A general [3 + 2 + 1] annulation strategy for the preparation of pyridine N-oxides

Article abstract of DOI:10.1021/ol006831r

equation presented Stabilized ketone, aldehyde, and ester enolates react with vinamidinium hexafluorophosphate salts and hydroxylamine hydrochloride to give access to the corresponding pyridine N-oxides. The annulation reactions proceed in good to excelle

Full text of DOI:10.1021/ol006831r

ORGANIC
LETTERS
2001
Vol. 3, No. 2
209-211
A General [3 + 2 + 1] Annulation
Strategy for the Preparation of Pyridine
N-Oxides
,†
Ian W. Davies,* Jean-Franc¸ois Marcoux,* and Paul J. Reider
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
ian_daVies1@merck.com
Received November 7, 2000
ABSTRACT
Stabilized ketone, aldehyde, and ester enolates react with vinamidinium hexafluorophosphate salts and hydroxylamine hydrochloride to give
access to the corresponding pyridine N-oxides. The annulation reactions proceed in good to excellent yields with vinamidinium salts with a
range of â-substituents (R3 ) halo, aryl, nitro, trifluoromethyl).
Pyridine N-oxides are used as antibacterial, antifungal, and
antiseborrheic agents.1 N-Oxides are very often metabolites
of pyridine-containing molecules and have been used to
determine structure-activity relationships. The most com-
monly used method for the preparation of these compounds
relies on oxidation of the parent pyridines.2 Cyclization of
nitroaromatics and oximes are also well-established methods
for preparation of fused pyridine N-oxides.3 Other less
general methods include reaction of pyrrilium salts or
dienones with hydroxylamine.4 N-Oxides are useful synthetic
intermediates since they exhibit different reactivity and
regioselectivity than the parent pyridine.
dinium salt 2, and ammonia in a [3 + 2 + 1] annulation
reaction (Scheme 1).5 The vinamidinium salts, which are
Scheme 1
The Cox-2 specific inhibitor Etoricoxib can be assembled
very efficiently in a single step from ketone 1, the vinami-
readily available from acetic acids, may contain a range of
functionality.6
† E-mail address: jeff_marcoux@merck.com.
(1) The Merck Index on CD-ROM, v. 12.3, Chapman & Hall, 2000.
(2) For example, see: Coperet, C.; Adolfsson, H.; Khuong, T.-A.; Yudin,
A. K.; Sharpless, K. B. J. Org. Chem. 1998, 63, 1740.
(3) For example, see: (a) Hirota, K.; Nakazawa, Y.; Kitade, Y.; Saijiki,
H. Heterocycles 1998, 47, 871. (b) Wrobel, Z.; Kwast, A.; Makosza, M.
Synthesis 1993, 1, 31. (c) Kusurkar, R. S.; Bhosdale, D. K. Tetrahedron
Lett. 1991, 32, 3199. (d) Nesi, R.; Giomi, D.; Papaleo, S.; Turchi, S.;
Dapporto, P.; Paoli, P. Heterocycles 1991, 32, 1913.
(4) Uncuta, C.; Caproiu, M. R.; Campeanu, V.; Petride, A.; Danila, M.
G.; Plaveti, M.; Balaban, A. T. Tetrahedron 1998, 54, 9747.
(5) Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai, D.-
W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.; DiMichele,
L.; Dormer, P.; Reider, P. J. Org. Chem. 2000, 65, 8415. Marcoux, J.-F.;
Corley, E. G.; Rossen, K.; Pye, P.; Wu, J.; Robbins, M. A.; Davies, I. W.;
Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2339.
(6) Davies, I. W.; Marcoux, J.-F.; Wu, J.; Palucki, M.; Corley, E. G.;
Robbins, M.; Tsou, N.; Ball, R. G.; Dormer, P.; Larsen, R. D.; Reider, P.
J. Org. Chem. 2000, 65, 4571.
10.1021/ol006831r CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/22/2000

Ammonia is not the only partner that should function as
the third component in the [3 + 2 + 1] annulation reaction.
For example, the use of hydroxylamine would lead directly
to a pyridine N-oxide.7 The use of a primary amine, e.g.,
methylamine, would lead directly to the N-methylpyridinium
salt. In this Letter we describe our preliminary results in this
area and demonstrate the generality of this [3 + 2 + 1]
strategy to access highly functionalized pyridine N-oxides.
Initial experiments were performed using ketosulfone 1
and vinamidinium salt 2 (CDT) using the standard reaction
conditions. Replacement of ammonia with ∼50 wt %
aqueous hydroxylamine hydrochloride led to the isolation
of the N-oxide 3 in 85% yield (Table 1).
reaction using the DABCO-promoted reaction conditions
failed for ketosulfone and CDT, for reasons that we still do
not fully understand. The reaction is however quite general,
and a range of vinamidinium salts were successfully em-
ployed as exemplified by the use of the nitro-vinamidinium
salt which gave the N-oxide in 52% unoptimized yield. The
use of the ketosulfide (entry 3) nicely illustrates the principle
of direct access to substrates inaccessible via oxidation
chemistry.
Aldehydes also took part in the reaction when KHMDS
was used to accomplish enolization and acetic acid/ TFA
was used to promote elimination. Phenylacetaldehyde led
to the desired N-oxide 7 in 61% yield.
The scope of the reaction was studied by reacting a range
of enolates and substituted vinamidinium salts (Table 2).
Table 1. Annulation of ketosulfone 1 with
N,N-dimethylvinamidinium hexafluorophosphatesa
Table 2. Annulation of MAA with vinamidinium saltsa
a Reactions were conducted in THF using 1.05 equiv of 20 wt % t-BuOK/
THF and 1.05 equiv of vinamidinium salt.8
a Reactions were conducted in THF using 1.05 equiv of 20 wt % t-BuOK/
THF, 1.00 equiv of DABCO, and 1.05 equiv of vinamidinium salt.10
This result is significant since mCPBA oxidation of
Etoricoxib led to the exclusive formation of the alternate
N-oxide regioisomer 6 in 89% isolated yield. Etoricoxib also
In these cases DABCO was used in the reaction to promote
the elimination. Methyl acetoacetate (MAA) was reacted as
a representative ketoester. The chloride 8 was isolated in an
unoptimized 78% yield. The phenyl 9 and 4-fluorophenyl
10 N-oxides were isolated in 71% and 76% yields, respec-
tively.
Cyclohexanedione reacted smoothly with the 4-nitrophenyl
vinamidinium salt to give the azatetralone derivative 11 in
70% yield. The nitrovinamidinium salt behaved similarly and
gave the nitroazatetralone 12 in 72% yield. The trifluoro-
methylazatetralone 13 was prepared in 45% yield.
undergoes oxidation at the same site in vitro.9 Attempted
(7) For a related reaction to form 2-aminopyridine N-oxides in two steps
using a vinamidinium salt and malonitrile, see: Hagen, V.; Jansch, H.-J. J.
Prakt. Chem. 1990, 332, 748.
(8) General experimental procedure for the annulation of ketosul-
fone: To a suspension of ketosulfone (25 mmol) in dry THF (50 mL) at 0
°C was added dropwise a 20 wt % solution of t-BuOK in THF (26.3 mmol).
The yellow slurry was stirred at room temperature for 45 min, and the
vinamidinium hexafluorophosphate salt (26.3 mmol) was added in one
portion. The resulting mixture was stirred at room temperature for 45 min
and transferred dropwise with a cannula under nitrogen to a solution of
acetic acid (175 mmol) and TFA (20 mmol) in THF (25 mL) at 25-30 °C.
The mixture was stirred for 45 min, and ∼50 wt % aqueous hydroxylamine
hydrochloride (50 mmol) was added. The resulting dark solution was heated
at reflux for 5 h, and then the organic phase was concentrated under reduced
pressure. The residue was directly purified by chromatography on silica
gel. All final products were characterized by 1H and 13C NMR and LC/
MS.
210
Org. Lett., Vol. 3, No. 2, 2001

The mechanism involves attack on the intermediate
dienone 14 in the case of MAA.11 On the basis of analogy
with the reaction of ammonia with 14, hydroxylamine attacks
at the δ carbon rather than at the carbonyl. The resulting
hydroxylamine dienone adduct undergoes cyclization and
elimination of water to form the pyridine N-oxide.
In conclusion, stabilized enolates react with 2-substituted
vinamidinium salts to give the pyridine N-oxides with high
regioselectivity in good to excellent yields. Further work is
in progress to expand the scope of the annulation reaction
to include other nucleophiles.
Supporting Information Available: Characterization
data: 1H and 13C NMR and LC/MS data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006831R
Hydroxylamine hydrochloride (60-75 mmol) was added in one portion.
The resulting dark solution was heated at reflux for 5 h and concentrated
under reduced pressure. The residue was directly purified by chromatography
on silica gel. All final products were characterized by 1H and 13C NMR
and LC/MS.
(11) The intermediate 14 is isolable in the reaction of MAA. C, H, N
characterization and spectral data are included in the Supporting Information.
For an example of the formation of a pyridine N-oxide from a dienone,
see: Bruni, F.; Chimichi, S.; Cosimelli, B.; Costanzo, A.; Guerini, G.;
Selleri, S. Heterocycles 1990, 31, 1635.
(9) Chauret, N.; Yergey, J. A.; Brideau, C.; Friesen, R. W.; Mancini, J.;
Riendeau, D.; Scheigetz, J.; Silva, J.; Styhler, A.; Trimble, L. A.; Nicoll-
Griffith. D. A. Submitted for publication.
(10) General procedure for the reaction of MAA: To a solution of
MAA (25 mmol) in dry THF (50 mL) at room temperature was added
dropwise a 20 wt % solution of t-BuOK in THF (26.3 mmol). The solution
was stirred at room temperature for 15 min, and then DABCO (25 mmol)
and the vinamidinium hexafluorophosphate salt (26.3 mmol) were added
sequentially. The resulting mixture was stirred at 40-45 °C for 4 h.
Org. Lett., Vol. 3, No. 2, 2001
211