Salicylic acids as readily available starting materials for the synthesis of meta-substituted biaryls

Article abstract of DOI:10.1039/c4cc09674f

Salicylic acids are shown to be readily available and versatile starting materials that easily undergo a tandem arylation-protodecarboxylation process under Pd-catalysis. The corresponding meta-arylphenols can subsequently be easily transformed into a var

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Salicylic Acids as Readily Available Starting Materials
for the Synthesis of meta-Substituted Biaryls
Junfei Luo,a,b Sara Preciadoa and Igor Larrosab,*
11
carbonylation/oxidation,
and ortho-lithiation of suitable O-
Salicylic acids are shown as readily available and versatile
starting materials that easily undergo a tandem arylation /
protodecarboxylation process under Pd-catalysis. The
corresponding meta-arylphenols can subsequently be easily
transformed into a variety of meta-functionalized biaryls,
highlighting the versatility of this approach to access this
structural motif.
substituted phenols, followed by reaction with CO2.12 Furthermore,
salicylic acids are also available in one step through Pd-catalyzed
hydroxylation of benzoic acids.13 Therefore, we envisaged that an
exploration of the suitability of salicylic acids for the general
synthesis of meta-substituted biaryls would be of significant utility
(Scheme 1b). In this report, we show that both electron-rich and
electron-poor salicylic acids react smoothly under our tandem
arylation / protodecarboxylation leading to the corresponding meta-
arylphenols. Furthermore, these substrates can then be easily
functionalized at the C-O bond, resulting in a highly versatile and
straightforward approach towards meta-biaryls.
Over the last decade, transition metal-catalysed C-H arylation of
aromatic rings has received great attention due to its power and
efficiency for accessing diversely functionalized aromatic motives
from simple starting materials.1 Thus, controlling the regioselectivity
of functionalization has become one of the most important
challenges in the field. 2 Whereas great many methods are now
available for the synthesis of ortho-arylated arenes,3 meta- and para-
arylation methods are still significantly underdeveloped.4,5 However,
meta-substituted biaryl motifs are widely found in drug candidates
and other bioactive molecules (Scheme 1a).6 We recently reported a
novel strategy for the meta-arylation of phenols in a one-pot
operation involving a Kolbe-Schmitt carboxylation followed by a
7
, 8
tandem arylation
/
protodecarboxylation process.
This
methodology allowed the synthesis of meta-arylphenols from
phenols containing moderately electron-rich or electron-poor
substitution at C2 and C3. However, due to the intrinsic harsh
requirements for the Kolbe-Schmitt carboxylation,9 these processes
required the use of high pressures of CO2 (25 atm), high
temperatures (190 °C) and, consequently, of specialized autoclave
equipment. Furthermore, significantly electron-deficient phenols
(such as 3-nitrophenol, or 3-trifluoromethylphenol) were not suitable
substrates due to lack of reactivity towards carboxylation.
It is noteworthy that salicylic acids themselves are readily
available starting materials, 10 and also easily synthesised from
phenols via
a
variety of routes, including carboxylation,
a School of Biological and Chemical Sciences, Queen Mary
University of London, Mile End Road, London, E1 4NS, UK.
b School of Chemistry, University of Manchester, Oxford
Road, Manchester, M13 9PL, UK.
Scheme 1. a) Representative examples of biologically active meta-substituted
biaryls. b) This report: salicylic acids can be used as starting materials for the
synthesis of a wide variety of meta-substituted biaryl motifs.
Electronic Supplementary Information (ESI) available: Full
experimental
details
are
available.
See
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Our optimized reaction conditions for the reaction of salicylic from the consumption of Ag2CO3 in an undesired aldehyde oxidation
acid 1 (1.0 equiv) with aryl iodides 2 (3 equiv) involved the use of 2 process. Surprisingly, when the salicylic acid was used in excess, 3ia
mol % PEPPSI-IPr as a catalyst, 0.5 equiv each of K2CO3 and could be obtained in an excellent (85%) yield. Similarly, iodoarenes
Ag2CO3, in AcOH at 150 °C (Scheme 1).14 Under these conditions a containing p-OMe (3ha), p-CH2OH (3ja) and m-COMe (3na)
number of substituted salicylic acids were tested and both electron- proceeded in better yields when the iodoarenes were used as limiting
withdrawing and electron-donating groups at C3 and C4 showed reagents. Ortho-substitution at the iodoarene is not well tolerated,
excellent compatibility with the reaction. It is important to note that with only the smaller F substituent leading to appreciable reactivity
in all cases the obtained yields were higher than those achieved in (24% of 3qa). Some heteroarenes such as iodoindole and
the one-pot methodology starting from phenols.7 Gratifyingly, the iodopyridine were found to be compatible with the reaction, leading
highly electron-withdrawing NO2 (3ad) and CF3 (3ae) groups, which to the corresponding meta-heteroarylphenols 3ra and 3sa in 30%
had been shown to be unreactive in the one-pot methodology, now and 70% yields, respectively.
furnished 52% and 67% isolated yields, respectively. In all cases, the
expected meta-arylphenol product was obtained with complete
regioselectivity. This was the case even in the presence of an
acetamido group (3aj), which has been shown to be a good ortho-
directing group, affording 3aj in 41% yield. The highly electron-rich
4-MeO-salicylic acid afforded only 22% yield of the desired product
3ak, due to competitive protodecarboxylation of the starting material,
highlighting one of the limitations of the methodology. Furthermore,
substitution at C5 of the salicylic acid is poorly tolerated, with Me
and Cl not reacting at all due to steric hindrance. On the other hand,
the smaller F substituent allowed the arylation to proceed, affording
3an in 53% of yield.
Scheme 3. Scope of the tandem arylation / protodecarboxylation process on
substituted iodoarenes (2b-s). Unless otherwise stated, all the reactions were
carried out using 0.5 mmol of 1a, 1.5 mmol of
2
and 0.5 mL of AcOH at 150 °C for
16 h. Yields are of isolated products. The reaction was carried out with 0.5
mmol of 1a and 0.167 mmol of
at 130 °C. b Yield determined by 1H NMR
a
2
Scheme 2. Scope of the tandem arylation / protodecarboxylation process on
substituted salicylic acids (1a-n). Unless otherwise stated, all the reactions were
c
analysis using an internal standard. p-iodobenzyl alcohol was used as starting
material.
carried out using 0.5 mmol of 1, 1.5 mmol of 2a and 0.5 mL of AcOH at 150 °C for
a
16 h. Yields are of isolated products. The reaction was carried out at 160 °C.
b 1.0 mL of AcOH were used. c K2CO3 was not used.
The great majority of reported methods for C-H arylation that
use iodoarenes as coupling partners require the stoichiometric use of
Ag-salts. 16 We have recently shown that for a range of such
methodologies, the Ag-salt can be conveniently replaced by a cheap
and readily available organic salt, NMe4Cl, which makes these
reactions increasingly attractive for large scale synthesis and
industrial processes.17 We therefore tested if NMe4Cl could also be a
suitable replacement for Ag2CO3 in the present methodology
(Scheme 4). Gratifyingly, good yields of the desired products could
be obtained without any optimization in a silver-free process.
Substitution in the iodoarene coupling partner 2 was then examined
(Scheme 3). The process is compatible with electron-withdrawing
(3ba-3ga, 3ka-3na) and electron-donating groups (3ha, 3oa) in meta
and para positions, leading to the corresponding meta-arylphenols in
good yields. Remarkably, the monoarylated 3ga was obtained
selectively from p-diiodobenzene as coupling partner without any
bisarylation product being observed.15 An aldehyde substituent (3ia)
led to no reaction under the standard conditions. This may result
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Scholarship Council and Queen Mary University of London for a
studentship (to J.L), and the Marie Curie Foundation for an Intra-
European Fellowship (to S.P) are gratefully acknowledged. EPSRC
National Mass Spectrometry Service (Swansea) is also
acknowledged.
Notes and references
Scheme 4. Silver-free method for the tandem arylation / protodecarboxylation of
salicylic acids.
Taking advantage of the myriad of methodologies available for
the functionalization of (and at) aromatic C-O bonds, the meta-
arylphenols here described are highly attractive intermediates
towards the synthesis of meta-functionalized biaryls providing an
efficient alternative to the most widely used Suzuki coupling. Thus,
the meta-arylphenol 3ai can be reacted with alkyl and aryl
electrophiles in the presence of bases to form, in good yields, O-
arylated 4a and O-alkylated 4b. Both of these motifs are common in
18
natural products and pharmaceuticals.
On the other hand,
transforming the OH into a triflate group, allowed a subsequent
Buchwald-Hartwig amination19 to 4c and Suzuki20 coupling to the
unsymmetrical meta-triaryl 4d to occur in 92% and 93% yields,
respectively. Finally, a cyano group could be easily installed in 90%
yield by preforming the tosylate of 3ai, followed by Pd-catalyzed
coupling.
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Scheme 5. Transformations of 3ai into a variety of meta-functionalized biaryls.
Reagents and conditions: a) 2-chloro-5-nitropyridine, NaH, DMF, rt, 16 h; b) MeI,
K2CO3, acetone, rt, 16 h; c) Tf2O, Pyridine, DCM, rt, 1 h; Then, aniline, Pd(OAc)2,
BINAP, Cs2CO3, PhMe, 120 °C, 16 h; d) Tf2O, Pyridine, DCM, rt, 1 h; Then,
PhB(OH)2, Pd(PPh3)4, Na2CO3, monoglyme/H2O, 95 °C, 2.5 h; e) TsCl, Et3N, MeCN,
rt, 1 h; Then, Pd(OAc)2, cm-Phos, K4[Fe(CN)6]•3H2O, K2CO3, tBuOH/H2O, 80 °C, 18
h.
In conclusion, we have demonstrated that salicylic acids can
undergo facile Pd-catalyzed tandem arylation/decarboxylation
leading to meta-arylated phenols with complete regioselectivity.
These products can be further transformed into a variety of meta-
functionalized biaryls highlighting salicylic acids as attractive
starting materials for the synthesis of these structural motifs.
Financial support from the European Research Council for a
Starting Grant (to I.L.), the Engineering and Physical Sciences
Research Council (EPSRC) for a research grant, the China
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