A Comparative Ancillary Ligand Survey in Palladium-Catalyzed C-O Cross-Coupling of Primary and Secondary Aliphatic Alcohols

Article abstract of DOI:10.1002/ejoc.201600198

The utility of RockPhos, Ad-BippyPhos, JosiPhos (CyPF-tBu), and Mor-DalPhos in palladium-catalyzed C-O cross-coupling reactions involving aliphatic alcohols and (hetero)aryl halides under analogous conditions was examined, both at room temperature and at

Full text of DOI:10.1002/ejoc.201600198

DOI: 10.1002/ejoc.201600198
Full Paper
Cross-Coupling
A Comparative Ancillary Ligand Survey in Palladium-Catalyzed
C–O Cross-Coupling of Primary and Secondary Aliphatic
Alcohols
Ryan S. Sawatzky,[a] Breanna K. V. Hargreaves,[a] and Mark Stradiotto*[a]
Abstract: The utility of RockPhos, Ad-BippyPhos, JosiPhos ligands examined also proved effective across a range of C–O
(CyPF-tBu), and Mor-DalPhos in palladium-catalyzed C–O cross-
coupling reactions involving aliphatic alcohols and (hetero)aryl
halides under analogous conditions was examined, both at
room temperature and at elevated temperature (90 °C). In gen-
eral, the RockPhos-based catalyst system proved superior, espe-
cially at room temperature, but catalysts based on the other
cross-couplings, in some cases providing better catalytic per-
formance than RockPhos. New reactivity was established in
terms of the scope of room temperature reactions. Proof-of-
principle examples of such cross-couplings involving aryl mesyl-
ates were also demonstrated.
Introduction
synthesis of aryl alkyl ethers.[3] Palladium-based catalysts have
proved to be particularly useful in such applications, although
a judiciously chosen ancillary ligand set is required when using
primary and secondary aliphatic alcohols in order to favor prod-
uct-forming C–O bond reductive elimination over unwanted ꢀ-
hydride elimination (Figure 2).
Aromatic ethers of primary and secondary aliphatic alcohols are
common structural motifs in many naturally occurring and syn-
thetic compounds with interesting biological activity;[1] a selec-
tion of top-selling pharmaceuticals featuring examples of this
core structure are presented in Figure 1.
Figure 1. Selected pharmaceuticals featuring the aryl alkyl ether structural
motif.
Figure 2. Generic catalytic cycle for the palladium-catalyzed cross-coupling
of aliphatic alcohols and (hetero)aryl halides, showing unwanted ꢀ-hydride
elimination.
Aromatic ethers have traditionally been prepared by nucleo-
philic aromatic substitution or Ullmann coupling,[2] but the re-
quired forcing reaction conditions and for highly reactive aryl
electrophiles in such protocols provide motivation for the de-
velopment of alternative synthetic methods that could run un-
der milder conditions and with a broader substrate scope. In
this regard, late-transition-metal-catalyzed C–O cross-coupling
reactions involving aliphatic alcohols and (hetero)aryl halides
have emerged as effective and complementary methods for the
The first reports of palladium-catalyzed C–O cross-coupling
reactions using primary and secondary aliphatic alcohols as re-
action partners were disclosed by Buchwald and coworkers in
2001 and 2005, respectively.[4] Since this time, the sterically de-
manding phosphines RockPhos (L1),[5] Ad-BippyPhos (L2),[6]
and JosiPhos CyPF-tBu (L3)[7] have emerged as some of the
most effective ancillary ligands reported to date for such chal-
lenging palladium-catalyzed C–O cross-couplings (Figure 3).
Although collectively the performance of palladium catalysts
featuring L1–L3 in the C–O cross-coupling of primary and sec-
ondary aliphatic alcohols is impressive, each catalyst system
shows some limitations. The reported catalyst system using L1
is attractive in its ability to promote transformations involving
both primary and secondary aliphatic alcohols in combination
[a] Department of Chemistry,Dalhousie University,
6274 Coburg Road, Halifax, NS, B3H 4R2, Canada
E-mail: mark.stradiotto@dal.ca
http://www.dal.ca/sites/stradiotto.html
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600198.
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more restricted in scope, and feature only a limited number of
primary aliphatic alcohols.[6] The L3-based catalyst system
shows an impressive scope with respect to the alcohol reaction
partner, but some limitations were encountered in terms of the
scope of the electrophile, even in reactions involving rather sim-
ple substrates such as bromo- or chlorobenzene, as well as 3-
bromo- or 3-chloropyridine.[7] One challenge that exists in at-
tempting to directly compare the reactivity profiles of L1–L3 is
that the catalytic reaction conditions differ significantly be-
tween these published reports,[5–7] most notably in terms of the
palladium loadings (1–10 mol-%) and the reaction temperatures
(80–140 °C).
In an effort to gain further insights into the relative catalytic
abilities of L1–L3 in palladium-catalyzed C–O cross-coupling re-
actions involving aliphatic alcohols and (hetero)aryl halides, we
initiated a two-part comparative reactivity survey. We studied
reactions carried out at 90 °C using relatively low catalyst load-
ings, as well as complementary room-temperature reactions us-
ing higher catalyst loadings. The latter set of experiments are
of particular significance, given the operational advantages of
Figure 3. Ancillary ligands evaluated in this study.
with electron-rich electrophiles. However, the need to carefully room-temperature reactions, especially when using lower-boil-
preform the catalyst, and the requirement for 4 Å molecular ing aliphatic alcohols, and also given the potential selectivity
sieves and/or trialkylamine additives make such protocols more benefits that might be derived from carrying out C–O cross-
complex than those reported involving L2 or L3.[5] Conversely, couplings at room temperature. Although several methods for
the reported transformations involving an L2-based catalyst are palladium-catalyzed room-temperature cross-coupling reac-
Figure 4. Cross-coupling of phenethyl alcohol (1) and (hetero)aryl chlorides. Estimated conversion to product 2 [%] after 16 h (unoptimized) on the basis of
GC data, with selected isolated yields given in parentheses. Reaction conditions: [A] [Pd(cinnamyl)Cl]2 (0.5 mol-%), ligand (1.5 mol-%), 90 °C. [B] [Pd(cinnam-
yl)Cl]2 (3.5 mol-%), ligand (11.5 mol-%), 25 °C; n.d.: not detected. *Using the corresponding aryl bromide.
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tions using relatively inexpensive and abundant (hetero)aryl under analogous conditions, we also observed that both L2 and
chloride electrophiles have been developed,[8] to the best of L4 gave high conversion to 2a. In moving to the previously
our knowledge, examples of analogous C–O cross-couplings of
aliphatic alcohols are limited to a single report by Cheung and
Buchwald,[8n] in which an L1-containing palladium precatalyst
was used in the arylation of methanol and ethanol (six exam-
ples).[9] As part of our reactivity survey of ancillary ligands, we
opted to include Mor-DalPhos (L4).[8i] The application of L4 in
palladium-catalyzed C–O cross-coupling reactions has not been
reported in the literature, but this ligand has proved to be par-
ticularly useful in related C–N cross-coupling chemistry.[8i,8k,10]
In this paper, we report the results of this comparative reactivity
survey of ancillary ligands.
unreported room temperature conditions outlined in Figure 4,
each of L1–L4 resulted in a high conversion to 2a. The reason
for the improved performance of L1 in this test reaction at
room temperature, relative to 90 °C, is unclear at present, but
it is plausible that the use of milder reaction conditions discour-
ages deleterious side reactions (e.g., ꢀ-hydride elimination;
hydrodehalogenation) that may be more competitive at higher
temperature. It is also worth mentioning that careful attention
to the preformation of the catalyst in situ has been shown to
be important when using L1 in such C–O cross-couplings;[5,7,11]
for operational simplicity, no special effort was made regarding
precatalyst formation for the experiments described here.
Our continued exploration of the electrophile scope in com-
bination with 1 revealed that, in contrast to L2–L4, the perform-
ance of L1 at room temperature using higher catalyst loadings
was invariably superior to that achieved by using lower catalyst
loadings at 90 °C; our attempts to use lower catalyst loadings
at room temperature with L1 were unsuccessful. Although cata-
lysts based on L2–L4 each proved effective across a range of C–
O cross-couplings involving 1 (Figure 4), the L1-based catalyst
system in general proved superior, both in terms of enabling
room-temperature transformations, and across each of the elec-
trophiles examined when both sets of catalytic conditions are
Results and Discussion
We began our catalytic screening by examining the C–O cross-
coupling of phenethyl alcohol (1) and with various (hetero)aryl
chlorides, using a base and a solvent that had proved effective
in previous studies involving L1–L3 (Figure 4).[5–7] Our initial
choice of 4-chloroquinaldine as the electrophilic reaction part-
ner was made so as to allow a comparison with the extensive
ligand screening conducted by Maligres et al.[7] In keeping with
their results, L1 performed poorly, whereas a high conversion
to the target compound (i.e., 2a) was achieved by using L3;
Figure 5. Cross-coupling of aliphatic alcohols and (hetero)aryl chlorides. Estimated conversion to product 3 [%] after 16 h (unoptimized) on the basis of GC
data, with selected isolated yields given in parentheses. Reaction conditions: [A] [Pd(cinnamyl)Cl]2 (0.5 mol-%), ligand (1.5 mol-%), 90 °C. [B] [Pd(cinnamyl)Cl]2
(3.5 mol-%), ligand (11.5 mol-%), 25 °C; n.d.: not detected. *Using the corresponding aryl bromide.
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Figure 6. Cross-coupling of phenethyl alcohol (1) and selected aryl mesylates, with isolated yields of 4 [%] obtained using L2 unless otherwise indicated.
considered. Indeed, only in the case of relatively activated sub- ates, L2 proved superior; selected transformations are pre-
strates, for example leading to 2a, 2f, 2g, and 2k, did one or sented in Figure 6.
more of L2–L4 prove competitive with L1 at room temperature;
the exception to this trend is found in the formation of 2l,
where L2 proved optimal. A comparative reactivity survey in-
Conclusions
The competitive reactivity survey disclosed in this paper allows
a direct comparison to be made between commercially avail-
able ligands L1–L4 in palladium-catalyzed C–O cross-coupling
reactions involving aliphatic alcohols and (hetero)aryl halides
under analogous conditions. New reactivity was established in
terms of the scope of room temperature reactions; proof-of-
principle examples of such cross-couplings involving aryl mesyl-
ates were also demonstrated. In general, the L1-based catalyst
system proved superior, both in terms of enabling room-tem-
perature transformations, and in terms of the (hetero)aryl chlor-
ides accommodated. But catalysts based on L2–L4 also proved
effective across a range of C–O cross-couplings, in some cases
providing superior catalytic performance relative to L1. Future
work in our laboratory will be directed toward the development
of new ancillary ligands in the quest to identify increasingly
effective catalysts for such transformations.
volving the formation of 2d revealed little difference in catalytic
performance when using electron-rich aryl chlorides vs. brom-
ides. Moreover, test reactions targeting product 2c, but using
NaOtBu in place of Cs2CO3 resulted in complete consumption of
the alcohol reagent, along with quantitative hydrodehalogen-
ation of the aryl chloride, thus underscoring the importance of
base selection with regard to achieving success in such C–O
cross-couplings.
We next turned our attention to palladium-catalyzed C–O
cross-couplings involving potentially more challenging linear
and branched aliphatic alcohols (Figure 5). In such transforma-
tions, no single ligand dominated; the observed catalytic per-
formance was substrate dependent. In most cases, poor conver-
sion (≤50 %) to the target product was achieved at room tem-
perature, with synthetically useful conversions limited to rela-
tively activated substrates leading to 3e and 3f. Absent from
Buchwald's[5,11] reports regarding the use of L1 in palladium-
catalyzed C–O cross-couplings are examples where both the
alcohol and the electrophile feature nitrogen-based hetero-
cyclic motifs. The challenge of such combinations when using
L1 is evident in transformations leading to 3j, especially when
compared to the successful formation of analogous phenethyl-
based product 2a at room temperature when using L1 (Fig-
ure 4). The ability of both P,P ligand L3 and P,N ligand L4 to
provide high conversion to 3j may be attributable to the
strongly chelating nature of such ligands, compared to L1 and
L2.
Experimental Section
General Remarks: All reactions were set up in a glovebox under a
nitrogen atmosphere, and products were isolated under standard
benchtop conditions. Toluene used in the glovebox was purified by
sparging with nitrogen followed by passing through a double col-
umn purification system equipped with one alumina-packed col-
umn and one copper-Q5-packed column. Solvents used in the
glovebox were stored over 4 Å molecular sieves. Aryl mesylates
were prepared using literature procedures.[14] All other reagents,
solvents, and materials were used as received from commercial sup-
pliers. Products were purified by column chromatography over
Notwithstanding the utility of the Williamson ether synthesis
in the preparation of unsymmetrical ethers from alcohols and Brockmann I activated neutral alumina. All 1H and 13C{1H} NMR
spectra were recorded with a Bruker AV-500 spectrometer at 300 K.
In some cases, fewer carbon resonances than anticipated were ob-
served, despite prolonged acquisition times. Chemical shifts are ex-
pressed in parts per million (ppm), and the residual CHCl3 solvent
peak (1H δ = 7.26 ppm, 13C δ = 77.0 ppm) was used as an internal
reference. Coupling constants (J) are reported in Hertz (Hz). Split-
ting patterns are described as follows: br, broad; s, singlet; d, dou-
blet; t, triplet; q, quartet; m, multiplet. Mass spectra were obtained
with ion-trap instruments using electrospray ionization in positive-
ion mode. GC data were obtained using an instrument equipped
alkyl (pseudo)halides, we sought to test the feasibility of using
aryl mesylates in palladium-catalyzed C–O cross-couplings of
aliphatic alcohols. In addition to being complementary to exist-
ing protocols, the use of aryl mesylates as coupling partners is
attractive as they are derived from abundant phenols,[12] and
the cross-coupling by-product formed upon hydrolysis (i.e.,
methanesulfonic acid) is naturally occurring, and can undergo
biodegradation under conventional waste-water processing.[13]
In a brief catalytic screening involving L1 and L2 in the palla-
dium-catalyzed cross-coupling of 1 with selected aryl mesyl- with a SGE BP-5, 30 m, 0.25 mm internal diameter column.
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General Screening Procedure for Reactions Conducted at Room
Temperature (GPA): [Pd(cinnamyl)Cl]2 (5.8 mg, 3.75 mol-%), ligand
(11.25 mol-%), Cs2CO3 (196 mg, 0.6 mmol), and toluene (0.6 mL)
were added to a glass vial equipped with a magnetic stirrer bar.
The vial was sealed with a screw cap fitted with a PTFE/silicone
septum and removed from the glovebox. Aryl halide (0.30 mmol)
and alcohol (0.36 mmol) were then added by microsyringe. The vial
was then placed on a stirrer plate, and the solution was stirred
magnetically for 16 h. After 16 h, an aliquot was filtered through a
small plug of silica, which was then washed with dichloromethane,
and the eluent was subjected to GC analysis.
was then filtered through an alumina and Celite filter with dichloro-
methane. The eluent containing the crude product was concen-
trated by rotary evaporation, and the residue was purified by col-
umn chromatography.
Characterization of Isolated Materials
2-Methyl-4-phenethoxyquinoline (2a): Following GPC [L1
(31.6 mg), aryl halide (121 μL), alcohol (86.2 μL)], compound 2a was
isolated (90 %) as a white solid. 1H NMR (500 MHz, CDCl3): δ = 8.17
(d, J = 8.5 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.68 (t, J = 7.5 Hz, 1 H),
7.47 (t, J = 7.5 Hz, 1 H), 7.38–7.39 (m, 4 H), 7.28–7.33 (m, 1 H), 6.63
(s, 1 H), 4.41 (t, J = 7 Hz, 2 H), 3.29 (t, J = 7 Hz, 2 H), 2.70 (s, 3 H)
ppm. 13C{1H} NMR (125.8 MHz, CDCl3): δ = 161.6, 160.2, 149.0, 138.0,
129.9, 129.2, 128.8, 128.2, 126.9, 124.9, 121.8, 120.0, 101.3, 69.1, 35.7,
26.1 ppm. HRMS (ESI+): calcd. for C18H18NO [M + H]+ 264.1344;
found 264.1383.
General Screening Procedure for Reactions Conducted at 90 °C
(GPB): [Pd(cinnamyl)Cl]2 (1.6 mg, 0.5 mol-%), ligand (1.5 mol-%),
Cs2CO3 (391 mg, 1.2 mmol), and toluene (1.2 mL) were added to a
glass vial equipped with a magnetic stirrer bar. The vial was sealed
with a screw cap fitted with a PTFE/silicone septum and removed
from the glovebox. Aryl halide (0.60 mmol) and alcohol (0.72 mmol)
were then added by microsyringe. The vial was then placed on a
temperature-controlled aluminum plate set to 90 °C, and the solu-
tion was stirred magnetically for 16 h. After 16 h, the vial was re-
moved from the heating block, and was cooled to room tempera-
ture. An aliquot was filtered through a small plug of silica, which
was then washed with dichloromethane, and the eluent was sub-
jected to GC analysis.
1-Methoxy-2-phenethoxybenzene (2b): Following GPC [L1
(31.6 mg), aryl halide (76.2 μL), alcohol (86.2 μL)], compound 2b
was isolated (83 %) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ =
7.33–7.40 (m, 4 H), 7.27–7.32 (m, 1 H), 6.94–7.00 (m, 4 H), 4.28 (t,
J = 7.6 Hz, 2 H), 3.92 (s, 3 H), 3.28 (t, J = 7.6 Hz, 2 H) ppm. 13C{1H}
NMR (125.8 MHz, CDCl3): δ = 150.0, 148.7, 138.5, 129.5, 128.9, 126.9,
121.6, 121.3, 113.9, 122.5, 70.3, 56.4, 36.2 ppm. HRMS (ESI+): calcd.
for C15H17O2 [M + H]+ 229.1184; found 229.1223.
General Procedure for the Formation and Isolation of Products
at Room Temperature (GPC): [Pd(cinnamyl)Cl]2 (11.6 mg, 3.75 mol-
%), ligand (11.25 mol-%), Cs2CO3 (196 mg, 1.2 mmol), and toluene
(1.2 mL) were added to a glass vial equipped with a magnetic stirrer
bar. The vial was sealed with a screw cap fitted with a PTFE/silicone
septum, and was then removed from the glovebox. Aryl halide
(0.60 mmol) and alcohol (0.72 mmol) were then added by microsyr-
inge. The vial was then placed on a stirrer plate, and the solution
was stirred magnetically for 16 h. After 16 h, the reaction mixture
was filtered through an alumina and Celite filter with dichloro-
methane. The eluent containing the crude product was concen-
trated by rotary evaporation, and the residue was purified by col-
umn chromatography.
Following GPD [L1 (6.0 mg), aryl halide (76.2 μL), alcohol (86.2 μL)],
compound 2b was isolated (90 %) as a colorless oil.
1-Phenethoxynaphthalene (2c): Following GPC [L1 (31.6 mg), aryl
halide (81.7 μL), alcohol (86.2 μL)], compound 2c was isolated
1
(>95 %) as a pale brown solid. H NMR (500 MHz, CDCl3): δ = 8.31
(d, J = 8.0 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.48–7.54 (m, 2 H), 7.46
(d, J = 8.5 Hz, 1 H), 7.36–7.43 (m, 5 H), 7.27–7.31 (m, 1 H), 6.85 (d,
J = 7.6 Hz, 1 H), 4.41 (t, J = 6.9 Hz, 2 H), 3.30 (t, J = 6.9 Hz, 2 H)
ppm. 13C{1H} NMR (125.8 MHz, CDCl3): δ = 154.8, 138.7, 134.7, 129.3,
128.7, 127.6, 126.7, 126.5, 126.0, 125.9, 125.3, 122.3, 120.4, 104.9,
69.1, 36.2 ppm. HRMS (ESI+): calcd. for C18H17O [M + H]+ 249.1235;
found 249.1274.
Following GPD [L2 (6 mg), aryl halide (81.7 μL), alcohol (86.2 μL)],
compound 2c was isolated (73 %) as a pale brown solid.
General Procedure for the Formation and Isolation of Products
at 90 °C (GPD): [Pd(cinnamyl)Cl]2 (1.6 mg, 0.5 mol-%), ligand
(1.5 mol-%), Cs2CO3 (391 mg, 1.2 mmol), and toluene (1.2 mL) were
added to a glass vial equipped with a magnetic stirrer bar. The vial
was sealed with a screw cap fitted with a PTFE/silicone septum, and
was then removed from the glovebox. Aryl halide (0.60 mmol) and
alcohol (0.72 mmol) were then added by microsyringe. The vial was
then placed on a temperature-controlled aluminum plate set to
90 °C, and the solution was stirred magnetically for 16 h. After 16 h,
the vial was removed from the heating block, and was cooled to
room temperature. The reaction mixture was then filtered through
an alumina and Celite filter with dichloromethane. The eluent con-
taining the crude product was concentrated by rotary evaporation,
and the residue was purified by column chromatography.
2-Phenethoxybenzo[d]thiazole (2j): Following GPC [L1 (31.6 mg),
aryl halide (78.1 μL), alcohol (86.2 μL)], compound 2j was isolated
1
(>95 %) as a white solid. H NMR (500 MHz, CDCl3): δ = 7.72 (d, J =
8.1 Hz, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.32–7.42 (m, 5 H), 7.24–7.31
(m, 2 H), 4.82 (t, J = 7.1 Hz, 2 H), 3.22 (t, J = 7.0 Hz, 2 H) ppm. 13C{1H}
NMR (125.8 MHz, CDCl3): δ = 172.9, 149.6, 137.6, 132.1, 129.2, 128.7,
126.9, 126.1, 123.6, 121.4, 121.0, 72.3, 35.4 ppm. HRMS (ESI+): calcd.
for C15H14NOS [M + H]+ 256.0751; found 256.0791.
Following GPD [L3 (47.2 mg), aryl halide (78.1 μL), alcohol (86.2 μL)],
compound 2j was isolated (90 %) as a white solid.
2-Methyl-4-(1-phenethoxy)quinoline (3e): Following GPD [L4
(4.2 mg), aryl halide (121 μL), alcohol (86.9 μL)], compound 3e was
isolated (>95 %) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ =
8.31 (d, J = 8.3 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.70 (t, J = 7.1 Hz,
1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.37–7.41 (m, 2 H), 7.43–7.47 (m, 2 H),
7.30–7.35 (m, 1 H), 6.51 (s, 1 H), 5.61 (q, J = 6.5 Hz, 1 H), 2.60 (s, 3
H), 1.82 (d, J = 6.5 Hz, 3 H) ppm. 13C{1H} NMR (125.8 MHz, CDCl3):
δ = 160.6, 160.0, 149.1, 142.1, 129.8, 129.0, 128.3, 128.1, 125.5, 124.9,
122.0, 120.4, 103.1, 76.5, 26.1, 24.4 ppm. HRMS (ESI+): calcd. for
C18H18NO [M + H]+ 264.1344; found 264.1383.
General Procedure for the Formation and Isolation of Products
Derived from Aryl Mesylates (GPE): [Pd(cinnamyl)Cl]2 (2.6 mg,
0.5 mol-%), ligand (1.5 mol-%), Cs2CO3 (652 mg, 2.0 mmol), and
toluene (2.0 mL) were added to a glass vial equipped with a mag-
netic stirrer bar. The vial was sealed with a screw cap fitted with a
PTFE/silicone septum, and was then removed from the glovebox.
Aryl halide (1.0 mmol) and alcohol (1.2 mmol) were then added by
microsyringe. The vial was then placed on a temperature-controlled
aluminum plate set to 90 °C, and the solution was stirred magneti-
cally for 16 h. After 16 h, the vial was removed from the heating
block, and was cooled to room temperature. The reaction mixture
2-Methyl-4-[2-(pyridin-2-yl)ethoxy]quinoline (3j): Following GPD
[L3 (4.7 mg), aryl halide (121 μL), alcohol (81.1 μL)], compound 3j
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was isolated (>95 %) as a brown solid. 1H NMR (500 MHz, CDCl3):
δ = 8.60–8.62 (m, 1 H), 8.09 (d, J = 8.3 Hz, 1 H), 7.96 (d, J = 8.5 Hz,
1 H), 7.64–7.70 (m, 2 H), 7.43 (t, J = 7.4 Hz, 1 H), 7.36 (d, J = 7.8 Hz,
1 H), 7.18–7.22 (m, 1 H), 6.51 (s, 1 H), 4.63 (t, J = 7.4 Hz, 2 H), 3.45
(t, J = 7.4 Hz, 2 H), 2.71 (s, 3 H) ppm. 13C{1H} NMR (125.8 MHz,
CDCl3): δ = 161.6, 160.3, 158.2, 149.7, 148.9, 136.7, 129.9, 128.1,
124.9, 123.9, 122.0, 121.8, 120.0, 101.4, 67.6, 37.9, 26.0 ppm. HRMS
(ESI+): calcd. for C17H17N2O [M]+ 265.1344; found 265.1335.
Keywords: Homogeneous catalysis · Palladium · Cross-
coupling · Ligand design · Ethers
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2-Phenethoxynaphthalene (4a): Following GPE [L2 (10.0 mg), aryl
mesylate (222.3 mg), alcohol (144 μL)], compound 4a was isolated
(75 %) as a white solid. 1H NMR (500 MHz, CDCl3): δ = 7.74–7.83 (m,
3 H), 7.48 (t, J = 7.3 Hz, 1 H), 7.36–7.42 (m, 5 H), 7.29–7.34 (m, 1 H),
7.18–7.23 (m, 2 H), 4.36 (t, J = 7.1 Hz, 2 H), 3.23 (t, J = 7.1 Hz, 2 H)
ppm. 13C{1H} NMR (125.8 MHz, CDCl3): δ = 157.0, 138.4, 134.7, 129.5,
129.2, 128.7, 127.8, 126.9, 126.7, 126.5, 123.8, 119.1, 106.9, 68.9,
36.0 ppm. HRMS (ESI+): calcd. for C18H17O [M + H]+ 249.1235; found
249.1274.
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Following GPE [L1 (31.6 mg), aryl mesylate (133.4 mg), alcohol
(86.2 μL)], compound 4a was isolated (42 %) as a white solid.
1-Phenethoxy-4-phenoxybenzene (4b): Following GPE [L2
(10.0 mg), aryl mesylate (264.3 mg), alcohol (144 μL)], compound
4b was isolated (70 %) as a pale yellow oil. 1H NMR (500 MHz,
CDCl3): δ = 7.33–7.46 (m, 7 H), 7.14 (apparent t, J = 7.4 Hz, 1 H),
7.04–7.09 (m, 4 H), 6.96–7.00 (m, 2 H), 4.26 (t, J = 7.1 Hz, 2 H), 3.21
(t, J = 7.1 Hz, 2 H) ppm. 13C{1H} NMR (125.8 MHz, CDCl3): δ = 158.6,
155.2, 150.3, 138.3, 129.7, 129.1, 128.6, 126.6, 122.5, 120.9, 117.7,
115.7, 69.3, 36.0 ppm. HRMS (ESI+): calcd. for C20H19O2 [M + H]+
291.1340; found 291.1380.
1-Methyl-2-phenethoxybenezne (4c): Following GPE [L2
(10.0 mg), aryl mesylate (200.3 mg), alcohol (144 μL)], compound
1
4c was isolated (64 %) as a colorless oil. H NMR (500 MHz, CDCl3):
δ = 7.40–7.45 (m, 4 H), 7.33–7.37 (m, 1 H), 7.22–7.26 (m, 2 H), 6.96
(t, J = 7.4 Hz, 1 H), 6.89–6.92 (m, 1 H), 4.28 (t, J = 6.9 Hz, 2 H), 3.22
(t, J = 6.9 Hz, 2 H), 2.33 (s, 3 H) ppm. 13C{1H} NMR (125.8 MHz,
CDCl3): δ = 157.0, 138.7, 130.7, 129.2, 128.4, 126.9, 126.8, 126.5,
120.4, 111.0, 68.7, 36.1, 16.3 ppm. HRMS (ESI+): calcd. for C15H16NaO
[M + Na]+ 235.1099; found 235.1093.
1-(4-Phenethoxyphenyl)-1H-pyrrole (4d): Following GPE [L2
(10.0 mg), aryl mesylate (237.3 mg), alcohol (144 μL)], compound
[9] For an intriguing example of nickel-catalyzed C–O cross-coupling at
room temperature enabled by photoredox catalysis, see: J. A. Terrett,
J. D. Cuthbertson, V. W. Shurtleff, D. W. C. MacMillan, Nature 2015, 524,
330–334.
1
4d was isolated (71 %) as a white solid. H NMR (500 MHz, CDCl3):
δ = 7.27–7.39 (m, 7 H), 7.02–7.04 (m, 2 H), 6.96–7.00 (m, 2 H), 6.35–
6.37 (m, 2 H), 4.24 (t, J = 7.1 Hz, 2 H), 3.16 (t, J = 7.1 Hz, 2 H) ppm.
13C{1H} NMR (125.8 MHz, CDCl3): δ = 156.9, 138.1, 134.6, 129.0,
128.5, 126.5, 122.1, 119.7, 115.3, 109.8, 69.1, 35.8 ppm. HRMS (ESI+):
calcd. for C18H18NO [M + H]+ 364.1344; found 264.1383.
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Supporting information (see footnote on first page of this article):
Copies of the 1H and 13C{1H} NMR spectra of the isolated com-
pounds.
Acknowledgments
[14] D. A. Wilson, C. J. Wilson, C. Moldoveanu, A. M. Resmerita, P. Corcoran,
L. M. Hoang, B. M. Rosen, V. Percec, J. Am. Chem. Soc. 2010, 132, 1800–
1801.
The authors are appreciative of the generous financial support
for this work from the Natural Sciences and Engineering Re-
search Council of Canada (NSERC).
Received: February 22, 2016
Published Online: April 24, 2016
Eur. J. Org. Chem. 2016, 2444–2449
www.eurjoc.org
2449
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim