A convenient and practical synthesis of anisoles and deuterated anisoles by palladium-catalyzed coupling reactions of aryl bromides and chlorides

Article abstract of DOI:10.1002/chem.201103347

Synthesis of anisole: Aryl and heteroaryl halides undergo selective C-O cross-coupling reactions with methanol in the presence of a Pd(OAc) ₂/L3 catalyst system. The corresponding ethers were obtained under mild conditions in good yields. The catalytic methodology was also used for the synthesis of labeled deuterated anisoles in good yields (see scheme). Copyright

Full text of DOI:10.1002/chem.201103347

DOI: 10.1002/chem.201103347
A Convenient and Practical Synthesis of Anisoles and Deuterated Anisoles
by Palladium-Catalyzed Coupling Reactions of Aryl Bromides and Chlorides
Saravanan Gowrisankar, Helfried Neumann, and Matthias Beller*[a]
Dedicated to Professor Hiriyakkanavar Ila on the occasion of his 68th birthday
In recent years, palladium- and copper-catalyzed cross-
coupling reactions have become useful tools for the synthe-
sis of (hetero)aryl ethers.[1–3] Due to the presence of aromat-
ic ether bonds in numerous natural products, pharmaceuti-
cals, fragrances, cosmetics, and polymers,[4] further develop-
À
ments of efficient C O bond-forming reactions are of con-
tinuing interest for organic chemistry. In particular, methyl
(hetero)aryl ethers (anisoles) represent an important struc-
tural motif present in numerous biologically active com-
pounds, such as acitretin, anisindione, pantoprazole, 2,5-
di([D3]methoxy)-4-methylamphetamine, aniracetam, asar-
one, anethole trithion, nabumeton, and naproxen
(Scheme 1).
Unfortunately, the straightforward substitution of aryl hal-
ides by methanol proceeds only with strongly electron-poor
aryl halides (chlorides and fluorides) under strong basic con-
ditions through a nucleophilic SNAr mechanism. Thus, in
general, the classical Williamson ether synthesis is still the
method of choice for the preparation of methyl (hetero)aryl
ethers.[5] However, this method is limited because of the
drastic conditions (high temperature), the low functional
group tolerance, and the necessity to use toxic methylation
agents, such as methyl iodide. More benign alkylations with
methanol have been reported only at high temperature,
which also leads to C-alkylations as side reactions.[6]
Although palladium-catalyzed coupling reactions of aryl
halides with phenols and tertiary alcohols are well devel-
oped, the apparently simple coupling reaction with metha-
nol has been scarcely explored, because of the competing b-
hydride elimination. So far, only two palladium catalyst sys-
Scheme 1. Selected examples of biologically active anisole derivatives.
tems have been reported for this transformation; however,
they have not been shown to function in a general manner
(Scheme 2). More specifically, Buchwald demonstrated
solely the synthesis of 3-nitroanisole by using ligand L1.[7]
Clarke and co-workers used a palladium catalyst and ligand
L2 for the methoxylation of aryl halides with vinyl trime-
thoxysilane and sodium hydroxide as activator to give ani-
soles in moderate yields.[8] However, this reaction was limit-
ed to substrates with electron-withdrawing substituents in
the para-position. In this context, a related approach from
Kwong and co-workers should also be noted. They elegantly
described the synthesis of substituted anisoles from aryl hal-
ides by palladium-catalyzed hydroxylation followed by the
addition of methyl iodide in a one-pot reaction.[9] In summa-
ry, no general methodology is available for the simple cross-
coupling reaction of aryl halides with methanol to date.
Based on our work on the development of novel palladi-
um catalysts and ligands for cross-coupling reactions,[10] we
[a] Dr. S. Gowrisankar, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103347.
2498
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Chem. Eur. J. 2012, 18, 2498 – 2502

COMMUNICATION
donors for the reduction of aryl halides. To overcome this
problem, bulky phosphine ligands[15] could be used to facili-
À
tate C O coupling reactions by promoting reductive elimi-
nation.
Here, we describe the first general procedure for the pal-
ladium-catalyzed arylation of methanol. The key to success
is the use of our di-Ad-substituted Bipyphos ligand L3
under carefully optimized conditions. At the start of our
work, we investigated the reaction of 2-bromotoluene with
MeONa as a model reaction. All catalytic test reactions
were carried out with 1 mol% PdACHTNUTRGNEUNG(OAc)2 and 2 mol% Bipy-
phos-Ad. Unfortunately, under the previously described
conditions,[12] no desired product was formed. Instead, we
observed reductive dehalogenation, which gave toluene III.
In addition, the formation of methyl formate IV is some-
what surprising, but can be explained by dehydrogenation of
the intermediate 1-methoxymethan-1-ol (Scheme 3). Nota-
bly, in this case the aryl halide acts as a stoichiometric oxi-
dant. Next, we studied the effect of different methoxylation
reagents, such as MeOH, (MeO)2CO, (MeO)4Si,
À
(MeO)3SiH, and (MeO)3Si CH=CH2 (Table 1). To our de-
light, the coupling process proceeded efficiently in 82%
yield within 5 h at 808C in the presence of methanol and
cesium carbonate (Table 1, entry 1).
Scheme 2. Palladium-catalyzed synthesis of anisoles from aryl halides.
À
recently became interested in more challenging C O bond
formations by using hydroxide[11] or primary aliphatic alco-
hols.[12] During these studies, we observed that the combina-
tion of palladium acetate and the adamantyl (Ad)-substitut-
ed Bipyphos derivative[13] L3 catalyzes the coupling of a
wide range of alcohols with aryl halides and heteroaryl hal-
ides. Although reactions of 1-butanol, 1-hexanol, 1-octanol,
1-hexadecanol, and benzyl alcohol occurred with a variety
of aryl halides, the related cross coupling of methanol with
aryl halides was still problematic under the described condi-
Table 1. Pd-catalyzed coupling reactions of 2-bromotoluene with differ-
ent methoxy sources.
Entry Methoxylation Reagent[a]
Base
Conversion Yield
[%]
[%]
1
2
3
4
5
MeONa (2 equiv)
MeOH/toluene (1:1)
T
–
45
100
61
62
21
<1
82
43
<1
<1
Cs2CO3
Cs2CO3
Cs2CO3
À
tions due to b-hydride elimination of the intermediate Ar
À
Pd OCH3 complex I.
E
A
As shown in Scheme 3, the chemoselectivity of the overall
À
process depends strongly on the relative rates of C O bond-
Reaction conditions: [a] PdACTHNUTRGNE(UGN OAc)2 (1 mol%), L3 (2 mol%), aryl halide
(1.0 mmol), Cs2CO3 (1.5 equiv), toluene (2 mL), 808C, 12 h. [b] 2.0 equiv.
forming reductive elimination and unwanted b-hydride elim-
ination. In most palladium(II)alkoxy complexes, b-hydride
elimination proceeds faster than reductive elimination.[14]
Hence, methoxides are known to be efficient hydride
Next, we investigated the influence of critical reaction pa-
rameters (palladium source and base) on the palladium-cat-
alyzed coupling of 2-bromotoluene with methanol in the
presence of L3. Notably, the chosen palladium precatalyst
has a major impact on the performance of the model reac-
tion. Apart from palladium(II) acetate, [Pd
2ACHTUNGTRENUN(NG dba)3] and [Pd-
AHCTUNGTRENNUNG
deneacetone). Variation of the solvent (arenes, amines, neat
alcohol) confirmed that toluene was optimal for this reac-
tion. In comparison with K2CO3, K3PO4, NaHCO3, and
NaOAc, Cs2CO3 worked best for this methoxylation. Al-
though the reaction proceeded sluggishly at 658C, it was
completed within 6 h at 808C in toluene (Table 2).
With the optimized conditions in hand, we examined the
reaction of activated, nonactivated, and hindered aryl hal-
ides with methanol. Substituents on the (hetero)aryl bro-
Scheme 3. Coupling reaction of methanol with aryl halides: product for-
mation and side reactions.
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2499

M. Beller et al.
Table 2. Pd-catalyzed coupling reaction of 2-bromotoluene with metha-
nol.[a]
chloroarenes to give the corresponding anisoles in good
yields (Table 3, entries 1–5, 11 and 12). Compared with the
reaction of 2-bromotoluene, the yield in the case of the cor-
responding chloroarene was only slightly lower demonstrat-
Entry
Palladium/Base
Conversion [%]
Yield [%]
1
2
3
4
5
6
7
8
9
Pd(OAc)2/Cs2CO3
G
100
100
100
100
100
100
28
82
48
54
46
73
10
<1
24
[Pd
[Pd
[Pd
ACHTUNGTRENNUNG
À
ing that oxidative addition of palladium(0) to C X is not
A
crucial. In addition, our conditions worked well for aryl bro-
mides and chlorides with electron-withdrawing substituents
in the para-position (Table 3, entries 6–11). The coupling of
meta-substituted aryl halides, the reactions of which are not
facilitated by the increased rate of reductive elimination,
took place in 54–85% yields (Table 3, entries 12–16). A
somewhat lower yield of the desired product was obtained
for 4-methoxy-2-bromotoluene with an electron-donating
group at the para-position (Table 3, entry 17).
A
A
U
Pd
Pd
Pd
Pd
N
99
31
<1
[a] Reaction conditions: palladium (1 mol%), L3 (2 mol%), 2-bromoto-
luene (1.0 mmol), base (1.5 equiv), toluene (2 mL), 808C, 12 h.
mides (chlorides) included electron-withdrawing and elec-
tron-donating groups. As shown in Table 3, methanol react-
ed smoothly with different alkyl-substituted bromo- and
Finally, we were interested in the performance of our cat-
alytic system with heteroaryl halides. Here, we were pleased
to find that 2- and 3-bromopyridine, 2-chloropyridine, 2-
Table 3. Pd-catalyzed coupling reactions of (hetero)aryl halides with methanol.[a,c]
Entry
1
Substrate
Product
Yield [%]
82[d]
Entry
12
Substrate
Product
Yield [%]
65[d]
2
3
4
73[d]
65
13
14
15
60
54
85
67
5
6
79
88
16
17
78
58
7
8
80
81
18
19
82
78
9
63
51
20
21
77[b]
89
10
11
68[d]
22
62
[a] Reaction conditions: PdACHTGNURTEN(NUNG OAc)2 (1 mol%), L3 (2 mol%), aryl halide (1.0 mmol), Cs2CO3 (1.5 equiv), methanol/toluene (1:1), 808C, overnight. [b] Pd-
ACHTUNGTRENNUNG(OAc)2 (2 mol%), L3 (4 mol%). [c] Isolated yield. [d] GC yield.
2500
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Chem. Eur. J. 2012, 18, 2498 – 2502

Synthesis of Anisoles and Deuterated Anisoles
COMMUNICATION
and 3-bromoquinoline are readily converted with methanol
into the corresponding ether products in moderate to good
yields (Table 3, entries 18–22).
expensive CD3OD for the preparation of labeled (hetero)ar-
yl alkyl ethers.
For the development of new pharmaceuticals, the use of
deuterated compounds becomes increasingly interesting.[16]
For example, deuterated derivatives are necessary for me-
tabolite studies and novel bioactive compounds can be syn-
Experimental Section
General procedure for intermolecular coupling: An oven-dried pressure
tube (10 mL) was charged with PdACHTNUTRGNENG(U OAc)2 (5 mg, 0.023 mmol, 1 mol%),
À
À
thesized by the exchange of C H for C D bonds. This latter
strategy aims to take advantage of the increased stability of
ligand L3 (31 mg, 0.047 mmol, 2 mol%), and Cs2CO3 (1143 mg,
3.50 mmol, 1.5 equiv). Toluene (2 mL), aryl halide (2.34 mmol), and
methanol (2 mL) were added. The reaction mixture was stirred at 808C
overnight, then cooled to RT, diluted with EtOAc (5 mL), filtered
through a pad of Celite, and concentrated. The crude product was puri-
fied by flash chromatography.
À
À
C D bonds. If a particular C H bond in a drug molecule is
known to be readily broken during metabolism, exchanging
that hydrogen for a heavier deuterium atom can in some in-
stances slow down the unwanted metabolic process. Obvi-
ously, our palladium-catalyzed methoxylation reaction is ide-
ally suited to prepare deuterated analogues of anisoles
simply by using inexpensive CD3OD. To the best of our
knowledge, such reactions have not been performed before.
As expected, the catalytic methoxylation with CD3OD
proceeded smoothly. Thus, coupling reactions with tert-butyl
4-bromobenzoate, 1-(4-bromophenyl)ethanone, 2-chloroto-
luene, and 2-bromoquinoline readily produce the corre-
sponding deuterated products in moderate to good yields
(Table 4, entries 1–5). Notably, in the case of 4-bromoaceto-
phone, deuteration was also observed at the a position of
the carbonyl group. This observation is in agreement with
reported results by Hashimoto and co-workers (Table 4,
entry 4).[17]
Acknowledgements
This work has been funded by the State of Mecklenburg-Western Pomer-
ania, the BMBF, and the DFG (Leibniz Prize). We thank Drs. W. Bau-
mann, C. Fischer, and Mrs. S. Buchholz (all LIKAT) for their support.
We thank Mr. Stephan Neumann for excellent technical assistance.
Keywords: anisole · cross-coupling · deuterium · palladium ·
synthetic methods
À
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À
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[13] The so-called Bipyphos ligand [(5-(di-tert-butylphosphino)-1-(1,3,5-
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À
and co-workers for palladium-catalyzed C O bond formation. It
was also used successfully for methoxylation of 2- and 3-bromopyri-
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Received: October 24, 2011
Published online: February 1, 2012
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