Visible-Light-Enabled Ruthenium-Catalyzed meta-C?H Alkylation at Room Temperature

Article abstract of DOI:10.1002/anie.201902258

Visible-light-induced ruthenium catalysis has enabled remote C?H alkylations with excellent levels of position control under exceedingly mild conditions at room temperature. The metallaphotocatalysis occurred under exogenous-photosensitizer-free conditions and features an ample substrate scope. The robust nature of the photo-induced mild meta-C?H functionalization is reflected by the broad functional group tolerance, and the reaction can be carried out in an operationally simple manner, setting the stage for challenging secondary and tertiary meta-C?H alkylations by ruthenaphotoredox catalysis.

Full text of DOI:10.1002/anie.201902258

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Accepted Article
Title: Visible-Light for Ruthenium-Catalyzed meta-C‒H Alkylation at
Room Temperature
Authors: Parthasarathy Gandeepan, Julian Koeller, Korkit Korvorapun,
Jens Mohr, and Lutz Ackermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902258
Angew. Chem. 10.1002/ange.201902258
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10.1002/anie.201902258
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Visible-Light for Ruthenium-Catalyzed meta-C‒H Alkylation at
Room Temperature
Parthasarathy Gandeepan,¶ Julian Koeller,¶ Korkit Korvorapun, Jens Mohr, and Lutz Ackermann*[a]
Abstract: Visible-light-induced ruthenium catalysis enabled remote
C‒H alkylations with excellent levels of position control under
exceedingly mild conditions at room temperature. The
metallaphotocatalysis occurred under exogenous-photosensitizer-
free conditions with ample substrate scope. The robust nature of the
photo-induced mild meta-C‒H functionalization was reflected by
broad functional group tolerance in an operationally-simple manner,
setting the stage for challenging secondary and tertiary meta-C‒H
alkylations via ruthenaphotoredox catalysis.
metallaphotoredox-catalyzed C‒H functionalization,[16] we have
now devised the unprecedented visible-light-induced meta-C‒H
alkylation at room temperature. Notable features of our findings
include a) expedient ruthenium-catalyzed meta-C‒H alkylations,
b) visible-light-induced metallaphotocatalysis for remote C‒H
functionalization,
c)
exogenous-photosensitizer-free
photocatalysis, and d) exceedingly mild reaction conditions at
room temperature.
The development of catalytic methods for the position-selective
functionalization of C‒H bonds represents a key challenge in
molecular syntheses.[1] Thus far, chelation assistance by directing
groups has been identified as a versatile tool for site-selective C‒
H metalations.[2] Thereby, proximity-induced C‒H activations
have set the stage for a plethora of ortho-selective C‒H
functionalizations. In sharp contrast, strategies for the assembly
of meta-substituted arenes continue to be scarce. To overcome
the challenge of meta-C‒H functionalization, useful approaches
have been devised (Figure 1).[3] Hence, exploiting the substrate’s
inherent substitution pattern has proven useful, but still largely
suffers from limited substrate scope.[4] Directing group-based
reactions via transient norbornene mediators,[5] hydrogen-
bonding ligands,[6] or template-directing groups[7] provided
significant recent momentum towards meta-decorated arenes.
While representing key advances, these methods require
multistep syntheses of ligands or templates, and often give
mixtures of regioisomeric products that are difficult to separate.
As a uniquely versatile alternative, meta C‒H functionalizations
through arene σ-activation[8] were realized by chelation-assisted
ortho-cycloruthenation.[9-13] Despite indisputable progress, the
σ-activation approach is limited to elevated reaction temperatures
that resulted in significantly reduced yields and low functional
group tolerance. Conversely, room temperature metal-catalyzed
meta-C‒H functionalization has thus far unfortunately proven
elusive.
During the past decade, photo-induced C‒H functionalization has
emerged as a powerful tool for molecular syntheses,[14] both in
terms of classical ortho-functionalizations or with electronically-
biased heteroarenes.[15] In sharp contrast, within our program on
Figure 1. Strategies for meta-selective C–H functionalization. a) Control by
steric interactions, b) Transient norbornene mediator enabled meta-selectivity,
c) Hydrogen-bond interactions controlled selectivity, d) Template auxiliaries
chelation assistance and e) Catalytic arene σ-activation by cycloruthenation.
We initiated our studies by probing reaction conditions for the
meta-C‒H alkylation of arene 1a with challenging tert-butyl
bromide (2a) (Table 1 and Tables S1-S5 in the Supporting
Information). After considerable experimentation, we were
pleased to obtain the meta-alkylated product 3a in 80% yield with
[RuCl2(p-cymene)]2 as the catalyst and diphenyl phosphoric
acid[17] as the ligand under blue light irradiation at room
temperature (Table 1, entry 1). Control experiments verified the
[a]
Dr. P. Gandeepan,[¶] J. Koeller,[¶] K. Korvorapun, Dr. J. Mohr, Prof.
Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Web: http://www.ackermann.chemie.uni-goettingen.de/index.html
These authors contributed equally to this work.
[¶]
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/anie.201902258
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essential role of the ruthenium catalyst (entries 2 and 3), the
ligand (entries 4-6), the base (entries 7 and 8), the solvent (entry
9), and light (entry 10). Notably, other commonly used transition
metal catalysts for C‒H activation, such as Pd(OAc)2, [Cp*RhCl2]2,
and [Cp*IrCl2]2, fell short in giving the desired product 3a under
otherwise identical reaction conditions (entry 11), highlighting the
unique features of the ruthenaphotocatalysis for meta-C‒H
functionalization at room temperature. The addition of external
photosensitizer, such as Ir(ppy)3, Ru(bpy)3Cl2, Eosin Y,
Rhodamine 6G, Rose Bengal, 9-Mesityl-10-methylacridinium
perchlorate, did not significantly affect the efficacy of the
ruthenaphotoredox catalysis (Table S4).
Table 1. Optimization of Photo-Induced Ruthenium(II)-Catalyzed meta-C‒H
Alkylation
Entry
Deviation from standard condition
Yield [%][a]
1
2
3
None
80
0
No [Ru]
Ru(bpy)3Cl2, [Ru(NCtBu)6][PF6]2 or [Ru(OAc)2(p- 0, 0, 35
cymene)] as the catalyst
4
5
BNDHP instead of (C6H5O)2P(O)OH
73
PivOH, MesCO2H or 1-AdCO2H instead of 14, 12, 19
(C6H5O)2P(O)OH
6
7
8
9
No (C6H5O)2P(O)OH
24
No K2CO3
0
KOAc, NaOAc or K3PO4 instead of K2CO3
19, 30, 70
THF, PhMe, DME, or DMA instead of 61, 0, 70, 79
1,4-dioxane
10
11
No light
0
0
Pd(OAc)2, [Cp*RhCl2]2, and [Cp*IrCl2]2 as the
catalyst
12
oil bath at 80 °C, no light
0
[a] Reaction conditions: 1a (0.4 mmol), 2a (1.2 mmol), [RuCl2(p-cymene)]2 (5.0
mol %), (C6H5O)2P(O)OH (30 mol %), K2CO3 (2.0 equiv), 1,4-dioxane (2.0 mL),
blue LEDs, 24 h, 25-30 °C, yield of isolated products. BNDHP = (±)-1,1'-
Binaphthyl-2,2'-diyl hydrogenphosphate. DME = 1,2-Dimethoxyethane.
With the optimized reaction conditions established, we
investigated the versatility of the photo-meta-C‒H alkylation of
arenes 1 (Scheme 1). We were delighted to observe that a variety
of both tertiary and secondary unactivated alkyl bromides 2 were
compatible electrophiles to provide the desired products 3 with
outstanding performance. Thus, alkyl bromides 2 bearing imides,
enones, piperidyl, and ester motifs were fully tolerated by the
ruthenaphotoredox meta-C‒H functionalization.
Scheme 1. Photo-induced meta-C‒H alkylation at room temperature.
The ruthenium-catalyzed visible-light-induced meta-C‒H
alkylation at ambient temperature was not limited to alkyl
bromides 2. Indeed, the ruthenaphotoredox catalysis proved also
applicable to the photo-induced C‒H functionalization with
synthetically meaningful α-bromoesters 4 (Scheme 2). Also, the
meta-substituted products 5c-e derived from alkyl bromides
containing sugar, menthol, or steroid motifs were selectively
converted, which should prove instrumental for applications to
2
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10.1002/anie.201902258
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pharmaceutical industries in terms of late-stage diversification
under mild conditions.[18,19]
Scheme 2. Photo-induced meta-alkylation with α-bromoesters 4.
Given the unique features of the photo-induced ruthenium-
catalyzed meta-C‒H functionalization, we became attracted to
elucidating its mode of action (Scheme 3). To this end, the chloro-
ruthenacycle[20] 6 was found to be catalytically competent,
provided that the ligand (PhO)2P(O)OH was present (Scheme 3a).
Likewise, the well-defined mesityl carboxylate-ruthenacycle[9d, 9n]
7
was effective for the photo-induced remote C‒H
functionalization, again solely in the presence of (PhO)2P(O)OH.
Interestingly, both cyclometalated complexes 6 and 7 gave the
product 3a with almost quantitative isolated yield. Thereafter, we
examined a single-electron-transfer (SET)-regime by the use of
typical radical scavengers TEMPO, BHT, galvinoxyl, and 1,1-
diphenylethylene (Scheme 3b), which significantly suppressed
the catalytic efficacy. Finally, competition experiments between
secondary and tertiary alkyl bromides 2 revealed the latter to be
preferentially converted (Scheme 3c)
Scheme 3. Key mechanistic studies.
In consideration of the mild nature of the photo-induced
ruthenium-catalyzed meta-C–H alkylation process, we became
interested in elucidating the role of visible light. Here, the
absorption spectra of ruthenium complexes 6 and 7 highlighted a
minor, yet significant light absorption in the relevant blue region
(Figure 2a). Furthermore, we performed fluorescent quenching
studies towards Stern-Volmer-plot analyses (Pages S-42-S-44 in
the Supporting Information), and monitored the conversion profile
of the photocatalytic meta-alkylation, revealing the remote-C–H
alkylation to be completely suppressed in the absence of light
(Figure 2b). These findings highlight the importance of visible-light
irradiation to the success of meta C‒H functionalization at room
temperature, while showing that constant irradiation is required
for effective product formation.[21] Cyclic voltammetric studies
3
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featured a reversible oxidation event with an oxidation peak at
0.98 V in DCE (Figure 2c).
On the basis of our mechanistic findings, we propose a
plausible catalytic cycle to commence by phosphate-assisted[22]
C‒H ruthenation[17] (Scheme 4). The cyclometalated ruthenium
complex B is then excited by blue-light absorption to give
intermediate B*, which is followed by SET to alkyl halides 2.
Thereby, ruthenium(III) complex C and alkyl radical D are
generated. Next, radical attack on the aromatic moiety at the
position para to ruthenium forms intermediate E, which undergoes
intramolecular SET and subsequent rearomatization to provide
ruthenacycle G. Finally, protodemetalation releases the desired
meta-alkylated product 3 and regenerates the catalytically
competent ruthenium(II) species A.
a)
1.0
6
7
0.14
0.8
1a
(PhO) P(O)OH
2
0.12
0.6
0.4
0.10
0.2
0.08
0.0
250
300
350
400
450
500
0.06
0.04
0.02
0.00
Wavelength [nm]
300
350
400
450
500
Wavelength [nm]
b)
Scheme 4. Plausible catalytic cycle.
c)
Finally, we examined the visible-light-enabled meta-C‒H
alkylation with alternative modifiable heteroarenes (Scheme 5).
To our delight, synthetically useful pyrazoles and oxazolines
enabled the synthesis of the desired meta-functionalized products
60
50
40
30
20
10
0
Blank
2-Phpy
6
7
9 and 11, which are readily converted into meaningful amino and
23]
carboxylic acid groups.[9b,
The power of our visible-light-
enabled meta-C‒H alkylation was further substantiated by the
late-stage modification towards the valuable piperidine moiety
(Scheme 5c).
-10
-20
-30
-0,5
0,0
0,5
1,0
1,5
2,0
Potential (V vs Ag/AgCl)
Figure 2. a) Absorption spectra of ruthenacycles 6 and 7. b) On/off light
experiments. c) Cyclic voltammograms at 100 mVs–1 in DCE. nBu4NPF6 (0.1 M
in DCE), concentration of substrate 4 mM. EOx of 6: 0.98 V, Eox of 7: 0.87 V.
DCE = 1,2-dichloroethane.
4
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Scheme 5. Late-Stage Diversification.
[6]
In conclusion, we have devised a novel strategy towards
meta-decorated arenes by unprecedented visible-light-induced
ruthenium-catalyzed remote C‒H functionalization. The versatile
metallaphotoredox protocol proceeded in the absence of
exogenous photosensitizers with outstanding efficacy and
functional group tolerance under exceedingly mild conditions at
room
temperature.
The
versatile
photo-meta-C‒H
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Generous support by the Alexander von Humboldt Foundation
(fellowship to PG), the DAAD (fellowship to KK), and the DFG
(fellowship to JM, Gottfried-Wilhelm-Leibniz-Preis to LA, and
SPP1807) are gratefully acknowledged.
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Keywords: C‒H activation • meta selectivity • photocatalysis •
remote C‒H functionalization • room temperature • ruthenium
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10.1002/anie.201902258
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Parthasarathy Gandeepan, Julian
Koeller, Korkit Korvorapun, Jens Mohr,
Lutz Ackermann*
Page No. – Page No.
Visible-Light for Ruthenium-
Catalyzed meta-C‒H Alkylation at
Room Temperature
meta-light: Visible-light enabled remote arene diversification under exceedingly
mild conditions for expedient meta-C‒H-functionalization at room temperature.
7
This article is protected by copyright. All rights reserved.