Redox-controlled selectivity of C-H activation in the oxidative cross-coupling of arenes

Article abstract of DOI:10.1002/anie.201209007

Gold brings us together: Taking advantage of the orthogonal reactivities of Au^I and Au^III towards C-H activation of electron-poor and electron-rich arenes, respectively, a novel approach for the synthesis of biaryls through double C-H activation is proposed. Stoichiometric studies demonstrate that these oxidative couplings occur with high selectivity at low temperature. Copyright

Full text of DOI:10.1002/anie.201209007

Angewandte
Chemie
DOI: 10.1002/anie.201209007
Oxidative Coupling
À
Redox-Controlled Selectivity of C H Activation in the Oxidative
Cross-Coupling of Arenes**
Xacobe C. Cambeiro, Tanya C. Boorman, Pengfei Lu, and Igor Larrosa*
À
The ultimate application of C H activation to the synthesis of
biaryl compounds is a reaction in which two non-prefunction-
alized arenes are cross-coupled.[1,2] Such an oxidative cross-
coupling would substantially streamline synthetic strategies,
resulting in greener methods. To date, these oxidative
couplings have been catalyzed almost exclusively by Pd,
with some recent examples using Cu.[3,4] However, several
drawbacks remain to be addressed before these methods can
be widely applied. First, harsh reaction conditions are
Scheme 1. AuI versus AuIII C H activation. EDG=electron-donating
À
commonly needed, with strong acids required as solvents
group, EWG=electron-withdrawing group.
and/or temperatures typically exceeding 1108C. Second, poor
regioselectivities are generally obtained with substituted
arenes. Finally, in most oxidative couplings, both coupling
partners are activated by PdII or PdIV species that have very
similar selectivities, which results in the need for using 30–
300 equiv of one of the two arenes to ensure that cross-
coupling, rather than homo-coupling, is achieved.[5]
We hypothesized that a transition metal capable of
À
presenting orthogonal C H activation selectivities depending
on its oxidation state would allow a new approach towards the
rational design of oxidative cross-coupling methods with high
selectivities. Herein, we demonstrate that Au species present
this unique redox-controlled selectivity and highlight their
potential use for the design of novel cross-couplings involving
Scheme 2. Hypothetical redox-controlled highly selective oxidative
cross-coupling of electron-rich and electron-poor arenes.
À
oxidative double C H activation. These Au-mediated trans-
formations proceed at lower temperatures than current Pd
systems, and display excellent regioselectivities, high cross-
À
versus homo-coupling selectivities (thus avoiding the need for
vast excesses of the arenes), and are compatible with Pd-
sensitive groups, such as I and Br.[6]
a completely selective double C H activation-based cross-
coupling method (Scheme 2). In our hypothetical process,
a mixture of an electron-poor (1) and an electron-rich (3)
We have recently reported that AuI salts are able to
arene would initially react with a AuI salt, leading to selective
I
À
À
mediate the C H activation of electron-poor arenes at just
C H activation of 1. Upon addition of an oxidant, aryl–Au
508C (Scheme 1a).[7] This contrasts with the well-known
species I would be oxidized to AuIII complex II, which in turn
ability of AuIII salts to perform C H activation of electron-
would perform selective C H activation on the electron-rich
À
À
rich arenes, even at room temperature (Scheme 1b).[8,9] We
thus hypothesized that, if AuI and (III) salts are completely
selective for electron-poor and -rich arenes, respectively, this
interesting property of Au could be exploited to provide
arene, forming biaryl 4 upon reductive elimination. The
development of such a process presents a number of
challenges: 1) Despite the few recent methods suggested to
proceed by a AuI/III redox cycle,[10,11] to date none involve the
I
À
oxidation of aryl–Au species I. 2) C H activation by aryl–
AuIII species II has never been demonstrated, although it may
be a step in the homocoupling of electron-rich arenes.[12]
3) Aryl–AuIII species have been suggested to undergo ligand
scrambling by transmetalation, giving rise to homocoupling
products.[9,10]
[*] Dr. X. C. Cambeiro, T. C. Boorman, Dr. P. Lu, Dr. I. Larrosa
School of Biological and Chemical Sciences, Queen Mary University
of London, Joseph Priestley Building
Mile End Road, E1 4NS, London (UK)
E-mail: i.larrosa@qmul.ac.uk
Homepage: http://webspace.qmul.ac.uk/ilarrosa/index.html
Initially, we explored the coupling of o-iodoanisole with
[**] We gratefully acknowledge the Engineering and Physical Sciences
Research Council for generous funding, the European Research
Council for a Starting Research Grant (to I.L.) and the EPSRC
National Mass Spectrometry Service (Swansea).
aryl–AuI 2a (Table 1), which was prepared under our
[7]
À
standard C H activation conditions (Scheme 1a) in 99%
yield. Oxidant optimization revealed that, whereas in the
absence of oxidant no product was obtained, the desired
cross-coupling product could be observed, albeit in low yields,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209007.
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Table 1: Optimization of the oxidative cross-coupling procedure with
aryl–AuI 2a and o-iodoanisole.[a]
Entry
Oxidant
Solvent
4aa [%]
1
2
3
4
5
6
7
8
9
10
–
DCE
DCE
DCE
DCE
DCE
DCE
DCE
dioxane
DMF
MeCN
0
traces
12
48
51
81
91
52
0
Selectfluor
XeF2
PhI(OAc)2
PhI(OCOCF3)2
PhI(OPiv)2
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
34
[a] Reactions were performed under N2 atmosphere with 2a (1 equiv),
o-iodoanisole (5 equiv), and oxidant (2 equiv). Yields were determined by
1H NMR spectroscopy using an internal standard. DCE=1,2-dichloro-
ethane, DMF=dimethylformamide, Piv=pivaloyl, Selectfluor=1-chlor-
omethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate),
Ts =p-toluenesulfonyl.
when using Selectfluor or XeF2, which are known to oxidize
AuI to AuIII (Table 1, entries 1–3). Gratifyingly, the use of
iodonium species, PhI(OH)OTs in particular, afforded 4aa in
high yield (entry 7). Aryl–AuI complexes have previously
been used to form biaryls in Pd- and Ni-catalyzed cross-
couplings with (pseudo)haloarenes,[13] but, to the best of our
À
knowledge, this is the first example of a direct C H arylation
using these species.
These optimized conditions were then applied to
a number of ortho-disubstituted aryl–AuI compounds 2
(Scheme 3a). We were pleased to observe that the desired
cross-coupling products (4aa–4ea) were isolated in good
yields. Furthermore, as we had hypothesized, the procedure
affords excellent selectivity, with the cross-coupling products
almost exclusively obtained in preference to their potential
homo-coupling counterparts,[14] and with no detection of
a second arylation onto the anisole unit of the biaryls.
Remarkably, this oxidative coupling tolerates both I (4aa–
4ea) and Br (4ca) substituents, which are generally not
compatible with Pd-mediated couplings. This provides a val-
uable highly reactive handle for subsequent Pd-based trans-
formations and illustrates the unique reactivity of this system.
Ar–AuI compounds bearing only one ortho electron-with-
drawing group (Cl, NO2, and Br) were also found to undergo
Scheme 3. Scope of the AuI/III-mediated oxidative cross-coupling.
Yields shown are of isolated products. [a] Reaction performed at 708C
with 3a (10 equiv). [b] Determined by 1H NMR analysis. [c] Determined
by GC-MS analysis. [d] 1,3-dimethoxybenzene was added after stirring
all the other reagents at 508C for 10 min.
[15]
À
the C H arylation process (4 fb–4hb).
On the contrary,
suggestive of an SEAr-type process (4gd–e and 4af–g). Thus,
monosubstituted toluene (4ge) and anisole (4af) display very
high para-selectivity (para/ortho 5:1 and 7:1, respectively),
again in contrast to Pd systems, which often provide mixtures
of the para, meta, and ortho products in non-useful ratios.[2,17]
Similarly, 1,3-xylene and 1,3-dimethoxybenzene afforded
exclusively 1,3,4-substituted adducts 4gd and 4ag, in contrast
to the mixtures commonly obtained with Pd, where 1,3,5-
arylation predominates.[1,2] Heteroarenes can also be used as
coupling partners (4ah–i, 4gj) with good regioselectivities.
when the electron-withdrawing substituent (NO2) is in the
para position (4ib), or absent altogether (4jb), no reaction is
observed.
To further explore the potential of the AuI/III redox couple
in oxidative couplings, we tested the reaction with electron-
rich arenes 3b–j (Scheme 3b). Even benzene reacts at 508C
(4ac) with an excess of only 5 equiv, in contrast to the much
more forcing conditions required for analogous processes
with Pd.[16] The regioselectivities of the arylation are clearly
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(2 equiv) led to selective arylation of 3a, leaving the remain-
ing 1b untouched, with formation of cross-coupling product
4ba in 47% yield (comparable to Table 1, entry 8). Only
traces of the homo-coupling products of both starting arenes
were detected by GC-MS analysis (< 1%). This experiment
demonstrates the powerful selectivity achievable by applying
redox selectivity control and opens the door to its application
in the design of novel dehydrogenative oxidative cross-
couplings.
Scheme 4. Mechanistic studies to test the intermediacy of AuIII
species.
To probe the intermediacy of the aryl–AuIII species II
suggested in Scheme 2, we prepared well-defined aryl–AuIII
species cis-5 (Scheme 4),[18] which proved unreactive when
treated with 1,3-dimethoxybenzene (3k) at 508C. Interest-
ingly, the addition of AgOPiv to replace the Cl ligands with
OPiv (Piv = pivaloyl) allowed the formation of the cross-
coupling adduct 4ag in 71% yield. This result closely matches
the yield obtained using PhI(OH)OTs as an oxidant
(Scheme 3), and can be explained by the formation of more
electrophilic AuIII–pivalate species similar to those that would
result upon oxidation of 2a with PhI(OPiv)2 (Table 1,
entry 6), which confirms that aryl–AuIII species are likely to
be involved in this highly selective process.[19] Alternative
additional mechanisms for the processes detailed in Scheme 3
that involve direct reaction of the IIII species with the starting
arenes were also considered and discarded.[20]
In conclusion, we have demonstrated that the selectivity
À
of C H activation between electron-rich and -poor arenes can
be completely controlled by switching the oxidation state of
Au species. These experiments provide a new approach
towards the rational design of highly selective systems for the
À
C H activation of arenes. This process has important
advantages compared to current Pd-based methods, such as
cross- versus homo-coupling selectivity, higher or comple-
mentary regioselectivity, and reactions that proceed at lower
temperatures. Future development in this area will involve
the development of dehydrogenative cross-coupling process-
es that are catalytic in gold. This will require addressing the
challenge of developing mutually compatible conditions for
À
each C H activation step and an oxidant that selectively
oxidizes aryl-AuI species in the presence of other AuI
intermediates.
Having demonstrated the high selectivity of the aryl–AuI/
electron-rich arene cross-coupling, it remained to examine
the overall selectivity of the process, starting from a 1:1 Experimental Section
General procedure for biaryl synthesis via oxidative cross-coupling:
mixture of both initial arenes. Thus, a combined procedure
A mixture of PhI(OH)OTs (118.0 mg, 0.30 mmol), arylgold(I) com-
pound 2 (0.15 mmol), and the arene coupling partner (0.75 mmol) in
1,2-dichloroethane (0.75 mL, 0.20m) was stirred at 508C for 16 h.
After this time, the resulting mixture was purified by column
chromatography to afford the desired coupling products 4. The
ratio of regioisomers was evaluated by GC-MS analysis of the crude
mixture.
À
where both C H activations occur in the presence of both
arenes was investigated. This presented a number of chal-
I
À
lenges: 1) the optimal solvent for Au -mediated C H activa-
tion (DMF) was incompatible with the AuIII process, and
I
À
conversely, DCE prevented Au -mediated C H activation;
2) the AuIII-mediated process is incompatible with the pres-
ence of bases, which are required for the AuI process. After
solvent screening, it was found that a mixture of 1,2,4,5-
tetrafluorobenzene (1b, 5 equiv) and 2-iodoanisole (3a,
5 equiv) treated with Ph3PAuCl (1 equiv) under our standard
Received: November 10, 2012
Published online: December 23, 2012
À
Keywords: biaryls · C H activation · cross-coupling · gold ·
oxidative coupling
À
C H activation conditions, but using dioxane as the solvent
.
(Scheme 5) led to exclusive formation of aryl–AuI 2b
(> 99%) and left 3a untouched, as shown by 1H and
31P NMR analysis. Filtration of the mixture of 1b, 3a, and
2b through Celite followed by the addition of PhI(OH)OTs
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I
À
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À
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(C6F5)2Au(OPiv)PPh3. See the Supporting Information for the
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[20] Some of the possibilities considered were: 1) A transmetallation
from Ar–AuI 2 to PhI(OH)OTs to form (ArIPh)OTs followed by
reaction with the electron-rich arene could occur; the compound
(C6H5IPh)OTs was synthesized, but all attempts to couple it with
1,3-dimethoxybenzene, both with and without the addition of
AuI salts, failed. 2) Alternatively, the initial reaction of the
electron-rich arene 3 with PhI(OH)OTs to form (Ar’IPh)OTs,
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the Supporting Information for details on these and other
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