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. 2022 Apr 13;2(4):906-916.
doi: 10.1021/jacsau.2c00039. eCollection 2022 Apr 25.

Merging Directed C-H Activations with High-Throughput Experimentation: Development of Iridium-Catalyzed C-H Aminations Applicable to Late-Stage Functionalization

Erik Weis  1   2 , Maria Johansson  3 , Pernilla Korsgren  3 , Belén Martín-Matute  1 , Magnus J Johansson  1   2
Affiliations

Merging Directed C-H Activations with High-Throughput Experimentation: Development of Iridium-Catalyzed C-H Aminations Applicable to Late-Stage Functionalization

Erik Weis et al. JACS Au. .

Abstract

Herein, we report an iridium-catalyzed directed C-H amination methodology developed using a high-throughput experimentation (HTE)-based strategy, applicable for the needs of automated modern drug discovery. The informer library approach for investigating the accessible directing group chemical space, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of reaction application guidelines to aid future users. Applicability to late-stage functionalization of complex drugs and natural products, in combination with multiple deprotection protocols leading to the desirable aniline matched pairs, serve to demonstrate the utility of the method for drug discovery. Finally, reaction miniaturization to a nanomolar range highlights the opportunities for more sustainable screening with decreased material consumption.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Selected examples of drugs containing an aniline moiety and (b) representative examples of challenging functional groups encountered with LSF applications and opportunities for directed C–H activations.
Figure 2
Figure 2
Strategy for HTE-enabled reaction discovery and applicability investigations for methodology development. DG = directing group.
Figure 3
Figure 3
Directing group informer library. A total of 48 substrates tested against four solvents under screening conditions. Productive DGs and key classes of unproductive DGs depicted.
Scheme 1
Scheme 1. Scope: Building Blocks (Directing Groups Highlighted in Blue; Isolated Yields Shown)
DCE used as solvent. Reaction scale 0.2 mmol. Reaction scale: 0.1 mmol. CPME as a solvent. EtOAc as a solvent. Isolated from DG informer library reaction plate. MozN3 (1.5 equiv), [Cp*Ir(H2O)3]SO4 (10 mol%).
Scheme 2
Scheme 2. Scope: LSF (Directing Groups Highlighted in Blue; Isolated Yields Shown)
C5H9COOH (1.0 equiv) used as additive. rsm = recovered starting material.
Scheme 3
Scheme 3. Deprotection Studies,
Isolated yields shown. Left: Deprotection of the isolated material. Right: One-pot amination/deprotection. Solvent = DCE. A higher isolated yield of 4j was obtained compared to the Moz-protected 3j as a result of better separation by HPLC for the former compound.
Figure 4
Figure 4
Miniaturization study. Reaction scale: 0.2 μmol, reaction volume: 1.0 μL. Analyzed by LCMS (UV trace). With an unsuccessful reaction, no substrate or product was detected.
Figure 5
Figure 5
Application guidelines for the C–H amination methodology.
See this image and copyright information in PMC

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