A Domino Oxidation/Arylation/Protodecarboxylation Reaction of Salicylaldehydes: Expanded Access to meta-Arylphenols

Article abstract of DOI:10.1002/asia.201500506

A method that allows salicylaldehydes to be efficiently transformed into meta-arylated phenol derivatives through a cascade oxidation/arylation/protodecarboxylation sequence is presented. We demonstrate that the aldehyde functional group can be used as a convenient removable directing group to control site selectivity in C-H activation. Aldehydes are easily introduced into the starting materials and the group is readily cleaved after the C-H functionalization event.

Full text of DOI:10.1002/asia.201500506

DOI: 10.1002/asia.201500506
Communication
CÀH Activation
A Domino Oxidation/Arylation/Protodecarboxylation Reaction of
Salicylaldehydes: Expanded Access to meta-Arylphenols
Junfei Luo,[a, b] Sara Preciado,[b] Solomon Olatokunbo Araromi,[b] and Igor Larrosa*[a]
rial, further synthetic steps are required to install, and possibly
Abstract: A method that allows salicylaldehydes to be effi-
ciently transformed into meta-arylated phenol derivatives
remove, the directing group, which is a substantial drawback
for synthetic applications. Significant research effort has there-
through a cascade oxidation/arylation/protodecarboxyla-
fore been focused on the development of directing groups
tion sequence is presented. We demonstrate that the al-
that are easily introduced and removed, and so are applicable
dehyde functional group can be used as a convenient re-
to the synthesis of a wider range of target molecules. We re-
movable directing group to control site selectivity in CÀH
cently developed a novel strategy using a transient carboxyl
activation. Aldehydes are easily introduced into the start-
group that facilitates a palladium-catalyzed cross-coupling re-
ing materials and the group is readily cleaved after the CÀ
action ortho- to the carboxylic acid (meta- to the hydroxyl sub-
H functionalization event.
stituent) which, followed by decarboxylation of the arene, af-
fords meta-arylated phenol derivatives (Scheme 1a).[6,7] This
Transition metal catalyzed CÀH activation provides an atom-
and step-economical alternative to the formation of CÀC, CÀX,
CÀO, and CÀN bonds.[1] Site-selective functionalization of ubiq-
uitous CÀH bonds is a highly attractive strategy as it allows ef-
ficient and reliable access to target molecules. There have
been tremendous advances in this field, in particular for the
functionalization of aromatic compounds.[2] In these cases, a re-
gioselective controlling group is usually required owing to the
similar reactivity of the CÀH bonds in benzene derivatives. The
most popular strategy is the use of directing groups, which
offer site-selective functionalization through chelation assis-
tance, and dozens of methods for ortho-functionalization
based on this strategy have been reported in recent years.[3,4]
Scheme 1. Traceless directing groups lead to meta-arylphenols.
However, it becomes more challenging to apply this type of
strategy when the target CÀH bond is distant from the direct-
ing group; the development of direct meta-selective function-
alization remains a significant challenge.[5] Additionally, if a di-
method allowed the synthesis of meta-arylphenols from cheap
recting group functionality is not present in the starting mate-
phenols in a single synthetic operational step, and substituents
including electron-donating and electron-withdrawing groups
are tolerated. However, the carboxyl group is installed by
a Kolbe–Schmitt carboxylation, requiring high CO2 pressure
(20–100 atm) and high temperature (120–3008C),[8] which can
limit the synthetic applications of the method.
[a] J. Luo, Prof. I. Larrosa
School of Chemistry
University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: igor.larrosa@manchester.ac.uk
[b] J. Luo, Dr. S. Preciado, S. O. Araromi
School of Biological and Chemical Science
Queen Mary University of London
To avoid the use of harsh conditions, it is key to find a re-
movable directing group that: (1) can be easily installed under
mild conditions; (2) can facilitate an ortho-functionalization;
(3) can be easily cleaved, revealing the desired meta-arylated
products. Salicylaldehyde motifs are widely found in natural
products as well as being key precursors to a variety of useful
molecules.[9] Importantly, the aldehyde group can be easily and
efficiently introduced into phenol derivatives under mild condi-
tions by a simple ortho-selective formylation (Scheme 1b).[10,11]
However, due to its sensitivity under common CÀH arylation
reaction conditions, the aldehyde group has rarely been used
Mile End Road, London, E1 4NS (UK)
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http://dx.doi.org/10.1002/asia.201500506.
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Communication
as a directing group before.[12] In this report, we describe how
aldehydes can be used as efficient traceless directing groups,
allowing the synthesis of meta-arylated phenol derivatives
under a palladium-catalyzed system.
As a starting point, the reaction between salicylaldehyde
(1a) and 1-iodo-3,5-dimethylbenzene (2a) catalyzed by
Pd(OAc)2 (2 mol%) in the presence of Ag2CO3 (0.5 equiv) in
AcOH, heating at 1508C for 16 h was studied (Table 1, entry 1).
Table 1. Optimization of meta-arylation from salicylaldehyde.[a]
Entries[a]
Pd (mol%)
Ag2CO3
[equiv]
K2CO3 [equiv]
Yield of 3aa [%]
1
2
3
4
5
6
7
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
PEPPSI-IPr (2)
PEPPSI-IPr (2)
PEPPSI-IPr (2)
PEPPSI-IPr (5)
PEPPSI-IPr (2)
PEPPSI-IPr (2)
0.5
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
0
0
0
0
0.5
2.0
2.0
2.0
2.0
17
27
18
35
54
60
72
0
Scheme 2. Scope of the domino oxidation/arylation/protodecarboxylation
process on substituted iodoarenes. 3.0 equiv of 2 with respect to 1a were
used. Yields are of isolated pure material. [a] Isolated yield of side arylation
product at the aldehyde CÀH bond.
8[b]
9[c]
0
[a] Unless otherwise noted, all the reactions were carried out using
0.25 mmol of 1a and 0.75 mmol of 2a. Yields were determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
[b] 1.0 equiv of p-benzoquinone was added into the reaction.
[c] 1.0 equiv of m-CPBA was added into the reaction.
taining both electron-donating (3ea, 3 fa, 3ja, and 3ka) and
electron-withdrawing groups (3ba–da, 3ga–ia) substituted at
the 3- and 4-positions were found to be suitable, and disubsti-
tuted salicylaldehyde (3ma) was obtained in fair yield. Howev-
er, low yield was obtained when the strongly electron-donat-
ing methoxy group was present (3la): in this case, 3-methoxy-
phenol was observed after formal protodecarbonylation of
starting material. Similarly to the lack of tolerance for ortho-
substituted iodoarenes, 5-substituted salicylaldehydes showed
no reactivity (Scheme 3).[16]
Interestingly, 17% of the desired product was obtained. The
amount of Ag2CO3 proved crucial, and 1.0 equivalent of
Ag2CO3 performed best (Table 1, entry 2). The source of the Pd
catalyst was found to be important, with PEPPSI-IPr (from the
pyridine enhanced precatalyst preparation stabilization and ini-
tiation family) leading to the best yield (Table 1, entry 4). More-
over, the addition of K2CO3 significantly improved the yields
(Table 1, entries 5 and 7). Finally, increasing the amount of Pd
to 5 mol% led to 72% yield (Table 1, entry 7). Further efforts
aiming to facilitate the oxidation of the formyl group in situ by
the addition of stronger oxidants, were unsuccessful. It was en-
visaged that oxidation to salicylic acid may be required before
ortho-metalation.[13] However, the addition of p-benzoquinone
and m-CPBA (m-chloroperoxybenzoic acid) completely shut
down the reaction (Table 1, entries 8 and 9).
We set out to examine how this transformation of salicylal-
dehydes to meta-arylphenols was occurring. A few examples of
the use of the aldehyde group as an ortho-directing group
under Pd-catalyzed conditions have been reported.[12a,b] Fur-
thermore, Pd-catalyzed decarbonylation of aldehydes has also
been shown by Maiti and co-workers.[17] Additionally, given
that Tollens’ reagent is known to oxidize an aldehyde into the
corresponding carboxylic acid, we postulated that the salicylal-
dehyde could be oxidized to salicylic acid in the presence of
Ag2CO3. Based on the above, we speculated that the transfor-
mation could occur through three possible pathways
(Scheme 4): (1) ortho-Arylation of salicylaldehyde, followed by
a palladium catalyzed decarbonylation, affording the meta-aryl-
phenol. (2) ortho-Arylation of salicylaldehyde, followed by oxi-
dation of the arylated salicylaldehyde intermediate to the cor-
responding acid, with protodecarboxylation generating meta-
arylated phenol. (3) Oxidation of the salicylaldehyde starting
material to salicylic acid, with arylation and protodecarboxyla-
tion of salicylic acid proceeding to meta-arylphenol.[13] The ex-
With suitable conditions in hand, we first examined different
substitution patterns on the aryl iodide (Scheme 2). Gratifying-
ly, both electron-donating (3aa, 3ad, and 3ah) and electron-
withdrawing groups (3ab, 3ac, 3ae, 3af, 3ai–al) were tolerat-
ed at meta- and para-positions, affording moderate yields.
However, only 21% of the desired product was achieved when
para-iodoanisole was used (3ag), with 53% product of aryla-
tion at the aldehyde CÀH bond instead.[14,15] ortho-Substituents
at the iodoarene are not tolerated, potentially due to the in-
creased steric hindrance.[16] Substituted salicylaldehydes con-
Chem. Asian J. 2016, 11, 347 – 350
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Communication
this mechanism further, we heated salicylaldehyde in the pres-
ence of Ag2CO3 but only starting materials were recovered
(Scheme 5b). However, 42% of salicylic acid was obtained
when salicylaldehyde was submitted to the standard arylation
conditions in the absence of iodoarene. A Wacker-type oxida-
tion process might be the explanation of this Pd-catalyzed oxi-
dation of salicylaldehyde.[18] Finally, the use of the iodide ab-
stractor NMe4OAc, which has been shown to be an efficient re-
placement for AgOAc when oxidation is not required,[19] result-
ed in no arylation reaction. These experiments suggest that
this transformation of salicylaldehydes to meta-arylated phenol
derivatives proceeds through an oxidation/arylation/proto-de-
carboxylation process.
In summary, we have described a method for the prepara-
tion of meta-arylated phenols from salicylaldehyde derivatives.
Importantly, unlike most directing groups, the aldehyde group
can be easily introduced into the starting material and re-
moved after CÀH functionalization in a tandem fashion. A pre-
liminary mechanistic study indicates that the reaction occurs
through three steps involving a palladium-catalyzed oxidation
of the salicylaldehyde followed by ortho-arylation of the salicyl-
ic acid intermediate and subsequent protodecarboxylation of
the arylated product. Remarkably, these three steps occur in
a cascade process, allowing for a simple and efficient synthetic
operation.
Scheme 3. Scope of the domino oxidation/arylation/protodecarboxylation
process on salicylaldehydes. 3.0 equiv of 2a with respect to 1 were used.
Experimental Section
General Information
All chemicals used in this work were obtained from commercial
sources and used without further purification. Salicylaldehyde start-
ing materials were prepared by Skattebø’s procedure[11b,f] except
1a and 1e, which were purchased from Sigma Aldrich. Analytical
thin-layer chromatography was performed on pre-coated Merck
silica gel F254 plates and visualized under UV light. Melting points
were obtained using a Bibby Stuart Scientific apparatus and are
uncorrected. IR spectra were recorded using a Bruker Tensor 37
FTIR machine and are quoted in cmÀ1. H NMR spectra, recorded at
400 MHz, are referenced to the residual solvent peak at 7.26 ppm
(CDCl3). 13C NMR spectra, recorded at 101 MHz, are referenced to
the residual solvent peak at 77.0 ppm (CDCl3).
1
Scheme 4. Possible reaction pathways.
General Procedure: A mixture of 1 (0.25 mmol), 2 (3.0 equiv),
PEPPSI-IPr (5 mol%), Ag2CO3 (1.0 equiv, and K2CO3 (2.0 equiv), in
AcOH (0.5 mL) was heated in a sealed vial at 1508C for 16 h. After
this time, the reaction mixture was filtered through a plug of Celite
with EtOAc (4”5 mL). The filtrate was evaporated to dryness. The
crude product was purified by column chromatography (hexanes/
EtOAc 90:10). The characterization data of compounds 3 are
shown in the Supporting Information.
Acknowledgements
Scheme 5. Investigation of reactions.
We gratefully thank the European Research Council for a Start-
ing Grant (to I.L.), the Engineering and Physical Sciences Re-
search Council (EPSRC) for a research grant, the China Scholar-
ship Council and Queen Mary University of London for a stu-
dentship (to J.L.), the Marie Curie Foundation for an Intra-Euro-
pean Fellowship (to S.P.) and the Royal Society of Chemistry for
amination of the crude reaction mixtures revealed that no
ortho-arylated salicylaldehyde intermediate was observed, with
20% of salicylic acid being obtained instead (Scheme 5a), thus
indicating that pathway three may be in operation. To probe
Chem. Asian J. 2016, 11, 347 – 350
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Communication
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an undergraduate research bursary (to S.O.A.). EPSRC National
Mass Spectrometry Service (Swansea) is also acknowledged.
Keywords: arylation
phenols · salicylaldehydes
·
CÀH activation
· meta-selective ·
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