An expedient approach to tetrahydrofuro[3,2-b]pyridine-2(3H)-ones via activation of pyridine N-oxide by triflic anhydride

Article abstract of DOI:10.1016/j.tetlet.2010.04.030

The double addition of bis(trimethylsilyl) ketene acetals [R₁, R₂ = CH₃, -(CH₂)₅-] to pyridine N-oxide promoted by triflic anhydride under mild conditions generates N-[(trifluoromethane)sulfonyl-1,2-dihydropyridine-2,4-dicarboxylic acids 2a-b. Subsequent reaction of these acids upon iodolactonization conditions affords tetrahydrofuro[3,2-b]pyridine-2(3H)-ones 3a-b containing an exo-insaturation on the products as a result of an unexpected decarboxylation.

Full text of DOI:10.1016/j.tetlet.2010.04.030

Tetrahedron Letters 51 (2010) 3186–3189
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Tetrahedron Letters
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An expedient approach to tetrahydrofuro[3,2-b]pyridine-2(3H)-ones via
activation of pyridine N-oxide by triflic anhydride
N. Gualo-Soberanes a, M. C. Ortega-Alfaro b, J. G. López-Cortés a, R. A. Toscano a, H. Rudler c,
C. Álvarez-Toledano a,
*
a Instituto de Química UNAM, Circuito Exterior, Ciudad Universitaria, México 04510, D.F., Mexico
b Instituto de Ciencias Nucleares, UNAM, Circuito Exterior, Cd. Universitaria, México 04510, D.F., Mexico
c Laboratoire de Chimie Organique, UMR CNRS 7611, Université P. M. Curie, Case 47, 4 place Jussieu, 75252 Paris Cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The double addition of bis(trimethylsilyl) ketene acetals [R1, R2 = CH3, –(CH2)5–] to pyridine N-oxide pro-
moted by triflic anhydride under mild conditions generates N-[(trifluoromethane)sulfonyl-1,2-dihydro-
pyridine-2,4-dicarboxylic acids 2a–b. Subsequent reaction of these acids upon iodolactonization
conditions affords tetrahydrofuro[3,2-b]pyridine-2(3H)-ones 3a–b containing an exo-insaturation on
the products as a result of an unexpected decarboxylation.
Received 8 March 2010
Revised 8 April 2010
Accepted 8 April 2010
Available online 14 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-activation
1,2-Dihydropyridines
Lactones
Ring-closing/decarboxylation
1. Introduction
such as pyrazine, quinoxaline, and pyrimidine, and the course of
the reaction in some cases depend on the nature of the nitrogen-
The functionalization of nitrogen heterocycles is a powerful tool
for the synthesis of natural products and bioactive substances. In
this context, dihydropyridines1 show interesting features that
make them attractive due to the high number of available deriva-
tives. Thus, DHPs can be easily obtained from pyridines and their
derivatives, which after activation react with a large variety of
nucleophiles.2 The activation of the pyridinium nucleus toward
carbon nucleophiles can be achieved by alkyl chloroformates,3 acid
chlorides4, or triflic anhydride,5,6 among others.
activating agent.9
Despite the use and application of these activating methods,
several research groups have also focused their attention on N-
oxide activation.10 The advantage of the former is the easy elimina-
tion of the activating agent and control on the regiochemistry of
nucleophilic addition. In this respect, pyridine N-oxide has
received wide attention as a synthetic intermediate, oxidant,11
catalyst, and ligand.12 In addition, some of the related compounds
also have important biological or pharmaceutical activities.13
Pyridine N-oxides have been used as an important tool to function-
alize the pyridine ring including nitration, halogenation, and cya-
nation. For example, considerable efforts have recently been
reported in the conversion of the N-oxides into (a) 2-aminopyri-
dine with Ts2O-tBuNH2 followed by in situ deprotection with
Following this approach, we and other research groups have de-
scribed the one-pot synthesis of functionalized d-lactones via a
double nucleophilic addition of bis-(TMS)ketene acetals to acti-
vated pyridines using methyl chloroformate as an activating agent
and the appropriated halogen to induce the formation of corre-
sponding halolactones (Scheme 1).7 A similar activation of the
pyridine directed to the synthesis of lactones can be achieved if
triflic anhydride is used as an activating agent, but in this case
better yields and more stable 1,4-dihydropyridines were obtained.
As in the previous case, in iodolactonization conditions, the corre-
R
R
R
R
O
O
O
O
N
+
1) ClCO2Me
2) I2
I
I
1) (CF3SO2)O
2) I2 /NaHCO3
sponding c
-lactones provided excellent yields.8 We have recently
described how a double nucleophilic addition reaction of ketene
acetals, which leads to lactones, can be extended to other diazines
R
R
OSiMe3
N
N
OSiMe3
O S O
CF3
O
OMe
R = -CH3, -CH2(CH2)3CH2-
* Corresponding author. Tel.: +52 5556224464; fax: +52 5556162217.
E-mail address: cecilio@servidor.unam.mx (C. Álvarez-Toledano).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.030

N. Gualo-Soberanes et al. / Tetrahedron Letters 51 (2010) 3186–3189
3187
TFA,14 (b) 2-aminopyridine amides with imidoyl chlorides,15 (c)
tetrazolopyridines with sulfonyl or phosphoryl azides16 and imi-
dazolopyridines with sulfuryl diimidazole,17 (d) 2-alkyl, alkynyl,
and arylpyridines with Grignard reagents,18 and (e) 3-(2-hydroxy-
aryl)pyridines via arynes.19 It is noteworthy that pyridine N-oxides
also served as an ideal choice to direct C–H functionalization of the
pyridine ring.20
With the aim of promoting a double nucleophilic addition of
(TMS)ketene acetals over pyridine, we describe a new one-pot
method that involves two simultaneous activation procedures, N-
oxide activation in the presence of triflic anhydride. This strategy
gave 1,2-dihydropyridines 2,4-disubstituted, which after an iodol-
actonization procedure affords tetrahydrofuro[3,2-b]pyridine-
2(3H)-ones containing an exo-insaturation on the products as a re-
sult of an unexpected decarboxylation.
2. Results and discussion
O
R1
R2
HO
(CF SO ) O
1)
/ CH2Cl2 -78°C
3
2 2
Triflic anhydride was added by a syringe to a solution of pyri-
dine N-oxide in dry CH2Cl2 at ꢀ78 °C, followed by 2.5 equiv of
bis-(trimethylsilyl)ketene acetal 1a, which led to the formation of
a white solid (Scheme 2). After the work-up the 1,2-dihydropyri-
dine 2,4-disubstituted 2a was obtained as a solid (mp 162–
164 °C) with 54.4% yield.
N
O
OH
O
R1 OSiMe3
R2 OSiMe3
N
2)
R1 R2
CF3O2S
R.T. 20h
1
2
The 1H NMR data are in agreement with the molecular structure
of 2a and confirmed the addition of two equivalents of 1a over the
2,4-position of the pyridine ring, giving signals at 1.1, 1.17, 1.23,
and 1.28 ppm as singlets for four methyl groups. We also observed
at 5.8 and 6.44 ppm two doublets assigned to H5 and H6, with
J = 7.2 Hz and a double signal at 5.57 ppm (J = 6.06 Hz) for H3,
which coupled with the signal shifted at 4.87 ppm assigned to
H2. Additionally, only one signal was observed at 5.04 ppm for
two carboxylic acids. The 13C NMR spectrum also exhibited signals
at 62.1, 117.6, 123.7, 115.7, and 62.1 ppm assigned to carbon 2–6
of the dihydropyridine ring, respectively. At 178.3 and 178.8 two
signals were shifted for the carboxylic groups.
a:
R1 and R2= -CH3
b:
R
1 and R2= -CH2(CH2)3CH2-
Scheme 2.
Product 2b (mp 179–180 °C) was obtained using the same pro-
cedure in 76.1% yield, and shows the nucleophilic addition of two
equivalents of the (TMS)ketene acetal 1b at the 2,4-position of pyr-
idine N-oxide. In contrast with the results obtained by Medley,21
the compounds 2a and 2b do not show rearomatization in the final
products, leading to N-[(trifluoromethane)sulphonyl]-1,2-dihydro-
pyridine-2,4-carboxylic acids. The structure of 2b was fully estab-
lished through an X-ray diffraction analysis (Fig. 1).22
In accordance with the experimental results, a possible mecha-
nism for the formation of 2a–b can be suggested (Scheme 3). First,
the pyridine N-oxide reacts with triflic anhydride in a similar way
to phosphine oxides23 that lead to intermediate A, then (TMS)ke-
tene acetal is additioned at 4-position, leading to B. Then a rearo-
matization of the system through the loss of OTf occurs, leading
to C. A subsequent activation of this new pyridine promoted by a
second equivalent of triflic anydride favors the nucleophilic
addition of a second molecule of (TMS)ketene acetal, to give the
Figure 1. ORTEP view of 2b.
R1 O SiMe3
R
O
1
R2
H
R2 OSiMe3
1a-b
O
(CF3O2S)2O
-CF3SO3H
OSO2CF3
N
N
N
O
-Me3SiOSO2CF3
OSO2CF3
OSO2CF3
B
A
O
O
R1
R2
R1 O SiMe3
O
R1
R1
R2
R2
O
HO
O
R2 OSiMe3
1a-b
(CF3O2S)2O
OH
O
H+
N
OSO2CF3
N
N
R2 R1
SO2CF3
D
CF3O2S
-Me3SiOSO2CF3
C
2a-b
Scheme 3.

3188
N. Gualo-Soberanes et al. / Tetrahedron Letters 51 (2010) 3186–3189
O
O
R1
R1
R2
R2
R1
R1 R2
R2
HO
HO
I
O
1)
2
O
O
NaHCO3
I2
OH
O
OH
O
O
R2
N
N
R2
R1
NaHCO
N
CF3O2S
N
2)
R1
3
CF3O2S
R2 R1
R1 R2
CF3O2S
CF3O2S
2a-b
3a-b
2a-b
3a-b
a: R1 and R2= -CH3
-CO2
R1
-I
b:
R
1 and R2=-CH2(CH2)3CH2-
O
O
R1
I
R1
I
O
Scheme 4.
R2
R2
R2
O
O
O
I
O
O
O
O
N
N
R2
N
O
O
R1
R1 R2
R1 R2
CF3O2S
CF3O2S
CF3O2S
E
Scheme 5.
The transformation of 2 into 3 could involve the formation of an
iodonium intermediate that favors the intramolecular ring-closing
reaction leading to iodolactone E, which undergoes decarboxyl-
ation promoted by the basic medium and the loss of the iodide
ion. This assumption is supported by an experiment performed in
the absence of iodine, which gave negative results (Scheme 5).
To summarize, we have developed a new means of obtaining
N-[(trifluoromethane)sulfonyl-1,2-dihydropyridine-2,4-dicarbox-
ylic acids 2a–b, under mild conditions, using as a strategy the
formation of a new activating group that promotes the nucleophilic
addition of (TMS)ketene acetal on 4-position as an initial step.
Using halolactonization protocol, compounds 2a–b provide
tetrahydrofuro[3,2-b]pyridine-2(3H)-ones 3a–b, containing an
exo-insaturation, as a result of an unexpected decarboxylation. Fur-
ther studies will widen the scope of this methodology.
Figure 2. ORTEP view of 3b.
corresponding N-[(trifluoromethane)sulphonyl]-1,2-dihydropyri-
dine-2,4-carboxylic acids. The formation of intermediate A is cru-
cial in explaining the obtention of an 1,2-dihydropyridine as the
end product, which indicates a high 4-regioselectivity in the addi-
tion of C-nucleophiles as (TMS)ketene acetals over pyridines N-
oxide.21
We have studied the transformation of the 2,4-dicarboxylic
acids 2a–b into iodolactones following the strategy of a halolacton-
ization protocol. Thus, when compounds 2a and 2b were reacted in
the condition described in Scheme 4, the bicyclic lactones [4.3.0]
3a (mp 132 °C, yield: 43.9%) and 3b (mp 126–128 °C, yield:
63.1%) were obtained, but surprisingly these do not contain iodine
in their structure and the presence of an exo-cyclic double bond as
a result of a decarboxylation at room temperature was observed.
These results are quite different from lactones previously obtained
by us under similar conditions.9,10
Acknowledgments
The authors appreciate the technical assistance provided by
Isabel Chavez, Rocío Patiño, Luis Velasco and Javier Pérez. They
would also like to thank the DGAPA-PAPIT IN222808 project and
CONACYT for Ph.D. Grant extended to N.G.-S.
Supplementary data
Supplementary data (spectroscopic characterization of products
2a, 2b, 3a and 3b and general methods) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2010.04.
030.
According to its 1H NMR, spectrum, 3a contains four simple sig-
nals shifted at 1.19, 1.39, 1.89, and 2.02 ppm assigned to methyls,
two coupled methine groups H2 and H3 (d = 4.64 and 6.36,
J = 8.79 Hz) consistent with a cis-fused lactone system. Addition-
ally, the double bond hydrogens in the tetrahydropyridine ring
are localized at 6.13 and 6.36 ppm. The 13C spectrum confirmed
the presence of an exo-cyclic double bond by signals at 118.4 and
118.9 ppm; the olefinic carbons of the tetrahydropyridine ring
(C5 and C6) at 113.8 and 141.0 ppm; the carbonyl group of the lac-
tone at 176.4 ppm, and lastly, the trifluoromethyl group at 119.6
(J = 321 Hz). Similar spectroscopic data were obtained for the anal-
ogous 3b. Crystals suitable for X-ray analysis were grown from 3b
and allowed an unambiguous assessment of their structure
(Fig. 2).24
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0
0
a = 15.194(4) ÅA, b = 12.243(3) ÅA, c = 12.143(3) ÅA, V = 2255.6(10) ÅA3, Z = 4,
Dc = 1.371 g cmꢀ3, (MoK
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0.1676. CCDC 768153.
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0
0
a = 13.696(1) ÅA, b = 14.484(1) ÅA, c = 9.789(1) ÅA, V = 1876.2(3) ÅA3, Z = 4,
13. (a) Balzarini, J.; Keyaerts, E.; Vijgen, L.; Vandermeer, F.; Stevens, M.; Clercq, E.
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Dc = 1.485 g cmꢀ3, (MoK
a, k = 0.71073), T = 173 K, R1, wR2, [I>2r(I)] = 0.0369,
0.0931. CCDC 768154.