Mild and general palladium-catalyzed synthesis of methyl aryl ethers enabled by the use of a palladacycle precatalyst

Article abstract of DOI:10.1021/ol401796v

A general method for the Pd-catalyzed coupling of methanol with (hetero)aryl halides is described. The reactions proceed under mild conditions with a wide range of aryl and heteroaryl halides to give methyl aryl ethers in high yield.

Full text of DOI:10.1021/ol401796v

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Mild and General Palladium-Catalyzed
Synthesis of Methyl Aryl Ethers Enabled
by the Use of a Palladacycle Precatalyst
Chi Wai Cheung and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
sbuchwal@mit.edu
Received June 25, 2013
ABSTRACT
A general method for the Pd-catalyzed coupling of methanol with (hetero)aryl halides is described. The reactions proceed under mild conditions
with a wide range of aryl and heteroaryl halides to give methyl aryl ethers in high yield.
Methyl aryl ethers, including anisoles and methoxy-
substituted heteroarenes, are structural components of
natural products,1 pharmaceuticals,2,3 and agrochemicals.4
Figure 1 shows some examples of approved drug molecules
containing methyl aryl ethers.2 The replacement of methoxy
groups with trideuteriomethoxy groups in drug molecules
can alter the metabolic activity of drugs and thus enhance
their pharmaceutical potency.5 Therefore, the development
of techniques for the intermoleculer construction of CÀO
bonds to synthesize methyl aryl ethers is of particular
importance.
nucleophilic aromatic substitution of aromatic halides with
alkali metal methoxides,6 the Williamson7 and Mitsunobu8
€
ether syntheses, and the Bronsted/Lewis acid mediated
condensation between methanol and phenols.9 These tradi-
tional methods often require harsh reaction conditions
and/or the use of toxic methylating agents (MeI, Me2SO4)
and sometimes have a limited substrate scope. Recently, the
multistep synthesis of methyl aryl ethers via Pd-catalyzed
arylation of hydroxide followed by the methylation of the
resulting phenols has beenreported.10 Methoxy-substituted
silanes [Si(OMe)3H,11 Si(OMe)412] are also utilized as the
methanol surrogates in Pd-catalyzed cross-coupling with
To date, various synthetic methods have been discovered
for the preparation of methyl aryl ethers. These include
(6) For examples, see: (a) Bunnett, J. F.; Zahler, R. E. Chem. Rev.
ꢀ
ꢁ
ꢁ ꢁ
1951, 49, 273–412. (b) Chauviere, G.; Viode, C.; Perie, J. J. Heterocycl.
Chem. 2000, 37, 119–126. (c) Zilberman, J. Org. Process Res. Dev. 2003,
7, 303–305.
(1) (a) Zhu, J. Synlett 1997, 133–144. (b) Manzan, A. C. C. M.;
Toniolo, F. S.; Bredow, E.; Povh, N. P. J. Agric. Food Chem. 2003, 51,
6802–6807. (c) Renouard, S.; Lopez, T.; Hendrawati, O.; Dupre, P.;
Doussot, J.; Falguieres, A.; Ferroud, C.; Hagege, D.; Lamblin, F.;
Laine, E.; Hano, C. J. Agric. Food Chem. 2011, 59, 8101–8107. (d)
Ovenden, S. P. B.; Nielson, J. L.; Liptrot, C. H.; Willis, R. H.; Tapiolas,
D. M.; Wright, A. D.; Motti, C. A. J. Nat. Prod. 2011, 74, 1335–1338.
(2) The approved drugs containing methyl aryl ether motifs could be
searched in the DrugBank (http://www.drugbank.ca/) (accessed on May
24, 2013).
(3) Vitaku, E.; Ilardi, E. A.; Njar{arson, J. T. Top 200 Pharmaceutical
Products by US Retail Sales in 2011 (http://cbc.arizona.edu/njardarson/
group/top-pharmaceuticals-poster/) (accessed on May 24, 2013).
(4) http://www.alanwood.net/pesticides/ (accessed on May 24, 2013)
(5) (a) Sanderson, K. Nature 2009, 458, 269. (b) Yarnell, A. T. Chem.
Eng. News 2009, 87, 36–39. (c) Dash, P.; Janni, M.; Peruncheralathan, S.
Eur. J. Org. Chem. 2012, 4914–4917.
ꢂ ꢁ
(7) For examples, see: (a) Jursic, B. Tetrahedron 1988, 44, 6677–6680.
(b) Fuhrmann, E.; Talbiersky, J. Org. Process Res. Dev. 2005, 9, 206–
211. (c) Massah, A. R.; Mosharafian, M.; Momeni, A. R.; Aliyan, H.;
Naghash, H. J. Synth. Commun. 2007, 37, 1807–1815.
(8) For examples, see: Gentles, R. G.; Wodka, D.; Park, D. C.;
Vasudevan, A. J. Comb. Chem. 2002, 4, 442–456.
(9) For examples, see: (a) Sowa, F. J.; Hennion, G. F.; Nieuwland,
J. A. J. Am. Chem. Soc. 1935, 57, 709–711. (b) Simons, J. H.; Passino,
H. J. J. Am. Chem. Soc. 1940, 62, 1624. (c) Oku, T.; Arita, Y.; Ikariya, T.
Adv. Synth. Catal. 2005, 347, 1553–1557.
(10) (a) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2006, 128, 10694–10695. (b) Chen, G.; Chan, A. S. C.;
Kwong, F. Y. Tetrahedron Lett. 2007, 48, 473–476.
(11) Milton, E. J.; Fuentes, J. A.; Clarke, M. L. Org. Biomol. Chem.
2009, 7, 2645–2648.
r
10.1021/ol401796v
XXXX American Chemical Society

aryl halides11 and in copper-catalyzed decarboxylative aryla-
tion with aromatic carboxylic acids.12 However, these meth-
ods are limited to electron-deficient and/or ortho-substituted
(e.g., NO2, Me, OMe) aryl coupling partners.10b,11,12
biarylphosphine ligand RockPhos (Table 1, L1).16,17 L1
could promote the productive reductive elimination of
the proposed (L1)Pd(aryl)(alkoxy) intermediate relative
to the undesirable, competing β-hydride elimination of the
alkoxy group, thus facilitating the formation of alkyl aryl
ethers rather than the arene side products.16 Thus, we
began our studies by examining the reaction of 4-chloro-
anisole with 5 equiv of methanol in 1,4-dioxane at 100 °C,
using a strong base, KOtBu, and a Pd catalyst based on
Pd2dba3 (2 mol % Pd) and L1 (4 mol %) (Table 1, entry 1).
Under the reaction conditions, the coupling reaction
proceeded smoothly to give the desired product, 1,4-
dimethoxybenzene (1), in excellent yield along with the
minimal formation of anisole side product (2). Similarly,
the use of the structurally related BrettPhos-based ligands,
tBuBrettPhos (L2)17 and AdBrettPhos (L3),18 also pro-
moted the reaction to give 1 in excellent yields (Table 1,
entries 2 and 3). In contrast, when the smaller ligands,
BrettPhos (L4) and tBuXPhos (L5), were employed, the
ratio of 1 to 2 dropped significantly (Table 1, entries 4
and 5), whereas the use of conformationally more rigid
ligand Me4tBuXPhos (L6) resulted in a very low conver-
sion (Table1, entry 6). AsL2isavailableon kilogramscale,
we selected it for subsequent studies.
Figure 1. Selected pharmaceutical molecules containing the
methyl aryl ether motifs.
The cross-coupling between methanol and aryl halides
represents a direct, convenient, and atom-economical ap-
proach to synthesize methyl aryl ethers. We have pre-
viously reported two examples of Pd-catalyzed coupling
of methanol with electron-deficient aryl halides.13 In 2012,
Beller14 and Peruncheralathan5c reported a more general
Pd-catalyzed coupling of methanol and methanol-d4 with
aryl halides to access a broader range of anisoles and
methoxypyridines and their trideuteriomethoxy deriva-
tives, by using a sterically demanding BippyPhos-based
phosphine ligand and tBuXPhos ligand, respectively. In
addition, copper-catalyzed coupling of methanol with aryl
iodides also serves as a convenient method to prepare
anisoles.15 Despite these advances, the substrate scope is
generally limited to aryl halides and halopyridines. More-
over, a relatively high temperature (g70 °C) is usually
required. Herein, we report an improved, general method
for the synthesis of a broader range of methyl aryl ethers
and their trideuteriomethyl derivatives under mild reaction
conditions enabled by the use of a bulky biarylphosphine
ligand and a palladacycle precatalyst.
In light of the recent success of the use of aminobiphenyl
palladacycle precatalysts to promote cross-coupling reac-
tions under mild conditions,19 we utilized the precatalyst
3,19b which contains L2 preligated to the Pd center, in the
Table 1. Ligand Screen for the Pd-Catalyzed Arylation of
MeOHa
temp
conv
(%)b
yield of
1 (%)b
yield of
2 (%)b
entry
ligand
(°C)
1
L1
L2
L3
L4
L5
L6
L2
L2
L2
L2
L2
L2
100
100
100
100
100
100
80
100
100
100
53
93
92
93
13
73
20
96
85
93
94
48
95
7
2
7
3
7
4
40
27
7
5
100
27
We recently reported an efficient arylation of primary
and secondary alcohols to synthesize a variety of alkyl
aryl ethers, using a Pd catalyst based on the bulky
6
7
100
94
4
8c
9d
10d
11d
12e
80
7
80
100
100
50
7
50
6
(12) Bhadra, S.; Dzik, W. I.; Goossen, L. J. J. Am. Chem. Soc. 2012,
134, 9938–9941.
rt
2
(13) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 3395–3396. (b) Torraca, K. E.; Huang, X.; Parrish, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 10770–10771.
(14) Gowrisankar, S.; Neumann, H.; Beller, M. Chem.;Eur. J. 2012,
18, 2498–2502.
(15) (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973–976. (b) Zhang, H.; Ma, D.; Cao, W. Synlett 2007,
243–246. (c) Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.;
Buchwald, S. L. J. Org. Chem. 2008, 73, 284–286. (d) Naidu, A. B.;
Sekar, G. Tetrahedron Lett. 2008, 49, 3147–3151. (e) Niu, J.; Zhou,
H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73, 7814–7817. (f)
Satyanarayana, P.; Maheswaran, H.; Kantam, M. L.; Bull, S. B. Chem.
Soc. Jpn. 2011, 84, 788–790.
rt
100
5
a Reaction conditions: 4-Chloroanisole (0.25 mmol), MeOH
(1.25 mmol), NaOtBu (0.35 mmol), Pd2dba3 (1 mol %), ligand (4 mol %),
1,4-dioxane (0.5 mL, 0.50 M), 20 h. b Determined by GC. c Pd2dba3
(0.5 mol %), L2 (2 mol %), 24 h. d3 (1 mol %), L2 (1 mol %). e3 (2 mol %),
L2 (2 mol %).
(17) For the synthesis of RockPhos (L1) and tBuBrettPhos (L2), see:
Hoshiya, N.; Buchwald, S. L. Adv. Synth. Catal. 2012, 354, 2031–2037.
(18) For the synthesis of AdBrettPhos (L3), see: Su, M.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2012, 51, 4710–4713.
(16) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
2011, 50, 9943–9947.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Pd-Catalyzed Arylation of Methanola
(1À2mol%) at50°C or at ambient temperature (Scheme 1).
Both electron-rich and -deficient aryl halides could be
coupled with methanol to afford anisoles in high yields
(4aÀd). Additionally, a wide range of heteroaryl halides
were shown to be suitable coupling partners, including
pyridines (4eÀ4g), (iso)quinolines (4hÀ4j), pyrazines
(4k), pyrimidines (4l), indoles (4m), benzothiophenes
(4n), benzofurans (4o), benzothiazoles (4p), benzoxazoles
(4q), benzo-2,1,3-thiadiazoles (4r), carbazoles (4s), and
dibenzothiophenes (4t). Significantly, the Pd-catalyzed
coupling of methanol with five-membered heteroaryl
halideswasalso demonstrated (4uÀ4w). Stericallyhindered
substrates were well-tolerated under the reaction condi-
tions (4f, 4g, 4i, 4j), while the use of a weaker base, Cs2CO3,
a
Scheme 2. Pd-Catalyzed Arylation of Methanol-d4
a Reaction conditions: (Het)ArX (1 mmol), MeOH (5 mmol), NaOtBu
(1.4 mmol), 3 (1 mol %), L2 (1 mol %), 1,4-dioxane (2 mL, 0.50 M);
isolatedyields, average of tworuns. b 3 (2 mol %), L2(2 mol %). c Cs2CO3
(1.5 equiv). d 1H NMR yield of crude product. e An inseparable mixture
of ether product and heteroarene (HetArH, 2À4%) was isolated.
coupling reaction of methanol. While the Pd catalyst based
on Pd2dba3/L2 still efficiently catalyzed the reaction at
80 °C (Table 1, entry 7), incomplete conversion of the
substrate was seen when the loading of Pd2dba3 was
decreased to 0.5 mol % (1 mol % Pd) (Table 1, entry 8).
Incontrast, 1 mol % precatalyst 3 was sufficient to catalyze
efficiently the reaction to afford 1 in excellent yield under
otherwise identical conditions and even at 50 °C (Table 1,
entries 9 and 10). At a higher loading of 3 (2 mol %), the
reaction proceeded smoothly at room temperature
(Table 1, entries 11 and 12).
Next, we explored the scope of the Pd-catalyzed synthe-
sis of methyl aryl ethers based on the use of precatalyst 3
a Reaction conditions: (Het)ArX (1 mmol), CD3OD (5 mmol), NaOtBu
(1.4 mmol), 3 (2 mol %), L2 (2 mol %), 1,4-dioxane (2 mL, 0.50 M);
b
c
isolated yields, average of two runs. Cs2CO3 (1.5 equiv). After the
reaction, the reaction mixture was further heated with H2O (100 equiv) for
20 min at the reported temperature to form RNHBoc. d 3 (1 mol %) and
L2 (1 mol %).
(19) (a) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013,
4, 916–920. (b) Bruno, N. C.; Buchwald, S. L. Org. Lett. 2013, 15, 2876–
2879. (c) Yang, Y.; Oldenhuis, N. J.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2012, 52, 615–619.
Org. Lett., Vol. XX, No. XX, XXXX
C

we found that the coupling of ethanol with heteroaryl
halides proceeded to afford the ethyl aryl ethers in good
yields under ambient conditions (Scheme 3).
Scheme 3. Pd-Catalyzed Arylation of Ethanola
In conclusion, we have developed a method for the
palladium-catalyzed arylation of methanol and methanol-
d4 under mild conditions, with excellent selectivity for
the formation of a variety of methyl and deuteriomethyl
aryl ethers. We also preliminarily demonstrated the
palladium-catalyzedarylationofethanolatroom tempera-
ture. We expect these methods to be widely applicable to
the synthesis of biologically active molecules containing
the methoxy and deuteriomethoxy groups.
a Reaction conditions: (Het)ArX (1 mmol), EtOH (2 mmol), NaOtBu
(1.4 mmol), 3 (2 mol %), L2 (2 mol %), 1,4-dioxane (2 mL, 0.50 M);
isolated yield, average of two runs. b EtOH (5 equiv).
Acknowledgment. We thank the National Institutes of
Health (GM58160) for financial support of this project.
We are grateful to Drs. J. Robb DeBergh (M.I.T.) and
Nathan Jui (M.I.T.), and James Colombe (M.I.T.), for
help with preparation of this manuscript. We acknowledge
Nicholas C. Bruno (M.I.T.) for providing the Pd precata-
lyst 3 used in this study and Dr. Naoyuki Hoshiya (M.I.T.)
for the preparation of L2. C.W.C. thanks the Croucher
Foundation (Hong Kong) for a postdoctoral fellowship.
The Bruker 400 MHz NMR spectrometer used in this
work was supported by the National Science Foundation
(Grants CHE-9808061 and DBI-9729592).
in place of NaOtBu, isnecessary when the couplingpartners
contain base-sensitive functional groups (4c, 4d, 4e, 4u).
For all substrates, we observed an excellent selectivity for
the formation of methyl aryl ethers over the reduced
products.20
The reaction protocol based on precatalyst 3 also
allowed for the coupling of methanol-d4 with a variety of
(hetero)aryl halides under mild conditions, forming the
corresponding trideuteriomethyl aryl ethers in good yields
(Scheme 2, 5aÀ5g). A trideuteriomethyl vinyl ether could
be prepared as well (5h).
The homologue of methanol, ethanol, has seldom been
studied in the Pd-catalyzed CÀO coupling reactions.21 By
utilizing the reaction protocol described above (Scheme 1),
Supporting Information Available. Experimental pro-
cedures along with experimental and spectroscopic data
for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) In the coupling reactions with most of the (hetero)aryl halides,
no or only a trace of (hetero)arene side-products ((Het)ArH) were
detected by GC-MS analysis. See Supporting Information for details.
(21) To our knowledge, there is only one example of the Pd-catalyzed
coupling of ethanol with aryl halide.13b
The authors declare the following competing financial interest(s):
M.I.T. has patents on some of the ligands and precatalysts used in this
work from which S.L.B. receives royalty payments.
D
Org. Lett., Vol. XX, No. XX, XXXX