reaction of various 1H-azoles with 2-((dimethylamino)methyl)pyridin-3-ol and 2-bromo-6-(hydroxymethyl)pyridin-3-ol as precursors of ortho- and para-quinone methides of 3-hydroxypyridine series, correspondingly. This process proved to be convenient and efficient for the synthesis of hybrid heterocycles containing both pyridine and azole moiety - 2- and 6-[(azolyl)methyl]pyridin-3-ols. The protocol has been successfully extended to 2,6-bis-(hydroxymethyl)pyridine-3-ol, which is simultaneously ortho- and para-quinone methide precursor, involving both functionalities. Finally, two new heterocyclic systems 9Н-pyrazolo[5,1-b]pyrido[2,3-e][1,3]oxazine and 12H-benzo[4,5]imidazo[2,1-b]pyrido[2,3-e][1,3]oxazine were obtained as a result of cascade aza-Michael/intramolecular nucleophilic substitution reactions from 2-((dimethylamino)methyl)pyridin-3-ol and 2-(methylthio)benzimidazole or 3,4,5-tribromopyrazole, correspondingly.

Accelerated and Concerted Aza-Michael Addition and SuFEx Reaction in Microdroplets in Unitary and High-Throughput Formats.

The sulfur fluoride exchange (SuFEx) reaction is significant in drug discovery, materials science, and chemical biology. Conventionally, it involves installation of SO2 F followed by fluoride exchange by a catalyst. We report catalyst-free Aza-Michael addition to install SO2 F and then SuFEx reaction with amines, both occurring in concert, in microdroplets under ambient conditions. The microdroplet reaction is accelerated by a factor of ∼104 relative to the corresponding bulk reaction. We suggest that the superacidic microdroplet surface assists SuFEx reaction by protonating fluorine to create a good leaving group. The reaction scope was established by performing individual reactions in microdroplets of 18 amines in four solvents and confirmed using high-throughput desorption electrospray ionization experiments. The study demonstrates the value of microdroplet-assisted accelerated reactions in combination with high-throughput experimentation for characterization of reaction scope.

Study on the deformation capacity of multi-material 4D-printed LCE actuators

Liquid crystal elastomers (LCEs) have attracted much attention because of their large, reversible, and anisotropic deformation, fast response to various external stimuli and excellent mechanical properties. LCE ink was prepared by a catalyst-free aza-Michael addition chemistry. A multi-material four-dimensional (4D)-printed laminated LCE actuator including Polydimethylsiloxane (PDMS), conductive circuits and LCEs was fabricated by direct ink writing (DIW) technology. The influence of the input current and resistance values on the thermal effect of conductive circuits was studied. The functional relationship between the LCE actuator’s bending angle and printing parameters was obtained. The LCE actuator with a bending angle controllable at 0-410° was fabricated. This research is expected to bring about new possibilities in novel intelligent LCE devices with programmable stimuli-responsive properties and optimal actuation capacities.

Catalyst-Free Aza-Michael Addition of Azoles To 3-Hydroxypyridine-Based Quinone Methides

Catalyst-Free Aza-Michael Addition of Azoles To 3-Hydroxypyridine-Based Quinone Methides

Catalyst-free aza-Michael addition for C–N coupling in active pharmaceutical ingredient synthesis: Modelling of thermodynamic, reaction kinetics and mass transfer considerations

The present research study describes a combined experimental-modelling approach to examine the three-phased catalyst-free reversible aza-Michael addition of NH3 to the vinyl sulfone pharmaceutical intermediate in water. A series of batch experiments using gaseous NH3 were performed to thoroughly evaluate the impact of reaction temperature, NH3 pressure, starting material loading, and starting material quality on reactant solubility, convective mass transfer, and reaction kinetics in the system. A rigorous in-house mechanistic mathematical model was developed. All unknown parameters were determined through nonlinear regression fitting of experimental and simulated quantitative results. Aza-Michael addition kinetics and starting material equilibrium solubility were found to be highly temperature-dependent and had the biggest applicative effect on the maximum aza-Michael reaction rate, which was also confirmed by sensitivity analysis technique. Boundary diffusion of reactants was shown not to be the limiting controlling factor under the chosen operating conditions. Ammonia pressure was found to be important through its impact on the saturated concentration of NH3. Varying starting material load had impact solely on the time required to reach system equilibrium due to solute concentration limitations. Reverse NH3 elimination reaction kinetics was shown to be independent on changing all input operating conditions. The specific methodology grants a novel engineering approach for treating complex interrelated multi-phased heterogeneous compositions in active pharmaceutical ingredient reaction systems, which may be applied early in industrial process development, when a small continuous amount of raw data sets is available, the quantity of impurities varies, and simulations can aid intensification. It may be easily transferred to other similar environments for assistance in process development, optimization, and scale-up.

Solvent-free, catalyst-free aza-Michael addition of cyclohexylamine to diethyl maleate: Reaction mechanism and kinetics

The aza-Michael reaction is the addition of an amine to an electron deficient C=C double bond. This reaction is also used in the synthesis of precursors of polymeric networks. In this study, we paid attention to the kinetics and mechanism of the aza-Michael addition of cyclohexylamine (CHXA) to diethyl maleate (DEM) performed as a solvent-free, catalyst-free reaction and to concurrent reactions. In situ Raman spectroscopy, NMR spectroscopy and gas chromatography/mass spectrometry have shown the occurrence of three simultaneous reactions: (i) the aza-Michael addition of CHXA to DEM leading to diethyl 2-(cyclohexylamino)succinate, (ii) isomerization of DEM to diethyl fumarate (DEF), and (iii) the aza-Michael addition of CHXA to DEF formed by the reaction (ii). All of these reactions proceed with third order kinetics, first order in DEM or DEF and second order in CHXA. We propose a kinetic model that allows kinetic constants to be estimated. Furthermore, a numerical solution of the set of differential equations confirms the expected kinetic equations of reactions (i) and (ii) and gives values of rate constants comparable to the estimated ones. A DFT mechanistic study illustrates the structure of the reaction intermediates and transition states of all reactions and explains the contribution of the second amine molecule in the reaction mechanism.

Synthesis of thermo- and photo-responsive polysiloxanes with tunable phase separationviaaza-Michael addition

Two kinds of thermo- and photo-dual-responsive polysiloxanes were synthesized through a facile, effective, and catalyst-free aza-Michael addition.

From LCST to UCST: the phase separation behaviour of thermo-responsive polysiloxanes with the solubility parameters of solvents

Thermo-responsive polysiloxanes with tunable LCST- and UCST-type phase separation in mixed solvents were synthesised via a facile, highly efficient, catalyst-free aza-Michael addition of poly(aminopropylmethylsiloxane) to N-isopropylacrylamide.

High-sensitivity stimuli-responsive polysiloxane synthesized via catalyst-free aza-Michael addition for ibuprofen loading and controlled release

High-sensitive stimuli-responsive polysiloxanes with high sensitive respond to three changes of thermo-, pH-, and salinity were synthesized via a facile, highly efficient, catalyst-free aza-Michael addition of poly(aminopropylmethylsiloxane) with N-isopropylacrylamide.

Catalyst-free aza-Michael addition of azole to β,γ-unsaturated-α-keto ester: an efficient access to C–N bond formation

An efficient aza-Michael addition of azoles to β,γ-unsaturated-α-keto esters under room temperature conditions has been developed. In this conjugate addition, no additional catalyst is employed. Azole reacts with β,γ-unsaturated-α-keto ester smoothly to afford new C–N bond adducts in good to excellent yields (up to 96%).