Ruthenium-Catalyzed meta-Selective C-H Bromination

Article abstract of DOI:10.1002/anie.201504390

The first example of a transition-metal-catalyzed, meta-selective C-H bromination procedure is reported. In the presence of catalytic [{Ru(p-cymene)Cl₂}₂], tetrabutylammonium tribromide can be used to functionalize the meta C-H bond of 2-phenylpyridine derivatives, thus affording difficult to access products which are highly predisposed to further derivatization. We demonstrate this utility with one-pot bromination/arylation and bromination/alkenylation procedures to deliver meta-arylated and meta-alkenylated products, respectively, in a single step. Taking position: 2-Phenylpyridines undergo meta-selective bromination using tetrabutylammonium tribromide under ruthenium catalysis, thus affording products that are highly predisposed to further derivatization. The bromination can be combined with arylation and alkenylation chemistry to access meta-arylated and meta-alkenylated products, respectively, in a one-pot operation.

Full text of DOI:10.1002/anie.201504390

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504390
German Edition: DOI: 10.1002/ange.201504390
À
C H Activation
À
Ruthenium-Catalyzed meta-Selective C H Bromination
Christopher J. Teskey, Andrew Y. W. Lui, and Michael F. Greaney*
Abstract: The first example of a transition-metal-catalyzed,
À
meta-selective C H bromination procedure is reported. In the
presence of catalytic [{Ru(p-cymene)Cl2}2], tetrabutylammo-
À
nium tribromide can be used to functionalize the meta C H
bond of 2-phenylpyridine derivatives, thus affording difficult to
access products which are highly predisposed to further
derivatization. We demonstrate this utility with one-pot bromi-
nation/arylation and bromination/alkenylation procedures to
deliver meta-arylated and meta-alkenylated products, respec-
tively, in a single step.
À
T
he field of catalytic C H bond functionalization has grown
significantly in recent years, thus offering new disconnections
which can streamline synthetic routes and produce less
waste.[1] Several molecular architectures are now established
À
À
for reliable C H transformation, with arene C H function-
alization ortho to a directing group, by cyclometalation, being
a prominent example.[2] By contrast, meta functionalization is
a more difficult reaction as the analogous cyclometalation
processes are not at the chemistsꢀ disposal. Given that
stepwise meta functionalization is often challenging using
classical arene chemistry, the development of new catalytic
À
Scheme 1. Transition-metal-catalyzed C H bromination.
À
methods that address meta C H functionality is of pressing
ortho bromination, and halogenation in general, undergoing
[12–17]
importance.[3] Several ground-breaking reaction systems have
extensive development in the C H activation literature.
À
been developed to tackle this problem, principally in the areas
of palladium and copper-catalyzed C C bond formation,
However, meta bromination has yet to be described using
transition-metal catalysis, and is restricted to very forcing
reaction conditions in Friedel–Crafts bromination of electron-
[4–8]
À
and iridium-catalyzed borylation.[9] A third way of achieving
meta functionalization has recently been described by the
groups of Frost and Ackermann, where ruthenium catalysis is
used for meta sulfonylation and alkylation, respectively.[10]
These reactions are thought to proceed by ortho ruthenation,
thus affording an arylruthenium intermediate which exhibits
À
poor arenes (e.g., N Br reagent in neat H2SO4 for bromina-
tion of nitrobenzene).[18] A one-step meta-selective bromina-
tion, under mild reaction conditions, would open up a new
pathway to valuable 1,3-bromo-functionalized arenes, which
are currently prepared by tedious multistep routes. More
generally, it would create a catalyst-controlled bromination
system, where bromination of the same arene substrate could
be directed to either the ortho- or meta-position depending
upon the choice in catalyst.
À
a strong directing effect for functionalization at the C H
position para to the C Ru bond. Addition of a suitable
electrophile will thus result in overall meta substitution upon
protonolysis of the C Ru bond and completion of the
[11]
À
À
catalytic cycle.
We began by screening electrophilic bromine sources in
the presence of a base, catalytic [{Ru(p-cymene)Cl2}2], and
2-phenylpyridine (1a), as the substrate. Initial results showed
that NBS, bromine, and pyridinium tribromide gave minimal
conversion to the desired meta-brominated product 2a
(Table 1, entries 1–5). The failure of pyridinium tribromide
is notable (entry 5) as this reagent has been successfully used
to stoichiometrically brominate organo-ruthenium com-
plexes.[11] Gratifyingly, we observed successful meta bromina-
tion on switching to tetrabutylammonium tribromide
(TBATB) in 1,4-dioxane, with 2a being formed with excellent
conversion (entry 10). Use of a carboxylate additive in
We were interested in exploring this concept in the
context of meta bromination (Scheme 1). Aryl bromides are
supremely versatile functional groups, with methods for C H
À
[*] C. J. Teskey, A. Y. W. Lui, Prof. M. F. Greaney
School of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: michael.greaney@manchester.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504390.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
À
ruthenium catalyzed C H activation chemistry has extensive
precedent in work from the group of Ackermann,[19] and acted
in the current case to increase yields of the isolated products
by 5–10%. The reaction did not occur in the absence of
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Table 1: Reaction development.
withdrawing groups (2e–g) in the para-position of the
aromatic ring were well tolerated, producing good to excel-
lent yields of the bromide. In cases where the para-substituent
possesses significant steric bulk the reaction still proceeds, but
at a slower rate, thus resulting in a low yield after 20 hours
(2d). It should be noted that in low-yielding cases, the
majority of the remaining material can be accounted for as
starting the 2-phenylpyridine substrate. The reaction is
remarkably selective for the monobrominated, rather than
the dibrominated, product, despite using an excess of
brominating agent. Over-bromination has been problematic
in some previous examples of metal-catalyzed ortho bromi-
nation.[13b, 15a] The selectivity obtained in the meta bromina-
tion relative to other transition-metal-catalyzed bromination
methods is exemplified by the reaction of benzo[h]quinoline
to give the 7-brominated compound 2j. This product could
not be obtained selectively by using existing bromination
Entry
Brominating agent
Solvent
1a/2a[a]
1
NBS
acetonitrile
1,4-dioxane
acetonitrile
1,4-dioxane
1,4-dioxane
acetonitrile
water
1,4-dioxane
1,4-dioxane
1,4-dioxane
>99:1
>95:5
>99:1
>99:1
>99:1
>99:1
>99:1
10:90
2
NBS
3
Br2
4
Br2
5
6
pyridinium tribromide
TBATB
7
TBATB
TBATB
TBATB
TBATB
8[b]
9[c]
10
>99:1
5:95
methods,[20] and it contains a new C Br bond at a useful site
À
for further modification. Functionalized benzoquinolines are
used extensively as ligands in areas such as photoredox
catalysis, metallo-supramolecular chemistry, and organic
electronics, where methods for modifying the ligand structure
are essential to fine-tune electronic properties.
[a] Ratio of 1a/2a is based on 1H NMR analysis of crude reaction
mixtures after work-up. [b] Reaction carried out without MesCO2H
additive. [c] Experiment carried out without ruthenium catalyst.
ruthenium catalyst (entry 9) and in solvents other than 1,4-
dioxane, no product was observed. Finally, the reaction was
observed to be air-sensitive. In cases where the reaction was
set up without rigorous removal of air, conversions were
inconsistent but generally much lower.
With the optimized reaction conditions in hand, we sought
to explore the substrate scope (Scheme 2). We were pleased
to find that both electron-donating (2b–d) and electron-
As with the sulfonylation system reported by Frost and co-
workers,[10a] meta substitution on the phenyl ring is not
tolerated. Ruthenation is presumably directed to the most
sterically accessible ortho position, meaning that the pre-
existing meta substituent is now blocking the site of bromi-
nation. Likewise, ortho substitution was not tolerated in
phenylpyridine substrates. It is likely that this additional
steric encumbrance prevents co-planarity of the phenyl–
pyridine biaryl, thus disrupting the directed metalation and
ensuing bromination. However, with substitution at other
positions on the pyridine directing group, the reaction
proceeds in excellent yield (2h,i). Pleasingly, we were able
to scale-up the reaction to a 5 mmol scale. By running the
reaction for 65 hours, but with half the catalyst loading
(2.5 mol%), the yield of isolated 2a remained at 76%, with
4% of the ortho-brominated product also isolated.
To demonstrate the versatility of this methodology, we
developed simple one-pot processes to further manipulate the
À
newly installed bromide group in C C bond-forming reac-
tions (Scheme 3).[21] We could meta-arylate by a one-pot
bromination/Suzuki–Miyaura coupling: additional base was
used in the first step, and after running the bromination for
20 hours, water, Pd(OAc)2 (3 mol%), PPh3 (6 mol%), and
either a boronic acid or ester (3 equiv) were added and the
reaction run for a further 15 hours. This one-pot meta-
arylation procedure worked well for ortho-, meta-, and para-
substituted boronic acids, and both electron-withdrawing and
electron-donating substituents were tolerated (3a–e). The
reaction was extended to heteroaromatic boronic esters, with
the use of N-Boc-pyrrole-2-boronic acid MIDA ester proving
effective for the synthesis of 3 f in 64% yield. A meta-
alkenylation process was also possible: by simply adding
Pd(OAc)2 (3 mol%) and three equivalents of a suitable
alkene, post-bromination, and heating the reaction to 1108C
a one-pot bromination/Heck reaction proceeded. Yields of
the alkenylated product over the two steps were good (4a and
Scheme 2. Substrate scope for meta bromination. Yields are those of
isolated products. [a] Average of three runs. [b] Average of two runs.
[c] Yield without ruthenium catalyst is 10%. NBS=N-bromosuccini-
mide.
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rapidly reduced the heteroarene,[22] thus leaving the aryl
bromide group intact for further manipulation.
To conclude, we report the first example of transition-
metal-catalyzed meta-selective bromination. The orthogonal
selectivity exhibited by ruthenium relative to copper, palla-
dium, and rhodium catalysis offers a catalyst-controlled route
to compounds which may have been previously difficult to
synthesize. Further, the reaction system is amenable to one-
pot, telescoped processes which enable meta arylation and
meta alkenylation. Further investigations into the scope of
this chemistry are currently underway in our laboratory.
Acknowledgements
We thank the EPSRC for funding (PhD studentship to C.J.T.
and Leadership Fellowship to M.F.G.). Dr. Scott Cockroft
(University of Edinburgh) is thanked for helpful discussions.
Dr. Nicolas Kern and Pauline Rabet (University of Man-
chester) are thanked for assistance with SmI2 and starting-
material synthesis, respectively.
À
Keywords: bromine · C H activation · cross-coupling ·
regioselectivity · ruthenium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11677–11680
Angew. Chem. 2015, 127, 11843–11846
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Received: May 14, 2015
Revised: July 3, 2015
Published online: August 18, 2015
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Angew. Chem. Int. Ed. 2015, 54, 11677 –11680