Use of 2-bromophenylboronic esters as benzyne precursors in the Pd-catalyzed synthesis of triphenylenes

Article abstract of DOI:10.1021/ol5006246

ortho-Substituted aryl boronates are introduced as aryne precursors for transition-metal-catalyzed transformations. On treatment with ^tBuOK and Pd(0), metal-bound aryne intermediates are formed that undergo effective trimerization to form useful triphenylene compounds. For meta-substituted arynes, the 3:1 product ratio in favor of non-C₃ symmetric material is indicative of a benzyne mechanism.

Full text of DOI:10.1021/ol5006246

Letter
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Use of 2‑Bromophenylboronic Esters as Benzyne Precursors in the
Pd-Catalyzed Synthesis of Triphenylenes
Jose-Antonio García-Lopez and Michael F. Greaney*
́
́
School of Chemistry, University of Manchester, Oxford Rd, Manchester M13 9PL, United Kingdom
S
* Supporting Information
ABSTRACT: ortho-Substituted aryl boronates are introduced
as aryne precursors for transition-metal-catalyzed trans-
t
formations. On treatment with BuOK and Pd(0), metal-
bound aryne intermediates are formed that undergo effective
trimerization to form useful triphenylene compounds. For
meta-substituted arynes, the 3:1 product ratio in favor of non-
C3 symmetric material is indicative of a benzyne mechanism.
ryne chemistry has flourished in recent years, driven by
the introduction of 2-trimethylsilylphenyl triflates, 1, as
Scheme 1. Proposed Benzyne Generation from ortho-
Substituted Arylboronic Acid Derivatives 4
A
precursors that function under mild reaction conditions.1
́ ́
Seminal observations from the groups of Per and
ez/Guitian2
Yamamoto3 established that these reagents were compatible
with transition metal (TM) catalysis, a field that was entirely
untapped in the classical era of benzyne chemistry. These
reports exemplified the versatility of 1, which has since being
exploited in a tremendous variety of both metal-mediated and
metal-free transformations.4,5
Our interest in transition-metal-catalyzed benzyne chemistry6
led us to speculate that an analogous ortho-substituted aryl
boronate, 4, could offer alternative reaction pathways in the
TM catalysis arena, while retaining the benefits of usability
conferred by silanes 1. Verbit and co-workers reported the
diazotization of o-amino boronic acid as a benzyne-generating
method as early as 1966, but the method did not find wider
application in synthesis.7 More recently, Hosoya and co-
workers showed that (2-trifluoromethanesulfonyloxy)aryl-
boronic esters (4, X = OTf) underwent activation with t-
BuLi or s-BuLi at −78 °C, affording arynes on warming that
could be trapped in a variety of σ-insertion and pericyclic
reactions.8 The Akai group then demonstrated that fluoride
could selectively activate the boron center of 2-boryl-6-
(trimethylsilyl)phenyl triflates at room temperature, generating
benzynes that were trapped with amines.9 Application of ortho-
substituted arylboronic acid derivatives as benzyne precursors
in transition metal catalysis, however, has yet to be reported.
We based our catalyst system on stoichiometric work from
Wenger, Bennett, and co-workers, who synthesized a series of
existing approaches, whereby free benzyne (2) is slowly
generated by fluoride treatment of 1 and then bound to a
metal catalyst in a subsequent step.
We chose to explore the scope of compounds 4 using metal-
catalyzed benzyne cyclotrimerization. Palladium-catalyzed aryne
trimerization is one of the best-studied and most used TM-
́
catalyzed aryne reactions, with the Pena and Guitian group
̃
having demonstrated extensive applications to the synthesis of
extended aromatic arrays (e.g., nanographenes, cloverphenes,
acenes, coronenes) for applications in organic materials
science.11,12
t
Pd(0) and Ni(0) benzyne complexes via BuOK treatment of
We began by examining 2-bromo-phenylboronic acid as a
substrate, as it is a commercially available, inexpensive
crystalline solid. An initial experiment using 2 equiv of
tBuOK, Pd(dba)2 (5 mol %), and PPh3 (10 mol %) in toluene
at 100 °C afforded triphenylene 6a in a low 15% yield.
the organometallic prepared from (2-bromophenyl)boronic
esters 4 (Scheme 1, shown for Pd(II) complex 5a).10 The
resulting complexes were characterized by X-ray crystallography
in many cases, revealing the symmetrical η-2 coordination of
the benzyne triple bond to the group 10 metal atom (3a).
If this approach could be adapted to a catalytic variant, it
would have the interesting property of generating arynes as
metal-bound intermediates immediately. This contrasts with
Received: February 28, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Letter
Switching to the pinacol ester (4a), however, gave 6a in a far
better 60% yield (Table 1, entry 1), so we chose to optimize the
Scheme 2. Triphenylene Substrate Scope
Table 1. Optimization of Pd-Catalyzed Triphenylene
a
Synthesis
b
yield
entry
1
X
conditions
(%)
Br
Pd(dba)2 (5 mol %), PPh3 (10 mol %),
60
tBuOK (2 equiv), toluene, 100 °C
2
Br
Pd(dba)2 (5 mol %), DPEphos (5 mol %),
78
tBuOK (1.1 equiv), toluene, 100 °C
c
3
4
Cl
as entry 2 at 125 °C
25
OTf as entry 2
80
a
Reactions carried out with 0.5 mmol of 4a in a Schlenk tube under a
b
c
N2 atmosphere at 100 °C. Isolated yields. NMR yield.
reaction around this substrate. Control experiments indicated
that both metal and base were necessary to form triphenylene,
and that the triphenylphosphine ligand enhanced the reaction
yield. A full optmization study (see Supporting Information for
details) established conditions of Pd(dba)2 (5 mol %), bis[(2-
diphenylphosphino)phenyl] ether (DPEphos, 5 mol %),
tBuOK (1.1 equiv) in toluene at 100 °C, affording triphenylene
in 78% yield (entry 2).
With an optimized procedure in hand, we examined
alternatives to bromide in the ortho-position to the boronic
ester. The 2-chloro substrate worked poorly, giving a 20% yield
of 6a, increasing slightly to 25% at 125 °C (entry 3). The 2-
triflato substrate, however, was highly effective, affording an
80% yield of triphenylene (entry 4). We elected, however, to
focus on the bromo derivatives for further investigation, as their
synthesis is easier and more economical. A range of 2-bromo-
phenylboronic esters were accordingly synthesized from the
corresponding 2-bromo-1-iodobenzenes using a simple two-
step procedure: metal−iodine exchange and boronation,
followed by esterification with pinacol. We focused initially
on 4-substituted substrates such as 4b, as the substituent
position in the product triphenylenes can provide insights into
the reaction mechanism (Scheme 2).
AB quartet (5JF−F = 142 Hz), the latter signal an example of the
very large “through-space” coupling experienced by the two
crowded fluorine atoms in the bay region of the triphenylene
structure.14 Methoxy substitution at this position, however, led
to a 1:1 mixture of products 6i and 6i′ in 45% yield. This lack
of regioselectivity contrasts with the highly selective Pd-
catalyzed cyclotrimerization of 3-methoxy-benzyne from 2-
(trimethylsilyl)phenyl triflate precursors (in favor of the
nonsymmetrical 6i′) reported by Guitian
́
et al.2 and suggests
this substrate undergoes cyclization through a hybrid
mechanism (vide infra). The symmetrical triphenylene 6j and
trinaphthylene 6k were then prepared from the appropriate 2-
bromoaryl boronic esters in moderate yield. Both compounds
have previously been synthesized from the analogous 2-
trimethylsilylphenyl triflates, in yields of 55% for 6j and 41%
for 6k.2,15
Trimerization of 4b gave a 1:3 mixture of triphenylenes 6b
(C3 symmetric) and 6b′ (no rotational symmetry) in 67%
While the precursors and reaction were designed in the
context of Pd-catalyzed aryne chemistry, it is conceivable that a
stepwise Suzuki−Miyaura mechanism may be in operation. The
consistent 1:3 ratio of triphenylene regioisomers from 4-
substituted starting materials, however, strongly supports an
aryne pathway. The Suzuki−Miyaura mechanism cannot be
operating via three successive intermolecular couplings (see
Supporting Information for a discussion on this mechanism), as
that would yield the C3-symmetric regioisomer 6 as the
exclusive product. The alternative aryne mechanism, however,
fits nicely with the observed product ratio via the pathway
shown in Scheme 3. Initial oxidative addition of Pd(0) is
followed by base-activated aryne formation to form complex 3,
in line with observations from Wenger and co-workers
(Scheme 1).10 Ligand exchange between two molecules of 3
sets up a cyclopalladation reaction to give the two isomeric
palladacycles 7a and 7b. We assume a 1:1 ratio of these two
intermediates, as meta-substitution typically exerts no regiocon-
trol in benzyne chemistry.
1
overall yield (ratio determined by H and 13C NMR and GC−
MS). Compound 6b′ has previously being prepared via Pd-
catalyzed aryne trimerization using benzoic acid (34% yield)6a
and phthalic anhydride (31% yield) precursors,12a whereas 6b
has been prepared through cyclohexanone cyclo-condensation
and subsequent oxidation (53% yield).13 The cyclotrimerization
reaction proved tolerant of both electron-withdrawing and
-donating groups at the 4-position of 4, affording moderate
yields for the methoxy- and chloro-substituted triphenylenes 6c
and 6f and good yields of the tert-butyl-, fluoro-, and
trifluoromethyl-substituted 6d, 6e, and 6g. In all cases a 1:3
mixture of regioisomers was observed in favor of the non-C3
symmetric product. Substitution at the 6-position, ortho to the
developing triple bond, gave a selective reaction for the fluoro
derivative in favor of the novel triphenylene 6h′ (35% total
yield, 6:94 of a separable mixture). The 19F NMR spectrum of
the major nonsymmetric isomer 6h′ showed a singlet and an
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Letter
results underline the involvement of Pd-bound benzyne
intermediates in the reaction mechanism.
Scheme 3. Mechanistic Pathway for Cyclotrimerization
Scheme 4. Triphenylene Synthesis Using Alternative
Precursors
In conclusion, we have introduced a new class of precursor to
transition-metal-catalyzed aryne chemistry. The 2-bromo-
phenylboronic esters are readily accessed in just two steps
from inexpensive haloarene starting materials. In contrast to
conventional 2-(trimethylsilyl)phenyl triflate precursors, where
fluoride is used to trigger benzyne formation, the Pd catalyst
itself initiates both benzyne formation and subsequent C−C
bond forming transformations. Further studies of these
precursors in aryne chemistry are underway in our group.
The C2-symmetric palladacycle 7a can lead only to the
unsymmetrical triphenylene isomer 6′, regardless of the
orientation of subsequent aryne insertion, thus accounting for
50% of the material (pathway shown in blue). Palladacycle 7b,
on the other hand, can give an equal amount of either the C3-
symmetric triphenylene 6 or the nonsymmetric product 6′,
again making the assumption that there will be no
regioselectivity in the orientation of meta-substituted aryne
insertion into the Pd−C bond (pathway shown in red).16
Hence, the total product ratio of 6:6′ is a statistical 1:3
mixture.17
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures for all new compounds and character-
ization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
To probe the possibility of free benzyne in the reaction, we
added 2,5-dimethylfuran (2 equiv) to the trimerization of 4a
and isolated triphenylene 6a in 40% yield. There was no trace
of any aryne Diels−Alder adduct, suggesting that free benzyne
is not present in the reaction in appreciable quantities. Next, we
used (2-triflato-5-methyl-phenyl)boronic ester 10b as a
substrate, obtaining a 55% yield of 6b and 6b′ in the same
1:3 regioisomeric mixture, using the same reaction conditions
as Scheme 2 (tBuOK and catalytic Pd(dba)2, toluene, 100 °C).
In a second experiment, we treated 10b with n-BuLi in THF at
−78 °C, conditions demonstrated by Hosoya to produce
benzynes on warming. Addition of Pd(dba)2 (5 mol %) and
DPEphos (5 mol %) and warming to room temperature gave a
50% yield of 6b and 6b′ as a 1:3 mixture. Finally, we compared
our results with o-bromophenyl boronic ester 4b to the
established aryne-generation route of fluoride activation of 2-
trimethylsilyl aryl triflates. Treating (4-methyl-2-
*E-mail: Michael.greaney@manchester.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC for funding (postdoctoral fellowship to
J.-A.G.L. and Leadership fellowship to M.F.G.). Mr. G. Smith
and Mrs. C. Webb (University of Manchester) are thanked for
assistance with GC−MS measurements.
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