and 2.4 mol% L12, which was previously the most efficient
catalyst system reported for this transformation.[6b]
Furthermore, switching to toluene from Bu3N as solvent
did not affect the efficiency of the coupling with basic-
nitrogen-containing heteroaryl halides as substrates, thus
allowing simplified isolation of the products (2g, 2i–2m). 6-
Chloroquinoline, however, was found to be an exception to
this trend. In toluene the reaction of 6-chloroquinoline and
cyclopentanol resulted in the formation of a significant
amount of reduced arene by-product. In this case switching
to Et3N as the solvent reduced the amount of quinoline
formation and resulted in a 62% yield of the desired product
2h. For the coupling of halopyridines and halopyrimidines, we
found it was necessary to premix the [(allylPdCl)2], L4,
Cs2CO3, and 2-butanol in toluene at 908C for 3 minutes with
subsequent addition of the aryl halide (presumably because of
the competitive binding of the substrateꢀs nitrogen atom to
the Pd center). In this way, 3-chloropyridine and 5-bromo-
pyrimidine were coupled with 2-BuOH in 71% and 76%
yields, respectively. Moreover, 5-chlorobenzoisoxazole, and 5-
chlorobenzothiazole proved to be proficient substrates in
these reactions, thus giving the desired products (2m and 2l)
in 61% and 63%, respectively. Therefore, this suggests that
the N atom of the pyridine rings (and related substrates)
interferes with catalyst generation, more than with the
catalyst itself.
We next decided to explore the application of L4 for the
cross-coupling of primary alcohols (Scheme 3). Excellent
yields were obtained for the combination of primary alcohols
with electron-rich, electron-neutral, and electron-deficient
aryl halides using 0.5 mol% [(allylPdCl)2] and 1.5 mol% L4.
The high efficiency displayed with L4 as the supporting ligand
allowed the reactions to be carried out in toluene, rather than
in Bu3N as the solvent as in our previous method.[6b] For
unactivated substrates, the coupling of aryl chlorides with
primary alcohols was generally less efficient than that of aryl
bromides and resulted in incomplete conversion of the
starting material. For instance, the reaction of nBuOH with
4-bromoanisole proceeded within 21 hours (see 3a) when
using only 1 mol% of palladium. However, the analogous
reaction with 4-chloroanisole using 2 mol% of palladium
resulted in only approximately 85% conversion within the
same time. Interestingly, the less nucleophilic fluorinated
primary alcohol was a more efficient coupling partner than
nBuOH.[13] Thus, the reaction of trifluoroethanol with 4-
chlorodiphenyl ether afforded an 83% yield of the desired
product 3e.[14] Furthermore, the coupling of N-Boc-d-prolinol
gave the desired product 3g with no erosion of enantiopurity
(86% yield, 98.5% ee). The catalyst combination of Pd-
(OAc)2 and the less bulky ligand L3 (tBuBrettPhos) was
optimal for the reaction of aryl bromides bearing ortho-alkyl
substituents to give 3h and 3i in comparable yields.[6b]
In contrast to a catalyst based on L2,[8] whose application
was limited to halopyridines and haloquinolines, a variety of
aryl alkyl ethers derived from five- and six-membered
heteroaryl halides could be accessed under our new con-
ditions (3j–3o). For example, 3-bromopyridine, 5-bromopyr-
imidine, and 3-bromoquinoline were all coupled with nBuOH
in good to excellent yields (see 3k, 3l, and 3m). The
Scheme 3. Coupling of aryl halides with primary alcohols. Reaction
conditions: ArX (1 mmol), alcohol (2 mmol), Cs2CO3 (1.5 mmol),
[(allylPdCl)2] (0.5 mol%), L4 (1.5 mol%), toluene (1 mL), 908C, 5–
21 h; yields are of of isolated products (average of two or more runs).
[a] 200 mg of 4 ꢀ molecular sieves was added. [b] [(allylPdCl)2]
(2 mol%) and L4 (4.8 mol%). [c] Alcohol (3 mmol). [d] Pd(OAc)2
(2 mol%) and L3 (2.4 mol%). [e] [(allylPdCl)2] (1 mol%) and L4
(2.4 mol%). Boc=tert-butoxycarbonyl.
conversion of 4-bromoisoquinoline into 3o proved more
difficult, but could be efficiently accomplished by using
3 equivalents of nBuOH and the premixing protocol de-
scribed above.
To highlight the generality and efficiency of a catalyst
based on L4, we directly compared it to several of the
previous reported systems. For the reaction of 4-bromoquino-
line with a secondary alcohol our new catalyst system gave an
88% yield of isolated product, whereas a catalyst based on
L12 (previously the best reported system for reactions of
secondary alcohols)[6b] gave no desired product (Scheme 4).
Furthermore, for the reaction of a primary alcohol with an
electron-rich aryl halide, a catalyst based on L4 gave an 84%
yield as determined by GC analysis; for the same reaction a
catalyst based on the recently reported L2[8] afforded no
desired product, and a catalyst based on L1 gave a 73% yield
Angew. Chem. Int. Ed. 2011, 50, 9943 –9947
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim