Palladium(II)-catalyzed c-h bond arylation of electron-deficient arenes at room temperature

Article abstract of DOI:10.1002/anie.201005990

Mild and tolerant: A novel Pd^II-catalyzed C-H bond arylation with aryl-BF₃K salts transforms various electron-deficient arenes under mild reaction conditions. Benzaldehydes are functionalized in the ortho position using a temporary imine directing group that controls the cyclopalladation. A broad range of benzaldimines are compatible with this process (see scheme).

Full text of DOI:10.1002/anie.201005990

Communications
DOI: 10.1002/anie.201005990
À
C H Functionalization
À
Palladium(II)-Catalyzed C H Bond Arylation of Electron-Deficient
Arenes at Room Temperature**
Matthew J. Tredwell, Moises Gulias, Nadine Gaunt Bremeyer, Carin C. C. Johansson,
Beatrice S. L. Collins, and Matthew J. Gaunt*
À
Despite the impressive array of metal-catalyzed C H bond
functionalization processes,[1] significant challenges remain
before their full potential as general strategies in complex
molecule synthesis can be realized. In relation to this, a key
goal in our laboratory is the development of PdII-catalyzed
À
site-selective C H bond functionalization reactions that
proceed at room temperature,[2] facilitating the assembly of
the architectures that define complex natural products,
medicines, and functionalized materials. Recent advances
have identified that PdII-catalysts are capable of performing
À
arene C H functionalization transformations at room tem-
perature, and these examples include the olefination,[3a]
arylation,[3b–g] carbonylation,[3h] and acylation[3i] of electron-
rich aromatic compounds (Scheme 1A).[3] The continued
advancement of this field would benefit from the develop-
II
À
ment of new processes that facilitate Pd -catalyzed C H
bond functionalization of the complimentary and versatile
electron-deficient arenes at room temperature.
Arenes substituted with carbonyl-related groups provide
an effective handle for cyclometalation.[1,4–8] With respect to
Pd catalysis, Yu and co-workers have pioneered the use of
carboxylate groups as effective promoters of Pd-catalyzed
[5]
À
selective C H functionalization, which has led to seminal
À
Scheme 1. Concepts for room temperature C H functionalization.
developments in cross-coupling with arylorganometallic
reagents;[5a,b,6] further developments have led to carbon-
ylation,[5c] alkylation,[5d] olefination,[5e,f] oxygenation,[5g] and
iodination[5h,i] reactions. Related to this, other carbonyl-based
directing groups such as amide derivatives,[7] ketones,[8] and
arene bearing an imine directing group would be less electron
withdrawing than other carbonyl directing groups, thereby
enhancing the cyclopalladation capacity at room temperature
and still providing easy access to the versatile aldehyde
functional group (Scheme 1B).
oximes[9] have also resulted in developments in catalytic C H
À
bond functionalization. However, many of these groups
impart a strong electron withdrawing effect on the parent
À
À
aromatic nucleus, and hence the C H bond palladation event
Herein, we report that the C H bond arylation of
often requires forcing reaction conditions that may not always
be compatible with more delicate molecular architecture.
With this in mind, we envisaged a design plan wherein an
benzaldimines with aryl-BF3K salts can be catalyzed by
Pd(OAc)2 at room temperature (Scheme 1C); the mild
reaction conditions enable the functionalization of substrates
displaying sensitive functionality.
The cyclopalladation of benzaldimines at room temper-
ature is well documented,[10] however, the paucity of catalytic
PdII reactions on this class of molecule[11] contrasts with the
extensive number of RhI- and RuII-catalyzed imine directed
[*] Dr. M. J. Tredwell, Dr. M. Gulias, Dr. N. Gaunt Bremeyer,
Dr. C. C. C. Johansson, B. S. L. Collins, Dr. M. J. Gaunt
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)1223-336-362
À
C H bond functionalization processes that have been
reported.[12] A common feature of oxidative PdII-catalyzed
E-mail: mjg32@cam.ac.uk
Homepage: http://www-gaunt.ch.cam.ac.uk
À
C H bond functionalization processes is the generation of
[**] We gratefully acknowledge the Leverhulme Trust (M.J.T. and
N.G.B.), the Marie Curie Foundation (M.G.), the EPSRC (C.C.C.J.),
the University of Cambridge (B.S.L.C.), the Royal Society, and Philip
and Patricia Brown (M.J.G.) for funding, and the EPSRC Mass
Spectrometry Service (University of Swansea).
acid in the oxidation step that returns the Pd0 species formed
at the end of a catalytic cycle back to the active catalyst.
Imines may display poor stability under such oxidative
conditions and are prone to hydrolysis; the release of a
primary amine would trap the catalyst in an inactive bis-
(amino)–PdII complex.[13] Despite these potential problems,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005990.
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II
[a]
À
Table 1: Optimization of the Pd -catalyzed C H bond arylation.
we were attracted by the apparent ease of cyclopalladation on
the intrinsically electron-deficient benzaldimine nucleus.[10]
We deemed that benzaldimines derived from aniline would
be unsuitable for our needs due to the likely instability
towards the mildly acidic conditions of the oxidative catalytic
cycle, and we proposed that increased steric bulk around the
aniline component would stabilize the imine towards hydro-
lytic cleavage. In light of this hypothesis, we selected 2,6-
diisopropylaniline as an ideal source of sterically demanding
Entry Pd(OAc)2 Additive Oxidant
Solvent
Conv. [%][b]
1
2
3
4
5
6
7
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
–
–
–
–
–
–
–
MeOH
MeOH
MeOH
18
–
–
–
50
50
oxone
Cu(OAc)2
À
amine to form the benzaldimine substrate for our catalytic C
PhI(OAc)2 MeOH
H bond functionalization strategy (Scheme 1C).[8,14]
tBuO2Bz
tBuO2H
tBuO2H
MeOH
MeOH
We focused our initial studies on benzaldimine 1a, and
upon treatment of 1a with 1 equivalent of Pd(OAc)2 at room
temperature in methanol, a cyclopalladated complex was
formed and subsequently identified as comprising a bridged
dimer 1a2·Pd and a trinuclear architecture 1a2·Pd3, whose
structures were confirmed by X-ray diffraction following
10 mol% Ac2O,
4 ꢀ M.S.
CH2Cl2/IPA 100 (95)
[a] BQ=benzoquinone, Bz=benzoyl, IPA=iPrOH. [b] Conversion
determined by 1H NMR spectroscopy. Yield of isolated product in
brackets.
À
recrystallization (Scheme 2). Making use of the C H cross-
derived from aniline in the catalytic reaction and no arylation
was observed, supporting the suspected decomposition of the
imine.
The capacity of the arylation process was assessed through
variation of the arylboronic acid component. We noticed a
strong reliance on the quality of arylboronic acid, in particular
the source of the reagent.[17] However, following the prece-
dent first identified by Yu and co-workers, we found that the
reaction proved superior and worked reliably with aryl-BF3K
salts (Table 2, 3a).[5b] Accordingly, a range of aryl groups can
be transferred in excellent yields, displaying electron-donat-
ing (3c, 3e, 3 f, 3k), and electron-withdrawing properties (3i,
3j). Unfortunately, aryl-BF3K salts displaying ortho-substitu-
ents and styryl-BF3K salts did not result in the desired
products (3h, 3l). Aryl groups containing halogens (3b–d, 3g)
Scheme 2. Cyclopalladation and functionalization of 1a.
coupling tactic introduced by Yu et al.,[5a,b,6] we determined
that 1a2·Pd underwent arylation when treated with PhB(OH)2
(2a) in methanol to give the ortho-arylated benzaldimine 3a
in excellent yields. Importantly, the aryl transfer only
proceeded in the presence of benzoquinone (BQ), a reliance
also identified by others.[6,15] We also confirmed that trinu-
clear complex 1a2·Pd3 underwent arylation to 3a, albeit in
lower yield.
À
Table 2: Scope of aryl transfer in the ortho-selective C H arylation.
Encouraged by these initial results, we next investigated
the reaction parameters towards a mild catalytic arylation
process and commenced screening by varying the nature of
the oxidant in the presence of 20 mol% of Pd(OAc)2 in
methanol and benzoquinone (2 equiv) (Table 1). Optimized
conditions were established which entailed the treatment of
1a with 10 mol% Pd(OAc)2, 2 equiv of PhB(OH)2 (2a),
2 equiv of BQ, 2 equiv of tBuO2H as oxidant, 1 equiv of Ac2O
and 4 ꢀ molecular sieves in a CH2Cl2/iPrOH (4:1) solvent
mixture to provide a 95% yield of the arylated imine 3a after
24 h at room temperature (Table 1, entry 7). We believe that
the presence of acetic anhydride ensures reformation of
Pd(OAc)2 during the oxidation step with tBuO2H.[16] Control
experiments ensured that no arylation took place on the
parent o-tolualdehyde[8] under the optimized conditions, or in
the absence of Pd(OAc)2. We also tested the benzaldimine
[a] 12 mol% Pd(OAc)2 used. [b] Acetone/iPrOH used as solvent.
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Communications
were transferred in excellent yields, demonstrating that the
À
C H arylation process is compatible with functionality
required for conventional Pd0-catalyzed cross-coupling reac-
tions.
Benzaldimines that display a variety of functional and
structural motifs are also compatible with the catalytic
arylation process (Table 3). The process readily transformed
[a]
À
Table 3: Scope of ortho-selective benzaldimine C H arylation.
Scheme 3. Dehydrogenative cross-coupling of benzaldimines.
compatible with this process, and to the best of our knowledge
II
À
this represents the first example of a Pd -catalyzed direct C
H bond arylation on electron-deficient arenes that proceeds
at room temperature. Using modified conditions we were also
À
À
able to demonstrate a dehydrogenative C H to C H cross-
coupling that even works on benzaldimines that display
further electron-withdrawing functional groups. We are
currently investigating aspects of the mechanistic pathway
of these processes to develop additional novel reactions based
À
on this room temperature C H activation, and these studies
will be reported in due course.
Received: September 24, 2010
Published online: December 22, 2010
À
Keywords: arylation · C H functionalization ·
palladium catalysis · site-selective reactions · synthetic methods
[a] Bn=benzyl, Ts=p-toluenesulfonate. [b] 20 mol% Pd(OAc)2. [c] 408C.
.
benzaldimines bearing halogens, (3q, 3t), tosyl (3s), silyl (3r),
aryl and alkyl substituents (3m–p, 3u) in good to excellent
yields. The significant advantage of this mild method is the
ability to arylate structurally complex molecules bearing
labile stereogenic centers. For example, an ibruprofen derived
benzaldimine could be arylated under our standard condi-
tions in good yield to give 3v without loss of chiral integrity.
Even when an additional electron-withdrawing group is
displayed on the benzaldimine, the arylation of this electron
deficient arene still proceeds in moderate yield at 408C (3w).
The enhanced stability that the isopropyl groups impart
on benzaldimine 1a suggested that it may also be possible to
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II
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À
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À
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