Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides

Acyl azides were safely generated by using nitrous acid in water and reacted in situ within a flow system. The acyl azide was efficiently extracted into the organic phase containing an amine nucleophile for a highly enantioselective peptide coupling.

Investigations of Thermally-Controlled Mechanochemical Milling Reactions

Mechanochemical milling reactions gained a lot of attention lately as a green and highly efficient path towards various relevant materials. The control over the fundamental reaction parameters in milling procedure, such as temperature and pressure of the reactor, is still in infancy and the vast majority of milling reactions is done with controlling just the basic parameters such as frequency and milling media weight. We demonstrate here how the milling under controlled, prolonged and variable heating programs accomplished in a new milling reactor introduces a new level of mechanochemical reactivity beyond what can be achieved by conventional mechanochemical or solution procedures, and also reduces the time and energy costs of the milling process. The methodology is demonstrated on four varied systems: C–C bond forming Knoevenagel condensation, selective C–N bond formation for amide/urea synthesis, selective double-imine condensation, and solid-state formation of an archetypal open metal-organic framework, MOF-74. The potential of this methodology is best demonstrated on the one-pot selective synthesis of four complex products containing combinations of amide, amine or urea functionalities from the same and simple acyl azide and diamine reactants. Principal control over this enhanced reactivity and selectivity stemmed from the application of specific heating regimes to mechanochemical processing accomplished by a new, in-house developed mechanochemical reactor. As even the moderate increase in temperature strongly affects the selectivity and the rate of mechanochemical reactions, the results presented are in line with recent challenges of the accepted theories of mechanochemical reactivity.

Investigations of Thermally-Controlled Mechanochemical Milling Reactions

Mechanochemical milling reactions gained a lot of attention lately as a green and highly efficient path towards various relevant materials. The control over the fundamental reaction parameters in milling procedure, such as temperature and pressure of the reactor, is still in infancy and the vast majority of milling reactions is done with controlling just the basic parameters such as frequency and milling media weight. We demonstrate here how the milling under controlled, prolonged and variable heating programs accomplished in a new milling reactor introduces a new level of mechanochemical reactivity beyond what can be achieved by conventional mechanochemical or solution procedures, and also reduces the time and energy costs of the milling process. The methodology is demonstrated on four varied systems: C–C bond forming Knoevenagel condensation, selective C–N bond formation for amide/urea synthesis, selective double-imine condensation, and solid-state formation of an archetypal open metal-organic framework, MOF-74. The potential of this methodology is best demonstrated on the one-pot selective synthesis of four complex products containing combinations of amide, amine or urea functionalities from the same and simple acyl azide and diamine reactants. Principal control over this enhanced reactivity and selectivity stemmed from the application of specific heating regimes to mechanochemical processing accomplished by a new, in-house developed mechanochemical reactor. As even the moderate increase in temperature strongly affects the selectivity and the rate of mechanochemical reactions, the results presented are in line with recent challenges of the accepted theories of mechanochemical reactivity.

Advancing the Reactivity and Selectivity in Covalent and Coordination Mechanochemistry by Thermally-Controlled Milling

Milling under controlled and variable heating programs introduces a new level of mechanochemical reactivity beyond what can be achieved by conventional mechanochemical or solution procedures. The methodology is demonstrated on three different systems: C–C bond forming Knoevenagel condensation, selective C–N bond formation for amide/urea synthesis, and solid-state formation of an archetypal open metal-organic framework, MOF-74. In all cases, the application of specific heating regimes enabled significant acceleration of milling reactions and increased overall energy efficiency, use of much milder milling conditions, and unprecedented product selectivity, best demonstrated on the one-pot selective synthesis of four complex products containing combinations of amide, amine or urea functionalities from the same and simple acyl azide and diamine reactants. Principal control over this enhanced reactivity and selectivity stemmed from the application of specific heating regimes to mechanochemical processing accomplished by a new, in-house developed mechanochemical reactor. As even the moderate increase in temperature strongly affects the selectivity and the rate of mechanochemical reactions, the results presented are in line with recent challenges of the accepted theories of mechanochemical reactivity.

Advancing the Reactivity and Selectivity in Covalent and Coordination Mechanochemistry by Thermally-Controlled Milling

Milling under controlled and variable heating programs introduces a new level of mechanochemical reactivity beyond what can be achieved by conventional mechanochemical or solution procedures. The methodology is demonstrated on three different systems: C–C bond forming Knoevenagel condensation, selective C–N bond formation for amide/urea synthesis, and solid-state formation of an archetypal open metal-organic framework, MOF-74. In all cases, the application of specific heating regimes enabled significant acceleration of milling reactions and increased overall energy efficiency, use of much milder milling conditions, and unprecedented product selectivity, best demonstrated on the one-pot selective synthesis of four complex products containing combinations of amide, amine or urea functionalities from the same and simple acyl azide and diamine reactants. Principal control over this enhanced reactivity and selectivity stemmed from the application of specific heating regimes to mechanochemical processing accomplished by a new, in-house developed mechanochemical reactor. As even the moderate increase in temperature strongly affects the selectivity and the rate of mechanochemical reactions, the results presented are in line with recent challenges of the accepted theories of mechanochemical reactivity.

Acyl Azides: Versatile Compounds in the Synthesis of Various Heterocycles­

Carbon–nitrogen bond formation is one of the most important reactions in organic chemistry. Various synthetic strategies for the generation of C–N bonds are described in the literature. For example, primary amines can be easily synthesized by the thermal decomposition of an acyl azide to an isocyanate, i.e. the Curtis rearrangement, followed by hydrolysis; the Curtius rearrangement has been used extensively. Furthermore, the advantage of the Curtius rearrangement is the isolation of acyl azides as well as the corresponding isocyanates. The isocyanates can be converted into various nitrogen-containing compounds upon reaction with various nucleophiles that can be used as important synthons for cyclization, in other words, for the synthesis of heterocycles. Therefore, this review demonstrates the importance of acyl azides not only in the synthesis acyclic systems, but also in the synthesis of various nitrogen-containing heterocycles.1 Introduction2 Synthesis of Acyl Azides2.1 Acyl Azides from Carboxylic Acid Derivatives2.2 Acyl Azides by Direct Transformation of Carboxylic Acids2.3 Acyl Azides from Aldehydes2.4 Carbamoyl Azides from Haloarenes, Sodium Azide, and N-Formylsaccharin3 Mechanism of Formation of Isocyanates4 Synthesis of Diacyl Azides5 Synthetic Applications5.1 Synthesis of Pyrimidinone Derivatives5.2 Dihydropyrimidinone and Isoquinolinone Derivatives5.3 Synthesis of Tetrahydroisoquinoline Skeleton5.4 Synthesis of Five-Membered Heterocycles5.5 Heterocycles Synthesized Starting from Homophthalic acid5.6 Heterocycles Synthesized from 2-(Ethoxycarbonyl)nicotinic Acid5.7 Formation of Aza-spiro Compounds5.8 Parham-Type Cyclization5.9 Diazepinone Derivatives5.10 Synthesis of Pyridine Derivatives5.11 Synthesis of Indole Derivatives6 Miscellaneous7 Conclusion