Ruthenium(II)-catalyzed C-H functionalizations on benzoic acids with aryl, alkenyl and alkynyl halides by weak-: O -coordination

Article abstract of DOI:10.1039/c6cc07773k

C-H arylations of weakly coordinating benzoic acids were achieved by versatile ruthenium(ii) catalysis with ample substrate scope. Thus, user-friendly ruthenium(ii) biscarboxylate complexes modified with tricyclohexylphosphine enabled C-H functionalizations with aryl electrophiles. The unique versatility of the ruthenium(ii) catalysis manifold was reflected by facilitating effective C-H activations with aryl, alkenyl and alkynyl halides.

Full text of DOI:10.1039/c6cc07773k

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Ruthenium(II)-Catalyzed C−H Functionalizations on Benzoic Acids with Aryl, Alkenyl and
Alkynyl Halides by Weak-O-Coordination
Ruhuai Mei,‡ Cuiju Zhu,‡ Lutz Ackermann*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
C−H transformations with challenging aryl, alkenyl and alkynyl
halides.
C−H arylations of weakly coordinating benzoic acids were
achieved by versatile ruthenium(II) catalysis with ample
substrate
scope.
Thus,
user-friendly
ruthenium(II)
biscarboxylate complexes modified with tricyclohexylphosphine
enabled C−H functionalizations with aryl electrophiles. The
unique versatility of the ruthenium(II) catalysis manifold was
reflected by facilitating facile C−H activations with aryl, alkenyl
and alkynyl halides.
(a) previous work on ruthenium(II) catalysis with organic electrophiles
N-containing directing groups
strong coordination
difficult to remove
challenging to modify
N
H
Ar
(b) this work: weak O-coordination
Introduction
Me
i-Pr
Ru
O
MesCO2
Transformations of unactivated C−H bonds have emerged as an
attractive alternative to conventional crossꢀcoupling approaches,
enabling stepꢀeconomical biaryl syntheses with reduced byꢀ
product formation.1 Major progress has been accomplished by
means of ruthenium(II)ꢀcatalyzed reactions with easily
accessible electrophilic2ꢀ6 aryl halides,7ꢀ10 with transformative
applications in material sciences,11 as well as agrochemical12
Mes
O
HO
O
HO
O
Hal Ar'
+
Ru
Ar'
H
Ar
Ar
PCy3, K2CO3
valuable benzoic acids
weak O-coordination
ample substrate scope
functional group tolerant
uniquely versatile & robust:
aryl, alkenyl & alkynyl halides
14
8
and pharmaceutical industries,13,
among others.7, Despite
these undisputable advances, ruthenium(II)ꢀcatalyzed C−H
arylations with organic electrophiles continue to be limited to
strongly coordinating nitrogenꢀcontaining directing groups,7, 8
which are difficult to remove15 or modify (Figure 1a).16 Within
Figure 1. Ruthenium(II)ꢀcatalyzed C–H arylation by weak coordination.
our ongoing program on rutheniumꢀcatalyzed C−H
18
functionalizations,17,
we have now developed the
Results and Discussion
unprecedented ruthenium(II)ꢀcatalyzed C−H arylations of
benzoic acids,19 on which we report herein (Figure 1b). The key
to success was represented by using a tricyclophosphineꢀ
derived ruthenium(II) complex, which we have previously
At the outset of our studies, we explored reaction conditions for
the envisioned ruthenium(II)ꢀcatalyzed C–H arylation of weakly Oꢀ
coordinating benzoic acids 1a (Table 1 and Table Sꢀ1 in the
Supporting Information).23 While typical phosphine or Nꢀ
heterocyclic carbene ligands fell short in providing access to any
developed for C−H functionalizations guided by strong
coordination.20 Notable features of our approach include (i) first
rutheniumꢀcatalyzed C−H arylations of weakly
Nꢀ
O
ꢀ
22
arylated benzoic acid products (entries 1−8), a PCy3ꢀderived catalyst
coordinating21,
benzoic acids, (ii) mechanistic insights on
– previously exploited for strongly Nꢀcoordinating 1,2,3ꢀtriazoles –20
facile carboxylateꢀassisted C−H activation, and (iii) a versatile
ruthenium(II) catalysis regime that set the stage for expedient
enabled the challenging C–H arylation process (entries 9 and 10). It
is noteworthy that the wellꢀdefined [RuCl2(PCy3)(pꢀcymene)] was
also identified as a userꢀfriendly single component catalyst,
allowing for the preparation of the orthoꢀarylated benzoic acid
3aa with comparable levels of efficacy (entry 11). The catalytic
performance was further significantly improved by exploiting
carboxylate24 assistance with the aid of the wellꢀdefined
ruthenium(II)biscarboxylate complex 425 (entries 12−14).
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Table 1. Optimization of ruthenium(II)-catalyzed C–H arylation with
benzoic acid 1a a
.
Entry
1
[Ru]
ligand
3aa (%)b
(11)
(<5)
(<5)
(7)
[RuCl2(p-cymene)]2
---
2
[RuCl2(p-cymene)]2
IPrHCl
3
[RuCl2(p-cymene)]2
IMesHCl
X-Phos
DavePhos
JohnPhos
4
[Ru(MesCO2)2(p-cymene)]
[RuCl2(p-cymene)]2
5
(<5)
(8)
6
[RuCl2(p-cymene)]2
7
[RuCl2(p-cymene)]2
(tBu)2POH (20)
8
[RuCl2(p-cymene)]2
P(tBu)3
PCy3
PCy3
---
(22)
81
---c
9
[RuCl2(p-cymene)]2
10
11
12
13
14
[RuCl2(p-cymene)]2
[RuCl2(PCy3)(p-cymene)]
[Ru(MesCO2)2(p-cymene)] (4)
[Ru(MesCO2)2(p-cymene)] (4)
75
PCy3
PCy3
(32)d
54e
87
Scheme 1. C–H activation of weakly
aryl bromides
Oꢀcoordinating benzoic acid 1a with
2
.
[Ru(MesCO2)2(p-cymene)] (4) PCy3
Subsequently, we probed the scope of viable benzoic acids in the
ruthenium(II)ꢀcatalyzed C–H arylation manifold (Scheme 2). Thus,
we were delighted to observe that various weaklyꢀcoordinating acids
1 could be converted with high catalytic efficacy and excellent
positional selectivity by the phosphineꢀmodified biscarboxylate
complex 4. Importantly, the versatile ruthenium(II) catalyst was not
restricted to arenes. Indeed, the biscarboxylate complex 4 also
allowed for the siteꢀselective C–H arylation of synthetically useful
indole 1n. Interestingly, the ligand JohnPhos outcompeted PCy3 in
the heteroarene diversification.
a
Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), [Ru] (10 mol %),
additive (10 mol %), K2CO3 (2.0 equiv), NMP (2.0 mL), 120 °C, 16 h; then
b
K2CO3 (3.0 equiv), MeI (5.0 equiv), MeCN (3.0 mL), 50 °C, 2 h. Yields of
isolated product; in parentheses: GC conversion after esterification with
1,3,5-trimethoxybezene as the internal standard. Without K2CO3. d DMPU
(2.0 mL) as the solvent. e DMA (2.0 mL) as the solvent.
c
With the optimized catalyst in hand, we probed its versatility in the
C–H arylation of differently substituted aryl halides 2 (Scheme 1).
Here, a representative set of synthetically meaningful functional
groups, such as halides, activated alkenes, esters or enolizable
ketones, was well tolerated by the optimized catalyst at different
positions of the organic electrophile 2. Moreover, the robustness of
the ruthenium(II) catalyst was reflected by efficiently converting
both electronꢀdeficient as well as more demanding electronꢀrich aryl
halides 2.
2 | Chem. Commun., 2016, 00, 1-3
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Scheme 4. Intramolecular competition experiment.
Moreover, we observed a significant H/D scrambling upon the
addition of an isotopically labeled cosolvent under otherwise
identical reaction conditions. The deuterium incorporation in the
reisolated substrate [D]nꢀ1o and product [D]nꢀ3oa is supportive of a
reversible C–H metalation event (Scheme 5).
47% D
H/D
50% D
H/D
2a
H
4 (10 mol %)
PCy3 (10 mol %)
CO2H
H
CO2Me
CO2Me
+
K2CO3,
Ph
Ph
H/D
Ph
NMP/D4-MeOH
(2.0/0.2 mL)
OMe
120 °C, 16 h
then K2CO3, MeI
1o
[D]n-1o:45%
[D]n-3oa: 9%
Scheme 2. C–H arylation of benzoic acids 1 by ruthenium(II) catalysis. a Isolated
b
c
Scheme 5. Facile C–H arylation in the presence of isotopically labeled cosolvent.
yield of the monoꢀarylated product. With ArI instead of 2a. 9% of the diꢀ
arylated product isolated. d JohnPhos (10 mol %) instead of PCy3
The wellꢀdefined ruthenacycle 7, that we had previously
employed for oxidative alkyne annulations,26 was shown to be
catalytically competent (Scheme 6), being indicative of an
organometallic mode of C–H activation.
In consideration of the unique efficiency of the ruthenium(II)
catalysis regime, we became intrigued by rationalizing its mode of
action. To this end, intermolecular competition experiments revealed
electronꢀdeficient aryl bromides to react preferentially (Scheme 3).
Scheme 3. Intermolecular competition experiment.
The challenging nature of the C–H arylation with weakly
coordinating benzoic acids became apparent by an intermolecular
competition experiment between benzoic acid 1h and arene 5d
displaying the strongly Nꢀcoordinating 1,2,3ꢀtriazole (Scheme 4).
Scheme 6. Ruthenacycle
7 for C–H arylation.
Finally, the unique versatility of the ruthenium(II) catalysis was
illustrated by the phosphineꢀmodified catalyst enabling the
4
unprecedented olefination and alkynylation of benzoic acids 1 by
alkenyl and alkynyl halides 8 and 10, respectively (Scheme 7). Both
types of C–H functionalization occurred by weak Oꢀcoordination
with excellent levels of positional selectivities, thereby providing
28
access to orthoꢀalkenylated benzoic acids 9 and phthalide27,
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Scheme 7. Weak
alkynylation.
Oꢀcoordination for (a) C–H alkenylation and (b) C–H
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The electronꢀrich phosphine ligand PCy3 is proposed to facilitate the
C–H functionalization on the weakly coordinating benzoic acid.
Conclusions
In summary, we have developed the first ruthenium(II)ꢀcatalyzed C–
H functionalization of weakly Oꢀcoordinating arenes with organic
halides. Thus,
a
versatile phosphineꢀmodified30 ruthenium(II)
biscarboxylate catalyst enabled C–H arylations of benzoic acids with
excellent positional selectivity and ample scope. The facile C–H
ruthenation manifold enabled the direct arylation of aromatic and
heteroaromatic carboxylic acids. Furthermore, the unique synthetic
utility of the ruthenium(II) catalysis regime also set the stage for
siteꢀselective C–H olefinations and C–H alkynylations of benzoic
acids under otherwise identical reaction conditions. Further studies
on ruthenium(II)ꢀcatalyzed C–H functionalization by weak
coordination are ongoing in our laboratories and will be reported in
due course.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Acknowledgements
Generous support by the European Research Council under the
European Community’s Seventh Framework Program (FP7
2007–2013)/ERC Grant agreement no. 307535, and the CSC
(fellowships to M.R. and C.Z.) is gratefully acknowledged.
29.
30.
References
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4 | Chem. Commun., 2016, 00, 1-3
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