Synthesis of N-aryl pyridin-2-ones via ligand coupling reactions using pentavalent organobismuth reagents

Article abstract of DOI:10.1246/cl.2005.1496

An efficient method for the synthesis of N-aryl pyridin-2-ones was established by way of ligand coupling reactions using pentavalent organobismuth reagents such as triarylbismuth dichlorides. Copyright

Full text of DOI:10.1246/cl.2005.1496

1496
Chemistry Letters Vol.34, No.11 (2005)
Synthesis of N-Aryl Pyridin-2-ones via Ligand Coupling Reactions
Using Pentavalent Organobismuth Reagents
Kazuhiro Ikegaiy;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received August 1, 2005; CL-050997)
Table 1. N-o-tolylation of various pyridin-2-ones
An efficient method for the synthesis of N-aryl pyridin-
2-ones was established by way of ligand coupling reactions
using pentavalent organobismuth reagents such as triarylbismuth
dichlorides.
R
t
KO Bu
(o-Tol) BiCl
(1.0 equiv.)
H
3
2
O
N
(2.0 equiv.)
N
O
Me
THF
Temp, 3 h
R
1
(2.0 equiv.)
rt, 10 min
Pyridin-2-ones and the related heterocyclic compounds are
important components in many active pharmaceuticals together
with their N-aryl derivatives that are frequently employed in the
investigation of their structure–activity relationships.1 It is
known that the copper-catalyzed Ullman reactions are carried
out under drastic reaction conditions and yields of the desired
products are moderate.2 Improved copper-catalyzed reactions
for N-arylation of pyridin-2-ones and the related heterocycles
by using aryl boronic acids or halides as arylating agents were
also reported.1,3
Various tri-, tetra-, and penta-arylbismuth(V) compounds4
such as Ph3BiCl2, Ph4BiOTs, and Ph5Bi are well-known re-
agents for C- or O-arylation of alcohols,5 phenols,6 active meth-
ylene or methyne compounds,7 metal-enolates,8 and enones.9
Covalently bonded BiV–substrate complexes are important inter-
mediates in these arylation reactions. On the other hand, N-aryl-
ation of amines and amides with bismuth(V) reagents was re-
ported to proceed smoothly only when copper catalysts were em-
ployed.10,11 Taking the reactions of C-phenylation of phenols
and enolates into consideration, however, N-phenylation of het-
eroaromatic lactams such as pyridin-2-one may proceed smooth-
ly via covalent bismuth(V)–OPy intermediates as shown in
Scheme 1. Here, we would like to report a new and efficient
method for N-arylation of pyridin-2-ones by using triarylbis-
muth dichloride and potassium tert-buthoxide (t-BuOK), which
provides various N-aryl pyridin-2-ones in good to excellent
yields.
Temp/°C
Entry
Substrate
Yield /% Product
H
N
O
1
2
rt
95
95
1a
1b
H
N
R = Me
rt
O
R
3
4
R = Br
R = NO
reflux
reflux
93
78
1c
1d
2
H
N
5
6
7
8
R = Cl
R = Br
R = CO Et
reflux
reflux
reflux
reflux
79
51
86
85
1e
1f
1g
O
2
R
R
R = NO
1h
2
H
N
O
9
10
R = Me
R = Cl
reflux
reflux
42
ND
1i
1j
a
H
N
O
O
11
reflux
71
1k
H
N
12
13
reflux
reflux
37
18
1l
H
N
O
1m
aNot detected.
then dried over Na2SO4. After evaporation of the solvent, the
crude product was purified by preparative TLC on silica gel
(hexane/EtOAc) to afford the desired arylated product.
A typical experimental procedure is as follows: a solution of
2.0 equimolar amounts of pyridin-2-one and t-BuOK in dry THF
was stirred at rt for 10 min., followed by the addition of 1.0
equivalent of a triarylbismuth dichloride. Solution thus resulted
was allowed to react at the temperatures shown in Tables 1 and
2. After completion of the reaction, the mixture was diluted with
ethyl acetate and washed with 1 M HCl, 2 M NaOH, and brine,
Various 1-(2-methylphenyl)pyridin-2-ones were easily syn-
thesized in good to excellent yields by using tri(o-tolyl)bismuth
dichloride under mild conditions (Table 1). It should be noted
that these o-tolylated products are not available by the copper-
catalyzed N-arylation reactions between pyridin-2-ones and 2-
halotoluene owing to the steric hindrance of o-tolyl group.1
While N-tolylation of simple pyridin-2-one and 3-methylpyri-
din-2-one proceeded smoothly at room temperature (Entries 1
and 2),12,13 refluxing conditions were needed when substrates
bearing electron-withdrawing functionalities were used (Entries
3–8). Although 6-chloropyridin-2-one did not afford the desired
product (Entry 10), 6-methylpyridin-2-one and quinorin-2-one
gave the N-tolylated compounds 1i and 1k under refluxing con-
ditions (42 and 71% yields, respectively). Aliphatic lactams gave
the desired products 1l and 1m in poor yields as expected from
N
K
O
N
O
N
Ar
+
O
(2 equiv.)
Ar BiCl
3
Ar
Ar
2
Bi Ar
Ar BiOPy
O
2
Py
Scheme 1. N-arylation of pyridin-2-one using Ar3BiCl2.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.11 (2005)
1497
Table 2. Substituent effects on bismuth reagents
This study was supported in part by the Grant of the 21st
Century COE Program from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
R1
R2
BiCl2
R1
KOtBu
References and Notes
3
H
O
N
(2.0 equiv.)
(1.0 equiv.)
1
2
3
a) C. S. Li and D. D. Dixon, Tetrahedron Lett., 45, 4257 (2004).
b) W. Wawzonek and T. V. Truong, J. Heterocycl. Chem., 25,
381 (1988), and references therein.
N
THF
Temp, 3 h
O
R2
(2.0 equiv.)
rt, 10 min
1
For reviews on copper-catalyzed Ullman reactions, see: a) J.
Lindley, Tetrahedron, 40, 1433 (1984). b) S. V. Ley and
A. W. Thomas, Angew. Chem., Int. Ed., 42, 5400 (2003).
a) W. W. K. R. Mederski, M. Lefort, M. Germann, and D. Kux,
Tetrahedron, 55, 12757 (1999). b) P. Y. S. Lam, G. Vincent,
C. G. Clark, S. Deudon, and P. K. Jadhav, Tetrahedron Lett.,
42, 3415 (2001). c) B. Renger, Synthesis, 1985, 856. d) M.
Sugahara and T. Ukita, Chem. Pharm. Bull., 45, 719 (1997).
For reviews on organobismuth chemistry, see: a) R. A.
Abramovitch, D. H. R. Barton, and J.-P. Finet, Tetrahedron,
44, 3039 (1988). b) J.-P. Finet, Chem. Rev., 89, 1487 (1989).
c) Y. Matano and H. Suzuki, Bull. Chem. Soc. Jpn., 69, 2673
(1996). d) H. Suzuki, T. Ikegaimi, Y. Matano, Synthesis,
1997, 249. e) N. Komatsu, in ‘‘Organobismuth Chemistry,’’
ed. by H. Suzuki and Y. Matano, Elsevier, New York (2001),
Chap. 5, p 371. f) G. I. Elliott and J. P. Konopelski, Tetrahedron,
57, 5683 (2001).
Entry
R1
R2
Temp/ꢂC
Yield/%
Product
1
2
3
4
5
6
H
Me
H
H
reflux
71
95
1n
1a
rt
rt
Me
Me
Cl
91
38 (47a)
71
1o
OMe
H
rt
1p (2p)
1q
1r (2r)
CF3
OMe
rt
reflux
47 (9a)
4
H
aYields of the corresponding O-arylated products 2.
Me
MeO
OMe
N
O
N
O
2p
2r
Table 3. Effects of organobismuth(V) reagentsa
5
6
a) D. H. R. Barton, J.-P. Finet, W. B. Motherwell, and C. Pichon,
J. Chem. Soc., Perkin Trans. 1, 1987, 251. b) S. David and
A. Thieffry, J. Org. Chem., 48, 441 (1983).
a) D. H. R. Barton, N. Y. Bhatnagar, J.-C. Blazejewski, B.
Charpiot, J.-P. Finet, D. J. Lester, W. B. Motherwell, M. T. B.
Papoula, and S. P. Stanforth, J. Chem. Soc., Perkin Trans. 1,
1985, 2657. b) D. H. R. Barton, N. Y. Bhatnagar, J.-P. Finet,
J. Khamsl, W. B. Motherwell, and S. P. Stanforth, Tetrahedron,
43, 323 (1987).
ꢁ
b
Ph3BiCl2 Ph3BiF2 [Ph4Biþ][BF4
]
Ph3Bi(OAc)2 Ph3BiCO3
0% 0%
71%
73%
51%
aN-phenylation of pyridin-2-one was carried out by using bis-
muth(V) reagents according to the general procedure under reflux-
ing conditions. b1.0 equiv. of pyridin-2-on and t-BuOK were used.
Barton’s reports10,11a (Entries 12 and 13).
Various ortho-substituted phenyl groups as well as simple
phenyl one were transferred to the nitrogen atom of pyridin-
2-on (Table 2). Importantly, triphenylbismuth dichloride
(Ph3BiCl2) was less reactive than bulky (o-tolyl)3BiCl2 and N-
phenylated product 1n was produced only when the reaction
was carried out under refluxing conditions (Entry 1). This is
probably due to the steric effects which make C–BiV bonds in
(o-tolyl)3BiCl2 weaker compared with those in Ph3BiCl2. Fur-
ther, the introduction of methoxy groups on the phenyl groups
attached to BiV atom resulted in the formation of a mixture of
N- and O-arylated products (Entries 4 and 6).
7
a) D. H. R. Barton, J.-C. Blazejewski, B. Charpiot, J.-P. Finet,
W. B. Motherwell, M. T. B. Papoula, and S. P. Stanforth,
J. Chem. Soc., Perkin Trans. 1, 1985, 2667. b) R. S. Fornicola,
E. Oblinger, and J. Montgomery, J. Org. Chem., 63, 3528
(1998). c) K. C. Santhosh and K. K. Balasubramanian, J. Chem.
Soc., Chem. Commun., 1992, 224.
a) T. Ooi, R. Goto, and K. Maruoka, J. Am. Chem. Soc., 125,
10494 (2003). b) T. Arnauld and D. H. R. Barton, J. Org. Chem.,
64, 6915 (1999).
8
9
P. K. Koech and M. J. Krische, J. Am. Chem. Soc., 126, 5350
(2004).
10 a) T. Arnauld, D. H. R. Barton, and E. Doris, Tetrahedron, 53,
4137 (1997). b) D. H. R. Barton, J.-P. Finet, and J. Khamsi,
Tetrahedron Lett., 30, 937 (1989). c) D. H. R. Barton, J.-P.
Finet, and J. Khamsi, Tetrahedron Lett., 27, 3615 (1986).
11 A few examples of N-phenylation with organobismuth
compounds in the absence of copper catalysts were reported.
a) D. H. R. Barton, J.-P. Finet, and C. Pichon, J. Chem. Soc.,
Chem. Commun., 1986, 65. b) M. S. Akhtar, W. J. Brouillette,
and D. V. Waterhous, J. Org. Chem., 55, 5222 (1990). See also
Ref. 5a.
12 When equimolar amounts of the potassium salt of pyridin-2-one
and (o-tolyl)3BiCl2 were mixed at room temperature, the
product 1a was formed only in 40% yield.
13 The use of sodium hydride or 1,1,3,3-tertramethylguanidine was
less effective compared with that of t-BuOK in N-o-tolylation of
pyridin-2-one (75 or 69% yield, respectively).
A postulated reaction mechanism is depicted in Scheme 1.
Two equivalents of potassium pyridin-2-one were substituted
at the BiV center and the corresponding O-adduct was generated
as a key intermediate. The adduct thermally decomposed to af-
ford the N-arylated product together with BiIII byproducts14
through ligand coupling processes. In order to further verify this
mechanism, the use of other organobismuth(V) reagents for
Ph3BiCl2 wasꢁalso examined (Table 3). The use of Ph3BiF2 or
[Ph4Biþ][BF4 15 gave 1n in good yields, whereas triphenylbis-
]
muth diacetate or carbonate did not afford N-phenylpyridin-2-
one under the same conditions. This might suggest that the for-
mation of a covalently bonded BiV–pyridin-2-one intermediate
is an important step in the present arylation method.
It is noted that an efficient method for N-arylation of
pyridin-2-ones using triarylbismuth dichlorides was developed.
These reactions proceeded smoothly under mild conditions
without any assistance of copper catalysis. Further studies on
aryl transfer reactions onto heterocycles by using hypervalent
organobismuth reagents are now in progress.
14 Unfortunately, our attempt to isolate bismuth(III)-byproducts
was unsuccessful owing to their labilities, while small amounts
of triarylbismuthines were detected together with N-arylated
products.
15 Y. Matano, S. A. Begum, T. Miyamatsu, and H. Suzuki, Orga-
nometallics, 17, 4332 (1998).
Published on the web (Advance View) October 1, 2005; DOI 10.1246/cl.2005.1496