A cooperative Pd-Cu system for direct C-H bond arylation

Article abstract of DOI:10.1039/c4cc03201b

A novel and efficient method for C-H arylation using well-defined Pd- and Cu-NHC systems has been developed. This process promotes the challenging construction of C-C bonds from arenes or heteroarenes using aryl bromides and chlorides. Mechanistic studies

Full text of DOI:10.1039/c4cc03201b

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A cooperative Pd–Cu system for direct C–H bond
arylation†
Cite this: Chem. Commun., 2014,
50, 8927
Mathieu Lesieur, Faıma Lazreg and Catherine S. J. Cazin*
¨
Received 29th April 2014,
Accepted 20th June 2014
DOI: 10.1039/c4cc03201b
www.rsc.org/chemcomm
A novel and efficient method for C–H arylation using well-defined required for its incorporation and subsequent removal.7 Synthetic
Pd– and Cu–NHC systems has been developed. This process strategies avoiding the need for a directing group have therefore
promotes the challenging construction of C–C bonds from arenes been developed, amongst them Pd systems show significant
or heteroarenes using aryl bromides and chlorides. Mechanistic promise, with challenging substrates such as tosylate derivatives.4,5
studies show that [Cu(OH)(NHC)] plays a key role in the C–H In such cases, the C–H activation is often believed to occur through
activation and is involved in the transmetallation with the Pd–NHC a concerted arene metalation/deprotonation pathway or via a
co-catalyst.
Friedel–Crafts type metallation/rearomatisation sequence leading
to a Pd–aryl intermediate, before or after oxidative addition of the
Cross-coupling reactions have emerged as a general method aryl halide.5c The resulting intermediate is similar to those found
for the construction of pharmaceutical scaffolds and natural in conventional cross-coupling chemistry. Mori et al. developed a
compounds.1 During the last 30 years, numerous methods for Pd/Cu system for the direct arylation of thiazole,8 while recently,
the formation of carbon–carbon bonds using transition metal Huang and co-workers reported a Pd–Cu system enabling the
catalysts2 have been reported: Negishi, Mizoroki–Heck, Stille, arylation of heterocycles using aryl bromides.9 The operative
Suzuki–Miyaura, Sonogashira and Grignard reagents are the mechanism proposed relies on the presence of a N-donor atom
most famous, requiring functionalisation of both coupling on the substrate, which can coordinate the Cu centre and rear-
partners.2,3 Recently, studies have focused on the unreactive range into a Cu–heteroaryl intermediate after deprotonation by a
C–H bond and the development of atom-economical and more base. The heteroaryl fragment is then transferred to the palladium
environmentally friendly catalytic transformations. In particular, centre, and the aryl–heteroaryl product is reductively eliminated.
systems enabling the formation of biaryl (or aryl-heteroaryl) Despite the elegance of this protocol, the substrate scope is limited
fragments through non-oxidative direct arylation4 have received to benzo-thiazole, -oxazole and -imidazole derivatives.
significant attention.5 In this area, two challenges exist, in
Herein, we report the development of a novel bimetallic
addition to the activation of the C–H bond: homocoupling of catalytic system (Fig. 1) permitting the intermolecular direct
the aryl halide must be avoided and the arylation must occur arylation of arenes and heteroarenes with aryl and alkenyl
selectively at a single site. Considering the superior reactivity of bromides and chlorides without the need for a directing group.
aryl halides versus that of arenes and the presence of multiple The working hypothesis is based on the ability of [Cu(OH)(NHC)]
C–H bonds in arenes, selective direct arylation remains a chal- to perform C–H activation,10 and the subsequent use of the
lenge. These issues can be addressed by the presence of directing efficiency of Pd–NHC complexes to allow transmetallation with
groups on the arene substrate.6 This strategy leads to increased copper11 after C–Cl or C–Br bond cleavage, leading to the release
regioselectivity and reactivity, however, the scope of accessible
products is limited as often only the C–H bond ortho to the
directing group can be activated. In addition, the need for a
directing group often means that additional synthetic steps are
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST,
UK. E-mail: cc111@st-andrews.ac.uk
† Electronic supplementary information (ESI) available: Catalyst optimisation,
mechanistic studies and NMR spectra of all products. See DOI: 10.1039/
Fig. 1 Palladium–NHC and copper–NHC enabling C–H arylation.
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Table 1 Optimisation of reaction conditionsa
Entry
[Pd] (1 mol%)
[Cu] (1 mol%)
Conv.b (%)
1
2
3
4
5
[Pd(Cl)(cin)(SIPr)] 2c
—
[Pd(Cl)(cin)(SIPr)] 2
[Pd(Cl)(cin)(SIPr)] 2
[Pd(Cl)(cin)(SIPr)] 2
—
0
0
14
[Cu(OH)(IPr)] 1
[Cu(OH)(IPr)] 1
[Cu(Cl)(IPr)] 3
[Cu(Cl)(ItBu)] 4
13
93(90)d
a
Reaction conditions: pentafluorobenzene (0.75 mmol), 4-chlorotoluene
(0.75 mmol), CsOH (0.975 mmol), [Pd(Cl)(cin)(SIPr)] (1 mol%),
[Cu(X)(NHC)] (1 mol%) (X = OH or Cl), toluene (3.0 mL), 110 1C, 15 h.
b
Conversion to the coupling product based on aryl halide determined by
c
d
GC. No conversion using 5 mol% Pd. Isolated yield.
of the desired compound. In order to validate this hypothesis,
pentafluorobenzene and chlorotoluene were selected as coupling
partners for the optimisation of reaction conditions. Background
reactions were first performed using only Pd–NHC or Cu–NHC,
and no conversion was observed in either case (Table 1, entries 1
and 2). Well-defined [Cu(OH)(IPr)] 110a (IPr = N,N0-bis[2,6-(di-iso-
propyl)phenyl]imidazol-2-ylidene) complex in combination with
[Pd(Cl)(cin)(SIPr)] 212 (SIPr = N,N0-bis[2,6-(di-iso-propyl)phenyl]
imidazolidin-2-ylidene; cin = cinnamyl = 3-phenylallyl) repre-
sents an initial proof-of-concept in providing the direct arylation
product in low conversion (14%, Table 1, entry 3). [Cu(Cl)(IPr)]
313 was next tested as it is likely to be the intermediate species
post transmetallation with Pd (see mechanistic discussion
below). This chloride derivative leads to the same catalytic
activity as its hydroxide congener [Cu(OH)(IPr)] 1 (Table 1,
entries
3 and 4), confirming the possible presence of
[Cu(Cl)(IPr)] 3 in the catalytic cycle. Several Pd–NHC and
[Cu(Cl)(NHC)] complexes were tested,14 and the combination
of [Pd(Cl)(cin)(SIPr)] 2 and [Cu(Cl)(ItBu)] 4 (ItBu = N,N0-(di-tert-
butyl)imidazol-2-ylidene) showed the best result using CsOH as
base and toluene as solvent (Table 1, entry 5).
Under the optimised reaction conditions, the scope of this
new direct C–H arylation using palladium–NHC and copper–
NHC co-catalyst was investigated and the results are presented
in Scheme 1. The catalytic system performs equally well with
aryl chlorides or bromides, suggesting that the oxidative addi-
tion of the aryl halide is not the rate-limiting step in this
reaction (7a–c). ortho and meta-substituted aryl halides, with
electron donating or withdrawing groups, led to high catalytic
activity (7d–h). Different fluoroarene derivatives were studied
and the results are included in Scheme 1. Tetrafluoroarenes
could be mono-arylated and di-arylated in good yield (7m–o).
Trifluoroarenes could also be arylated in good yields (7q–r).
Scheme 1 Scope of the reaction.a,b
2,3,5,6-Fluoropyridine affords the cross-coupling product in an biaryls by Suzuki–Miyaura cross-coupling.15 Arylation of a- and
excellent 98% yield (7p). Highly challenging and sterically b-bromostyrenes was achieved with full conversion and high
congested tetra-ortho-substituted compounds can be synthe- isolated yields (7j–k). Coupling with an sp3 carbon is also possible
sised in good isolated yields (7i) using a very bulky NHC as shown by the reaction of pentafluorobenzene with benzyl
palladium complex [Pd(Cl)(cin)(IPr*)] (IPr* = N,N0-bis(2,6- bromide, leading to a 94% isolated yield of the coupling product
bis(diphenylmethyl)-4-methylphenyl)-imidazo-2-ylidene) devel- (7l). Imidazopyridine could also be efficiently and selectively
oped initially for the preparation of tetra-ortho-substituted arylated at the 5-position (7s). C–H arylation of challenging
8928 | Chem. Commun., 2014, 50, 8927--8929
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perform the direct arylation of C–H bonds without the use of a
directing group. The mechanistic studies indicate that the Cu
species performs an activation involving acid–base concepts,
which then transmetallates to Pd to deliver an aryl or heteroaryl
fragment. This methodology is efficient for a broad range of
aryl, benzyl and alkenyl bromides and chlorides reacting with
aryl and heteroaryl substrates. Ongoing studies focusing on
increasing the C–H reactivity of the copper-based system
should permit the broadening of the range of coupling partners
in this very powerful reaction sequence.
The authors are grateful to the Royal Society (University
Research Fellowship to CSJC) for financial support. We also
thank the EPSRC National Mass Spectrometry Service Centre in
Swansea for High Resolution Mass Spectrometry and Umicore
for the generous gift of Pd starting materials.
Scheme 2 Stoichiometric reactions.17
Notes and references
1 J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651.
2 Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and
F. Diederich, Wiley-VCH, Weinheim, 2004.
3 (a) A. O. King, N. Okukado and E.-i. Negishi, J. Chem. Soc., Chem.
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(g) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
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1943, 65, 504; (i) M. Yamamura, I. Moritani and S.-I. Murahashi,
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Scheme 3 Proposed mechanism.
4 (a) L.-C. Campeau and and K. Fagnou, Chem. Commun., 2006, 1253;
(b) M. Lafrance, C. N. Rowley, T. K. Wo and and K. Fagnou, J. Am.
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substrates such as 1,4-disubstituted-1,2,3-triazole (7t) is also
achieved in good isolated yield (78%) using 1 mol% of Pd and
10 mol% of the copper co-catalyst.
In order to better understand the role played by each metal-
complex in the transformation, stoichiometric reactions were
carried out (Scheme 2).16 [Cu(C6F5)(IPr)] 8 was obtained quan-
titatively by the reaction between [Cu(OH)(IPr)] 1 and penta-
fluorobenzene via C–H activation.17 This possible intermediate
species 8 was reacted with [Pd(Cl)(cin)(SIPr)] 2 in the presence
of 4-chlorotoluene and CsOH. This led to the concomitant
formation of [Cu(Cl)(IPr)] 3 and of the expected coupling
product.14
From these observations a proposed catalytic cycle is
depicted in Scheme 3. On the copper side of this dual catalytic
cycle (left), the first step consists of the in situ formation of the
hydroxide [Cu(OH)(NHC)] B from the chloride [Cu(Cl)(NHC)] A
in a reaction involving CsOH. The following step consists of the
C–H activation of the aryl or heteroaryl via an acid–base
reaction, producing [Cu(Ar/Het)(NHC)] C after formation of
H2O. At this stage the transmetallation with the Ar0–Pd inter-
mediate D (obtained from oxidative addition of the aryl halide
to Pd(0)) occurs, leading concomitantly to the regeneration of
[Cu(Cl)(NHC)] A and to the formation of the Ar/Het-Pd-Ar0
¨
5 For reviews, see (a) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius,
Chem. Soc. Rev., 2011, 40, 4740; (b) O. Daugulis, Top. Curr. Chem.,
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7 G. Rousseau and B. Breit, Angew. Chem., Int. Ed., 2011, 50, 2450.
8 Example of Pd/Cu systems for direct arylation of heterocycles:
A. Mori, A. Sekiguchi, K. Masui, T. Shimada, M. Horie,
K. Osakada, M. Kawamoto and T. Ikeda, J. Am. Chem. Soc., 2003,
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and M. M. Faul, J. Am. Chem. Soc., 2010, 132, 3674.
10 (a) G. C. Fortman, A. M. Z. Slawin and S. P. Nolan, Organometallics,
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Organometallics, 2012, 31, 7969; (c) S. Gaillard, C. S. J. Cazin and
S. P. Nolan, Acc. Chem. Res., 2012, 45, 778.
11 M. R. L. Furst and C. S. J. Cazin, Chem. Commun., 2010, 46, 6924.
12 N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M. Scott and
S. P. Nolan, J. Am. Chem. Soc., 2006, 128, 4101.
13 C. A. Citadelle, E. Le Nouy, F. Bisaro, A. M. Z. Slawin and
C. S. J. Cazin, Dalton Trans., 2010, 39, 4489.
14 See ESI† for more details.
intermediate, which can release the coupling product after 15 A. Chartoire, M. Lesieur, L. Falivene, A. M. Z. Slawin, L. Cavallo,
C. S. J. Cazin and S. P. Nolan, Chem. – Eur. J., 2012, 18, 4517.
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17 The reaction involving 1 was also successfully carried out in toluene,
reductive elimination and regenerate the Pd(0) catalyst.
In conclusion, a dual metal system involving [Cu(Cl)(NHC)]
and [Pd(Cl)(cin)(NHC)] has been employed to very effectively
but requires a longer reaction time.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 8927--8929 | 8929