A versatile copper-catalyzed coupling reaction of pyridin-2(1H)-ones with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2006.08.112

A robust method has been developed to couple a wide variety of pyridin-2-ones and aryl halides. This C-N bond forming reaction makes use of catalytic copper(I) iodide and the ligand 8-hydroxyquinoline. These conditions tolerate a wide degree of functional

Full text of DOI:10.1016/j.tetlet.2006.08.112

Tetrahedron Letters 47 (2006) 7677–7680
A versatile copper-catalyzed coupling reaction of
pyridin-2(1H)-ones with aryl halides
Kevin J. Filipski,a,* Jeffrey T. Kohrt,a Agustin Casimiro-Garcia,a Chad A. Van Huis,a
Danette A. Dudley,a Wayne L. Cody,a Christopher F. Bigge,a Shrilakshmi Desiraju,b
Shaoyi Sun,b Samarendra N. Maiti,b Mohamad R. Jaberc and Jeremy J. Edmundsa
aPfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
bNaeja Pharmaceutical Inc., 4290-91A Street, Edmonton, Alberta, Canada, T6E 5V2
cPharmAgra Labs Inc., 40 McLean Rd, Brevard, NC 28712, USA
Received 19 May 2006; revised 28 August 2006; accepted 29 August 2006
Available online 18 September 2006
Abstract—A robust method has been developed to couple a wide variety of pyridin-2-ones and aryl halides. This C–N bond forming
reaction makes use of catalytic copper(I) iodide and the ligand 8-hydroxyquinoline. These conditions tolerate a wide degree of func-
tionality on both the aryl halide and pyridin-2-one reactants and have resulted in numerous examples being synthesized.
Ó 2006 Elsevier Ltd. All rights reserved.
In recent years there have been significant improvements
in the utility of carbon–nitrogen bond-forming reac-
tions. Several published reviews detail the recent pro-
gress of copper-mediated coupling reactions for C–N
bond formation.1 Key to these improvements has been
the work of Buchwald and co-workers on the use of
catalytic copper in the presence of diamino ligands for
the reaction of amines, amides, and nitrogen heterocy-
cles with aryl halides.2 Buchwald and co-workers have
also effectively used palladium catalysis to effect C–N
bond formation3 and more recently reported room
temperature copper-catalyzed C–N coupling reactions
of amines using diketones as ligands.4
published on the use of a phenylstannane for this type
of transformation.8 Avoiding the use of boronic acids
and stannanes, Li and later Leung reported on the use
of copper-catalyzed Buchwald-like conditions to couple
pyridin-2-ones with aryl halides and heterocyclic bro-
mides.9 Also, Cristau et al. has reported on the coupling
of phenyl halides with nitrogen heterocycles, including
2-hydroxypyridine, using Schiff bases as ligands.10 More
recent work by Mukaiyama and co-workers uses aryl
organobismuth(V) reagents for the N-arylation of pyri-
din-2-ones and related heterocycles.11 Alternatively, Li
and Hu have demonstrated an alternative use of Buch-
wald-like conditions to form substituted lactams via
the intramolecular vinylation of amides.12
An important class of these C–N bond formation reac-
tions is that involving pyridin-2-ones and aryl partners.
Previous reports related to this type of coupling have
appeared in the literature. Renger has used freshly
prepared Cu/SiO2 to react 2-hydroxypyridine with aryl
bromides.5 Ukita and Sugahara have published on the
reaction of pyridin-2-ones and other similar nitrogen
heterocycles with aryl halides using catalytic copper(I)
iodide without a ligand present.6 Lam and Mederski
have developed conditions for the arylation of pyridin-
2-one with phenyl boronic acids.7 Lam et al. has also
F
NH2
F
O
H2N
H2N
O
NH2
HN
+
ð1Þ
N
CuI, K3PO4
dioxane, reflux
4 - 10%
I
1
2
3
2, ethylene glycol
3
1
CuI, K3PO4
ð2Þ
iPrOH, 80 o
0%
C
*
In our research we desired a variety of intermediates that
resulted from the reaction of substituted pyridin-2-ones
Corresponding author. Tel.: +1 734 622 1374; fax: +1 734 622
3909; e-mail: kevin.filipski@pfizer.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.112

7678
K. J. Filipski et al. / Tetrahedron Letters 47 (2006) 7677–7680
Table 1. Reaction of substituted pyridin-2-ones with 2-fluoro-4-
iodoaniline
and similar nitrogen heterocycles with halo-substituted
anilines and related heterocycles. Although we previ-
ously used Buchwald’s conditions to successfully couple
halo-substituted anilines with lactams, these conditions,
as well as Buchwald’s conditions using ethylene glycol as
a ligand,13 did not translate for use with pyridin-2-ones
as coupling partners (Eqs. 1 and 2, respectively). Also, in
our hands the ligand-free conditions of Ukita gave both
C–O and C–N bond formation (Eq. 3).
F
O
F
H2N
N
O
H2N
HN
OH
3
4
+
N
CuI, K2CO3
I
DMSO, 130 o
C
R
6
R
5
1
7-28
R
Yield19 (%)
7
H
62
78
81
81
6
31
58
0
74
30
0
55
49
51
47
50
0
O2N
8
3-Me
4-Me
5-Me
6-Me
3-F
3,5-DiF
6-Cl
4-OMe
O
O2N
O2N
+
2
9
CuI, K2CO3
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
I
O
N
DMF, 150 oC, 27h
4
5
6
68%
4.2:1
ð3Þ
3-CF3
3-OH
Herein, we report on general conditions, complementary
to those already published that broaden the range of
C–N bond-forming reactions to the additional partners
of halo-substituted anilines and halo-substituted amino-
pyridines as well as some uniquely substituted pyridin-
2-ones. These conditions are suitable for medicinal
chemistry where a wide diversity of products is desired.
3-OPMB
3-OC2H4OBn
3-SEt
3-COPh
5-CO2Et
3-OAc
3-NO2
3-NH2
3-NHBoc
3-N(Me)PMB
4-NCPh2
4
38
2a
60
44
A search of the chemical literature yielded a list of
potential conditions and ligands that could be used
to perform C–N cross-coupling reactions.14 Experi-
mentation identified the ligand 8-hydroxyquinoline in
the presence of potassium carbonate, and catalytic cop-
per(I) iodide in DMSO, at 130 °C as being suitable for
the coupling of a diverse group of pyridin-2-ones and
halo-partners.15 This ligand had been previously used
in the copper-catalyzed reaction of 2-bromoanilines with
alkoxides to form aryl ethers14 and the reaction of
anilines and imidazoles to form biaryl species.16
a The deprotected amine, 25, was isolated as major product in 14%
yield.
likely due to the electronic effects reducing the nucleo-
philicity of the pyridin-2-one nitrogen.
Table 2 explores the reaction of differently functional-
ized aryl halides with pyridin-2-ones using these condi-
tions. Both aryl iodides and aryl bromides can be
used, with the former providing superior yields (com-
pare 29 and 30). Electron-rich and electron-poor
aryl halides both resulted in adequate yields of products.
Ester, aniline, nitrile, alkoxy, nitro, and halo groups are
all well tolerated. Also, heterocyclic halides like
pyridines to form 36 and 37 and pyrimidine to give 38
coupled under these conditions.
Table 1 shows a wide variety of pyridin-2-ones arylated
with 2-fluoro-4-iodoaniline using the herein reported
conditions. Pyridin-2-ones substituted at all but the
6-position participated well in this reaction. As
observed with Li’s conditions, the poor yields of 6-
methyl 11 and 6-chloro 14 are most likely due to steric
effects.
Noteworthy is the wide variety of functionalized pyri-
din-2-ones that are tolerated under these conditions.
Pyridin-2-ones substituted by keto, ester, amino, halo,
alkoxy, and thio groups all coupled well under these
conditions. Interestingly, 3-acetoxypyridin-2-one did
not yield the desired product 23. It was hypothesized
that under these reaction conditions, the acetate was
cleaved to the free hydroxyl compound, which subse-
quently did not participate in the coupling reaction as
was shown for derivative 17. The t-butoxy carbonyl
(Boc) group of compound 26 also was not tolerated
under these conditions and generated the deprotected
amine as major product likely due to the thermal insta-
bility of this moiety. Also, as observed by Li, 3-nitro-
pyridin-2-one coupled to give 24 in a poor yield most
Other nitrogen heterocycles also participated success-
fully in this reaction using the conditions reported.
Table 3 shows the yields received for the reaction of
several fused-ring nitrogen heterocycles. Interestingly,
coupling products 4217 and 43 formed in good yields.
The steric hindrance problems observed with 6-substi-
tuted pyridin-2-ones did not translate to these fused
examples. Unexpectedly, 3-isoquinolinone 44 reacted
through the oxygen instead of the nitrogen to form a
biaryl ether.
Table 3 also summarizes the reactions of several non-
fused nitrogen heterocycles. Pyrazinone 46, pyrimidin-
4(3H)-one 47,18 pyridazinone 48, and triazinone 49 all

K. J. Filipski et al. / Tetrahedron Letters 47 (2006) 7677–7680
7679
Table 2. Reaction of pyridin-2-ones with aryl halides
Table 3. Reaction of nitrogen heterocycles with 2-fluoro-4-iodoaniline
F
F
O
O
N
N
H2N
H2N
Aryl
R
R
OH
OH
N
HN
Het
Aryl-X
+
+
CuI, K2CO3
CuI, K2CO3
I
Het
DMSO, 130 o
C
DMSO, 130 o
C
29-38
1
39-49
Aryl-X
R
Yield (%)
31
Het
Yield (%)
66
Cl
Cl
O
O
O
H2N
39
29
H
HN
I
H2N
40
41
76
92
HN
HN
HN
30
31
H
H
11
22
N
O
Br
MeO2C
I
I
O
O
32
33
Me
Me
37
58
H N
2
42
43
54
40
NC
I
OiPr
F
H2N
HN
HN
34
H
56
N
Br
Br
H2N
F
O
35
36
H
H
41
46
44
0a
N
Br
N
O
O
O
H2N
45
46
0
HN
HN
HN
N
37
38
H
H
59
16
I
I
H2N
N
43
N
N
47
28
formed in good yields. One example that did not pro-
ceed under these conditions was pyrimidin-2(1H)-one,
which failed to produce 45.
N
O
HN
N
48
49
59
22
F
S
F
N
H2N
H2N
HN
OH
+
O
N
CuI, K2CO3
DMSO, 130 o
I
S
N
C
HN
1
50
51
N
92%
a Coupling through the oxygen forms the biaryl ether.
ð4Þ
Eqs. 4 and 5 show that these conditions did not extend
to thiopyridones or naphthyridinamines. Pyridine-
2(1H)-thione 50 reacted through sulfur instead of nitro-
gen to form thioether 51 (Eq. 4). Likewise, 1,7-naph-
thyridin-8-amine 52 reacted through the exocyclic

7680
K. J. Filipski et al. / Tetrahedron Letters 47 (2006) 7677–7680
7. (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000,
5, 674–676; (b) Lam, P. Y. S.; Vincent, G.; Clark, C. G.;
Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42,
3415–3418; (c) Mederski, W. W. K. R.; Lefort, M.;
Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757–
12770.
8. Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G.
Tetrahedron Lett. 2002, 43, 3091–3094.
9. (a) Li, C. S.; Dixon, D. D. Tetrahedron Lett. 2004, 45,
4257–4260; (b) Wang, P.-S.; Liang, C.-K.; Leung, M.-k.
Tetrahedron 2005, 61, 2931–2939.
nitrogen rather than the ring nitrogen to form an amine
(Eq. 5).
F
NH2
H2N
N
N
N
N
OH
1
+
ð5Þ
N
CuI, K2CO3
DMSO, 130 oC
H
N
52
53
46%
10. Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607–5622.
11. Ikegai, K.; Nagata, Y.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 2006, 79, 761–767.
12. Hu, T.; Li, C. Org. Lett. 2005, 7, 2035–2038.
13. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581–584.
14. Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A.
J. Am. Chem. Soc. 2000, 122, 5043–5051.
In conclusion, a robust method for the coupling of a
variety of aryl halides with pyridin-2-ones and similar
nitrogen heterocycles has been reported. The coupling
products of halo-anilines and halo-substituted amino
heterocycles with pyridin-2-ones were accessible through
these conditions. This C–N bond-forming reaction made
use of catalytic CuI and the ligand 8-hydroxyquinoline.
These conditions tolerated a wide degree of functionality
on both partners as shown by the numerous examples
synthesized and broaden the scope of C–N bond-form-
ing reactions.
15. Typical experimental procedure: 2-Fluoro-4-iodoaniline
(1.0 g, 4.2 mmol), 2-hydroxy-4-methylpyridine (0.55 g,
5.1 mmol), 8-hydroxyquinoline (0.09 g, 0.63 mmol), cop-
per iodide (0.12 g, 0.63 mmol), and potassium carbonate
(0.64 g, 4.6 mmol) were combined in a round bottom flask
with 5 mL DMSO under a nitrogen atmosphere and
heated to 130 °C overnight. The reaction was cooled to
room temperature and poured into a mixture of 10% aq
ammonium hydroxide and ethyl acetate. Charcoal was
added and the mixture filtered through a pad of Celite,
washing with ethyl acetate. The layers were separated with
the aqueous portion being back extracted with ethyl
acetate. The combined organic extracts were washed with
brine, dried over MgSO4, and concentrated in vacuo.
Purification by silica gel chromatography gave 0.76 g
Acknowledgment
Special thanks go to Michael Stier for his collaboration
support.
References and notes
1
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J. Am. Chem. Soc. 2001, 123, 7727–7729; (b) Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
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2005, 7, 3965–3968; (b) Tundel, R. E.; Anderson, K. W.;
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8742–8743.
(81%) of desired material 9 as a solid. H NMR (DMSO-
d6) d 7.42 (1H, d, J = 7.1 Hz), 7.03 (1H, dd, J = 12,
2.2 Hz), 6.81 (2H, m), 6.21 (1H, d, J = 1.7 Hz), 6.09 (1H,
dd, J = 6.8, 1.7 Hz), 5.34 (2H, s), 2.13 (3H, d,
J = 0.98 Hz); MS (AP+) m/z 219 (MH+).
16. Zhou, J. C.; Confalone, P. N.; Li, H.; Oh, L. M.; Rossano,
L. T.; Clark, C. G.; Teleha, C. A. WO 0208199.
17. Ukita reported a 0% yield for a similar reaction of
iodobenzene coupling to 2-hydroxyquinoline using the
ligand-free conditions.
18. Ukita reported a 0% yield for a similar reaction of
iodobenzene coupling to 4(3H)-pyrimidone using the
ligand-free conditions.
5. Renger, B. Synthesis 1985, 856–860.
6. Sugahara, M.; Ukita, T. Chem. Pharm. Bull. 1997, 45,
719–721.
19. All reported yields were based on the isolated products,
1
which gave satisfactory H NMR and MS data.