Tetrabutylammonium pyridin-2-olate: A new reagent for the efficient synthesis of N-aryl pyridin-2-ones

Article abstract of DOI:10.1055/s-2008-1072569

A new reagent, tetrabutylammonium pyridin-2-olate, was prepared and its application to the efficient synthesis of N-aryl pyridine-2-ones was demonstrated using CuI-catalyzed coupling reactions with aryl iodides. This coupling reaction is mild, high-yielding, and remarkably chemoselective (N- vs. O-arylation). It is also compatible with substrates containing labile functional groups. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072569

PAPER
1523
Tetrabutylammonium Pyridin-2-olate: A New Reagent for the Efficient
Synthesis of N-Aryl Pyridin-2-ones
Synthesis of
N
-
Ary
u
l
Pyridin-2-o
i
nes
w
i
p
th
T
etrabutyl
i
a
mmon
n
ium Pyridin
g-2-olate Zhang,* Bang-Chi Chen, Bei Wang, Sam T. Chao, Rulin Zhao, Ngiapkie Lim, Balu Balasubramanian
Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA
Fax +1(609)2526804; E-mail: huiping.zhang@bms.com
Received 28 November 2007; revised 17 January 2008
on the reaction temperature, rate and yield. By choosing
an appropriate reaction system, based on the nature of the
starting aryl counterpart, the desired N-arylation products
could be obtained in high yields. However, by-products
Abstract: A new reagent, tetrabutylammonium pyridin-2-olate,
was prepared and its application to the efficient synthesis of N-aryl
pyridine-2-ones was demonstrated using CuI-catalyzed coupling
reactions with aryl iodides. This coupling reaction is mild, high-
yielding, and remarkably chemoselective (N- vs. O-arylation). It is resulting from competitive dehalogenation, O-arylation
also compatible with substrates containing labile functional groups.
and other side-reactions, often complicated the product
isolation and purification, making it less attractive for
large-scale synthesis. Recently, N-arylation of pyridin-
2(1H)-ones with pentavalent organobismuth reagents to
give N-aryl pyridin-2-ones under copper-free conditions
was also reported.16
Key words: preparation, tetrabutylammonium pyridin-2-olate, aryl
iodides, CuI-catalyzed coupling reaction, N-aryl pyridin-2-ones
The N-Aryl pyridin-2-one moiety is an important synthet-
ic intermediate1,2 and an important structural motif that
features in many biologically active molecules (e.g.
HMG-CoA reductase inhibitors,3 reverse transcriptase in-
hibitors,4 and selective serotonin reuptake inhibitors5).
More recently, pyridine-2-one-containing inhibitors of
coagulation factor Xa have been reported.6,7
Recently we required easy excess to large amounts of py-
ridin-2-onyl aromatic carboxylic esters. While these com-
pounds could be generated via the aforementioned
copper-catalyzed Ullmann type N-arylation of pyridin-
2(1H)-one with iodo arylcarboxylates, the desired prod-
ucts were obtained in poor yields after flash column chro-
matography purification (~25% yield).17 The major
byproducts were identified by LC-MS to be from reduc-
tion (des-iodo compounds) and hydrolysis (carboxylic ac-
ids) in addition to the corresponding O-arylated
compounds. In most cases, the byproducts eluted closely
with the desired products, making the separation very dif-
ficult. Thus, development of an improved method for the
preparation of pyridin-2-onyl aromatic carboxylic esters
was highly desired. Herein, we describe a new and effi-
cient method for the synthesis of pyridin-2-onyl aromatic
carboxylic esters using a novel intermediate, tetrabutyl-
ammonium pyridin-2-olate (3), and demonstrate its appli-
cation to the general synthesis of other N-aryl pyridin-2-
ones in general (Scheme 1). Our strategy was to study the
previously unexplored effect of pyridin-2-olate (3), de-
rived from pyridine-2(1H)-one (1), on the coupling.
A number of methods have previously been developed for
the synthesis of N-aryl 2-pyridinones. While routes in-
volving rearrangement of 2-aryloxypyridines and reac-
tions of pyridin-2(1H)-one with benzynes and
cycloaddition of aryl isocyanates with ethyne, all give rise
to the desired N-aryl pyridin-2-one products,8–10 the most
straightforward and versatile approach to N-aryl pyridin-
2-ones is the coupling reaction of pyridin-2(1H)-one with
an aryl counterpart. A number of protocols have been suc-
cessfully developed for such C–N bond formation reac-
tions. For some highly electron-deficient aryl halides, the
coupling reaction could proceed through nucleophilic ar-
omatic substitution,11 however, the most general and syn-
thetically useful method is the copper-catalyzed Ullmann-
type N-arylation.12–15 Aryl counterparts successfully uti-
lized for this coupling reaction include aryl halides,12 aryl
boronic acids,13 aryl stannanes,14 and triarylbismuthines.15
These reactions can all be carried out with or without ac-
companying ligands. In all of these methods, emphasis
was on the effects of catalyst, leaving group, and ligands
The impetus for the strategy was our observation that the
yield of the desired coupling reaction was significantly
improved and the reaction time was shortened, by con-
ducting the reaction in the presence of tetrabutylammoni-
Bu
N+
O–
O
O
Bu
Bu
Bu
N+
ArI 4
Ar
Bu
Bu
toluene
NH
+
OH–
Bu
N
N
CuI/DMF
Bu
1
2
3
5
Scheme 1
SYNTHESIS 2008, No. 10, pp 1523–1526
x
x.
x
x
.
2
0
0
8
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1072569; Art ID: M08907SS
© Georg Thieme Verlag Stuttgart · New York

1524
H. Zhang et al.
PAPER
um chloride as a phase-transfer catalyst. Thus, we
speculated that the generation of a novel pyridinolate in-
termediate in situ during the coupling reaction was re-
sponsible for the increased reactivity. Based on this
reasoning, we decided to prepare and isolate tetrabutylam-
monium pyridin-2-olate (3) and test its ability to undergo
N-arylation with aryl iodides with various functional
groups.
Table 1 Reaction of Tetrabutylammonium Pyridin-2-olate (3) with
Aryl Iodides (4)
Entry ArI
Product
(5)
Isolated yield
(%)
(4)
O
O
N
O
O
O
1
91
I
Considering the relative acidity of the NH on pyridin-
2(1H)-one (1), we envisioned that the intermediate 3
could be prepared by reaction of 1 with tetrabuylammoni-
um hydroxide (2; Scheme 1). Indeed, treatment of pyri-
din-2(1H)-one (1) with one equivalent of 2 (40% aqueous
solution) and azeotropic removal of water under reduced
pressure, provided 3 in quantitative yield as an off-white
solid. The structure of 3 was determined by NMR as well
as microanalysis. Using this procedure, we were able to
prepare 3 in multi-hundred gram batches.
4a
5a
NO2
O
I
NO2
2
91
89
N
4b
5b
O
O
I
O
3
N
With significant amounts of 3 in hand, we studied its re-
action with ethyl 4-iodobenzoate (Table 1, entry 1). The
coupling reaction was carried out in N,N-dimethylform-
amide (DMF) at 95 °C for 12 hours. LC/MS analysis of
the reaction mixture indicated that the reaction was com-
plete and that none of the previously observed byproducts
were present. The desired pyridin-2-onyl benzoate prod-
uct 5a was isolated in 91% yield (Table 1, entry 1).
4c
5c
O
N
I
4
95
89
4d
We next studied the coupling reaction of 3 with other sub-
stituted aryl iodides 4, as summarized in Table 1.
5d
NO2
NO2
NH2
NH2
All the reactions proceeded smoothly to afford the desired
products in excellent yields (Table 1, entries 2–5). The re-
action worked well with both electron-deficient (entries 1
and 2), and electron-rich (entries 3 and 4) iodobenzenes.
It should be pointed out that under the new reaction con-
ditions, 4-iodo-2-methyl-6-nitroaniline (4e) reacted with
3 to give the desired coupled pyridine-2-one 5e as the sole
product in 89% isolated yield (Table 1, entry 5). No
homo-coupling of the iodoaniline starting material was
observed. More importantly, the C–N bond formation was
highly chemoselective; no O-arylation byproducts were
detected in any of these reactions.
O
N
I
5
4e
5e
All of the reagents and solvents are commercially available and
were used as purchased, without further purification unless other-
wise stated. All glassware was dried and purged with nitrogen or ar-
gon prior to use. Reactions were monitored by HPLC using the
following conditions: YMC Pack Pro column s-3 mm 4.6 × 150 mm.
Solvent: A = H2O with 0.05% TFA; B = MeCN with 0.05% TFA;
gradient: 100% A to 100% B over 4 min. Flow rate = 1 mL/min;
l = 215 nm. All 1H NMR and 13C NMR spectra were recorded on a
Bruker 400 MHz spectrometer using CDCl3 as the solvent. Mass
spectra were recorded with a Shimadzu LC-MS spectrometer.
In summary, we have developed a novel reagent, tetrabu-
tylammonium pyridin-2-olate (3), and studied its coupling
reactions with aryl iodides using CuI as a catalyst. Com-
pared to those reported previously, the new method, using
3 for the preparation of N-aryl pyridin-2-ones, is not only
highly chemoselective (N- vs O-arylation) and high-
yielding, but also very general and tolerable to a number
of sensitive functional groups. The method is also amena-
ble for large-scale synthesis and has been applied success-
fully to the preparation of multi-hundred grams of
important pharmaceutical intermediates containing N-aryl
pyridine-2-one subunits for use in our ongoing drug dis-
covery programs. As the coupling reaction is also carried
out under essentially neutral conditions, it is expected that
this new reagent 3, and its related analogs, will find wide
application in organic synthesis.
Synthesis of Tetrabutylammonium Pyridin-2-olate (3)
A 1 L round-bottom flask was charged with pyridin-2(1H)-one (1;
47.5 g, 0.5 mol, 1 equiv), tetrabutyl ammonium hydroxide (40% aq
soln, 324.3 g, 0.5 mol, 1 equiv) and toluene (300 mL). After stirring
for 2 h at r.t., the solvent was removed under reduced pressure
(55 °C, 65 Torr) and the residual water was removed azeotropically
with toluene (3 × 300 mL) to afford an amber oil which changed
into a colorless solid upon cooling to r.t. The solid was dried under
vacuum over P2O5 at 50 °C for 12 h to afford the desired product 3.
Yield: 173 g (100%); light-yellow solid.
1H NMR (400 MHz, CDCl3): d = 7.70 (d, J = 5.5 Hz, 1 H), 7.27 (d,
J = 8.7 Hz, 1 H), 6.40 (d, J = 8.7 Hz, 1 H), 6.13 (t, J = 6.1 Hz, 1 H),
Synthesis 2008, No. 10, 1523–1526 © Thieme Stuttgart · New York

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Synthesis of N-Aryl Pyridin-2-ones with Tetrabutylammonium Pyridin-2-olate
1525
3.28 (t, J = 8.3 Hz, 8 H), 1.55 (m, 8 H), 1.37 (m, 8 H), 0.94 (t,
J = 7.4 Hz, 12 H).
13C NMR (75 MHz, CDCl3): d = 67.53, 139.98, 135.10, 118.68,
106.22, 58.99, 29.57, 20.01, 14.01.
Acknowledgment
The authors thank Dr. Joel C. Barrish for his valuable input and
helpful discussion in the preparation of this manuscript.
Anal. Calcd for C21H40N2O·H2O: C, 70.94; H, 11.92; N, 7.83.
Found: C, 70.84; H, 12.03; N, 7.85.
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Reaction of Tetrabutylammonium Pyridin-2-olate (3) with Aryl
Iodides (4); General Procedure
A 50 mL round-bottom flask was charged with iodide (4, 10 mmol)
and tetrabutylammonium pyridin-2-olate (3; 5.19 g, 15 mmol).
Trace water was removed azeotropically with toluene (2 × 20 mL).
CuI (950 mg, 5 mmol) and DMF (10 mL) were added and the reac-
tion mixture was heated at 95 °C for 12 h under N2. The mixture was
then cooled to r.t. and the precipitated product slurry was trans-
ferred slowly into aq NH4OH (3 N, 50 mL). The solid was collected
by filtration, re-dissolved in CH2Cl2 (50 mL) and washed with
NH4OH (3 N, 2 × 25 mL) and H2O (3 × 30 mL). The organic solu-
tion was concentrated in vacuo to provide the desired product 5.
Ethyl 4-(2-Oxopyridin-1(2H)-yl)benzoate (5a)
Yield: 91%.
1H NMR (400 MHz, CDCl3): d = 7.94 (d, J = 8.4 Hz, 2 H), 7.25 (d,
J = 8.4 Hz, 2 H), 7.18 (d, J = 7.8 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 1 H),
6.43 (d, J = 9.3 Hz, 1 H), 6.43 (d, J = 6.7 Hz, 1 H), 4.18 (q, J = 7.1
Hz, 2 H), 1.19 (t, J = 7.1 Hz, 3 H).
MS (ESI): m/z = 244 [M + H]+.
1-(4-Nitrophenyl)pyridin-2(1H)-one (5b)
Yield: 91%.
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 9.2 Hz, 2 H), 7.56 (d,
J = 9.2 Hz, 2 H), 7.37 (t, J = 7.0 Hz, 1 H), 7.26 (d, J = 6.7 Hz, 1 H),
6.61 (d, J = 9.5 Hz, 1 H), 6.25 (t, J = 6.4 Hz, 1 H).
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1-(4-Methoxyphenyl)pyridin-2(1H)-one (5c)
Yield: 91%.
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(d, J = 11.9 Hz, 2 H), 6.55 (d, J = 9.1 Hz, 1 H), 6.13 (t, J = 7.1 Hz,
1 H), 3.75 (s, 3 H).
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115.44, 106.7, 56.71.
MS (ESI): m/z = 202 [M + H]+.
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1-(4-Isopropylphenyl)pyridin-2(1H)-one (5d)
Yield: 95%.
1H NMR (400 MHz, CDCl3): d = 7.34 (m, 6 H), 6.66 (d, J = 9.3 Hz,
1 H), 6.22 (t, J = 7.2 Hz, 1 H), 2.97 (m, 1 H), 1.28 (d, J = 6.9 Hz,
6 H).
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1-(4-Amino-3-methyl-5-nitrophenyl)pyridin-2(1H)-one (5e)
Yield: 89%.
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(d, J = 6.2 Hz, 1 H), 6.59 (d, J = 9.12 Hz, 1 H), 6.33 (br s, 2 H), 6.20
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MS (ESI): m/z = 246 [M + H]+.
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1526
H. Zhang et al.
PAPER
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Synthesis 2008, No. 10, 1523–1526 © Thieme Stuttgart · New York