Late-Stage Diversification by Selectivity Switch in meta-C-H Activation: Evidence for Singlet Stabilization

Article abstract of DOI:10.1021/acscatal.9b04592

The full control of site selectivity in C-H activation is paramount for the programmed late-stage functionalization of structurally complex structures. During the past decade, directing groups have revolutionized molecular synthesis in terms of ortho-selective C-H activation. In sharp contrast, a selectivity switch that guides the typical ortho- to remote meta-C-H activation has thus far proven elusive. Herein, we describe the realization of such a concept for a robust selectivity control in ruthenium catalysis. The distal C-H transformation was guided by key mechanistic insights into the mild, synergistic action of carboxylates and phosphines in ruthenium(II) catalysis. Our findings allowed remote selectivity in broadly effective late-stage diversification of structurally complex drugs and natural product molecules, tolerating sensitive fluorescent dyes, drugs, lipids, peptides, nucleosides, and carbohydrates.

Full text of DOI:10.1021/acscatal.9b04592

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Article
Late-Stage Diversification by Selectivity Switch in meta-
C–H Activation: Evidence for Singlet Stabilization
Korkit Korvorapun, Rositha Kuniyil, and Lutz Ackermann
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04592 • Publication Date (Web): 25 Nov 2019
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Late-Stage Diversification by Selectivity Switch in meta-C–H Activation:
Evidence for Singlet Stabilization
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Korkit Korvorapun, Rositha Kuniyil, and Lutz Ackermann*
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077
Göttingen (Germany)
ABSTRACT: The full control of site selectivity in C–H activation is paramount for the programmed late-stage functionalization of
structurally complex structures. During the past decade, directing groups have revolutionized molecular synthesis in terms of ortho-
selective C–H activation. In sharp contrast, a selectivity switch that guides the typical ortho- to remote meta-C–H activation has thus
far proven elusive. Herein, we describe the realization of such a concept for a robust selectivity-control in ruthenium-catalysis. The
distal C–H transformation was guided by key mechanistic insights into the mild, synergistic action of carboxylates and phosphines
in ruthenium(II) catalysis. Our findings allowed remote selectivity in broadly-effective late-stage diversification of structurally
complex drugs and natural product molecules, tolerating sensitive fluorescent dyes, drugs, lipids, peptides, nucleosides and
carbohydrates.
KEYWORDS: C–H activation, ruthenium, meta-selectivity, remote functionalization, late-stage diversification, DFT, purines
a)
2-py
H
INTRODUCTION
off
ortho
Ru
The transformation of otherwise inert C–H bonds has
emerged as an increasingly powerful tool in molecular sciences,
with transformative applications to among others material
sciences, drug discovery, crop protection and pharmaceutical
industries.1 The key towards the development of synthetically
useful C–H transformation is the full control of site selectivity.2
In this regard, chelation assistance has been identified as a
particularly effective approach towards proximity-induced
ortho-C–H functionalization.3 In sharp contrast, considerably
more challenging remote C–H functionalizations continue to be
in high demand.4 In this context, notable recent progress was
accomplished through ruthenium catalysis,5 with meta-
benzylations being underdeveloped.5h, 5i Particularly, the distal
late-stage diversification of bioactive compounds6 bears unique
potential for the identification of novel therapeutic agents of
relevance to agrochemical and pharmaceutical industries.7
2-py
H
H
switch ortho to meta
+
Cl
PR3
2-py
H
Ru
PR3
on
meta
b)
O
n(HO)
Sugar
Nucleoside
Drug
A2
N
N
N
N
N
N
N
N
R
N
N
N
N
R
R
BODIPY
A1
Fluorescent Tag
Amino Acids/Peptides
N
N
N
N
N
N
N
N
Lipid
N
R
N
N
N
R
R
Figure 1. Site selectivity control by ortho- to meta-selective
ruthenium-catalyzed C–H functionalization switch. a)
Mechanistic insights enable a general platform for site-selective
C–H benzylation by phosphine/carboxylates cooperation in
ruthenium catalysis. b) Transformative ruthenium-catalyzed
remote meta-C–H functionalizations of biorelevant molecules,
featuring saccharides, nucleosides, amino acids, peptides,
triglycerides, and fluorescence labeling.
5i,
8
5l, 5m
While the effect of phosphate5a,
and phosphine5c-e,
additives has been noted, a mechanistic rationale for the meta-
selectivity has proven elusive. Based on detailed mechanistic
insights into the cooperative action of carboxylates and
phosphines in ruthenium9 catalysis, we have now unravelled a
uniquely versatile manifold for the chemo-selective late-stage
modification of structurally complex molecules (Figure 1a).
Notable features of our findings include (i) the cooperative
action of ruthenium(II) biscarboxylates and phosphines for a
programmable ortho- to meta-C–H functionalization switch,
(ii) mild reaction conditions, (iii) tolerance of a broad range of
functional groups, and (iv) bioorthogonal late-stage C–H
conjugation of biorelevant motifs, including monosaccharides,
nucleotides, amino acids, peptides, and triglycerides, as well as
BODIPY labels for fluorescence spectroscopy (Figure 1b).
RESULTS AND DISCUSSION
Given the unique potential of ruthenium catalysis for remote
arene functionalization, we set out to delineate the coordination
environment of the key C–H activated ruthenacycles towards
meta-selective C–H functionalization (Scheme 1). The
cooperation of [Ru(OAc)2(p-cymene)] with a phosphine10
ligand resulted in the meta-benzylated product 3aa (Scheme
1a).11 In the absence of the phosphine ligand, the selectivity
completely switched from meta to ortho, yielding 4aa.
Likewise, the ruthenium complex Ru-I gave by carboxylate
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a) Synthesis of Cyclometallic Complex
assistance the ortho-substituted products 4aa (Scheme 1b). In
PPh3
O
Ru
[Ru(OAc)2(p-cymene)]
1
2
sharp contrast, the cooperative action of carboxylates and
phosphines led again to a switch in site-selectivity to furnish the
meta-decorated arene 3aa upon the judicious addition of
phosphine. The sole action of phosphine complexes gave
unsatisfactory results.
2-py
H
H
Me
(1 equiv)
O
N
PPh3 (2 equiv)
THF, 60 °C, 4 h
PPh3
3
4
1a
Ru-II
82%
(mixture cis- and trans-isomer = 1:1)
Ru-II
trans-
CCDC 1915676
PF6
NCMe
NCMe
5
6
7
8
TBAOAc (1 equiv)
Ru-II
trans-
48%
Ru
NCMe
N
PPh3 (2 equiv)
1,4-dioxane, 60 °C, 1 h
NCMe
a) Selectivity Switch
Ru-I
Me
iPr
Me
Ph3P
2-py
H
PPh
with
Ru
3
O
N
Ar
TBAOAc (1 equiv)
MeCO2
Me
Ru
O
O
O
Ru-I
9
N
Ru-III
CCDC 1915689
PPh3 (1 equiv)
1,4-dioxane, 60 °C, 1 h
(10 mol %)
2-py
H
H
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Me
3aa
: 55%
Ar
Ru-III
Ar
Cl
75%
K2CO3 (2 equiv)
1,4-dioxane, 20 h
Ar = 4-MeOC6H4
2-py
H
[Ru(OAc)2(p-cymene)]
2a
1a
O
2-py
H
H
(1 equiv)
Ph2P
PPh
without
PPh2
O
3
Ru
O
DPEPhos (1 equiv)
THF, 60 °C, 4 h
Ar
4aa
N
: 91%
1a
(mono:di = 1:3.8)
Me
Ru-IV
65%
Ru-IV
CCDC 1915688
b) Position-Switch by Cooperativity
PF6
NCMe
NCMe
b) Catalytic Reaction
2-py
Ru
NCMe
N
NCMe
H
Ar
2-py
H
[Ru] (10 mol %)
K2CO3 (2 equiv)
1,4-dioxane, 60 °C, 20 h
Ar = 4-MeOC6H4
Ar
Ar
Cl
Ru-I
(10 mol %)
2-py
H
2-py
H
2-py
H
Ar
+
H
Ar
Cl
H
2a
3aa
1a
K2CO3 (2 equiv)
1,4-dioxane, 60 °C, 20 h
Ar = 4-MeOC6H4
Ar
Ru-II
trans-
Ru-III
Ru-IV
54% (39%)
59% (50%)
0% (0%)
2a
3aa
4aa
1a
PPh3 KOAc
(9%)
(5%)
(14%, only mono)
(2%, only mono)


Ru-II
c) Stoichiometric Reaction of
PPh3
 
 
 
1. K2CO3 (2 equiv)
2-py
H
1,4-dioxane, 80 °C, 20 h
O
Me
Ar
Ru
---
66% (76%, mono:di = 1.0:7.4)
(15%, mono:di = 1.0:2.8)
Ar
Cl
O
N
2. bpy (3 equiv)
AcOH (5 equiv)
1,2-DCE, rt, 16 h
Ar = 4-MeOC6H4
PPh3
Ru-II
72% (80%)
2a
3aa
Ru-II
40%
48%
cis-/trans-
Scheme 1. Switching selectivity. a) Switch of site selectivity
by carboxylate and phosphine cooperation. b) Identification of
synergistic carboxylate/phosphine assistance with well-defined
complex Ru-I. The conversion in parentheses was determined
by 1H-NMR using 1,3,5-trimethoxybenzene as the internal
standard.
Ru-II
trans-
d) Reaction with Radical Scavenger
[Ru(OAc)2(p-cymene)]
(10 mol %)
PPh3 (10 mol %)
2-pym
H
2-pym
H
H
Ar
+
+
Ar
TEMPO
Ar
Cl
K2CO3 (2 equiv)
1,4-dioxane, 60 °C, 20 h
Ar = 4-MeOC6H4
1d
2a
3da
59%
0%
9
---
TEMPO
without
Given this switch in selectivity, we became intrigued to
prepare a series of well-defined ruthenacyles Ru-I–Ru-V,
among others the novel ruthenium(II) complexes Ru-II, Ru-
III, and Ru-IV. All new complexes were fully characterized,
including X-ray diffraction analysis, as depicted in Scheme 2a.
Here, the unique selectivity of the carboxylate and phosphine
synergistic cooperation was reflected by the efficacy of
ruthenacycles Ru-II and Ru-III with two and one phosphines,
respectively (Scheme 2a), both of which were effective in
catalytic transformations (Scheme 2b). In contrast, the
ruthenacycle Ru-IV with a bidentate bisphosphine failed to
provide the desired product 3aa.12 The stoichiometric
experimentation further reflected the central importance of
carboxylate and phosphine additives for the meta-selective C–
H functionalization manifold (Scheme 2c). These findings are
in good agreement with an analysis of the optimal metal to
ligand stoichiometry that featured an ideal ruthenium to
phosphine ratio of 1:1, with an excess of phosphine being
beneficial.12 The typically used radical scavenger12 (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) fully inhibited the
ruthenium-catalyzed meta-C–H functionalization (Scheme 2d).
Instead, the TEMPO-adduct was isolated, being indicative of
homolytic C–X scission by single-electron-transfer to deliver
an alkyl radical.
TEMPO
17%
with
(1 equiv)
Scheme 2. Mechanistic Studies. a) Synthesis of ruthenacycles
Ru-II–Ru-IV. b) Catalytic meta-C–H functionalization. The
yield in parentheses was obtained in the absence of KOAc. c)
Stoichiometric transformations of ruthenacycles. d) Reaction
with radical scavenger.
We have previously studied site-selectivity of the meta-C−C
5e
formation by means of Fukui indices analysis.5d, In stark
contrast, we here probed the nature of the thus-formed key
intermediate by DFT calculation at the PBE0-
D3(BJ)/def2-TZVP+SMD(1,4-dioxane)//TPSS-
D3(BJ)/def2-TZVP level of theory (Figure 2).12 Our detailed
orbital analysis unravel for the first time a mechanistic rational
for the site-selective C–C formation para to ruthenium. Thus,
the highly reactive triplet radical is significantly stabilized as
the singlet metallacycle C by 20 kcal mol–1 via ligand-to-metal
charge transfer.
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PF6
Me
PPh3
O
Ru
NCMe
NCMe
Ph3P
Ru
Triplet state
N
Me
1
2
3
4
5
6
Ru
O
NCMe
O
N
N
N
WBI = 0.83
PPh3
PPh3
NCMe
O
H
O
Me
Me
Ar
Ru
Cl
O
Ru-I
Ru-II
Ru-III
trans-
N
60
Blank
2-Phpy
PPh3
B
20.0 kcalmol1
40
20
0
Ru-I
trans-Ru-II
Ru-III
single occupied metal orbital single occupied ligand orbital
7
8
9
Singlet state
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WBI = 1.18
PPh3
H
O
Me
-20
-40
Ar
Ru
N
O
Cl
C
0.0 kcalmol1
-0.5
0.0
0.5
1.0
1.5
2.0
double occupied metal orbital
vacant ligand orbital
Potential (V vs Ag/AgCl)
Me
iPr
Figure 2. Computational DFT analysis unravels significant
stabilization of the singlet ruthenacycle by 20 kcal mol–1. WBI
= Wiberg Bond Indices.
O
Ru
Ph2P
OAc
PPh2
Ru
N
N
O
O
Me
Moreover, cyclic voltammetry studies of ruthenacycles Ru-
I, Ru-II, Ru-III, and Ru-IV showed reversible redox processes
at E1/2 = 0.75 V (Ru-I), E1/2 = 0.32 V (trans-Ru-II), E1/2
0.47 V (Ru-III), and E1/2 = 0.44 V (Ru-IV) versus Ag/AgCl,
respectively (Figure 3). Contrarily, the p-cymene-coordinated
ruthenacycle Ru-V exhibited an irreversible oxidation event at
E = 0.81 V.
Ru-IV
Ru-V
Blank
=
2-Phpy
DPEPhos
Ru-IV
60
40
20
0
Ru-V
-20
-40
-0.5
0.0
0.5
1.0
1.5
2.0
Potential (V vs Ag/AgCl)
Figure 3. Cyclic voltammetry studies in 1,2-DCE containing
0.1 mol L–1 nBu4NPF6, scan rate 100 mV s–1.
A plausible catalytic cycle, hence, features carboxylate-
assisted ortho-C–H ruthenation to generate complex Ru-II
(Scheme 3). Then, single-electron-transfer (SET) from the
ruthenium(II) complex Ru-II to the benzyl halide 2, generates
the ruthenium-(III) intermediate A. The benzyl radical attacks
on the arene moiety at the position para to ruthenium, providing
triplet species B. Next, ligand-to-metal charge transfer leads to
the significantly stabilized singlet ruthenacycle C. Finally, re-
aromatization and ligand exchange delivers the desired meta-
benzylated product 3 and regenerates ruthenium(II) complex
Ru-II.
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2-py
[Ru(OAc)2(p-cymene)]
(10 mol %)
H
Cl
PPh3 (10 mol %)
[Ru(OAc)2(p-cymene)]
PPh3
+
+
H
1
2
3
4
5
6
7
8
N
N
H
K2CO3 (2 equiv)
1,4-dioxane, 6080 °C, 20 h
H
H
1
2-py
1
2
3
AcOH
+
p-cymene
H
Ar = 4-MeOC6H4
primary benzylation
Ar
Cl
Ar
OMe
PPh3
O
Me
O
2
3
Ru
N
2-py
2-pym
Ar
Ar
N
H
Ar
PPh3
Ru-II
1
H
R1
H
R2
3da
R1 = H
R1 = OMe (
(
): 55%
CCDC 1915683
R2 = H (
R2 = F (
): 59%
ligand exchange
single-electron
transfer
3aa
3ca
: 65%
3da
3ba
): 62%
3ea
): 51%
PPh3
O
Ar
9
Me
PPh3
Ru
O
N
O
O
Me
N
10
11
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2-pym
Ru
Cl
A
O
H
R4
H
PPh3
Ar
N
H
.
R3
H
D
N
N
H
N
N
Ar
3ea
CCDC 1915686
R3 = H
R3 = Br (
(
3db
: 52%
3fa
): 60%
3ga
): 50%
i-Pr
KHCO3, KCl
re-
R4 = H
(
(
(
(
(
(
(
): 71%
): 74%
): 62%
): 73%
): 72%
3hb
3ha
3hc
3hd
3he
3hf
aromatization
radical addition
R4 = OMe
R4 = Me
R4 = CF3
R4 = CO2Et
R4 = F
R4 = Cl
R4 = Br
Ar
PPh3, K2CO3
H
3hf
N
N
N
): 71%
CCDC 1915675
PPh3
O
PPh3
O
Ru
3hg
): 73%
(3hh): 70%
H
H
N
Me
Me
Ar
Ru
Ar
O
O
N
N
Cl
Cl
C
3ia
CCDC 1915681
B
Me
O
3ia
: 68%
3hg
F
CCDC 1915610
Ar
Scheme 3. The proposed catalytic cycle highlights meta-
selective C–H functionalization by singlet stabilization para
to ruthenium.
Ar
H
N
N
Me
H
H
N
N
N
N
N
N
N
N
N
N
i-Pr
O
To explore the synthetic utility of the carboxylate-phosphine
cooperation, we probed its robustness with a representative set
of arenes 1 and electrophiles 2 under the optimized reaction
conditions (Scheme 4). Our strategy proved to be generally
applicable for primary and secondary meta-benzylations,
leading to monobenzylated products without the observation of
dialkylated products. The ruthenium catalyst was not limited to
pyridine guidance, but indeed also allowed for the use of
transformable oxazolines and biorelevant purine bases.13 The
mild reaction conditions were mirrored by fully tolerating
sensitive functional groups, including ester (3he), halides (3hf–
3hh),14 ketone (3ia), and amide (3la). Likewise, twofold meta-
C–H functionalization proved to be viable, providing bis-purine
hybrid 3hk. The connectivities of the meta-products 3 were
unambiguously confirmed by two-dimensional nuclear
magnetic resonance (2D-NMR) spectroscopy and X-ray crystal
structure analyses for select compounds.
N(i-Pr)2
3jc
: 50%
3la
O
: 63%
CCDC 1915682
3ka
3la
: 75%
H
MeO
N
H
H
N
H
N
OMe
N
N
N
N
N
N
N
N
N
N
N
N
N
i-Pr
i-Pr
i-Pr
3hk
: 48%
i-Pr
3hi
3hj
: 67%
: 67%
secondary benzylation
Me
2-pym
H
R5
): 68%, 68%,a (1%)b
R5 = H
R5 = F
(
Me
3dl
3dl
3dm
CCDC 1915687
CCDC 1915684
3dm
(
): 81%
H
Me
Me Cl
O
Me
2-py
H
2-pym
H
N
N
N
N
N
H
i-Pr
3al
3dn
3fl
: 52%
: 74%
: 52%
3hl
: 87%
Scheme 4. Ruthenium-catalyzed remote meta-C–H
functionalization by carboxylate-phosphine cooperation
occurs with ample substrate scope in a programmable
manner. a With Ru(OAc)2(PPh3)2 (10 mol %) as the catalyst at
100 °C. b Without PPh3, determined by H-NMR using 1,3,5-
1
trimethoxybenzene as the internal standard.
The singlet stabilization manifold was not restricted to
synergistic cooperation towards simple electrophile
transformations. Instead, the transformative potential of our
approach was harnessed for the late-stage diversification with
fluorescence labels of relevance to spectroscopy (Scheme 5).
Thus, purine bases were directly transformed with BODIPY
labels by the singlet stabilization in carboxylate-phosphine
ruthenium catalysis (6a and 6b). Electrophiles bearing amino
acids were efficiently converted to meta-products 6c–6i with
high levels of chemo-selectivity without any evidence for
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racemization. Thereby, otherwise reactive free hydroxyl groups
marketed drugs was accomplished, including transformations
of neuroprotective agent gastrodin, and the fully anti-
inflammatory salicin. The ruthenium catalysis was not
restricted to benzylic electrophiles, but synthetically useful
monosaccharide bromoesters furnished the desired meta-
products 6u–6w with high catalytic efficacy. Notably, hybrids
6x and 6y were obtained by the synergistic catalysis via
unprecedented nucleoside ligation. It is noteworthy that for the
first time fully unprotected OH-free monosaccharides proved to
be amenable substrates (6t).
1
2
3
4
5
6
7
8
in serine and tyrosine as well as free NH-indole in tryptophan
were fully tolerated. Even more structurally complex peptides
underwent the desired chemical ligation15 towards products 6j
and 6k, featuring among others sensitive methionine. The
synergistic ruthenium(II) catalyst proved also fully compatible
with vitamin D-a-tocopherol (6l), and triglycerides derived
from saturated and unsaturated fatty acids (6m–6p).
Particularly, the chemo-selectivity of the meta-C–H
transformation in the presence of unsaturated fatty acids is
noteworthy, since they are normally prone to olefinic and allylic
functionalizations. Importantly, the late-stage modification of
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R3
H
N
R2
[Ru(OAc)2(p-cymene)]
(10 mol %)
PPh3 (10 mol %)
1
2
3
4
H
H
X
N
N
R1
R2 R3
N
N
K2CO3 (2 equiv)
1,4-dioxane, 6080 °C, 20 h
N
R1
N
N
1
5
6
5
BODIPY Labeling
Amino Acids
6
7
8
9
Me
Me
H
H
MeO2C
Me
N
MeO2C
Me
N
Me
Me
N
B
H
H
N
N
B
H
H
F
F
O
O
N
N
N
N
N
N
Me
Me
N
N
N
N
N
Me
N
F
F
EtO
EtO
O
Me
O
EtO
EtO
N
O
N
N
N
N
Me
P
Me
P
O
i-Pr
i-Pr
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
O
6a
: 45%
6a
6b
: 15%
6c
6d
: 59%
: 74%
CCDC 1915685
Me Me
Me Me
H
H
H
H
H
N
MeO2C
Me
N
MeO2C
Me
N
MeO2C
HO
N
MeO2C
S
N
MeO2C
H
H
H
H
H
O
O
O
O
O
N
N
N
N
N
N
N
N
Me
N
Me
N
N
N
N
HN
N
N
N
N
N
N
N
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me
6h
: 67%
S-6f: 50% (98% ee, from R-Cl >99% ee)
6g: 79%
S-6e: 70% (>99% ee)
R-Cl (>99% ee)
R-6e: 77% (>99% ee)
R-Cl (>99% ee)
6f
rac- : 55% (0% ee, from R-Cl 0% ee)
Dipeptides
Me
S
O
H
Me
H
MeO2C
N
N
O
N
Me
O
H
H MeO2C
N
H
N
H
H
O
O
Me
O
N
N
N
N
N
N
N
HN
MeO2C
Me
O
N
Me
Me
Me
O
Me
N
Me
N
N
HO
N
N
N
Me
N
Me
i-Pr
i-Pr
i-Pr
i-Pr
Me
6j
: 72%
6k
: 74%
6l
: 65% (from Vitamin E or D-Tocopherol)
6i
: 53%
Triglycerides
Me
Me
O
O
O
O
O
O
Me
O
Me
O
H
H
O
O
O
O
N
N
N
N
N
N
6n
: 70% (from Lauric acid)
R-6m: 75% (98% ee, from R-Cl 92% ee)
rac- : 75% (2% ee, from R-Cl 6% ee)
TBSO
N
N
6m
O
i-Pr
(from Lauric acid)
TBSO
Me
Me
O
O
O
O
O
O
O
O
Me
H
Me
H
O
O
O
O
O
N
N
N
N
N
N
EtO
EtO
N
N
P
O
i-Pr
O
6o
6p
: 55% (from Oleic acid)
: 71% (from Oleic acid)
O
O
Me Me
HO
HO
OH
Monosaccharides
OH
OAc
OAc
OAc
O
O
O
O
O
O
O
O
AcO
AcO
AcO
AcO
AcO
H
AcO
H
H
AcO
AcO
AcO
N
N
N
N
N
N
N
N
N
H
EtO
EtO
O
P
AcO
N
N
N
N
N
N
O
O
i-Pr
O
N
O
O
AcO
OAc
i-Pr
6t
: 55% (from Salicin)
Me Me
: 69% (from Gastrodin)
6q
6r
6s
: 71% (from Gastrodin)
: 67% (from Gastrodin)
Me
Me
Me
O
O
O
O
Me
Me
Nucleoside Ligation
O
O
O
O
O
Me
Me
Me
Me
O
O
O
O
Me Me
Me Me
O
O
O
O
O
O
Me
HO
Me
O
O
O
O
Me
Me
Me
O
O
O
O
O
N
H
O
N
H
H
H
H
O
O
N
N
N
N
N
N
N
N
HN
N
HN
N
N
N
N
EtO
EtO
P
O
N
N
O
N
O
N
N
N
N
O
i-Pr
i-Pr
i-Pr
i-Pr
O
O
O
6u
6v
6w
6x
6y
: 54%
: 76%
: 68%
: 55% (from Uridine)
: 37% (from Uridine)
Me Me
Scheme 5. Carboxylate-phosphine cooperation allows for late-stage diversification by singlet stabilization in terms of meta-
C–H functionalization of arenenucleobases with fluorescence tags, peptides, lipids, drugs, unprotected sugars and nucleosides.
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overview of directing groups applied in metal-catalysed C–H
CONCLUSIONS
functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603–6743. (b)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C−C
Bond Formation via Heteroatom-Directed C−H Bond Activation.
Chem. Rev. 2010, 110, 624–655. (c) Satoh, T.; Miura, M. Oxidative
Coupling of Aromatic Substrates with Alkynes and Alkenes under
Rhodium Catalysis. Chem. Eur. J. 2010, 16, 11212–11222. (d) Chen,
X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Palladium(II)-Catalyzed C–
1
2
3
4
5
6
7
8
Mechanistic insights into the working mode of ruthenium-
catalyzed meta-C–H functionalization have unraveled
a
carboxylate-phosphine synergistic manifold for effective
singlet stabilization. Thereby, a uniquely effective catalytic
system for remote arene functionalization was identified for
remote C–H functionalization, fully tolerating purine and
uridine nucleobases, sensitive lipids, functionalized amino
acids and peptides, fluorescent tags as well as unprotected sugar
motifs. The high levels of site- and chemo-selectivity of our
robust, synergistic ruthenium catalysis should prove invaluable
for enabling late-stage modifications of biorelevant compounds
in academia as well as by practitioners in agrochemical and
pharmaceutical industries.
H
Activation/C–C Cross-Coupling Reactions: Versatility and
Practicality. Angew. Chem. Int. Ed. 2009, 48, 5094–5115.
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Yrezabal, I. J.; Larrosa, I. Cyclometallated ruthenium catalyst enables
late-stage directed arylation of pharmaceuticals. Nat. Chem. 2018, 10,
724–731. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak
Coordination as a Powerful Means for Developing Broadly Useful C–
H Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788–802. (c)
Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-Directed
C−H Functionalization Reactions. Chem. Rev. 2010, 110, 1147–1169.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data for all new compounds
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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Nature 2017, 551, 489–493. (b) Kuninobu, Y.; Ida, H.; Nishi, M.;
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interaction between ligand and substrate. Nat. Chem. 2015, 7, 712–717.
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M.; Yu, J.-Q. Ligand-enabled meta-C–H activation using a transient
mediator. Nature 2015, 519, 334–338. (d) Leow, D.; Li, G.; Mei, T.-S.;
Yu, J.-Q. Activation of remote meta-C–H bonds assisted by an end-on
template. Nature 2012, 486, 518–522. (e) Phipps, R. J.; Gaunt, M. J. A
Meta-Selective Copper-Catalyzed C–H Bond Arylation. Science 2009,
323, 1593–1597. (f) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R.
E.; Smith, M. R. Remarkably Selective Iridium Catalysts for the
Elaboration of Aromatic C–H Bonds. Science 2002, 295, 305–308.
AUTHOR INFORMATION
Corresponding Author
*Lutz.Ackermann@chemie.uni-goettingen.de (L.A.)
ORCID
Lutz Ackermann: 0000-0001-7034-8772
Notes
(5)
(a) Gandeepan, P.; Koeller, J.; Korvorapun, K.; Mohr, J.;
The authors declare no competing financial interest.
Ackermann, L. Visible-Light-Enabled Ruthenium-Catalyzed meta-
C−H Alkylation at Room Temperature. Angew. Chem. Int. Ed. 2019,
58, 9820–9825. (b) Sagadevan, A.; Greaney, M. F. meta-Selective C−H
Activation of Arenes at Room Temperature Using Visible Light: Dual-
Function Ruthenium Catalysis. Angew. Chem. Int. Ed. 2019, 58, 9826–
9830. (c) Wang, X.-G.; Li, Y.; Liu, H.-C.; Zhang, B.-S.; Gou, X.-Y.;
Wang, Q.; Ma, J.-W.; Liang, Y.-M. Three-Component Ruthenium-
Catalyzed Direct Meta-Selective C–H Activation of Arenes: A New
Approach to the Alkylarylation of Alkenes. J. Am. Chem. Soc. 2019,
141, 13914–13922. (d) Fumagalli, F.; Warratz, S.; Zhang, S.-K.;
Rogge, T.; Zhu, C.; Stückl, A. C.; Ackermann, L. Arene-Ligand-Free
Ruthenium(II/III) Manifold for meta-C−H Alkylation: Remote Purine
Diversification. Chem. Eur. J. 2018, 24, 3984–3988. (e) Korvorapun,
K.; Kaplaneris, N.; Rogge, T.; Warratz, S.; Stückl, A. C.; Ackermann,
L. Sequential meta-/ortho-C–H Functionalizations by One-Pot
Ruthenium(II/III) Catalysis. ACS Catal. 2018, 8, 886–892. (f) Mihai,
M. T.; Genov, G. R.; Phipps, R. J. Access to the meta position of arenes
through transition metal catalysed C–H bond functionalisation: a focus
on metals other than palladium. Chem. Soc. Rev. 2018, 47, 149–171.
(g) Leitch, J. A.; Frost, C. G. Ruthenium-catalysed σ-activation for
remote meta-selective C–H functionalisation. Chem. Soc. Rev. 2017,
46, 7145–7153. (h) Li, B.; Fang, S.-L.; Huang, D.-Y.; Shi, B.-F. Ru-
Catalyzed Meta-C–H Benzylation of Arenes with Toluene Derivatives.
Org. Lett. 2017, 19, 3950–3953. (i) Li, G.; Li, D.; Zhang, J.; Shi, D.-
Q.; Zhao, Y. Ligand-Enabled Regioselectivity in the Oxidative Cross-
coupling of Arenes with Toluenes and Cycloalkanes Using Ruthenium
Catalysts: Tuning the Site-Selectivity from the ortho to meta Positions.
ACS Catal. 2017, 7, 4138–4143. (j) Li, J.; Korvorapun, K.; De Sarkar,
S.; Rogge, T.; Burns, D. J.; Warratz, S.; Ackermann, L. Ruthenium(II)-
catalysed remote C–H alkylations as a versatile platform to meta-
decorated arenes. Nat. Commun. 2017, 8, 15430. (k) Li, Z.-Y.; Li, L.;
Li, Q.-L.; Jing, K.; Xu, H.; Wang, G.-W. Ruthenium-Catalyzed meta-
Selective C−H Mono- and Difluoromethylation of Arenes through
ortho-Metalation Strategy. Chem. Eur. J. 2017, 23, 3285–3290. (l)
Paterson, A. J.; Heron, C. J.; McMullin, C. L.; Mahon, M. F.; Press, N.
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secondary and tertiary C–H alkylations by ruthenium catalysis. Org.
ACKNOWLEDGMENT
Generous support by the DAAD (fellowship to K.K.) and the DFG
(Gottfried-Wilhelm-Leibniz prize) is gratefully acknowledged. We
thank Dr. Christopher Golz (University Göttingen) for the X-ray
diffraction analysis.
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Cost-effective triphenylphosphine (PPh3) was selected from
23 different phosphine ligands in the synergistic ruthenium(II) meta-
C–H benzylation. See the supporting information for more details.
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Ru(OAc)2(PPh3)2 as the catalyst was effective in the remote
functionalization at 100 °C, while it failed to give conversion at a lower
reaction temperature of 60 °C.
(12)
(13)
For detailed information, see the Supporting Information.
Under identical reaction conditions, azobenzenes, O-
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