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Manganese(II/III/I)-Catalyzed C–H Arylations in Continuous Flow Cuiju Zhu, João C. A. Oliveira, Zhigao Shen, Huawen Huang, and Lutz Ackermann ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00166 • Publication Date (Web): 09 Apr 2018 Downloaded from http://pubs.acs.org on April 9, 2018
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ACS Catalysis
Manganese(II/III/I)-Catalyzed C–H Arylations in Continuous Flow Cuiju Zhu, João C. A. Oliveira, Zhigao Shen, Huawen Huang, and Lutz Ackermann* Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttingen, Germany ABSTRACT: Versatile manganese-catalyzed C–H arylations on synthetically meaningful pyridines were accomplished with sustainable MnCl2 as the catalyst. The oxidative C–H functionalizations proved viable with a user-friendly and safe continuous flow set-up by weak amide-assisted C–H cleavage via a facile C–H activation regime.
KEYWORDS: C–H activation, arylation, flow, manganese, mechanism, pyridines
INTRODUCTION C–H activation has emerged as a transformative platform in molecular synthesis.1 Particularly, arene C–H arylations have been identified as powerful alternatives to traditional cross-couplings, avoiding the use and multistep preparation of prefunctionalized arenes.2 While the majority of arene C–H arylations was thus far accomplished with precious, toxic transition metals,2 recent focus has shifted towards the use of more sustainable 3d transition metals.3 Despite of tremendous advances in redox-neutral manganese(I)4 catalysis,5 arene C–H arylations with earth-abundant, less toxic manganese complexes have as of yet proven elusive. In contrast, we have now unraveled the first manganese-catalyzed arene C–H arylations, on which we report herein. Hence, a novel manganese(II/III/I)-catalyzed organometallic6 C–H activation regime enabled versatile azine C–H arylations7 with ample substrate scope, on which we report herein. Notable features of our findings include (a) fist manganese-catalyzed C–H arylations, (b) C–H functionalizations on the privileged pyridine motif, (c) excellent levels of positional selectivity, and (d) mechanistic insights on facile manganese(II/III/I)-catalyzed C–H metalation (Figure 1). It is particularly noteworthy that we also disclose the first use of continuous flow technology8 for low-valent metal-catalyzed C–H activation.5j,9 This strategy represents an user-friendly tool for the safe handling of reactive reagents on scale by improved control of heat and mass transfer, thereby enabling the efficient gram-scale C–H activation in only 100 minutes.
Figure 1. Low-valent manganese-catalyzed C–H arylation in flow.
We initiated our studies by exploring reaction conditions for the desired manganese-catalyzed C–H arylation in continuous flow (Table 1 and Table S-1 in the Supporting Information).10 Thus, among a variety of additives and ligands, TMEDA and neocuproine emerged as ideal, respectively, with DCIB being the oxidant of choice (entries 1 and 2). The flow rate had a minor effect on the overall efficacy (entries 1-3). Control experiments highlighted the essential role of the oxidant, the ligand and the manganese catalyst (entries 3-13), while the back pressure exerted a minor effect (entries 3-5). The unique performance of the manganese catalysis regime was reflected by iron, copper, nickel, ruthenium and even palladium catalysts falling short in delivering the desired product 3aa (entries 14 and 18).
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Table 1. Optimization of Catalyzed C–H Arylation in Flowa
entry
[TM]
oxidant
rate/ (µL/min)
yield (%)
1
MnCl2
DCIB
200
53
2
MnCl2
DCB
100
61
3
MnCl2
DCIB
100
70
4
MnCl2
DCIB
100
74
5
MnCl2
DCIB
100
72
6
MnCl2
---
100
