Synthesis of furo[2,3-b]pyridin-4(7H)-ones and related quinolinone via Br?nsted acid-promoted cyclisation of alkynes

Article abstract of DOI:10.1016/j.tetlet.2008.11.073

N-Alkyl-4-alkoxy-3-alkynylpyridin-2(1H)-ones readily undergo acid-promoted 5-endo-heteroannulation to furopyridinium intermediates that are dealkylated in situ to provide the corresponding furo[2,3-b]pyridin-4(7H)-ones. The same strategy applies to the fo

Full text of DOI:10.1016/j.tetlet.2008.11.073

Tetrahedron Letters 50 (2009) 614–616
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of furo[2,3-b]pyridin-4(7H)-ones and related quinolinone
via Brønsted acid-promoted cyclisation of alkynes
a,
Emmanuel Bossharth a, Philippe Desbordes b, Nuno Monteiro a, , Geneviève Balme
*
*
a ICBMS, Institut de Chimie et de Biochimie Moléculaire et Supramoléculaire (UMR 5246 du CNRS), Université Lyon 1, ESCPE Lyon,
43 Bd du 11 novembre 1918, 69622 Villeurbanne, France
b Bayer CropScience, 14/20 rue Baizet, BP9163, 69623 Lyon Cedex 09, France
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkyl-4-alkoxy-3-alkynylpyridin-2(1H)-ones readily undergo acid-promoted 5-endo-heteroannulation
to furopyridinium intermediates that are dealkylated in situ to provide the corresponding furo[2,3-b]-
pyridin-4(7H)-ones. The same strategy applies to the formation of furo[2,3-b]quinolin-4(9H)-ones. In
the case of Me3Si-substituted alkynes, hydration of the triple bond was observed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 30 October 2008
Revised 14 November 2008
Accepted 18 November 2008
Available online 24 November 2008
Keywords:
Electrophilic annulation
3-Alkynyl-2-pyridones
Brønsted acids
Furopyridinium salts
Furo[2,3-b]pyridin-4-ones
As part of a drug development programme, we recently started
exploring the reactivity of 4-alkoxy-3-alkynyl-2-pyridones (I) as
potential precursors of the furo[2,3-b]pyridin-4-one ring system
(II), a key-structural subunit prevalent in a number of natural
products and structural analogues associated with interesting
biological activities.1 We have already successfully developed
organopalladium- as well as iodonium-promoted heteroannulation
processes as two complementary synthetic entries to 3-substituted
furopyridones.2 These one-pot transformations have been demon-
strated to proceed via cationic cyclisation with subsequent in situ
cleavage of the pyridonyl alkyl ether via nucleophilic displacement
by a halide anion (Scheme 1).
R2
E-X
OP
O
OP
E
E
- P-X
R2
R2
O
O
N
R1
N
R1
N
R1
O
X
II
I
Isolable
intermediates
P = Me, Bn
E-X = I2, organopalladium halide
Scheme 1.
In an effort to broaden the scope of this class of reactions, we set
out to develop an alternative cyclisation process that may provide
access to the analogous 3-unsubstituted furan derivatives (II with
E = H), and have therefore turned our attention to the possible use
of Brønsted acids as possible promoters of the electrophilic cyclisa-
tion/dealkylation reactions.3
Preliminary experiments conducted with 2-pyridone 1a as
model substrate indicated that acetic acid would effectively pro-
mote the desired transformation when used as solvent at refluxing
temperature. It was also confirmed that the cyclisation process
would generate 4-alkoxypyridinium salts as cationic intermediates
and that benzyl, as the 4-oxy-2-pyridone protecting group, would
show better acid lability compared to methyl, and would therefore
ensure efficient collapse of the pyridiniums to the desired pyri-
dones. Indeed, when stirred in refluxing AcOH for 5 h, 4-meth-
oxy-2-pyridone 1a was totally converted to a cyclisation product
leaving the methoxy group untouched, the structure of which
was tentatively assigned to furopyridinium 2a (Scheme 2).4 Pleas-
ingly, demethylation of 2a could be observed when heating was
prolonged. However, the process proved sluggish providing the de-
sired furopyridone 3a in only 35% isolated yield (50% conversion
from 2a) after 36 h reaction time.5 In contrast, 4-benzyloxypyri-
done 1b was found to undergo much faster cyclisation–dealkyla-
tion compared to 1a as only 3 h was needed to achieve 70% yield
of 3a.
Although the spectroscopic data supported the formation of
furo[2,3-b]pyridin-4(7H)-one 3a, the structure was unambiguously
secured by an X-ray crystal structure analysis (Fig. 1).6
* Corresponding authors. Tel.: +33 0472431416; fax: +33 0472431214 (G.B.).
E-mail addresses: monteiro@univ-lyon1.fr (N. Monteiro), balme@univ-lyon1.fr
(G. Balme).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.073

E. Bossharth et al. / Tetrahedron Letters 50 (2009) 614–616
615
O
Table 1 (continued)
OMe
OR
N
Ph
2-Pyridone
Product
Yieldb (%)
Ph
Ph
O
O
OBn
O
N
N
O
(AcO
)
52
O
N
Bn
3a
2a
1a R = Me
1b R = Bn
N
Bn
O
3e
1g
Scheme 2.
O
OMe
N
77
O
N
O
3f
1h
a
Reactions performed overnight in refluxing AcOH ensuring complete
conversion.
b
c
Isolated yields (single runs).
Yield determined after 3 h reaction time (see text).
OAc
Ph
O
O
Ph
O
H
R2
Figure 1. ORTEP representation of 3a.
R2
R2
O
O
N
R1
O
N
R1
N
R1
Table 1
Reaction of 3-alkynyl-2-pyridones in AcOHa
A
B
2-Pyridone
Product
Yieldb (%)
Scheme 3.
O
OBn
The generality of the cyclisation process was then explored with
70c
other N,O-dialkylated pyridones (Table 1). The results summarized
in Table 1 demonstrate that AcOH was efficient in most cases, and a
variety of 2-substituted furopyridones were obtained under the
standard reaction conditions.7 Interestingly, aryl- as well as al-
kyl-substituted acetylenes participated equally well in the cyclisa-
tion process. However, trimethylsilyl acetylenic compound 1f
showed a different behaviour, furnishing 3-acetyl-2-pyridone 48
as the only reaction product (65% isolated yield) upon concomitant
desilylation and regioselective hydration of the alkyne. It is likely
that the trimethylsilyl group was initially cleaved from the alkyne,
which then underwent acidic hydrolysis to the corresponding
3-acetylpyridone.9,10 We also examined the cyclisation of the ben-
zo-homologated substrate 1h11 that might open access to analo-
gous derivatives of the linearly fused furoquinoline alkaloids.12
To our satisfaction, 1h afforded the desired furoquinolinone 3f12c
under identical reaction conditions in a good 77% isolated yield.
A plausible mechanism for the cyclisation–debenzylation pro-
cess is depicted in Scheme 3. The alkynylpyridone is activated by
AcOH (intermediate A) and undergoes intramolecular nucleophilic
attack by the carbonyl oxygen of the amide group to form the furo-
pyridinium intermediate B. The latter would undergo cleavage of
the O-benzyl group by action of the counteranion resulting in the
formation of the neutral furopyridone.
O
N
N
O
3a
1b
CO2Me
O
N
OBn
CO2Me
45
O
N
O
3b
1c
OMe
OMe
OMe
O
N
OMe
OMe
OMe
OBn
56
O
N
O
3c
1d
OBn
O
N
63
O
N
O
In conclusion, we have enlarged the scope of our electrophilic
heteroannulation processes of N-alkylated-3-alkynyl-2-pyridones
to include access to 3-unsubstituted furo[2,3-b]pyridin-4(7H)-
ones. The procedure is very simple only requiring heating of the
2-pyridones in acetic acid in the absence of any catalyst.
3d
1e
OBn
SiMe3
OBn
O
O
Acknowledgements
65
N
O
N
This research was assisted financially by a Grant to E.B. from
Bayer CropScience and the Centre National de la Recherche
1f
4

616
E. Bossharth et al. / Tetrahedron Letters 50 (2009) 614–616
7. Representative procedure for AcOH-promoted cyclisation–debenzylation
reactions: solution of acetylenic pyridone 1b (225 mg, 0.68 mmol) in
Scientifique. We thank Dr. E. Jeanneau (Centre de Diffractométrie
Henri Longchambon, Université Lyon 1) for the X-ray crystallo-
graphic analysis, and Dr. D. Bouchu for mass spectroscopic analysis.
A
glacial acetic acid (4 mL) was refluxed for 3 h. The solvent was then removed
in vacuo, and the residue was subjected to column chromatography (SiO2,
acetone) to afford 107 mg (70% yield) of 7-methyl-2-phenylfuro[2,3-b]pyridin-
4(7H)-one (3a) as a solid: mp 170 °C (dec.). 1H NMR (300 MHz, CD3OD): 3.84 (s,
3H), 6.21 (d, J = 7.3 Hz, 1H), 7.09 (s, 1H), 7.25–7.35 (m, 3H), 7.51 (d, J = 7.3 Hz,
1H), 7.60–7.65 (m, 2H). 13C NMR (75 MHz, CD3OD): 36.6, 100.5, 113.1, 114.2,
124.1, 128.8, 129.0, 137.5, 151.9, 154.4, 175.7. HRMS (ESI): MH+, 226.0867;
calcd for C14H11NO2: 226.0868.
References and notes
1. Michael, J. P. Nat. Prod. Rep. 2005, 22, 627. and previous reports cited therein.
2. (a) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett. 2003, 5, 2441;
(b) Aillaud, I.; Bossharth, E.; Conreaux, D.; Desbordes, P.; Monteiro, N.; Balme,
G. Org. Lett. 2006, 8, 1113.
3. For recent reports dealing with cyclisation/dealkylations of acetylenic
compounds in acidic media see: (a) Hellal, M.; Bourguignon, J.-J.; Bihel, F. J.-J.
Tetrahedron Lett. 2008, 49, 62; (b) Ermolat’ev, D. S.; Mehta, V. P.; Van der
Eycken, E. V. Synlett 2007, 3117; (c) LeBras, G.; Provot, O.; Peyrat, J.-F.; Alami,
M.; Brion, J.-D. Tetrahedron Lett. 2006, 47, 5497; For previous acid-promoted
syntheses of furopyridines, see: (d) VanSickle, A. P.; Rapoport, H. J. Org. Chem.
1990, 55, 895.
8. Selected data for 4: 1H NMR (300 MHz, CDCl3): 2.52 (s, 3H), 3.49 (s, 3H), 5.15 (s,
2H), 6.06 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.31–7.38 (m, 5H). 13C NMR
(75 MHz, CDCl3): 31.7, 37.2, 70.7, 95.5, 115.9, 126.9, 128.4, 128.8, 135.4, 164.4,
200.0 (C4 not observed). HRMS (CI): MH+, 258.1128; calcd for C15H16NO3:
258.1130.
9. The acid-induced desilylation of silylacetylenes has been documented: Siehl,
H.-U.; Kaufmann, F.-P.; Hori, K. J. Am. Chem. Soc. 1992, 114, 9343; For reviews
dealing with acid-promoted hydrations of alkynes, see: Beller, M.; Seayad, J.;
Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368; Olivi, N.; Thomas, E.;
Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synlett 2004, 2175. and references cited
therein.
10. The peculiar reactivity of TMS-substituted alkynylpyridones in acidic media
was previously observed in our laboratories, see for instance: Conreaux, D.;
Bossharth, E.; Monteiro, N.; Desbordes, P.; Vors, J.-P.; Balme, G. Org. Lett. 2007,
9, 271. It is interesting to note that when heated in boiling TFA, 1f underwent
concomitant O-debenzylation to afford the corresponding 3-acetyl-4-hydroxy-
2-pyridone 6 in 71% isolated yield. Selected data: mp: 82 °C; 1H NMR (300
MHz, CD3COCD3): 2.64 (s, 3H), 3.46 (s, 3H), 5.93 (d, J = 8.5 Hz, 1H), 7.83 (d, J =
8.5 Hz, 1H). 13C NMR (75 MHz, CD3COCD3): 31.9, 37.8, 100.1, 108.1, 147.3,
162.3, 177.9, 206.9. HRMS (CI): MH+, 168.0662; calcd for C8H10NO3: 168.0661.
4. Diagnostic data obtained on analytical sample of furopyridinium 2a collected
by column chromatography (neutral alumina, 5–50% ethanol–acetone): solid,
mp 165 °C (dec.). The NMR spectra did not exhibit signals ascribable to the
counteranion: 1H NMR (300 MHz, CD3OD): 4.33 (s, 3H), 4.40 (s, 3H), 7.46 (d,
J = 7.5 Hz, 1H), 7.50–7.60 (m, 3H), 7.68 (s, 1H), 7.95–8.05 (m, 2H), 8.56 (d,
J = 7.5 Hz, 1H). 13C NMR (75 MHz, CD3OD): 40.7, 59.8, 100.7, 106.7, 116.5 126.9,
129.1, 130.8, 132.2, 142.6, 157.0, 159.5, 167.8. HRMS (ESI): M+, 240.1023; calcd
for C15H14NO þ: 240.1025.
5. It is worthy o2f note that the use of TFA in lieu of AcOH allowed the cyclisation
process to take place at room temperature. However, selective cleavage of the
4-methoxy group proved problematic as decomposition of the resulting
furopyridinium salt occurred at higher temperatures. Isolation of 2-pyridone
5 as the major side product indicated that competitive cleavage of the furan
ring was taking place. For an application of this type of process to the synthesis
of quinolin-2-one alkaloids, see: Gaston, J. L.; Grundon, M. F. J. Chem. Soc., Perkin
Trans. 1 1989, 905.
OH
O
O
TFA
1f
reflux, 48 h
71%
N
OMe
Ph
6
O
N
O
11. Compound 1h was prepared from 4-methoxy-1-methylquinolin-2-one via
iodination (NIS/TFA:1/1, MeCN, rt, 90%), and subsequent Sonogashira coupling
5
of
the
resulting
3-iodo-4-methoxy-1-methylquinolin-2-one
with
phenylacetylene (see Ref. 2b).
6. Crystallographic data for compound 3a have been deposited with the
Cambridge Crystallographic Data Centre, No CCDC 684693. Copies of the data
can be obtained, free of charge, on application to CCDC (e-mail:
deposit@ccdc.cam.ac.uk).
12. (a) Pirrung, M. C.; Blume, F. J. Org. Chem. 1999, 64, 3642. and references cited
therein; (b) Boyd, D. R.; Sharma, N. D.; Barr, S. A.; Carroll, J. G.; Mackerracher,
D.; Malone, J. F. J. Chem. Soc., Perkin Trans. 1 2000, 3397; (c) Bar, G.; Parsons, A.
F.; Thomas, C. B. Tetrahedron 2001, 57, 4719.