Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals

Article abstract of DOI:10.1038/s41557-018-0062-3

Biaryls are ubiquitous core structures in drugs, agrochemicals and organic materials that have profoundly improved many aspects of our society. Although traditional cross-couplings have made practical the synthesis of many biaryls, C-H arylation represents a more attractive and cost-effective strategy for building these structural motifs. Furthermore, the ability to install biaryl units in complex molecules via late-stage C-H arylation would allow access to valuable structural diversity, novel chemical space and intellectual property in only one step. However, known C-H arylation protocols are not suitable for substrates decorated with polar and delicate functionalities, which are commonly found in molecules that possess biological activity. Here we introduce a class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily functionalized substrates. The design and development of this class of catalysts was enabled by a mechanistic breakthrough on the Ru(ii)-catalysed C-H arylation of N-chelating substrates with aryl (pseudo)halides, which has remained poorly understood for nearly two decades.

Full text of DOI:10.1038/s41557-018-0062-3

Articles
https://doi.org/10.1038/s41557-018-0062-3
Cyclometallated ruthenium catalyst enables
late-stage directed arylation of pharmaceuticals
Marco Simonetti1,2, Diego M. Cannas1,2, Xavier Just-Baringo1, Iñigo J. Vitorica-Yrezabal1 and Igor Larrosa1*
Biaryls are ubiquitous core structures in drugs, agrochemicals and organic materials that have profoundly improved many
aspects of our society. Although traditional cross-couplings have made practical the synthesis of many biaryls, C–H arylation
represents a more attractive and cost-effective strategy for building these structural motifs. Furthermore, the ability to install
biaryl units in complex molecules via late-stage C–H arylation would allow access to valuable structural diversity, novel chemi-
cal space and intellectual property in only one step. However, known C–H arylation protocols are not suitable for substrates
decorated with polar and delicate functionalities, which are commonly found in molecules that possess biological activity. Here
we introduce a class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily function-
alized substrates. The design and development of this class of catalysts was enabled by a mechanistic breakthrough on the
Ru(ii)-catalysed C–H arylation of N–chelating substrates with aryl (pseudo)halides, which has remained poorly understood for
nearly two decades.
he installation of the biphenyl fragment via cross-coupling valuable when exploring new target classes that necessitate different
reactions has become a staple of drug design1,2. Due to the spatial arrangements to bind and attain the desired effect2.
T
pivotal role of aromatic non-covalent interactions in protein–
In the context of ortho-directed C–H arylation reactions with
ligand recognition3, the placement of aryl motifs in drug candidates aryl (pseudo)halides, whereas palladium-catalysed processes are by
can lead to derivatives with higher activities4–7. Although during far the most studied13,28–33, the use of ruthenium often brings several
the past years some statistical studies have tried to start to ratio- benefits. In addition to being more than 15 times cheaper than pal-
nalize the impact of aromatic ring count on drug developability8–10
,
ladium, electrophiles such as aryl chlorides, triflates and bromides
it is widely acknowledged that only a small portion of the avail- can be coupled by ruthenium with similar levels of efficiency13,34
.
able chemical space has been explored and that safe compounds Since the pioneering work on the Ru(ii)-catalysed C–H arylation
can be identified outside the conventional drug-like chemical of DG-containing arenes with aryl halides in 200135, tremendous
space8,11,12. Consequently, the development of reliable C–H aryla- efforts have been dedicated towards the establishment of more
tion technologies would provide a more sustainable alternative to general and efficient reaction conditions13,34,36–40. However, state-of-
cross-coupling reactions13 and grant access to a rapid and valuable the-art methodologies still require high temperatures and often a
explorationofthestructuraldiversityvialate-stageC–Harylation14–17
,
several-fold excess of the aryl (pseudo)halide (Fig. 1a). Furthermore,
which would make them extremely desirable within drug discovery the exceptional binding affinity of the Ru(ii) metal centre to sp2
and development. nitrogen atoms—widespread in ortho DGs—has not flourished
The vast majority of drugs contain several polar functionalities, as an in-built selection device able to discriminate between sp2
often as part of oxygen, nitrogen and sulfur heterocycles18–20, that nitrogens over other heteroatoms or functional groups that pos-
are essential to maximize the drug–target interaction and main- sess lesser coordinating abilities. Thus, directed Ru(ii)-catalysed
tain acceptable levels of pharmacokinetics and toxicity21. However, C–H activation reactions have yet to be shown to withstand polar
despite the need to manipulate polar functionalities in medicinal sensitive groups, which are ubiquitous in pharmaceuticals and
chemistry, a statistical analysis revealed that “the more polar prod- natural products. This is probably because the harsh working
ucts in an array tended to systematically fail more often in synthesis”, conditions commonly required in these methodologies facilitate
which may correlate with the crisis of productivity of the drug-dis- detrimental reaction paths, either by preventing the desired DG–
covery process22. Specifically, polar groups are often problematic in catalyst interaction or by initiating thermal decomposition of these
C–H activation as the presence of Lewis basic heteroatoms can pro- delicate functionalities.
mote catalyst poisoning or substrate decomposition23–25. Moreover,
Here we report the discovery of a key catalytic species in the
in directed C–H activation reactions, strongly coordinating moi- mechanism of the Ru(ii)-catalysed C–H arylation of DG-containing
eties add a further challenge as they can outcompete the directing arenes with aryl (pseudo)halides. For nearly two decades, this reac-
group (DG) for catalyst binding, and thus prevent its approach into tion has been proposed to operate via a catalytic cycle (Fig. 1b) that
the proximity of the targeted C–H bond26. Nonetheless, despite the involves an initial C–H activation step to form cycloruthenated spe-
historical bias towards para-substitution observed in medicinal cies I, which undergoes oxidative addition with the aryl halide to
chemistry, which favours the synthesis of ‘flat’ products27, ortho- generate the Ru(iv) intermediate II. The latter, after the reductive
directed C–H activation protocols have the capability of expanding elimination step, will then release the biaryl product, which restarts
the chemical space. Due to the twisting and disruption of the planar the cycle13,34,41,42. We speculate that this oversimplified mechanism
structure, ortho regioisomers have different physicochemical prop- has, to date, prevented the discovery of truly reactive catalysts.
erties relative to para and meta ones, and they may prove themselves Contrary to previous postulations, our mechanistic investigations
1School of Chemistry, University of Manchester, Manchester, UK. 2These authors contributed equally: Marco Simonetti, Diego M. Cannas.
*e-mail: igor.larrosa@manchester.ac.uk
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NATuRe CHemisTRy
Articles
a
c
Me
iPr
N
N
N
Ru II
Ru II
N
N
H
H
II
Ru
H
X
RuA
+
I
High temperature
N
Excess
Poor atom economy
Limited substrate scope
N
Revised
catalytic
cycle
Ru II
b
N
N
III
N
N
H
RuIV
N
X
Ru II
X
IV
Postulated
for nearly
2 decades
d
cat.
N
N
9 functional
molecules
N
N
N
Ru II
N
IV
Ru
Ru
H
X
RuB
34 examples
10 examples
4 examples
I
X
II
Low temperature
X
N
34 functional
molecules
Ideal atom economy
Greatly improved
substrate scope
Fig. 1 | ru(ii)-catalysed C–h arylation of DG-containing arenes with aryl (pseudo)halides. a, State-of-the-art methodologies that rely on common Ru(ii)
catalysts still suffer from limited functional group compatibility and poor atom economy. b, Previously proposed catalytic cycle for the C–H arylation
reaction (for clarity, not all of the ligands on ruthenium are shown). c, This revised catalytic cycle for the C–H arylation reveals the crucial formation of
intermediate III prior to the oxidative addition step. d, Establishment of cyclometallated Ru(ii) complexes (RuB) as superior catalysts, which enabled the
coupling of complex functional molecules.
Me
(PF6)
(PF6)
Me
Me
Me
Me
N
N
iPr
N
iPr
MeCN
Ru(MeCN)4
I
Ru
N
Me
Me
Me
Me
Me
Ru1
Ru2
1 ( )
2
3 ( )
4 ( )
2 (2 equiv.)
KOAc (2 equiv.)
2 (2 equiv.)
KOAc (2 equiv.)
Ru1
(1 equiv.)
Ru2
(1 equiv.)
2 (2 equiv.)
KOAc (2 equiv.)
2 (2 equiv.)
KOAc (2 equiv.)
Ru2
(1 equiv.)
Ru1
(1 equiv.)
+
+
1
1 + 3 + 4
1 + 4
1 + 3 + 4
1 + 4
NMP, 90 °C
With time
NMP, 90 °C
With time
NMP, 90 °C
With time
NMP, 90 °C
With time
1
(0.2 equiv.)
(0.2 equiv.)
i
ii
iii
iv
10
60
60
60
60
10
6
0
0
40
20
40
20
40
20
40
20
10
0
0
10 16
30
0
0
0
0
0
0
0
0
10
20
10
20
30
10
20
30
10
20
30
Time (min)
Time (min)
Time (min)
Time (min)
Fig. 2 | Kinetic evidence that supports the involvement of a bis-cycloruthenated intermediate in the ru-catalysed C–h arylation of DG-containing
arenes with aryl (pseudo)halides. Reaction kinetic profiles for the stoichiometric arylation of Ru1 (i and iii) and Ru2 (ii and iv) with 5-iodo-m-xylene 2
in the absence (i and ii) or in the presence (iii and iv) of 0.2ꢀequiv. of 2-(o-tolyl)pyridine 1 show the evolution of free 3 (fuchsia triangles), free 1 (orange
rhombi) and biaryl product 4 (blue dots). The reactions were analysed by gas chromatography–flame ionization detection (GC–FID) using hexadecane as
the internal standard.
revealed that a second C–H activation event is required to form the and characterization of the bis-cycloruthenated intermediate III
bis-cyclometallated Ru(ii) complex III, prior to the oxidative addi- was made possible by kinetic studies, which allowed us to hypoth-
tion step that leads to the Ru(iv) species IV (Fig. 1c). The detection esize its fundamental role in the catalytic cycle. Furthermore, our
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NATuRe CHemisTRy
Articles
(PF6)
(PF6)
Me
Me
Me
Me
Me
F
Me
F
Me
Me
Me
KOAc (30 mol%)
K2CO3 (3 equiv.)
C6D6/NMP
25 °C
N
N
N
Me
F
F
N
Me
Me
Me
Ru(L)4
F
Ru(L)4
F
+
Ru
N
F
F
N
N
C6D6/NMP, 80 °C
With time (0–180 min.)
Me
Me
Me
F
Me
F
Me
Me
Me
Me
Me
Ru3 (1 equiv.)
Ru4 (1 equiv.)
5 (1.05 equiv.)
Ru5
X-ray structure of Ru5
L = MeCN
L = MeCN or NMP
Me
+
Me
Me
Me
Me
Me
Me
Me
Me
2 (2.5 equiv.)
I
N
N
N
+
Ru(L)3I
F
+
Ru(L)4
F
F
F
Me
C6D6/NMP, 25 °C
With time (3–600 min.)
Me
F
Me
Me
F
Me
Me
Me
Ru4
Ru6
6
L = MeCN or NMP
L = MeCN or NMP
(100% conversion)
Ru3
Ru3
Ru3
Ru3
(i)
Ru3
+
Ru4
Ru3
+
Ru4
Ru4
+
Ru3
Ru4
+
Ru3
C6H6
(ii)
(iii)
(iv)
5
5
5
5
5
0
Ru5
Ru5
Ru5
Ru5
20
40
80
180
2
2
3
20
Ru4
Ru4
Ru4
Ru4
60
100
260
600
6
6
6
6
6
Ru6
6
(v)
Ru6
Ru6
Ru6
(vi)
10.6
9.2
8.8
8.4
8.0
7.6
7.2
6.8
–106
–107
–108
–122 –123
19F δ (ppm)
–124
–125
–126
1H δ (ppm)
Fig. 3 | Detection, isolation and reactivity of the bis-cycloruthenated complex ru5. In situ 1H and 19F NMR monitoring of the reaction between Ru3 and
5 that generated Ru5 is shown in the light blue box. In situ 1H and 19F NMR monitoring of the reaction between Ru5 and 2 that produced 6, ru6 and ru4
is shown in the light yellow box. 1H and 19F NMR spectra of: Ru3 in CD3CN (i); a freshly prepared sample of Ru3 in C6D6/NMP that reveals the formation
of ru4 (ii); a sample of Ru3 in C6D6/NMP after 12ꢀh (iii); 5 in C6D6/NMP (iv); 6 in C6D6/NMP (v); and a freshly prepared sample of Ru3ꢀ+ꢀKI (excess)
in C6D6/NMP that reveals the instantaneous formation of ru6 (vi) are also shown for clarity (Supplementary Section 4). The X-ray of Ru5 is an ORTEP
diagram at 60% probability ellipsoids; co-crystallized Et2O molecules and hydrogen atoms are omitted for clarity (Supplementary Section 16).
studies reveal that cycloruthenated complexes like I (Fig. 1d, RuB) robust and established methodologies are relentlessly preferred.
are able to catalyse the C–H arylation at remarkably low tempera- Consequently, the uptake of new synthetic methods in medicinal
tures, with equimolar amounts of the aryl (pseudo)halide. Owing chemistry is a function of the extents of the substrate scope pre-
to the commercial and competitive aspects of drug discovery, sented in the methodology43,44. Therefore, with the aim to provide a
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NATuRe CHemisTRy
Articles
a
[Ru] (10 mol%)
100
80
60
40
20
0
KOAc (0 or 20 mol%)
K2CO3 (3 equiv.)
Me
8 + 9
4
8 + 9 (Ru7)
8 + 9 (Ru8)
(Ru2 + 20 mol% KOAc)
N
N
N
N
Xyl
I
+
Xyl
Xyl
Xyl
Me
Xyl
NMP, 35 °C
With time
+
+
Time = 420 min
Me
8 + 9 (89%)
4 (8%)
8 + 9 (<1%)
8 + 9 (<1%)
7 (1 equiv.)
2 (2 equiv.)
8
9
4
Me
O
(PF6)
Me
O
Me
Me
N
iPr
[Ru]
Me
Ru
0
100
200
300
400
Ru(MeCN)4
O
O
Me
iPr
Time (min)
Me
Me
Ru
O
OCOMe
O
Me
Me
Ru2 (
,
)
Ru7 (
)
Ru8 (
)
b
(PF6)
Me
N
Me
Me
Me
Ru(MeCN)4
Ru9 (10 mol%)
KOAc (30 mol%)
Me
Me
Me
Me
N
N
N
Me
Me
NMe2
I
NMe2 Me
+
+
+
+
Me
Me
Me
K2CO3, NMP (1M),
35 °C, 24 h
Me
Me
7 (1 equiv.)
2 (2 equiv.)
8, 0%
9, 96%
10, 0%
11, 0%
Standard optimized
conditions
Fig. 4 | Cycloruthenated complexes as a superior class of catalysts for the C–h arylation of DG-containing arenes with aryl (pseudo)halides. a,
Comparison of the catalytic activity of the system constituted by Ru2 and KOAc with respect to Ru7 and Ru8. The reactions were analysed by GC–FID
using hexadecane as the internal standard. b, Establishment of Ru9 as the catalyst of choice for the Ru(ii)-catalysed directed C–H arylation. The reactions
were analysed by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal standard.
truthful and solid platform to evaluate the possibility of implement- kinetics in which this species is a reaction intermediate in the ary-
ing our technology in the synthesis of drug-like compounds, we lation process. Thus, we hypothesized that a C–H activation step
6
targeted heavily functionalized molecules by performing late-stage between an η -arene-free cycloruthenated species, such as Ru2 and 1,
arylation on pharmaceuticals, agrochemicals, natural products and must happen before reaction with iodoarene 2 (for example, I to III
organic electronic materials.
in Fig. 1c). Indeed, when the concentration profiles for the aryla-
tion reactions of Ru1 and Ru2 were monitored after the addition
of 0.2equiv. of 2-(o-tolyl)pyridine 1, a fast consumption of 1 and
results and discussion
Kinetic evidence that supports the involvement of a bis-cyclo- a significant increase in the arylation rate were observed (Fig. 2,
ruthenated intermediate. Recently, we described the first Ru(ii)- graphs iii and iv). Furthermore, in agreement with the generation of
catalysed C–H arylation methodology for ‘simple’ electron-deficient a bis-cyclometallated complex like III (Fig. 1c), the omission of the
arenes45. During the development of this methodology, we discov- base required for C–H activation, KOAc, substantially reduced the
ered that, contrary to previous hypotheses41, the p-cymene ligand arylation rate46 (Supplementary Section 3).
present in state-of-the-art ruthenium catalysts (Fig. 1a, RuA) is an
inhibitor in the reaction. This disparity prompted a more thorough Detection and reactivity of the bis-cycloruthenated intermedi-
investigation of the general mechanism of Ru(ii)-catalysed C–H ate. To validate further this mechanistic hypothesis, we followed
arylation. We began our investigation by examining the mechanism the reaction of cyclometallated complex Ru3 with 2-arylpyridine 5
of the directed arylation of 2-(o-tolyl)pyridine 1 with 5-iodo-m-xy- (Fig. 3, light blue shading) by 1H and 19F NMR spectroscopy. A rapid
lene 2 to form 4 (Fig. 2). We assessed the reactivity of two proposed ligand exchange took place at room temperature between the aceto-
catalytic intermediates, Ru1 and Ru2 (corresponding to complex I nitrile ligands of Ru3 and NMP to produce Ru4 (Fig. 3, spectra i–
in Fig. 1b,c), in their stoichiometric reaction with aryl iodide 2 in iii). After 180 minutes at 80°C, Ru3/Ru4 had quantitatively reacted
the presence of KOAc in NMP (N-methyl-2-pyrrolidone) at 90°C with 5 to form the predicted bis-cyclometallated Ru(ii) species Ru5,
(Fig. 2). Surprisingly, both Ru1 and Ru2 reacted sluggishly with 2, whose structure was confirmed by X-ray analysis. Then, iodoarene
which suggests that a more complex mechanism than that depicted 2 was added and the reaction was monitored at 25°C (Fig. 3, light
in Fig. 1b was in operation. Specifically, the reaction profile of Ru1 yellow shading). Over 600 minutes, Ru5 quantitatively reacted with
revealed: (1) a fast release of p-cymene 3, (2) a rapid build-up of 2 to form the arylated product 6, along with the cyclometallated
decomplexed 2-(o-tolyl)pyridine 1, which then decreased over complexes Ru6 and Ru4 derived from reductive elimination. This
time, and (3) an induction period in the formation of biaryl 4 that experiment is fully consistent with our mechanistic hypothesis, and
correlated with the evolution of free 1 (Fig. 2, graph i). p-Cymene- provides strong evidence that the catalytic cycle reported in Fig. 1c
free Ru2 displayed a similar behaviour, albeit with a much faster is, indeed, operating.
arylation rate (Fig. 2, graph ii), which confirms the inhibitory role
of the p-cymene ligand in this directed arylation. Importantly, the Monocycloruthenated complexes as a superior class of catalysts.
observed formation and consumption of free 1 is consistent with Having discovered evidence for the intermediacy of a bis-cycloru-
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NATuRe CHemisTRy
Articles
a
(PF6)
Me
ArN
N
Me
X
= Cl, Br, I, OTf
Ru(MeCN)4
N
N
+
Me
H
Me
Ru9 (10 mol%)
X
KOAc (30 mol%)
K2CO3, NMP (1 M), 35 °C, 24 h
1 (1 equiv.)
X1–X34 (1 equiv.)
A1–A34
O
Me
O
O
ArN
b
Me
NH
N
MeO
H
N
OMe
Me
Me
ArN
Me Me
O
Me
O
Me Me
S
O
ArN
O
HO
O
ArN
O
O
N
Me
O
O
O
A1, 90%a
A2, 90%
A3, 92%
From indometacin:
NSAID
A4, 93%
From chlormezanone:
anxiolytic
A5, 92%
From chlorpropham:
herbicide
O
ArN
From bezafibrate: lipid lowering
From fenofibrate: lipid lowering
O
O
O
N
N
ArN
S
O
F
Me
N
O
N
O
N
N
Me
N
N
N
N
N
N
N
Me
PhO
ArN
OH
N
H
N
N
A6, 91%a
From diazoxide:
vasodilatator
A7, 91%b
A8, 92%
From nefazodone:
antidepressant
A9, 93%c
From trazodone:
antidepressant
A10, 92%a
From haloperidol:
neuroleptic
ArN
ArN
ArN
From azelastine:
antihistamine
S
N
O
ArN
H
HN
ArN
N
Me
N
Me
Me Me
A11, 83%c
From bupropion:
antidepressant
N
N
ArN
N
N
Me
NMe2
ArN
N
Me
A12, 97%
A12, 95%a,d
(10 g scale with 3 mol% Ru9)
A13, 96%a
From clozapine: neuroleptic
A14, 85%a,c
From prochlorperazine: neuroleptic
From clomipramine: antidepressant
H
H
ArN
Me2N
N
ArN
NMe2
N
Me
O
S
O
N
O
N
N
O
N
S
ArN
N
N
A16, 90%c
From meclizine:
antihistamine
A17, 81%b,c,e
From chlorpheniramine:
antihistamine
A18, 56%b,c,f
From loratadine:
antihistamine
A19, 78%b,c,g,h
From glyburide:
antidiabetic
H
ArN
ArN
A15, 90%a
From chlorprothixene: antipsychotic
MeO
O
OEt
c
d
ArN
N
H
HN
O
Me
O
N
NH2
Me
ArN
ArN
H
N
N
Me
F
N
NH
H
H
O
HN
ArN
N
Me
O
ArN
O
O
A20, 91%a
From strychnine (from
A21, 69%b,c,e
A22, 94% from pharmaceutical formulation
A23, 84%
From trametinib: antineoplastic
From bromhexine: mucolytic From ladasten (bromantane): immunostimulant, Parkinson's disease
Strychnos nux-vomica)
e
ArN
ArN
OH
A30, 71%a
From naltrexone:
opioid antagonist
Me
ArN
Me
Me
Me
OH
H
O
H
Me
O
H
H
Me
N
Me
F
HO
H
A24, 90%
ArN
N
O
From δ-tocopherol (from vitamin E)
O
A27, 97%
A33, 91%
From ezetimibe: lipid lowering
From oestradiol: HRT
O
F
ArN
Me
OMe
ArN
NMe2
N
Me
H
A31, 78%b
From bufotenin
A28, 92%a,c,g
From hymecromone:
choleretic
O
Me
A25, 71%b
N
From capsaicin (from chilli pepper)
(from psychoactive toad)
ArN
O
H
O
OH
O
Me
Me
ArN
ArN
H
HO
HO
OH
O
O
ArN
OMe
N
ArN
Me
Me
O
N
Me
Me
OMe
H
Me
H
H
Me
A26, 84%b,c,g,h
From γ-oryzanol: antioxidant
A29, 62%b,g,h
From vanillin: flavouring agent
A32, 70%a,c
From harmol: antineoplastic
A34, 88%a
From arbutin (from bearberry)
Fig. 5 | Substrate scope of the C–h arylation with respect to the aryl (pseudo)halide-containing drugs. The 2-(o-tolyl)pyridine 1 component (ArN)
is shown in light blue and the aryl (pseudo)halide-containing drug part is shown in green. a, C–H arylation coupling of 1 with aryl (pseudo)halides. b,
Coupling with chloride-containing drugs X1, X2, X4 and X6–X19, chloride-containing drug derivative X3 and chloride-containing agrochemical X5. c,
Coupling with bromide-containing drugs X21 and X22 and bromide-containing natural product derivative X20. d, Coupling with iodide-containing drug
X23. e, Coupling with triflate-containing drug derivatives X27, X28, X30 and X33 and triflate-containing natural product derivatives X24–X26, X29, X31,
X32 and X34. All of the yields are isolated yields. Reaction conditions: Ru9 (10ꢀmol%), KOAc (30ꢀmol%), 1 (1ꢀequiv.), X1–X34 (1ꢀequiv.), K2CO3 (2–4ꢀequiv.
(Supplementary Information)), NMP (1ꢀM), 35ꢀ°C, Ar atmosphere, 24ꢀh. a48ꢀh. b72ꢀh. c50ꢀ°C. dX12 (1ꢀequiv.), 1 (1.03ꢀequiv.), Ru9 (3ꢀmol%). e1 (2ꢀequiv). f1
(3ꢀequiv). gKOBz used in replacement of KOAc. hNMP (0.5ꢀM). HRT, hormone replacement therapy; NSAID, non-steroidal anti-inflammatory drug.
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Articles
(PF6)
a
Me
N
Me
X = I (2), Br (12)
Me
N
Ru(MeCN)4
Me
N
X
Ru9 (10 mol%)
Xyl
+
H
KOAc (30 mol%)
K2CO3, NMP (1 M), 35 °C, 72 h
Me
Me
NEt2
N1–N9 (1 equiv.)
2 or 12 (1 or 2 equiv.)
B1–B9, C1
Me
N
O
O
N
B1, 80%a,b
N
Me
From atazanavir:
HIV treatment
Xyl
N
Xyl
N
Xyl
Xyl
N
N
Cl
Cl
N
N
Xyl
Xyl
F
Xyl
O
O
Bn
O
H
Me
Xyl
S
Xyl
N
OMe
Me
NMe2
O
tBu
N
N
H
O
NH OH
tBu O
B2, 82%a
B3, 86%a
B4, 95%c
B5, 92%d,e,f
MeO
Me
N
H
From zolimidine: gastroprotective
From zolpidem: hypnotic
From diazepam: anxiolytic From flurazepam: hypnotic
O
Me
O
O
N
N
Xyl/H
N
H
O
O
S
N
OMe
tBu
OH
N
H/Xyl
N
O
N
O
N
N
N
Xyl
Xyl
Xyl
H2N
N
a
b
Xyl
N
HO
Xyl
N N
Xyl/H
Xyl/H
OH
C1, 95%b,g
From diazepam: anxiolytic
B6, 60% (bis) + 14% (mono)c,d,f
From 6-phenylpurine riboside:
RNA-fragment derivative
B7, 63% (mono) + 4% (bis)f,h
From oxaprozin: NSAID
B8, 86%f,g
From sulfaphenazole:
antibacterial
B9, 42% (bis) + 33% (mono, a:b = 88:12)c,f
From TAZ: OLED
b
(PF6)
Me
N
Me
X
= Cl, Br, I, OTf
Ru(MeCN)4
N
N
Ru9 (10 mol%)
X
+
H
KOAc (30 mol%)
K2CO3, NMP (1M), 35 °C, 72 h
N1, N3, N5, N8
X13, X20, X23, X28
D1–D4
(1 equiv.)
(1 or 2 equiv.)
Et2N
O
H
O
Me
N
H
N
H
N
N
H
Me
Me
N
S
N
Me
O
Me
N
O
N
H
O
O
N
H
N
Cl
N
Me
Me
O
H
H2N
F
O
N
O
O
O
N
O
O
O
N
O
N
N
Me2N
N
N
N
N
NH
O
Me
Me
D3, 90%c,d,e
D4, 67%c,d
HN
N
NH
From flurazepam and hymecromone
From sulfaphenazole and strychnine
F
F
D1, 65%a
From atazanavir
and trametinib
D1 = (Ru7, <1%f), (Ru8, <1%f)
Me
D2, 76%b
From zolpidem
and clozapine
Bn
O
Me
O
Me
Me
H
N
D2 = (Ru7, <1%f), (Ru8, <1%f)
D3 = (Ru7, 2%f), (Ru8, <1%f)
D4 = (Ru7, <1%f), (Ru8, <1%f)
OMe
Ru7, R =
Me
O
tBu
N
N
H
iPr
R
Ru
NH OH
tBu
O
MeO
N
Ru8, R = Me
O
OCOR
H
O
Fig. 6 | Substrate scope of the C–h arylation with respect to the DG-containing drugs and C–h arylation between DG-containing drugs and aryl
(pseudo)halide-containing drugs. The DG-containing drug component is shown in light blue, whereas 5-bromo-m-xylene 12 or 5-iodo-m-xylene 2 (Xyl)
(the aryl (pseudo)halide-containing drug part) is shown in green, and the 2-(o-tolyl)pyridine 1 component of C1 is shown in orange. a, C–H arylation of
DG-containing drugs N1–N5, N7 and N8, DG-containing drug-like N6 and DG-containing organic material N9. All of the yields are isolated yields. Reaction
conditions: Ru9 (10ꢀmol%), KOAc (30ꢀmol%), N1–N9 (1ꢀequiv.), 12 or 2 (1 or 2ꢀequiv.), K2CO3 (2–4ꢀequiv. (Supplementary Information)), NMP (1ꢀM), 35ꢀ°C,
Ar atmosphere, 72ꢀh. a12 (2ꢀequiv). bNMP (0.5ꢀM). c2 (2 equiv). d48ꢀh. e2 (1 equiv). f50ꢀ°C. g(i) 2 (2 equiv), 72ꢀh; then (ii) 1 (1.5 equiv), 72ꢀh. h12 (1 equiv).
b, C–H arylation of N1, N3, N5 and N8 with X23, X13, X28 and X20, respectively. All of the yields are isolated yields. Reaction conditions: Ru9 (10ꢀmol%),
KOAc (30ꢀmol%), N1, N3, N4 and N8 (1ꢀequiv.), X23 (2ꢀequiv.), X13, X20 and X28 (1ꢀequiv.), K2CO3 (2–3ꢀequiv. (Supplementary Information)), NMP (1ꢀM),
35ꢀ°C, Ar atmosphere, 72ꢀh. aNMP (0.5ꢀM). b144ꢀh. c48ꢀh. d50ꢀ°C. eKOBz used instead of KOAc. fReaction set up under identical optimized conditions for
each particular case, but Ru7 and Ru8 were used instead of Ru9 without KOAc or KOBz; the yield was evaluated by NMR spectroscopy. OLED, organic
light-emitting diode.
thenated complex, we compared the rate of the reaction catalysed by Thus, the C–H arylation of 2-phenylpyridine 7 with 5-iodo-m-xylene
Ru2 and KOAc to the rates with Ru7 and Ru8, which are the most 2 was monitored over time at 35°C. Remarkably, although the cyclo-
widely employed state-of-the-art ruthenium catalysts13,34,46,47 (Fig. 4a). metallated Ru2 catalyst afforded a combined yield of 89% of mono
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(8) and diarylated (9) adducts in 420minutes, Ru7 and Ru8 were other heterocycles with a sp2-nitrogen DG, which include imid-
essentially inactive. These results demonstrate that catalysts based azopyridines (zolimidine to give B2 and zolpidem to give B3),
on on-cycle intermediates, such as I (RuB in Fig. 1d), possess a far dihydrodibenzoazepin-2-ones (diazepam to B4 and flurazepam
superior catalytic activity than the commonly employed Ru(ii) spe- to B5), purine (to B6), oxazole (oxaprozin to B7), pyrazole (sul-
cies (RuA in Fig. 1a), which enables reactivity to occur at unprec- faphenazole to B8) and 1,2,4-triazole (TAZ (3-(biphenyl-4-yl)-
edentedly low temperatures. However, 8% of biaryl 4, derived from 5-(4-t-butylphenyl)-4-phenyl-4H-1,2,4-triazole) to B9) gave
arylation of the cyclometallating ligand in Ru2, was also formed. A good-to-excellent yields of the corresponding ortho-arylated func-
similar scenario was also observed with other aryl (pseudo)halides tional molecules (B2–B9). Consequently, more sensitive moieties,
(Supplementary Section 6). It was hypothesized that this was due to such as sulfonyl (B2), the hemiaminal ether of the purine riboside
the non-selective reductive elimination from a Ru(iv) complex that B6, sulfonamide (B8) and chloride (B4 and B5) were also tolerated.
featured two different cyclometallated arenes, which implies that Remarkably, the diazepam derivative C1 was obtained in 95% yield
catalysts such as Ru2 still suffered from a major drawback. In an in a one-pot fashion simply by the sequential addition of iodoarene
attempt to overcome this limitation, we tested cycloruthenated com- 2 and 2-(o-tolyl)pyridine 1. To illustrate further the power of our
plexes that featured different nitrogen ligands. Gratifyingly, the N,N- catalytic system, the coupling between two highly functionalized
dimethylbenzylamine-containing Ru9 provided diarylated adduct 9 drugs was achieved (Fig. 6b). Atazanavir N1, zolpidem N3, fluraz-
in 96% yield and suppressed the undesired ‘catalyst arylation’ degrada- epam N5 and sulfaphenazole N8 were, respectively, reacted with
tion pathway that produces 10 and 11 (Fig. 4b).
trametinib X23, clozapine X13, hymecromone derivative X28 and
Br-strychnine X20 and provided superb yields of the targeted com-
Investigation of the scope of the reaction with respect to the aryl pounds (D1–D4). Conversely, when the current state-of-the-art
(pseudo)halide coupling partners. Having identified Ru9 as an Ru(ii) catalysts Ru7 and Ru8 were tested, neither catalyst afforded
ideal catalyst able to couple equimolar amounts of DG-containing D1–D4 in synthetically useful yields (Fig. 6b, bottom right).
arenes with aryl (pseudo)halides under exceptionally mild reaction
conditions, we decided to demonstrate the synthetic utility of this Conclusion
catalytic system. Towards this aim, pharmaceuticals and natural Our study highlights the factors that promote oxidative addition at
products that possess an aromatic chloride, bromide, iodide or a Ru(ii) centres in C–H arylation processes of N–chelating substrates
phenol moiety transformed into its triflate derivative (X1–X34), with aryl (pseudo)halides and demonstrates how comprehensive
were selected as coupling partners for the C–H arylation of mechanistic studies can inform the development of more-efficient
2-(o-tolyl)pyridine 1 (Fig. 5). The scope of the reaction is striking; catalysts. In particular, we identified a bis-cycloruthenated species
many ubiquitous heterocycles and functional groups in medicinal as the key intermediate that is required for the oxidative addition
chemistry18–20 were well tolerated and provided good-to-excellent step to occur. Based on this knowledge, we designed a more-robust
yields (A1–A34). O-, N-, S- and C-containing (hetero)cycles, catalytic system capable of performing late-stage arylation on com-
such as piperidine (A10 and A18), pyridine (A17, A18 and A32), plex functionalized molecules and that tolerates functional groups
piperazine (A8, A9, A13, A14 and A16), azepane (A7), indole (A3 generally considered incompatible with C–H arylation.
and A31), carbazole (A32), phenothiazine (A14), dihydrodiben-
According to the PubChem database, there are 6.4million (het-
zoazepine (A12), dibenzodiazepine (A13), thioxanthene (A15), ero)aromatic compounds with a sp2 nitrogen suitable for ortho-
triazolone (A8 and A9), pyrimidinedione (A23), pyridone (A23), ruthenation via a five-membered intermediate, and 22million
morphinan (A30), steroid (A26 and A27), β-lactam (A33), glucose (hetero)aromatic chlorides, bromides, iodides and phenols that
(A34), coumarin (A28), chromane (A24), phtalazinone (A7), ben- have biological activity. Owing to this impressive pool of potential
zothiadiazine (A6) and thiazinane (A4), were shown to be compat- coupling partners that bear diverse functionalities, our efficient and
ible with our system. More specifically, sensitive functional groups, cost-effective technology promises to be a powerful and reliable tool
which included tertiary (A12, A15, A17, A20, A21 and A31) and for drug discovery and development. Finally, we anticipate that the
secondary amines (A11), carbamates (A5 and A18), a sulfonylurea presented mechanistic discovery could be extended to other C–H
(A19), alkenes (A15, A18, A20, A25 and A26), acryloyl groups activation transformations under current development.
(A26 and A28), benzylic (A10, A33), tertiary (A10 and A30), sec-
ondary (A27 and A34) and primary alcohols (A34), an acetal (A34), Methods
General procedure for C–H arylation. All of the liquid reagents and solvents
a thiohemiaminal derivative (A4), amidine derivatives (A6 and
were dried over 4Å molecular sieves and degassed with three freeze–pump–thaw
A13), cyclopropyl groups (A23, A26 and A30), an aniline (A21),
cycles prior to use. KOAc and K2CO3 were dried at 140°C in a vacuum oven for
a carboxylic acid (A1), an aldehyde (A29), amides (A1, A19, A23
48h prior to use. Unless otherwise indicated, in a glovebox, an oven-dried crimp-
and A25), esters (A2, A3 and A26), an α-amino ketone (A11) and
cap microwave vial equipped with a magnetic stirring bar was charged with Ru9
(10mol%), KOAc (30mol%), K2CO3 (2–4equiv.), the appropriate DG-containing
arene (1equiv.) and aryl (pseudo)halide (1equiv.) and NMP (1M). Te vial was
capped and stirred at 35°C for 24h. Upon completion, the vial was transferred out
of the glovebox and the crude mixture was loaded onto a silica gel column and
purifed by fash chromatography.
ketones (A2 and A30) were all tolerated. The efficiency of this cata-
lytic system was also demonstrated by conducting the reaction with
clomipramine X12 on a 10g scale with the catalyst loading lowered
to 3mol%. The corresponding product, A12, was yielded in 95%
after a simple aqueous work-up. To highlight further the robustness
of our method, bromantane could be used in its pharmaceutical for-
mulation of Ladasten, X22, to provide A22 in 94% yield despite the
presence of possibly interfering excipients.
Data availability. The data reported in this paper are available in
the Supplementary Information. Metrical parameters for the structure of bis-
cyclometallated complex Ru5 are available free of charge from the Cambridge
Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/data_request/cif)
under reference number CCDC 1567316.
Investigation of the scope of the reaction with respect to the
DG-containing arene coupling partners. We then turned our
attention to the generality of this reaction with respect to the
DG-containing coupling partner (Fig. 6a). Towards this purpose,
we tested the 2-phenylpyridine derivative atazanavir N1, a peptido-
mimetic human immunodeficiency virus-1 protease inhibitor that
features a complex azadipeptide isoester, which provided B1 in 80%
yield. This methodology is not limited to 2-arylpyridine analogues:
Received: 17 December 2017; Accepted: 4 April 2018;
Published online: 21 June 2018
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acknowledgements
We gratefully acknowledge the Engineering and Physical Sciences Research Council
(EPSRC, EP/L014017/2 and EP/K039547/1) for funding and the European Research
Council for a Starting Grant (to I.L.).
author contributions
M.S. and I.L. conceived the work and prepared the manuscript. M.S., D.M.C. and I.L.
designed the experiments. M.S. and D.M.C. performed the experiments and analysed
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Competing interests
A patent protecting the findings disclosed in this manuscript has been filed by the
University of Manchester (application number 1807672.9).
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Reprints and permissions information is available at www.nature.com/reprints.
Correspondence and requests for materials should be addressed to I.L.
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