Copper(II)-catalyzed ether synthesis from aliphatic alcohols and potassium organotrifluoroborate salts

Article abstract of DOI:10.1021/ol034454n

(Matrix presented) A protocol for the copper(II)-catalyzed etherification of aliphatic alcohols under mild and essentially neutral conditions is described. Air- and moisture-stable potassium alkenyl- and aryltrifluoroborate salts undergo cross-coupling with a variety of aliphatic primary and secondary alcohols and phenols, and are tolerant of a range of functional groups. The optimized conditions utilize catalytic copper(II) acetate with 4-(dimethylamino)pyridine as ligand in the presence of 4 A molecular sieves under an atmosphere of oxygen.

Full text of DOI:10.1021/ol034454n

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1381-1384
Copper(II)-Catalyzed Ether Synthesis
from Aliphatic Alcohols and Potassium
Organotrifluoroborate Salts
Tan D. Quach and Robert A. Batey*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received March 14, 2003
ABSTRACT
A protocol for the copper(II)-catalyzed etherification of aliphatic alcohols under mild and essentially neutral conditions is described. Air- and
moisture-stable potassium alkenyl- and aryltrifluoroborate salts undergo cross-coupling with a variety of aliphatic primary and secondary
alcohols and phenols, and are tolerant of a range of functional groups. The optimized conditions utilize catalytic copper(II) acetate with
4-(dimethylamino)pyridine as ligand in the presence of 4 Å molecular sieves under an atmosphere of oxygen.
The formation of carbon-heteroatom bonds using metal
catalysis is emerging as one of the most significant classes
of cross-coupling reactions. In the area of C-O ether bond
formation, there has been a resurgence of interest in Cu-
mediated reactions beyond that of the classical Ullmann ether
synthesis.1 Buchwald and others have demonstrated that Cu(I)
salts effectively promote the cross-coupling of aryl halides
with phenoxides, phenols, and aliphatic alcohols.2 This is
an alternative to the analogous Pd-catalyzed reactions
developed by Buchwald and Hartwig.3 Although these Pd-
and Cu-catalyzed etherifications occur under milder condi-
tions than the classical protocols, the reactions are still
performed under refluxing conditions in the presence of
strongly basic alkoxides, and in the case of the Pd-based
methods, require expensive catalyst/ligand systems. An
alternative approach to ether synthesis is the cross-coupling
of alcohols or phenols with organometalloid reagents such
as organo-Bi,4 -Sn,5 and -B6-8 compounds. Chan and Evans
simultaneously reported the Cu-mediated cross-coupling of
arylboronic acids with phenols at room temperature to
produce diaryl ethers.6 An obvious limitation of this reaction
is that stoichiometric amounts of Cu(OAc)2 and base are
required,7 with substoichiometric quantities of catalyst result-
ing in poor yields of diaryl ethers.6b Moreover, aliphatic
alcohols do not participate in cross-coupling even under
(1) (a) Lindley, J. Tetrahedron 1984, 40, 1433-1456. (b) Theil, F.
Angew. Chem., Int. Ed. 1999, 38, 2345-2347. (c) Finet, J. P.; Fedorov, A.
Y.; Combes, S.; Boyer, G. Curr. Org. Chem. 2002, 6, 597-626. (d) Hassan,
J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359-1469.
(2) (a) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 10539-10540. (b) Zhu, J.; Price, B. A.; Zhao, S. X.; Skonezny,
P. M. Tetrahedron Lett. 2000, 41, 4011-4014. (c) Wolter, M.; Nordmann,
G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 973-976.
(3) (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109-
13110. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 3395-3396. (c) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J.
F. J. Am. Chem. Soc. 2000, 122, 10718-10719. (d) Torraca, K. E.; Huang,
X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 10770-
10771. (e) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202-12206. (f) Parrish, C. A.; Buchwald, S. L. J. Org. Chem.
2001, 66, 2498-2500.
(4) Finet, J. P. Chem. ReV. 1989, 89, 1487-1501 and references therein.
(5) Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66, 9043-9045.
(6) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P. Tetrahedron Lett.
1998, 39, 2933-2936. (b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron
Lett. 1998, 39, 2937-2940.
(7) A catalytic variant of the protocol utilizing a stoichiometric chemical
oxidant to regenerate the Cu catalyst has been reported, but, the optimal
oxidant used in the reaction varied as the nucleophilic component was
changed; furthermore, competitive oxidation of the boronic acids was
problematic. See: Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415-3418.
(8) (a) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976-
2977. (b) Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3,
139-142. (c) Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3,
1029-1032.
10.1021/ol034454n CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003

Table 1. Copper(II)-Catalyzed O-Phenylation of Alcoholsa
a Reaction times are not optimized for individual substrates. b Isolated yields. c Yields in parentheses are obtained using PhB(OH)2 under the same conditions.
d Yield of the homocoupled diaryldiyne product. e Yield of the diphenylated product. f Unreacted starting material was isolated.
stoichiometric conditions,6a and the process has thus far been
limited to the coupling of phenol derivatives6-8a,c and
N-hydroxyphthalimides.8b These problems have clearly lim-
ited the scope of the reaction. As part of our interest in the
chemistry of organoboron compounds,9 we now report the
first catalytic coupling of organoboron compounds with
primary and secondary aliphatic alcohols under essentially
neutral conditions at room temperature.
Suzuki-Miyaura cross-couplings9,10 and Rh(I)-catalyzed
additions to aldehydes11a and enones.11 These salts offer an
air- and moisture-stable alternative to other organoboron
compounds. They can be stored under normal atmospheric
(10) (a) Darses, S.; Michaud, G.; Geneˆt, J. P. Eur. J. Org. Chem. 1999,
1875, 5-1883. (b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020-4028. (c) Batey, R. A.; Quach, T. D. Tetrahedron Lett.
2001, 42, 9099-9103. (d) Molander, G. A.; Katona, B. W.; Machrouhi, F.
J. Org. Chem. 2002, 67, 8416-8423. (e) Molander, G. A.; Bernardi, C. R.
J. Org. Chem. 2002, 67, 8424-8429. (f) Frohn, H. J.; Adonin, N. Y.; Bardin,
V. V.; Starichenko, V. F. Tetrahedron Lett. 2002, 43, 8111-8114.
(11) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1,
1683-1686. (b) Pucheault, M.; Darses, S.; Geneˆt, J. P. Eur. J. Org. Chem.
2002, 21, 3552-3557.
Organotrifluoroborate salts have recently been utilized in
various metal-catalyzed reactions, including Pd-catalyzed
(9) Batey, R. A.; Quach, T. D.; Shen, M.; Thadani, A. N.; Smil, D. V.;
Li, S. W.; MacKay, D. B. Pure Appl. Chem. 2002, 74, 43-55.
1382
Org. Lett., Vol. 5, No. 8, 2003

conditions for extended periods; are readily synthesized from
the corresponding boronic acids by treatment with KHF2,12
and several are now commercially available. The initial goal
of our study was the development of conditions suitable for
the formation of aryl alkyl ethers, since these products were
reported to be inaccessible using the original Chan and Evans
at reaction with tertiary alcohols also did not furnish cross-
coupled ethers.
Boronic acids also undergo cross-coupling under the
optimized conditions, although yields are appreciably lower.
For example, cross-coupling of cinnamyl alcohol with
-
PhBF3 K+ and PhB(OH)2 occurred in 89% and 65% yields,
-
protocol. PhBF3 K+ and cinnamyl alcohol were chosen as
respectively. Similarly, furfuryl alcohol underwent coupling
in 90% and 60% yields, respectively. The poorer reactivity
profile exhibited by boronic acids appears to be linked to
their greater propensity toward Cu promoted oxidation.6b GC
analysis revealed a greater rate of biaryl ether formation using
boronic acids rather than trifluoroborate salts, resulting in
greater isolated yields of the undesired phenol and homo-
coupled biphenyl ether byproducts. From an experimental
standpoint it should be noted that these oxidation side
products are not only produced with trifluoroborates, but also
occur under Evans’ conditions for diaryl ether formation.
Lowering the amount of organoboron reagent, below 2 equiv,
results in a steady decrease in the yield of both product and
side products.
model coupling partners. Optimization experiments for the
formation of cinnamyl phenyl ether included the effect of
the copper catalyst, ligand, solvent, atmosphere, and the
presence of molecular sieves. The optimal copper source is
Cu(OAc)2‚H2O, based on reaction yield, cost, and ease of
handling. Of the nitrogen-based ligands examined, the sec-
ondary diamine, DMEDA, gave none of the desired product,
while the tertiary aliphatic amines (DIPEA, TMEDA, Et3N)
and 1,10-phenanthroline afforded only moderate yields. The
N-heterocyclic ligands (pyridine, imidazole, DMAP) gave
the highest yields under an atmosphere of air. Under an inert
atmosphere (N2) the reaction yields were significantly
lowered, often resulting in only one turnover of catalyst.
Performing the reaction under an atmosphere of O2 generally
increased the yields by ∼10% over those obtained in air.
These observations are consistent with those made by
Evans.6b Finally, the presence of 4 Å MS was required, as
reaction in their absence gave only trace amounts of the
cross-coupled ether.
Finally, the nature of the organotrifluoroborate was
examined, using 2-furfuryl alcohol as a model primary
alcohol cross-coupling partner (Table 2). Electron-rich aryl
Table 2. Copper(II)-Catalyzed O-Arylation/Alkenylation of
2-Furfuryl Alcohol with Various RBF3-K+ Salts
Optimized conditions employed reaction of 2 equivalents
of potassium organotrifluoroborate salt 1 with 1 equivalent
of an unactivated aliphatic alcohol in the presence of 10 mol
% Cu(OAc)2‚H2O, 20 mol % DMAP, and 4 Å MS in CH2Cl2
at room temperature under an atmosphere of O2 for 24 h.
The scope and limitations of this protocol were explored
-
using a series of alcohols with PhBF3 K+ (Table 1). Phenols,
aliphatic, allylic, internal propargylic alcohols undergo cross-
coupling without complication. A variety of functionalities
are tolerated including arylhalides which do not participate
in cross-coupling (Table 1, entry 5), and alkylhalides which
do not undergo nucleophilic displacement under these
reaction conditions (Table 1, entries 11-13). Alkene isomer-
ization did not occur under these conditions (Table 1, entries
1, 17-19, 28), nor did epimerization of an R-stereocenter
in an enantiomerically pure ester (Table 1, entry 20).
Terminal alkyne and N-H amine functionality are not
compatible with the reaction as catalytic, oxidative homo-
coupling (Eglinton reaction)13 and competitive N-arylation
occurs respectively (Table 1, entries 10 and 23). Secondary
aliphatic alcohols also undergo cross-coupling, although in
lower yields than primary alcohols (Table 1, entries 24-
29). The reaction appears to be quite sensitive to steric effects
around the hydroxyl group. Thus, arylation of cyclohexanol,
stigmasterol, and menthol occurred in 67%, 48% and 0%
yields (Table 1, entries 27-29). Unsurprisingly, all attempts
a Isolated yield. b 48 h reaction time.
(12) Vedejs, E.; Fields, S. C.; Schrimpf, M. R. J. Am. Chem. Soc. 1993,
115, 11612-11613.
(13) (a) Eglinton, G.; Galbraith, A. R. Chem. Ind. (London) 1956, 737-
738. (b) Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J.
Chem. Soc. 1960, 3614-3625. (c) Hay, A. S. J. Org. Chem. 1962, 27,
3320-3321.
trifluoroborates such as 4-methoxyphenyltrifluoroborate (Table
2, entry 1) give the best results, whereas electron-deficient
salts such as 4-acetylphenyltrifluoroborate did not couple
Org. Lett., Vol. 5, No. 8, 2003
1383

(Table 2, entry 3). Heterocyclic and alkenyl trifluoroborate
salts are effective partners in the reaction. However, alkyl-
trifluoroborate derivatives do not act as effective reagents
under these conditions, presumably because of their lower
reactivity toward transmetalation with Cu salts.
In conclusion, we have developed a mild and essentially
neutral protocol for the synthesis of alkyl-aryl and alkyl-
vinyl ethers via the Cu(II)-catalyzed cross-coupling of
potassium organotrifluoroborate salts with unactivated pri-
mary and secondary aliphatic alcohols. Arylboronic acids
also participate in the reaction, although product yields are
lower. This reaction further extends the scope of aryl and
alkenyl boron cross-coupling chemistry, and we anticipate
its use in both complex molecule synthesis and parallel
synthesis applications. Further investigations on this and
related chemistry is currently under way in our laboratory.
Acknowledgment. The Natural Science and Engineering
Research Council (NSERC) of Canada, the Ontario Research
and Development Challenge Fund (ORDCF), and Merck-
Frosst funded this work. T.D.Q. acknowledges the receipt
of an Ontario Graduate Scholarship in Science and Technol-
ogy and the Walter C. Sumner Foundation for funding.
R.A.B. gratefully acknowledges receipt of a Premier’s
Research Excellence Award. We thank Dr. A. B. Young for
mass spectroscopic analysis.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds isolated.
1H and 13C spectra of all novel compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL034454N
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Org. Lett., Vol. 5, No. 8, 2003