A general and efficient catalyst for palladium-catalyzed C-O coupling reactions of aryl halides with primary alcohols

Article abstract of DOI:10.1021/ja103248d

An efficient procedure for palladium-catalyzed coupling reactions of (hetero)aryl bromides and chlorides with primary aliphatic alcohols has been developed. Key to the success is the synthesis and exploitation of the novel bulky di-1-adamantyl-substituted bipyrazolylphosphine ligand L6. Reaction of aryl halides including activated, nonactivated, and (hetero)aryl bromides as well as aryl chlorides with primary alcohols gave the corresponding alkyl aryl ethers in high yield. Noteworthy, functionalizations of primary alcohols in the presence of secondary and tertiary alcohols proceed with excellent regioselectivity.

Full text of DOI:10.1021/ja103248d

Published on Web 07/30/2010
A General and Efficient Catalyst for Palladium-Catalyzed C-O
Coupling Reactions of Aryl Halides with Primary Alcohols
Saravanan Gowrisankar, Alexey G. Sergeev, Pazhamalai Anbarasan,
Anke Spannenberg, Helfried Neumann, and Matthias Beller*
Leibniz-Institut fu¨r Katalyse e.V. an der UniVersita¨t Rostock, Albert-Einstein-Strasse 29a,
18059 Rostock, Germany
Received April 17, 2010; E-mail: matthias.beller@catalysis.de
Abstract: An efficient procedure for palladium-catalyzed coupling reactions of (hetero)aryl bromides and
chlorides with primary aliphatic alcohols has been developed. Key to the success is the synthesis and
exploitation of the novel bulky di-1-adamantyl-substituted bipyrazolylphosphine ligand L6. Reaction of aryl
halides including activated, nonactivated, and (hetero)aryl bromides as well as aryl chlorides with primary
alcohols gave the corresponding alkyl aryl ethers in high yield. Noteworthy, functionalizations of primary
alcohols in the presence of secondary and tertiary alcohols proceed with excellent regioselectivity.
during the past decade, was an important step forward.4 Clearly,
each of these protocols has its own virtues; however, limitations
Introduction
The synthesis of (hetero)aryl amines, anilines, (hetero)aryl
ethers, and phenols via palladium- and copper-catalyzed cross-
coupling methodologies has become an efficient and funda-
mental tool for advanced organic synthesis in both academic
and industrial laboratories.1 In addition to well established
Buchwald-Hartwig amination reactions, in particular C-O
bond forming reactions are interesting in organic synthesis due
to the presence of these bonds in numerous natural products,
biological compounds, pharmaceuticals, fragrances, cosmetics,
and polymers.2
still exist with respect to substrate scope as well as an excess
of alkoxides, undesirable solvents, etc. Thus, palladium-
catalyzed intra- and intermolecular cross-coupling reactions of
aryl halides with alcohols offer an interesting complementary
method for the synthesis of aryl ethers under comparably mild
conditions.5 It is important to note that, in contrast to well-
established palladium-catalyzed coupling reactions of tertiary
alcohols and phenols,6 only a few studies on the formation of
alkyl aryl ethers with primary and secondary alcohols have been
performed. On the other hand, aromatic ethers of aliphatic
primary alcohols represent a structural motif in many naturally
occurring and medicinal compounds (Scheme 1).
Traditionally, aryl ethers have been prepared by copper-
mediated Ullmann coupling reactions of aryl bromides/iodides
and phenols with the drawback of harsh reaction conditions and
the need of a stoichiometric amount of metal.3 Thus, the
development of improved procedures, which allowed for the
catalytic use of copper reagents and ligands initiated by
Buchwald and co-workers and followed by many other groups
The general problem in the formation of these aromatic ethers
is the competition of the desired reductive elimination to form
(4) For selected Cu-catalyzed C-O bond formations, see: (a) Marcoux,
J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539.
(b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937. (c) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A.
J. Am. Chem. Soc. 2000, 122, 5043. (d) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315. (e) Gujadhur, R. K.;
Venkataraman, D. Synth. Commun. 2001, 31, 2865. (f) Wolter, M.;
Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 973.
(g) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.;
Reider, P. J. Org. Lett. 2002, 4, 1623. (h) Kunz, K.; Scholz, U.; Ganzer,
D. Synlett 2003, 2428. (i) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
(j) Naidu, A. B.; Jaseer, E. A.; Sekar, G. J. Org. Chem. 2009, 74,
3675. (k) Cristau, H. J. A.; Pascal, P. C.; Hamada, S.; Francis, J. S.;
Taillefer, M. Org. Lett. 2004, 6, 913. (l) Hosseinzadeh, R.; Tajbakhsh,
M.; Mohadjerani, M.; Alikarami, M. Synlett 2005, 1101. (m) Frlan,
R.; Kikelj, D. Synthesis 2006, 2271. (n) Chen, Y. J.; Chen, H. H.
Org. Lett. 2006, 8, 5609. (o) Zhang, H.; Ma, D.; Cao, W. Synlett 2007,
243. (p) Zhao, Y.; Wang, Y.; Sun, H.; Li, L.; Zhang, H. Chem.
Commun. 2007, 3186. (q) Miao, T.; Wang, L. Tetrahedron Lett. 2007,
48, 95. (r) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863. (s) Niu, J.;
Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73, 7814. (t)
Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L.
J. Org. Chem. 2008, 73, 284. (u) Niu, J.; Guo, P.; Kang, J.; Li, Z.;
Xu, J.; Hu, S. J. Org. Chem. 2009, 74, 5075. (v) Jammi, S.; Sakthivel,
S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, P.;
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(1) For selected reviews see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-
F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (b) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046. (c) Yang, B. H.; Buchwald,
S. L. J. Organomet. Chem. 1999, 576, 125. (d) Prim, D.; Campagne,
J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041. (e)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 2337.
(f) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. ReV.
2004, 2283. (g) Muci, A. R.; Buchwald, S. L. Practical Palladium
Catalysts for C-N and C-O Bond Formation. In Topics in Current
Chemistry; Miyaura, N., Ed.; Springer-Verlag: Berlin, Germany, 2001;
Vol. 219, p 131. (h) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience:
New York, 2002; p 1051.
(2) (a) Buckingham, J. Dictionary of Natural Products; University Press:
Cambridge, MA, 1994. (b) Czarnik, A. W. Acc. Chem. Res. 1996, 29,
112. (c) Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345. (d) Sawyer,
J. S. Tetrahedron 2000, 56, 5045. (e) Thomas, A. W.; Ley, S. V.
Angew. Chem., Int. Ed. 2003, 42, 5400. (f) Cristau, P.; Vors, J.-P.;
Zhu, J. Tetrahedron 2003, 59, 7859. (g) Muci, A. R.; Buchwald, S. L.
Top. Curr. Chem. 2002, 219, 131.
(3) (a) Ullmann, F. Chem. Ber. 1904, 37, 853. (b) Lindley, J. Tetrahedron
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9
11592 J. AM. CHEM. SOC. 2010, 132, 11592–11598
10.1021/ja103248d  2010 American Chemical Society

Pd-Catalyzed C-O Coupling Aryl Halides with Alcohols
A R T I C L E S
Scheme 1. Selected Examples of Biologically Important Aromatic Ethers of Primary Alcohols
Scheme 2. Coupling Reaction of Primary Alcohols and Aryl
Buchwald and co-workers reported in 2001 for realization of
the first example of Pd-catalyzed coupling of primary alcohols
with aryl bromides and chlorides in the presence of bulky (2-
(N,N-dimethylamino)-2′-di-tert-butylphosphinobinaphthyl.9 Ex-
cellent results were obtained with aryl halides with electron-
poor and one or two ortho-substituents, which facilitate the rate
of reductive elimination. However, other aryl halides gave only
poor to moderate yields. Later on in 2005, the Buchwald group
introduced an improved, more tunable ligand system based on
alkylated biaryls, which allowed for the coupling of primary
and secondary, including allylic alcohols.10 Here, the successful
coupling was based on the ability to match the size of the ligand
to that of the combination of substrates. However, elaborate
synthesis of arylnaphthyl ligands, necessity to use a specific
ligand for each group of aryl halides and alcohols, and the use
of tri-n-butylamine as a solvent for arylation of secondary
alcohols limit the general application of this methodology.
Surprisingly, apart from Buchwald’s biaryl phosphines, to date
no other ligands have been successfully developed for pal-
ladium-catalyzed intermolecular coupling reactions of aliphatic
alcohols.
Halides: Product Formation and Side Reactions
the product and unwanted ꢀ-hydride elimination of the inter-
mediate Ar-Pd-OCH2R complex I (Scheme 2).
The chemoselectivity of the overall process depends strongly
on relative rates of C-O bond-forming reductive elimination
and ꢀ-hydride elimination. With most palladium alkoxy com-
plexes ꢀ-hydride elimination proceeds faster compared to
reductive elimination. Hence, alkoxides are known to be efficient
hydride donors for reduction of aryl halides.7 It is well-known
that bulky nucleophilic phosphine ligands facilitate Pd-catalyzed
reductive elimination at the expense of ꢀ-hydride elimination.8
In this regard, this observation was successfully used by
In this paper we describe the application of air-stable easy-
to-prepare bipyrazole phosphine ligand L6 for general alkoxy-
lation of aryl and heteroaryl bromides with primary and
secondary alcohols.
Results and Discussion
(5) For selected Pd-catalyzed C-O bond formation, see: (a) Palucki, M.;
Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333.
(b) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109. (c)
Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 3395. (d) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron
Lett. 1999, 40, 8837. (e) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig,
J. F. J. Am. Chem. Soc. 2000, 122, 10718. (f) Torraca, K. E.; Kuwabe,
S.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907. (g) Parrish,
C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498. (h) Kataoka,
N.; Shelby, Q.; Stambuli, J.; Hartwig, J. F. J. Org. Chem. 2002, 67,
5553. (i) Mucci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
133. (j) Schlummer, B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 1599.
(k) Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.; Jackstell, R.;
Rataboul, F.; Riermeier, T.; Monsees, A.; Beller, M. Tetrahedron Lett.
2005, 46, 3237. (l) Burgos, C. H.; Barder, T. E.; Haung, X.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2006, 45, 4321.
For some years we have been interested in the development
of palladium catalysts, which should be applicable for coupling
reactions on both laboratory and industrial scale. In this respect,
we have introduced in the past decade novel types of ligands
such as di-1-adamantylalkylphosphines,11 and especially 2-di-
alkylphosphino-N-arylindoles, pyrroles, and 2-dialkylphosphino-
N-arylimidazoles.12 Some of these ligands have been scaled up
to kg-scale and commercialized.13 Inspired by our recent work
(8) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 3224.
(9) (a) Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 10770. (b) Kuwabe, S.; Torraca, K. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202.
(6) (a) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 10694. (b) Hartwig, J. F. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., de
Meijere, A., Eds.; Wiley: New York, 2002; Vol. 1, p 1097. (c) Zapf,
A.; Beller, M.; Riermeier, T. In Transition Metals for Organic
Synthesis. Building Blocks and Fine Chemicals; Beller, M., Bolm, C.,
Eds.; Wiley: Weinheim, 2004; Vol. 1, p 231.
(7) (a) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. J. Org. Chem.
2004, 69, 3173. (b) Navarro, O.; Marion, N.; Oonishi, Y.; Kelly, R. A.,
III; Nolan, S. P. J. Org. Chem. 2006, 71, 685. (c) Chen, J.; Zhang,
Y.; Yang, Z.; Liu, J.; Li, L.; Zhang, H. Tetrahedron 2007, 63, 4266.
(10) Vorogushin, A. V.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 8146.
(11) (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
39, 4153. (b) Ehrentraut, A.; Zapf, A.; Beller, M. J. Mol. Catal. 2002,
182-183, 515. (c) Ehrentraut, A.; Zapf, A.; Beller, M. AdV. Synth.
Catal. 2002, 344, 209. (d) Neumann, H.; Brennfu¨hrer, A.; Gross, P.;
Riermeier, T.; Almena, J.; Beller, M. AdV. Synth. Catal. 2006, 348,
1255. (e) Klaus, S.; Neumann, H.; Zapf, A.; Stru¨bing, D.; Hu¨bner, S.;
Almena, J.; Riermeier, T.; Gross, P.; Sarich, M.; Krahnert, W.-R.;
Rossen, K.; Beller, M. Angew. Chem., Int. Ed. 2006, 45, 154.
9
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Table 1. Ligands Tested in the Pd-Catalyzed C-O Coupling of
o-Bromotoluene with nBuOHa
dehalogenation and only low yields of the desired product (37
and 23%, respectively). Also little difference was observed on
changing Pd(OAc)2 to Pd(dba)2. The results were even more
disappointing with imidazolylphosphines L3 and L4 as well as
with ligands L7-L14.
However, experiments performed in the presence of Singer’s
di-tert-butyl-substituted Bippyphos ligand L516 provided the best
yield (57%) of the corresponding n-butyl aryl ether. Based on
this promising result, we prepared the more bulky adamantyl-
substituted analogue of L5. The straightforward synthesis of
the new ligand L6 is shown in Scheme 3. One-pot bromination
of dibenzoyl methane with NBS followed by alkylation with
pyrazole and condensation with phenylhydrazine resulted in the
corresponding bipyrazolyl derivative in good yield. Subsequent
lithiation and trapping of the intermediate with di-1-adaman-
tylchlorophosphine afforded L6 in excellent yield (86%). The
1
structure of ligand L6 is confirmed by H, 13C, 31P NMR and
mass spectra, and eventually by X-ray analysis (Scheme 3,
ORTEP drawing of L6). Notably, L6 is relatively air-stable and
can be conveniently handled in air.
To our delight, the use of L6 in the benchmark reaction
resulted in the desired coupling product in 86% yield! Next,
we investigated the influence of critical reaction parameters
(palladium source, solvent system, base, and temperature) on
the palladium-catalyzed coupling of o-bromotoluene with n-
BuOH in the presence of L6. The source of palladium has no
impact on the performance of the model reaction as Pd(dba)2,
Pd2(dba)3, Pd(COD)(CH2TMS)2, and Pd(OAc)2 can be used
interchangeably. Variation of the solvent (aromatics, amines,
neat alcohol) confirmed that toluene was optimal for this
reaction. Compared to K2CO3 and KOH, Cs2CO3 worked best
for these reactions. While the reaction proceeded sluggishly at
65 °C, it is completed within 3 h at 80 °C in toluene.
a Reaction conditions: Pd(OAc)2 (1 mol %), 2-bromotoluene (1.0
mmol), nBuOH (3.0 equiv), Cs2CO3 (1.5 equiv), toluene, 80 °C, 3-24
h, GC yield. b Pd(dba)2.
on the reaction of aryl halides with hydroxide in the presence
of sterically hindered 2-phosphino-N-arylimidazoles,14 we de-
cided to investigate these catalysts in coupling processes with
aliphatic alcohols.
With the optimized conditions in hand, we examined the
reaction of several nonactivated aryl bromides and two aryl
chlorides with nBuOH. As shown in Table 2, a series of alcohols
such as 1-butanol, 1-hexanol, 1-octanol, 1-hexadecanol, and
benzyl alcohol was reacted with o-bromotoluene. The corre-
sponding tolyl alkyl ethers are obtained in 56-85% yield (Table
2, entries 1-5). Similarly, o-chlorotoluene yielded the desired
product in 70% yield (Table 2, entry 6). Next, we examined
the coupling of m- and p-bromotoluene whose reactions are not
facilitated by the increased rate of reductive elimination from I
due to ortho-substitution. However, both substrates are converted
smoothly to the corresponding ethers in good yield (75 and 80%
At the start of our work the reaction of o-bromotoluene with
nBuOH was investigated as a model system in the presence of
1 mol % Pd(OAc)2 and ligands L1-L14 (Table 1). Unfortu-
nately, in most cases dehalogenated toluene III and n-butyl
butanoate IV were observed as main or side products. The
formation of the latter ester is somewhat surprising but can be
explained by dehydrogenation of the intermediate 1-butoxy-
butan-1-ol (Scheme 2). In this case the aryl halide acts as a
stoichiometric oxidant. While such Pd-catalyzed reactions are
rare, similar ruthenium-catalyzed processes are known.15
Both the commercially available Buchwald ligand L1 and
our imidazolylphosphine ligand L2 gave mainly reductive
Scheme 3. Synthesis of the New Biheteroaryl Ligand L6
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A R T I C L E S
Table 2. Pd-Catalyzed Coupling Reactions of Aryl Halides with Primary Alcoholsa
a Reaction conditions: Pd(OAc)2 (1 mol %), L6 (2 mol %), aryl halide (1.0 equiv), nBuOH (3.0 equiv), Cs2CO3 (1.5 equiv), toluene, 80 °C, 3-6 h.
b Isolated yield. c 65 °C, 10 h. d 10% of the starting material was recovered, 12 h. e 10% of the starting material was recovered, 9 h.
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A R T I C L E S
Gowrisankar et al.
Table 3. Comparison of Ligands L6 and L5a
and 4-bromo-3-methylanisole are achieved in 76 and 62% yield,
respectively (Table 2, entries 11 and 14). On the other hand
substrates with electron-withdrawing substituents, e.g. CN,
COMe, CO2nBu, and CHO, are also coupled successfully in
moderate to excellent yields (Table 2, entry 15-20).
Then, we compared the performance of ligand L6 and the
commercially available ligand L5 in the coupling of various
aryl bromides with n-butanol (Table 3). In all cases the novel
ligand L6 gave considerably higher yields of coupling products
(Table 3, entry 1-5).
To the best of our knowledge, only one example of the
coupling of (hetero)aryl halides with primary alcohols has been
reported.8a Hence, we were interested in the performance of our
catalytic system with (hetero)aryl halides. Notably, aliphatic
ethers of pyridine and quinoline are a common scaffold found
in current drugs.17 Thus, we were pleased to find that 2- and
3-bromopyridine, 2-chloropyridine, 2- and 3-bromoquinoline,
and 4-bromoisoquinoline are readily transformed with n-butanol
into the corresponding products (Table 4, entries 1-8). Apart
from 3-bromopyridine, 3-bromoquinoline, and 4-bromoiso-
quinoline, all substrates were converted to the n-butyl ethers in
excellent yield.
Next, we examined the selective functionalization of primary
aliphatic alcohols in the presence of secondary and tertiary
alcohols. For example, 1,3-butanediol has both a primary and
secondary hydroxyl group, which obviously competes for the
synthesis of the respective alkyl aryl ethers. To our delight
conversion of 1,3-butanediol proceeded with complete regiose-
lectivity (99%) for the primary alcohol to give the ether in 69%
yield (Table 5, entry 1). Similarly, 3-methylbutane-1,3-diol with
primary and tertiary hydroxyl groups gave the ether of the
primary alcohol in 71% yield with excellent selectivity (>99%).
The regioselectivity of these couplings are confirmed by GC-
a Reaction conditions: Pd(OAc)2 (1 mol %), L6 (2 mol %), aryl
halide (1.0 equiv), nBuOH (3.0 equiv), Cs2CO3 (1.5 equiv), toluene, 80
°C. b 5% of the starting material was recovered.
respectively, Table 2, entries 7 and 8). Likewise, 1-bromo- and
1-chloronaphthalene as well as 9-bromoanthracene gave the aryl
alkyl ethers in 74-87% yield (Table 2, entries 9, 10, and 12).
Reactions of methoxy-substituted 2-bromo-6-methoxynapthalene
Table 4. Palladium-Catalyzed Coupling Reactions of Heteroaryl Halides with Primary Alcoholsa
a Reaction conditions: Pd(OAc)2 (1 mol %), L6 (2 mol %), heteroaryl halide (1 mmol), Cs2CO3 (1.5 equiv), nBuOH (3.0 equiv), toluene, 80 °C, 3-6
h. b Isolated yield. c 5-10% of the straring material was recovered, 7 h.
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A R T I C L E S
Table 5. Selective Pd-Catalyzed Arylation of Functionalized Alcoholsa
a Reaction conditions: Pd(OAc)2 (1 mol %), L6 (2 mol %), 2-bromotoluene (1 mmol), Cs2CO3 (1.5 equiv), alcohol (3.0 equiv), toluene, 80 °C, 3 h.
b Isolated yield. c 18 h.
Scheme 4. Synthesis of Butoxycaine 4
MS studies of the reaction mixture. Product characterization is
confirmed by 2D NMR correlation techniques. In addition, other
functionalized alcohols such as 4,4,4-trifluoro-1-butanol and
N,N-dimethylbutanol afforded the coupling products under
standard conditions in good yields (74-93%).
Finally, we envisioned a short application of our methodology
for the synthesis of butoxycaine 4, which represents a local
anesthetic drug.18 Straightforward palladium-catalyzed C-O
bond formation of methyl 4-bromobenzoate 1 proceeded in the
presence of Pd(OAc)2 (1 mol %), L6 (2 mol %), and Cs2CO3
(1.5 equiv) with nBuOH (3.0 equiv) at 80 °C in 3 h to produce
2 with a trace amount of the trans-esterified butyl ester (20:1
ratio, based on GC). Without purification 2 was subjected to
alkaline hydrolysis (LiOH) to give 3 in 74% yield over two steps.
Subsequent DCC coupling with 2-(diethylamino)ethanol provided
the current drug butoxycaine 4 in 72% yield (Scheme 4).
In conclusion, we describe the synthesis of the novel sterically
hindered, air-stable bispyrazolylphosphine ligand L6 and its
application in the palladium-catalyzed synthesis of alkyl aryl ethers.
(Hetero)aryl alkyl ethers are obtained in moderate to excellent yields
from activated, nonactivated, and (hetero)aryl substrates with
primary alcohols. Furthermore, we have demonstrated for the first
time the regioselective C-O bond-forming arylation of primary
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A R T I C L E S
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Acknowledgment. This work has been funded by the State of
Mecklenburg-Western Pomerania, the BMBF, and the DFG (Leib-
niz Prize). We thank Ms. Sandra Leiminger for excellent technical
assistance and Drs. W. Baumann, C. Fisher, and Mrs. S. Buchholz
(all LIKAT) for their analytical support.
alcohols in the presence of secondary and tertiary alcohols. Our
catalyst system tolerates a variety of functional groups including
amines. The presented protocol is complementary to the two known
catalyst systems of Buchwald and co-workers and allows for
interesting applications in organic synthesis.
Supporting Information Available: Detailed experimental
procedures and characterization of products. The material is
available free of charge via the Internet at http://pubs.acs.
org.
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Synthesis 2003, 1727. (b) Withbroe, G. J.; Singer, R. A.; Sieser, J. E.
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(18) The Merck index: An encyclopedia of chemicals, drugs, and biologicals
(12th edition), p 254, compound 1566.
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