Divergent synthesis of arylated pyridin-2(1H)-one derivatives via metal-catalysed cross-coupling processes

Article abstract of DOI:10.1016/j.tet.2010.05.108

1,5-Di(hetero)arylated-pyridin-2(1H)-one derivatives have been readily obtained in good yields starting from 2-fluoro-5-pyridylboronic acid. The sequence comprises three steps: (i) palladium-catalysed Suzuki-Miyaura reaction; (ii) base-catalysed hydrolysi

Full text of DOI:10.1016/j.tet.2010.05.108

Tetrahedron 66 (2010) 6138e6149
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Tetrahedron
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Divergent synthesis of arylated pyridin-2(1H)-one derivatives via metal-catalysed
cross-coupling processes
,
Jamie S. Siddle a, Andrei S. Batsanov a, Stuart T. Caldwell b, Graeme Cooke b, Martin R. Bryce a
*
a Department of Chemistry, Durham University, Durham DH1 3LE, UK
b Department of Chemistry, WestCHEM, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
1,5-Di(hetero)arylated-pyridin-2(1H)-one derivatives have been readily obtained in good yields starting
from 2-fluoro-5-pyridylboronic acid. The sequence comprises three steps: (i) palladium-catalysed Su-
zuki-Miyaura reaction; (ii) base-catalysed hydrolysis; (iii) copper-catalysed CeN coupling. X-ray crystal
structures are reported for selected pyridin-2(1H)-one derivatives. These compounds are of interest as
new scaffolds for drug discovery.
Received 18 March 2010
Received in revised form 30 April 2010
Accepted 28 May 2010
Available online 8 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Pyridone
Palladium catalysis
Cross-coupling
Suzuki-Miyaura reaction
Arylation
Boronic acid
CeN coupling
Copper catalysis
1. Introduction
arylamides to 4-hydroxyquinazolines.33 There is interest in se-
quential metal-catalysed routes to functionalised heteroaryl sys-
Functionalised pyridones are of continued interest due to their
prevalence in naturally occurring compounds,1e3 bioactive com-
pounds and drugs,4e14 coordination chemistry15 and their catalytic
acitivity.16 New routes for their synthesis and functionalisation
continue to be developed.17,18 Metal-catalysed cross-coupling re-
actions have revolutionised the modification of pyridones19 and
related heterocycles, with CeC, CeN, CeO bond forming processes
now widely utilised.20,21 Notably, Suzuki-Miyaura, Buchwald-
Hartwig and Ullmann type reactions have become ubiquitous in the
post-functionalisation of heterocycles. Access to N-arylpyridones
was traditionally achieved using harsh Ullmann-Goldberg condi-
tions22 resulting in low yields and poor functional group tolerance.
Ligand-accelerated and copper-catalysed approaches have led to
much milder coupling conditions.23e28 Other methods for N-ary-
lating pyridones and related heterocycles include: copper-
mediated coupling with arylboronic acids,24,29,30 lead-mediated
coupling to aryl halides31,32 and HATU-mediated coupling of
tems.34e39 The aim of the present work was to develop an efficient
divergent route to tri-(hetero)aryl systems based on the pyridin-2
(1H)-one framework starting from the commercially-available 2-
fluoro-5-pyridylboronic acid 1.40 We also report related reactions of
2,6-difluoro-5-pyridylboronic acid.
2. Results and discussion
An overview of our methodology is shown in Scheme 1. Suzuki-
Miyaura cross-coupling of 2-fluoro-5-pyridylboronic acid 1 with
(hetero)aryl bromides 2e4 furnished compounds 5e7 under stan-
dard conditions41,42 in high isolated yields (Table 1).
Conversion of 5e7 into the 2-pyridone derivatives 8e10 was
achieved in high yields by hydrolysis under basic conditions (Table
1).43 Compounds 6 and 7 reacted faster than 5, presumably due to
the electron withdrawing effect of the quinolyl and pyridyl sub-
stituents, respectively.
It has previously been observed that the copper-catalysed cou-
pling of 2-pyridones can lead to both CeN and CeO arylated
products.28,44 To explore this reaction, pyridone derivative 8 was
reacted with 11 (Scheme 2). After isolation of the N-heteroarylated
product 12a vide infra, a comparison with the crude 1H NMR
* Corresponding author. Tel.: þ44 191 3342018; e-mail address: m.r.bryce@
durham.ac.uk (M.R. Bryce).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.108

J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
6139
(het)Ar-Br
B(OH)2
(het)Ar
(het)Ar
(het)Ar
2-4
KOH
Hydrolysis
(het)Ar'-X
Cu catalysis
Pd catalysis
F
N
F
N
O
N
H
O
N
(het)Ar'
1
5-7
8-10
12-22
Scheme 1. Protocol for the three-step synthesis of 1,5-di(hetero)arylpyridin-2(1H)-one derivatives.
Table 1
Synthesis of fluoropyridines 5e7 and pyridones 8e10
Entry
(het)AreBr
Cross-coupling productc
Yielda (%)
Hydrolysis productd
Yieldb (%)
OMe
OMe
OMe
1
98
83
88
Br
O
O
N
H
F
N
2
5
6
8
9
N
N
N
2
89
Br
N
F
N
3
H
N
OMe
N
OMe
3
97
92
O
N
H
10
F
N
4
7
a
The quoted yields are for isolated product after purification by chromatography and/or recrystallisation.
The quoted yields are for isolated product after acidification and filtration.
Reagents and conditions: 1 (1.2e1.5 equiv), (hetero)arylbromide (1.0 equiv), Pd(PPh3)2Cl2, Na2CO3 (3 equiv, 1 M in H2O), 1,4-dioxane, reflux, 1e20 h under argon.
Reagents and conditions: compound 5, 6 or 7, KOH (1 M in H2O), 1,4-dioxane, reflux, 24e66 h.
b
c
d
OMe
O
OMe
Br
OMe
+
Cu source
ligand
N
+
O
N
N
base
solvent
O
N
H
N
N
CF3
8
11
CF3
12a
CF3
12b (not purified)
Scheme 2. Coupling of 8 and 11. For conditions see Table 2.
spectrum and GCeMS traces confirmed that 12a was the major
product. The other product, presumed to be 12b, could not be
obtained pure. An initial screening was undertaken utilising com-
monly employed conditions and ligands for the CeN coupling of
2-pyridones, 2-pyridazinones and NH-heterocycles (Table 2). Using
1,10-phenanthroline (1,10-phen) with conditions used previously
for the N-heteroarylation of benzimidazole and other NH-hetero-
cycles,39 conversion was complete after 24 h with a 79:21 ratio of
12a:12b (Table 2, entry 1). Buchwald’s 4,7-dimethoxy-1,10-phe-
nanthroline ligand has proved to be effective for the copper-cata-
lysed N-arylation of 2-pyridone;28 however, the high cost of the
ligand led us to try cheaper alternatives. Whilst keeping the same
base (Cs2CO3), the solvent was changed to dioxane, 8-hydrox-
yquinoline (8-HQ) was employed as the ligand and PEG was added
as a solideliquid transfer catalyst.45 However, despite 8-HQ being
previously used to N-arylated pyridones44 and pyridazinones,27
these conditions resulted in a low conversion and a reduced ratio
Table 2
Screening of conditions for arylation of 8 with 11
Entry
Cu source
Ligand
Base
Solvent
GCeMS analysis
11:12a:12b
1
2
3
4
5
CuI
CuI
CuI
CuI
1,10-phen
8-HQ
DMCDA
DMCDA
ChxnePyeAl
Cs2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
DMF
0:79:21
69:20:11
0:95:5
3:97:0
39:50:11
dioxanea
toluene
DMSO
MeCN
Cu2O
Conditions and reagents: 8 (0.735 mmol), 11 (0.700 mmol), Cu source (0.07 mmol),
ligand (0.140 mmol), base (1.40 mmol), anhydrous solvent (2 mL), 100 ꢀC, 36 h
under argon.
a
PEG (43 mg) additive used.

6140
J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
Table 3
Copper-catalysed CeN cross-coupling reactions of pyridone derivatives
Entry
Pyridone
(het)AreX
Product
Yielda (%)
OMe
Br
N
OMe
O
N
1
80
N
O
N
H
CF3
CF3
8
11
12a
OMe
OMe
Br
O
N
2
82
O
N
H
OMe
OMe
8
2
13
OMe
OMe
Br
N
O
N
3
77
N
O
N
H
F
F
23
14
8
OMe
OMe
Br
N
O
N
4
83
N
O
N
H
NO2
NO2
24
15
8
N
N
Br
O
N
5
66
O
N
H
OMe
OMe
16
9
2

J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
(het)AreX
6141
Table 3 (continued)
Entry
Pyridone
Product
Yielda (%)
N
O
N
72
N
CF3
Br
N
N
17a
6
N
O
N
H
CF3
9
11
O
N
5
N
CF3
17b
N
N
Br
O
N
N
7
70
N
O
N
H
OMe
OMe
18
9
4
N
OMe
Br
O
N
N
OMe
9
74
O
N
H
OMe
OMe
10
2
19
N
OMe
I
O
N
N
N
N
N
OMe
10
51
N
O
N
H
Br
Br
10
25
20
(continued on next page)

6142
Table 3 (continued)
J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
(het)AreX
Entry
Pyridone
Product
Yielda (%)
N
OMe
Br
O
N
N
N
N
OMe
11
40
N
O
N
H
N
NH2
NH2
10
26
21
N
OMe
Br
S
O
N
S
N
OMe
12
60
O
N
H
NO2
NO2
22
10
27
a
The quoted yields are for isolated product after purification by chromatography and/or recrystallisation. Conditions and reagents: Pyridone, (hetero)aryl halide, CuI,
DMCDA, K2CO3, anhydrous toluene, 100 ꢀC, 20e88 h under argon.
of 12a:12b (Table 2, entry 2). When N,N0-dimethylcyclohexane-1,2-
diamine (DMCDA) was employed using K2CO3 in toluene26 (Table 2,
entry 3) the conversion was complete with a high ratio (95:5) of
12a:12b and 12a was isolated in 80% yield (Table 3, entry 3). By
changing the solvent to DMSO,28 12a was the sole product observed
(Table 2, entry 4). It has been observed previously that more polar
solvents favour the 2-(1H)pyridone tautomer.25 Utilising the po-
tentially tetradentate Schiff base ligand ChxnePyeAl with condi-
tions developed by Cristau et al., for the N-arylation of 2-
pyridone,25 conversion was improved compared to 8-HQ with an
enhanced 12a:12b ratio of 50:11 (Table 2, entry 5).
4-Bromoanisole 2 was used as a more challenging substrate
with pyridone 8. Using the best conditions from Table 2 (entry 3:
CuI, DMCDA, K2CO3 in toluene) gave clean conversion to 13, which
was isolated in 82% yield: no other product was detected by GC
analysis (Table 3, entry 2) (Scheme 3). However, when using the
same base, solvent and copper source, but changing the ligands to
those used in the previous screening (Table 2, entries 1, 2 and 5), no
reaction of 8 with 2 was observed. The structure of 13 was con-
firmed by single crystal X-ray analysis (Fig. 1).
Having found suitable conditions for N-arylation, 2-pyridone
derivatives 8, 9 and 10 were coupled with a variety of aryl and
heteroaryl halides to give the functionalised 2-pyridones 12e22
Figure 1. X-ray molecular structure of 13. Interplanar angles: i/ii 68.6, i/iii 28.7ꢀ.
Henceforth thermal ellipsoids are drawn at the 50% probability level.
OMe
(Table 3, entries 1e12 and Scheme 4). High yields were also
obtained when using more activated heteroaryl bromides (Table 3,
entries 1, 3 and 4). Pyridone 9 coupled with both 4-bromoanisole 2
and 2-bromo-5-(trifluoromethyl)pyridine 11 giving 16 (66%) and
17a (72%), respectively (Table 3, entries 5 and 6). Alongside the
major product 17a, the CeO coupled product 17b was isolated in
low yield (Table 3, entry 6). Coupling of 9 was also performed with
4 giving 18 in a good yield. Pyridone 10 coupled to 2 under the
same conditions, giving 19 in 74% isolated yield. Coupling at the
iodo site of 25 afforded 20 (entry 10) leaving an active bromo
Br
OMe
CuI
DMCDA
+
O
N
K2CO3
toluene
O
N
H
OMe
8
2
OMe
13 82% yield
Scheme 3. Coupling of 8 and 2 to yield 13.

J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
6143
facing away from the lone pair of the pyridyl nitrogen and out of the
plane of the pyridine ring (Fig. 2).
3-Aryl-2,6-difluoropyridines 32 and 33 were synthesised via
Suzuki cross-coupling of 2,6-difluoro-3-pyridylboronic acid 30
with 2 and 31 in good yields (Scheme 6 and Table 4). Hydrolysis of
32 gave a 1:1.4 ratio of 35a and 35b, as judged by 1H NMR analysis
of the crude mixture, indicating a slight preference for nucleophilic
attack by the hydroxide anion at the less hindered C(6) site of 32.
The isolated crude yield of 35aþ35b was ca. 80%. Separation was
very difficult and the two isomers were isolated pure in 10 and 8%
yields, respectively. The parent compound 3646 was synthesised
from 2,6-difluoropyridine 34 via basic hydrolysis (Table 4, entry 3);
the reaction was sluggish, giving 36 in 62% yield after 114 h at reflux
(Scheme 7). Similar isomers of 2- and 5-arylpyridone derivatives
have been synthesised by Cheng et al.43 Fluoropyridones have been
reported as potential bioactive compounds in previous studies.5,47
X-ray crystal structure determinations of fluoropyridone de-
rivatives 35b and 36 (Fig. 3) revealed that both exist as lactim
(2-hydroxypyridine) tautomers. In both structures, pairs of
hydroxypyridine groups related by a crystallographic inversion
centre and practically coplanar, are linked together by pairs of
strong linear hydrogen bonds OeH/N, with the proton un-
equivocally localised at the oxygen. Tautomerism of 2-pyridones
has been extensively investigated.48e53 In the solid state the
parent 2-pyridone exists as the lactam tautomer as do 5-chloro-
2-pyridone, 2-thiopyridone, 4-hydroxy-2-pyridone and 5-nitro-2-
pyridone.51,52 Functionalisation of 2-pyridones at C-6 with in-
ductively electron withdrawing groups affects the acidity of the
OeH group (in the 2-hydroxypyridine form) and the NeH group
Scheme 4. Synthesis of 12e22. For conditions see Table 3.
group for further functionalisation. Aminopyrazine derivative 26
coupled to 10 to give 21 in 40% yield (entry 11). 2-Bromo-5-
nitrothiophene 27 coupled to 10 to give 22 in 60% yield. Functional
group tolerance is notable, with fluoro, trifluoromethyl, methoxy,
primary amino and nitro-substituted (hetero)aryl bromides cou-
pling in good yields.
O
O
OMe
+
N
N
N
CuI, DMCDA
K2CO3
Br
N
Br
O
N
H
toluene 88 h
28 (2.2 equiv.)
100 o
C
8
OMe
OMe
29 69% yield
Scheme 5. Synthesis of 29 via two-fold N-arylation.
Two-fold coupling of 8 with 2,6-dibromopyridine 28 (2.2 equiv)
provided the penta-aryl system 29 in 69% yield (Scheme 5). X-ray
crystallographic analysis of 29 confirmed the bis-CeN coupled
structure, with both amide carbonyls lying parallel to each other,
(in the 2-pyridone form) via
a bimolecular proton transfer
mechanism leading to the lactim tautomer.52 Polar solvents
favour the lactam tautomer and interaction with another non-
solvent species can have an effect on the tautomeric
equilibrium.16,53
Arylation of 5-fluoro-2-pyridone 36 was attempted using the
optimised conditions for the arylation of 2-pyridone 8 (Table 2,
entry 3). However, no reaction was observed after 72 h at reflux
and starting material was recovered. Copper-catalysed arylation
of amides is known to be very dependent on base strength with
the optimal pKa below that of the amide.54 Although the solu-
bility of K2CO3 in toluene is expected to be low, if the acidity of
the 6-fluoro-2-pyridone is significantly greater than 2-pyridone
(pKa¼17.0 in DMSO),55 then deprotonation could occur faster
than arylation leading to inactive cuprate complexes. A screening
of different bases was carried out whilst keeping all other con-
ditions unchanged. Despite changing to weak inorganic bases
such as KHCO3 and weak organic bases such as Et3N (pKa¼9.0 in
DMSO)56 and pyridine (pKa¼3.4 in DMSO)56 no reaction was
observed after 48 h at reflux. On the basis of these results it is
more likely that the steric effect of a 6-fluoro substituent ham-
pers the arylation of 36, as well as the electron withdrawing
effect of the fluorine atom resulting in a reduced nucleophilic-
ity.44 An attempt to arylate 36 by copper-catalysed coupling with
phenylboronic acid (DCM, room temperature, 48 h)24 gave an
intractable reaction mixture.
Figure 2. X-ray molecular structure of 29. Interplanar angles (ꢀ): i/ii 36.0, ii/iii 25.1, iii/
iv 34.6, iv/v 10.9, i/v 4.3.
(het)Ar-Br
B(OH)2
F
(het)Ar
(het)Ar
(het)Ar
2 or 31
KOH
+
F
Pd catalysis
F
N
F
N
F Hydrolysis
O
N
H
F
N
H
O
30
35b
32, 33
35a
Scheme 6. Synthesis of 32, 33, 35a, 35b. For conditions see Table 4.

6144
J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
Table 4
Synthesis of difluoropyridines 32 and 33 and fluoropyridones 35a, 35b and 36
Entry
(het)AreBr
Cross-coupling product/difluoropyridine
Yielda (%)
Hydrolysis productc
Yielda (%)
(80)d 10
OMe
O
F
N
H
F
35a
OMe
OMe
OMe
1
76b
Br
8
F
N
F
N
H
O
35b
2
32
H2N
H2N
Br
N
F
2
83c
d
d
N
F
N
F
31
33
3
d
d
92d
O
N
H
F
F
N
34
36
a
The quoted yields are for isolated product after purification by chromatography and/or recrystallisation. Yield in parenthesis refers to combined isolated yield of both
isomers 35a and 35b before purification.
b
Reagents and conditions: 30 (1.2 equiv), 2 (1.0 equiv), Pd(PPh3)2Cl2, Na2CO3 (3 equiv, 1 M in H2O), 1,4-dioxane, reflux, 1 h under argon.
Reagents and conditions: 30 (1.5 equiv), 31 (1.0 equiv), Pd2(dba)3, PCy3, Na2CO3 (3 equiv, 1 M in H2O), 1,4-dioxane, reflux, 22 h under argon.
Reagents and conditions: KOH (1e6 M in H2O), 1,4-dioxane, reflux, 16e114 h.
c
d
KOH
F
N
F
O
N
H
F
Hydrolysis
34
36
Scheme 7. Synthesis of 36. For conditions see Table 4.
On the premise that a compound with complementary hydro-
gen bonding sites could form hosteguest complexes with 36, we
have investigated the interaction of this compound with dia-
minopyridine derivative 37 (Fig. 4a). DFT calculations (Fig. 4b)
performed on structure 36 predict that although the carbonyl ox-
ygen possess a significantly larger negative electrostatic potential
than the fluoride, this derivative could have the propensity to form
complementary hydrogen bonds with 37 (principally through the
carbonyl oxygen and NH components of the pyridinone moiety
with the amide NeH and pyridyl nitrogen of 37, respectively).57 We
have investigated the ability of 36 to form hydrogen bonding in-
teractions with 37 using 1H and 19F NMR spectroscopy in CDCl3. A
1:1 admixture of 36 and 37 resulted in a broadening and a small
downfield shift (ꢁ0.2 ppm) of the pyridinone NH resonance using
1H NMR spectroscopy, features, which are characteristic of weak
hydrogen bonding interactions. The proton-decoupled 19F spec-
trum of the admixture revealed a 2 ppm shift from ꢁ75 ppm to
ꢁ73 ppm in the single fluorine resonance,58 suggesting that weak
F/HeN interactions may be occuring.59 Thus, the data are con-
sistent with the formation of a low-affinity complex between 36
and 37 in CDCl3.
Figure 3. X-ray molecular structures of 35b and 36, showing independent molecules,
their inversion equivalents (primed) and hydrogen bonds (dashed lines). Interplanar
angle i/ii 50.1ꢀ. Bond distances (Å): C(2)eO(2) 1.337(2), NeC(2) 1.339(2), NeC(6) 1.323
(2), O(2)/N0 2.758(2), O(2)eH 0.92(2) in 35b; C(1)eO(1) 1.330(1), N(1)eC(1) 1.342(1),
N(1)eC(5) 1.320, C(6)eO(2) 1.335(1), N(2)eC(6) 1.342(1), N(2)eC(10) 1.323(1), O(1)/
N(10) 2.735(1), O(1)eH 0.88(2), O(2)/N(20) 2.760(1), O(2)eH 0.89(2) in 36 indicate 2-
hydroxypyridine tautomeric structures.

J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
6145
Classic spectrometer equipped with an atmospheric pressure
chemical ionisation source. High resolution APþ spectra were
obtained on a Waters Xevo QToF spectrometer equipped with an
atmospheric solids analysis probe. GCeMS analysis was obtained
using a Thermo-FinniganTrace GCeMS with EI ionisation. IR spectra
were recorded on a Perkin Elmer Paragon 1000 FTIR instrument.
Elemental analyses were obtained on an Exeter analytical Inc. CE-
440 elemental analyser.
4.2. General method for Suzuki-Miyaura cross-coupling
reactions
Figure 4. (a) Possible hydrogen bonding interactions between 37 and 36. (b) DFT
(B3LYP-/6-31G ) derived electrostatic potential map for compound 36.
To an argon purged flask was added the (hetero)aryl halide, bo-
ronic acid, palladium source and additional ligand (when applica-
ble). Degassed 1,4-dioxane and aqueous base were added and the
mixture was heated to reflux, with stirring. The reaction was mon-
itored by TLC and on completion (1e20 h) the reaction was cooled to
room temperature and the solvent was removed in vacuo. The res-
idue was extracted into ethyl acetate and washed with brine. The
organic layers were dried over Na2SO4, filtered and then concen-
trated in vacuo. Purification was achieved by flash chromatography
on a silica gel column followed in some cases by recrystallisation.
*
3. Conclusion
We have described efficient and flexible procedures that afford
a range of 1,5-di(hetero)arylated-pyridin-2(1H)-one derivatives
starting from the readily-available 2-fluoro-5-pyridylboronic acid 1.
These protocols are amenable to further exploitation in the syn-
thesis of libraries of functionalised heterocycles of high diversity
derived from 1, especially compounds of potential utility as new
pharmacophores and scaffolds for drug discovery.
4.3. General method for pyridone CeN cross-coupling
reactions
4. Experimental
4.1. General
To an argon purged flask was added the pyridone, aryl halide,
copper source, ligand, additive (where applicable), base and dry
degassed solvent. The mixture was heated to 100 ꢀC under argon
and monitored by TLC. Upon completion, the reaction mixture was
allowed to cool to room temperature and passed through a silica
plug, eluting with EtOAc. The concentrated residue was purified via
column chromatography.
All cross-coupling reactions were performed under an argon
atmosphere, which was dried by passage through a column of
phosphorus pentoxide. All reagents used were of standard reagent
grade, used as supplied unless otherwise stated and purchased from
SigmaeAldrich or Alfa Aesar, except for (2-fluoro-5-pyridyl)boronic
acid 1,40 (2,6-difluoro-3-pyridyl)boronic acid 30,60 5-bromo-2-
iodopyrimidine 25,61 2-amino-5-bromopyrazine 26,62 ChxnePy-
eAl63 and Pd(PPh3)4 which were prepared in-house. Anhydrous
toluene, DMSO, DMF and MeCN were dried through a HPLC column
on an Innovative Technology Inc. solvent purification system. Trie-
thylamine was dried over calcium hydride, distilled and stored un-
der dry nitrogen prior to use. All other solvents were used without
prior purification. Solvents were degassed by bubbling dry argon at
a steady rate through the solvent for ca. 20 min. Column chroma-
4.3.1. 2-Fluoro-5-(4-methoxyphenyl)pyridine 5. In accordance with
the general method for Suzuki-Miyaura cross-coupling reactions
outlined above was reacted (2-fluoro-5-pyridyl)boronic acid 1
(1.18 g, 8.40 mmol), 4-bromoanisole
2 (1.31 g, 7 mmol), Pd
(PPh3)2Cl2 (0.122 g, 0.18 mmol) and Na2CO3 (21 mL, 21 mmol, 1 M
in water) in 1,4-dioxane (50 mL) at reflux for 14 h. Standard work-
up and concentration gave a brown solid, which was purified via
column chromatography (SiO2, eluent 5:1 EtOAc:hexane) yielding 5
as a white solid (1.39 g, 98%); mp: 69.8e70.9 ꢀC; dH (400 MHz,
CDCl3) 8.35 (1H, d, J 2.6), 7.90 (1H, ddd, J 8.5, 7.7, 2.6), 7.45 (2H, d, J
8.9), 7.03e6.92 (3H, m), 3.84 (3H, s); dC (126 MHz, CDCl3) 162.9 (d,
JCF 238.4), 159.9, 145.5 (d, JCF 14.7), 139.5 (d, JCF 7.8), 134.7 (d, JCF 4.6),
129.3, 128.4, 114.8, 109.5 (d, JCF 37.5), 55.6. Anal. Calcd for
C12H10FNO: C, 70.93; H, 4.96; N, 6.89. Found: C, 70.99; H, 4.94; N,
6.85; m/z (EI) 203 (Mþ, 100%); nmax (film)/cmꢁ1 2939, 2833, 1612,
1594, 1518, 1476, 1373, 1246, 1187, 1047, 1013, 1000, 826, 813, 796.
tography was carried out using 40e63 mm mesh silica. Thin-layer
chromatography (TLC) was performed on 20 mm pre-coated plates
of silica gel (Merck, silica gel 60F254), visualisation was made using
ultraviolet light (254 nm). GCeMS analysis was recorded on
a Thermo-Finnigan Trace mass spectrometer with positive ionisa-
tion mode. NMR spectra were recorded on: a Bruker Avance-400
spectrometer [1H NMR (400 MHz), 13C NMR (100 MHz)], a Varian
Inova-500 spectrometer [1H NMR (500 MHz), 13C NMR (125 MHz)]
and a Varian NMR system 700 spectrometer using deuterated sol-
ventas a lock. Chemical shifts arequoted inparts per million, relative
to the residual solvent as internal reference for 1H and 13C. The fol-
lowing abbreviations are used in listing NMR spectra: s¼singlet,
d¼doublet, dd¼doublet of doublets, ddd¼doublet of doublet of
doublets, dt¼doublet of triplets, t¼triplet, td¼triplet of doublets,
m¼multiplet, br¼broad. J values are quoted in hertz. Melting points
were determined on a Stuart Scientific SMP3 melting point appa-
ratus and are uncorrected. Electron Impact (EI) mass spectra were
recorded on a Thermo-Finnigan Trace mass spectrometer with
positive ionisation mode. Electrospray (ESþ) mass spectra were
recorded on a Thermo-Finnigan LTQ FT mass spectrometer or
a Micromass Autospec LCT mass spectrometer. High resolution ESþ
mass spectra were recorded on a Thermo-Finnigan LTQ FT mass
spectrometer. APþ mass spectra were obtained on a Waters LCT
4.3.2. 3-(6-Fluoropyridin-3-yl)quinoline 6. In accordance with the
general method for Suzuki-Miyaura cross-coupling reactions out-
lined above was reacted (2-fluoro-5-pyridyl)boronic acid 1 (2.03 g,
14.4 mmol), 3-bromoquinoline 3 (2.40 g, 12.0 mmol), Pd(PPh3)2Cl2
(0.126 g, 0.180 mmol) and Na2CO3 (36 mL, 36 mmol,1 M in water) in
1,4-dioxane (65 mL) at reflux for 20 h. Standard work-up and con-
centrationyielded an off-white solid, which was purified via column
chromatography (SiO2, eluent 1:1 EtOAc:hexane) yielding 6 as an
off-white solid (2.39 g, 89%); mp: 265 ꢀC (decomp.); dH (700 MHz,
CDCl3) 9.10 (1H, d, J 2.3), 8.55 (1H, d, J 2.6), 8.29 (1H, d, J 8.4), 8.15 (1H,
d, J 8.4), 8.10 (1H, ddd, J 8.4, 7.5, 2.6), 7.89 (1H, d, J 8.2), 7.76 (1H, ddd, J
8.4, 6.9, 1.4), 7.61 (1H, ddd, J 8.4, 6.9, 1.4), 7.10 (1H, dd, J 8.5, 3.1); dC
(176 MHz, CDCl3) 163.8 (d, JCF 241.1), 149.1, 147.7, 146.5 (d, JCF 15.1),
140.2 (d, JCF 8.1), 134.0, 132.0 (d, JCF 4.7), 130.4, 129.8, 129.5, 128.2,
128.0,127.8,110.3 (d, JCF 37.6); m/z (EI) 224 (Mþ,100%). Anal. Calcd for

6146
J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
C14H9FN2: C, 74.99; H, 4.05; N, 12.49. Found: C, 74.97; H, 4.13;
N, 12.23; nmax (film)/cmꢁ1 3041, 2921, 2845, 1597, 1583, 1570,
1491, 1394, 1345, 1298, 1255, 1124, 1052, 1023, 954, 913, 825, 788,
741, 668.
followed by drying in vacuo yielding 10 as a white solid (1.85 g,
92%); mp: 277 ꢀC (decomp.); dH (500 MHz, CDCl3) 13.25 (1H, s), 8.24
(1H, d, J 2.2), 8.13 (1H, dd, J 9.5, 2.6), 7.58 (1H, dd, J 8.2, 7.5), 7.08 (1H,
d, J 7.4), 6.68 (1H, d, J 9.5), 6.63 (1H, d, J 8.2), 3.96 (3H, s); dC
(126 MHz, CDCl3) 165.4, 164.0, 150.8, 140.2, 139.6, 133.8, 119.9, 119.7,
110.9, 109.5, 53.5; m/z (ESþ) 202 (MþþH, 100%). Anal. Calcd for
C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.47; H, 5.04; N,
13.66; nmax (film)/cmꢁ1 2842, 1666, 1576, 1466, 1433, 1327, 1263,
1123, 1077, 1029, 790, 745, 693.
4.3.3. 2-(6-Fluoropyridin-3-yl)-6-methoxypyridine 7. In accordance
with the general method for Suzuki-Miyaura cross-coupling re-
actions outlined above was reacted (2-fluoro-5-pyridyl)boronic
acid 1 (1.69 g, 12.0 mmol), 2-bromo-6-methoxypyridine 4 (1.88 g,
10 mmol), Pd(PPh3)2Cl2 (0.176 g, 0.25 mmol) and Na2CO3 (30 mL,
30 mmol, 1 M in water) in 1,4-dioxane (60 mL) at reflux for 14 h
although completion by TLC noted after 10 min at reflux. Standard
work-up and concentration gave a black residue, which was puri-
fied via column chromatography (SiO2, eluent 5:1 EtOAc:hexane)
yielding 7 as a white solid (1.98 g, 97%); mp: 67.2e67.7 ꢀC; dH
(700 MHz, CDCl3) 8.83 (1H, d, J 2.5), 8.43 (1H, ddd, J 8.5, 7.8, 2.5),
7.64 (1H, dd, J 8.3, 7.4), 7.29 (1H, d, J 7.4), 7.00 (1H, ddd, J 8.5, 3.0,
0.6), 6.73 (1H, d, J 8.3), 4.00 (3H, s); dC (176 MHz, CDCl3) 164.2, 164.1
(d, JCF 240.5), 151.2, 146.4 (d, JCF 15.3), 139.7 (d, JCF 8.1), 139.6, 133.0
(d, JCF 4.7), 112.8, 110.5, 109.5 (d, JCF 37.5), 53.56 (3H, s); m/z (EI) 204
(Mþ, 68%), 203 (100, MþꢁH). Anal. Calcd for C11H9FN2O: C, 64.70; H,
4.44; N, 13.72. Found: C, 64.82; H, 4.50; N, 13.63; nmax (film)/cmꢁ1
2957, 1607, 1579, 1494, 1463, 1434, 1372, 1329, 1291, 1245, 1165,
1029, 797, 685.
4.3.7. 1-(5-(Trifluoromethyl)pyridin-2-yl)-5-(4-methoxyphenyl)pyr-
idin-2(1H)-one 12a. In accordance with the general procedure for
pyridone CeN cross-coupling, 8 (0.211 g, 1.05 mmol), 2-bromo-6-
(trifluoromethyl)pyridine 11 (0.226 g, 1.00 mmol), CuI (0.038 g,
0.200 mmol), DMCDA (0.057 g, 0.400 mmol) and K2CO3 (0.276 g,
2.00 mmol) in toluene (6 mL) were reacted for 20 h. Standard work-
up and column chromatography (SiO2, eluent 1:1 EtOAc:hexane)
yielded 12a as a white solid (0.276 g, 80%); mp: 101.1e102.7 ꢀC; dH
(400 MHz, CDCl3) 8.83 (1H, dd, J 1.6, 0.8), 8.26 (1H, d, J 8.6), 8.12 (1H,
dd, J 2.7, 0.6), 8.07 (1H, dd, J 8.6, 2.4), 7.67 (1H, dd, J 9.5, 2.7), 7.39
(2H, d, J 8.9), 6.95 (2H, d, J 8.9), 6.72 (1H, dd, J 9.5, 0.7), 3.83 (4H, s);
dC (176 MHz, CDCl3) 161.6, 159.6, 154.5, 146.1 (q, JCF 4.1), 141.0, 135.3
(q, JCF 3.2), 131.7 (d, JCF 14.6), 128.8, 127.3, 126.0 (q, JCF 33.6), 123.4 (q,
JCF 272.4), 122.4, 121.4, 120.9, 114.7, 55.6; m/z (APþ) 347.1006
(MþþH, C18H13F3N2O2 requires 347.1007); nmax (film)/cmꢁ1 3056,
2801, 1659, 1600, 1587, 1269, 1248, 1297, 1156, 1001, 809.
4.3.4. 5-(4-Methoxyphenyl)pyridin-2(1H)-one 8. To
5
(1.40 g,
6.89 mmol) was sequentially added 1,4-dioxane (26 mL) and KOH
(1 M, 40 mL) and the resulting mixture was heated at reflux and
judged complete by TLC (SiO2, eluent 2:1 hexane:EtOAc, Rf¼0) after
66 h. The mixture was cooled to room temperature and acidified to
pH 6 with 4 M HCl. The precipitate was filtered and washed with
hexane (2ꢂ50 mL), water (2ꢂ50 mL) and acetone (2ꢂ20 mL) fol-
lowed by drying in vacuo yielding 8 as a white solid (1.145 g, 83%);
mp: 191 ꢀC(decomp.); dH (400 MHz, CDCl3)13.04 (1H, s), 7.72 (1H, dd,
J 9.4, 2.6), 7.52 (1H, d, J 2.6), 7.32 (2H, d, J 8.7), 6.94 (2H, d, J 8.7),
6.66 (1H, d, J 9.4), 3.82 (3H, s); dC (176 MHz, DMSO-d6) 161.6, 158.3,
140.0, 131.8, 128.6, 126.4, 119.9, 117.7, 114.3, 55.1; m/z (APþ) 202
(MþþH, 100%), 201 (69, Mþ). Anal. Calcd for C12H11NO2: C, 71.63; H,
5.51; N, 6.96. Found: C, 71.47; H, 5.89; N, 6.78; nmax (film)/cmꢁ1 2843,
1738, 1657, 1622, 1514, 1468, 1283, 1244, 1183, 1037, 1020, 950,
881, 821.
4.3.8. 1,5-Bis(4-methoxyphenyl)pyridin-2(1H)-one 13. In accor-
dance with the general procedure for pyridone CeN cross-coupling,
8 (0.211 g, 1.05 mmol), 4-bromoanisole 2 (0.187 g, 1.00 mmol), CuI
(0.019 g, 0.100 mmol), DMCDA (0.029 g, 0.200 mmol) and K2CO3
(0.276 g, 2.00 mmol) in toluene (3 mL) were reacted for 20 h.
Standard work-up and column chromatography (SiO2, eluent
EtOAc) yielded 13 as a white solid, which was recrystallised from
hexane/DCM (0.251 g, 82%); mp: 147.0e148.2 ꢀC; dH (400 MHz,
CDCl3) 7.64 (1H, dd, J 9.5, 2.7), 7.46 (1H, d, J 2.7), 7.33 (4H, dd, J 8.7,
1.5), 6.99 (2H, d, J 8.9), 6.92 (2H, d, J 8.7), 6.71 (1H, d, J 9.5), 3.83 (3H,
s), 3.81 (3H, s); dC (176 MHz, CDCl3) 162.1, 159.7, 159.4, 139.9, 135.0,
134.2, 129.0 (2C), 127.9 (2C), 127.2, 121.8, 120.0, 114.8 (2C), 114.7
(2C), 55.8, 55.6; m/z (EI) 307 (Mþ, 100%). Anal. Calcd for C19H17NO3:
C, 74.25; H, 5.58; N, 4.56. Found: C, 74.34; H, 5.60; N, 4.49; nmax
(film)/cmꢁ1 3058, 2834, 1662, 1610, 1598, 1514, 1275, 1249, 1180,
1026, 818. Crystal data: C19H17NO3, M¼307.34, T¼120 K, mono-
clinic, space group P21/c (no. 14), a¼10.6471(4), b¼12.5157(5),
4.3.5. 5-(Quinolin-3-yl)pyridin-2(1H)-one 9. To 6 (2.24 g, 10 mmol)
was sequentially added 1,4-dioxane (26 mL) and KOH (1 M, 50 mL)
and the resulting mixture was heated at reflux and judged com-
plete by TLC (SiO2, eluent 2:1 hexane:EtOAc, Rf¼0) after 24 h. The
mixture was cooled to room temperature and acidified to pH 6 with
4 M HCl. The precipitate was filtered and washed with hexane
(2ꢂ50 mL), water (2ꢂ50 mL) and acetone (2ꢂ20 mL) followed by
drying in vacuo yielding 9 as an off-white solid (1.95 g, 88%); mp:
290 ꢀC (decomp.); dH (700 MHz, DMSO-d6) 12.03 (1H, s), 9.17 (1H, d,
J 2.3), 8.52 (1H, d, J 2.2), 8.06e7.99 (3H, m), 7.97 (1H, d, J 7.9), 7.73
(1H, t, J 7.6), 7.62 (1H, t, J 7.4), 6.52 (1H, d, J 9.5); dC (176 MHz, DMSO-
d6) 161.7, 148.5, 146.3, 139.9, 133.8, 130.7, 129.1 (2C), 128.6, 128.0,
127.6, 127.0, 120.4, 114.8; m/z (APþ) 223 (MþþH). Anal. Calcd for
C14H10N2O: C, 75.66; H, 4.54; N, 7.20. Found: C, 75.56; H, 4.53; N,
7.03; nmax (film)/cmꢁ1 2823,1659,1618,1590,1435,1316,1297,1258,
1122, 952, 866, 832, 784, 752, 672.
c¼11.4966(4) Å,
b
¼93.900(8)ꢀ, V¼1528.4(1) Å3, Z¼4, R(F)¼0.049 on
3602 data with Iꢃ2
s
(I), CCDC 767480.
4.3.9. 1-(5-Fluoropyridin-2-yl)-5-(4-methoxyphenyl)pyridin-2(1H)-
one 14. In accordance with the general procedure for pyridone CeN
cross-coupling, 8 (0.423 g, 2.10 mmol), 2-bromo-5-fluoropyridine
23 (0.352 g, 2.00 mmol), CuI (0.038 g, 0.200 mmol), DMCDA
(0.057 g, 0.400 mmol) and K2CO3 (0.553 g, 4.00 mmol) in toluene
(6 mL) were reacted for 20 h. Standard work-up and column
chromatography (SiO2, eluent EtOAc) yielded 14 as a white solid
(0.533 g, 77%); mp: 140.9e142.2 ꢀC; dH (500 MHz, CDCl3) 8.40 (1H,
d, J 2.6), 8.01 (1H, dd, J 8.9, 4.0), 7.98 (1H, dd, J 2.7, 0.6), 7.66 (1H, dd, J
9.5, 2.7), 7.56 (1H, ddd, J 8.9, 7.5, 3.0), 7.38 (2H, d, J 8.9), 6.94 (2H, d, J
8.8), 6.71 (1H, dd, J 9.5, 0.6), 3.82 (3H, s); dC (126 MHz, CDCl3) 161.6,
159.4, 158.8 (d, JCF 257.1), 148.0 (d, JCF 2.9), 140.8, 136.9 (d, JCF 25.8),
132.6, 129.0, 127.3 (2C), 125.0 (d, JCF 19.8), 122.9 (d, JCF 5.0), 122.2,
120.7, 114.7 (2C), 55.6; m/z (EI) 296 (Mþ, 100%). Anal. Calcd for
C17H13FN2O2: C, 68.91; H, 4.42; N, 9.45. Found: C, 69.07; H, 4.39; N,
9.21; nmax (film)/cmꢁ1 3076, 2940, 2834, 1674, 1619, 1514, 1473,
1394, 1286, 1248, 1184, 1024, 819.
4.3.6. 5-(6-Methoxypyridin-2-yl)pyridin-2(1H)-one 10. To 7 (2.04 g,
10 mmol) was sequentially added 1,4-dioxane (26 mL) and KOH
(1 M, 40 mL) and the resulting mixture was heated at reflux and
judged complete by TLC (SiO2, eluent 2:1 hexane:EtOAc, Rf¼0) after
24 h. The mixture was cooled to room temperature and acidified to
pH 6 with 4 M HCl. The precipitate was filtered and washed with
hexane (2ꢂ50 mL), water (2ꢂ50 mL) and acetone (2ꢂ20 mL)
4.3.10. 5-(4-Methoxyphenyl)-1-(5-nitropyridin-2-yl)pyridin-2(1H)-
one 15. In accordance with the general procedure for pyridone CeN

J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
6147
cross-coupling, 8 (0.211 g, 1.05 mmol), 2-bromo-5-nitropyridine 24
(0.203 g, 1.00 mmol), CuI (0.019 g, 0.100 mmol), DMCDA (0.028 g,
0.200 mmol) and K2CO3 (0.276 g, 2.00 mmol) in toluene (2 mL) were
reacted for 20 h. Standard work-up and column chromatography
(SiO2, eluent 1:1 hexane:EtOAc) yielded 15 as a yellow solid, which
was precipitated from EtOAc (0.268 g, 83%); mp: 184.9e185.5 ꢀC; dH
(400 MHz, CDCl3) 9.38 (1H, dd, J 2.7, 0.6), 8.60 (1H, dd, J 9.0, 2.7), 8.44
(1H, dd, J 9.0, 0.6), 8.22 (1H, dd, J 2.6, 0.6), 7.68 (1H, dd, J 9.5, 2.6), 7.40
(2H, d, J 8.9), 6.96 (2H, d, J 8.9), 6.73 (1H, dd, J 9.5, 0.6), 3.84 (3H, d, J
3.7); dC (126 MHz, CDCl3) 161.6,159.7,155.6,149.1,144.7,141.3,133.3,
131.1,128.61,127.4,122.6,121.4,121.3,114.8, 55.6; m/z (APþ) 323 (Mþ,
100%). Anal. Calcd for C17H13N3O4: C, 68.16; H, 4.05; N,13.00. Found:
C, 68.06; H, 4.19; N, 12.70; nmax (film)/cmꢁ1 3073, 2839, 1680, 1610,
1576,1513,1464, 1393,1348,1298,1248,1230, 1191,1142,1119,1038,
1019, 858, 814, 770.
4.3.13. 1-(6-Methoxypyridin-2-yl)-5-(quinolin-3-yl)pyridin-2(1H)-
one 18. In accordance with the general procedure for pyridone
CeN cross-coupling, 9 (0.233 g, 1.05 mmol), 2-bromo-6-methox-
ypyridine
4 (0.188 g, 1.00 mmol), CuI (0.038 g, 0.200 mmol),
DMCDA (0.057 g, 0.400 mmol) and K2CO3 (0.276 g, 2.00 mmol) in
toluene (6 mL) were reacted for 20 h. Standard work-up and col-
umn chromatography (SiO2, eluent EtOAc) yielded 18 as a white
solid (0.230 g, 70%); mp: 187 ꢀC (decomp.); dH (700 MHz, CDCl3)
9.07 (1H, d, J 2.3), 8.28 (1H, d, J 2.6), 8.19 (1H d, J 2.2), 8.11 (1H, d, J
8.5), 7.84 (1H, d, J 8.0), 7.77 (1H, dd, J 9.5, 2.7), 7.76e7.73 (1H, m),
7.71 (1H, ddd, J 8.3, 6.9, 1.4), 7.62e7.53 (2H, m), 6.85e6.76 (2H, m),
3.94 (3H, s); dC (176 MHz, CDCl3) 164.1, 161.6, 148.9, 148.7, 147.5,
140.5, 139.5, 134.2, 132.1, 129.8, 129.7, 129.6, 128.1, 128.0, 127.6,
123.1, 117.1, 113.7, 110.6, 54.0; m/z (APþ) 330.1252 (MþþH,
C20H15N3O2 requires 330.1243); nmax (film)/cmꢁ1 2983, 2892,
1680, 1620, 1574, 1470, 1434, 1414, 1321, 1286, 1249, 1215, 1148,
1073, 918, 821, 739.
4.3.11. 1-(4-Methoxyphenyl)-5-(quinolin-3-yl)pyridin-2(1H)-one
16. In accordance with the general procedure for pyridone CeN
cross-coupling, 9 (0.355 g, 1.60 mmol), 4-bromoanisole 2 (0.285 g,
1.52 mmol), CuI (0.058 g, 0.304 mmol), DMCDA (0.087 g,
0.609 mmol) and K2CO3 (0.421 g, 3.04 mmol) in toluene (4.5 mL)
were reacted for 72 h. Standard work-up and precipitation from
EtOAc yielded 16 as an off-white solid (0.328 g, 66%); mp:
179.8e181.2 ꢀC; dH (500 MHz, CDCl3) 9.05 (1H, d, J 2.3), 8.19 (1H,
d, J 2.3), 8.15 (1H, d, J 8.1), 7.87 (1H, d, J 7.8), 7.83 (1H, dd, J 9.5,
2.8), 7.79e7.72 (2H, m), 7.61 (1H, ddd, J 8.0, 7.0, 0.9), 7.41 (2H, d, J
9.0), 7.06 (2H, d, J 9.0), 6.86 (1H, dd, J 9.5, 0.6), 3.89 (3H, s); dC
(126 MHz, CDCl3) 162.1, 159.9, 148.6, 147.5, 146.4, 141.1, 139.5,
136.5, 133.8, 132.0, 129.8, 129.5, 128.0, 127.9 (2C), 127.6, 122.6,
117.0, 115.0 (2C), 55.8; m/z (EI) 328 (Mþ, 100%). Anal. Calcd for
C21H16N2O2: C, 76.81; H, 4.91; N, 8.53. Found: C, 77.08; H, 4.99; N,
8.32; nmax (film)/cmꢁ1 3061, 2830, 1650, 1613, 1587, 1510, 1282,
1247, 1175, 1020, 809.
4.3.14. 1-(4-Methoxyphenyl)-5-(6-methoxypyridin-2-yl)pyridin-2
(1H)-one 19. In accordance with the general procedure for pyr-
idone CeN cross-coupling, 10 (0.302 g, 1.49 mmol), 4-bromoanisole
2 (0.266 g, 1.42 mmol), CuI (0.054 g, 0.285 mmol), DMCDA (0.081 g,
0.569 mmol) and K2CO3 (0.393 g, 2.85 mmol) in toluene (4.5 mL)
were reacted for 72 h. Standard work-up and column chromatog-
raphy (SiO2, eluent EtOAc) yielded 19 as a white solid (0.326 g, 74%);
mp: 62.9e64.0 ꢀC; dH (500 MHz, CDCl3) 8.13 (1H, d, J 2.5), 8.02 (1H,
dd, J 9.6, 2.6), 7.57 (1H, dd, J 8.1, 7.6), 7.34 (2H, d, J 8.9), 7.07 (1H, d, J
7.4), 7.00 (2H, d, J 8.9), 6.71 (1H, d, J 9.6), 6.62 (1H, d, J 8.2), 3.92 (3H,
s), 3.84 (3H, s); dC (126 MHz, CDCl3) 164.0, 162.7, 159.8, 151.0, 139.7,
138.5, 137.5, 134.1, 127.9 (2C), 121.3, 118.5, 114.9 (2C), 111.1, 109.2,
55.8, 53.5; m/z (EI) 308 (Mþ, 100%). Anal. Calcd for C18H16N2O3: C,
70.12; H, 5.23; N, 9.09. Found: C, 70.27; H, 5.39; N, 9.34; nmax (film)/
cmꢁ1 3010, 2949, 1736, 1664, 1588, 1575, 1506, 1409, 1314, 1244,
1124, 1023, 901, 830, 799.
4.3.12. 1-(5-(Trifluoromethyl)pyridin-2-yl)-5-(quinolin-3-yl)pyridin-
2(1H)-one 17a and 3-(6-(5-(trifluoromethyl)pyridin-2-yloxy)pyridin-
3-yl)quinoline 17b. In accordance with the general procedure for
pyridone CeN cross-coupling, 9 (0.233 g, 1.05 mmol), 2-bromo-5-
(trifluoromethyl)pyridine 11 (0.226 g, 1.00 mmol), CuI (0.038 g,
0.200 mmol), DMCDA (0.057 g, 0.400 mmol) and K2CO3 (0.276 g,
2.00 mmol) in toluene (3 mL) were reacted for 48 h. Standard work-
up and column chromatography (SiO2, eluent 4:1 EtOAc:hexane)
yielded 17a as a white solid (0.264 g, 72%) followed by 17b as
a white solid (0.017 g, 5%).
4.3.15. 1-(5-Bromopyrimidin-2-yl)-5-(6-methoxypyridin-2-yl)pyr-
idin-2(1H)-one 20. In accordance with the general procedure for
pyridone CeN cross-coupling, 10 (0.202 g, 1.000 mmol), 5-bromo-
2-iodopyrimidine 25 (0.313 g, 1.10 mmol), CuI (0.042 g,
0.220 mmol), DMCDA (0.063 g, 0.440 mmol) and K2CO3 (0.304 g,
2.22 mmol) in toluene (4 mL) were reacted for 28 h. Standard work-
up and column chromatography (SiO2, eluent 1:1 hexane:EtOAc)
yielded 20 as an off-white solid (0.203 g, 51%); mp: 172.3e173.9 ꢀC;
dH (400 MHz, CDCl3) 9.06 (1H, s), 8.38 (1H, d, J 2.6), 8.06 (1H, ddd, J
9.7, 2.6, 1.7), 7.58 (1H, td, J 7.4, 3.7), 7.10 (1H, ddd, J 7.4, 1.0, 0.6), 6.73
(1H, ddd, J 9.7, 1.7, 0.7), 6.64 (1H, dt, J 8.2, 0.7), 3.94 (3H, s); dC
(126 MHz, CDCl3) 164.8,164.0,161.6, 161.6, 160.0, 150.5, 139.6, 139.2,
134.4, 122.3, 118.9, 111.2, 109.6, 53.5; m/z (EI) 359 (Mþ, 60%), 279
(100, MþꢁBr). Anal. Calcd for C15H11BrN4O2: C, 50.16; H, 3.09; N,
15.60. Found: C, 50.44; H, 3.30; N, 15.37; nmax (film)/cmꢁ1 2937,
2899,1707, 1645, 1573,1549, 1509, 1387, 1234, 1100,1094, 1006, 914,
824.
Compound 17a mp: 156.0e157.8 ꢀC; dH (700 MHz, CDCl3) 9.04
(1H, d, J 2.3), 8.37 (1H, d, J 2.6), 8.28 (1H, d, J 8.6), 8.19 (1H, d, J
2.0), 8.13e8.04 (2H, m), 7.83 (1H, d, J 8.1), 7.79 (1H, dd, J 9.5, 2.7),
7.71 (1H, ddd, J 8.3, 6.9, 1.3), 7.61e7.54 (1H, m), 6.81 (1H, d, J 9.5);
m/z (EI) 367 (Mþ, 100%); dC (176 MHz, CDCl3) 161.4, 154.1, 148.5,
147.6, 146.2 (q, JCF 4.1), 140.3, 135.5 (q, JCF 3.2), 133.3, 132.3, 129.9,
129.5, 129.2, 127.98, 127.95, 127.6, 126.4 (q, JCF 33.6), 123.3 (q, JCF
272.4), 123.2, 121.3, 118.0; m/z (APþ) 367 (Mþ, 100%). Anal. Calcd
for C20H12F3N3O: C, 65.40; H, 3.29; N, 11.44. Found: C, 65.73; H,
3.50; N, 11.42; nmax (film)/cmꢁ1 3033, 2858, 1609, 1583, 1299,
1280, 1235, 1177, 1016.
4.3.16. 1-(5-Aminopyrazin-2-yl)-5-(6-methoxypyridin-2-yl)pyridin-
2(1H)-one 21. In accordance with the general procedure for
pyridone CeN cross-coupling, 10 (0.425 g, 2.10 mmol), 2-amino-5-
bromopyrazine 26 (0.348 g, 2 mmol), CuI (0.076 g, 0.400 mmol),
DMCDA (0.114 g, 0.800 mmol) and K2CO3 (0.553 g, 4.00 mmol) in
toluene (6 mL) were reacted for 42 h. The reaction mixture was
quenched by stirring in saturated ammonium chloride solution
(50 mL) for 1 h then the organic component was extracted into
EtOAc (3ꢂ250 mL) and washed with brine (2ꢂ50 mL). After drying
over Na2SO4, filtration, concentration and a precipitation from
EtOAc, the yellow solid was purified twice consecutively by column
chromatography (SiO2, eluent 20:1 EtOAc:MeOH & SiO2, eluent 20:1
DCM:MeOH) yielding 21 as a yellow solid (0.238 g, 40%); mp: 169 ꢀC
Compound 17b mp: 127.8e128.3 ꢀC; dH (700 MHz, CDCl3) 9.13
(1H, d, J 2.2), 8.65 (1H, d, J 2.2), 8.54 (1H, s), 8.30 (1H, s), 8.14 (1H, d, J
8.7), 8.13 (1H, dd, J 8.4, 2.6), 8.00 (1H, dd, J 8.6, 2.2), 7.89 (1H, d, J 8.1),
7.75 (1H, t, J 7.5), 7.60 (1H, t, J 7.5), 7.28 (1H, d, J 8.4), 7.23 (1H, d, J
8.6); dC (176 MHz, CDCl3) 164.4, 161.0, 149.33, 147.9, 147.0, 145.9 (q,
JCF 4.3), 138.9, 137.3 (q, JCF 3.2), 133.7, 131.4, 130.2, 130.1, 129.6, 128.2,
128.0, 127.6, 123.7 (q, JCF 271.7), 123.3 (q, JCF 33.4), 115.2, 113.7. Anal.
Calcd for C20H12F3N3O: C, 65.40; H, 3.29; N, 11.44. Found: C, 65.48;
H, 3.20; N, 11.09; nmax (film)/cmꢁ1 3023, 2836, 1628, 1555, 1304,
1281, 1257, 1220, 1183, 1002.

6148
J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
(decomp.); dH (500 MHz, DMSO-d6) 8.48 (1H, d, J 2.4), 8.28e8.24
(2H, m), 7.85 (1H, d, J 1.3), 7.72 (1H, t, J 7.8), 7.43 (1H, d, J 7.5), 6.81 (2H,
br s), 6.70 (1H, d, J 8.1), 6.61 (1H, d, J 9.6), 3.88 (3H, s); dC (126 MHz,
DMSO-d6) 163.1, 161.0, 155.6, 150.3, 140.3, 140.1, 138.8, 137.5, 136.3,
129.8, 120.1, 117.2, 111.4, 108.6, 52.9; m/z (APþ) 295 (Mþ, 100%), 296
(69, MþþH). Anal. Calcd for C15H13N5O2: C, 61.01; H, 4.44; N, 23.72.
Found: C, 61.33; H, 4.60; N, 23.65; nmax (film)/cmꢁ1 3333, 3174,1666,
1577, 1538, 1465, 1398, 1331, 1269, 1156, 1125, 1013, 826, 788.
(1.09 g, 6.29 mmol), Pd2(dba)3 (0.144 g, 0.157 mmol), PCy3 (0.088 g,
0.315 mmol) and Na2CO3 (18.9 mL, 18.9 mmol, 1 M in water) in 1,4-
dioxane (45 mL) at reflux for 22 h. Standard work-up and concen-
tration followed by column chromatography (SiO2, eluent 2:1
EtOAc:hexane) yielded 33 as a white solid (1.09 g, 83%); mp:
156.9e157.7 ꢀC; dH (400 MHz, DMSO-d6) 8.16 (1H, dt, J 9.5, 8.1), 7.86
(1H, dd, J 4.2, 1.8), 7.25 (1H, ddd, J 8.1, 2.5, 0.8), 7.18e7.03 (2H, m),
5.25 (2H, s); dC (126 MHz, DMSO-d6) 160.0 (dd, JCF 243.0,14.0), 157.7
(dd, JCF 245.4, 14.6), 147.8 (dd, JCF 8.0, 5.1), 143.2, 137.2, 135.8 (d, JCF
4.1), 124.3, 121.8, 118.7 (dd, JCF 28.7, 5.6), 106.8 (dd, JCF 34.6, 5.3); m/z
(APþ) 208 (MþþH, 100%). Anal. Calcd for C10H7F2N3: C, 57.97; H,
3.41; N, 20.28. Found: C, 58.31; H, 3.77; N, 20.08; nmax (film)/cmꢁ1
3384, 3308, 3201, 1640, 1602, 1587, 1478, 1458, 1444, 1402, 1307,
1274, 1254, 1226, 1211, 1106, 1023, 997, 972, 846, 834, 804, 736.
4.3.17. 5-(6-Methoxypyridin-2-yl)-1-(5-nitrothiophen-2-yl)pyridin-
2(1H)-one 22. In accordance with the general procedure for
pyridone CeN cross-coupling, 10 (0.212 g, 1.05 mmol), 2-bromo-5-
nitrothiophene 27 (0.208 g, 1.00 mmol), CuI (0.038 g, 0.200 mmol),
DMCDA (0.057 g, 0.400 mmol) and K2CO3 (0.276 g, 2.00 mmol) in
toluene (6 mL) were reacted for 20 h. Standard work-up and column
chromatography (SiO2, eluent 3:2 hexane:EtOAc) yielded 22 as
a yellow solid (0.196 g, 60%); mp: 227 ꢀC (decomp.); dH (400 MHz,
DMSO-d6) 8.93 (1H, d, J 2.1), 8.38 (1H, dd, J 9.6, 2.3), 8.21 (1H, d, J 5.0),
7.94 (1H, d, J 5.1), 7.87e7.76 (1H, m), 7.70 (1H, d, J 7.4), 6.90 (1H, d, J
9.6), 6.79 (1H, d, J 8.1), 3.96 (3H, s); dC (126 MHz, CDCl3) 164.2,162.9,
160.2, 149.2,144.3, 139.9, 138.3, 130.4, 126.1, 121.5, 121.4, 114.4, 111.8,
110.6, 53.6; m/z (APþ) 329 (Mþ 66%), 330 (100, MþþH). Anal. Calcd
for C15H11N3O4S: C, 54.71; H, 3.37; N,12.76. Found: C, 55.00; H, 3.56;
N, 12.40; nmax (film)/cmꢁ1 2924, 2848, 1667, 1611, 1575, 1542, 1494,
1460, 1425, 1334, 1284, 1258, 1017, 800, 701.
4.3.21. 6-Fluoro-5-(4-methoxyphenyl)pyridin-2(1H)-one 35a and 6-
fluoro-3-(4-methoxyphenyl)pyridin-2(1H)-one 35b. To 32 (0.481 g,
2.17 mmol) was sequentially added 1,4-dioxane (4 mL) and KOH
(1 M, 11 mL) and the resulting mixture was heated at reflux and
judged complete by TLC (SiO2, eluent 2:1 hexane:EtOAc, Rf¼0.33,
0.29) after 16 h. The mixture was cooled to room temperature and
acidified to pH 6 with 4 M HCl. The mixture was extracted into
EtOAc, dried over Na2SO4, filtered and concentrated. The crude
mixture was purified by column chromatography (SiO2, eluent 2:1
hexane:EtOAc) to give a pure mixture of 35a and 35b as a white
solid (0.383 g, 80%). The mixture was separated by column chro-
matography (SiO2, eluent 3:1 hexane:EtOAc) followed by pre-
parative TLC (SiO2, eluent 3:1 hexane:EtOAc) giving 35b as a white
solid, which was recrystallised from hexane (0.036 g, 8%). Further
column chromatography provided 35a as a white solid, which was
recrystallised from hexane (0.046 g, 10%).
4.3.18. 2,6-Di(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)pyridine
29. In accordance with the general procedure for pyridone CeN
cross-coupling, 8 (0.460 g, 2.28 mmol), 2,6-dibromopyridine 28
(0.246 g, 1.04 mmol), CuI (0.079 g, 0.415 mmol), DMCDA (0.118 g,
0.830 mmol) and K2CO3 (0.574 g, 4.15 mmol) in toluene (12 mL)
were reacted for 88 h. Standard work-up and column chromatog-
raphy (SiO2, eluent 19:1 EtOAc:Et3N) yielded 29 as a white solid,
which was recrystallised from hot EtOAc/hexane (0.340 g, 69%); mp:
229.9e231.1 ꢀC; dH (700 MHz, CDCl3) 8.06e7.98 (3H, m), 7.96 (2H, d, J
2.5), 7.68 (2H, dd, J 9.5, 2.7), 7.35 (4H, d, J 8.8), 6.92 (4H, d, J 8.8), 6.74
(2H, d, J 9.5), 3.80 (6H, s); dC (176 MHz, CDCl3) 161.5, 159.5, 151.3,
140.8, 139.8, 132.5, 128.8, 127.3, 122.2, 121.1, 120.7, 114.7, 55.5; m/z
(APþ) 478 (Mþ,100%). Anal. Calcd for C29H23FN3O4: C, 72.94; H, 4.85;
N, 8.80. Found: C, 73.02; H, 4.5.13; N, 8.69; nmax (film)/cmꢁ1 2959,
1683, 1610,1516,1436,1295, 1246,1205, 1181, 1025, 821, 798. Crystal
data: C29H23N3O4, M¼477.50, T¼120 K, orthorhombic, space group
Pbca (no. 61), a¼22.0189(6), b¼7.5416(2), c¼26.8158(9) Å, V¼4453.0
Compound 35a mp: 195 ꢀC (decomp.); dH (400 MHz, CDCl3) 7.80
(4H, dd, J 10.1, 8.2), 7.42 (9H, dd, J 8.9,1.5), 6.96 (9H, d, J 8.9), 6.72 (4H,
dd, J 8.2, 0.9), 3.84 (15H, s); dC (176 MHz, DMSO-d6) 161.4 (d, J 15.7),
158.6, 157.7 (d, J 238.1),143.4 (d, J 4.6),129.4 (d, J 3.0), 126.0 (d, J 5.1),
114.1, 112.4 (d, J 27.0), 106.9 (d, J 4.8), 55.1; m/z (APþ) 220 (MþþH,
100%). Anal. Calcd for C12H10FNO2: C, 65.75; H, 4.60; N, 6.39. Found:
C, 65.70; H, 4.60; N, 6.41; nmax (film)/cmꢁ1 2936, 1613, 1591, 1509,
1448, 1390, 1290, 1200, 1192, 1104, 1003, 855, 817, 760, 707.
Compound 35b mp: 200 ꢀC (decomp.); dH (700 MHz, CDCl3)
10.32 (1H, s), 7.73 (1H, t, J 8.0), 7.53 (2H, d, J 8.9), 6.97 (2H, d, J 8.8),
6.53 (1H, dd, J 8.0, 1.7), 3.84 (3H, s); dC (126 MHz, CDCl3) 160.5 (d, J
244.7), 159.4, 159.4 (d, J 11.2), 143.9 (d, J 8.1), 130.3, 127.8, 120.3 (d, J
5.3),114.2,100.4 (d, J 32.3), 55.6; m/z (APþ) 220 (MþþH,100%). Anal.
Calcd for C12H10FNO2: C, 65.75; H, 4.60; N, 6.39. Found: C, 65.89; H,
4.87; N, 6.23; nmax (film)/cmꢁ1 2927, 1613, 1590, 1516, 1448, 1379,
1285, 1253, 1217, 1178, 1100, 1034, 1019, 841, 806, 773, 742. Crystal
data: C12H10FNO2, M¼219.21, T¼120 K, triclinic, space group P1 (no.
(2) Å3, Z¼8, R(F)¼0.040 on 4292 data with Iꢃ2
s(I), CCDC 767481.
4.3.19. 2,6-Difluoro-3-(4-methoxyphenyl)pyridine 32. In accordance
with the general method for Suzuki-Miyaura cross-coupling re-
actions outlined above was reacted (2,6-difluoro-3-pyridyl)boronic
acid 30 (0.953 g, 6 mmol), 4-bromoanisole 2 (0.935 g, 5 mmol), Pd
(PPh3)2Cl2 (0.175 g, 0.25 mmol) and Na2CO3 (15 mL, 15 mmol, 1 M
in water) in 1,4-dioxane (40 mL) at reflux for 1 h. Standard work-up
and concentration followed by column chromatography (SiO2, el-
uent 1:3 EtOAc:hexane) yielded 32 as a white solid (0.839 g, 76%);
mp: 33.4e34.9 ꢀC; dH (700 MHz, DMSO-d6) 8.18 (1H, dd, J 17.9, 8.0),
7.48 (2H, dd, J 8.6, 1.2), 7.14 (1H, dd, J 8.1, 2.6), 7.02 (2H, d, J 8.8), 3.80
(3H, s); dC (176 MHz, DMSO-d6) 157.8, 157.6 (dd, JCF 243.2, 13.9),
155.3 (dd, JCF 245.4, 14.5), 144.0,128.2, 122.9 (d, JCF 4.8),118.3 (dd, JCF
25.4, 5.8), 112.5, 105.3 (dd, JCF 40.1, 9.3), 53.5; m/z (EI) 221 (Mþ,
100%). Anal. Calcd for C12H9F2NO: C, 65.16; H, 4.10; N, 6.33. Found:
C, 65.05; H, 4.11; N, 6.20; (film)/cmꢁ1 3095, 1642, 1602, 1589, 1511,
1370, 1245, 1176, 1053, 1004, 995, 831, 780.
2), a¼5.9326(6), b¼9.2981(9), c¼9.5566(10) Å,
a
¼90.95(1),
b
¼97.56(1),
g
¼104.41(1)ꢀ, V¼505.5(1) Å3, Z¼2, R(F)¼0.041 on 1656
data with Iꢃ2
s(I), CCDC 767482.
4.3.22. 6-Fluoropyridin-2(1H)-one 36. To 2,6-difluoropyridine 34
(2.24 g, 10 mmol) was sequentially added 1,4-dioxane (26 mL) and
KOH (6 M, 50 mL) and the resulting mixturewas heated at reflux and
judged complete by TLC (SiO2, eluent EtOAc, Rf¼0) after 114 h. The
mixturewas cooled to roomtemperature, concentrated invacuo and
acidified to pH 6 with 4 M HCl. After extraction into DCM
(2ꢂ200 mL) and washing with brine (2ꢂ50 mL) the organic layer
was dried over Na2SO4, filtered and concentrated. The resulting
residue was recrystallised from a mixture of DCM and hexane
yielding 36 as white needles (0.703 g, 62%); mp: 127.2e128.2 ꢀC; dH
(400 MHz, CDCl3) 11.87 (1H, s), 7.71 (1H, dd, J 16.2, 8.1), 6.73e6.53
(1H, m), 6.53e6.35 (1H, m); dC (101 MHz, CDCl3) 163.7 (d, JCF 11.7),
161.8 (d, JCF 245.7),144.6 (d, JCF 8.7),107.4 (d, JCF 5.0), 99.5 (d, JCF 31.6);
m/z (APþ) 114 (MþþH,100%), 113 (35, Mþ). Anal. Calcd for C5H4FNO:
4.3.20. 2-(2,6-Difluoropyridin-3-yl)-3-aminopyridine 33. In accor-
dance with the general method for Suzuki-Miyaura cross-coupling
reactions outlined above was reacted (2,6-difluoro-3-pyridyl)bo-
ronic acid 30 (1.50 g, 9.44 mmol), 3-amino-2-bromopyridine 31

J.S. Siddle et al. / Tetrahedron 66 (2010) 6138e6149
6149
24. Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55,
12757e12770.
25. Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.dEur. J. 2004, 10,
5607e5622.
26. Wang, P.-S.; Liang, C.-K.; Leung, M.-k. Tetrahedron 2005, 61, 2931e2939.
27. Pu, Y.-M.; Ku, Y.-Y.; Grieme, T.; Henry, R.; Bhatia, A. V. Tetrahedron Lett. 2006, 47,
149e153.
28. Altman, R. A.; Buchwald, S. L. Org. Lett. 2007, 9, 643e646.
29. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933e2936.
C, 53.10; H, 3.57; N, 16.80. Found: C, 52.86; H, 3.39; N, 17.11; nmax
(film)/cmꢁ1 3320, 2696, 1632, 1596, 1574, 1486, 1456, 1344, 1242,
1143, 1070, 1017, 996, 787, 744, 723. Crystal data: C5H4FNO,
M¼113.09, T¼120 K, monoclinic, space group P21/n (no. 14),
a¼16.023(1), b¼3.6830(2), c¼16.910(1) Å,
b
¼103.41(1)ꢀ, V¼970.7
(1) Å3, Z¼8, R(F)¼0.038 on 2279 data with Iꢃ2
s(I), CCDC 767483.
30. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941e2944.
Acknowledgements
31. Pattison, G.; Sandford, G.; Yufit, D. S.; Howard, J. A. K.; Christopher, J. A.; Miller,
We thank EPSRC for funding (J.S.S.) and Dr. G. Hughes for the
D. D. Tetrahedron 2009, 65, 8844e8850.
synthesis of compound 26.
32. Kim, J.-J.; Park, Y.-D.; Cho, S.-D.; Kim, H.-K.; Chung, H. A.; Lee, S.-G.; Falck, J. R.;
Yoon, Y.-J. Tetrahedron Lett. 2004, 45, 8781e8784.
33. Xiao, Z.; Yang, M. G.; Li, P.; Carter, P. H. Org. Lett. 2009, 11, 1421e1424.
34. Sutherland, A.; Gallagher, T. J. Org. Chem. 2003, 68, 3352e3355.
35. Siddle, J. S.; Ward, R. M.; Collings, J. C.; Rutter, S. R.; Porres, L.; Applegarth, L.;
Beeby, A.; Batsanov, A. S.; Thompson, A. L.; Howard, J. A. K.; Boucekkine, A.;
Costuas, K.; Halet, J.-F.; Marder, T. B. New J. Chem. 2007, 31, 841e851.
36. Daykin, L. M.; Siddle, J. S.; Ankers, A. L.; Batsanov, A. S.; Bryce, M. R. Tetrahedron
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Supplementary data
Supplementary data for this article can be found in the online
version, at doi:10.1016/j.tet.2010.05.108.
37. Clapham, K. M.; Batsanov, A. S.; Greenwood, R. D. R.; Bryce, M. R.; Smith, A. E.;
Tarbit, B. J. Org. Chem. 2008, 73, 2176e2181.
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