Palladium-catalyzed methoxylation of aromatic chlorides with borate salts

Article abstract of DOI:10.1002/adsc.201300687

Herein we disclose a simple palladiumcatalyzed transformation for the methoxylation of aromatic chlorides with tetramethoxyborate salts. The procedure provides a new and efficient synthetic tool for the introduction of a methoxy group into aromatic systems. In addition, the reaction can be achieved using a wide range of aromatic and heteroaromatic chlorides, the cheapest class of halides.

Full text of DOI:10.1002/adsc.201300687

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DOI: 10.1002/adsc.201300687
Palladium-Catalyzed Methoxylation of Aromatic Chlorides with
Borate Salts
+a
+a
a
a,
˝
Gergely L. Tolnai, Bꢀlint Petho, Pꢁter Krꢀll, and Zoltꢀn Novꢀk *
a
MTA-ELTE “Lendꢂlet” Catalysis and Organic Synthesis Research Group, Institute of Chemistry, Eçtvçs University,
Pꢀzmꢀny Pꢁter stny. 1/a, H-1117 Budapest, Hungary
E-mail: novakz@elte.hu
+
These authors contributed equally to the present work.
Received: August 10, 2013; Revised: October 23, 2013; Published online: January 13, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300687.
Abstract: Herein we disclose a simple palladium-
catalyzed transformation for the methoxylation of
aromatic chlorides with tetramethoxyborate salts.
The procedure provides a new and efficient synthet-
ic tool for the introduction of a methoxy group into
aromatic systems. In addition, the reaction can be
achieved using a wide range of aromatic and
ligand system that is able to promote the coupling of
primary and secondary alcohols with aromatic and
heteroaromatic bromides.[6] However, the introduc-
tion of the simple methoxy group is still challenging.
Beller and co-workers recently published the first pal-
ladium-catalyzed method for methoxylation based on
the utilization of the adamantly-BiPyphos ligand.[7]
Their catalyst system reduces the ratio of b-hydride
elimination by accelerating the reductive elimination
step. The described method works excellently with
electron-deficient bromides in MeOH, in the presence
of Cs2CO3 as base. It is of note that the methoxylation
of chlorides, especially those which are functionalized
with electron-donating groups, is still unprecedented.
hetero
ides.
ACHTUNGTRENNUNGaromatic chlorides, the cheapest class of hal-
Keywords: borates; cross-coupling; Lewis acids;
palladium
Aromatic ethers are in great interest of organic
chemistry. They appear in many natural products and
active pharmaceutical ingredients (Scheme 1). Due to
the strong electron-donating property of the methoxy
group, its presence significantly modifies the electron-
ic properties of aromatic compounds to ensure unique
properties in several materials.[1]
Besides the traditional Ullmann coupling,[2] in the
last decades the Buchwald–Hartwig-type coupling has
À
become a general tool for the construction of C N
and C O bonds between the heteroatom and the aro-
À
matic ring. Despite the existence of versatile palladi-
[3]
À
um-catalyzed C N bond forming reactions,
the
À
methodologies for the C O coupling reaction be-
tween aryl halides and oxygen nucleophiles are still
limited.[4] The main difficulty in these transformations
is the presence of competing b-hydride elimination
side reactions. The first report of Buchwald describes
a convenient palladium-catalyzed method that only
enables the coupling of ortho-substituted aryl bro-
mides with primary alcohols containing at least four
carbons.[5] Later improvements gave a more tuneable Scheme 1. Selected biologically active methoxy compounds.
Adv. Synth. Catal. 2014, 356, 125 – 129
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Gergely L. Tolnai et al.
Table 1. Ligand screening study.[a]
However, the application of chlorides is more benefi-
cial than other halides or triflates.
Very recently, Gooßen demonstrated with a slightly
different approach that the introduction of the me-
thoxy group is possible using a copper/silver catalyst
system via decarboxylative coupling with tetrame-
thoxysilane.[8]
Boranes and borate salts are widely used in cross-
coupling reactions due to the high importance of
Suzuki reactions.[9] The only example for the utiliza-
tion of methoxyborate salts instead of trifluoroborate
salts in cross-coupling chemistry is Gooßenꢄs copper-
catalyzed trifluoromethylation of aryl iodides with tri-
fluoromethyltrimethylborate salts.[10] To the best of
our knowledge the approach based on alkoxyborates
has never been used for carbon-oxygen bond forma-
tion.
Taking into consideration that the trialkoxyboranes
can bind nucleophilic heteroatoms via the formation
of Lewis acid–base adduct, we aimed to develop a cat-
alytic method for the methoxylation of aromatic
chlorides without the use of a large excess of strong
base or methanol. The easily accessible air-stable tet-
ramethoxyborates salts[11] could provide methoxy
groups via transmetallation for a general palladium-
catalyzed cross-coupling cycle in a Suzuki-type C O
bond forming reaction. However, this type of reaction
is as yet not known.
For preliminary optimization, we examined the me-
thoxylation of 4-chloroacetophenone using sodium
tetramethoxyborate salt in the presence of Pd2ACTHNUTRGEN(UNG dba)3
Entry
Pd
(dba)3
Ligand
Conversion[b] [%]
1
2
3
4
5
6
7
8
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
1 mol%
0.5 mol%
4 mol%, L1
4 mol%, L2
4 mol%, L3
4 mol%, L4
4 mol%, L5
4 mol%, L6
4 mol%, L7
4 mol%, L8
2 mol%, L8
1 mol% L8
0
0
2
25
15
49
81
98
98
98
À
in dioxane at 1008C Table 1).
9
10
We tested several phosphane ligands and, to our
delight, we were able to achieve the desired coupling
in the presence of several triarylphosphanes and
Buchwald-type biphenyl-based ligands, but we found
[a]
0.5 mmol aryl chloride, 0.5 mmol NaB
oxane.
Followed by GC-FID using mesitylene as a standard.
ACHTUNGRTEN(NUNG OMe)4, 500 mL di-
[b]
that
2-di-tert-butylphosphino-2’,4’,6’-triisopropylbi-
Table 2. Study of solvent effects.[a]
phenyl (t-BuXPhos) was essential for the efficient
coupling (Table 1). In the case of this electron-defi-
cient aryl chloride the catalyst loading could be re-
duced to 0.5 mol%.[12]
Further optimization of the methoxylation with
a less reactive chloride, 4-chloroanisole, and freshly
prepared K[BACHTUNGTRENNUNG(OMe)4] demonstrated the real synthet-
Entry Pd
(dba)3 Ligand
Solvent Conver-
sion[b] [%]
[mol%]
ic power of the method (Table 2). We found that the
reaction is even more sensitive to the choice of the li-
gands, and only t-BuXPhos provided the desired para-
dimethoxybenzene with 68% conversion after 1 hour
(entries 1–5).
1
2
3
4
5
5
5
5
10% XPhos
10% DPPE
10% DPPF
10% BINAP
DMF
DMF
DMF
DMF
7
0
0
0
5
5
10% t-BuXPhos DMF
68
Regarding the appropriate choice of solvent we
found that a coupling conducted in DMF provides the
best conversions (entries 5–8), and the formation of
the dehalogenated by-product was not significant in
this solvent. In the case of this electron rich-substrate
6
7
8
9
5
5
5
1
10% t-BuXPhos dioxane 36
10% t-BuXPhos CPME 26
10% t-BuXPhos diglyme 59
10% t-BuXPhos DMF
5.5% t-BuXPhos DMF
33
67
10
2.5
[a]
the addition of 2.5 mol% Pd
2ACHTUNGTREN(NNUG dba)3 is necessary for
0.5 mmol 4-chloroanisole, 0.5 mmol KB
solvent.
followed by GC-FID using mesitylene as a standard.
ACHTUNGRTENUN(NG OMe)4, 500 mL
the coupling (entries 5, 9, and 10).[12]
[b]
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Palladium-Catalyzed Methoxylation of Aromatic Chlorides
Table 3. Substrate scope for the palladium-catalyzed me-
thoxylation reaction.
[a]
[b]
[c]
[d]
[e]
1 mmol substrate, 1.5 equiv. KBACTHNUGRTNE(NUNG OMe)4, 2.5% Pd CHTUNGTRENNUNG(dba)3,
5.5% t-BuXPhos, 500 mL DMF.
1 mmol substrate, 3 equiv. KBACTHNUGRTEN(NUNG OMe)4, 2.5% Pd CHTUNGTRENNUNG
5.5% t-BuXPhos, 1000 mL DMF.
2A
2A(dba)3,
1 mmol substrate, 1.5 equiv. NaBAHCUTNTGERG(NNUN OCD3)4, 2.5%
Pd2ACHTNUTRGENNG(U dba)3, 5.5% t-BuXPhos, 500 mL DMF.
5 mmol substrate, 1.5 equiv. KBACTHNUGRTNE(NUNG OMe)4, 2.5% Pd CHTUNGTRENNUNG(dba)3,
2A
5.5% t-BuXPhos, 2.5 mL DMF.
5 mmol substrate, 1.5 equiv. NaB
Pd2A(dba)3, 5.5% t-BuXPhos, 2.5 mL DMF.
ACHTUNGTRNEN(UNG OCD3)4, 2.5%
CTHUNGTRENNUNG
With these results in hand we turned our attention
to the substrate scope of the reaction (Table 3.). The
scope was examined on a 1–5 mmol scale and the re-
actions provided the products with good to excellent
yields in the presence of electron-donating functional
groups on the aromatic chlorides (Scheme 1, 2a–d).
Methoxylation of benzyl-protected 4-chlorophenol
was also successful and the appropriate anisole deriv-
ative (2e) was obtained in 65% yield. The presence of
carbonyl functionalities was also well tolerated pro-
viding products (2f–h) with excellent yields. Utilizing
the developed conditions, the sterically demanding
double methoxylation of dichlorbenzophenone was
also successful, however, the yield of compound 2i
was surprisingly low (21%) compared to other sub-
strates. By comparison, 2-and 4-chlorobenzonitriles
showed that smaller electron-withdrawing groups
have no steric impact on the reaction result, and both
4-methoxy- (2j) and 2-methoxybenzonitrile (2k) were
isolated with good yields (85% and 81%, respective-
ly). When a methylene group was present in the sub-
strate between the nitrile and the aromatic core the
methoxyphenylacetonitrile (2l) was obtained with
lower (52%) yield.
Electron-deficient 4-chloronitrobenzene was me-
thoxylated smoothly under the standard conditions
and compound 2m was isolated in 92% yield. Double
methoxylation of dichloronitrobenzene provided the
expected dimethoxynitrobenzene product (2n) in 69%
yield. The methoxylation of a cinnamic acid derivative
provided product 2o in excellent yield (88%), and
electron-rich 5-chlorobenzo[d]ACTHNUTRGNEUNG[1,3]dioxole was also
converted to the corresponding sesamol derivative
(2p).
Heterocyclic compounds are very important struc-
tures from medicinal and biochemical aspects, there-
fore we examined the reactivity of several heterocy-
clic chlorides in the palladium-catalyzed alkoxylation.
The reaction of 6-chloroquinoline provided 6-
methoxyACTHNUTRGNEUGqN uinoline (2q) with an excellent 93% yield,
while 6-chloroindole was also successfully methoxylat-
ed and provided the desired 6-methoxy product 2r in
51% yield, which is an expensive starting material for
total syntheses. The non-fluorescent chlorocoumarin
derivative was also successfully converted to the ap-
propriate highly fluorescent methoxycoumarin (52%).
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Gergely L. Tolnai et al.
lyzed cross-coupling reactions, further applications
beyond methoxylation can be envisioned for the con-
struction of carbon-heteroatom bonds. Studies on the
expansion of borate chemistry in the field of cross-
coupling reactions are currently underway in our lab-
oratory.
Experimental Section
General Procedure
The Pd2ACTHNUGTRNE(UNG dba)3 (22.9 mg, 0.025 mmol, 2.5%), the 2-di-tert-
butylphosphino-2’,4’,6’-triisopropylbiphenyl
(tBuXphos,
22.8 mg, 0.055 mmol, 5.5%) and the KBAHCTUNTGERG(NNUN OMe)4 (260 mg,
1.50 mmol, 1.5 equiv.) or NaBACHTNUGTRNEUNG(OCD3)4 (235 mg, 1.50 mmol,
Scheme 2. The proposed catalytic cycle.
1.50 equiv.) and the substrate if a solid (1 mmol) were
charged into a 4-mL screw-cap vial, equipped with a stirrer
bar. The atmosphere was changed 3 times to argon, and dry
DMF (500 mL) was filled in. The substrate was then added if
a liquid (1 mmol) and stirred at 1008C for 60–180 min until
the reaction was completed. The mixture was allowed to
cool down to room temperature, diluted with EtOAc
(20 mL), washed with water (20 mL), and brine (20 mL),
dried over MgSO4. The solvent was evaporated under re-
duced pressure. The crude mixture was purified by column
chromatography (SiO2, hexanes/EtOAc).
The isotopic labelling of different groups is an im-
portant task in SAR or metabolism studies in medici-
nal chemistry.[13] The introduction of a trideuterome-
thoxy group via palladium-catalyzed cross coupling is
also possible in CD3OD as solvent.[6e,13c]
With our method, due to the small excess of trideu-
teromethoxides and the low price of starting materi-
als, a practical method could be achieved. Due to the
more efficient preparation of Na[BACHTNURTGNE(UNG OCD3)4] we used
this salt instead of the potassium derivative. The
sodium salt proved to be a stable and effective me-
thoxylating agent for aromatic chlorides. Utilizing the
deuterated salt in the cross-coupling under the devel-
Acknowledgements
This project was supported by the “Lendꢀlet” Research
oped conditions we prepared deuteromethoxylated Scholarship of the Hungarian Academy of Sciences, and by
TꢁT 10-1-2011-0245. The help of Dr. Zs. Eke for providing
the necessary analytical background is gratefully acknowl-
edged. The authors thank Dr. Tamꢂs Gꢂti for the NMR
measurements of the borate salts. The authors also thank
Prof. Tim Peelen for the proof-reading of this manuscript.
compounds bearing electron-donating and electron-
withdrawing groups (2t–v).
Our working model for the reaction is depicted on
Scheme 2. The reaction likely begins with an oxida-
tive addition of the aromatic chloride to the palladi-
um center, which is promoted by the bulky phosphane
ligand. Then transmetallation occurs from the borate
salt, providing the arylpalladium alkoxide species. The
transmetallated palladium complex may be stabilized
by the boron, to prevent b-hydride elimination. Fol-
lowing reductive elimination, the desired carbon-
oxygen bond forms along with regeneration of the
Pd(0) catalyst.
In conclusion, we have developed a new, simple
and efficient synthetic tool for the palladium-cata-
lyzed methoxylation of various electron-rich and elec-
tron-deficient aromatic and heteroaromatic chlorides
utilizing stable, easy-to-prepare tetramethoxyborate
salts as methoxylating agents. This methodology can
be used to introduce methoxy or trideuteromethoxy
groups into the aromatic core. The transformation has
good functional group tolerance and the desired prod-
ucts can be prepared in good to excellent yields in
short reaction time. Taking advantage of the efficient
anion transfer from borate salts in palladium-cata-
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