No abstract

In the present paper we report the synthesis of condensed pyrimidone heterocycles (including novel ones) prepared by the Gould−Jacobs reaction using an in-house-built vacuum-to-high pressure multipurpose "three-mode" pyrolysis reactor. Four of the ring systems have not been described in the literature to date. The pyrolysis reactor has (i) a flash vacuum pyrolysis (FVP) module that applies high vacuum (10 −3 mbar), letting the starting material through the reactor chamber heated up to 1000 °C; (ii) a pneumatic spray pyrolysis (PSP) module that can inject nonvolatile reactants to the heated reactor zone; and (iii) a high-pressure pyrolysis (HPP) continuous-flow module that operates from atmospheric to 400 bar pressure and between room temperature and 600 °C. The capabilities of the pyrolysis reactor were demonstrated by comparison experiments on two different condensed pyrimidone bicyclic ring systems, and the established reaction conditions were then successfully applied to the synthesis of another six condensed pyrimidone bicyclic systems.

Aromatic or heteroaromatic ring precursors with 2-3 identical functionalities are often used in sequential derivatization depending on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. Continuous flow chemistry offers an enhanced parameter space (pressure and temperature) with rapid parameter optimization that ensures selectivity in many cases. We developed a flow chemistry procedure to carry out a stepwise aromatic nucleophilic substitution of difluoro-benzenes having an activating group in meta position to the fluorines. The mono-aminated products were obtained in high yield and selectivity in an extremely short reaction time, while applying higher temperature, longer reaction zone (or time), and employing higher excess of another amine reactant, the subsequent introduction of the second amino group was also successfully achieved leading to an unsymmetrically substituted 3,5-diamino-benzonitrile library.

A novel method for C-H functionalization of heteroaromatic rings by using continuous-flow reactors is reported. Direct alkylation reactions were investigated under heterogeneous catalytic conditions using simple transition metal catalysts at elevated temperature and pressure. As a model reaction, the alkylation of indole was attempted using cheap Raney W Nickel catalyst. Alcohols served both as alkylating agent and as reaction media. The targeted 3-alkyl-indoles were obtained in moderate to good yield with reasonable selectivity. Transient protection on the N-atom increased the selectivity up to 80%. The scope and limitations were also investigated. In summary, direct alkylation with alcohols represents a rapid (residence time of <1 min) and traceless process with high atom economy (88-92%, in those cases where transient protection was not applied).

Gould—Jacobs and Conrad—Limpach‐type thermal cyclization and benzannulation reactions are investigated from readily prepared functional precursors using a high pressure and high temperature flow reactor system with very short residence times.