Generation of benzyne from benzoic acid using C-H activation

Article abstract of DOI:10.1039/c0cc02547j

ortho C-H activation of benzoic acids with Pd(ii) generates an oxapalladacycle that can decarboxylate to produce a palladium-associated aryne. The arynes then undergo [2+2+2] trimerisation to afford triphenylenes.

Full text of DOI:10.1039/c0cc02547j

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Generation of benzyne from benzoic acid using C–H activationw
Alastair A. Cant,a Lee Robertsb and Michael F. Greaney*a
Received 13th July 2010, Accepted 30th September 2010
DOI: 10.1039/c0cc02547j
ortho C–H activation of benzoic acids with Pd(II) generates an
oxapalladacycle that can decarboxylate to produce a palladium-
associated aryne. The arynes then undergo [2+2+2] trimerisa-
tion to afford triphenylenes.
Pt oxapalladacycles in stoichiometric studies.6c,8 A single
report from Kim and co-workers, however, describes the
successful Pd(0)-mediated generation of benzyne from
o-bromobenzoic acid, implying that decarboxylation of 2 is
possible under the right conditions.9
To assess the viability of benzoic acid as a benzyne
precursor we chose the TM-mediated trimerisation of benzyne
to triphenylene as a model reaction. First described in seminal
work from Rees and Gilchrist using platinum catalysis,8,10 the
reaction was applied to precursor 1 using catalytic Pd(0) by
Guitian, Perez and co-workers in 1998.11 This pioneering
report marked the beginning of modern TM-catalysed aryne
chemistry, and has itself been widely applied to polyphenylene
synthesis for use as functional molecules.12
Transition-metal (TM) catalysed aryne chemistry has undergone
rapid growth in recent years, sparked by the introduction of
O-triflato silanes 1 as aryne precursors.1 Activated by fluoride
at room temperature, this class of precursor has been applied
to a number of innovative TM-catalysed transformations,
frequently involving insertion of the aryne moiety into a
conventional Pd(0) or Ni(0) cross-coupling (Fig. 1).2 Despite
these successes, use of precursor 1 has economic drawbacks
that may hinder more widespread applications. Its doubly
functionalised character, containing a triflate group, makes it
expensive as a starting material for aromatic chemistry.3
Analogs are not commercially available and must be synthesised
from the appropriate halo-phenol,4 and the process of aryne
generation is poorly atom economic.
Initial screening used Pd(OAc)2 as the catalyst and varied
oxidant, solvent and ligand in the presence of K2HPO4 as
base, a phase transfer catalyst and 4 A molecular sieves
(Table 1).
Early results were not encouraging, with little if any tri-
phenylene being formed. Surprisingly, only copper(II) acetate
was found to have an impact on the reaction with all other
oxidants giving no yield of triphenylene (entries 1–4). The only
positive result obtained in early runs was a 4% yield of
triphenylene using diphenylphosphinobutane (dppb) as
ligand and Cu(OAc)2 in DMF at 150 1C (entry 4). Screening
for ligands indicated that both 1,10-phenanthroline and
We envisaged the possibility of generating arynes from
benzoic acids, 3, via Pd-mediated ortho C–H bond activation
(Fig. 1). Benzoic acids would be superbly versatile aryne
precursors, being extremely cheap, commercially available
compounds that are easy to handle and functionalise. Further-
more, a Pd-activated benzyne generation step would simplify
and even expand the subsequent aryne capture chemistry, as
the dual roles of benzyne production and subsequent C–C/
C–X bond formation would be handled by a single catalyst.5
Ample precedent exists for the first step of the proposed
pathway, ortho-palladation of benzoic acid. Cyclopalladated
complexes 4 have been prepared and characterised,6 and are
likely intermediates in a host of catalytic Pd-catalysed C–H
functionalisation transformations discovered in recent years.7
The second step, by contrast, is far less precedented in the
literature. Indeed, it has been reported to fail for both Pd and
Table 1 Selected optimisation conditions for triphenylene synthesis
Yielda
(%)
Entry
Oxidant
Solvent
Ligand
1
2
3
4
5
6
7
8
Air
Ag2CO3
Benzoquinone
DMF
DMF
DMF
DMF
dppb
dppb
dppb
dppb
phen
phen
phen
phen
phen
phen
phen
0
0
0
4
Cu(OAc)2 (1 equiv.)
Cu(OAc)2 (1 equiv.)
Cu(OAc)2 (1 equiv.)
Cu(OAc)2 (0.75 equiv.)
Cu(OAc)2 (0.5 equiv.)
Cu(OAc)2 (0.75 equiv.)
Cu(OAc)2 (0.75 equiv.)
Cu(OAc)2 (0.75 equiv.)
DMF
7
DMFc
DMFc
DMFc
Sulfolanec
Sulfolanec
Sulfolaned
13
20
17b
37
13
47e
9
10
11
Reaction conditions: solvent (0.5 mL), Pd(OAc)2 (10 mol %), ligand
(10 mol %) and benzoic acid (111 mg, 0.9 mmol) were sonicated
together for 1 min. K2HPO4 (2 equiv.), TBAB (1 equiv.), 4 A MS,
and oxidant were then added and the reaction was heated to 150 1C for
16 h, open to air.a Yields determined by GC with triphenylene as
Fig. 1 Generation of benzyne from benzoic acid by C–H activation.
a School of Chemistry, University of Edinburgh, King’s Buildings,
West Mains Rd, Edinburgh, UK.
E-mail: Michael.Greaney@ed.ac.uk; Tel: +44(0) 131 6504726
b Discovery Chemistry Pfizer Global R & D, Sandwich CT13 9NJ, UK
w Electronic supplementary information (ESI) available: Preparation
and characterisation of all new compounds. See DOI: 10.1039/
c0cc02547j
b
c
d
external standard. No sonication. 1.5 mL of solvent used. 2.5 mL
e
of solvent used. Isolated yield; dppb = diphenylphosphinobutane;
phen = 1,10-phenanthroline.
c
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(2-biphenyl) di-tert-butylphosphine lead to slightly improved
reaction yield, with the former found to be superior in later
screens (entry 5). It was also found that reaction favoured
dilute conditions and adding an extra 1 mL of DMF to the
reaction resulted in a doubling of the yield (entry 6). The
stoichiometry of the copper(II) acetate was also found to be an
important parameter: too little and catalyst turnover is
harmed, too much and the dibenzopyranone 7 appeared as a
side product (entries 7–9), presumably formed via insertion of
benzyne into palladacycle 4 without decarboxylation (Fig. 2).
Compound 7 could be isolated in a 25% yield by increasing
the amount of copper(II) acetate to 2 equivalents and using
tert-butyl XPhos as ligand.
acids, with unsymmetrical triphenylenes 6b–f being isolated
as single isomers, albeit in modest yield. Fluorinated tri-
phenylenes 6d and 6f are novel compounds that have not been
previously accessed using conventional triphenylene syntheses.
This selectivity was replicated for the meta-substituted starting
materials, such that m-toluic acid produced the same 2,6,11-
trimethyltriphenylene 6b in very similar yield as when p-toluic
acid was used as starting material. Importantly, no trace of
triphenylenes 8 could be detected, indicating that aryne genera-
tion from m-benzoic acids proceeds, as expected, via activation
of the C–H bond distal from the meta-substituent.7 The
identical regioselectivities across meta and para-substituted
starting materials are supporting evidence for an aryne
intermediate.
Lastly, screens of solvents with varying dilutions showed a
dilute sulfolane solvent system to be the best for the reaction.
With DMF as solvent dilutions of greater than 1.5 mL of
solvent resulted in diminished yields due to the reaction of
DMF decomposition products with the benzoic acid starting
materials. This does not occur with the more thermally
stable sulfolane, affording a highest isolated yield of 47% of
triphenylene from benzoic acid (entry 11).
Aryne intermediacy is further indicated by the observed
triphenylene regioisomers matching those formed from Pt
and Pd-catalysed trimerisations of conventional aryne
precursors.9,10,12 ortho-Substituted benzoic acids were generally
ineffective in the reaction, with only o-toluic acid affording a
23% yield of the unsymmetrical isomer 8a.11
We investigated the effect of adding a ground state alkyne
into the reaction mixture, as mixed aryne/alkyne trimeri-
sations are well known to afford phenanthrene and naphthalene
products.13,14 Using diphenylacetylene, we were pleased to
observe the controlled formation of either phenanthrene 9 or
naphthalene 10, depending on the reaction stoichiometry.
Excess benzoic acid produced 9 (48% yield) containing two
benzyne derived aromatic rings, whereas excess alkyne at the
slightly lower reaction temperature of 120 1C afforded a good
yield of the naphthalene 10 (Fig. 4).
We applied these reaction conditions to a range of simple
benzoic acids to establish substrate scope (Fig 3.). Aryne
trimerisation of para-substituted benzoic acids can yield a pair
of regio-isomeric triphenylene products, 6 and 60. Likewise,
ortho-substituted starting materials can produce 8 and 80. In
both cases one isomer of each pair is C3-symmetric (60 and 80)
and the other is unsymmetric (6 and 8). For meta-substituted
benzoic acids, the possibility of regio-isomeric aryne genera-
tion exists (2a and 2b), permitting access to all four tripheny-
lene regioisomers. We were pleased to observe very high levels
of selectivity in the cyclisation of para-substituted benzoic
In conclusion, a novel method of generating benzyne from
cheap and readily available benzoic acids has been developed.
The method was used to make various tri and bi-cyclic
aromatic compounds along with arene fused lactones. Benzoic
acid is over 1000 times cheaper than O-triflato silane 1,15
making it an attractive starting material for simple triphenylene
synthesis. Whilst the yields of substituted triphenylenes are
generally low, a one step transformation of cheap and readily
available substituted benzoic acids is competitive with the
multi-step routes required for substituted aryne precursor
synthesis and subsequent trimerisation. More importantly,
we have demonstrated for the first time that arynes may be
generated from simple benzoic acid through C–H activation
and decarboxylation. Optimisation of this process will be the
subject of future work in our laboratory.
Fig. 2 Dibenzopyranone formation from complex 4.
We thank Sally-Ann Fancy for technical assistance in
setting up the GC-MS screen and the EPSRC mass spectro-
metry service at the University of Swansea. We thank Pfizer,
CRUK, and the University of Edinburgh for funding (A.A.C)
and the EPSRC for the award of a Leadership Fellowship
to M.F.G.
Fig. 3 Monosubstituted benzoic acid trimerisation. Conditions as in
Table 1.
Fig. 4 Naphthalene and phenanthrene synthesis from benzoic acid.
c
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c
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Chem. Commun., 2010, 46, 8671–8673 8673