the aromatic moiety. Although the conversion of substrates
with free -NH2 groups in para- and ortho-position is
complete after ∼24 h, the desired products were isolated in
moderate yield as a result of decomposition of the starting
materials. Notably, these results are superior to those
observed in analogous Pd-catalyzed transformations where
free anilines on the aryl halide moiety are detrimental.16 For
free benzylic -OH groups (entry 13) the yield could be
significantly improved by switching to a lower reaction
temperature of 80 °C. The electron-withdrawing substituent
CN seemed to be more sensitive under the coupling condi-
tions, likely because the nitriles are good ligands for copper.
In neat alcohol, mixtures of the corresponding amide and
ester as well as other decomposition products were observed
even at lower temperatures and shorter reaction times. Thus,
this reaction was performed with only 4 equiv of alcohol in
toluene as a solvent to give the desired products in high yields
(entries 6 and 7). A heterocyclic substrate such as 3-iodopy-
ridine (entry 15) can also be successfully coupled.
Table 3. Copper-Catalyzed Coupling of Aryl Iodides with
Aliphatic Alcohols Using Toluene as Solventa
The generation of alkyl aryl ethers from secondary alcohols
represents a more challenging synthetic problem7b,17 that thus
far cannot be generally solved using palladium catalysts,
where â-hydride elimination often imposes serious restric-
tions. Thus, we examined the possibility of coupling common
secondary alcohols that could also serve as solvents. The
results of this study, summarized in Table 2, indicate that
secondary aryl alkyl ethers can be obtained by this method,
albeit sometimes in lower yields than their primary coun-
terparts (see Table 1). This is in part due to incomplete
conversion under the reaction conditions after 24 h. In the
case of cyclopentanol (Table 2; entry 4), the reaction
temperature had to be elevated to 120 °C in order to achieve
complete conversion to provide the coupling product in good
yield.
a Reaction conditions: 1 mmol of aryl iodide, 2 equiv of R2OH, 1.4 or
2 equiv of Cs2CO3, 0.5 mL of toluene, under air in a sealed test tube.
Reaction time not optimized for each substrate. b See Table 1.
coupling components. Table 3 displays some of our results.
It should be mentioned that the reactions have to be carried
out at high concentrations (usually 0.5 mL toluene/1 mmol
substrate) in order to maintain a highly active catalytic
system.
During our preliminary studies, we found that the method
can be successfully applied when toluene is used as solvent.
For more precious alcohols, it is desirable to run the reaction
in a solvent using only a moderate excess of one of the
To demonstrate the scope of the method, several allylic
alcohols (entries 1-3), pyridine-2-methanol (entry 4), and
2-iodo-bromobenzene (entry 5) were used as substrates. Since
para-substituted electron-rich aryl halides are difficult sub-
strates for the corresponding palladium-catalyzed transforma-
tions, we chose 4-iodoanisole as the aromatic coupling
component for the allylic alcohols. The primary allylic
alcohols afforded the corresponding ethers in good yield
(entries 1 and 2).18 For a secondary allylic alcohol (entry 3)
the moderate yield can be ascribed to enhanced steric
hindrance at the reaction center. Similar to our observations
in Cu-catalyzed C-N bond formations,8-12 this system is
relatively insensitive to electronic effects.
(9) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657.
(10) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727-7729.
(11) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(12) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581.
(13) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(14) Recently, Venkataraman showed that similar reaction conditions can
be utilized, employing an isolated, air stable, triphenyl phosphine complex
of (1,10-phenanthroline)CuI for the preparation of triarylamines and diaryl
ethers and for the Sonogashira-type arylation of terminal alkynes. Gujadhur,
R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315.
(15) Typical Experimental Procedure. A test tube was charged with
CuI (10 mol %), 1,10-phenanthroline (20% mol), Cs2CO3 (1.4-2.0 mmol),
aryl iodide (1.0 mmol), and either (a) the alcohol (1 mL) or (b) the alcohol
(2 mmol) and toluene (0.5 mL). The test tube was sealed, and the reaction
mixture was stirred at 110 °C for ∼24 h. The resulting suspension was
cooled to room temperature and filtered through a 0.5 × 1 cm pad of silica
gel, eluting with diethyl ether. The filtrate was concentrated. Purification
of the residue by flash chromatography on silica gel gave the desired product
(see Supporting Information).
Notably, the cross-coupling of an unactivated aryl halide
(e.g., 3-iodoanisole) and an enantiomeric pure benzylic
alcohol proceeded with complete retention of configuration
(Scheme 1). This mild and efficient route to enantiopure
benzylic aryl alkyl ethers19,20 is particularly important because
(16) Harris, M. C.; Buchwald, S. L. Unpublished results.
(17) For some recent Ullmann-type reactions with secondary alcohols,
see for example: (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.;
Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020. (b) Morishima, Y.; Fujita,
J.; Ikeda, T.; Kamachi, M. Chem. Lett. 1994, 557.
(18) To date, allylic alcohols are poor substrates in the analogous Pd-
catalyzed couplings. Torraca, K. E.; Huang, X.; Buchwald, S. L. Unpub-
lished results.
Org. Lett., Vol. 4, No. 6, 2002
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