Quinoline Ligands Improve the Classic Direct C?H Functionalisation/Intramolecular Cyclisation of Diaryl Ethers to Dibenzofurans

Article abstract of DOI:10.1002/ejoc.202001416

The C?H functionalisation approach to the synthesis of dibenzofurans is hampered by a number of problems. Herein we describe the evolution of a cheap, bench stable quinoline ligand, which obviates most of the current limitations and allows for a high yielding synthesis of a range of valuable dibenzofurans. Dibenzofurans are important motifs in natural products and compounds with wide biological activity.

Full text of DOI:10.1002/ejoc.202001416

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Quinoline ligands improve the classic direct C–H
functionalisation/intramolecular cyclisation of diaryl ethers to
dibenzofurans
Authors: Katrina Mackey, David Jones, Leticia Pardo, and Gerard P.
McGlacken
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001416
Link to VoR: https://doi.org/10.1002/ejoc.202001416
01/2020

10.1002/ejoc.202001416
European Journal of Organic Chemistry
COMMUNICATION
Quinoline ligands improve the classic direct C–H
functionalisation/intramolecular cyclisation of diaryl ethers to
dibenzofurans
Katrina Mackey,[a,b] David J. Jones,[a,b] Leticia M. Pardo[a,b] and Gerard P. McGlacken[a,b]*
[a] Dr. G. P. McGlacken, Dr. K. Mackey, Dr. L. M. Pardo, Dr. D. J. Jones, School of Chemistry, University College Cork, Cork T12 YN60, Ireland
[b] Dr. G. P. McGlacken, Dr. K. Mackey, Dr. L. M. Pardo, Dr. D. J. Jones, Analytical and Biological Chemistry Research Facility (ABCRF), University College Cork,
Cork T12 YN60, Ireland
E-mail: g.mcglacken@ucc.ie
Supporting information for this article is given via a link at the end of the document.
+
Abstract: The C–H functionalisation approach to the synthesis of
dibenzofurans is hampered by a number of problems. Herein we
describe the evolution of a cheap, bench stable quinoline ligand,
which obviates most of the current limitations and allows for a high
halogen, CO2H, BF3K, OTs, N2 ) and b) Cu or Pd catalysed O-
arylation of 2-arylphenols (Figure 1).[9, 10] Of these noteworthy
developments, transition metal catalysed cyclisation of mono-
halogenated diaryl ethers via C–H functionalisation is
a
yielding synthesis of
a
range of valuable dibenzofurans.
particularly useful route to form dibenzofurans.
Dibenzofurans are important motifs in natural products and
compounds with wide biological activity.
Direct arylation via C–H functionalisation has emerged as a useful
methodology for the synthesis of important bi(hetero)aryls.[1]
Traditional,
well-established
methodologies
to
access
bi(hetero)aryls, such as the Suzuki-Miyaura, Stille, Negishi and
other similar reactions, require pre-activation of two coupling
partners. As documented by Fagnou,[2] this can prove problematic
when intramolecular coupling reactions are required, owing to the
difficulty in preparing substrates containing both halide and
organoboron, organotin, organozinc or other functionalities. Direct
arylation protocols can avoid these issues and display potential
improvements in step-economy and waste generation.[3] C–H
Functionalisation methodologies are important to access new
bi(hetero)aryl ring systems, and have been well recognised by
both academia[4] and the pharmaceutical industry.[5]
Figure 1. General preparation of dibenzofurans and examples of bioactive
benzofuran natural products.
Since the early report of the intramolecular arylation of diaryl
ethers by Ames[8a] and subsequent seminal work, in the context
of C–H functionalisation by Fagnou[2] and others[8b, 8c] (Scheme 1),
the intramolecular coupling of mono-halogenated ethers would
appear to be a go-to method for the formation of dibenzofurans.
However, there remains a number of significant challenges, which
we believe dissuade a broader up-take. These include the use of
an inert atmosphere and air-sensitive phosphine ligands, in
addition to the use of expensive additives. Most notable, in a
practical sense, were the problems driving the reaction to
completion and associated separations, and using excess of one
coupling partner to obviate this problem, was obviously not an
option.
Dibenzofuran derivatives are an important class of structural
motifs and are found in many natural products, bioactive
molecules and pharmaceuticals (Figure 1).[6] Excellent biological
activity has been exhibited by many members of this class of
compound, with
a
large number of naturally occurring
dibenzofurans possessing anti-cancer, anti-inflammatory and
anti-bacterial properties (Figure 1).[6]
However, despite the prominence of this molecular framework,
the synthesis of dibenzofurans is often hampered by tedious
synthetic steps, harsh reaction conditions and difficulties
associated with substrate availability, as detailed above.[7] To date,
a number of approaches have emerged for the synthesis of
dibenzofurans:[7] a) transition metal catalysed C–C bond
formation via cyclisation of 2-substituted phenoxy benzenes[8] (X=
In the course of our group’s research program on the
development of robust C–H functionalisation methodology to
prepare heterocyclic scaffolds,[11] we turned our attention to
addressing the above-listed limitations associated with classical
intramolecular C–H functionalisation in the context of
dibenzofurans. Furthermore, owing to the growing interest in
2
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10.1002/ejoc.202001416
European Journal of Organic Chemistry
COMMUNICATION
dibenzofurans, the simple and efficient method described herein
offers a new complimentary route to substituted dibenzofurans,
which highlights the synthetic utility of this approach.
(Scheme 2). The addition of 10 mol% quinoline (L1) resulted in
no improvement in the yield of 2a compared to the no-added-
ligand reaction (both 72%). Three quinoline based ligands
possessing substituents at C-6 on the quinoline ring were then
investigated (L2-L4). Pleasingly, incorporation of electron
donating groups at C-6 tended to improve the consumption of
starting material. In particular L2 containing a methoxy group
provided complete conversion of 1a, and an isolated yield of 99%
of 2a was achieved. Use of L3 (containing a methyl group)
allowed for a yield of 90%. Addition of a fluoro group at C-6 (L4)
had a minimal impact. The yield was improved to 83% when a
methyl group was positioned at C-4 in L5. Perhaps surprisingly,
incorporation of a strongly electron withdrawing group at the C-2
position of the quinoline and the pyridine did lead to an increase
in yield of 2a (L6, 80% and L7, 81% respectively). DMAP (L9) also
performed excellently providing a yield of 94%. Overall, the more
sterically bulky phenoxy quinoline ligands (L10-13) performed
less well with yields ranging from 76-84%. Changing to 3-pyridine
sulfonic acid as ligand (L8), resulted in a significant decrease in
yield (60%). The sterically encumbered benzofuroquinoline (L14)
was less effective and 6-methoxy quinoline N-oxide (L15)
inhibited the reaction. On the basis of these findings we deemed
L2 to be the optimal ligand for further study (for screening of
reaction solvents and catalyst:ligand loadings, see Supporting
Information).
Scheme 1. Palladium catalysed intramolecular direct arylation of diarylethers
and benzyloxy ethers.
We initiated our studies by investigating the cyclisation of diaryl
ether 1a, using palladium acetate and potassium carbonate in N-
methylpyrrolidinone (NMP) (Scheme 2). These conditions were
chosen as the starting point as we had previously found them to
be optimal for the analogous cyclisation of phenoxyquinolines.[11d]
Post-reaction analysis revealed that the crude reaction mixture
comprised of unreacted starting material 1a, alongside
dibenzofuran 2a, which had formed in 72% yield (NMR).
Subsequent attempts at separating the product from the
unreacted starting material proved challenging. In particular,
column chromatography on conventional silica gel was found to
be unsuitable as both compounds are very non-polar.
Unfortunately, increasing the reaction temperature and
prolonging the reaction time did not result in improved
consumption of the starting material, probably due to aggregation
of the catalyst as palladium black.
It is worth highlighting that direct arylation protocols are often
carried out in the presence of added phosphine ligands. However,
a major drawback of the use of phosphine ligands is their
sensitivity to air oxidation,[15] which thus necessitates an inert
atmosphere. Additionally, their sometimes high cost and the
difficulty in phosphine/phosphine oxide removal post-reaction,
further hinders their usefulness. In comparison, nitrogenous
ligands represent an excellent alternative as they are typically air
stable and easier to remove. In addition, nitrogen-based ligands
also offer far more scope for electronic and steric tuning
compared to phosphine ligands, which are often tedious and
expensive to prepare.[15b] The successful application of quinoline
ligands to this process, therefore, represents a significant
improvement, in many respects.
We recently reported the intramolecular cyclisation of phenoxy
quinolines (Scheme 1) without recourse to added ligand.[12] We
suspected that the quinoline starting material itself was acting as
an N-ligand to the palladium, facilitating efficient catalysis either
by facilitating a required precatalyst, or by rescuing aggregated
Pd and returning Pd back into the catalytic cycle.[13f] Thus we were
curious to determine if added quinoline could be used to improve
the performance of another C–H functionalisation reaction. Yu,
Sanford and others[13] have also reported quinolines and pyridines
acting as useful ligands in C–H functionalisation reactions
(Scheme 2).
Thus a series of monodentate pyridine and quinoline type ligands,
varying in electronic and steric character were evaluated
2
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10.1002/ejoc.202001416
European Journal of Organic Chemistry
COMMUNICATION
with strongly electron donating substituents did not progress quite
as well. That said, when a methyl group was located at the para
position of the aryl ring, the desired product 2j could be isolated
in a moderate yield of 42%. Gratifyingly, a number of more
complex substrates with electron withdrawing substituents on
both aryl rings could be efficiently synthesised in good to excellent
yields allowing access to a number of novel dibenzofurans
(Scheme 4, 2l-2o). Notably, all of these cyclised products feature
a valuable fluoro substituent (2b, 2m, 2o, 2l and 2n).
Scheme 2. Ligand evaluation for Pd catalysed direct arylation of o-bromo diaryl
ether. Yields were determined using 1H NMR spectroscopy with 1,3,5-
trimethoxybenzene as the internal standard for quantification. [a] Average of
three reactions. [b] 50% yield with 1,4-dioxane as reaction solvent. [c] Isolated
yields in parenthesis.
With the optimal conditions in hand, the substrate scope of the
reaction was evaluated. Overall, the substrates bearing electron
withdrawing substituents were very well tolerated (Scheme 3).
The methodology was applicable to both weakly and strongly
electron withdrawing substituents (2b-2e). Fluoro analogue 2b
was obtained in an excellent yield of 99%. Other electron
withdrawing substituents on 2c and 2d led to cyclization of the
diaryl ether in excellent yields of 97% and 86% respectively. In
the case of the trifluoromethoxy analogue 2e, a decrease in
isolated yield was obtained and the fused product was isolated in
a 66% yield. Complete regioselectivity toward the least hindered
position was observed for 2f (with a trifluoromethyl substituent)
and a single regioisomer was isolated in 96% yield. Pleasingly,
compound 2g, incorporating a potentially problematic pyridine
moiety, was obtained in a good yield of 70%. Additionally, the
reaction of a 2, 4-dichloro substituted diaryl ether 1h also
proceeded smoothly (70% yield), and the chlorides in 2h were
retained as a useful synthetic handle.
Scheme 3. Substrate scope for palladium catalysed intramolecular direct
arylation of o-bromo diarylethers. Reaction conditions: 1a-1j (1 equiv.),
Pd(OAc)2 (5 mol%), 6-methoxy quinoline (10 mol%), K2CO3 (2 equiv.), NMP (2
mL/mmol), 135 ºC, air, 22 h.
In the case of the para-chloro analogue 2k (where the chloride
was located on the same aryl ring bearing the bromide), the
cyclised product was obtained in an excellent yield of 95%.
The exact role of the quinoline (L2) in this reaction/transformation
is undetermined at this time. However, we postulate that the
ligand could be prolonging the lifetime of the catalyst by acting as
a Pd-scavenger. In this case, the ligand could prevent the
aggregation of Pd0, or rescue aggregated Pd. Sanford
demonstrated that a quinoline carboxylate ligand played a role in
rescuing off-cycle Pd species from a precipitate that was formed
during the course of a C-H arylation reaction.[13f] Emmert
previously demonstrated that electron rich pyridines help to
prevent catalyst decomposition in the Pd catalysed aerobic
oxidation of alchohols.[17] The authors noted that Pd black was
observed with 4-CF3 and 3-NO2 pyridines but not with 4-OMe and
4-dimethyl amino pyridines. On the other hand, Yu, Stoltz, Fagnou
and Stahl previously demonstrated the applicability of electron
Carbazole containing molecules have garnered much interest due
to their wide range of biological activity including antibacterial,
antimalarial, anticancer and anti-Alzheimer properties.[16]
Pleasingly, application of our optimised direct arylation conditions
on the diphenylamine precursor 1i provided 9H-carbazole 2i in
50% yield. On the contrary, it is important to note that substrates
2
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10.1002/ejoc.202001416
European Journal of Organic Chemistry
COMMUNICATION
deficient pyridine and pyridone ligands in Pd catalysed C-H
functionalisation reactions, suggesting that they either act to
stabilise Pd0 before re-oxidation or to facilitate the formation of a
more electrophilic and therefore more reactive Pd catalyst.[13a], [14]
Keywords: synthesis • catalysis • direct arylation • C-H
functionalisation • benzofurans
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optimised conditions allow for the use of a pyridyl moiety and an
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N-H linker to give
a carbazole, and novel disubstituted
dibenzofurans can be formed, in a regioselective manner, in the
substrates tried. Current work within the group is focused on
probing the mechanistic details of the reaction and further
broadening the scope of the current transformation to more
electron-rich substrates.
[12]
[13]
Acknowledgements
This research was supported by Science Foundation Ireland
(SFI/12/IP/1315 and SFI/12/RC/2275) and the Synthesis and
Solid State Pharmaceutical Centre (SSPC).
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2
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COMMUNICATION
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2
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Entry for the Table of Contents
An efficient catalytic protocol aided by a cheap and commercially available quinoline ligand for the construction of dibenzofuran motifs
has been developed, thus improving on the existing protocols for the classic intramolecular C-H functionalisation of diarylethers. This
simple and efficient method allows the synthesis of a wide range of valuable dibenzofurans in good to excellent yields.
2
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