A robust and efficient catalyst possessing an electron-deficient ligand for the palladium-catalyzed direct arylation of heteroarenes

Article abstract of DOI:10.1002/ejoc.201402586

The exploration of the direct arylation capacity of a unique, thermally stable, and air-stable Pd⁰-phosphine catalyst is reported. Besides decisively contributing to catalyst robustness, the electron-deficient trifluoromethyl-substituted triphenylphosphine ligands make the palladium center more electron-deficient and accelerate the direct arylation step. The combination of only 0.5-2 mol-% of the catalyst and a substoichiometric quantity of pivalic acid generates an efficient system to promote biaryl-forming reactions of a broad range of electronically varied hetarenes and aryl bromides. The observed regioselective arylations suggest that a concerted metalation-deprotonation pathway is involved in the C-H activation step.

Full text of DOI:10.1002/ejoc.201402586

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DOI: 10.1002/ejoc.201402586
A Robust and Efficient Catalyst Possessing an Electron-Deficient Ligand for
the Palladium-Catalyzed Direct Arylation of Heteroarenes
Alexandra Jakab,[a] Zoltán Dalicsek,[b] and Tibor Soós*[a]
Keywords: C–H activation / Palladium / Fluorinated ligands / Biaryls / Electron-deficient compounds
The exploration of the direct arylation capacity of a unique,
substoichiometric quantity of pivalic acid generates an ef-
thermally stable, and air-stable Pd0–phosphine catalyst is re- ficient system to promote biaryl-forming reactions of a broad
ported. Besides decisively contributing to catalyst robust-
ness, the electron-deficient trifluoromethyl-substituted tri-
phenylphosphine ligands make the palladium center more
electron-deficient and accelerate the direct arylation step.
The combination of only 0.5–2 mol-% of the catalyst and a
range of electronically varied hetarenes and aryl bromides.
The observed regioselective arylations suggest that a con-
certed metalation–deprotonation pathway is involved in the
C–H activation step.
of the coupling partners in excess amount and require pro-
longed reaction times (typically Ͼ12 h). Further practical
deficiency of these methodologies is that the utilization of
a different set of reaction conditions for each class of sub-
strates has really caught on and has remained the norm.
Whereas catalyst development has been centered on the
study of electron-rich and sterically bulky ligands, there is
recent evidence by Fagnou,[6] Gevorgyan,[7] and Baudoin[8]
that shows that electron-deficient phosphine ligands can be
used effectively for palladium-catalyzed C–H functionaliza-
tion reactions, as they can accelerate the concerted met-
alation–deprotonation step.[6]
Recently, we developed unprecedentedly thermo- and air-
stable Pd0 complex 1, the stability of which is associated
with enhanced ligand dispersion interaction between the tri-
fluoromethylated phenylphosphine ligands (Figure 1).[9]
Contrary to the electron-poor nature of the ligand, this
complex proved to be an efficient and robust catalyst for
Suzuki reactions. As a subsequent step to chart its synthetic
utility, we became interested in exploring the applicability
of this catalyst toward C–H activation reactions, as the
thermal robustness of the complex combined with the pres-
ence of the electron-poor ligand was expected to be advan-
tageous for the direct arylation processes. Herein, we report
the results of catalyst 1 promoting direct arylation of a
broad variety of heteroarenes.
Introduction
Generally recognized as a privileged structure, the biaryl
motif has received increased attention by both academic
and industrial chemists having pharmaceutical, agrochem-
ical, and materials science interests.[1] Accordingly, its syn-
thesis has been a perpetual focus of activity, which has re-
sulted in the discovery and development of several efficient
synthetic routes. Among the myriad of catalytic reactions
to afford biaryls, the transition-metal-catalyzed direct aryl-
ation of aryl (pseudo)halides is an appealing approach.[2]
This non-oxidative, catalytic C–C bond-forming methodol-
ogy represents one of the most elegant and straightforward
synthetic pathways, as it eliminates the need to synthesize
organometallic coupling partners, and only 1 equiv. of the
halide salt is produced as a side product. Accordingly, a
growing number of studies have been directed toward the
development of suitable catalyst and catalytic conditions to
effect this transformation. Despite these focused efforts, sev-
eral practical challenges still remain to be solved. The re-
ported procedures generally employ a relatively high (5–
10 mol-%) catalyst load[2b,3] or a stoichiometric amount of
a quaternary ammonium salt additive,[4] presumably as a
result of thermal decomposition of the applied palladium
catalysts at the elevated reaction temperature. This synthetic
problem has been partially relieved by the utilization of
phosphine-free catalysts for a limited class of substrates.[5]
However, most of the methods developed to date utilize one
[a] Institute of Organic Chemistry, Research Centre for Natural
Sciences of the Hungarian Academy of Sciences,
P. O. Box 286, 1519 Budapest, Hungary
E-mail: soos.tibor@ttk.mta.hu
www.ttk.mta.hu/organo
[b] H4Sep Ltd.,
Berlini út. 47–49, 1045 Budapest, Hungary
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402586.
Figure 1. Superstable Pd0 catalyst.
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A. Jakab, Z. Dalicsek, T. Soós
SHORT COMMUNICATION
(Table 2, Entries 1–12).[3c,14] Nevertheless, these reactions
indicated the strength and practical merit of catalyst 1 in
direct arylation. Owing to its robustness, the employment
of catalyst 1 did not necessitate strictly inert conditions and
allowed the catalyst loading (0.5 mol-%) and the reaction
time to be reduced significantly without compromising the
yield. Next, a more challenging hetarene was selected to
test the utility of catalyst 1. 1-Methylimidazole, previously
recognized as a poor substrate,[14a] reacted smoothly to give
biaryl 8 regioselectively in excellent yield. In a similar man-
ner, the direct arylation of oxazole occurred regioselectively
in favor of the C5 position and in accordance with the pre-
sumed concerted metalation–deprotonation mechanism.[3b]
Although the cross-coupling of electron-rich and electron-
deficient aryl bromides proceeded smoothly, the reaction
failed if sterically congested 2-bromo-1,3,5-triisoprop-
ylbenzene (3n) or the less reactive 4-chloroacetophenone
(3m) was used as the coupling partner.
Results and Discussion
Since the seminal work of Ohta[10] in 1990, many palla-
dium-catalyzed methodologies have been developed for the
direct arylation of (het)arenes. In 2006, Fagnou and co-
workers discovered enabling reaction conditions for this
type of reaction by using a combination of a substoichi-
ometric pivalate additive with N,N-dimethylacetamide
(DMA) as the solvent.[11]
At the outset of our study, the direct arylation of benzene
under the “Fagnou-type” reaction conditions was taken as
a model reaction to investigate the efficiency of previously
developed “superstable” Pd catalyst 1 (Table 1). Under
these reaction conditions, catalyst 1 gave the biaryl product
in 61% yield within 12 h at 120 °C (Table 1, Entry 1). The
utilization of pivalic acid and DMA (Table 1, Entries 2–4)
proved to be indispensable, as no biaryl formation was
found in their absence.[12] These trends suggested that a
concerted metalation–deprotonation pathway was op-
erating during this direct arylation process. In accordance
with the suggested mechanism,[5d] there was no beneficial
effect of the utilization of phosphine additives (Table 1, En-
tries 5 and 6).[13] Finally, employing more forcing condi-
tions resulted in a slightly improved yield (Table 1, Entry 7).
Conclusions
We demonstrated the capacity and synthetic utility of su-
perstable Pd0 catalyst 1 in the direct arylation of benzene
and heteroaryl molecules. Owing to the robustness of the
catalyst at higher temperatures, there was no need to run
the reaction under a strictly inert atmosphere, and the cata-
lyst loading could be reduced without compromising the
yields. Applying “Fagnou-type” conditions, a wide range of
heteroaromatic biaryls were obtained within reasonable
times and with high regioselectivity. Efforts are underway
to further study the applicability of catalyst 1 in additional
palladium-catalyzed reactions.
Table 1. Influence of the reaction conditions in the palladium-cata-
lyzed direct arylation of benzene with 4-bromotoluene by using Pd0
complex 1.[a]
Entry Ligand Solvent
Conv.[b] [%] Yield[c] [%]
1
2
3
4
none
none
none
none
SPhos
dppb
none
DMA
DMF
MeOH/H2O (10:1)
nBuOH
DMA
DMA
DMA
Ͼ99
65
33
Ͼ99
44[d]
33[d]
Ͼ99
61
(6)
(Ͻ5)
(Ͻ5)
(Ͻ5)
(Ͻ5)
64
Experimental Section
5
General Procedure for the Direct Arylation of Heteroarenes: A mix-
ture of K2CO3 (207 mg, 1.5 mmol), catalyst 1 (0.5–2 mol-%), piv-
alic acid (31 mg, 30 mol-%), aryl halide (1 mmol) and heteroarene
(1 mmol) dissolved in DMA (3 mL) was stirred and heated in a
screw-cap vial at 140 °C for the indicated time. After cooling to
room temperature, the mixture was diluted with ethyl acetate
(7 mL), washed with water (2ϫ 10 mL), and dried with Na2SO4.
The solvent was evaporated in vacuo, and the crude product was
further purified by flash chromatography (hexane/ethyl acetate) to
provide the desired product.
6
7[e][f]
[a] Reaction conditions: Catalyst 1 (3 mol-%), ligand (3 mol-%),
K2CO3 (2.5 equiv.), additive (30 mol-%), 4-bromotoluene
(0.6 mmol), benzene (3 mL), solvent (3.5 mL), 120 °C, 12 h. SPhos
= 2-dicyclohexylphosphino-2Ј,6Ј-dimethoxybiphenyl, dppb = 1,4-
bis(diphenylphosphino)butane. [b] Conversion of 4-bromotoluene
was determined by GC–MS. [c] Yield of isolated product. Yields
determined by GC–MS are given in parentheses. [d] The reaction
was conducted at 140 °C. [e] Reaction time was 72 h. [f] The em-
ployment of 52 equiv. of benzene was critical; the use of only
26 equiv. resulted in a dramatic drop in the yield (Ͻ5%).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and copies of the 1H NMR and
13C NMR spectra for all biaryl products.
To gauge the synthetic potential of catalyst 1 in direct
arylation reactions, a survey of a broad range of heteroar-
enes and bromobenzene derivatives was performed by uti-
lizing a strict 1:1 cross-coupling partner stoichiometry
(Table 2). Gratifyingly, the direct arylation proceeded
smoothly within 2–12 h in the presence of catalyst 1 to af-
ford the products in synthetically useful yields. Molecules
containing furan, thiazole, and benzothiophene rings re-
sulted in biaryl products in moderate to good yields, similar
to previously reported direct arylation methodologies
Acknowledgments
T. S. is grateful to the Lendület Foundation for financial support.
[1] Selected recent examples: a) J. Yamaguchi, A. D. Yamaguchi,
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aryls, Elsevier, Oxford, 2004.
2
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Palladium-Catalyzed Direct Arylation of Heteroarenes
Table 2. Palladium-catalyzed arylation of heteroarenes with aryl halides.[a]
[a] Reaction conditions: Catalyst 1 (0.5–2 mol-%), K2CO3 (1.5 equiv.), pivalic acid (30 mol-%), aryl halide (1 equiv.), heteroarene (1 mmol),
140 °C, 2–12 h. [b] Yield of isolated product. [c] 1.5 equiv. of oxazole was used.
[2] Recent reviews on direct arylation: a) D. Alberico, M. E. Scott,
M. Lautens, Chem. Rev. 2007, 107, 174–238; b) L. Ackermann,
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Engle, D. H. Wang, J. Q. Yu, Angew. Chem. Int. Ed. 2009, 48,
5094–5115; Angew. Chem. 2009, 121, 5196–5217; d) N. Kuhl,
M. N. Hopkinson, J. W. Delord, F. Glorius, Angew. Chem. Int.
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SHORT COMMUNICATION
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[11]
[12]
For details, see the Supporting Information.
[13] For the beneficial effects of bidentate ligands, see: a) S. Pascual,
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Received: May 15, 2014
[9] This complex was patented: A. Jakab, Z. Dalicsek, T.
Holczbauer, A. Hamza, I. Pápai, Z. Finta, G. Timári, T. Soós,
WO 2012/093271 A1, 2012; A. Jakab, Z. Dalicsek, T.
Holczbauer, A. Hamza, I. Pápai, Z. Finta, G. Timári, T. Soós,
Eur. J. Org. Chem., 10.1002/ejoc.201403214..
Publication delayed on the authors’ request.
Published Online: ᭿
4
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Palladium-Catalyzed Direct Arylation of Heteroarenes
C–H Activation
A. Jakab, Z. Dalicsek, T. Soós* ....... 1–5
A Robust and Efficient Catalyst Possessing
an Electron-Deficient Ligand for the Pal-
ladium-Catalyzed Direct Arylation of Het-
eroarenes
Application of a unique, thermally stable,
and air-stable Pd0 catalyst for the direct
arylation of heteroarenes is described.
The combination of only 0.5–2 mol-% of
the Pd0 complex possessing an electron-
deficient fluorinated phosphine ligand with
a substoichiometric quantity of pivalic acid
(PivOH) generates an efficient system to
promote the C–H activation of a broad
range of heteroarenes.
Keywords: C–H activation / Palladium /
Fluorinated ligands / Biaryls / Electron-
deficient compounds
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