A R T I C L E S
Vorogushin et al.
Table 3. Coupling of Aryl Bromides with Primary Alcoholsa
Scheme 2. Cu- and Pd-Catalyzed Sequential C-O Couplinga
a Conditions: (a) 10 mol % of CuI, 20 mol % of 1,10-phenanthroline, 2
equiv of Cs2CO3, iPrOH neat, 110 °C, 24 h, 81%; (b) 3 mol % of Pd (OAc)2,
3.6 mol % of L10, 1.5 equiv of Cs2CO3, Bu3N, 50 °C, 18 h, 84%.
than seen with saturated alcohols. This method avoids the
regiochemical issues that arise in Pd-10 and Rh-catalyzed11 allylic
alkylation reactions of phenols. Yields were lower for the
coupling of a monosubstituted allylic alcohol than for a
trisubstituted one (compare 2n and 2o). Functional group
tolerance for substituents on the aryl bromides was moderate
and allowed for the formation of ester- and heterocycle-
containing products 2s-v. Although the reactions of most meta-
and para-substituted aryl halides that we examined were well-
behaved, little progress was realized with more electron-rich
o- and p-bromoanisoles due to the extensive formation of arene
and diaryl ether side products. Success with ortho-substituted
aryl halides required the use of ligand L11, which is a less
hindered analogue of L10. But even then the yields of 2p and
2q were only moderate, with the rest of the mass balance being
3 and 4. Coupling of (R)-1-phenylethanol (98% ee) gave the
product (R)-2f (98% ee) without racemization.
a Isolated yields. b In Bu3N. c With L5. d With L4. e Pd2(dba)3 (1%) was
used. f Slow addition of the alcohol. g 50 °C. h 24 h. i 5% Pd, 6% L4.
In summary, we have developed a tunable ligand system for
the coupling of primary and secondary alcohols with aryl
halides. These ligands, in combination with Bu3N as a solvent,
suppress the â-H elimination pathway, allowing for the first
time for the efficient coupling of secondary, including allylic,
alcohols. All of these ligands are accessible by variations of
our benzyne route.13 The most general ligands L6 and L10 have
been prepared on >10 g scale without the need for chromato-
graphic purification. We hope to have these as well as L4 and
L5 commercially available soon.
As was the case with C-N bond formation,12 Pd- and Cu-
catalyzed reactions can be used to advantage when performed
in a tandem manner. Thus, the latter methodology allows for
i
the selective coupling of bromoiodide 6 with PrOH. The
resulting bromide 7 can then be further transformed by treatment
with secondary alcohol as shown (Scheme 2).
Major improvements in the coupling reaction of primary
alcohols were achieved when the bulkier ligand, L6, was used
in place of L2, which was previously the best ligand3 (Table
3). Reduction was suppressed, where necessary, by running the
reactions in Bu3N. For ortho-substituted aryl bromides, L5 must
be utilized (12c). The most challenging substrates, electron-
rich p- and o-bromoanisole, gave good yields of the coupling
products 12d and 12e using exceptionally hindered L4; poor
yields had previously been seen3 with L2. With L4, the selective
arylation of the primary hydroxyl of 1,3-dihydroxybutane was
also possible (12k), without detectable coupling of the secondary
hydroxyl.
The choice of ligand for Pd-catalyzed C-O bond formation
is based on the nature of substrate combination being coupled
(Table 4). Thus, as previously described,3 ortho,ortho′-disub-
stituted aryl halides can be easily coupled using L1 as a
supporting ligand (entry 1). Less hindered ortho-substituted aryl
halides (except for R ) EDG) require the bulkier ligands L2
or L5 for the successful reaction with primary alcohols and L11
with secondary alcohols (entry 2). Electron-rich aryl halides are
the most challenging substrates. Their coupling with primary
alcohols works moderately well using L4. The analogous
reaction, however, with secondary alcohols could not be
achieved (entries 3, 4). For all other meta- and para-substituted
aryl halides, the use of L6 and L10 is recommended, with
primary and secondary alcohols, respectively (entry 5).
Experimental Section
General Procedure for the Intermolecular Coupling of Alcohols
with Aryl Halides. An oven-dried Schlenk tube was cooled in vacuo,
back-filled with argon, and charged with Pd(OAc)2, ligand, and
Cs2CO3. The Schlenk tube was fitted with rubber septum, evacuated,
and back-filled with argon. The aryl halide and alcohol were added
through the septum via syringe, followed by the solvent. The septum
was replaced with a Teflon screw cap under a counterflow of argon,
and the tube was sealed and placed in an oil bath. The reaction was
conducted under the conditions indicated in Tables 2 and 3. After the
reaction mixture was allowed to cool to room temperature, it was filtered
through a layer of Celite with the aid of ethyl acetate. In the cases
where toluene was used as the solvent, the filtrate was concentrated in
vacuo and the crude product was purified chromatographically (silica
gel). In the cases where Bu3N was used as the solvent, the filtrate was
extracted with 10% HCl. The organic layer was isolated and the aqueous
layer was back-extracted with diethyl ether. The combined organic
extracts were dried over MgSO4, and the crude product was purified
chromatographically (silica gel). The yields of the coupling products
are indicated in Tables 2 and 3. Three representative examples are
shown below.
1-(1,3-Dimethylbut-2-enyloxy)-3,5-dimethylbenzene (2e). The gen-
eral procedure was followed using Pd(OAc)2 (4.5 mg, 0.02 mmol), L10
(11.4 mg, 0.024 mmol), Cs2CO3 (489 mg, 1.5 mmol), 5-bromo-m-xylene
(10) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(11) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012.
(12) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(13) Kaye, S.; Fox, J. M.; Hicks, F. A.; Buchwald, S. L. AdV. Synth. Catal.
2001, 343, 789.
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8148 J. AM. CHEM. SOC. VOL. 127, NO. 22, 2005