Distal Weak Coordination of Acetamides in Ruthenium(II)-Catalyzed C?H Activation Processes

Article abstract of DOI:10.1002/anie.201711108

C?H activations with challenging arylacetamides were accomplished by versatile ruthenium(II) biscarboxylate catalysis. The distal C?H functionalization offers ample scope—including twofold oxidative C?H functionalizations and alkyne hydroarylations—throug

Full text of DOI:10.1002/anie.201711108

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Accepted Article
Title: Distal Weak Coordination of Acetamides in Ruthenium(II)-
Catalyzed C-H Activation Processes
Authors: Qingqing Bu, Torben Rogge, Vladislav Kotek, and Lutz
Ackermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711108
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10.1002/anie.201711108
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Distal Weak Coordination of Acetamides in Ruthenium(II)-
Catalyzed C–H Activation Processes
Qingqing Bu,+ Torben Rogge,+ Vladislav Kotek, and Lutz Ackermann*
Abstract: C–H activations with challenging arylacetamides were
accomplished by versatile ruthenium(II) biscarboxylate catalysis. The
distal C–H functionalization was characterized by ample scope,
including twofold oxidative C–H functionalizations and alkyne
hydroarylations, through facile base-assisted internal electrophilic-
type substitution (BIES) C–H ruthenation by weak O-coordination.
Within our program on cost-effective C–H activation,[8] we have
now developed uniquely effective oxidative C–H alkenylations[9]
of weakly coordinating acetamides, on which we report herein.
Notable features of our approach include (i) efficient C–H
activation of challenging arylacetamides by ruthenium(II)
catalysis, (ii) ample substrate scope with tertiary, secondary and
primary amides, (iii) step- and atom-economical alkyne
hydroarylations,[10] and (iv) key mechanistic insights by detailed
experimental and computational studies.
Substituted acetamides are key structural motifs in a plethora of
bioactive compounds, drugs and crop protection agents (Figure
1). For instance, atenolol is a selective β1-receptor antagonist
primarily used for cardiovascular diseases,[1] while 1-
naphthaleneacetamide serves as auxin for rooting hormone.[2]
As a consequence, there is a continued strong demand for
general strategies that provide access to substituted
arylacetamides in a sustainable fashion.
In recent years, catalyzed C–H activation has emerged as a
transformative tool for molecular syntheses.[3] While direct
functionalizations of simple benzamides have thus been
accomplished,[4] C–H activations of distal weakly-coordinating
acetamides via unfavorable six-membered metalacycles
continue to be scarce, with pioneering contributions by inter alia
Yu, Maiti and Dong in palladium catalysis.[5,6] Despite of
undisputable recent progress by versatile, less expensive[7a]
ruthenium catalysis,[7] C–H functionalizations of challenging
arylacetamides have thus far proven elusive, which is largely
due to the tautomerizable nature of the distal O-coordinating
acetamides.
We initiated our studies by probing various reaction
parameters for the envisioned oxidative C–H olefination of
challenging arylacetamide 1a (Table 1). We were pleased to
observe that cationic ruthenium(II) carboxylate[11a] complexes
that were generated in situ from [RuCl2(p-cymene)]2 and
Cu(OAc)2•H2O displayed outstanding performance. Biomass-
derived γ-valerolactone (GVL)[11b] and THF emerged as the
optimal solvents (entries 1-8). It is noteworthy that typical
rhodium, iridium and cobalt catalysts delivered less satisfactory
results (entries 9–11).
Table 1. Development of oxidative C–H alkenylation of acetamide 1a.[a]
Entry
[TM]
Additive
Solvent
Yield [%]
1
[RuCl2(p-cymene)]2
KPF6
DCE
THF
13
––
––
––
––
72
73
84
74
30
––
2
[Ru3(CO)12
]
––
3
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[Cp*RhCl2]
––
THF
4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
DMA
MeCN
tAmOH
GVL
THF
5
6
Figure 1. Selected bioactive compounds featuring arylacetamides.
7
8
9
THF
[*]
Q. Bu, T. Rogge, Dr. V. Kotek, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
10
11
[Cp*IrCl2]
THF
[Cp*Co(CO)I2]
THF
Tammannstraße 2, 37077 Göttingen
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
These authors contributed equally.
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [TM] (5.0 mol %),
additive (20 mol %), Cu(OAc)2∙H2O (1.0 mmol), solvent (2.0 mL), 110 °C, 24 h,
yields of isolated products.
[+]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
With the optimized ruthenium(II) catalyst in hand, we
explored its scope in the C–H olefination by distal O-acetamide
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10.1002/anie.201711108
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COMMUNICATION
assistance, first exploring the influence of the arene substitution
pattern (Scheme 1). Thus, both electron-donating and electron-
withdrawing substituents were smoothly accommodated in the
oxidative C–H alkenylation. The robustness of the ruthenium(II)
catalysis was reflected by an excellent chemo-selectivity,
tolerating valuable electrophilic groups, such as bromo or nitro
substituents, racemization-free conditions, and the gram-scale
synthesis of product 3lb.
Scheme 2. Oxidative C–H alkenylation of primary amides 4. [a] 120 °C, 1,4-
dioxane/PhMe (9:1).
Intrigued by the versatility of the ruthenium(II) carboxylate
catalysis, we became attracted by C–H alkenylations through
redox-neutral alkyne hydroarylations. By simply switching the
carboxylate source from Cu(OAc)2·H2O to 1-AdCO2H the
desired C–H addition onto alkynes 6 proved viable (Table S1 in
the SI[12] and Scheme 3). Thereby, the ruthenium(II)-catalyzed
C–H activation provided a complementary diastereo-selectivity
in accessing tri-substituted alkenes 7 and 8, again with both
secondary and challenging primary amides 1 and 4, respectively.
Scheme 1. C–H alkenylation of secondary and tertiary acetamides 1.
The versatile ruthenium(II) catalyst was not limited to secondary
and tertiary acetamides 1. Indeed, we were pleased to identify
more challenging primary amides 4 as viable substrates in the
oxidative C–H alkenylation likewise (Scheme 2). Here, the
ruthenium(II) catalyst was characterized by high chemo-
selectivity, highlighting aryl chlorides and bromides as well as
the sensitive cholesteryl moiety.
Scheme 3. Ruthenium(II)-catalyzed hydroarylation of alkynes. [a] [RuCl2(p-
cymene)]2 (10 mol %) in 1,4-dioxane as solvent.
Given the high catalytic efficacy of the ruthenium(II)
biscarboxylates by distal weak coordination, we became
intrigued by delineating its mode of action. To this end, C–H
alkenylations with isotopically-labeled compounds provided
evidence for a facile C–H activation (Scheme 4a), with no
significant kinetic isotope effect as explored by in-operando IR
spectroscopy (kH/kD = 1.02).[12] Further, competition experiments
were performed, highlighting the challenging nature of distal
acetamide C–H functionalizations, particularly, with primary
amides being even more difficult than ketones. (Scheme 4b,c).
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Electron-rich arenes reacted preferentially (Scheme 4d), which
is not in agreement with a concerted metalation/deprotonation
(CMD)[13] mechanism. Instead, the observations are better
rationalized by an base-assisted internal electrophilic-type
substitution (BIES) manifold,[14] which is supported by Mayer
through DFT studies. Geometry optimizations and frequency
calculations were performed at the TPSS-D3(BJ)/def2-TZVP[15]
level of theory, and single point energies at the COSMO-B3LYP-
D3(BJ)/def2-TZVP[16] level of theory.[12] The key six-membered
ruthenacycle C is formed within a carboxylate-assisted BIES[14]
bond order analysis of the transition state structure (Table S2).[12] C–H activation of O-coordinated intermediate B (Figure 2). Here,
the formation of an agostic complex[17] was not found. Compared
to the corresponding five-membered analogue C5 the six-
membered ruthenacycle C is destabilized by 6.9 kcal mol–1,
whilst the deprotonative transition-state is 2.8 kcal mol–1 higher
in energy (Figure S2 in the SI).[12] Overall, these findings mirror
the challenging nature of arylacetamides in C–H activation.
Thereafter, ligand exchange and rate-limiting migratory insertion
delivers eight-membered ruthenacycle E, which finally
undergoes β-hydride elimination to form alkene-coordinated
complex G. A careful analysis of Grimme’s D3 dispersion
correction revealed a significant stabilization[18] of intermediates
and transition states,[19] with energy differences of up to
10.6 kcal mol–1 for the key eight-membered intermediate E
(Figure S3 in the SI).[12] Comparable results were obtained when
using Truhlar’s PW6B95 with D3 correction.[20]
Scheme 4. Key experimental mechanistic findings.
Based on our experimental studies, we became attracted to
better understand the details of the catalyst’s working mode
Figure 2. . Relative Gibbs free energy profile for the reaction of 1r with 2b at the B3LYP-D3(BJ) (black) or PW6B95-D3(BJ) (red) level of theory.
In summary, we have reported on the first ruthenium(II)-
access to substituted olefines with high levels of chemo-,
positional- and stereo-selectivity control. Mechanistic studies
unraveled a facile BIES C–H activation, and highlighted the
challenging nature of C–H functionalizations with distal
acetamides.
catalyzed
arylacetamides
C–H
activations
through
of
weakly-O-coordinating
six-membered
challenging
ruthenacycles. Thus, oxidative C–H alkenylations and alkyne
hydroarylations proved viable with ample scope on tertiary,
secondary and even primary amides, providing step-economical
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Acknowledgements
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For selected examples of C–H alkenylations see: a) W. Ma, H. Dong, D.
Wang, L. Ackermann, Adv. Synth. Catal. 2017, 359, 966-973; b) J. A.
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Bechtoldt, C. Tirler, K. Raghuvanshi, S. Warratz, C. Kornhaaß, L.
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Generous support by the CSC (fellowship to Q.B.), the DFG
(SPP 1807 and Gottfried-Willhelm-Leibniz prize), the Experientia
Foundation of the Czech Republic (fellowship V.K.), and the
COST program (CA15106 CHAOS) is gratefully acknowledged.
Keywords: C–H activation • Density functional theory •
homogeneous catalysis • mechanism • ruthenium
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COMMUNICATION
C–H Activation
Q. Bu,+ T. Rogge,+ V. Kotek, L
Ackermann*
Page No. – Page No.
Distal Weak Coordination of
Acetamides in Ruthenium(II)-
Catalyzed C–H Activation Processes
From a distance: Distal C–H activations were accomplished by versatile ruthenium(II)
catalysis through facile C–H cleavage by weak coordination.
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