Continuous Visible-Light Photoflow Approach for a Manganese-Catalyzed (Het)Arene C?H Arylation

Article abstract of DOI:10.1002/anie.201805644

Manganese photocatalysts enabled versatile room-temperature C?H arylation reactions by means of continuous visible-light photoflow, thus allowing for efficient C?H arylations in 30 minutes with ample scope. The robustness of the manganese-catalyzed photoflow strategy was shown by visible light-induced gram-scale synthesis, clearly outperforming the batch performance.

Full text of DOI:10.1002/anie.201805644

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Accepted Article
Title: Continuous Visible Light-Photo-Flow for Manganese-Catalyzed
(Het)Arene C−H Arylation
Authors: Yu-Feng Liang, Ralf Steinbock, Long Yang, and Lutz
Ackermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805644
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10.1002/anie.201805644
Angewandte Chemie International Edition
COMMUNICATION
Continuous Visible Light-Photo-Flow for Manganese-Catalyzed
(Het)Arene C−H Arylation
Yu-Feng Liang, Ralf Steinbock, Long Yang, and Lutz Ackermann*
Abstract: Manganese photocatalysts enabled versatile room-
temperature C–H arylations by means of continuous visible light-
photo-flow, thus allowing for efficient C–H arylations in 30 minutes
with ample scope. The robustness of the manganese-catalyzed
photo-flow strategy was demonstrated by visible light-induced gram-
scale synthesis, clearly outperforming the batch performance.
The catalytic functionalization of otherwise inert C–H bonds has
emerged as a transformative platform in molecular sciences.[1]
Considerable recent progress in C–H functionalization chemistry
Figure 1. Manganese-catalyzed C−H arylation in continuous photo-flow.
was accomplished with earth-abundant 3d metals,[2] with key
contributions in manganese catalysis[3] by Takai/Kuninobu,[4]
Wang,[5] and Ackermann,[6] among others.[7] Despite of
We initiated our studies by probing various reaction conditions
indisputable advances, the vast majority of manganese-
for the envisioned manganese-catalyzed C–H arylation of arene
catalyzed C–H functionalizations continue to be limited to rather
2a in continuous photo-flow at room temperature (Table 1 and
harsh reaction conditions, with typical reaction temperatures of
Table S1 in the Supporting Information). We were delighted to
up to 120 °C.[3-7]
observe that the desired C–H arylation product 3aa was
In recent years, light-induced metal catalysis has been
obtained in 62% yield when CpMn(CO)3 was employed as the
identified as a powerful tool for mild single-electron-transfer-
photocatalyst in DMSO for only 30 minutes (Table 1, entry 1).
based organic transformations.[8] However, photoredox C–H
Control experiments confirmed the essential role of the
functionalizations were primarily realized with precious[9] iridium
manganese catalyst and the light (Table 1, entries 2-3). Further
and ruthenium catalysts, with notable contributions by Reiser,[10]
optimization studies revealed MnCl2 and Mn(OAc)2 falling short
Rueping,[11] and Stephenson,[12] among others.[13] In sharp
in improving the performance, while Eosin Y, MnBr(CO)5, and
contrast, photo-induced room temperature C–H arylations by
Mn2(CO)10 displayed significantly lower catalytic efficacy (Table
earth-abundant base-metal manganese catalysis have thus far
1, entries 4-8). Aprotic solvents proved mandatory for the C–H
proven elusive.[14],[15] Within our program on sustainable C–H
arylation, with DMSO being optimal (Table 1, entries 9-13). The
activation by base-metal catalysis,[16] we have now devised a
flow rate of the photo-flow C–H functionalization displayed a
protocol for unprecedented photo-induced C–H arylations by
considerable effect (Table 1, entries 14-15). It is noteworthy that
non-toxic manganese catalysis, on which we report herein.
the reaction in batch furnished biaryl 3aa in significantly lower
Notable features of our findings include (a) earth abundant base-
yields due to the improved mass- and energy transfer in flow,
metal as photoredox catalysis[17] for C–H functionalization, (b)
thus highlighting the beneficial assets of photo-flow for C–H
excellent levels of positional control, and (c) visible light-induced
functionalizations (Table 1, entry 16).
manganese catalyzed C–H arylations at room temperature
(Figure 1). It is particularly worthy of note that we have also
devised the first continuous photo-flow strategy[18],[19] for 3d
metal-catalyzed C–H functionalizations, thereby enabling
efficient gram-scale C–H arylations, which outperformed the
corresponding batch approach.
Table 1. Optimization of reaction conditions in continuous photo-flow.[a]
Entry
1
Deviation from above
Yield of 3aa [%][b]
None
62
7
2
Without light
3
Without CpMn(CO)3
13
10
8
4
MnCl2 instead of CpMn(CO)3
Mn(OAc)2 instead of CpMn(CO)3
MnBr(CO)5 instead of CpMn(CO)3
Mn2(CO)10 instead of CpMn(CO)3
Eosin Y instead of CpMn(CO)3
DMF instead of DMSO
5
6
29
44
35
41
32
trace
34
6
7
8
[*]
Dr. Y.-F. Liang, R. Steinbock, L. Yang, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
9
10
11
12
13
14
15
16
MeOH instead of DMSO
MeCN instead of DMSO
Acetone instead of DMSO
Benzene instead of DMSO
With 500 µL/min flow rate for 20 min
With 250 µL/min flow rate for 40 min
Reaction in batch instead of flow
Tammannstraße 2, 37077 Gottingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
49
61
33
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201805644
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COMMUNICATION
[a] Reaction conditions: 1a (0.5 mmol), 2a (7.5 mmol), Cat. (10 mol %), DMSO
(0.3 mL), with 330 µL/min flow rate, 30 min, under 24 W blue LED irradiation (λ
= 450 nm) in continuous flow at room temperature of 25 ± 3 °C. [b] Yield of
isolated product.
With the optimized reaction conditions in hand, we probed the
scope of the visible-light-enabled C−H arylation of arenes 2
(Scheme 1). The versatility of the continuous photo-flow C−H
arylation was reflected by tolerating valuable functional groups,
including fluoro, chloro, ester, and nitro substituents.
Scheme 1. Manganese-catalyzed C−H arylation by visible-light photo-flow.
Scheme 2. Room temperature hetroarene C−H arylation by photo-flow.
The robustness of the manganese-catalyzed C−H
functionalization in continuous photo-flow was next explored with
heteroarenes 4 (Scheme 2). The manganese-catalyzed C−H
arylation was again characterized by ample substrate scope,
featuring chloro, bromo, ester, cyano, ketone and nitro
functionalities, which should prove invaluable for further late-
stage manipulation. The manganese catalysis manifold enabled
the direct C−H arylation of substituted furans, pyrolles and
thiophenes with improved levels of positional control.
Scheme 3. Key mechanistic findings.
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10.1002/anie.201805644
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Subsequently, we conducted mechanistic studies to gain
insights into the catalyst’s mode of action (Scheme 3). First,
intermolecular competition experiments indicated electron-poor
arenes 1 to react preferentially (Scheme 3a). This observation
can be rationalized by the occurrence of a radical-controlled
SOMO–HOMO interaction.[20] A notable intermolecular kinetic
isotope effect (KIE, kH/kD ≈ 1.0) was not observed (Scheme 3b),
indicating a non-kinetically relevant C–H cleavage. The reaction
was completely stopped by the radical inhibitor 1,1-
diphenylethylene 6. Here, the trapped intermediate 7 could be
isolated (Scheme 3c), suggesting an aryl radical pathway.
Detailed absorption studies provided strong support for the initial
formation of an photochemically-competent complex generated
by CpMn(CO)3 and the substrates (Figure 2).
Scheme 4. Proposed mode of action.
Scalable processes continue to be scarce for visible-light
photoredox catalysis.[21] The synthetic potential of our
manganese-catalyzed C–H arylation in continuous photo-flow
was hence illustrated by the gram-scale synthesis of product
3aa within 60 minutes (Scheme 5a). In sharp contrast, the
reaction in batch delivered the biaryl 3aa in only 25% yield, thus
clearly highlighting the beneficial features of the photo-flow
approach for scale-up operations. Furthermore, the C–H
arylation of biomass-derived furfural 4e, followed by
condensation, afforded Dantrolene 8 (Scheme 5b) – a valuable
drug for the treatment of porcine and human malignant
hyperthermia.[22]
Figure 2. Absorption studies.
Based on our mechanistic studies and literature
precedence,[8-13] we propose a plausible reaction mechanism
depicted in Scheme 4. First, ligand exchange on CpMn(CO)3
with the arene substrate occurs to afford the manganese
species A, along with subsequent coordination by substrate 1 to
deliver the complex B. Then, photoexcitation and electron
transfer from excited-state complex
C gives aryl radical
intermediate D and manganese radical cation E. The addition of
aryl radical to arene 2 affords intermediate F, which is further
oxidized by the manganese radical cation E or the aryl
diazonium salt 1 to generate carbocation intermediate G. Finally,
deprotonation delivers the desired arylated product 3.
Scheme 5. Gram-scale synthesis and synthetic utility.
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Scheme 6. Versatile manganese-catalyzed photo-induced transformations:
[Mn2(CO)10] (10 mol %), RT.
In summary, inexpensive and earth-abundant manganese
complexes were employed as photocatalysts for mild visible-
light-induced C–H arylations of (het)arenes. Thus, a robust and
user-friendly
manganese
catalyst
enabled
C–H
functionalizations at room temperature, being fully compatible
with a wide array of functional groups with excellent position-
selectivity. Mechanistic studies provided strong support for an
efficient SET process. Our findings highlight the practical value
of performing manganese-catalyzed visible light-induced C–H
functionalizations in continuous photo-flow for large scale
application.
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Acknowledgements
Generous support by the Alexander von Humboldt Foundation
(fellowship to Y.L.), and the DFG (Gottfried-Wilhelm-Leibniz
prize) is gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: continuous photo-flow • visible light • manganese •
C−H arylation • mechanism
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10.1002/anie.201805644
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Yu-Feng Liang, Ralf Steinbock, Long
Yang, and Lutz Ackermann*
Page No. – Page No.
Continuous Visible-Photo-Flow for
Manganese-Catalyzed (Het)Arene
C−H Arylation
Text for Table of Contents
Photo in Flow: Earth-abundant manganese catalysts enabled visible-light-induced C−H arylations at room
temperature in a continuous photo-flow manifold.
This article is protected by copyright. All rights reserved.