Practical Pd/C-catalysed suzuki-miyaura reactions for the preparation of 3-aryl-4-oxypyridin-2(1H)-ones, 3-aryl-2,4-oxypyridines and 3-aryl-2,4- oxyquinolines as useful intermediates for the synthesis of biologically active compounds

Article abstract of DOI:10.1002/ejoc.201200721

Practical heterogeneous Pd/C-catalysed Suzuki-Miyaura cross-coupling reactions of 3-iodo-4-oxypyridin-2(1H)-ones, 3-iodo-2,4-oxypyridines, and 3-iodo-2,4-oxyquinolines with arylboronic acids are described as a useful and efficient alternative to homogeneous conditions. The methodology features ligand-free and environmentally friendly conditions, and tolerates a wide range of boronic acids. The cross-coupled products can be viewed as useful intermediates for the preparation of 3-aryl-4-hydroxypyridin-2(1H)-ones, which can be used as new nucleobases for antiherpetic agents.

Full text of DOI:10.1002/ejoc.201200721

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FULL PAPER
DOI: 10.1002/ejoc.201200721
Practical Pd/C-Catalysed Suzuki–Miyaura Reactions for the Preparation of
3-Aryl-4-oxypyridin-2(1H)-ones, 3-Aryl-2,4-oxypyridines and
3-Aryl-2,4-oxyquinolines as Useful Intermediates for the Synthesis of
Biologically Active Compounds
Marc Lamblin,[a] Hugo Bares,[b] Jean Dessolin,[a] Christel Marty,[c] Nathalie Bourgougnon,[c]
and François-Xavier Felpin*[d]
Keywords: Heterogeneous catalysis / Palladium / Cross-coupling / Nitrogen heterocycles / Nucleosides / Medicinal
chemistry / Antiviral agents
Practical heterogeneous Pd/C-catalysed Suzuki–Miyaura
cross-coupling reactions of 3-iodo-4-oxypyridin-2(1H)-ones,
3-iodo-2,4-oxypyridines, and 3-iodo-2,4-oxyquinolines with
features ligand-free and environmentally friendly conditions,
and tolerates a wide range of boronic acids. The cross-cou-
pled products can be viewed as useful intermediates for the
arylboronic acids are described as a useful and efficient alter- preparation of 3-aryl-4-hydroxypyridin-2(1H)-ones, which
native to homogeneous conditions. The methodology
can be used as new nucleobases for antiherpetic agents.
a practical and inexpensive catalyst have proved to be an
excellent method,[3] as exemplified by reported industrial
applications.[4] In the recent past, we have reported our own
contribution to the development of various practical Pd/C-
catalysed cross-coupling reactions for the formation of C–
C bonds.[5]
In the context of two independent programs of medicinal
chemistry, we have been interested in the preparation of 3-
aryl-4-hydroxypyridin-2(1H)-ones as the central skeleton
for anticancer[6] and antiviral compounds.[7] In this paper,
we wish to present our results on Pd/C-catalysed Suzuki–
Miyaura reactions[8] for the preparation of 3-aryl-4-oxypyr-
idin-2(1H)-ones and 3-aryl-2,4-oxypyridines as useful het-
erocycles.
Introduction
The rapid access to structurally relevant skeletons for
molecular diversity is an ongoing challenge for synthetic
chemists. The development of efficient, practical, and envi-
ronmentally friendly methodologies directed at the prepara-
tion of useful intermediates that can be incorporated into
biologically active compounds is highly desired by medici-
nal chemists. To this end, metal-mediated reactions, and es-
pecially palladium-catalysed couplings for carbon–carbon
bond formation, have gained a predominant place in the
organic chemist’s arsenal. The myriad of palladium-cata-
lysed reactions can usually be carried out with high turn-
over numbers (TONs) and turnover frequencies (TOFs) un-
der mild conditions.[1] However, economic and environmen-
tal considerations, as well as the importance of a clean syn-
thesis for biologically active compounds, make the use of
easily recoverable palladium catalysts crucial.[2] In this con-
text, heterogeneous cross-coupling reactions using Pd/C as
Results and Discussion
Our initial strategy involved the preparation of 3-halo-
pyridones followed by a Pd0/C-catalysed Suzuki–Miyaura
cross-coupling reaction, as depicted in Scheme 1.[9]
[a] Université de Bordeaux, CNRS UMR 5248, CBMN, IECB,
2 rue Robert Escarpit, 33607 Pessac, France
[b] Université de Bordeaux, UMR CNRS 5255, Institut des
Sciences Moléculaires,
351 cours de la Libération, 33405 Talence Cedex, France
[c] Université de Bretagne-Sud, PRES Université Européenne de
Bretagne, Laboratoire de Biotechnologie et Chimie Marines,
Campus de Tohannic,
56017 Vannes, France
[d] Université de Nantes, CNRS UMR 6230, CEISAM, UFR des
Sciences et des Techniques,
2 rue de la Houssinière, 44322 Nantes Cedex 3, France
Fax: +33-2-51125402
E-mail: fx.felpin@univ-nantes.fr
Homepage: http://f-x.felpin.voila.net/Index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200721.
Scheme 1. General strategy for the preparation of 3-aryl-4-hy-
droxypyridin-2(1H)-ones.
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Although the cross-coupling of aryl bromides with tivity of pyridone 2. While activation of the boronic acid
boronic acids using Pd0/C under ligand-free conditions has with TBAB or KF (1 equiv.) did not affect the reaction out-
been well documented,[10] the use of sterically hindered come (Table 1, entries 6–7), it appeared that Ph3P (20 mol-
ortho-bromo compounds often gave low to moderate yields %) considerably improved the conversion and the reaction
of cross-coupled products.[11] Moreover, we also noticed in yield (Table 1, entry 8). However, we next found that 3-
a previous report that the Pd0/C-catalysed Suzuki–Miyaura iodopyridone 3 was much more reactive, even at tempera-
reaction of 2-bromocycloenones with arylboronic acids tures as low as 35 °C (Table 1, entry 9). Nevertheless, the
gave only degradation and dehalogenated by-products.[5c] reaction was best carried out at 60 °C to give cross-coupled
With these issues in mind, we prepared both 3-bromopyr- product 4a in 94% yield (Table 1, entry 10).
idone 2 and 3-iodopyridone 3 with the aim of studying their
Table 1. Optimisation studies for the cross-coupling of 2 and 3.
reactivity. Their preparation was optimised on a multi-gram
scale, and pure intermediates were mostly isolated by pre-
cipitation or crystallisation, without the need for tedious
chromatographic separation. Bromination of commercially
available 4-hydroxypyridin-2(1H)-one (1),[12] followed by
benzylation with a combination of K2CO3 and benzyl
bromide in DMF, gave 2 in good yield over two steps (62%;
Scheme 2). Alternatively, initial benzylation of 4-hydroxy-2-
pyridone (1), and subsequent iodination with NIS, allowed
the preparation of iodopyridone 3 in a similar yield (62%).
It should be noted that the combination of K2CO3 and
DMF for the benzylation step proved to be crucial for opti-
mal results. Other combinations of solvents and bases gave
inferior results in terms of selectivity (O-alkylation vs. N-
alkylation) and yield. It is important to mention that an-
other useful procedure, under homogeneous conditions, was
published by the Balme group a few months after we
started this program.[13]
Entry SM
Solvent,
ratio (1:1)
Base
Additive
[equiv.]
T [°C] Conv. [%][a]
1
2
3
4
5
6
7
8
9
10
2
2
2
2
2
2
2
2
3
3
DME/H2O Na2CO3
DME/H2O Na2CO3
iPrOH/H2O Na2CO3
iPrOH/H2O Na2CO3
iPrOH/H2O Cs2CO3
iPrOH/H2O Na2CO3
iPrOH/H2O Na2CO3
iPrOH/H2O Na2CO3 Ph3P (0.2)
iPrOH/H2O Na2CO3
iPrOH/H2O Na2CO3
–
–
–
–
–
35
60
35
60
60
60
60
60
35
60
0
25
0
44
41
35
49
91 (83)
82
TBAB (1)
KF (1)
–
–
99 (94)
[a] Conversion determined by 1H NMR spectroscopy. Isolated
yields in parentheses.
Using the optimised reaction conditions, we then scre-
ened a variety of boronic acids bearing electron-donating
or electron-withdrawing substituents (Table 2). Gratifyingly,
cross-coupled products were obtained with excellent yields
and purity, even when using β-styrylboronic acid (leading
to 4n). Maximum conversions of 3-iodopyridone 3 to the
corresponding products were usually reached within 6–10 h,
but we stirred for 12 h for convenience. The use of Pd0/C
greatly simplified the separation of the palladium catalyst
from the crude product by allowing the separation to be
Scheme 2. Synthesis of 3-bromo- and 3-iodopyridones.
We next studied the arylation of 3-bromopyridone 2 by accomplished by an easy filtration. Indeed, when a homo-
means of a Suzuki–Miyaura reaction using Pd0/C as hetero- geneous palladium catalyst [Pd(PPh3)4] was used during our
geneous catalyst. As predicted, compound 2 showed a very preliminary studies, it was extremely difficult to remove col-
low reactivity when aqueous DME or iPrOH were used as oured by-products (assumed to be palladium residues), es-
solvents and Na2CO3 was used as a base under ligand-free pecially for the highly polar compound 4i, even after flash
conditions (Table 1, entries 1–4). Although these results chromatography. The only failure encountered in this
were disappointing, we noticed that the combination of iPr- screening was observed with 4-(methylthio)phenylboronic
OH and water was more efficient than DME. The role of acid (see compound 4m). This result suggested that the
iPrOH in the activation of homogeneous palladium com- sulfur atom acts as a poison for the metal centre.
plexes has been discussed by Nolan and co-workers,[14] and
We next investigated the extension of this methodology
this role could be extended to heterogeneous catalysis. It to the arylation of 4-hydroxy-5-phenylpyridin-2(1H)-one 5.
should be mentioned that the use of pure water as solvent Unfortunately, the protocol previously developed for the
led to the aggregation of the Pd/C catalyst and irreprod- formation of 3 from 4-hydroxy-2-pyridone (1) failed to give
ucible results. The use of Cs2CO3 as a base instead of a useful yield of the corresponding iodinated product (i.e.,
Na2CO3 did not improve the conversion (Table 1, entry 5). 6).[15] Indeed, the benzylation–iodination sequence applied
We also tested a few additives in order to improve the reac- to pyridone 5 gave less than 5% overall yield (two steps) of
2
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Pd/C-Catalysed Suzuki–Miyaura Reactions
Table 2. Screening of boronic acids.
Scheme 4. Example of a Suzuki–Miyaura reaction with pyridone
7.
trast to the brominated derivative, which was preferentially
benzylated in its pyridone form. The reason for such diver-
gent pathways is still unclear at this time. This trend was
also observed, albeit to a lesser extent, when starting with
4-hydroxy-2-quinolone 10 [Scheme 5, Equation (2)]. In this
case, a lower overall yield of the corresponding iodinated
quinoline (i.e., 11) was obtained, due to competing de-
iodination pathways during the benzylation step.
[a] Isolated yields.
Scheme 5. Preparation of 3-iodopyridine 9 and 3-iodoquinoline 11.
target compound 6 (Scheme 3). In contrast, the bromin-
ation–benzylation sequence furnished brominated pyridine
7 in acceptable yields (40% overall). However, as expected,
the Pd0/C Suzuki–Miyaura reaction carried out with 7 gave
From these unexpected results, we found an opportunity
to develop an unprecedented Pd0/C-catalysed Suzuki–
Miyaura cross-coupling reaction of highly substituted 2,4-
alkoxypyridines and 2,4-alkoxyquinolines. To this end, we
tested the cross-coupling reactins of 9 and 11 with boronic
acids under the optimised reaction conditions described
above. Although reactions run under these conditions pro-
ceeded smoothly, we later found that a slight increase in
temperature, from 60 to 80 °C, allowed the use of only
1 mol-% of the heterogeneous catalyst. We screened a vari-
ety of boronic acids bearing electron-donating and electron-
withdrawing groups (Table 3). Whatever the electronic na-
ture of the substituent borne by the boronic acid, we con-
sistently isolated the targeted cross-coupling products in
high yields. The only exception to this trend was found with
the O-tosylated products (i.e., 12i and 13i). In general, we
did not observe a significant difference in reactivity between
pyridine 9 and quinoline 11 in the cross-coupling reactions.
This result could be easily explained by the closely related
only
a moderate yield of cross-coupled product 8
(Scheme 4). This result was consistent with our findings re-
ported in Table 1 with 3-bromopyridone 3.
Scheme 3. Synthesis of 3-bromo- and 3-iodopyridones.
With these disappointing results in mind, we reasoned electronic structures of these two heterocycles.
that the benzylation could be carried out after the iodin- These methodologies were optimised for use in two me-
ation step. After considerable optimisation studies, we were dicinal chemistry projects. For instance, we used this strat-
surprised to find that pyridone 5 was almost exclusively egy for the construction of unnatural C-3-arylated nucleo-
benzylated in its pyridinic tautomer to give 3-iodopyridine bases (Scheme 6). As an example, debenzylation of arylated
9 [Scheme 5, Equation (1)]. This result was in sharp con- pyridone 4e under reductive conditions gave free pyridone
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Table 3. Screening of boronic acids.
says will be reported shortly on a library of 3-arylated de-
azauridines.
Conclusions
We have developed new applications of the Pd/C-cata-
lysed Suzuki–Miyaura reactions for the synthesis of 4-oxy-
3-arylpyridin-2(1H)-ones and 2,4-oxy-3-arylpyridines. This
work extends the scope of Pd/C catalysis for C–C bond for-
mation with nitrogen-containing heterocycles. The opti-
mum conditions use inexpensive reagents and solvents with
low toxicities, which makes the method environmentally be-
nign, very practical, and scalable. A preliminary application
of the methodology in the preparation of promising new
antiherpetic nucleosides has been disclosed. Extensive bio-
logical studies are still ongoing, and the results will be re-
ported in due course.
Experimental Section
General Methods: Chemical shifts from proton and carbon NMR
spectra are reported in ppm relative to tetramethylsilane, using re-
sidual solvent peaks [CDCl3: δ = 7.26 ppm (1H) or 77.0 ppm (13C);
[D6]DMSO: δ = 2.50 ppm (1H) or 39.5 ppm (13C)] as internal refer-
ences. Infrared (IR) spectra were recorded as neat samples on NaCl
plates or with KBr pellets. Yields refer to isolated material deter-
mined to be pure by NMR spectroscopy and thin layer chromatog-
raphy (TLC), unless specified otherwise in the text. The 10% Pd/C
used in this study was commercially available from Sigma–Aldrich.
[a] Yields of isolated products.
3-Bromo-2,4-dihydroxypyridine:
A
solution of Br2 (447 μL,
8.71 mmol) in AcOH (4 mL) was slowly added to a solution of 2,4-
dihydroxypyridine 1 (1 g, 9 mmol) in 48% aqueous HBr (3.5 mL)
at 0 °C over 20 min. After 10 min of stirring, the ice-bath was re-
moved, and the solution was diluted with cold water (40 mL). The
white solid was filtered, washed with cold Et2O, and dried under
vacuum at 60 °C for 12 h to give 3-bromo-2,4-dihydroxypyridine
14, which was then treated, without purification, with tetra-
O-acetyl-d-ribose under Vorbrüggen conditions[16] to yield
the corresponding acetylated nucleoside (i.e., 15).
(1.64 g, 96%), m.p. 263 °C [lit.[17] 261–262 °C]. IR (KBr): ν = 1636,
˜
2845, 3004, 3102 cm–1. 1H NMR (250 MHz, [D6]DMSO): δ = 6.00
(d, J = 7 Hz, 1 H), 7.25 (d, J = 7 Hz, 1 H), 11.33 (br. s, 1 H), 11.46
(br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 95.3, 98.6,
134.1, 160.3, 163.9 ppm.
3-Bromo-1-benzyl-4-benzyloxypyridin-2(1H)-one (2): A solution of
3-bromo-2,4-dihydroxypyridine (1.64 g, 8.63 mmol) in DMF
(35 mL) was treated with K2CO3 (6.22 g, 45 mmol) and benzyl
bromide (4.2 mL, 36 mmol) at room temperature. The resulting
mixture was stirred for 24 h, and then water (30 mL) was added.
The white powder was filtered, washed with cold Et2O (3ϫ) and
dried under vacuum at 60 °C for 12 h to give 2 (2.16 g, 65%), m.p.
168 °C. IR (KBr): ν = 1603, 1644, 1662, 2933, 2960, 3033 cm–1. 1H
˜
NMR (250 MHz, CDCl3): δ = 5.15 (s, 2 H), 5.21 (s, 2 H), 6.05 (d,
J = 7.9 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 7.26–7.41 (m, 10 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 52.7, 71.0, 96.0, 99.8, 126.8,
128.2, 128.3, 128.4, 128.8, 128.9, 135.3, 135.9, 136.3, 160.0,
163.1 ppm. HRMS (LSIMS): calcd. for C19H16BrNO2 [M]+
370.0443; found 370.0440.
Scheme 6. Preparation of an antiviral nucleoside.
Compound 15 was tested for its antiherpetic activity
against HSV-1 on the Vero cell-line by cell viability, and
showed an EC50 value of 33 μm, while an EC50 value of
22 μm was found for the commercially available drug Zovi-
rax® (acyclovir) at MOI 0.01 ID50/cells. It should be also
mentioned that no cytotoxic side-effects were detected on
1-Benzyl-4-benzyloxypyridin-2(1H)-one:
27.03 mmol) and benzyl bromide (2.52 mL, 21.62 mmol) were
added to solution of 2,4-dihydroxypyridine (600 mg,
K2CO3
(3.73 g,
a
1
Vero, HeLa and HL-60 cell-lines. Additional biological as- 5.41 mmol) in DMF (20 mL) at room temperature. After being
4
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Pd/C-Catalysed Suzuki–Miyaura Reactions
stirred for 24 h, cold water (60 mL) was added, and the white solid
was filtered and washed twice with cold Et2O. The filtrate was con-
centrated, diluted with Et2O and stored in the freezer (–20 °C) for
5 h to give a further amount of a white solid. The combined solids
were dried under vacuum at 60 °C for 12 h to give the title com-
1 H), 7.27–7.53 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
31.3, 34.5, 52.1, 70.3, 96.9, 115.7, 124.6, 126.4, 127.9, 127.9, 128.4,
128.5, 128.7, 129.8, 130.3, 136.2, 136.4, 136.5, 149.6, 162.3,
162.7 ppm. HRMS (ESI): calcd. for C29H30NO2 [M + H]+
424.2271; found 424.2277.
pound (1.05 g, 67%), m.p. 130 °C. IR (KBr): ν = 1603, 1659, 2974,
˜
1-Benzyl-4-benzyloxy-3-(4-cyclohexylphenyl)pyridin-2(1H)-one (4d):
Purification by flash chromatography (40% EtOAc/petroleum
3032 cm–1. 1H NMR (250 MHz, CDCl3): δ = 4.99 (s, 2 H), 5.09 (s,
2 H), 5.95 (dd, J = 2.7, 7.6 Hz, 1 H), 6.04 (d, J = 2.8 Hz, 1 H),
7.12 (d, J = 7.3 Hz, 1 H), 7.26–7.41 (m, 10 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 51.0, 70.2, 98.4, 101.4, 127.7, 127.9, 128.0,
128.5, 128.7, 128.8, 135.3, 136.7, 137.1, 164.1, 167.0 ppm. HRMS
(ESI): calcd. for C19H18NO2 [M + H]+ 292.1332; found 292.1341.
ether) gave 4d (239 mg, 74%) as a colourless oil. IR (neat): ν =
˜
1643, 2923, 3031, 3062 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.28–1.56 (m, 5 H), 1.78–1.97 (m, 5 H), 2.52–2.60 (m, 1 H), 5.09
(s, 2 H), 5.15 (s, 2 H), 6.12 (d, J = 7.7 Hz, 1 H), 7.23 (d, J = 7.7 Hz,
1 H), 7.27–7.37 (m, 12 H), 7.50 (d, J = 8.2 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 26.1, 26.8, 34.2, 44.3, 51.9, 70.2, 96.6,
115.6, 126.0, 126.4, 127.8, 128.3, 128.4, 128.6, 130.2, 130.5, 136.1,
136.3, 136.6, 146.5, 162.1, 162.6 ppm. HRMS (ESI): calcd. for
C31H32NO2 [M + H]+ 450.2427; found 450.2449.
1-Benzyl-4-benzyloxy-3-iodopyridin-2(1H)-one (3): A solution of the
previously obtained benzylated pyridone 2 (500 mg, 1.72 mmol) in
CH3CN (15 mL) was stirred with NIS (425 mg, 1.89 mmol) and
TFA (40 μL, 0.52 mmol) at room temperature for 4 h. The mixture
was diluted with CH2Cl2 (50 mL) and washed with saturated aque-
ous Na2S2O3 solution (50 mL). The aqueous phase was extracted
with CH2Cl2 (3ϫ). The collected organic extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure. Purifi-
cation by flash chromatography (50% EtOAc/petroleum ether) gave
1-Benzyl-4-benzyloxy-3-biphenylpyridin-2(1H)-one (4e): Purification
by flash chromatography (40% EtOAc/petroleum ether) gave 4e
(248 mg, 78%) as a white solid. IR (KBr): ν = 1643, 3028 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 5.11 (s, 2 H), 5.16 (s, 2 H), 6.14 (d,
J = 7.7 Hz, 1 H), 7.25 (d, J = 7.7 Hz, 1 H), 7.28–7.40 (m, 11 H),
7.48 (tm, J = 8.6 Hz, 2 H), 7.67–7.70 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 52.0, 70.3, 96.5, 115.0, 126.3, 126.5, 126.9,
127.0, 127.8, 127.9, 128.3, 128.5, 128.6, 128.7, 131.2, 132.1, 136.0,
136.5, 136.7, 139.5, 141.2, 162.3, 162.5 ppm. HRMS (ESI): calcd.
for C31H26NO2 [M + H]+ 444.1958; found 444.1959.
3 (659 mg, 92%) as a white solid, m.p. 127 °C. IR (KBr): ν = 1599,
˜
1639, 1654, 1700, 3031 cm–1. 1H NMR (250 MHz, CDCl3): δ =
5.15 (s, 2 H), 5.20 (s, 2 H), 5.97 (d, J = 7.6 Hz, 1 H), 7.23 (d, J =
7.6 Hz, 1 H), 7.26–7.41 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 53.0, 71.1, 95.7, 126.7, 128.1, 128.3, 128.4, 128.7,
128.9, 135.3, 136.0, 137.7, 161.1, 166.4 ppm. HRMS (ESI): calcd.
for C19H17NO2I [M + H]+ 418.0298; found 418.0312.
1-Benzyl-4-benzyloxy-3-(4-methoxyphenyl)pyridin-2(1H)-one (4f):
Purification by flash chromatography (50% EtOAc/petroleum
ether) gave 4f (268 mg, 94%) as a white solid, m.p. 128 °C. IR
General Procedure for the Suzuki–Miyaura Coupling of Iodopyr-
idone 3: Na2CO3 (229 mg, 2.16 mmol), ArB(OH)2 (1.08 mmol), and
Pd/C (38 mg, 5 mol-%) were added to a solution of iodopyridone
3 (300 mg, 0.719 mmol) in iPrOH (2 mL) and H2O (2 mL). The
resulting mixture was stirred for 12 h at 60 °C and then filtered.
The catalyst was washed with H2O (3 mL) and CH2Cl2 (5 mL).
The aqueous phase was extracted twice with CH2Cl2. The collected
organic extracts were dried (MgSO4), filtered, and concentrated un-
der reduced pressure. The crude compound was purified by flash
chromatography to give the cross-coupled product.
(KBr): ν = 1591, 1645, 2922, 2946, 3028, 3060 cm–1. 1H NMR
˜
(200 MHz, CDCl3): δ = 3.85 (s, 3 H), 5.11 (s, 2 H), 5.16 (s, 2 H),
6.14 (d, J = 7.8 Hz, 1 H), 6.97 (dm, J = 8.9 Hz, 1 H), 7.24 (d, J =
7.8 Hz, 2 H), 7.28–7.42 (m, 10 H), 7.51 (dm, J = 8.9 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 52.0, 55.1, 70.3, 96.7, 113.1,
115.3, 125.3, 126.5, 127.8, 127.9, 128.3, 128.5, 128.7, 131.9, 136.2,
136.6, 158.4, 162.1, 162.8 ppm. HRMS (LSIMS): calcd. for
C26H24NO3 [M + H]+ 398.1756; found 398.1755.
1-Benzyl-4-benzyloxy-3-(4-ethoxyphenyl)pyridin-2(1H)-one
Purification by flash chromatography (50% EtOAc/petroleum
ether) gave 4g (308 mg, 99%) as a colourless oil. IR (KBr): ν =
(4g):
1-Benzyl-4-benzyloxy-3-phenylpyridin-2(1H)-one (4a): Purification
by flash chromatography (50% EtOAc/petroleum ether) gave 4a
˜
(230 mg, 87%) as a white solid, m.p. 161 °C. IR (KBr): ν = 1593,
˜
1642, 2928, 2982, 3036, 3065 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 1.42 (t, J = 7.0 Hz, 3 H), 4.06 (q, J = 7.0 Hz, 2 H), 5.08 (s, 2
H), 5.14 (s, 2 H), 6.12 (d, J = 7.7 Hz, 1 H), 6.93 (d, J = 8.7 Hz, 2
H), 7.20–7.33 (m, 11 H), 7.45 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.9, 52.0, 63.3, 70.4, 96.8, 113.8, 115.4,
125.0, 126.5, 127.9, 128.4, 128.6, 128.8, 131.9, 136.1, 136.2, 136.6,
157.9, 162.1, 162.9, 179.9 ppm. HRMS (ESI): calcd. for
C27H26NO3Na [M + Na]+ 435.1804; found 435.1802.
1643, 2920, 3021, 3062, 3085 cm–1. 1H NMR (250 MHz, CDCl3):
δ = 5.09 (s, 2 H), 5.14 (s, 2 H), 6.13 (d, J = 7.6 Hz, 1 H), 7.24 (d,
J = 7.9 Hz, 1 H), 7.29–7.43 (m, 13 H), 7.51–7.55 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 52.0, 70.3, 96.6, 115.7, 126.5,
127.0, 127.6, 127.9, 128.4, 128.5, 128.8, 130.8, 133.1 136.1, 136.6,
136.6, 162.3, 162.6 ppm. HRMS (ESI): calcd. for C25H22NO2 [M
+ H]+ 368.1645; found 368.1658.
1-Benzyl-4-benzyloxy-3-tolylpyridin-2(1H)-one (4b): Purification by
flash chromatography (40% EtOAc/petroleum ether) gave 4b
1-Benzyl-4-benzyloxy-3-(4-trifluoromethoxyphenyl)pyridin-2(1H)-
one (4h): Purification by flash chromatography (40% EtOAc/petro-
leum ether) gave 4h (321 mg, 99%) as a white solid, m.p. 95 °C. IR
(255 mg, 93%) as a white solid, m.p. 168 °C. IR (KBr): ν = 1642,
˜
2919, 3029, 3061, 3083 cm–1. 1H NMR (250 MHz, CDCl3): δ =
2.37 (s, 3 H), 5.09 (s, 2 H), 5.14 (s, 2 H), 6.10 (d, J = 7.6 Hz, 1 H),
7.20–7.44 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3,
51.9, 70.3, 96.6, 115.6, 126.5, 127.9, 128.4, 128.4, 128.5, 128.7,
130.0, 130.6, 136.2, 136.3, 136.5, 136.6, 162.1, 162.7 ppm. HRMS
(ESI): calcd. for C26H24NO2 [M + H]+ 382.1801; found 382.1815.
(KBr): ν = 1644, 2937, 3037, 3068 cm–1 1H NMR (400 MHz,
.
˜
CDCl3): δ = 5.08 (s, 2 H), 5.13 (s, 2 H), 6.14 (d, J = 7.9 Hz, 1 H),
7.20–7.34 (m, 13 H), 7.54 (dm, J = 8.3 Hz, 2 H) ppm. HRMS (ESI):
calcd. for C26H20NO3F3Na [M + Na]+ 474.1287; found 474.1285.
1-Benzyl-4-benzyloxy-3-(3,4-dimethoxyphenyl)pyridin-2(1H)-one
(4i): Purification by flash chromatography (20% EtOAc/CH2Cl2)
1-Benzyl-4-benzyloxy-3-(4-tert-butylphenyl)pyridin-2(1H)-one (4c):
Purification by flash chromatography (40% EtOAc/petroleum
gave 4i (295 mg, 96%) as a white solid, m.p. 60 °C. IR (KBr): ν =
˜
1
ether) gave 4c (222 mg, 73%) as a colourless oil. IR (neat): ν =
1641, 2933, 3030 cm–1. H NMR (250 MHz, CDCl3): δ = 3.81 (s,
˜
1651, 2962, 3033, 3064, 3087 cm–1. 1H NMR (300 MHz, CDCl3):
3 H), 3.89 (s, 3 H), 5.08 (s, 2 H), 5.15 (s, 2 H), 6.14 (d, J = 7.9 Hz,
1 H), 6.91 (d, J = 8.2 Hz, 1 H), 7.07 (d, J = 1.9 Hz, 1 H), 7.13 (dd,
δ = 1.39 (s, 9 H), 5.13 (s, 2 H), 5.18 (s, 2 H), 6.16 (d, J = 7.7 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20721
/KAP1
Date: 21-08-12 17:20:31
Pages: 10
F.-X. Felpin et al.
FULL PAPER
J = 2.2, 8.6 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.24–7.37 (m, 10
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 52.0, 55.7, 55.8, 70.5,
96.7, 110.7, 114.3, 115.4, 123.5, 125.5, 126.7, 127.9, 128.0, 128.4,
128.6, 128.8, 136.1, 136.3, 136.6, 148.0, 148.1, 162.2, 162.8 ppm.
HRMS (ESI): calcd. for C27H26NO4 [M + H]+ 428.1856; found
428.1860.
HRMS (ESI): calcd. for C11H10NO2 [M + H]+ 188.0706; found
188.0700.
3-Bromo-5-phenylpyridin-2(1H)-one (7): Br2 (0.40 mL, 7.70 mmol)
was added to a solution of 4-hydroxy-5-phenyl-2(1H)-pyridone (5)
(1.2 g, 6.42 mmol) in HBr (48%, 9.6 mL) and AcOH (2.4 mL), and
the mixture was stirred for 1 h. The resulting mixture was diluted
with water (60 mL) and filtered, and the solid was washed with
pentane (25 mL) to give a pale yellow solid (1.35 g, 79%), m.p.
1-Benzyl-4-benzyloxy-3-(3,4-methylenedioxyphenyl)pyridin-2(1H)-
one (4j): Purification by flash chromatography (50% EtOAc/petro-
leum ether) gave 4j (260 mg, 88%) as a white solid, m.p. 165 °C. IR
243 °C. IR (KBr): ν = 1645, 2943, 3393 cm–1. 1H NMR (300 MHz,
˜
(KBr): ν = 1591, 1646, 2923, 3028, 3063 cm–1. 1H NMR (250 MHz,
[D6]DMSO): δ = 7.30–7.46 (m, 6 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 97.6, 113.4, 127.0, 128.1, 129.1, 133.1, 134.1, 159.3,
161.4 ppm. HRMS (ESI): calcd. for C11H8NO2NaBr [M + Na]+
(for 79Br) 287.9630; found 287.9639.
˜
CDCl3): δ = 5.09 (s, 2 H), 5.13 (s, 2 H), 5.94 (s, 2 H), 6.10 (d, J =
7.9 Hz, 1 H), 6.86 (dd, J = 1.2, 7.6 Hz, 1 H), 6.99 (dd, J = 1.8,
7.6 Hz, 1 H), 7.00 (s, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 7.24–7.39 (m,
10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 52.1, 70.4, 96.6,
100.7, 107.8, 111.4, 115.4, 124.4, 126.5, 127.9, 128.0, 128.4, 128.6,
128.8, 136.1, 136.4, 136.6, 146.4, 147.0, 162.3, 162.7 ppm. HRMS
(ESI): calcd. for C26H22NO4 [M + H]+ 412.1543; found 412.1558.
A solution of the 3-bromo-4-hydroxy-5-phenyl-2(1H)-pyridone
(1 g, 3.76 mmol) in DMF (19 mL) was treated with K2CO3 (2.59 g,
18.8 mmol) and BnBr (1.75 mL, 15.04 mmol). The resulting mix-
ture was stirred at 25 °C for 12 h, and then diluted with H2O
(19 mL). After 10 min of stirring, the white precipitate was filtered,
1-Benzyl-4-benzyloxy-3-(4-methylsulfonylphenyl)pyridin-2(1H)-one
(4k): Purification by flash chromatography (20% EtOAc/petroleum
and washed with cold Et2O (3ϫ) to give 7 (830 mg, 50%) as a
1
white solid, m.p. 158 °C. IR (KBr): ν = 1647, 2958, 3036 cm–1. H
ether) gave 4k (227 mg, 71%) as a colourless oil. IR (neat): ν =
˜
˜
1645, 2923, 3002, 3033 cm–1. 1H NMR (300 MHz, CDCl3): δ =
3.03 (s, 3 H), 5.11 (s, 2 H), 5.14 (s, 2 H), 6.19 (d, J = 7.7 Hz, 1 H),
7.20–7.36 (m, 11 H), 7.73 (d, J = 8.6 Hz, 2 H), 7.92 (d, J = 8.5 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 44.6, 52.2, 70.7, 96.3,
113.3, 126.5, 126.7, 128.1, 128.3, 128.7, 128.9, 131.9, 135.4, 136.1,
137.9, 138.3, 139.3, 162.1, 162.9 ppm. HRMS (ESI): calcd. for
C26H23NO4NaS [M + Na]+ 468.1240; found 468.1233.
NMR (300 MHz, CDCl3): δ = 4.64 (s, 2 H), 5.24 (s, 2 H), 7.14 (br.
s, 2 H), 7.27–7.39 (m, 14 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 53.1, 74.5, 109.0, 118.4, 128.0, 128.3, 128.3, 128.4, 128.5, 128.6,
128.7, 129.0, 133.7, 135.3, 135.5, 135.8, 159.9, 163.0 ppm. HRMS
(ESI): calcd. for C25H20NO2NaBr [M + Na]+ (for 79Br) 468.0569;
found 468.0575.
1-Benzyl-4-benzyloxy-3-(4-methoxyphenyl)-5-phenylpyridin-2(1H)-
one (8): Na2CO3 (159 mg, 1.5 mmol), ArB(OH)2 (114 mg,
0.75 mmol), and Pd/C (26.5 mg, 5 mol-%) were added to a solution
of bromopyridone (7) (223 mg, 0.5 mmol) in iPrOH (1.5 mL) and
H2O (1.5 mL). The resulting mixture was stirred at 60 °C for 12 h
and then filtered. The catalyst was washed with H2O (3 mL) and
CH2Cl2 (5 mL). The aqueous phase was extracted twice with
CH2Cl2. The collected organic extracts were dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The crude com-
pound was purified by flash chromatography to give 8 as a white
1-Benzyl-4-benzyloxy-3-(3-nitrophenyl)pyridin-2(1H)-one (4l): Puri-
fication by flash chromatography (5% EtOAc/CH2Cl2) gave 4l
(276 mg, 93%) as a yellow solid, m.p. 134 °C. IR (KBr): ν = 1594,
˜
1
1646, 2928, 3032 cm–1. H NMR (300 MHz, CDCl3): δ = 5.12 (s,
2 H), 5.16 (s, 2 H), 6.21 (d, J = 7.9 Hz, 1 H), 7.26–7.37 (m, 11 H),
7.51 (app t, J = 7.9 Hz, 1 H), 7.91 (dm, J = 7.9 Hz, 1 H), 8.11 (dm,
J = 8.3 Hz, 1 H), 8.45 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 52.1, 70.7, 96.1, 112.7, 121.8, 126.2, 126.8, 128.1, 128.3, 128.7,
128.9, 134.8, 135.3, 136.1, 137.3, 137.9, 147.7, 162.0, 162.9 ppm.
HRMS (ESI): calcd. for C25H20N2O4Na [M + Na]+ 435.1315;
found 435.1335.
solid (120.6 mg, 51%), m.p. 108 °C. IR (KBr): ν = 1644, 2932,
˜
3033 cm–1. 1H NMR (250 MHz, CDCl3): δ = 3.87 (s, 3 H), 4.27 (s,
2 H), 5.22 (s, 2 H), 6.68 (d, J = 6.7 Hz, 2 H), 6.98 (d, J = 8.8 Hz,
2 H), 7.09–7.19 (m, 3 H), 7.31–7.44 (m, 11 H), 7.53 (d, J = 8.6 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 52.4, 55.3, 74.1, 113.5,
118.7, 121.9, 125.5, 127.4, 127.9, 128.0, 128.3, 128.4, 128.5, 128.8,
129.2, 132.0, 134.7, 135.2, 135.8, 136.5, 159.0, 161.8, 162.9 ppm.
HRMS (ESI): calcd. for C32H28NO3 [M + H]+ 474.2063; found
474.2086.
1-Benzyl-4-benzyloxy-3-styrylpyridin-2(1H)-one (4n): Purification
by flash chromatography (40% EtOAc/petroleum ether) gave 4n
(240 mg, 85%) as a white solid, m.p. 133 °C. IR (KBr): ν = 1593,
˜
1640, 2942, 3026, 3053 cm–1. 1H NMR (250 MHz, CDCl3): δ =
5.16 (s, 2 H), 5.20 (s, 2 H), 6.11 (d, J = 7.6 Hz, 1 H), 7.17 (d, J =
7.6 Hz, 1 H), 7.19–7.52 (m, 15 H), 7.55 (d, J = 16.5 Hz, 1 H), 8.10
(d, J = 16.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 51.8,
70.7, 96.0, 111.6, 119.5, 126.5, 126.9, 127.0, 127.9, 128.0, 128.3,
128.4, 128.7, 128.8, 131.8, 135.6, 135.8, 136.5, 139.2, 162.2,
162.8 ppm. HRMS (ESI): calcd. for C27H24NO2 [M + H]+
394.1801; found 394.1796.
2,4-Bis(benzyloxy)-3-iodo-5-phenylpyridine (9): A solution of iodine
(1.75 g, 6.9 mmol) in dioxane (10 mL) was added dropwise over a
period of 5 min to a refluxing solution of 4-hydroxy-5-phenylpyr-
idin-2(1H)-one (5) (1.16 g, 6.2 mmol) and Na2CO3 (1.25 g,
11.8 mmol) in H2O (25 mL). The solution was heated at reflux for
a further 5 min, and then cooled to 5 °C. NaHSO3 was added por-
tionwise until decolouration of the solution had occurred. The mix-
ture was then acidified with AcOH, which resulted in the precipi-
tation of the 2,4-dihydroxy-3-iodopyridine. The product was fil-
tered and then dried under vacuum with protection from light. The
product was suspended in anhydrous benzene under argon,
Ag2CO3 (3.42 g, 12.4 mmol) was added, and the resulting slurry
was homogenised by magnetic stirring at room temperature for
5 min to give a yellowish suspension. Benzyl bromide (3.28 mL,
27.6 mmol) was added dropwise to the suspension, and the mixture
was further stirred at room temperature in the dark for 3 d. After
4-Hydroxy-5-phenylpyridin-2(1H)-one (5): Malonyl dichloride
(6 mL, 62 mmol) and phenylacetonitrile (3.6 mL, 31 mmol) were
stirred without solvent under an atmosphere of argon at room tem-
perature for 5 d. The resulting gum was triturated with Et2O
(20 mL) to give a brown powder. After filtration, the powder was
transferred into a flask and stirred for 30 min with EtOAc (20 mL)
and then filtered. This operation was repeated twice. The collected
buff solid was diluted in EtOH (120 mL), and treated with Pd(OH)
2/C (20 mol-%). The resulting mixture was heated for 12 h at reflux,
and then filtered to give a white solid (4.75 g, 82% over two steps),
m.p. 175 °C. IR (KBr): ν = 1645, 2957, 3072, 3391 cm–1. 1H NMR
˜
(300 MHz,
[D4]-
methanol): δ = 6.60 (s, 1 H), 7.38–7.54 (m, 5 H) 7.95 (s, 1 H) ppm. this period, the suspension was diluted with EtOAc, and filtered
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20721
/KAP1
Date: 21-08-12 17:20:31
Pages: 10
Pd/C-Catalysed Suzuki–Miyaura Reactions
through Celite, and the remaining greenish solid was washed five
times with small portions of EtOAc. The solution was then concen-
trated, and the residual solid was recrystallised from hexane/tolu-
CDCl3): δ = 162.2, 161.6, 146.6, 137.9, 137.2, 136.1, 135.7, 130.7,
129.6, 129.5, 128.7, 128.6, 128.4, 128.3, 128.1, 128.0, 127.4, 127.4,
127.2, 126.3, 118.1, 74.6, 67.7, 21.6 ppm. HRMS (ESI): calcd. for
ene to give pure product 9 (1.86 g, 61%) as a white solid, m.p. 113– C32H28NO2 [M + H]+ 458.2041; found 458.2120.
114 °C. IR (ZnSe): ν = 1577, 1457, 1435, 1367, 1360, 1204, 1069,
˜
2,4-Bis(benzyloxy)-3-p-tolylquinoline
recrystallisation from petroleum ether/EtOAc gave 13b (75.9 mg,
(13b):
Purification
by
737, 696 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.57 (s, 2 H), 5.52
(s, 2 H), 7.16–7.26 (m, 2 H), 7.29–7.61 (m, 13 H), 8.05 (s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 167.0, 161.7, 149.0, 136.6,
135.4, 133.7, 130.8, 129.0, 128.73, 128.70, 128.62, 128.58, 128.55,
128.53, 128.1, 127.9, 76.5, 75.1, 69.8 ppm. HRMS (ESI): calcd. for
C25H21INO2 [M + H]+ 494.0617; found 494.0628.
88%) as a white solid, m.p. 137–138 °C. IR (ZnSe): ν = 3061, 3030,
˜
1
2938, 2877, 1582 cm–1. H NMR (300 MHz, CDCl3): δ = 8.17 (s,
1 H), 7.58 (d, J = 6.7 Hz, 2 H), 7.52–7.08 (m, 13 H), 6.68 (d, J =
7.0 Hz, 2 H), 5.51 (s, 2 H), 4.29 (s, 2 H), 2.47 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 162.2, 161.6, 146.5, 137.8, 137.1,
136.0, 135.6, 130.7, 129.5, 129.5, 128.7, 128.5, 128.4, 128.3, 128.0,
127.9, 127.3, 127.3, 127.2, 126.3, 118.1, 74.5, 67.6, 21.4 ppm.
HRMS (ESI): calcd. for C30H26NO2 [M + H]+ 432.1964; found
432.1959.
2,4-Bis(benzyloxy)-3-iodoquinoline (11): Following the procedure
described for the synthesis of 9, compound 11 was obtained from
2,4-dihydroxyquinoline (10) after recrystallisation from hexane/tol-
uene, as a white solid (898 mg, 31%), m.p. 141–142 °C. IR (ZnSe):
ν = 3064, 3033, 2935, 1613, 1597 cm–1. 1H NMR (300 MHz,
˜
2,4-Bis(benzyloxy)-3-(4-methoxyphenyl)-5-phenylpyridine (12c): Pu-
rification by flash chromatography (50% CH2Cl2/petroleum ether)
gave 12c (74.9 mg, 79%) as a white solid, m.p. 132–133 °C. IR
CDCl3): δ = 8.01 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 1 H),
7.75–7.61 (m, 5 H), 7.57–7.34 (m, 7 H), 5.68 (s, 2 H), 5.22 (s, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 165.3, 160.0, 147.2, 137.1,
136.2, 130.5, 128.7, 128.6, 128.4, 127.8, 127.6, 127.4, 124.5, 122.1,
121.9, 77.5, 76.0, 69.0 ppm. HRMS (ESI): calcd. for C23H19INO2
[M + H]+ 468.0460; found 468.0477.
(ZnSe): ν = 3035, 2375, 1582, 1513 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 8.17 (s, 1 H), 7.62–7.56 (m, 2 H), 7.54–7.10 (m, 13 H),
7.02 (d, J = 8.9 Hz, 2 H), 6.74–6.68 (m, 2 H), 5.51 (s, 2 H), 4.30
(s, 2 H), 3.91 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.2,
161.6, 159.0, 146.4, 137.8, 136.0, 135.6, 132.0, 129.5, 128.5, 128.4,
128.3, 128.1, 128.0, 127.4, 127.4, 127.1, 126.3, 124.7, 117.8, 113.4,
74.5, 67.7, 55.3 ppm. HRMS (ESI): calcd. for C32H28NO3 [M +
H]+ 474.2094; found 474.2069.
General Procedure for the Suzuki Coupling of 2,4-Bis(benzyloxy)-3-
iodo-5-phenylpyridine (9) and 2,4-Bis(benzyloxy)-3-iodoquinoline
(11): A suspension of 9 or 11 (0.2 mmol), boronic acid (0.24 mmol),
Na3CO3 (64 mg, 0.6 mmol), and Pd/C (10.6 mg, 5 mol-%) in a mix-
ture of iPrOH (0.5 mL) and H2O (0.5 mL) was stirred at 80 °C for
12 h. The mixture was then diluted with EtOAc (5 mL) and hot-
filtered through a Celite pad. The pad was washed with two por-
tions of warm EtOAc, and then the combined fractions were
washed with brine and dried with Na2SO4. The solution was fil-
tered and concentrated under reduced pressure to give the crude
product, which was purified by recrystallisation or flash
chromatography.
2,4-Bis(benzyloxy)-3-(4-methoxyphenyl)quinoline (13c): Purification
by flash column chromatography (15% EtOAc/petroleum ether)
gave 13c (76.0 mg, 85%) as a white solid, m.p. 124–125 °C. IR
(ZnSe): ν = 3064, 3033, 2935, 1613, 1597, 1572 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 8.10 (d, J = 8.3 Hz, 1 H), 7.90 (d, J =
7.9 Hz, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 2 H),
7.49–7.26 (m, 9 H), 7.25–7.18 (m, 2 H), 7.04 (d, J = 8.8 Hz, 2 H),
5.62 (s, 2 H), 4.66 (s, 2 H), 3.91 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.7, 160.7, 159.1, 146.3, 137.8, 136.6, 132.2, 129.7,
128.4, 128.3, 128.2, 128.2, 127.4, 127.3, 127.0, 125.0, 123.9, 122.7,
121.8, 121.2, 113.6, 75.2, 67.6, 55.3 ppm. HRMS (ESI): calcd. for
C30H25NO3Na [M + Na]+ 470.1732; found 470.1733.
2,4-Bis(benzyloxy)-3,5-diphenylpyridine (12a): Purification by
recrystallisation from petroleum ether gave 12a (68.2 mg, 77%) as
a white solid, m.p. 111–112 °C. IR (ZnSe): ν = 3031, 2920, 2850,
˜
1
1633, 1583 cm–1. H NMR (300 MHz, CDCl3): δ = 8.21 (s, 1 H),
7.61 (d, J = 6.5 Hz, 2 H), 7.56 (d, J = 6.5 Hz, 2 H), 7.53–7.29 (m,
11 H), 7.25–7.10 (m, 3 H), 6.67 (d, J = 6.7 Hz, 2 H), 5.52 (s, 2 H),
4.29 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.2, 161.5,
146.8, 137.7, 135.9, 135.6, 132.6, 130.9, 129.5, 128.5, 128.5, 128.3,
128.1, 128.0, 128.0, 127.5, 127.5, 127.4, 127.1, 126.3, 118.2, 74.6,
67.7 ppm. HRMS (ESI): calcd. for C31H25NO2Na [M + Na]+
466.1783; found 466.1771.
2,4-Bis(benzyloxy)-3-(3,4-dimethoxyphenyl)-5-phenylpyridine (12d):
Purification by flash chromatography (CH2Cl2) gave 12d (96.6 mg,
96%) as a white solid, m.p. 94–95 °C. IR (ZnSe): ν = 3062, 3031,
˜
1
2934, 2834, 1585 cm–1. H NMR (300 MHz, CDCl3): δ = 8.18 (s,
1 H), 7.59 (d, J = 6.5 Hz, 2 H), 7.52–7.29 (m, 8 H), 7.26–7.11 (s, 4
H), 7.08 (d, J = 1.9 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 6.76–6.69
(m, 2 H), 5.51 (s, 2 H), 4.32 (s, 2 H), 3.99 (s, 3 H), 3.80 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 162.1, 161.5, 148.3, 146.4,
137.7, 136.1, 135.6, 129.5, 128.5, 128.4, 128.3, 128.3, 128.1, 128.0,
127.5, 127.4, 127.3, 126.4, 124.9, 123.6, 117.7, 114.1, 110.7, 74.5,
67.7, 55.9, 55.8 ppm. HRMS (ESI): calcd. for C33H29NO4Na [M +
Na]+ 526.1994; found 526.2008.
2,4-Bis(benzyloxy)-3-phenylquinoline (13a): Purification by flash
chromatography (50:50 CH2Cl2/petroleum ether) gave 13a
(65.9 mg, 79%) as a white solid, m.p. 74–75 °C. IR (ZnSe): ν =
˜
3066, 3032, 2944, 1614, 1595, 1570 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.17 (d, J = 8.3 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 1 H),
7.76–7.63 (m, 3 H), 7.60–7.29 (m, 11 H), 7.26–7.17 (m, 2 H), 5.67
(s, 2 H), 4.70 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.9,
160.6, 146.6, 147.8, 137.8, 136.5, 133.1, 131.1, 129.9, 128.5, 128.4,
128.4, 128.3, 128.3, 128.2, 127.8, 127.3, 127.3, 127.1, 121.8, 116.6,
75.5, 76.7 ppm. HRMS (ESI): calcd. for C29H23NO2Na [M +
Na]+ 440.1626; found 440.1632.
2,4-Bis(benzyloxy)-3-(3,4-dimethoxyphenyl)quinoline (13d): Purifi-
cation by flash chromatography (15% EtOAc/petroleum ether) gave
13d (84.9 mg, 89%) as a white solid, m.p. 98–100 °C. IR (ZnSe): ν
˜
1
= 3064, 3031, 2935, 1597 cm–1. H NMR (300 MHz, CDCl3): δ =
8.14 (d, J = 8.1 Hz, 1 H), 7.93 (d, J = 8.2 Hz, 1 H), 7.75–7.62 (m,
1 H), 7.61–7.11 (m, 13 H), 7.01 (d, J = 8.2 Hz, 1 H), 5.65 (s, 2 H),
4.71 (s, 2 H), 4.00 (s, 3 H), 3.84 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.7, 160.6, 148.6, 148.5, 146.3, 137.7, 136.6, 129.8,
128.7, 128.5, 128.3, 128.2, 127.6, 127.5, 127.1, 125.2, 124.1, 123.7,
2,4-Bis(benzyloxy)-5-phenyl-3-p-tolylpyridine (12b): Purification by
flash chromatography (50:50 CH2Cl2/petroleum ether) gave 12b
(79.5 mg, 87%) as a white solid, m.p. 136–137 °C. IR (ZnSe): ν =
˜
1
3031, 1582, 1498 cm–1. H NMR (300 MHz, CDCl3): δ = 8.21 (s,
1 H), 7.66–7.59 (m, 2 H), 7.54–7.12 (m, 15 H), 6.76–6.68 (m, 2 H), 122.7, 121.8, 116.1, 114.2, 110.8, 75.2, 67.8, 55.9, 55.8 ppm. HRMS
5.55 (s, 2 H), 4.33 (s, 2 H), 2.60 (s, 3 H) ppm. 13C NMR (75 MHz, (ESI): calcd. for C31H28NO4 [M + H]+ 478.2039; found 478.2018.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 21-08-12 17:20:31
Pages: 10
F.-X. Felpin et al.
FULL PAPER
3-(Benzo[d][1,3]dioxol-5-yl)-2,4-bis(benzyloxy)-5-phenylpyridine
(12e): Purification by recrystallisation from petroleum ether/EtOAc
gave 12e (78.9 mg, 81%) as a white solid, m.p. 139–140 °C. IR
1
IR (ZnSe): ν = 3064, 3032, 2949, 1723, 1610, 1572 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 8.28 (d, J = 8.5 Hz, 2 H), 8.21 (d, J =
8.2 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 2 H),
(ZnSe):
ν =
˜
3063, 3031, 2941, 2884, 1580 cm–1. 1H NMR 7.74 (t, J = 8.5 Hz, 1 H), 7.53–7.32 (m, 9 H), 7.29–7.20 (m, 2 H),
(300 MHz, CDCl3): δ = 8.15 (s, 1 H), 7.56 (d, J = 8.1 Hz, 2 H),
7.48–7.29 (m, 8 H), 7.21–7.12 (m, 3 H), 7.02–6.97 (m, 2 H), 6.99–
6.85 (m, 1 H), 6.74 (d, J = 6.6 Hz, 2 H), 6.02 (s, 2 H), 5.49 (s, 2
H), 4.32 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.3,
161.6, 147.4, 147.0, 146.7, 137.8, 136.1, 135.6, 129.5, 128.5, 128.4,
128.2, 127.5, 127.3, 126.4, 126.1, 124.6, 117.8, 111.5, 108.1, 101.1,
74.7, 67.8 ppm. HRMS (ESI): calcd. for C32H26NO4 [M + H]+
488.1862; found 488.1801.
5.71 (s, 2 H), 4.73 (s, 2 H), 4.05 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.1, 161.2, 160.1, 146.9, 138.2, 137.5, 136.3, 131.3,
130.3, 129.4, 128.6, 128.4, 128.4, 128.4, 128.3, 127.6, 127.6, 127.4,
124.3, 122.9, 121.6, 115.9, 75.9, 68.0, 52.2 ppm. HRMS (ESI): m/z
calcd. for C31H26NO4 [M + H]+ 476.1862; found 476.1871.
2,4-Bis(benzyloxy)-3-(4-nitrophenyl)-5-phenylpyridine (12h): Purifi-
cation by flash chromatography (50% CH2Cl2-petroleum ether)
gave 12h (69.3 mg, 71%) as a yellow solid, m.p. 159–160 °C. IR
3-(Benzo[d][1,3]dioxol-5-yl)-2,4-bis(benzyloxy)quinoline (13e): Puri-
fication by recrystallisation from petroleum ether/toluene gave 13e
(ZnSe): ν = 3063, 3031, 2939, 1600, 1580, 1519 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 8.25 (s, 1 H), 8.23 (d, J = 9.9 Hz, 2 H),
7.63–7.58 (m, 4 H), 7.52–7.43 (m, 3 H), 7.35–7.30 (m, 5 H), 7.23–
7.18 (m, 1 H), 7.14–7.08 (m, 2 H), 6.64 (d, J = 7.2 Hz, 2 H), 5.47
(s, 2 H), 4.29 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.1,
(76.5 mg, 83%) as a white solid, m.p. 120–121 °C. IR (ZnSe): ν =
˜
3064, 3031, 2884, 1596, 1571 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 8.11 (d, J = 8.2 Hz, 1 H), 8.34 (d, J = 8.3 Hz, 1 H), 7.67 (t, J
= 7.6 Hz, 1 H), 7.51–7.22 (m, 11 H), 7.14–7.06 (m, 2 H), 6.97 (dd, 160.9, 148.4, 147.0, 140.0, 137.1, 135.3, 135.2, 132.1, 129.3, 128.8,
J = 8.4, J = 1.5 Hz, 1 H), 6.06 (s, 2 H), 5.64 (s, 2 H), 4.74 (s, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 160.9, 160.6, 147.5, 147.1,
146.3, 137.8, 136.6, 129.8, 128.5, 128.3, 128.2, 128.2, 127.5, 127.4,
127.1, 126.3, 124.7, 124.0, 122.7, 121.8, 116.1, 111.5, 108.2, 101.1,
75.3, 67.7 ppm. HRMS (ESI): calcd. for C30H24NO4 [M + H]+
462.1697; found 462.1705.
128.5, 128.4, 128.3, 127.9, 127.8, 127.4, 126.1, 122.9, 116.3, 75.2,
68.1 ppm. HRMS (ESI): calcd. for C31H25N2O4 [M
489.1814; found 489.1904.
+
H]+
2,4-Bis(benzyloxy)-3-(4-nitrophenyl)quinoline (13h): Purification by
flash chromatography (50% CH2Cl2-petroleum ether) gave 13h
(67.5 mg, 73%) as a yellow solid, m.p. 136–137 °C. IR (ZnSe): ν =
˜
4-[2,4-Bis(benzyloxy)-5-phenylpyridin-3-yl]benzoic Acid (12f): Puri-
fication by recrystallisation from petroleum ether/EtOAc gave 12f
(69.2 mg, 71%) as a light yellow solid, m.p. 197–198 °C. IR (ZnSe):
3065, 3033, 2945, 1602, 1571 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 8.42–8.25 (m, 2 H), 8.14 (d, J = 8.2 Hz, 1 H), 7.99 (d, J =
8.2 Hz, 1 H), 7.82–7.70 (m, 3 H), 7.62–7.24 (m, 9 H), 7.22–7.10 (m,
2 H), 5.64 (s, 2 H), 4.75 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
ν = 3062, 3031, 2947, 2877, 2547, 1610, 1582 cm–1. 1H NMR
˜
(300 MHz, CD3OD): δ = 8.13 (s, 1 H), 8.04 (d, J = 8.3 Hz, 2 H), δ = 161.4, 159.5, 147.1, 147.1, 144.9, 140.2, 137.2, 135.8, 132.1,
7.56 (d, J = 6.5 Hz, 2 H), 7.56–7.37 (m, 5 H), 7.34–7.11 (m, 6 H), 130.7, 128.6, 128.5, 128.3, 128.2, 127.8, 127.7, 127.4, 123.1, 122.4,
7.06 (t, J = 7.3 Hz, 2 H), 6.62 (d, J = 7.0 Hz, 2 H), 5.40 (s, 2 H), 121.3, 115.1, 76.4, 68.1 ppm. HRMS (ESI): calcd. for C29H23N2O4
4.27 (s, 2 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 171.7, 162.1, [M + H]+ 463.1658; found 463.2123.
161.1, 147.0, 137.3, 135.7, 135.3, 130.7, 129.0, 129.0, 128.8, 128.2,
4-[2,4-Bis(benzyloxy)-5-phenylpyridin-3-yl]phenyl
enesulfonate (12i): Purification by flash column chromatography
(20% EtOAc/petroleum ether) gave 12i (69.9 mg, 57%) as a white
4-Methylbenz-
128.2, 128.0, 127.9, 127.7, 127.7, 127.3, 127.2, 127.0, 126.3, 117.6,
74.4, 67.6 ppm. HRMS (ESI): calcd. for C32H26NO4 [M + H]+
488.1862; found 488.1873.
solid, m.p. 161–162 °C. IR (ZnSe): ν = 2921, 2851, 1652, 1635,
˜
1
4-[2,4-Bis(benzyloxy)quinolin-3-yl]benzoic Acid (13f): Purification
by recrystallisation from petroleum ether/EtOAc gave 13f (61.8 mg,
1577, 1558 cm–1. H NMR (300 MHz, CDCl3): δ = 8.20 (s, 1 H),
7.75 (d, J = 8.3 Hz, 2 H), 7.59 (d, J = 6.5 Hz, 2 H), 7.52–7.12 (m,
15 H), 7.07 (d, J = 8.8 Hz, 2 H), 6.67 (d, J = 7.8 Hz, 2 H), 5.46 (s,
2 H), 4.24 (s, 2 H), 2.43 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 161.0, 161.2, 148.9, 147.3, 145.3, 137.4, 135.6, 135.3, 132.5,
132.2, 131.7, 129.8, 129.7, 129.3, 128.6, 128.4, 128.3, 128.2, 128.2,
127.6, 127.5, 127.1, 126.1, 121.9, 117.0, 74.7, 67.8, 21.7 ppm.
67%) as a light yellow solid, m.p. 161 °C (decomp). IR (ZnSe): ν
˜
= 3064, 3031, 2945, 1694, 1598 cm–1. 1H NMR (300 MHz,
CD3OD): δ = 8.08 (d, J = 8.0 Hz, 2 H), 8.02 (d, J = 8.2 Hz, 1 H),
7.82 (d, J = 8.4 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.53 (d, J =
8.0 Hz, 2 H), 7.42–7.17 (m, 9 H), 7.14–7.03 (m, 2 H), 5.49 (s, 2 H),
4.60 (s, 2 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 173.3, 160.8, HRMS (ESI): calcd. for C38H32NO5S [M + H]+ 614.2001; found
160.3, 146.4, 137.3, 136.3, 135.3, 133.7, 130.3, 129.7, 128.7, 128.0,
127.9, 127.9, 127.1, 127.0, 126.6, 123.8, 122.4, 121.5, 116.3, 108.7,
75.3, 67.5 ppm. HRMS (ESI): calcd. for C30H24NO4 [M + H]+
462.1705; found 462.1700.
614.1989.
4-[2,4-Bis(benzyloxy)quinolin-3-yl]phenyl 4-Methylbenzenesulfonate
(13i): Purification by flash column chromatography (20% EtOAc/
petroleum ether) gave 13i (50.5 mg, 43%) as a white solid, m.p.
Methyl 4-[2,4-Bis(benzyloxy)quinolin-3-yl]benzoate (12g): Purifica-
tion by flash column chromatography (50% CH2Cl2/petroleum
132–134 °C. IR (ZnSe): ν = 3063, 3358, 3062, 2921, 2850, 1657,
˜
1
1596 cm–1. H NMR (300 MHz, CDCl3): δ = 8.08 (d, J = 8.2 Hz,
ether) gave 12g (95.2 mg, 95%) as a white solid, m.p. 153–154 °C.
1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 2 H), 7.66 (d,
J = 6.9 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 2 H), 7.46–6.98 (m, 15 H),
5.58 (s, 2 H), 4.61 (s, 2 H), 2.41 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.9, 160.1, 149.1, 146.7, 145.3, 137.4, 136.1, 132.4,
132.3, 132.0, 130.2, 129.7, 128.5, 128.5, 128.4, 128.3, 128.2, 127.5,
127.3, 127.2, 124.2, 122.7, 122.1, 121.5, 115.5, 75.6, 67.7, 21.7 ppm.
HRMS (ESI): calcd. for C36H29NO5S [M + Na]+ 610.1664; found
610.1678.
1
IR (ZnSe): ν = 2949, 2374, 1720, 1579, 1528, 1498 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 8.24 (s, 1 H), 8.15 (d, J = 8.5 Hz, 2 H),
7.66–7.59 (m, 4 H), 7.55–7.10 (m, 11 H), 6.71–6.63 (m, 2 H), 5.51
(s, 2 H), 4.31 (s, 2 H), 4.01 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.1, 162.1, 161.2, 147.6, 137.8, 137.4, 135.6, 135.4,
131.1, 130.2, 129.4, 129.1, 129.1, 128.6, 128.5, 128.4, 128.2, 127.6,
127.6, 127.2, 126.2, 117.3, 74.8, 67.9, 52.2 ppm. HRMS (ESI):
calcd. for C33H28NO4 [M + H]+ 502.2018; found 502.2018.
3-Biphenyl-4-hydroxypyridin-2(1H)-one (14): Pd(OH)2/C (20 mol-
%) was added to a solution of pyridone 4a (184 mg, 0.5 mmol)
in AcOH (5 mL), and the mixture was stirred at 60 °C under an
atmosphere of H2 for 12 h. The mixture was filtered and concen-
Methyl 4-[2,4-Bis(benzyloxy)quinolin-3-yl]benzoate (13g): Purifica-
tion by flash column chromatography (15% EtOAc/petroleum
ether) gave 13g (90.3 mg, 95%) as a white solid, m.p. 133–134 °C.
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20721
/KAP1
Date: 21-08-12 17:20:31
Pages: 10
Pd/C-Catalysed Suzuki–Miyaura Reactions
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trated under reduced pressure, and the residue was precipitated
from Et2O. The resulting grey solid was filtered and used in the
next step without further purification, due to its insolubility in
most organic solvents.
Nucleoside 15: N,O-Bis(trimethylsilyl)acetamide (245 μL, 1 mmol)
was added to a solution of 1,2,3,5-tetra-O-acetyl-β-d-ribofuranose
(207 mg, 0.65 mmol) and compound 14 (0.5 mmol) in CH3CN
(3 mL) at room temperature. The resulting mixture was stirred for
2 h, and then TMSOTf (181 μL, 1 mmol) was added dropwise. Af-
ter being stirred for 18 h at room temperature, the solution was
diluted with CH2Cl2 (10 mL) and washed with water (1ϫ) and sat-
urated aqueous NaHCO3 solution (2ϫ). The aqueous phase was
extracted with CH2Cl2 (3ϫ). The combined organic extracts were
dried (MgSO4), filtered, and concentrated under reduced pressure.
Purification by flash chromatography (80% EtOAc/petroleum
ether) gave 15 (161.5 mg, 62% over two steps) as a white foam.
[α]2D5 = +92.2 (c 1.09, CHCl ). IR (KBr): ν = 1652, 1750, 2939,
˜
3
3031, 3082, 3401 cm–1. H NMR (CDCl3, 300 MHz): δ = 2.03 (s,
1
[6] Unpublished results.
3 H), 2.05 (s, 3 H), 2.13 (s, 3 H), 4.30–4.39 (m, 3 H), 5.29 (t, J =
6.2 Hz, 1 H), 5.45 (dd, J = 3.4, 5.6 Hz, 1 H), 6.08 (d, J = 7.7 Hz,
1 H), 6.18 (d, J = 3.4 Hz, 1 H), 7.24 (br. s, 1 H), 7.32–7.37 (m, 1
H), 7.41–7.46 (m, 5 H), 7.56–7.64 (m, 4 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 20.4, 20.7, 62.6, 69.3, 74.1, 78.9, 89.1, 100.9,
112.1, 127.1, 127.4, 127.7, 128.8, 130.0, 130.9, 131.9, 140.7, 140.9,
162.0, 162.2, 169.5, 170.3 ppm. HRMS (ESI): calcd. for
C28H27NO9Na [M + Na]+ 544.1578; found 544.1571.
[7] F.-X. Felpin, N. Bourgougnon, M. Zanese, Patent
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
Acknowledgments
This work was supported by the Ligue Contre Le Cancer, the Uni-
versité de Bordeaux, the Centre National de la Recherche Sci-
entifique (CNRS), and Aquitaine Valo. The Association pour la
Recherche sur le Cancer (ARC) is gratefully acknowledged for a
postdoctoral grant to M. L. Dr. Hélène Bonin (Université de Lille
1) is gratefully acknowledged for fruitful discussions.
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Received: June 5, 2012
Published Online: ᭿
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Job/Unit: O20721
/KAP1
Date: 21-08-12 17:20:31
Pages: 10
F.-X. Felpin et al.
FULL PAPER
Heterogeneous Catalysis
M. Lamblin, H. Bares, J. Dessolin,
C. Marty, N. Bourgougnon,
F.-X. Felpin* ................................... 1–10
Practical Pd/C-Catalysed Suzuki–Miyaura
Reactions for the Preparation of 3-Aryl-4-
oxypyridin-2(1H)-ones, 3-Aryl-2,4-oxypyr-
idines and 3-Aryl-2,4-oxyquinolines as
Useful Intermediates for the Synthesis of
Biologically Active Compounds
A heterogeneous Pd/C-catalysed Suzuki–
Miyaura cross-coupling reaction for the
preparation of 3-aryl-4-oxypyridin-2(1H)-
ones, 3-aryl-2,4-oxypyridines, and 3-aryl-
2,4-oxyquinolines represents a useful and
efficient alternative to homogeneous con-
ditions. These interesting heterocycles can
be used as platforms for the synthesis of
biologically active compounds.
Keywords: Heterogeneous catalysis / Pal-
ladium / Cross-coupling / Nitrogen hetero-
cycles / Nucleosides / Medicinal
chemistry / Antiviral agents
10
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