A general Suzuki cross-coupling reaction of heteroaromatics catalyzed by nanopalladium on amino-functionalized siliceous mesocellular foam

Article abstract of DOI:10.1021/jo500409r

Suzuki-Miyaura cross-coupling reactions of heteroaromatics catalyzed by palladium supported in the cavities of amino-functionalized siliceous mesocellular foam are presented. The nanopalladium catalyst effectively couples not only heteroaryl halides with

Full text of DOI:10.1021/jo500409r

Article
pubs.acs.org/joc
A General Suzuki Cross-Coupling Reaction of Heteroaromatics
Catalyzed by Nanopalladium on Amino-Functionalized Siliceous
Mesocellular Foam
Emma Bratt,† Oscar Verho,‡ Magnus J Johansson,† and Jan-Erling Backvall*,‡
̈
†AstraZeneca R&D, Innovative Medicines, Cardiovascular and Metabolic Diseases, Medicinal Chemistry, Pepparedsleden 1, SE-431
83 Molndal, Sweden
̈
‡Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Suzuki−Miyaura cross-coupling reactions of
heteroaromatics catalyzed by palladium supported in the cavities
of amino-functionalized siliceous mesocellular foam are
presented. The nanopalladium catalyst effectively couples not
only heteroaryl halides with boronic acids but also heteroaryl
halides with boronate esters, potassium trifluoroborates, MIDA
boronates, and triolborates, producing a wide range of
heterobiaryls in good to excellent yields. Furthermore, the
heterogeneous palladium nanocatalyst can easily be removed
from the reaction mixture by filtration and recycled several times
with minimal loss in activity. This catalyst provides an
alternative, environmentally friendly, low-leaching process for
the preparation of heterobiaryls.
of the reaction and enables efficient recycling of the catalyst.
INTRODUCTION
■
With ligand-free catalytic systems, the reaction also becomes
more environmentally friendly and the work-up is further
simplified.15 Various supports for palladium have been
explored,16−20 such as carbon-based materials,21,22 metal−
organic frameworks (MOF),23,24 Al2O3,25 and polystyrene.26
To this end, we decided to investigate a relatively new support,
namely, mesocellular foam (MCF), which is a silica-based
mesoporous material with a large surface area and a large pore
volume, as well as an adjustable pore size.27,28 The MCF
support has the advantage of presenting surface silanol groups
that can be functionalized, with a range of diverse ligands,
making it a great support for chemical catalysts and
biocatalysts.29−31 Palladium immobilized on aminopropyl
(AmP)-functionalized siliceous mesocellular foam (Pd0-AmP-
MCF) is a recently developed heterogeneous catalyst in our
laboratories.32 This catalyst has been used successfully in
transfer hydrogenation of alkenes and Suzuki cross-couplings
with aryl halides,33 in racemization of amines,32 in aerobic
oxidation of primary and secondary alcohols,34 and in selective
transfer hydrogenation of nitroarenes to anilines.35 Recently,
both enzyme Candida antarctica Lipase B and palladium
nanoparticles were immobilized in MCF (in the same cavity)
and used for dynamic kinetic resolution (DKR) of amines.36
The Suzuki−Miyaura cross-coupling reaction is one of the most
commonly employed transformations for formation of carbon−
carbon bonds. Because of the mild reaction conditions, the
availability of reagents, and the broad functional group
tolerance of this transformation, it has found extensive use in
synthetic organic chemistry.1−3 Heterobiaryls are common
structural motifs in biologically active compounds, including
drugs in clinical use (Figure 1),4 and these compounds should
be readily available via cross-coupling methodology.
However, there are only a handful of Suzuki−Miyaura
procedures that tolerate a wider scope of heterocycles as these
cross-coupling reactions typically result in low yields or
complete catalyst inhibition.7−9 A majority of the cross-
coupling reactions used in the pharmaceutical industry rely
on homogeneous catalysis, which requires recycling of often
expensive and toxic catalysts. These catalysts may generate
poisonous waste, and there is also a profound risk for metal
contamination in the desired product. From a patient safety
perspective, removal of toxic metal residues in the pharmaceuti-
cally active ingredient is very important.10,11 The acceptable
level of the platinoids (Pt, Pd, Ir, Rh, Ru) in a compound for
oral administration is less than 10 ppm.12,13 For this reason, the
development of new techniques and supports for immobiliza-
tion of the catalytic metal species has gained increased
attention.10,14 Thus, a heterogeneous palladium catalyst where
the metal is immobilized to a solid support allows for easier
separation of the catalyst from the reaction mixture at the end
Received: February 20, 2014
Published: March 28, 2014
© 2014 American Chemical Society
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Figure 1. Drugs containing heterobiaryl motif.5,6
Scheme 1. Suzuki Couplings of Six-Membered Heteroaromatic Halides, Triflates, and 4-Methoxyphenylboronic Acid Using Pd0-
a
AmP-MCF as Catalyst
a
Reaction conditions (unless otherwise noted): aryl halide (0.30 mmol), boronic acid (0.39 mmol), K2CO3 (0.90 mmol), Pd (1 mol %), EtOH (95%
b
c
aq):H2O (1:1, 2 mL, 0.15M), 90 °C, μw, 30 min. Reaction run for 15 min. Reaction run for 1 h at 130 °C, the yield was determined by LCMS.
d
e
f
0.1 mol % Pd. The yield was determined by 1H NMR using 1,2,4,5-tetramethylbenzene as internal standard. Reaction conditions: aryl halide (2.0
g
mmol), boronic acid (2.6 mmol), K2CO3 (6.0 mmol), Pd (1 mol %), EtOH (95% aq):H2O (1:1, 13.3 mL, 0.15M), 90 °C, μw, 30 min. Reaction run
for 1 h. Reaction run in EtOH (95% aq), 0.5 M.
h
Herein, we report on the use of Pd0-AmP-MCF as a
heterogeneous catalyst in Suzuki cross-coupling reactions, using
a wide range of heteroaromatic halides and boron derivatives.
in high to excellent yields from the corresponding iodopyridine.
Synthesis of 1 using 3-iodopyridine was also evaluated at room
temperature and yielded 30% product after 20 h, thus making it
impractically slow. Substituting the iodine for chlorine resulted
in only 25% yield and a slow reaction even at 130 °C.
Furthermore, the corresponding triflate gave no product (1),
and only hydrolysis of the triflate was observed. Exploring the
electronic effect in substituted halopyridines revealed that 5-
bromopyridine substituted in the 2-position with an electron-
donating group, such as methoxy (4), gave the same high yield
compared to the unsubstituted pyridine 1. The yield of 4 could
not be improved by prolonged reaction time. Introducing an
electron-withdrawing group in the same position, exemplified
by products 5 and 6, afforded the biaryl compound in excellent
RESULTS AND DISCUSSION
■
We initially examined the Suzuki cross-coupling of 3-
iodopyridine and 4-methoxyphenylboronic acid with potassium
carbonate37 as base, using Pd0-AmP-MCF (1 mol % palladium)
as catalyst in ethanol/water (1:1). The reaction was run at 90
°C for 30 min in a microwave reactor. To our delight,
heterobiaryl 1 was obtained in 94% yield.
The same reaction conditions were applied to a range of
heteroaromatic halides to investigate the substrate scope. As
shown in Scheme 1, the coupled products, 1−3, were obtained
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a
Scheme 2. Suzuki Couplings of 4-Iodoanisole and Various Heteroaryl Boronic Acids Using Pd0-AmP-MCF as Catalyst
a
Reaction conditions (unless otherwise noted): 4-iodoanisole (0.30 mmol), boronic acid (0.39 mmol), K2CO3 (0.90 mmol), Pd (1 mol %), EtOH
b
(2 mL, 0.15M), 90 °C, μw, 30 min. Reaction run for 1 h.
Scheme 3. Suzuki Couplings of Fused Heteroaryl Bromides and 4-Methoxyphenylboronic Acid Using Pd0-AmP-MCF as
a
Catalyst
a
Reaction conditions (unless otherwise noted): aryl halide (0.30 mmol), boronic acid (0.39 mmol), K2CO3 (0.90 mmol), Pd (1 mol %), EtOH/H2O
b
(1:1, 2 mL), 90 °C, μw, 30 min. Reaction run for 1 h.
yield for both the bromo and the iodo derivatives, although a
longer reaction time, 1 h, was needed for the bromo
compounds. To demonstrate the practical utility of this
method, a larger scale synthesis of 5 was performed, giving
the compound in 98% yield (Scheme 1). In addition, the
methodology was found to be efficient also for substrates that
contain multiple heteroatoms, such as 5-iodopyrimidine, and 2-
iodopyrazine, giving the coupling products, 7 and 8,
respectively, in excellent yields. The reaction of 5-iodopyridone
was unsuccessful, but there is ample support in the literature
that more basic nitrogens (pKa = 11 for pyridone38) can
coordinate to palladium and inhibit the reaction.7,39 In the
above-mentioned reaction, a color change of the palladium
from black to transparent was noticed in the end of the
reaction, indicating that the palladium may have been
deactivated by nitrogen coordination.7 However, by using the
corresponding methylated derivative, the N-methyl pyridone,
10, could be prepared but in a disappointingly low yield. In
general, 1 mol % catalyst loading was used for all reactions
reported herein. Reduction of the catalyst loading to 0.1 mol %
of palladium, under otherwise identical reaction conditions,
afforded a 90% yield of biaryl product 2, whereas, with only
0.01 mol % of palladium, merely 20% conversion to product 2
was observed after 13 h.
With these results, we were encouraged to include a variety
of heteroaryl boronic acids. As shown in Scheme 2, the
heterobiaryl products, 4, 5, 11−13, were obtained in high to
excellent yields independently of electronic effects. It is
noteworthy that these transformations failed with the
previously employed water/ethanol mixture, probably due to
the low solubility of 4-iodoanisole. When ethanol (95% aq) was
used as the solvent, good to excellent yields were obtained.
To further evaluate the substrate scope, the reaction
conditions were applied to a number of fused heteroaromatic
ring systems. These type of aromatics, particularly 6,5-fused
rings, are very common in drug discovery.4 As shown in
Scheme 3, 6-bromoisoquinoline and 3-bromoquinoline,
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Scheme 4. Suzuki Couplings with Five-Membered Heteroaryl Halides and 4-Methoxyboronic Acid Using Pd0-AmP-MCF as
a
Catalyst
a
Reaction conditions (unless otherwise noted): aryl halide (0.30 mmol), boronic acid (0.39 mmol), K2CO3 (0.90 mmol), Pd (1 mol %), EtOH/H2O
b
1
(1:1, 2 mL), 90 °C, μw, 30 min. The yield was determined by H NMR using 1,2,4,5-tetramethylbenzene as internal standard.
coupled with 4-methoxyphenylboronic acid, gave excellent to
moderate yields of 14 and 15, respectively.
and are at present an alternative to some boronic acids,
especially heteroaromatic substrates, where there is a risk of
hydrolytic cleavage of the carbon−boron bond under basic
aqueous conditions.41,42 The lithium salt of 3-pyridyl
triolborate coupled in high yield to give the heterobiaryl
product 32 (entry 8).
The protocol was also found to be efficient for indole
substrates, producing 16 and its structual isomer 17 in high
yields. Again, with substrates containing slightly acidic N-H, no
heterobiaryl products were obtained, as exemplified by 18 and
20, while the methylated indazole product, 19, was obtained in
moderate yield. According to the recent literature, indazole and
benzimidazole, which have pKa’s40 of 13.8 and 12.9,
respectively, can, under the reaction conditions used,
coordinate to palladium and deactivate the catalyst.7 This
explanation is supported by our own findings, as evidenced by
18 and 20. Interestingly, an indole N-H (pKa38 = 16.97) was
well-tolerated (16, 17).
We then went on to prove the generality of this protocol by
including five-membered heteroaryl halides. To our surprise,
the steric hindrance of the substrates, 4-iodo-3,5-dimethylisox-
azole and 4-iodo-1,3,5-trimethyl-1H-pyrazole, did not appreci-
ably affect the yield of the products 21 and 22, which were both
coupled in high yields (Scheme 4). Furthermore, 2-
iodothiophene and 2-iodofurane were both successfully coupled
to produce 23 and 24, again in excellent yield. In accordance
with the indazole and benzimidazole substrates, 4-iodopyrazole
failed to give the desired product (pKa38 = 14.2 for pyrazole),
while the methylated pyrazole derivatives were coupled with 4-
methoxy boronic acid to generate the biaryl products 26 and 27
in 16% and 62% yield, respectively.
As recently reported by us, the nanocatalyst shows excellent
reusability for Suzuki couplings with aryl halides.33 To ensure
that this was also true for heteroaromatics, which potentially
may act as ligands for palladium, the Pd0-AmP-MCF was
recycled several times. To our satisfaction, the catalyst could be
recycled at least three times without any loss of activity (see
Scheme 1, products 7 and 8, respectively). Interestingly,
analysis of the reused MCF catalyst by transmission electron
microscopy (TEM) revealed that the palladium nanoparticles
had aggregated to larger particles (Figure 2) compared with the
unused Pd(0)-AmP-MCF where the palladium was well-
distributed across the support. This agglomeration was not
found to have any observable effect on the outcome of the first
three reactions of the recycling study; however, it is expected
that the Pd(0)-AmP-MCF will gradually exhibit reduced
catalytic efficiency over the next cycles due to increased
agglomeration of the Pd nanoparticles that lead to a decreased
surface-to-volume ratio.
To investigate whether any palladium had leached from the
MCF, a leaching test of the MCF particles was performed. The
filtrates from two different coupling reactions producing
heterobiaryl 1 and 7, respectively, were analyzed with
inductively coupled plasma atomic emission spectroscopy
(ICP-AES). Using this technique, we could demonstrate that
only small amounts, 2.5 and 5.7 ppm, respectively, of palladium
had leached out into solution. A hot filtration test was also
performed by using the coupling reaction with 5-bromo-2-
methoxypyridine, biaryl 4, as a representative case. After 10 min
of reaction, the catalyst was filtered off and the yield was
determined to be 57% by LCMS (with anisole as internal
standard). The filtrate was further stirred under the same
reaction conditions for 23 h, and according to LCMS, the yield
was still 57%. The fact that the yield has not increased shows
that there is no active palladium in solution and hence confirms
that the catalyst is a truly heterogeneous catalyst.
Finally, we wanted to evaluate if we could use the same
reaction conditions with other boron derivatives, such as
boronate esters, potassium trifluoroborates, MIDA boronates,
and triolborates.
Gratifyingly, the pinacol ester worked perfectly and gave 7 in
93% yield (Table 1, entry 1). Running this reaction at room
temperature for 24 h gave, to our surprise, the heterobiaryl in
an excellent yield of 90% (entry 1). Continuing with the phenyl
and methoxyphenyl potassium trifluoroborates, as well as the
MIDA boronate, the corresponding products 7 and 28 were
generated in excellent yield (entries 2−4). Boronic acids
possessing different functional groups (entries 5−7) were well-
tolerated and coupled nicely with 5-iodopyrimidine to give 29−
31 in excellent yield. Cyclic triolborates are air- and water-stable
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onic acids but also for the corresponding boronate esters,
potassium trifluoroborates, MIDA boronates, and triolborates.
The Pd nanocatalyst can easily be removed from the product by
filtration and leaves very low amounts of residual palladium in
the product. Repeated recycling of catalyst revealed minimal
loss in activity, despite alteration of the overall morphology of
the nanoparticles toward larger agglomerates. The procedure
reported herein provides an alternative, environmentally
friendly process for the preparation of nitrogen-containing
biaryls using a heterogeneous palladium nanocatalyst.
Table 1. Suzuki Couplings with Boronate Esters, Potassium
Trifluoroborates, MIDA Boronates, and Triolborate
a
EXPERIMENTAL SECTION
■
General Information. All solvents and reagents were obtained
from commercially available sources and used without further
purification. The microwave syntheses were performed in a Biotage
initiator with an external surface IR probe. Flash chromatography was
carried out on prepacked silica gel columns and used on automated
flash instruments. 1H NMR and 13C NMR spectra were generated on a
500 MHz cryo instrument. Chemical shifts (δ) are given in parts per
million (ppm), with the residual solvent signal used as a reference.
Coupling constants (J) are reported as Hz. NMR abbreviations are
used as follows: br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. Analytical HPLC/MS was conducted on a
QTOF mass spectrometer using a UV detector monitoring either at
(a) 210 nm with a BEH C18 column (2.1 × 100 mm, 1.7 μm, 0.7 mL/
min flow rate), using a gradient of 2% v/v CH3CN in H2O
(ammonium carbonate buffer pH10) to 98% v/v CH3CN in H2O or at
(b) 230 nm with an HSS C18 column (2.1 × 100 mm, 1.8 μm, 0.7
mL/min flow rate), using a gradient of 2% v/v CH3CN in H2O
(ammonium formate buffer pH3) to 98% v/v CH3CN in H2O.
Preparative HPLC was conducted on a C18 column (10 μm 250 × 50
ID mm) using a gradient of 20 → 60% acetonitrile in H2O/ACN/NH3
95/5/0.2 buffer over 20 min with a flow of 100 mL/min. HRMS data
were recorded using TOF ESI detection. Transmission electron
miscroscopy (TEM) was used for analyzing the palladium nano-
particles after the recycling study. The amount of palladium leaching
into the reaction was measured with inductively coupled plasma-
atomic emission spectroscopy (ICP-AES). The palladium(0) nano-
particles immobilized in aminopropyl-functionalized mesocellular foam
were synthesized as previously described.34
General Procedure for the Preparation of Biaryls 1−10 and
14−32. Heteroaryl halide (0.30 mmol), (4-methoxyphenyl)boronic
acid (0.39 mmol), potassium carbonate (0.90 mmol), and Pd0-AmP-
MCF (3.99 mg, 0.003 mmol) were suspended in a 1:1 mixture of
ethanol (95% aq)/water (2 mL) in a microwave vial. The sealed vial
was heated at 90 °C (fixed hold time, normal absorption) for an
appropriate time in a microwave reactor. The mixture was diluted with
dichloromethane and washed with water. The phases were separated.
The organic phase was run through a phase separator and purified by
flash chromatography using a gradient of ethyl acetate/heptane to give
the desired product after evaporation of solvent. All compounds were
a
Reaction conditions (unless otherwise noted): aryl halide (0.30
mmol), boronic acid (0.39 mmol), K2CO3 (0.90 mmol), Pd (1 mol
%), EtOH/H2O (1:1, 2 mL), 90 °C, μw, 30 min. Reaction run at
room temperature for 24 h. The yield was determined by H NMR
using 1,2,4,5-tetramethylbenzene as internal standard. Reaction was
run for 1 h at 90 °C.
1
characterized by high-resolution MS, H NMR, and 13C NMR.
b
c
1
General Procedure for the Preparation of Biaryls 4, 5, 11−
13. The same procedure as above, but with ethanol (95% aq, 2 mL) as
solvent.
d
Procedure for the Recycling Study. 2-Iodopyrazine (0.063 g, 0.31
mmol), (4-methoxyphenyl)boronic acid (0.085 g, 0.39 mmol),
potassium carbonate (0.124 g, 0.90 mmol), and Pd0-AmP-MCF
(3.99 mg, 0.003 mmol) were suspended in a 1:1 mixture of ethanol/
water (2 mL) in a microwave vial. The sealed vial was heated at 90 °C
(fixed hold time, normal absorption) for 30 min in a microwave oven.
The catalyst was separated by centrifugation, and the supernatant was
collected. The solid material was washed with ethyl acetate three times,
and the organic layers were pooled with the supernatant. The catalyst
was further washed with water three times. The water phases were
combined with the organic phases. The organic phase was separated,
filtered through a small silica plug, and concentrated. The catalyst was
used in another cycle under identical conditions. This procedure was
CONCLUSION
■
In summary, we have shown that the heterogeneous nano-
particle catalyst Pd0-AmP-MCF is very efficient in Suzuki cross-
coupling reactions with heteroaromatic halides with a practical
and simple reaction procedure to provide nitrogen-containing
biaryls in good to excellent yields. The procedure is efficient for
a range of heteroaromatic iodides and bromides with various
boronic acids; however, it is not efficient when triflates and
heteroaryl chlorides are employed as starting materials. In
addition, this protocol is effective not only for heteroarylbor-
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Figure 2. TEM images of unused Pd(0)-AmP-MCF catalyst. A shows the nanopalladium well-distributed in MCF. B shows the catalyst after being
reused three times.
repeated twice. The palladium catalyst was then collected and analyzed
with TEM.
8.6, 0.7 Hz, 1H), 3.98 (s, 3H), 3.86 (s, 3H), 1.57 (s, 1H); 13C NMR
(126 MHz, CDCl3) δ 163.2, 159.2, 144.5, 137.2, 130.4, 129.8, 127.7,
114.4, 110.7, 55.4, 53.5; HRMS (ESI+) m/z calculated for
[C13H13NO2 + H+]: 216.1025, found 216.1014.
Procedure for the Leaching Study. 3-Iodopyridine (0.102 g, 0.50
mmol), (4-methoxyphenyl)boronic acid (0.141 g, 0.65 mmol),
potassium carbonate (0.207 g, 1.50 mmol), and Pd0-AmP-MCF
(6.65 mg, 5.00 μmol) were suspended in a 1:1 mixture of ethanol/
water (3.4 mL) in a sealed microwave vial. The capped vial was heated
at 90 °C (fixed hold time, normal absorption) for 30 min in a
microwave oven. The mixture was filtered through a small silica plug,
and the mother liquor was sent for ICP analysis.
Procedure for the Hot Filtration Study. 5-Bromo-2-methoxypyr-
idine (0.056 g, 0.30 mmol), (4-methoxyphenyl)boronic acid (0.085 g,
0.39 mmol), potassium carbonate (0.124 g, 0.90 mmol), and Pd0-
AmP-MCF (3.99 mg, 0.003 mmol) were suspended in ethanol (1 mL)
and water (1 mL) in a sealed microwave vial. Anisole was added as an
internal standard.
2-Fluoro-5-(4-methoxyphenyl)pyridine45 (5). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 0 → 40%
1
ethyl acetate gave 56 mg (92%) of 5 as a white solid. H NMR (500
MHz, CDCl3) δ 8.38 (d, J = 2.5 Hz, 1H), 7.93 (ddd, J = 8.4, 7.7, 2.6
Hz, 1H), 7.44−7.51 (m, 2H), 6.95−7.05 (m, 3H), 3.87 (s, 3H); 13C
NMR (151 MHz, CDCl3) δ 163.7, 162.2, 159.9, 145.6, 145.5, 139.5,
139.4, 134.7, 134.7, 129.3, 128.3, 114.8, 109.7, 109.4, 55.6; HRMS
(ESI+) m/z calculated for [C12H10FNO + H+]: 204.0825, found
204.0814.
1-(5-(4-Methoxyphenyl)pyridin-2-yl)ethanone46 (6). Purification
by flash chromatography using a gradient of ethyl acetate/heptane, 0
→ 40% ethyl acetate gave 65 mg (95%) of 6 as a white solid. 1H NMR
(500 MHz, CDCl3) δ 8.89 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 8.2 Hz,
1H), 7.98 (dd, J = 8.2, 2.3 Hz, 1H), 7.55−7.64 (m, 2H), 7.00−7.10
(m, 2H), 3.89 (s, 3H), 2.76 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
199.8, 160.4, 151.7, 146.9, 139.4, 134.3, 129.2, 128.5, 121.8, 114.8,
55.4, 25.8; HRMS (ESI+) m/z calculated for [C14H13NO2 + H+]:
228.1025, found 228.1023.
The capped vial was heated at 90 °C in a metal block for 10 min.
The mixture was filtered directly through a plug of Celite. Potassium
carbonate was added to the mother liquor, and the mixture was heated
at 90 °C in a metal block for 23 h in a sealed microwave vial. The
reaction was analyzed by LCMS against the internal standard.
3-(4-Methoxyphenyl)pyridine43 (1). Purification by flash chroma-
tography using a gradient of ethyl acetate/heptane, 0 → 40% ethyl
5-(4-Methoxyphenyl)pyrimidine40 (7). Purification by flash chro-
matography using a gradient of ethyl acetate/heptane, 0 → 40% ethyl
acetate to give 56 mg (99%) of 7 as a white solid. 1H NMR (600 MHz,
CDCl3) δ 9.17 (s, 1H), 8.93 (s, 2H), 7.51−7.57 (m, 2H), 7.03−7.10
(m, 2H), 3.88 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 160.4, 156.9,
154.4, 133.9, 128.1, 126.5, 114.9, 55.4; HRMS (ESI+) m/z calculated
for [C11H10N2O + H+]: 187.0871, found 187.0877.
1
acetate gave 52 mg (94%) of 1 as a white solid. H NMR (500 MHz,
CDCl3) δ 9.02−9.11 (m, 1H), 8.79 (d, J = 4.3 Hz, 1H), 8.07 (d, J = 7.9
Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 7.8, 4.8 Hz, 1H), 7.26
(d, J = 8.6 Hz, 2H), 4.11 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
159.7, 148.0, 147.9, 136.2, 133.8, 130.3, 128.2, 123.5, 114.5, 55.4;
HRMS (ESI+) m/z calculated for [C12H11NO + H+]: 186.0919, found
186.0918.
2-(4-Methoxyphenyl)pyrazine47 (8). Purification by flash chroma-
tography using a gradient of ethyl acetate/heptane, 0 → 40% ethyl
4-(4-Methoxyphenyl)pyridine44 (2). Purification by flash chroma-
tography using a gradient of ethyl acetate/heptane, 0 → 40% ethyl
1
acetate gave 53 mg (95%) of 8 as a white solid. H NMR (500 MHz,
1
acetate afforded 51 mg (92%) of 2 as a light yellow solid. H NMR
CDCl3) δ 8.99 (d, J = 1.5 Hz, 1H), 8.59 (dd, J = 2.5, 1.6 Hz, 1H), 8.45
(d, J = 2.5 Hz, 1H), 7.9−8.06 (m, 2H), 7.00−7.11 (m, 2H), 3.89 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 161.2, 152.5, 142.0, 142.1,
141.6, 128.9, 128.3, 114.5, 55.4; HRMS (ESI+) m/z calculated for
[C11H10N2O + H+]: 187.0871, found 187.0860.
(500 MHz, CDCl3) δ 8.55−8.73 (m, 2H), 7.55−7.70 (m, 2H), 7.42−
7.53 (m, 2H), 6.98−7.09 (m, 2H), 3.88 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 160.5, 150.2, 147.8, 130.4, 128.1, 121.0, 114.5, 55.4; HRMS
(ESI+) m/z calculated for [C12H11NO + H+]: 186.0919, found
186.0921.
5-(4-Methoxyphenyl)-1-methylpyridin-2(1H)-one48 (10). Purified
by preparative HPLC on a XBridge C18 column (10 μm 250 × 50 ID
mm) using a gradient of 20 → 60% acetonitrile in H2O/ACN/NH3
95/5/0.2 buffer over 20 min with a flow of 100 mL/min to give 18 mg
(7%) of 10 as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.59 (dd,
J = 9.4, 2.6 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.29−7.36 (m, 2H),
6.92−6.99 (m, 2H), 6.66 (d, J = 9.4 Hz, 1H), 3.85 (s, 3H), 3.62 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 162.3, 159.1, 139.4, 134.9,
129.0, 127,0, 120.6, 120.0, 114.5, 55.4, 37.9. HRMS (ESI+) m/z
calculated for [C13H13NO2 + H+]: 216.1024, found 216.1013.
3-(4-Methoxyphenyl)-5-(methylsulfonyl)pyridine (11). Purification
by flash chromatography using a gradient of ethyl acetate/heptane, 40
2-(4-Methoxyphenyl)pyridine44 (3). Purification by flash chroma-
tography using a gradient of ethyl acetate/heptane, 0 → 40% ethyl
1
acetate gave 41 mg (74%) of 3 as a white solid. H NMR (500 MHz,
CDCl3) δ 8.64−8.70 (m, 1H), 7.92−8.02 (m, 2H), 7.65−7.77 (m,
2H), 7.18 (ddd, J = 7.2, 4.8, 1.2 Hz, 1H), 6.98−7.06 (m, 2H), 3.88 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 160.4, 157.1, 149.5, 136.6,
132.04, 128.1, 121.4, 119.8, 114.1, 55.3; HRMS (ESI+) m/z calculated
for [C12H11NO + H+]: 186.0919, found 186.0923.
2-Methoxy-5-(4-methoxyphenyl)pyridine40 (4). Purification by
flash chromatography using a gradient of ethyl acetate/heptane, 0 →
1
40% ethyl acetate gave 60 mg (93%) of 4 as a white solid. H NMR
1
(500 MHz, CDCl3) δ 8.35 (dd, J = 2.5, 0.7 Hz, 1H), 7.75 (dd, J = 8.6,
2.6 Hz, 1H), 7.42−7.49 (m, 2H), 6.96−7.03 (m, 2H), 6.81 (dd, J =
→ 60% ethyl acetate gave 63 mg (80%) of 11 as a white solid. H
NMR (500 MHz, CDCl3) δ 9.08 (t, J = 2.4, 2.4 Hz, 2H), 8.36 (t, J =
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2.2, 2.2 Hz, 1H), 7.49−7.67 (m, 2H), 6.97−7.14 (m, 2H), 3.89 (s,
3H), 3.17 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.6, 152.2,
146.1, 137.0, 132.4, 128.4, 127.8, 114.9, 55.5, 44.9; HRMS (ESI+) m/z
calculated for [C13H13NO3S + H+]: 264.0694, found 264.0692.
3-Chloro-5-(4-methoxyphenyl)pyridine (12). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 0 → 40%
4-(4-Methoxyphenyl)-3,5-dimethylisoxazole50 (21). Purification
by flash chromatography using a gradient of ethyl acetate/heptane,
10 → 40% ethyl acetate afforded 60 mg (97%) of 21 as a transparent
oil. 1H NMR (500 MHz, CDCl3) δ 7.16−7.22 (m, 2H), 6.95−7.02 (m,
2H), 3.86 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H).13C NMR (126 MHz,
CDCl3) δ 164.8, 159.0, 158.8, 130.3, 122.6, 116.2, 114.2, 55.3, 11.5,
10.8; HRMS (ESI+) m/z calculated for [C12H13NO2 + H+]: 204.1025,
found 204.1033.
1
ethyl acetate afforded 57 mg (86%) of 12 as a white solid. H NMR
(500 MHz, CDCl3) δ 8.69 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 2.2 Hz,
1H), 7.83 (t, J = 2.1, 2.1 Hz, 1H), 7.46−7.56 (m, 2H), 7.03 (dd, J =
9.2, 2.4 Hz, 2H), 3.88 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.2,
146.5, 145.7, 137.5, 133.5, 132.1, 128.7, 128.3, 114.7, 55.4; HRMS
(ESI+) m/z calculated for [C12H10ClNO + H+]: 220.0529, found
220.0524.
N-(5-(4-Methoxyphenyl)pyridin-3-yl)-N-methylmethane-
sulfonamide (13). Purification by flash chromatography using a
gradient of ethyl acetate/heptane, 0 → 40% ethyl acetate gave 83 mg
(95%) of 13 as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.74 (d,
J = 2.0 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 7.90 (t, J = 2.3, 2.3 Hz, 1H),
7.51−7.58 (m, 2H), 6.99−7.06 (m, 2H), 3.88 (s, 3H), 3.43 (s, 3H),
2.93 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.2, 146.4, 144.2,
138.1, 136.9, 131.9, 129.2, 128.9, 128.4, 114.7, 55.4, 38.0, 35.8; HRMS
(ESI+) m/z calculated for [C14H16N2O3S + H+]: 293.0960, found
293.0959.
6-(4-Methoxyphenyl)isoquinoline (14). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 10 →
40% ethyl acetate gave 69 mg (98%) of 14 as a yellow solid. 1H NMR
(500 MHz, CDCl3) δ 9.26 (s, 1H), 8.54 (d, J = 5.7 Hz, 1H), 8.03 (d, J
= 8.5 Hz, 1H), 7.96 (s, 1H), 7.85 (dd, J = 8.5, 1.7 Hz, 1H), 7.64−7.73
(m, 3H), 7.02−7.09 (m, 2H), 3.90 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 159.9, 152.2, 143.4, 142.6, 136.2, 132.6, 128.7, 128.1, 127.5,
126.7, 123.3, 120.5, 114.4, 55.4; HRMS (ESI+) m/z calculated for
[C16H13NO + H+]: 236.1075, found 236.1070.
4-(4-Methoxyphenyl)-1,3,5-trimethyl-1H-pyrazole51 (22). Purifica-
tion by flash chromatography using a gradient of ethyl acetate/
heptane, 20 → 60% ethyl acetate gave 22 mg (80%) of 22 as a white
1
solid. H NMR (500 MHz, CDCl3) δ 7.11−7.23 (m, 2H), 6.9−7.02
(m, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 2.23 (d, J = 4.6 Hz, 6H); 13C
NMR (126 MHz, CDCl3) δ 158.0, 145.0, 136.0, 130.5, 126.6, 118.8,
113.9, 55.3, 36.0, 12.4, 10.2; HRMS (ESI+) m/z calculated for
[C13H16N2O + H+]: 217.1341, found 217.1338.
2-(4-Methoxyphenyl)thiophene52 (23). After extraction, the crude
product was run through a small silica plug and the solid was
1
evaporated. Gave 55 mg (96%) of 23 as a white solid. H NMR (500
MHz, CDCl3) δ 7.51−7.58 (m, 2H), 7.20−7.24 (m, 2H), 7.06 (dd, J =
5.1, 3.6 Hz, 1H), 6.90−6.95 (m, 2H), 3.85 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 159.2, 144.3, 127.9, 127.7, 127.3, 127.2, 123.8, 122.1,
114.3, 114.1, 55.4; HRMS (ESI+) m/z calculated for [C11H10OS +
H+]: 191.0530, found 191.0529.
2-(4-Methoxyphenyl)furan53 (24). Purification by flash chromatog-
raphy using a gradient of ethyl acetate/heptane, 0 → 30% ethyl acetate
gave 48 mg (82%) of 24 as a white solid. 1H NMR (500 MHz, CDCl3)
δ 7.58−7.65 (m, 2H), 7.44 (dd, J = 1.8, 0.7 Hz, 1H), 6.90−6.96 (m,
2H), 6.52 (dd, J = 3.3, 0.7 Hz, 1H), 6.45 (dd, J = 3.3, 1.8 Hz, 1H), 3.85
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.0, 154.0, 141.4, 125.2,
124.0, 114.2, 114.1, 111.5, 103.3, 55.3, 55.3.
4-(4-Methoxyphenyl)-1-methyl-1H-pyrazole54 (26). After extrac-
tion, the crude product was run through a small silica plug and the
solid was evaporated. Gave 9 mg (16%) of 26 as a light beige solid. 1H
NMR (500 MHz, CDCl3) δ 7.68−7.72 (m, 1H), 7.54 (s, 1H), 7.36−
7.43 (m, 2H), 6.88−6.95 (m, 2H), 3.94 (s, 2H), 3.83 (s, 2H); 13C
NMR (126 MHz, CDCl3) δ 158.3, 136.5, 126.7, 126.3, 125.3, 123.0,
114.3, 55.3, 39.0; HRMS (ESI+) m/z calculated for [C11H12N2O +
H+]: 189.1028, found 189.1021.
3-(4-Methoxyphenyl)quinoline49 (15). Purification by flash chro-
matography using a gradient of ethyl acetate/heptane, 10 → 40% ethyl
acetate gave 37 mg (52%) of 15 as a white solid. 1H NMR (500 MHz,
CDCl3) δ 9.17 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.13 (d, J
= 8.4 Hz, 1H), 7.84−7.91 (m, 1H), 7.64−7.77 (m, 3H), 7.54−7.63 (m,
1H), 7.04−7.12 (m, 2H), 3.90 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 159.8, 149.9, 147.0, 133.5, 132.4, 130.3, 129.2, 129.0, 128.5, 128.1,
127.9, 126.9, 114.7, 55.4, 41.0; HRMS (ESI+) m/z calculated for
[C16H13NO + H+]: 236.1075, found 236.1072.
3-(4-Methoxyphenyl)-1-methyl-1H-pyrazole (27). Purification by
flash chromatography using a gradient of ethyl acetate/heptane, 20 →
50% ethyl acetate afforded 40 mg (62%) of 27 as a light beige solid. 1H
NMR (500 MHz, CDCl3) δ 7.69−7.77 (m, 2H), 7.36 (d, J = 2.2 Hz,
1H), 6.90−6.97 (m, 2H), 6.47 (d, J = 2.3 Hz, 1H), 3.94 (s, 3H), 3.84
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.2, 151.5, 131.2, 126.7,
126.6, 126.5, 126.4, 114.0, 102.3, 55.3, 38.9.; HRMS (ESI+) m/z
calculated for [C11H12N2O+H+]: 189.1028, found 189.1038.
5-Phenylpyrimidine55 (28). Purification by flash chromatography
using a gradient of ethyl acetate/heptane, 40 → 70% ethyl acetate
afforded 46 mg (98%) of 28 as a transparent oil. 1H NMR (600 MHz,
CDCl3) δ 9.22 (s, 1H), 8.97 (s, 2H), 7.57−7.62 (m, 2H), 7.51−7.57
(m, 2H), 7.46−7.51 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 157.7,
155.1, 134.5, 134.4, 129.6, 129.2, 127.2. HRMS (ESI+) m/z calculated
for [C10H8N2 + H+]: 157,0765, found 157,0759.
5-(4-Methoxyphenyl)-1H-indole35 (16). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 20 →
60% ethyl acetate afforded 42 mg (62%) of 16 as a light beige solid. 1H
NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 7.78−7.86 (m, 1H), 7.56−
7.63 (m, 2H), 7.38−7.49 (m, 2H), 7.24−7.26 (m, 1H), 6.96−7.05 (m,
2H), 6.61 (ddd, J = 2.9, 2.0, 0.7 Hz, 1H), 3.87 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 158.5, 135.2, 135.0, 133.1, 128.4, 128.3, 124.7, 121.7,
118.7, 114.1, 111.1, 102.9, 55.3; HRMS (ESI+) m/z calculated for
[C15H13NO + H+]: 224.1075, found 224.1072.
6-(4-Methoxyphenyl)-1H-indole35 (17). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 10 →
1
40% ethyl acetate gave 42 mg (62%) of 17 as a light beige solid. H
NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H),
7.54−7.63 (m, 3H), 7.36 (dd, J = 8.2, 1.6 Hz, 1H), 7.24 (dd, J = 3.2,
2.4 Hz, 1H), 6.96−7.04 (m, 2H), 6.58 (ddd, J = 3.1, 2.0, 1.0 Hz, 1H),
3.87 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 158.9, 136.6, 135.5,
135.1, 128.5, 127.0, 124.7, 121.0, 119.9, 114.3, 109.2, 102.7, 55.6;
HRMS (ESI+) m/z calculated for [C15H13NO + H+]: 224.1075, found
224.1052.
1-(4-(Pyrimidin-5-yl)phenyl)ethanone56 (29). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 40 → 60%
ethyl acetate gave 56 mg (94%) of 29 as a white solid. 1H NMR (500
MHz, CDCl3) δ 9.27 (s, 1H), 9.01 (s, 2H), 8.11−8.14 (m, 2H), 7.68−
7.74 (m, 2H), 2.67 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 197.3,
158.2, 155.0, 138.7, 137.2, 133.3, 129.4, 127.2, 26.7; HRMS (ESI+) m/
z calculated for [C12H10N2O + H+]: 199.0871, found 199.0869.
3-(Pyrimidin-5-yl)benzonitrile (30). Purification by flash chroma-
tography using a gradient of ethyl acetate/heptane, 40 → 60% ethyl
acetate gave 47 mg (86%) of 30 as a white solid. 1H NMR (500 MHz,
CDCl3) δ 9.30 (s, 1H), 8.97 (s, 2H), 7.89 (t, J = 1.5, 1.5 Hz, 1H), 7.83
(ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.79 (dt, J = 7.8, 1.3, 1.3 Hz, 1H),
7.65−7.71 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 158.4, 154.9,
135.8, 132.4, 131.3, 130.5, 130.4, 118.0, 113.9; HRMS (ESI+) m/z
calculated for [C11H7N3 + H+]: 182.0718, found 182.0713.
5-(4-Methoxyphenyl)-1-methyl-1H-indazole (19). Purification by
flash chromatography using a gradient of ethyl acetate/heptane, 10 →
1
40% ethyl acetate gave 38 mg (53%) of 19 as a white solid. H NMR
(500 MHz, CDCl3) δ 8.02 (d, J = 0.9 Hz, 1H), 7.86 (dd, J = 1.6, 0.8
Hz, 1H), 7.62 (dd, J = 8.7, 1.7 Hz, 1H), 7.54−7.60 (m, 2H), 7.45 (dt, J
= 8.7, 0.8, 0.8 Hz, 1H), 6.98−7.04 (m, 2H), 4.11 (s, 3H), 3.88 (s, 3H);
13C NMR (151 MHz, CDCl3) δ 159.0, 139.3, 134.3, 133.9, 133.2,
128.5, 126.5, 124.8, 118.7, 114.4, 109.3, 55.6, 35.8; HRMS (ESI+) m/z
calculated for [C15H14N2O + H+]: 239.1184, found 239.1176.
3952
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tert-Butyl 3-(pyrimidin-5-yl)benzoate (31). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 20 → 50%
ethyl acetate afforded 76 mg (99%) of 31 as a white solid. H NMR
(16) Pavia, C.; Ballerini, E.; Bivona, L. A.; Giacalone, F.; Aprile, C.;
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1
(500 MHz, CDCl3) δ 9.25 (s, 1H), 9.00 (s, 2H), 8.22 (t, J = 1.6, 1.6
Hz, 1H), 8.10 (dt, J = 7.8, 1.3, 1.3 Hz, 1H), 7.75 (ddd, J = 7.7, 1.9, 1.2
Hz, 1H), 7.59 (t, J = 7.8, 7.8 Hz, 1H), 1.63 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 165.0, 157.8, 155.0, 134.4, 133.7, 133.3, 130.7, 129.9,
129.4, 127.9, 81.7, 28.2, 28.0; HRMS (ESI+) m/z calculated for
[C15H16N2O2 + H+]: 257.1290, found 257.1301.
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5-(6-Methoxypyridin-3-yl)pyrimidine57 (32). Purification by flash
chromatography using a gradient of ethyl acetate/heptane, 40 → 80%
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1
ethyl acetate afforded 38 mg (68%) of 32 as a light beige solid. H
NMR (500 MHz, CDCl3) δ 9.22 (s, 1H), 8.92 (s, 2H), 8.41 (d, J = 2.5
Hz, 1H), 7.80 (dd, J = 8.6, 2.6 Hz, 1H), 6.91 (dd, J = 8.6, 0.5 Hz, 1H),
4.01 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.7, 157.5, 154.4,
145.2, 137.0, 131.5, 123.3, 111.7, 53.8; HRMS (ESI+) m/z calculated
for [C10H9N3O + H+]: 188.0824, found 188.0811.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jeb@organ.su.se.
(28) Wu, S.; Mou, C.; Lin, H. Chem. Soc. Rev. 2013, 42, 3862−3875.
(29) Ping, E. W.; Pierson, J.; Wallace, R.; Miller, J. T.; Fuller, T. F.;
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Catal. 2007, 252, 97−109.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(32) Shakeri, M.; Tai, C.-W.; Gothelid, E.; Oscarsson, S.; Backvall, J.-
̈
̈
Financial support from the Berzelii Center EXSELENT is
gratefully acknowledged. We thank Ms. A. Nagendiran
(Stockholm University) and Dr. O. Karlsson (AstraZenceca)
for helpful discussions, Dr. A. Gill (AstraZeneca) for his
generous support, and Dr. C.-W. Tai (Stockholm University)
for TEM analyses.
E. Chem.Eur. J. 2011, 17, 13269−13273.
(33) Verho, O.; Nagendiran, A.; Johnston, E. V.; Tai, C.-W.; Backvall,
̈
J.-E. ChemCatChem 2013, 5, 612−618.
(34) Johnston, E. V.; Verho, O.; Karkas, M. D.; Shakeri, M.; Tai, C.-
̈
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W.; Palmgren, P.; Eriksson, K.; Oscarsson, S.; Backvall, J.-E. Chem.
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Eur. J. 2012, 18, 12202−12206.
(35) Verho, O.; Nagendiran, A.; Tai, C.-W.; Johnston, E. V.; Backvall,
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