Research Article

A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow

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Science  26 Jan 2018:
Vol. 359, Issue 6374, pp. 429-434
DOI: 10.1126/science.aap9112
  • Fig. 1 Flow system setup and segment preparation.

    (A) Schematic depiction of the flow system. (B) Segment preparation and injection into flow stream showing potential mixing and diffusion outcomes, (B1) idealized–no diffusion, (B2) no mixing, and (B3) observed. (C) Portrayal of UV trace of the emerging reactions segments and fractionation into alternating LC-MS units.

  • Fig. 2 Model Suzuki-Miyaura cross-coupling.

    (A) Coupling evaluates electrophiles 1a–1d/2d, with 2a–2c/1e–1g evaluated across a matrix of 11 ligands (plus one blank) × 7 bases (plus one blank) × 4 solvents. (B) UV analysis of internal standards (see legend) in the fractionated reaction segment derived from increasing volumes of components confirming adequate mixing.

  • Fig. 3 Complete heatmap visualization.

    A total of 5760 reactions of 1a–1d with 2a–2c, and the reaction of 2d with 1e–1g evaluated across a matrix of 11 ligands (plus one blank) × 7 bases (plus one blank) × 4 solvents.

  • Fig. 4 Data analysis of model Suzuki-Miyaura cross-coupling.

    (A) Box plot comparison of quinoline electrophiles 1a–1d in reactions with boronic acid 2a and boronic ester derivatives, 2b and 2c, across different solvents. (B) Heatmap of coupling of quinoline electrophiles 1a–1d with 2a evaluated across a matrix of 11 ligands (plus one blank) × 7 bases (plus one blank) × 4 solvents.

  • Fig. 5 Suzuki-Miyaura cross-coupling—successful conditions.

    Conditions with ≥85% yield for all quinoline-based electrophiles 1a–1d with 2a. This indicates that 181 conditions work for one electrophile, 103 conditions work for two electrophiles, and 33 conditions work for three electrophiles, whereas only 3 sets of reaction conditions (specified in the table) work for all four electrophiles.

  • Fig. 6 Scale-up validation and PMC optimization.

    (A) Scale-up validation of reaction conditions in both batch and flow for the Suzuki-Miyaura cross-coupling of 1b with 2b. (B) PMC optimization via flow-screening and validation in batch for the coupling of 4 with 5 evaluating a matrix of 11 ligands (plus one blank) × 7 bases (plus one blank) × 6 solvents. (C) Complete heatmap visualization of the 576 reactions.

Supplementary Materials

  • A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow

    Damith Perera, Joseph W. Tucker, Shalini Brahmbhatt, Christopher J. Helal, Ashley Chong, William Farrell, Paul Richardson, Neal W. Sach

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Supplementary Text
    • Figs. S1 to S24
    • Tables S1 to S3
    • References
    Data File S1

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