Domino N-/C-Arylation via In Situ Generation of a Directing Group: Atom-Efficient Arylation Using Diaryliodonium Salts

Article abstract of DOI:10.1002/anie.201701523

Both aryl components of diaryliodonium salts can be used in a domino one-pot reaction via in situ generation of a directing group. A number of heterocycles undergo N-arylation which is followed by ruthenium-catalyzed C-arylation. Notably the reaction extends well to unsymmetrical diaryliodonium salts with a number of highly selective examples shown.

Full text of DOI:10.1002/anie.201701523

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201701523
German Edition: DOI: 10.1002/ange.201701523
Domino Arylation
Hot Paper
Domino N-/C-Arylation via In Situ Generation of a Directing Group:
Atom-Efficient Arylation Using Diaryliodonium Salts
Christopher J. Teskey+, Shariar M. A. Sohel+, Danielle L. Bunting, Sachin G. Modha, and
Michael F. Greaney*
Abstract: Both aryl components of diaryliodonium salts can
be used in a domino one-pot reaction via in situ generation of
a directing group. A number of heterocycles undergo N-
arylation which is followed by ruthenium-catalyzed C-aryla-
tion. Notably the reaction extends well to unsymmetrical
diaryliodonium salts with a number of highly selective
examples shown.
D
iaryliodonium salts have seen extensive application as
arylating agents in recent years, as they possess desirable
qualities of high reactivity, ease of use as stable, crystalline
solids, and compatibility with a wide variety of metal
catalysts.[1] Their major drawback, however, is the generation
of one equivalent of “waste” aryl iodide in the vast majority of
transformations, an unsustainable feature that limits future
exploitation. We recently addressed this issue by capturing
the generated aryl iodide in an iodonium arylation through
a one-pot, tandem C-/N-arylation of indole (Scheme 1A).[2]
Similar concepts of atom economy have been set out by
Dauban and co-workers, who demonstrated a sequential
oxidant/arylation role for ArI(OAc)2,[3] MuÇiz and co-work-
ers, who performed tandem borylation/Suzuki–Miyaura
cross-coupling of diaryliodoniums,[4] and Jiang and co-work-
ers, who described diaryl sulfide synthesis from a single
iodonium species.[5,6] In each case (and, perforce, all intra-
molecular applications of cyclic diaryliodoniums)[7] the iodo-
nium compound undergoes functionalization at the two ipso-
positions. We were interested in developing alternative
pathways to create new arylation patterns from iodoniums
while preserving the atom-economic approach. Our plan is set
out in Scheme 1B, which proposes a domino reaction
whereby an intermediate generated in step 1 opens up new
reactivity to harness the aryl iodide in step 2: The N-hetero-
cycle 1 can undergo arylation with 2 to give an N-aryl product
3, where the heterocycle can then act as a directing group for
Scheme 1. Atom-economical use of diaryliodoniums.
having greater diversity for application as building blocks in
the chemical sciences.
To develop the proposed sequence we required a hetero-
arene substrate offering versatile scope with respect to
reaction conditions for the two arylations. Pyrazoles were
appealing as they are known to react with iodoniums under
both metal-catalyzed and metal-free conditions,[8] and func-
tionalized pyrazoles have been extensively employed as
privileged motifs in medicinal chemistry.[9] We elected to
À
investigate ruthenium catalysis for the key C H arylation
step, given the robust literature precedent,[10] the affordability
of many Ru catalysts,[11] and our own recent experiences in
[12]
À
developing Ru-catalyzed C H functionalization chemistry.
Preliminary reaction screening of the two steps in
isolation established that the first N-arylation step could be
performed in a variety of solvents with 1.2 equivalents of
diphenyliodonium triflate (2a), pyrazole (1a), and potassium
carbonate as base at 708C (Scheme 2). Catalytic copper
iodide was observed to accelerate the reaction, but it was not
a requirement for good conversions in this simple case. The
second step was interrogated using N-phenyl pyrazole (3a),
iodobenzene (4), and a [RuCl2(p-cymene)]2 catalyst system.
While conversions were good using xylene and, critically, the
same K2CO3 base as in step 1, the system suffered from
competitive diarylation with poor selectivity between mono-
arylated 5a and doubly arylated 5aa. This presents a problem
for the overall stoichiometry of the projected domino process.
To prevent the unwanted second arylation we switched to the
sterically hindered 1-phenyl,3,5-dimethyl pyrazole (3b),
À
subsequent ortho C H arylation taking place in situ with the
released aryl iodide. Crucially, this second arylation breaks
the symmetry of the starting iodonium, creating structures
[*] Dr. C. J. Teskey,[+] Dr. S. M. A. Sohel,[+] D. L. Bunting, Dr. S. G. Modha,
Prof. Dr. M. F. Greaney
School of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: michael.greaney@manchester.ac.uk
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201701523.
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that two new bonds are being formed. Both electron-rich (5c–
5e) and electron-deficient (5 f–5i) aromatics were tolerated
well though 5 mol% of copper iodide was added for the first
step in the most polarized of examples. meta-Substituted
diaryliodoniums were also tolerated (5j and 5k). We demon-
strated that pyrazole itself can be used as a substrate with di-
ortho-tolyl iodonium triflate to give product 5l in good yield.
Finally, we were gratified to find that benzotriazole was
a competent heterocycle for our reaction conditions giving
the diarylated compound 5m in 55% yield.
With these results in hand, we turned our attention to
unsymmetrical iodonium salts (Scheme 3). Recent work from
Novak and co-workers has described selective arylation of
Scheme 2. Substrate scope with symmetrical diaryliodonium salts.
[a] CuI (5 mol%) was added in the first step and the reaction run for
8 h. [b] Iodonium trifluoroacetate salt was used.
[15]
Scheme 3.
Substrate scope with unsymmetrical diaryliodonium
salts. [a] Iodonium tosylate salt was used. [b] CuI (5 mol%) was added
in the first step.
which gave the expected monoarylated product 5b in good
conversions. To merge the two processes we used p-xylene as
solvent and an initial reaction temperature of 708C, increas-
3,5-diphenylpyrazole with diaryliodoniums,[8a] suggesting that
a selective domino arylation reaction could be developed.
Beginning with electronic differentiation, we found that
treatment of 3,5-dimethylpyrazole (1b) with (2,4-
dimethoxyphenyl)(phenyl)iodonium tosylate afforded prod-
uct 5n exclusively, in 44% yield, where the N-arylation has
been selective for the less electron-rich phenyl group. Similar
selectivity was observed with phenyl(2-thiophenyl)iodonium
triflate, which transferred the phenyl group initially in the N-
arylation, followed by C-arylation with the 2-iodothiophene
À
ing to 1408C for the C H arylation, and were delighted to
isolate 5b in good overall yield for the domino arylation
process. Best results were obtained from adding the ruthe-
nium catalyst to the reaction following completion of the
initial N-arylation.
A comprehensive range of symmetrical diaryliodonium
salts[13] proved to be successful under the optimized reaction
conditions (Scheme 2). Salts with para-substitution (5c–5i)
gave the diarylated products in very good yields considering
2
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generated in situ. Turning to steric differentiation, which is
steric demand of N-heteroarene and/or iodonium compo-
known to significantly influence aryl transfer in diaryliodo-
nium chemistry,[14] we treated pyrazole with (o-tolyl)arylio-
donium salts and found that regardless of the electronics of
the second aryl group, the ortho-tolyl aromatic transferred
first with complete selectivity (5p and 5q). In these two
examples, despite the second aromatic group being more
electron rich in one case, and more electron deficient in the
other, we still obtain products where the more sterically
hindered group transfers first. Pleasingly, both compounds
were obtained in excellent yield. To further explore this steric
control, we showed that 1,2,3-triazole reacted smoothly under
the reaction conditions with an unsymmetrical iodonium to
give compound 5r. Finally, given the importance of trifluor-
omethyl groups in medicinal chemistry and agrochemistry we
synthesized compound 5s where the aromatic group bearing
an ortho CF3 group selectively transfers in the first step.
Given the excellent selectivity obtained with sterically and
electronically differentiated iodonium salts, we were inter-
ested to see if the domino process could extend to alternative
motifs such as alkenes, which could in principle be introduced
using (E)-styryl(phenyl)iodoniums (6, Scheme 4).[16,17] Grat-
nents.
Acknowledgements
We thank the EPSRC (Doctoral Prize Fellowship to C.J.T.),
and Marie Curie actions (intra-European fellowship to
S.M.A.S.) for funding.
Conflict of interest
The authors declare no conflict of interest.
Keywords: arylation · C–H activation · iodonium compounds ·
N-heterocycles
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Manuscript received: February 11, 2017
Final Article published: && &&, &&&&
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Communications
Domino Arylation
C. J. Teskey, S. M. A. Sohel, D. L. Bunting,
S. G. Modha,
M. F. Greaney*
&&&& — &&&&
Domino N-/C-Arylation via In Situ
Generation of a Directing Group: Atom-
Efficient Arylation Using Diaryliodonium
Salts
First the one, then the other: Diaryl- and
alkenyl(aryl)iodonium salts react with N-
heteroarenes in domino fashion. N-func-
tionalization is followed by ortho-arylation
under ruthenium catalysis, capturing the
aryl iodide by-product of the first step.
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