Suzuki-Miyaura cross-coupling of potassium alkoxyethyltrifluoroborates: Access to aryl/heteroarylethyloxy motifs

Article abstract of DOI:10.1021/jo3021665

The introduction of an alkoxyethyl moiety onto aromatic substructures has remained a long-standing challenge for synthetic organic chemists. The main reasons are the inherent instability of alkoxyethylmetallic species and the lack of general procedures to access them. A new method utilizing a cross-coupling strategy based on the exceptional properties of organotrifluoroborates has been developed, and the method allows an easy and efficient installation of this unit on a broad range of aryl and heteroaryl bromides.

Full text of DOI:10.1021/jo3021665

Article
pubs.acs.org/joc
Suzuki−Miyaura Cross-Coupling of Potassium
Alkoxyethyltrifluoroborates: Access to Aryl/Heteroarylethyloxy
Motifs
Nicolas Fleury-Bregeot,† Marc Presset,‡ Floriane Beaumard,† Virginie Colombel,‡ Daniel Oehlrich,‡
́
Frederik Rombouts,*,‡ and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
‡Neuroscience Medicinal Chemistry, Research & Development, Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium
S
* Supporting Information
ABSTRACT: The introduction of an alkoxyethyl moiety onto
aromatic substructures has remained a long-standing challenge
for synthetic organic chemists. The main reasons are the
inherent instability of alkoxyethylmetallic species and the lack
of general procedures to access them. A new method utilizing a
cross-coupling strategy based on the exceptional properties of organotrifluoroborates has been developed, and the method allows
an easy and efficient installation of this unit on a broad range of aryl and heteroaryl bromides.
dramatically improve this situation and make the introduction
of the alkoxyethyl group a very simple and straightforward
process.
INTRODUCTION
■
The Suzuki−Miyaura reaction has become a predominant asset
in the toolbox of chemical transformations regularly employed
by organic chemists.1 Among the metal-catalyzed carbon−
carbon bond forming reactions, this cross-coupling reaction
between a boron species and an electrophile has gained
dramatic interest owing to its robustness, versatility, and the
relative lack of toxicity of its generated byproducts.
Our research group has devoted its efforts toward the
development of organotrifluoroborates as new and efficient
boron coupling partners.2 Their tetracoordinate nature confers
increased stability upon them, and when placed in specific
reaction conditions, they slowly release in situ the reactive
boron species that can undergo the desired cross-coupling
reaction.3 These unique features make them highly useful,
functional group tolerant, bench-stable reagents that perform
very well in the Suzuki−Miyaura reaction. Based on these
properties, it has been possible to synthesize and cross-couple a
large array of functionalized methyltrifluoroborates such as
alkoxymethyl-, aminomethyl-, amidomethyl-, and carbamato-
methyltrifluoroborates, providing new and useful methods to
access those motifs.2e,4
To complement those useful synthons, our attention had
been drawn to the development of alkoxyethyltrifluoroborates
as an unprecedented way to synthesize alkoxyethylarenes. The
current common methods to introduce the alkoxyethyl moiety
are limited to reaction sequences such as the addition of an
organometallic reagent to ethylene oxide or 2-haloethers, or
hydroboration/oxidation/alkylation of a styrene derivative.
Aside from requiring several steps, these routes suffer from
harsh reaction conditions, low yields, and sensitivity/toxicity as
well as poor availability of the reagents, all of which greatly limit
their general application. A cross-coupling strategy would
However, this concept is ultimately based on the ability to
synthesize alkoxyethylboron coupling partners, several potential
routes to which are depicted in Scheme 1. In general, these
routes are fraught with challenges. Indeed, it is well
documented that halogenoethylboron compounds are unsta-
ble.5 For instance, β-bromoethylboronate species experience
facile deboronobromination in the presence of weak
nucleophiles such as potassium cyanate, aniline, pyridine, or
even water.5b The mechanism of the decomposition, yielding
ethylene and boron byproducts, transpires through a concerted
anti elimination pathway that can be triggered by a Lewis base.6
On the other hand, the hydroboration of vinyl ethers, the
products of which are a bit more stable depending on the steric
hindrance on the boron atom,7 is not a suitable route either, as
the intermediates are prone to transfer and elimination
reactions.8 Elimination can proceed through a syn or an anti
mechanism depending on the presence or absence of a Lewis
acid. Another synthetic pathway would employ the use of an
alkoxyethylorganometallic species (such as organomagnesium
or organolithium species) reacting with a borate, but
unfortunately, such organometallic species are not stable and
tend to decompose rapidly.9
RESULTS AND DISCUSSION
■
Given that the desired alkoxyethylboron compounds were not
easily accessible, their use as reagents remained on hold until
the development of metal-catalyzed borylation reactions. In
Received: October 5, 2012
© XXXX American Chemical Society
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Scheme 1. Potential Synthetic Routes to Alkoxyethylboron Species
Scheme 2. Synthesis of Alkoxyethyltrifluoroborates via a Copper Catalyzed Borylation Procedure
2004, Hartwig reported the synthesis of an alkoxyethyl
pinacolboronate via a Rh-catalyzed borylation of an ethyl
ether with bis(pinacolato)diborane followed by its subsequent
cross-coupling with an aryl bromide or hydrolysis of the
boronate to a trifluoroborate.10 Unfortunately, besides being
run on a very small scale (0.14 mmol in NMR tubes) without
isolation of the products (GC and NMR yields), the reaction
conditions, which require a 10-fold excess of ethyl ether and
heating the reaction mixture at 150 °C for 24 h, were not
suitable for a large variety of substrates.
More recently, and in a very short time period, the borylation
of nonactivated alkyl halides has attracted much interest in the
chemical community.11 Several research groups have developed
reactions with mild conditions (rt to 60 °C) based on copper,
nickel, or palladium catalysis. Although they all possess wide
functional group tolerability, only two examples of alkoxye-
thylboron derivatives have been reported via one of these
methods.11a−c Our attention was focused on the method
developed by Marder and Liu, as it relies on the use of
inexpensive PPh3 and copper(I).11a A few modifications of the
reaction conditions allowed us to synthesize various alkox-
yethyltrifluoroborates. In particular, the use of polystyrene-
supported triphenylphosphine (PS-PPh3) as mentioned in the
original report improved both the efficiency and the yield of the
process, as various alkoxyethyltrifluoroborates could be
prepared by the addition of KHF2 to the reaction mixture
after the borylation step, avoiding contamination by triphenyl-
phosphine oxide.12 The different alkoxyethyltrifluoroborates
prepared in this manner are summarized in Scheme 2.
groups on the oxygen such as alkyl, benzyl, or aryl substituents
(yields of 1a−d ranging from 55 to 68%). However, more
sensitive substrates provided lower yields, as illustrated by the
acetoxyethyltrifluoroborate 1f and the silyl ether derivative 1i,
which were obtained in 40 and 43% yields, respectively. Cyclic
secondary alkoxyethyl bromides did not react as well, and the
corresponding trifluoroborates (1g, 1h) were isolated in slightly
lower yields. Attempts at using the Ni-based procedure
reported by Fu et al.,11d which was developed for unactivated
tertiary halides, did not provide better results. It is interesting to
note that bromoethyl ethers bearing various easily removable
protecting groups, such as benzyl, acetate, THP, or TBDPS
could be utilized, and thus would easily provide access to a free
hydroxyl group for further functionalization after the Suzuki−
Miyaura coupling step.13
Direct conversion of the boronate esters to the correspond-
ing potassium trifluoroborates helped to solve some stability
issues of the alkoxyethylboron derivatives.14 Even if the
alkoxyethylpinacolatoborons are more stable than their boronic
acid counterparts, they still remain sensitive and prone to
decomposition. The benzyloxyethyltrifluoroborate 1c could be
recrystallized, and its X-ray structure was elucidated (Figure 1).
Notably, the potassium cation can be seen bridging the oxygen
and one of the fluorine atoms, rigidifying the structure of the
molecule. A comparative study on the rate of degradation of an
alkoxyethyltrifluoroborate has been conducted. It showed that,
in the presence of 18-crown-6, the trifluoroborate degrades
faster, suggesting an important role of the potassium ion in
stabilizing the complexes.15
The desired alkoxyethyltrifluoroborates were obtained with
moderate to good yields (24−68%), and are all white powders
that showed no sign of decomposition after several months of
being stored on the bench with no particular precautions. The
borylation procedure tolerates a wide variety of functional
Extensive screening using High Throughput Experimentation
(HTE) techniques allowed us to define efficient conditions to
perform the Suzuki−Miyaura cross-coupling of the benzylox-
yethyltrifluoroborate 1c and various aryl bromides (Table 1).
The best catalytic system was found to be PdCl2AtaPhos2 in the
B
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or without substituents afforded the desired products in
moderate to good yields (Table 2, entries 1−2). Quinoline
and isoquinoline also responded well to the reaction conditions,
coupling with yields up to 83% (entries 4−5). Indole-based
electrophiles were also reactive; however, better yields were
obtained when the nitrogen was protected (89% vs 55%, entries
6, 7). Pyrimidine, which is a particularly difficult substrate, was
cross-coupled efficiently to give the corresponding product 3h
in 69% yield. Five-membered heterocycles were also tolerated;
3-bromothiophene gave the expected product 3i in 88% yield
(entry 9). 2-Halopyridines were also engaged in the reaction
and could be cross-coupled, albeit in a much lower yield (entry
3). Interestingly, the chloropyridine reacted better than its
bromo-counterpart owing to its lower tendency to undergo
homocoupling.
Figure 1. X-ray structure of potassium benzyloxyethyltrifluoroborate
1c.
The versatility of this new method was then demonstrated by
employing different alkoxyethyltrifluoroborates as coupling
partners under the same conditions (Table 3). Alkyl-substituted
trifluoroborates provided the desired cross-coupled products in
moderate to good yields (entries 1−3, 5−6), while the
phenoxyethyl derivative 1d afforded the expected product 4d
in only 31% yield. This substrate showed higher reactivity, as
numerous byproducts were observed after the reaction (Heck,
dimer, degradation...). It is interesting to note that for several
substrates the yields could be improved by lowering the
reaction temperature to 85 °C (entries 2, 6). Secondary
alkoxyethyltrifluoroborates also proved to be suitable partners,
providing yields up to 70% (entries 5−6). Trifluoroborates
bearing more sensitive functional groups such as a silyl ether or
an acetate moiety failed to give the cross-coupled products
under the reaction conditions. When trifluoroborate 1i (entry
7) was used, the corresponding silanol and bromoanisole were
retrieved after the reaction, suggesting that the fluoride ions
released during the hydrolysis of the trifluoroborate salt caused
the cleavage of the silyl group and led to degradation before the
cross-coupling could take place. The acetate group has been
reported not to survive the reaction conditions;19 however, the
deprotected coupled product was not detected either, even
when using milder reaction conditions.
presence of cesium carbonate in toluene/water at 100 °C. This
di-tert-butyl(4-dimethylamino)phenylphosphine was developed
in 2006 by Guram et al.16 and showed very interesting results in
Suzuki−Miyaura cross-coupling reactions, especially when used
as the air stable PdCl2L2 complex.15,17 The steric and electronic
properties of this ligand seem to help reduce β-hydride
elimination when compared to P(t-Bu)3,18 and the ligand has
been shown to provide very good results in the cross-coupling
of alkyl α-cyanohydrin triflates with arylboronic acids.16
c
As shown in Table 1, the substrate scope of the reaction
between benzyloxyethyltrifluoroborate 1c and aryl bromides is
very broad. The reaction conditions seem to be extremely
general, as they allow both electron-rich (entries 1−8) and
electron-poor (entries 9−17, 19) bromides to be coupled with
very good results. Electron-donating groups are tolerated on all
positions of the aryl bromide, as illustrated by the ortho-, meta-,
and para-bromoanisoles, affording the desired benzyloxyethy-
lanisole derivatives with yields ranging from 82 to 93% (entries
1−3). Electron-withdrawing substituents at the para position
seem to provide better results than at the ortho position (entries
9, 10 and 12, 13). Steric hindrance might not be the factor
responsible for this observed trend, as other mono- or
disubstituted electrophiles (entries 5, 6) cross-coupled
efficiently with excellent yields (93 and 82%, respectively).
The conditions are applicable to a large variety of functional
groups such as aldehydes (entry 14), ketones (entry 15), esters
(entry 16), nitriles (entries 12−13), nitro (entry 17), and even
amides and sulfonamides (entries 18−19).
The robustness of the method was tested by performing the
reaction on a larger scale (3 mmol of electrophile, entries 9 and
18). When using ortho-tolyl bromide, the cross-coupling
product was obtained with an excellent 93% isolated yield,
even after reducing the catalyst loading to 2.5 mol %. para-
Acetamidobenzyl bromide was also tested on a larger scale and
provided the expected cross-coupled product 2r in a slightly
lower yield (78%) after recrystallization (hexanes/ethyl acetate)
when using only 1 mol % palladium and a 1:1 trifluoroborate/
electrophile ratio. The reaction conditions were also tested with
several aryl chlorides with less success. Electron-rich chlorides
such as para-chloroanisole failed to react efficiently (30%
conversion, entry 1), whereas electron-poor substrates cross-
coupled smoothly, providing the desired benzyloxyethylben-
zene derivatives with moderate to excellent yields (entries 12,
14).
CONCLUSIONS
■
In summary, a robust and efficient method for the introduction
of ethyloxy motifs based on a Suzuki−Miyaura cross-coupling
of the alkoxyethyltrifluoroborates has been developed. These
coupling partners are synthesized using an inexpensive copper
catalyzed borylation reaction. The scope of the method has
been studied and includes aryl and heteroaryl bromides.
Depending on the functional group on the alkoxyethyl unit,
the resulting compounds can easily be deprotected to the
corresponding alcohols.20 This method is based on the unique
properties offered by the trifluoroborates salts, as well as the
versatility of the Suzuki−Miyaura reaction, and provides a
novel, complementary means to generate alkoxyethylarenes
that takes advantage of the wide availability of aryl halides as
synthetic partners in the cross-coupling reaction.
EXPERIMENTAL SECTION
■
General Considerations. All commercially available reagents were
used without purification. Both solvents and deionized water were
degassed with N2 each time prior to use. Standard benchtop
techniques were employed for handling air-sensitive reagents. Melting
points (°C) are uncorrected. NMR spectra were recorded on a 500,
400, or 300 MHz spectrometer. The resonance of the carbon center
The scope of the method was then further extended to
heteroaryl bromides using the same set of optimized
conditions. They proved to be effective, resulting in yields up
to 89% for a wide array of heteroaryls. 3-Bromopyridines with
C
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a
Table 1. Suzuki Cross-Coupling of Benzyloxyethyltrifluoroborate 1c and Various Aryl Bromides
a
General conditions: aryl bromide/chloride (0.25 mmol), trifluoroborate (0.275 mmol), PdCl2AtaPhos2 (12.50 μmol), Cs2CO3 (0.75 mmol) in
b
toluene (1 mL)/H2O (0.25 mL) at 100 °C for 24 h. Isolated yield after purification by flash chromatography on silica gel or recrystallization.
c
d
e
Reaction performed on a 3 mmol scale using 2.5 mol % catalyst. Product contains up to 8% impurity. Reaction performed on a 3 mmol scale using
a 1:1 trifluoroborate/electrophile ratio and 1 mol % Pd.
D
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Table 2. Suzuki Cross-Coupling of
Table 3. Suzuki Cross-Coupling of Various
Alkoxyethyltrifluoroborates and para-Bromoanisole
a
Benzyloxyethyltrifluoroborate 1c and Various Heteroaryl
a
Bromides
a
General conditions: 4-bromoanisole (0.25 mmol), trifluoroborate
(0.275 mmol), PdCl2AtaPhos2 (12.50 μmol), Cs2CO3 (0.75 mmol) in
toluene (1 mL)/H2O (0.25 mL) at 100 °C for 24 h. Isolated yield
after purification by flash chromatography on silica gel. Contaminated
by 7% impurity. Reaction performed at 85 °C. Reaction also
b
c
d
e
performed at 85 °C in 10:1 toluene/H2O and 2 equiv of base.
was effected with ultraviolet light, KMnO4, or ceric ammonium
molybdate.
a
General conditions: heteroaryl bromide/chloride (0.25 mmol),
trifluoroborate (0.275 mmol), PdCl2AtaPhos2 (12.50 μmol), Cs2CO3
(0.75 mmol) in toluene (1 mL)/H2O (0.25 mL) at 100 °C for 24 h.
General Procedure for the Preparation of Potassium
Alkoxyethyltrifluoroborates. This procedure was adapted from
the borylation procedure reported by Marder and Liu:11a in air,
bis(pinacolato)diboron (1.5 equiv), LiOMe (2.0 equiv), triphenyl-
phosphine polymer-bound (13 mol %), and CuI (99.999%, 10 mol %)
were weighed in a round-bottomed flask equipped with a stir bar. The
flask was closed with a septum, evacuated, and backfilled with N2.
DMF (25 mL, c = 0.2 M) and alkoxyethyl bromide (1.0 equiv) were
successively added by syringes (or, if the alkoxyethyl bromide was
solid, it was added as a solution in DMF), and the resulting mixture
was vigorously stirred at rt for 20 h. The reaction mixture was then
diluted with CH2Cl2 (25 mL) and filtered through a pad of Celite and
then rinsed with CH2Cl2 (2 × 50 mL). The resulting solution was
concentrated, poured into sat. aq NH4Cl (50 mL), and extracted with
Et2O (2 × 50 mL). The combined organic layers were washed
successively with H2O (300 mL) and brine (50 mL), dried (MgSO4),
and concentrated. The residue was solubilized in THF (25 mL) in a
b
Isolated yield after purification by flash chromatography on silica gel.
c
Contaminated by up to 8% impurity.
linked to the boron atom was not observed. 19F NMR chemical shifts
were referenced to external CFCl3 (0.0 ppm). 11B NMR spectra were
obtained on a spectrometer equipped with the appropriate decoupling
accessories. All 11B NMR chemical shifts were referenced to external
BF3·OEt2 (0.0 ppm) with a negative sign indicating an upfield shift.
Data are presented as follows: chemical shift (ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling
constant J (Hz), and integration. Analytical thin-layer chromatography
(TLC) was performed on TLC silica gel plates (0.25 mm) precoated
with a fluorescent indicator. Standard flash chromatography
procedures were followed using 32−63 μm silica gel. Visualization
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round-bottomed flask equipped with a stir bar, and sat. aq KHF2 (4.0
equiv) was added. The flask was closed with a septum, and the
resulting mixture was stirred for 2 h at rt. The reaction mixture was
evaporated to dryness, and the resulting salt was extracted several
times with hot acetone (5 × 50 mL). The filtrate was concentrated to
∼5 mL, and precipitation was achieved by dropwise addition of Et2O
(60 mL) at 0 °C. The resulting product was collected by gravity
filtration on a fritted funnel and dried to the corresponding potassium
alkoxyethyltrifluoroborate as a white solid.
Potassium ((Tetrahydro-2H-pyran-2-yl)methyl)trifluoroborate
1g. Following the general procedure, the reaction performed with 2-
(bromomethyl)tetrahydro-2H-pyran (2.79 g, 15.60 mmol) afforded
759 mg (24%) of the title compound, using a Soxhlet apparatus
1
overnight for the hot acetone extraction. Mp > 200 °C. H NMR
(DMSO-d6, 400 MHz): δ 3.73−3.69 (m, 1H), 3.25−3.11 (m, 2H),
1.82−1.79 (m, 1H), 1.66−1.62 (m, 1H), 1.36−1.29 (m, 3H), 0.93−
0.90 (m, 1H), 0.35−0.33 (m, 1H), 0.16−0.11 (m, 1H). 13C NMR
(DMSO-d6, 100 MHz): δ 78.4, 67.0, 33.3, 26.3, 23.8. 11B NMR
(DMSO-d6, 128 MHz): δ = 4.13 (br s). 19F NMR (DMSO-d6, 377
MHz): δ −134.4. IR: ν 2925, 1266, 1077, 1031, 950, 880, 722 cm−1.
HRMS (ESI-TOF) m/z calcd for C6H11BOF3 (M − K)− 167.0855,
found 167.0856.
Potassium (2-Methoxyethyl)trifluoroborate 1a. Following the
general procedure, the reaction performed with 2-bromoethyl methyl
ether (730 mg, 5.32 mmol) afforded 576 mg (68%) of the title
1
compound. Mp = 123−125 °C. H NMR (acetone-d6, 400 MHz): δ
3.40−3.36 (m, 2H), 3.18 (s, 3H), 0.62−0.43 (m, 2H).13C NMR
(acetone-d6, 100 MHz): δ 73.7, 57.6. 11B NMR (acetone-d6, 128
MHz): 4.90 (br s). 19F NMR (acetone-d6, 377 MHz): δ −139.8. IR: ν
2904, 1105, 1060, 1009, 984, 916, 608 cm−1. HRMS (ESI-TOF) m/z
calcd for C3H7BOF3 (M − K)− 127.0542, found 127.0547.
Potassium 2-Trifluoroboratomethyl-1,4-benzodioxane 1h. Fol-
lowing the general procedure, the reaction performed with 2-
bromomethyl-1,4-benzodioxane (3.06 g, 13.38 mmol) afforded 1.26
1
g (37%) of the title compound. Mp > 200 °C. H NMR (acetone-d6,
400 MHz): δ 6.75−6.69 (m, 4H), 4.48 (dd, J = 11.3, 2.1 Hz, 1H),
4.16−4.09 (m, 1H), 3.64 (dd, J = 11.3, 8.5 Hz, 1H), 0.87−0.81 (m,
1H), 0.53−0.42 (m, 1H). 13C NMR (acetone-d6, 100 MHz): δ 146.0,
144.9, 121.5, 120.9, 117.9, 117.4, 75.5, 70.9. 11B NMR (acetone-d6, 128
MHz): δ 4.30 (br s). 19F NMR (acetone-d6, 377 MHz): δ −138.6. IR:
ν 1594, 1495, 1255, 1036, 939, 897, 751 cm−1. HRMS (ESI-TOF) m/z
calcd for C9H9BO2F3 (M − K)− 217.0648, found 217.0648.
Potassium (2-Ethoxyethyl)trifluoroborate 1b. Following the
general procedure, the reaction performed with 2-bromoethyl ethyl
ether (678 mg, 3.99 mmol) afforded 488 mg (68%) of the title
compound. Mp = 112−114 °C.1H NMR (acetone-d6, 400 MHz): δ
3.44−3.38 (m, 2H), 3.34 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H),
0.59−0.46 (m, 2H). 13C NMR (acetone-d6, 100 MHz): δ 71.1, 65.5,
15.8. 11B NMR (acetone-d6, 128 MHz) δ 4.91 (br s). 19F NMR
(acetone-d6, 377 MHz): δ −139.9. IR: ν 2872, 1251, 1069, 1041, 938,
884, 732 cm−1. HRMS (ESI-TOF) m/z calcd for C4H9BOF3 (M −
K)− 141.0699, found 141.0704.
Synthesis of Potassium {2-[(tert-Butyldiphenylsilyl)oxy]-
ethyl}trifluoroborate. (2-Bromoethoxy)(tert-butyl)diphenyl-
silane.21 Freshly distilled 2-bromoethanol (881 mg, 7.05 mmol, 1
equiv) was added to a solution of imidazole (1.2 g, 2.5 equiv) and tert-
butyldiphenylsilyl chloride (2.3 g, 1.2 equiv) in DMF (5 mL)
according to Corey’s procedure.22 The resulting solution was stirred at
rt for 24 h, treated with H2O (10 mL), and extracted with EtOAc (3 ×
10 mL). The organic layers were combined and dried (MgSO4), and
the solvent was removed under vacuum. The crude material was then
purified by flash column chromatography on silica gel using hexanes/
Potassium (2-Benzyloxyethyl)trifluoroborate 1c. Following the
general procedure, the reaction performed with 2-bromoethyl benzyl
ether (1.09 g, 5.06 mmol) afforded 755 mg (62%) of the title
1
compound. Mp = 180−184 °C. H NMR (acetone-d6, 400 MHz): δ
7.35−7.27 (m, 4H), 7.22 (tt, J = 6.4, 1.8 Hz, 1H), 4.41 (s, 2H), 3.55−
3.51 (m, 2H), 0.65−0.59 (m, 2H). 13C NMR (acetone-d6, 100 MHz):
δ 141.3, 128.9, 128.2, 127.7, 72.4, 71.6. 11B NMR (acetone-d6, 128
MHz) δ 4.81 (br s). 19F NMR (acetone-d6, 377 MHz): δ −139.8. IR: ν
2867, 1328, 1076, 977, 914, 692 cm−1. HRMS (ESI-TOF) m/z calcd
for C9H11BOF3 (M − K)− 203.0855, found 203.0863.
1
EtOAc as the eluent to give 1.53 g of a colorless oil (60%). H NMR
(CDCl3, 500 MHz): δ 7.70−7.68 (m, 4H), 7.45−7.39 (m, 6H), 3.94 (t,
J = 6.5 Hz, 2H), 3.44 (t, J = 6.5 Hz, 2H), 1.09 (s, 9H). 13C NMR
(CDCl3, 125.8 MHz): δ 135.5, 133.2, 129.7, 127.7, 63.9, 33.0, 26.7,
19.2. IR: ν 2921, 2857, 2358, 1428, 823, 700 cm−1. HRMS (ESI-TOF)
m/z calcd for C18H24OSiBr (M + H) 363.0780, found 363.0770.
Potassium {2-[(tert-Butyldiphenylsilyl)oxy]ethyl}trifluoroborate
1i. The synthesis was adapted from the borylation procedure reported
by Marder and Liu:11a a 20 mL vial was charged with CuI (55 mg, 10
mol %) and PPh3 (99 mg, 13 mol %). Inside the glovebox, MeOLi
(220 mg, 2 equiv) and B2Pin2 (1.1 g, 1.5 equiv) were then added. The
vial was then sealed and removed from the glovebox. (2-
Bromoethoxy)(tert-butyl)diphenylsilane (1.05 g, 2.89 mmol, 1 equiv)
in dry DMF (15 mL) was added, and the resulting mixture was stirred
at rt overnight. The color of the solution rapidly changed from cloudy
white to dark black. The reaction mixture was then diluted with EtOAc
(20 mL), filtered through silica gel with copious washings (EtOAc, 20
mL), and concentrated. The crude mixture was then dissolved in
MeOH (5 mL), and aqueous KHF2 (4.5 M, 3 mL) was added
dropwise at 0 °C. After 30 min of stirring, the solvents were removed
using a lyophilizer. The resulting white solid was dissolved in hot
MeCN (10 mL) and sonicated, and the solution was filtered. The
volume of the solution was reduced to ∼2 mL, and the trifluoroborate
was precipitated by addition of hexanes (10 mL) and Et2O (5 mL),
filtration, and drying under vacuum to give 484 mg of the desired
Potassium (2-Phenyloxyethyl)trifluoroborate 1d. Following the
general procedure, the reaction performed with 2-phenoxyethyl
bromide (1.00 g, 4.97 mmol) afforded 621 mg (55%) of the title
1
compound. Mp > 200 °C. H NMR (acetone-d6, 400 MHz): δ 7.22−
7.18 (m, 2H), 6.85−6.83 (m, 2H), 6.79 (tt, J = 7.3, 1.0 Hz, 1H), 4.03−
3.99 (m, 2H), 0.76−0.71 (m, 2H). 13C NMR (acetone-d6, 100 MHz):
δ 161.1, 130.0, 120.1, 115.4, 69.3. 11B NMR (acetone-d6, 128 MHz): δ
4.51 (br s). 19F NMR (acetone-d6, 377 MHz): δ −140.2. IR: ν 1491,
1224, 1082, 1006, 940, 762 cm−1. HRMS (ESI-TOF) m/z calcd for
C8H9BOF3 (M − K)− 189.0699, found 189.0701.
Potassium (2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)trifluoroborate
1e. Following the general procedure, the reaction performed with 2-
(2-bromoethoxy)tetrahydro-2H-pyran (2.77 g, 13.2 mmol) afforded
1
1.96 g (63%) of the title compound. Mp = 182−185 °C. H NMR
(DMSO-d6, 400 MHz): δ 4.45−4.43 (m, 1H), 3.75−3.72 (m, 1H),
3.60−3.55 (m, 1H), 3.36−3.34 (m, 1H), 3.28−3.22 (m, 1H), 1.72−
1.68 (m, 1H), 1.58−1.54 (m, 1H), 1.43−1.35 (m, 4H), 0.43−0.26 (m,
2H). 13C NMR (DMSO-d6, 100 MHz): δ 97.5, 67.7, 61.3, 30.8, 25.3,
19.7. 11B NMR (DMSO-d6, 128 MHz): δ 4.28 (br s). 19F NMR
(DMSO-d6, 377 MHz): δ −136.0. IR: ν 2938, 1250, 1070, 1026, 945,
878, 648 cm−1. HRMS (ESI-TOF) m/z calcd for C7H13BO2F3 (M −
K)− 197.0961, found 197.0960.
1
product as a white solid (43%). Mp > 200 °C. H NMR (DMSO-d6,
500 MHz): δ 7.62 (m, 4H), 7.40 (m, 6H), 3.66−3.62 (m, 2H), 0.95 (s,
9H), 0.51 (m, 2H). 13C NMR (DMSO-d6, 125.8 MHz): δ 135.4,
135.0, 129.7, 128.0, 65.3, 27.2, 19.1. 11B NMR (DMSO-d6, 128.38
MHz): δ 5.16 (m). 19F NMR (DMSO-d6, 470.84 MHz): δ −135.8. IR:
ν 2929, 1472, 1428, 1247, 1061, 1031, 940, 706 cm−1. HRMS (ESI-
TOF) m/z calcd for C18H23OSiF3B (M − K)− 351.1563, found
351.1564.
General Procedure for the Cross-Coupling of Alkoxyethyl-
trifluoroborates and Aryl or Heteroaryl Halides. In an oven-
dried 8 mL microwave vial were introduced bis(di-tert-butyl(4-
Potassium 2-(Trifluoroborato)ethyl Acetate 1f. Following the
general procedure, the reaction performed with 2-bromoethyl acetate
(756 mg, 4.53 mmol) afforded 348 mg (40%) of the title compound.
1
Mp = 165−167 °C. H NMR (acetone-d6, 400 MHz): δ 4.09−4.05
(m, 2H), 1.89 (s, 3H), 0.57−0.54 (m, 2H). 13C NMR (acetone-d6, 100
MHz): δ 171.5, 67.1, 21.4. 11B NMR (acetone-d6, 128 MHz): δ 4.35
(q, J = 63 Hz). 19F NMR (acetone-d6, 377 MHz): δ −140.4. IR: ν
1728, 1244, 1065, 1038, 975, 901, 835 cm−1. HRMS (ESI-TOF) m/z
calcd for C4H7BO2F3 (M − K)− 155.0491, found 155.0494.
F
dx.doi.org/10.1021/jo3021665 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
dimethylaminophenyl)phosphine)dichloropalladium(II) (9 mg, 5 mol
%), the alkoxyethyltrifluoroborate (0.275 mmol, 1.1 equiv), and
Cs2CO3 (244 mg, 3 equiv). The vial was sealed with a cap lined with a
disposable PTFE septum and evacuated under vacuum and purged
with N2 (×3). Degassed toluene (1 mL) and H2O (0.25 mL) were
added by syringe, followed by the desired electrophile (1 equiv).
(When the aryl or heteroaryl halide was a solid, it was added after the
base.) The reaction mixture was then placed in an oil bath preheated at
100 °C and stirred for 24 h at this temperature. After cooling to rt, the
vial was uncapped and diluted with H2O (3 mL) and EtOAc (5 mL ×
2). The combined organics were dried (MgSO4) and filtered through
Celite and concentrated in vacuo. Purification of the crude was
performed by flash chromatography with hexanes/EtOAc: 100/0 to
80/20 with 1% Et3N.
125.9, 125.5, 125.4, 123.7, 73.0, 70.6, 33.4. IR: ν 2856, 1454, 1361,
1100, 1027, 776, 608 cm−1. HRMS (ESI-TOF) m/z calcd for
C19H18ONa (M + Na) 285.1255, found 285.1250.
2-(2-(Benzyloxy)ethyl)naphthalene 2h. Obtained as a yellow solid
1
(58.5 mg, 89%). Mp = 35−36 °C. H NMR (CDCl3, 500 MHz): δ
7.88 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.75 (br s, 1H),
7.54−7.49 (m, 2H), 7.45 (dd, J = 8.5, 1.2 Hz, 1H), 7.42−7.38 (m, 4H),
7.34−7.37 (m, 1H), 4.62 (s, 2H), 3.86 (t, J = 7.0 Hz, 2H), 3.18 (t, J =
7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 138.4, 136.6, 133.6,
132.2, 28.4, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 125.9, 125.3, 73.0,
71.1, 36.5. IR: ν 2866, 1368, 1098, 1074, 821, 740 cm−1. HRMS (ESI-
TOF) m/z calcd for C19H18O (M+) 262.1358, found 262.1353.
1-(2-(Benzyloxy)ethyl)-2-(trifluoromethyl)benzene 2i. Obtained as
a colorless oil (53.6 mg, 76%). 1H NMR (CDCl3, 500 MHz): δ 7.65−
7.67 (m, 1H), 7.50−7.46 (m, 1H), 7.45−7.42 (m, 1H), 7.40−7.28 (m,
6H), 4.56 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H).
13C NMR (CDCl3, 125.8 MHz): δ 138.2, 137.4, 131.8, 131.5, 128.6 (q,
J = 29.5 Hz), 128.3, 127.5, 127.4, 126.2, 125.8 (q, J = 5.7 Hz), 124.5
(d, J = 273.9 Hz), 72.8, 70.5, 32.9. 19F NMR (CDCl3, 470.84 MHz): δ
−59.6. IR: ν = 2980, 1313, 1114, 769, 741 cm−1. HRMS (ESI-TOF)
m/z calcd for C16H15OF3 (M+) 280.1075, found 280.1071.
1-(2-(Benzyloxy)ethyl)-4-methoxybenzene 2a.23 Obtained as a
1
colorless oil (49.5 mg, 82%). H NMR (CDCl3, 500 MHz): δ 7.37−
7.30 (m, 5H), 7.18 (d, J = 8.5 Hz, 2H), 6.87 (dd, J = 7.0, 2.5 Hz, 2H),
4.56 (s, 2H), 3.82 (s, 3H), 3.69 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 7.0 Hz,
2H). 13C NMR (CDCl3, 125.8 MHz): δ 158.0, 138.4, 131.0, 129.8,
128.3, 127.5, 127.4, 113.7, 72.9, 71.4, 55.2, 35.4. IR: ν 2931, 2855,
1512, 1246, 1100, 1036, 739 cm−1. HRMS (ESI-TOF) m/z calcd for
C16H18O2Na (M + Na) 265.1204, found 265.1194.
1-(2-(Benzyloxy)ethyl)-4-(trifluoromethyl)benzene 2j. Obtained as
a white solid (62.1 mg, 89%). Mp = 44−46 °C. 1H NMR (CDCl3, 500
MHz): δ 7.58 (d, J = 8.0 Hz, 2H), 7.38−7.35 (m, 3H), 7.33−7.30 (m,
4H), 4.56 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.01 (t, J = 7.0 Hz, 2H).
13C NMR (CDCl3, 125.8 MHz): δ 143.3, 138.1, 129.2, 128.5 (q, J =
32.0 Hz), 128.3, 127.6, 127.5, 125.1 (q, J = 3.9 Hz), 124.3 (d, J = 271.6
Hz), 73.0, 70.4, 36.1. 19F NMR (CDCl3, 470.84 MHz): δ −62.3. IR: ν
2868, 2362, 1322, 1114, 1066, 738 cm−1. HRMS (ESI-TOF) m/z
calcd for C16H14OF3 (M − H) 279.0997, found 279.0994.
1-(2-(Benzyloxy)ethyl)-2-methoxybenzene 2b. Obtained as a
colorless oil (56.0 mg, 92%). 1H NMR (CDCl3, 500 MHz): δ
7.37−7.35 (m, 4H), 7.32−7.30 (m, 1H), 7.24 (t, J = 7.0 Hz, 2H), 6.93
(td, J = 7.5, 1.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.58 (s, 2H), 3.83 (s,
3H), 3.73 (t, J = 7.0 Hz, 2H), 3.02 (t, J = 7.0 Hz, 2H). 13C NMR
(CDCl3, 125.8 MHz): δ 157.6, 138.6, 130.6, 128.2, 127.5, 127.4, 127.3,
127.1, 120.3, 110.2, 72.7, 69.8, 55.2, 30.8. IR: ν 2360, 1494, 1243,
1099, 1028, 751 cm−1. HRMS (ESI-TOF) m/z calcd for C16H18O2Na
(M + Na) 265.1204, found 265.1212.
1-(2-(Benzyloxy)ethyl)-4-fluorobenzene 2k. Obtained as a yellow
1-(2-(Benzyloxy)ethyl)-3-methoxybenzene 2c. Obtained as a
1
oil (44.3 mg, 77%). H NMR (CDCl3, 300 MHz): δ 7.37−7.31 (m,
1
yellow oil (56.4 mg, 93%). H NMR (CDCl3, 500 MHz): δ 7.40−
5H), 7.24−7.20 (m, 2H), 7.19−6.98 (m, 2H), 4.56 (s, 2H), 3.71 (t, J =
7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz):
δ 161.4 (d, J = 243.8 Hz), 138.3, 134.6 (d, J = 3.0 Hz), 130.2 (d, J = 8.3
Hz), 128.3, 127.5, 127.4, 115.0 (d, J = 21.1 Hz), 72.9, 71.0, 35.5. 19F
NMR (CDCl3, 282.40 MHz): δ −117.3. IR: ν = 2861, 1509, 1221,
1098, 834, 825, 736 cm−1. HRMS (ESI-TOF) m/z calcd for C15H15OF
(M+) 230.1107, found 230.1100.
7.30 (m, 5H), 7.26 (t, J = 7.0 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.83
(br s, 1H), 6.81 (dd, J = 8.5, 2.0 Hz, 1H), 4.57 (s, 2H), 3.82 (s, 3H),
3.74 (t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3,
125.8 MHz): δ 159.6, 140.5, 138.4, 129.2, 128.3, 127.6, 127.5, 121.3,
114.6, 111.6, 72.9, 71.1, 55.1, 36.4. IR: ν 2855, 1602, 1488, 1259, 1100,
737, 696 cm−1. HRMS (ESI-TOF) m/z calcd for C16H18O2 (M+)
242.1307, found 242.1311.
4-(2-(Benzyloxy)ethyl)benzonitrile 2l. Obtained as a white solid
4-(2-(Benzyloxy)ethyl)-N,N-dimethylaniline 2d. Obtained as a
1
1
[52.3 mg, 88% (from X = Cl)]. Mp = 45−47 °C. H NMR (CDCl3,
yellow oil (32.4 mg, 51%). H NMR (CDCl3, 500 MHz): δ 7.37−
500 MHz): δ 7.58 (d, J = 8.0 Hz, 2H), 7.36−7.33 (m, 4H), 7.31 (m,
1H), 7.30−7.27 (m, 2H), 4.52 (s, 2H), 3.72 (t, J = 7.0 Hz, 2H), 2.99 (t,
J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 144.9, 138.0,
132.0, 129.7, 128.3, 127.6, 127.5, 119.0, 110.0, 73.0, 69.9, 36.4. IR: ν
2866, 2224, 1608, 1364, 1096, 1077, 847, 746 cm−1. HRMS (ESI-
TOF) m/z calcd for C16H15NO (M+) 237.1154, found 237.1165.
4-(2-(Benzyloxy)ethyl)benzonitrile 2m. Obtained as a yellow oil
7.34 (m, 4H), 7.31−7.30 (m, 1H), 7.14 (d, J = 8.5 Hz, 2H), 6.73 (d, J
= 8.5 Hz, 2H), 4.57 (s, 2H), 3.69 (t, J = 7.0 Hz, 2H), 2.95 (s, 6H), 2.89
(t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 149.3, 138.5,
129.5, 128.3, 127.6, 127.4, 126.8, 112.9, 72.9, 71.8, 40.8, 35.3. IR: ν
2852, 1615, 1522, 1345, 1099, 947, 810, 644 cm−1. HRMS (ESI-TOF)
m/z calcd for C17H22NO (M + H) 256.1701, found 256.1689.
2-(2-(Benzyloxy)ethyl)-1,3-dimethylbenzene 2e. Obtained as a
yellow oil (49.6 mg, 82%). 1H NMR (CDCl3, 500 MHz): δ 7.40−7.38
(m, 4H), 7.35−7.33 (m, 1H), 7.08−7.04 (m, 3H), 4.60 (s, 2H), 3.62 (t,
J = 7.0 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 2.39 (s, 6H). 13C NMR
(CDCl3, 125.8 MHz): δ 138.4, 136.7, 135.0, 128.3, 128.1, 127.5, 126.1,
72.9, 68.8, 30.2, 19.9. IR: ν 2855, 1453, 1361, 1100, 1028, 770, 644
cm−1. HRMS (ESI-TOF) m/z calcd for C17H19O (M − H) 239.1436,
found 239.1439.
1
(39.7 mg, 67%). H NMR (CDCl3, 500 MHz): δ 7.63 (d, J = 7.5 Hz,
1H), 7.53 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.35−7.31 (m,
3H), 7.30−7.27 (m, 3H), 4.55 (s, 2H), 3.79 (t, J = 7.0 Hz, 2H), 3.18 (t,
J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 143.0, 138.0,
132.7, 132.5, 130.3, 128.3, 127.5, 127.4, 126.8, 118.0, 112.7, 72.8, 69.5,
34.8. IR: ν 2861, 2224, 1452, 1361, 1099, 762, 738 cm−1. HRMS (ESI-
TOF) m/z calcd for C16H16NO (M + H) 238.1232, found 238.1229.
4-(2-(Benzyloxy)ethyl)benzaldehyde 2n. Obtained as a yellow oil
1-(2-(Benzyloxy)ethyl)-2-methylbenzene 2f. Obtained as a color-
1
1
(44.7 mg, 74%). H NMR (CDCl3, 500 MHz): δ 10.00 (s, 1H), 7.82
less oil (630.5 mg, 93%). H NMR (CDCl3, 500 MHz): δ 7.38−7.36
(d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.0 Hz, 2H),
7.30−7.28 (m, 3H), 4.54 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.02 (t, J =
7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 191.9, 146.6, 138.1,
134.7, 129.8, 129.5, 128.3, 127.6, 127.5, 73.0, 70.2, 36.5. IR: ν 2856,
1698, 1607, 1212, 1169, 1099, 741 cm−1. HRMS (ESI-TOF) m/z
calcd for C16H17O2 (M + H) 241.1229, found 241.1222.
(m, 4H), 7.31−7.29 (m, 1H), 7.20−7.16 (m, 4H), 4.58 (s, 2H), 3.70 (t,
J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.35 (s, 3H). 13C NMR
(CDCl3, 125.8 MHz): δ 138.4, 136.8, 136.3, 130.1, 129.3, 128.3, 127.5,
127.4, 126.3, 125.9, 72.9, 70.2, 33.5, 19.3. IR: ν = 2857, 1494, 1454,
1361, 1099, 1028, 740 cm−1. HRMS (ESI-TOF) m/z calcd for
C16H18O (M+) 226.1358, found 226.1367.
1-(4-(2-(Benzyloxy)ethyl)phenyl)ethanone 2o. Obtained as a
1-(2-(Benzyloxy)ethyl)naphthalene 2g. Obtained as a colorless oil
1
1
yellow oil (52.4 mg, 82%). H NMR (CDCl3, 500 MHz): δ 7.91 (d,
(48.3 mg, 74%). H NMR (CDCl3, 500 MHz): δ 8.11 (d, J = 8.0 Hz,
J = 8.0 Hz, 2H), 7.35−7.33 (m, 4H), 7.33−7.29 (m, 3H), 4.54 (s, 2H),
3.73 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H), 2.60 (s, 3H). 13C
NMR (CDCl3, 125.8 MHz): δ 197.7, 144.9, 138.1, 135.3, 129.1, 128.4,
128.3, 127.6, 127.5, 72.9, 70.4, 36.3, 26.5. IR: ν 2863, 2363, 1681,
1H), 7.91 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.57−7.51 (m,
2H), 7.47−7.43 (m, 2H), 7.39−7.33 (m, 5H), 4.60 (s, 2H), 3.89 (t, J =
7.0 Hz, 2H), 3.48 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz):
δ 138.3, 134.8, 133.8, 132.1, 128.7, 128.3, 127.6, 127.5, 127.0, 126.8,
G
dx.doi.org/10.1021/jo3021665 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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1607, 1359, 1267, 1100, 956, 644 cm−1. HRMS (ESI-TOF) m/z calcd
for C17H19O2 (M + H) 255.1385, found 255.1383.
1H), 8.0 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.71 (m, 1H),
7.61 (m, 1H), 7.34−7.27 (m, 5H), 4.55 (s, 2H), 3.84 (t, J = 7.0 Hz,
2H), 3.36 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ
151.5, 143.3, 138.1, 134.8, 130.2, 128.4, 128.3, 128.2, 128.1, 127.6,
127.5, 126.8, 122.8, 73.0, 70.0, 30.5. IR: ν 2918, 2362, 1622, 1100, 896,
748 cm−1. HRMS (ESI-TOF) m/z calcd for C18H18NO (M + H)
264.1388, found 264.1380.
Methyl 4-(2-(Benzyloxy)ethyl)benzoate 2p. Obtained as a yellow
solid (62.2 mg, 92%). Mp = 27−29 °C. 1H NMR (CDCl3, 500 MHz):
δ 7.98 (d, J = 8.0 Hz, 2H), 7.36−7.29 (m, 7H), 4.53 (s, 2H), 3.92 (s,
3H), 3.73 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H). 13C NMR
(CDCl3, 125.8 MHz): δ 167.0, 144.6, 138.1, 129.6, 128.9, 128.3, 128.1,
127.6, 127.5, 72.9, 70.4, 51.9, 36.3. IR: ν 2862, 1719, 1610, 1278, 1105,
645 cm−1. HRMS (ESI-TOF) m/z calcd for C17H19O3 (M + H)
271.1334, found 271.1336.
1-(2-(Benzyloxy)ethyl)-4-nitrobenzene 2q. Obtained as an orange
solid (60.0 mg, 93%). Mp = 45−46 °C. 1H NMR (CDCl3, 500 MHz):
δ 8.15 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.35−7.33 (m,
2H), 7.31−7.27 (m, 3H), 4.53 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.03 (t,
J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 147.2, 146.6,
137.9, 129.7, 128.3, 127.6, 127.5, 123.4, 73.0, 69.8, 36.1. IR: ν 2862,
1598, 1508, 1341, 1123, 856, 739 cm−1. HRMS (ESI-TOF) m/z calcd
for C15H16NO3 (M + H) 258.1130, found 258.1138.
tert-Butyl 5-(2-(Benzyloxy)ethyl)-1H-indole-1-carboxylate 3f. Ob-
1
tained as a yellow solid (78.4 mg, 89%). Mp = 28−30 °C. H NMR
(CDCl3, 500 MHz): δ 8.08 (m, 1H), 7.60 (d, J = 3.5 Hz, 1H), 7.44 (d,
J = 1.0 Hz, 1H), 7.38−7.34 (m, 4H), 7.32−7.30 (m, 1H), 7.22 (dd, J =
8.5, 1.5 Hz, 1H), 6.54 (d, J = 3.5 Hz, 1H), 4.57 (s, 2H), 3.76 (t, J = 7.0
Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 1.70 (s, 9H). 13C NMR (CDCl3,
125.8 MHz): δ 149.7, 138.4, 133.8, 133.2, 130.7, 128.3, 127.6, 127.4,
126.0, 125.3, 120.9, 114.9, 107.1, 83.4, 72.9, 71.7, 36.2, 28.1. IR: ν
2851, 1729, 1470, 1372, 1352, 1163, 1091, 1026, 648 cm−1. HRMS
(ESI-TOF) m/z calcd for C22H25NO3Na (M + Na) 374.1732, found
374.1727.
N-(4-(2-(Benzyloxy)ethyl)phenyl)acetamide 2r. Obtained as a
white solid (59.0 mg, 87%). Mp = 102−104 °C. H NMR (CDCl3,
5-(2-(Benzyloxy)ethyl)-1H-indole 3g. Obtained as a yellow oil
(34.4 mg, 55%). 1H NMR (CDCl3, 500 MHz): δ 8.14 (br s, 1H), 7.53
(s, 1H), 7.38 (m, 4H), 7.32 (m, 2H), 7.17 (t, J = 2.5 Hz, 1H), 7.11 (d, J
= 8.5 Hz, 1H), 6.53 (m, 1H), 4.60 (s, 2H), 3.79 (t, J = 7.0 Hz, 2H),
3.09 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 138.5,
134.6, 130.0, 128.3, 128.1, 127.6, 127.4, 124.3, 123.3, 120.5, 110.8,
102.2, 72.9, 72.2, 36.4. IR: ν 3414, 1477, 1332, 1093, 726, 648 cm−1.
HRMS (ESI-TOF) m/z calcd for C17H18NO (M + H) 252.1388,
found 252.1379.
5-(2-(Benzyloxy)ethyl)pyrimidine 3h. Obtained as an orange oil
(36.8 mg, 69%). 1H NMR (CDCl3, 500 MHz): δ 9.09 (s, 1H), 8.64 (s,
2H), 7.34−7.29 (m, 2H), 7.29−7.23 (m, 3H), 4.51 (s, 2H), 3.70 (t, J =
7.0 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz):
δ 157.1, 157.0, 137.7, 132.6, 128.4, 127.7, 127.5, 73.1, 69.3, 30.9. IR: ν
2853, 2359, 1560, 1409, 1097, 728 cm−1. HRMS (ESI-TOF) m/z
calcd for C13H14N2O (M+) 214.1106, found 214.1099.
1
500 MHz): δ 7.42 (d, J = 8.5 Hz, 2H), 7.34−7.28 (m, 6H), 7.18 (d, J =
8.5 Hz, 2H), 4.53 (s, 2H), 3.68 (t, J = 7.0 Hz, 2H), 2.90 (t, J = 7.0 Hz,
2H), 2.16 (s, 3H). 13C NMR (CDCl3, 125.8 MHz): δ 168.2, 138.3,
136.0, 135.0, 129.3, 128.3, 127.5, 127.4, 119.9, 72.9, 71.1, 35.7, 24.4.
IR: ν 3310, 1660, 1607, 1322, 1114, 834, 738 cm−1. HRMS (ESI-
TOF) m/z calcd for C17H20NO2 (M + H) 270.1494, found 270.1487.
4-(2-(Benzyloxy)ethyl)benzenesulfonamide 2s. Obtained as a
1
white solid (25.0 mg, 34%). Mp = 114−115 °C. H NMR (CDCl3,
500 MHz): δ 7.85 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.36−
7.33 (m, 2H), 7.30−7.27 (m, 3H), 4.89 (br s, 2H) 4.52 (s, 2H), 3.72 (t,
J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8
MHz): δ 144.8, 139.7, 137.9, 129.6, 128.3, 127.6, 127.5, 126.4, 73.0,
70.1, 36.1. IR: ν 3335, 3263, 2868, 2360, 2342, 1307, 1160, 903, 686
cm−1. HRMS (ESI-TOF) m/z calcd for C15H16NO3S (M − H)
290.0851, found 290.0864.
3-(2-(Benzyloxy)ethyl)thiophene 3i:24 Obtained as a colorless oil
(48.1 mg, 88%). 1H NMR (CDCl3, 500 MHz): δ 7.38−7.33 (m, 4H),
7.32 (m, 1H), 7.28 (m, 1H), 7.06 (m, 1H), 7.03 (m, 1H), 4.58 (s, 2H),
3.74 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3,
125.8 MHz): δ 139.2, 138.3, 128.5, 128.3, 127.6, 127.5, 125.1, 121.1,
72.9, 70.4, 30.7. IR: ν 2360, 2341, 1453, 1099, 737, 648 cm−1. HRMS
(ESI-TOF) m/z calcd for C13H14OS (M+) 218.0765, found 218.0766.
1-Methoxy-4-(2-methoxyethyl)benzene 4a.25 Obtained as a color-
3-(2-(Benzyloxy)ethyl)pyridine 3a. Obtained as a yellow oil (28.8
1
mg, 54%). H NMR (CDCl3, 500 MHz): δ 8.51 (s, 1H), 7.48 (d, J =
5.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.40−7.33 (m, 2H), 7.32−7.28
(m, 3H), 7.21 (dd, J = 5.0, 7.5 Hz, 1H), 4.52 (s, 2H), 3.70 (t, J = 7.0
Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ
150.2, 147.6, 138.0, 136.3, 134.5, 128.3, 127.6, 127.5, 123.1, 73.0, 70.3,
33.4. IR: ν 2858, 2362, 1361, 1100, 1028, 699 cm−1. HRMS (ESI-
TOF) m/z calcd for C14H16NO (M + H) 214.1232, found 214.1223.
5-(2-(Benzyloxy)ethyl)-2-methoxypyridine 3b. Obtained as a
1
less oil (26.3 mg, 63%). H NMR (CDCl3, 500 MHz): δ 7.15 (d, J =
8.5 Hz, 2H), 6.85 (dd, J = 7.0, 2.0 Hz, 2H), 3.80 (s, 3H), 3.58 (t, J =
7.0 Hz, 2H), 3.37 (s, 3H), 2.84 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3,
125.8 MHz): δ 158.0, 130.9, 129.7, 127.3, 114.0, 113.7, 73.8, 58.5,
55.1, 35.2. IR: ν 2833, 1513, 1246, 1114, 1034, 833 cm−1. HRMS (ESI-
TOF) m/z calcd for C10H15O2 (M + H) 167.1072, found 167.1069.
1-(2-Ethoxyethyl)-4-methoxybenzene 4b. Obtained as a colorless
1
yellow oil (42.6 mg, 70%). H NMR (CDCl3, 500 MHz): δ 8.18 (d,
J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.35−7.27 (m, 5H), 7.10 (s, 1H), 4.52
(s, 2H), 3.83 (s, 3H), 3.71 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H).
13C NMR (CDCl3, 125.8 MHz): δ 155.4, 142.5, 138.0, 135.3, 128.3,
127.6, 127.5, 127.4, 121.1, 73.0, 70.3, 55.4, 33.3. IR: ν 2852, 2362,
1588, 1283, 1100, 868, 699 cm−1. HRMS (ESI-TOF) m/z calcd for
C15H18NO2 (M + H) 244.1338, found 244.1328.
2-(2-(Benzyloxy)ethyl)pyridine 3c. Obtained as a colorless oil [16.5
mg, 31% (from X = Cl)]. 1H NMR (CDCl3, 500 MHz): δ 8.54 (d, J =
5.0 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.34−7.27 (m, 5H), 7.23 (m,
1H), 7.13 (t, J = 7.5 Hz, 1H), 4.54 (s, 2H), 3.88 (t, J = 7.0 Hz, 2H),
3.12 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ 159.2,
149.2, 138.3, 136.1, 128.2, 127.5, 127.4, 123.5, 121.2, 72.9, 69.5, 38.6.
IR: ν 2851, 2362, 1592, 1093, 749, 698 cm−1. HRMS (ESI-TOF) m/z
calcd for C14H16NO (M + H) 214.1232, found 214.1225.
1
oil (32.5 mg, 72%). H NMR (CDCl3, 500 MHz): δ 7.16 (d, J = 8.5
Hz, 2H), 6.85 (dd, J = 7.0, 2.0 Hz, 2H), 3.80 (s, 3H), 3.61 (t, J = 7.5
Hz, 2H), 3.52 (q, J = 7.0 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 1.22 (t, J =
7.0 Hz, 3H). 13C NMR (CDCl3, 125.8 MHz): δ 158.0, 131.0, 129.7,
127.3, 113.7, 71.8, 66.1, 55.1, 35.4, 15.1. IR: ν 2854, 1612, 1513, 1245,
1109, 1037, 830 cm−1. HRMS (ESI-TOF) m/z calcd for C11H16O2 (M
+) 180.1150, found 180.1152.
2-(4-Methoxyphenethoxy)tetrahydro-2H-pyran 4c.26 Obtained as
1
a colorless oil (45.5 mg, 77%). H NMR (CDCl3, 500 MHz): δ 7.17
(d, J = 8.5 Hz, 2H), 6.84 (dd, J = 7.0, 2.0 Hz, 2H), 4.60 (t, J = 3.5 Hz,
1H), 3.95−3.90 (m, 1H), 3.85−3.77 (m, 1H), 3.79 (s, 3H), 3.62−3.57
(m, 1H), 3.48−3.46 (m, 1H), 2.87 (t, J = 7.0 Hz, 2H), 1.89−1.79 (m,
1H), 1.74−1.68 (m, 1H), 1.63−1.47 (m, 4H). 13C NMR (CDCl3,
125.8 MHz): δ 158.0, 131.1, 129.8, 113.6, 98.6, 68.4, 62.1, 55.1, 35.4,
30.6, 25.4, 19.4. IR: ν 2939, 1513, 1246, 1120, 1030, 824 cm−1. HRMS
(ESI-TOF) m/z calcd for C14H20O3 (M+) 236.1412, found 236.1406.
1-Methoxy-4-(2-phenoxyethyl)benzene 4d.27 Obtained as a color-
5-(2-(Benzyloxy)ethyl)quinoline 3d. Obtained as a yellow oil (55.0
1
mg, 83%). H NMR (CDCl3, 500 MHz): δ 8.91 (d, J = 1.5 Hz, 1H),
8.38 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 8.5, 7.5
Hz, 1H), 7.44 (d, J = 7.0 Hz, 1H), 7.39 (dd, J = 7.5, 4.5 Hz, 1H),
7.33−7.26 (m, 5H), 4.53 (s, 2H), 3.81 (t, J = 7.0 Hz, 2H), 3.39 (t, J =
7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ = 149.9, 148.6, 138.1,
135.5, 132.2, 129.0, 128.3, 127.6, 127.5, 127.2, 127.1, 120.7, 73.0, 70.4,
32.6. IR: ν = 2855, 2362, 1500, 1362, 1100, 802 cm−1. HRMS (ESI-
TOF) m/z calcd for C18H18NO (M + H) 264.1388, found 264.1380.
4-(2-(Benzyloxy)ethyl)isoquinoline 3e. Obtained as a yellow oil
(50.5 mg, 77%). 1H NMR (CDCl3, 500 MHz): δ 9.16 (s, 1H), 8.44 (s,
1
less oil (18.0 mg, 31%). H NMR (CDCl3, 500 MHz): δ 7.31−7.28
(m, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.93 (d, J =
8.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.16 (t, J = 7.0 Hz, 2H), 3.82 (s,
3H), 3.06 (t, J = 7.0 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz): δ
H
dx.doi.org/10.1021/jo3021665 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
158.7, 158.2, 130.2, 129.9, 129.3, 120.6, 114.5, 113.8, 68.7, 55.2, 34.8.
IR: ν 2360, 1513, 1243, 1176, 1034, 825, 754 cm−1. HRMS (ESI-
TOF) m/z calcd for C15H16O2 (M+) 228.1150, found 228.1144.
2-(4-Methoxybenzyl)tetrahydro-2H-pyran 4e. Obtained as a
particular, see: (b) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.;
Lloyd-Jones, G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49,
5156. (c) Lennox, A. J. J.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2012,
134, 7431.
(4) For selected recent examples of preparation and use of
functionalized methyltrifluoroborate salts, see: for alkoxymethyl:
(a) Molander, G. A.; Beaumard, F. Org. Lett. 2011, 13, 3948.
(b) Colombel, V.; Rombouts, F.; Oehlrich, D.; Molander, G. A. J. Org.
1
colorless oil (36.3 mg, 70%). H NMR (CDCl3, 500 MHz): δ 7.14
(d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.00−3.98 (m, 1H), 3.80
(s, 3H), 3.46−3.39 (m, 2H), 2.83 (dd, J = 14.0, 7.0 Hz, 1H), 2.60 (dd, J
= 14.0, 7.0 Hz, 1H), 1.82 (dd, J = 13.0, 2.0 Hz, 1H), 1.63−1.55 (m,
2H), 1.52−1.47 (m, 1H), 1.46−1.41 (m, 1H), 1.32−1.24 (m, 1H). 13C
NMR (CDCl3, 125.8 MHz): δ 157.9, 130.8, 130.2, 113.5, 78.9, 68.5,
55.1, 42.2, 31.3, 26.0, 23.4. IR: ν 2934, 1512, 1245, 1090, 1039, 648
cm−1. HRMS (ESI-TOF) m/z calcd for C13H19O2 (M + H) 207.1385,
found 207.1385.
́
Chem. 2012, 77, 2966. For aminomethyl: (c) Fleury-Bregeot, N.;
Raushel, J.; Sandrock, D. L.; Dreher, S. D.; Molander, G. A. Chem.
Eur. J. 2012, 18, 9564. (d) Molander, G. A.; Beaumard, F. Org. Lett.
2011, 13, 1242. For amidomethyl: (e) Devulapally, R.; Fleury-
Breg
́
eot, N.; Molander, G. A.; Seapy, D. G. Tetrahedron Lett. 2012, 53,
eot, N.; Hiebel, M.-A. Org. Lett.
2-((4-Methoxyphenethoxy)methyl)-2,3-dihydrobenzo[b][1,4]-
1051. (f) Molander, G. A.; Fleury-Breg
́
dioxine 4f. Obtained as a white solid (31.2 mg, 49%). Mp = 68−71
2011, 13, 1694. For carbamatomethyl: (g) Molander, G. A.; Shin, I.
Org. Lett. 2012, 14, 3138. (h) Molander, G. A.; Shin, I. Org. Lett. 2011,
13, 3956.
1
°C. H NMR (CDCl3, 500 MHz): δ 7.20 (d, J = 8.0 Hz, 2H), 6.91−
6.84 (m, 4H), 6.89 (d, J = 8.0 Hz, 2H), 4.33 (qd, J = 7.2, 2.0 Hz, 1H),
4.19 (dd, J = 11.2, 2.2 Hz, 1H), 3.91 (dd, J = 11.2, 7.0 Hz, 1H), 3.83 (s,
3H), 3.07 (dd, J = 14.0, 7.0 Hz, 1H), 2.85 (dd, J = 14.0, 7.0 Hz, 1H).
13C NMR (CDCl3, 125.8 MHz): δ = 158.4, 143.2, 143.1, 130.3, 128.3,
121.4, 121.1, 117.3, 116.9, 114.0, 73.8, 66.9, 55.2, 36.6. IR: ν 1610,
1592, 1514, 1493, 1268, 1243, 1036, 754 cm−1. HRMS (ESI-TOF) m/
z calcd for C16H16O3 (M+) 256.1099, found 256.1104.
(5) (a) Hawthorne, M. F.; Dupont, J. A. J. Am. Chem. Soc. 1958, 80,
5830. (b) Matteson, D. S.; Liedtke, J. D. J. Org. Chem. 1963, 28, 1924.
(c) Matteson, D. S.; Peacock, K. J. Organomet. Chem. 1964, 2, 190.
(6) Matteson, D. S.; Liedtke, J. D. J. Am. Chem. Soc. 1965, 87, 1526.
(7) Hawthorne, M. F. J. Am. Chem. Soc. 1961, 83, 2541.
(8) (a) Pasto, D. J.; Cumbo, C. C. J. Am. Chem. Soc. 1964, 86, 4343.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C, 11B, and 19F spectra for all compounds
(9) Tallman, R. C. J. Am. Chem. Soc. 1934, 56, 126.
prepared by the method described. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) (a) Lawrence, J. D.; Takahashi, M.; Bae, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2004, 126, 15334. For a Ru-based C−H, see: (b) Murphy,
J. M.; Lawrence, J. D.; Kawamura, K.; Incarvito, C.; Hartwig, J. F. J.
Am. Chem. Soc. 2006, 128, 13684. For a recent publication dealing
with the Ir-catalyzed borylation of C−H bonds in cyclic ethers, see:
(c) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 12422.
(11) (a) Yang, C.-T.; Zhang, Z.-Q.; Tajuddin, H.; Wu, C.-C.; Liang,
J.; Liu, J.-H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L.
Angew. Chem., Int. Ed. 2012, 51, 528. (b) Yi, J.; Liu, J.-H.; Liang, J.; Dai,
J.-J.; Yang, C.-T.; Fu, Y.; Liu, L. Adv. Synth. Catal. 2012, 354, 1685.
(c) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890. (d) Dudnik, A. S.; Fu,
G. C. J. Am. Chem. Soc. 2012, 134, 10693. (e) Joshi-Pangu, A.; Ma, X.;
Diane, M.; Iqbal, S.; Kribs, R. J.; Huang, R.; Wang, C.-Y.; Biscoe, M. R.
J. Org. Chem. 2012, 77, 6629.
(12) The procedure for converting boronic acids and boronate esters
to potassium trifluoroborate salts using milder conditions was also
tested but did not provide better yields. See: Lennox, A. J. J.; Lloyd-
Jones, G. C. Angew. Chem., Int. Ed. 2012, 51, 9385.
(13) (a) Wuts, P. G. M.; Greene, T. W. In Protecting Groups in
Organic Synthesis, 3rd ed.; Greene, T. W., Wuts, P. G. M., Eds.; John
Wiley & Sons, Inc.: Hoboken, NJ, 1999; pp 76−86. (b) Kocienski, P. J.
In Protecting Groups, 3rd ed.; Kocienski, P. J., Ed.; Georg Thieme
Verlag: Stuttgart, 2005; pp 241−257.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu; FROMBOUT@its.jnj.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Science
Foundation (GOALI), and the NIGMS (R01 GM-081376).
AllyChem is acknowledged for the generous donation of
bispinacolatodiboron. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data. Dr.
Patrick Caroll (University of Pennsylvania) is acknowledged for
performing the X-ray analysis.
REFERENCES
■
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I
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