Practical one-pot syntheses of regioisomeric furan-fused pyridinones (and Quinolinones) from common precursors

Article abstract of DOI:10.1055/s-0029-1218692

3-Alkynyl-4-methoxypyridin-2(1H)-ones undergo cyclization via divergent pathways when heated in acetic acid or triethylamine as reagent-solvent under microwave irradiation to furnish selectively furo[2,3-b]pyridin-4-ones or their regioisomeric furo[3,2-c]

Full text of DOI:10.1055/s-0029-1218692

PRACTICAL SYNTHETIC PROCEDURES
1741
Practical One-Pot Syntheses of Regioisomeric Furan-Fused Pyridinones
(and Quinolinones) from Common Precursors
D
ivergent Synth
h
esis of
F
ura
n
-Fused
e
Pyridinon
r
e
s
ry Delaunay,a David Conreaux,a Emmanuel Bossharth,a Philippe Desbordes,b Nuno Monteiro,*a
Geneviève Balme*a
a
ICBMS, Institut de Chimie et Biochimie Moléculaire et Supramoléculaire, CNRS UMR 5246, Université Lyon 1, ESCPE Lyon,
43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
Fax +33(4)72431214; E-mail: balme@univ-lyon1.fr; E-mail: monteiro@univ-lyon1.fr
Bayer Crop Science, 14/20 rue Baizet, BP9163, 69623 Lyon Cedex 09, France
b
PSP
Received 15 January 2010; revised 1 February 2010
No184
Abstract: 3-Alkynyl-4-methoxypyridin-2(1H)-ones undergo cyclization via divergent pathways when heated in acetic acid or triethyl-
amine as reagent–solvent under microwave irradiation to furnish selectively furo[2,3-b]pyridin-4-ones or their regioisomeric furo[3,2-c]py-
ridin-4-ones, respectively. The same strategy applies to the synthesis of furoquinolinones.
Key words: annulation, furan, alkyne, cross-coupling reaction, microwave irradiation
Ph
O
N
O
OMe
N
Ph
Et3N, DMF
AcOH
Ph
μW, 180 °C, 2 h
μW, 150 °C, 1 h
O
N
O
O
92%
63%
Bn
Bn
Bn
5a
procedure 1
1b
10
procedure 2
Scheme 1 Divergent access to regioisomeric furo[2,3-b]pyridin-4-ones and furo[3,2-c]pyridin-4-ones from 3-alkynyl-4-methoxypyridin-2-
ones
Introduction
attack of the alkyne by the carbonyl oxygen of the amide
group to form a furopyridinium intermediate A. The latter
The furopyridinone system is present in a wide range of undergoes cleavage of the O-methyl group by action of
biologically relevant synthetic targets as well as in natu- the associated counteranion resulting in the formation of a
rally occurring furoquinolinone alkaloids.1 In recent furo[2,3-b]pyridin-4-one II. On the other hand (path b),
years, our group has demonstrated the synthetic value of triethylamine-induced SN2-type deprotection of the meth-
diversely halogenated 4-alkoxypyridin-2-one scaffolds as oxy oxygen atom unmasks a delocalized b-ketoenolate B
precursors of differently fused furopyridinones via acetyl- that undergoes regioselective anionic cycloisomerization
ide cross-coupling reactions followed by heteroannula- to furnish, upon hydrolysis, the regioisomeric furo[3,2-
tions.2–6 Herein, we wish to disclose practical, one-step c]pyridin-4-one III.
procedures that allow selective access to regioisomeric fu-
ropyridinones of type II and III from common 3-alkynyl-
4-methoxypyridin-2-one precursors I (Schemes 1 and 2).
The procedures may also be applied to the synthesis of
linearly or angularly fused furoquinolinones.
Scope and Limitations
3-Alkynylpyridin-2-ones 1 and 2 and related quinolin-2-
ones 3 (Figure 1) are easily prepared from the correspond-
ing iodo precursors using classical Sonogashira cross-
coupling procedures.2–5 Efficient and reliable protocols
are also available to iodinate C3 of 4-alkoxypyridin-2-
ones and 4-alkoxyquinolin-2-ones on a large scale and in
high yields using N-iodosuccinimide.2,4 Introduction of an
aryl moiety at C5 of the pyridin-2-one nucleus may be
achieved by regioselective Suzuki cross-coupling reac-
tions of 3,5-diiodopyridin-2-ones with arylboronic acids.7
Our strategy takes advantage of the presence of two po-
tential nucleophilic oxygen centers in the 4-oxypyridin-2-
one system that can be amenable to addition onto the
alkyne in a selective manner to form a furan ring. Hence,
by varying the reagents and reaction conditions, two dis-
tinct mechanistic pathways may arise. On the one hand
(path a), the presence of an electrophilic species such as
acetic acid, capable of activating the triple bond, triggers
SYNTHESIS 2010, No. 10, pp 1741–1744
x
x.
x
x
.
2
0
1
0
Advanced online publication: 09.03.2010
DOI: 10.1055/s-0029-1218692; Art ID: Z00510SS
© Georg Thieme Verlag Stuttgart · New York

1742
T. Delaunay et al.
PRACTICAL SYNTHETIC PROCEDURES
In an effort to widen the substrate scope of our tandem cy-
clization/dealkylation process to include 4-methoxypyri-
din-2-ones, we envisaged the possibility of accelerating
demethylation of furopyridiniums 4 by performing the re-
actions under microwave irradiation. Hence, as illustrated
with the syntheses of furopyridinones 5a and 7a (Table 1),
simple microwave heating (150 °C, 1 h) of 3-alkynyl-4-
methoxypyridin-2-ones in acetic acid allowed rapid pro-
duction of the desired compounds in good yields (92%
and 80%, respectively) after simple removal of the vola-
tiles in vacuo and chromatographic purification. The same
procedure applied nicely to the synthesis of the linearly
fused furoquinolinone 8 in quantitative yield.9
OMe
R4
R1
(path a)
(path b)
Et3N
+
AcOH
R2
Et3NMe
N
R3
O
O–
R4
OMe
R1
R2
H
+
I
R1
R2
R4
AcO–
O
N
R3
O
N
R3
B
anionic
cyclization
electrophilic
cyclization
R4
OMe
O
–
R1
R1
+
Et3NMe
R4
+
N
O
R2
N
R3
O
R2
OMe
R3
A
AcO–
R1 = Me
H2O
R4
R3
(1)
Et3NMe,OH
AcOMe
N+
R2
O
O
O
AcO–
R1
R2
R1
4
R4
R2 = Me; R3 = Ph; ca. 80%
O
R2
N
R3 II
N
R3
O
OR1
R3
AcOH
O
III
R
1 = Bn
45–70%
Scheme 2 Two possible cyclization pathways leading to regioiso-
R3
(2)
reflux
overnight
meric furan-fused pyridinones
O
N
R2
N
R2
1
O
5
OR1
R3
OR1
R3
OR1
R3
R2 = Me, Bn
3 = Ph, 3,4,5-(MeO)3C6H2,
Ar
R
4-MeO2CC6H4, n-Bu
N
R2
2
O
N
R2
1
O
N
R2
3
O
OR1
O
R1, R2 = Me, Bn
R
3 = SiMe3
(3)
N
R2
O
Figure 1 Various alkyne substrates for heteroannulations
6
R1 = Bn; R2 = Me; 65%
Procedure 1: Tandem electrophilic heteroannulation/
dealkylation
Scheme 3 Acetic acid promoted cyclization of alkynylpyridinones
under conventional heating
4-Alkoxy-3-alkynylpyridin-2-ones 1 have been shown to
undergo electrophilic heteroannulation in refluxing acetic
acid under conventional heating.4 When 4-methoxypyri-
din-2-ones were involved, the cyclization reaction led to
the formation of relatively stable furopyridiniums 4 that
did not undergo facile demethylation under the reaction
conditions to deliver the desired furo[2,3-b]pyridin-4-
ones [Scheme 3 (1)]. In contrast, 4-(benzyloxy)pyridin-2-
ones were found to undergo clean cyclization/dealkyla-
tion due to the better acid lability of the benzyl protecting
group with respect to methyl. Thus, a variety of 2-substi-
tuted furopyridinones 5 could be obtained under standard
reaction conditions. Aryl- as well as alkyl-substituted
acetylenes participated equally well in the cyclization pro-
cess [Scheme 3 (2)]. However, trimethylsilyl acetylenic
compounds showed different behavior, furnishing 3-
acetylpyridin-2-ones 6 as the sole reaction products upon
concomitant desilylation and regioselective hydration of
the alkyne8 [Scheme 3 (3)].
Procedure 2: Tandem dealkylation/anionic heteroannula-
tion
3-Alkynyl-5-aryl-4-methoxypyridin-2-ones 2, generated
under classical Sonogashira cross-coupling conditions
from the corresponding 3-iodopyridinones, have been
shown to suffer in situ triethylamine-induced demethyla-
tion and subsequent anionic cyclization to furo[3,2-c]py-
ridin-4-ones 9 when reaction times longer than normally
required were applied.5 After optimization, the process
was found to be effective for the synthesis of diversely
substituted furopyridin-2-ones in moderate to good yields
from both electron-rich and electron-poor arylpyridin-
ones. Besides, in addition to arylacetylenes, (trimethylsi-
lyl)acetylene took also part in the process [Scheme 4 (1)].
From a mechanistic point of view, it was demonstrated
that triethylamine, used as co-solvent, was the sole re-
agent responsible for the demethylation/heteroannulation
Synthesis 2010, No. 10, 1741–1744 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Divergent Synthesis of Furan-Fused Pyridinones
1743
R2
lacking the 5-aryl group was subjected to the same reac-
tion conditions [Scheme 4 (2)].10
O
OMe
Ar
We were concerned that the synthetic value of this chem-
ical transformation was limited by the inconvenience of
the long reaction times (5–6 days) needed to achieve ac-
ceptable yields of the desired compounds due to an ex-
ceedingly slow demethylation step. We therefore
envisaged the possibility that microwave irradiation may
again enhance this type of process significantly and possi-
bly extend its substrate scope. Indeed, complete conver-
sion of 5-arylpyridin-2-one 2b into the corresponding
furo[3,2-c]pyridin-4-one 9b was achieved in 90 minutes
reaction time in a mixture of triethylamine–acetonitrile
(2:1) under microwave irradiation (150 °C). After remov-
al of the volatiles in vacuo and chromatographic purifica-
tion, 9b was obtained in 62% isolated yield (Table 1). The
same reaction conditions applied to the preparation of the
linearly fused furoquinolinone 119 in nearly quantitative
yield. Interestingly, even 5-unsubstituted pyridin-2-one
1b reacted by this procedure to give furopyridinone 10
(63% yield), albeit a higher temperature (DMF, 180 °C)
and longer reaction time were required.
Ar
I
R2
(1)
[ 2 ]
PdCl2(PPh3)2 (10 mol%)
CuI (20 mol%)
Et3N, DMF, 80 °C, 6 days
N
R1
O
N
R1
O
37–75%
9
R1 = Me, Bn
R2 = Ph, 4-MeOC6H4, 4-MeO2CC6H4, SiMe3
Ar = Ph, 4-MeOC6H4, 4-MeO2CC6H4
Ph
O
OMe
Ph
R
Et3N, MeCN
R
(2)
80 °C, 6 days
N
O
N
O
Me
Me
1a R = H
R = H; not observed
R = 4-MeOC6H4, 67% (9a)
2a R = 4-MeOC6H4
Scheme 4 Triethylamine-promoted cyclization of alkynylpyridin-
ones under conventional heating
of 3-alkynyl-4-methoxypyridin-2-ones 2. For example,
furopyridinone 9a was isolated in 67% yield upon simple
conventional heating (80 °C) of 3-alkynylpyridin-2-one
2a in a mixture of triethylamine–acetonitrile (2:1) as sol-
vent. Interestingly, the presence of an aryl group at the C5
position of the pyridinone nucleus was shown to have a
beneficial effect on the demethylation step. Indeed, no re-
action was observed when 3-alkynylpyridin-2-one 1a
In summary, we have shown that microwave irradiation of
3-alkynyl-4-methoxypyridin-2-ones allows access to ei-
ther furo[2,3-b]pyridin-4-ones or their regioisomeric fu-
ro[3,2-c]pyridin-4-ones depending on the solvent system
used (AcOH or Et3N/co-solvent, respectively), the same
strategy was applied to the synthesis of linearly and angu-
larly fused furoquinolinones. These metal-free procedures
Table 1 Acetic Acid versus Triethylamine-Promoted Heteroannulations under Microwave Irradiation
Entry Substrate
AcOH-Promoted annulations
Conditions Product
Et3N-Promoted annulations
Yielda Conditions Product
Yielda
(%)
(%)
Ph
O
OMe
Ph
O
Et3N–DMF,
mW, 180°C,
2 h
AcOH, mW,
150 °C, 1 h
Ph
1
92
63
O
N
N
O
N
O
Ph
Ph
Ph
1b
5a
10
Ph
O
MeO
MeO
MeO
OMe
Ph
O
O
Et3N–
AcOH, mW,
MeCN, mW,
150 °C,
1.5 h
Ph
2
80
99
62
96
150 °C, 1 h
O
N
O
N
N
Ph
Ph
Ph
Ph
2b
7a
9b
O
N
OMe
Ph
O
Et3N–
AcOH, mW,
150 °C, 1 h
MeCN, mW,
150 °C,
1.5 h
Ph
3
O
N
O
N
O
Me
Me
Me
8
3a
a Isolated yields.
11
Synthesis 2010, No. 10, 1741–1744 © Thieme Stuttgart · New York

1744
T. Delaunay et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS (CI): m/z [M + H]+ calcd for C20H16NO2: 302.1181; found:
302.1177.
are simple and inexpensive, only requiring off-the-shelf
reagent–solvents.
Experimental Section
Acknowledgment
Commercially available reagents and solvents were used as pur-
chased. 1H and 13C NMR were recorded in CDCl3 with the solvent
resonance as the internal standard. Yields refer to spectroscopically
(1H and 13C NMR) homogeneous materials. Chromatography was
performed using Acros silica gel, 35–70 mm, 60A. Melting points
are uncorrected.
This research was assisted financially by Bayer CropScience and
the Centre National de la Recherche Scientifique.
References
(1) (a) Schnute, M. E.; Brideau, R. J.; Collier, S. A.; Cudahy, M.
M.; Hopkins, T. A.; Knechtel, M. L.; Oien, N. L.; Sackett, R.
S.; Scott, A.; Stephan, M. L.; Wathen, M. W.; Wieber, J. L.
Bioorg. Med. Chem. Lett. 2008, 18, 3856. (b) Brookings,
D.; Davenport, R. J.; Davis, J.; Galvin, F. C. A.; Lloyd, S.;
Mack, S. R.; Owens, R.; Sabin, V.; Wynn, J. Bioorg. Med.
Chem. Lett. 2007, 17, 562. (c) Blanchard, J. E.; Elowe, N.
H.; Huitema, C.; Fortin, P. D.; Cechetto, J. D.; Eltis, L. D.;
Brown, E. D. Chem. Biol. 2004, 11, 1445. (d) Butenschoen,
I.; Moeller, K.; Haensel, W. J. Med. Chem. 2001, 44, 1249.
(e) Chang, G.-J.; Wu, M.-H.; Chen, W.-P.; Kuo, S.-C.; Su,
M.-J. Drug Dev. Res. 2000, 50, 170. (f) Huang, A.-C.; Lin,
T.-P.; Kuo, S.-C.; Wang, J.-P. J. Nat. Prod. 1995, 58, 117.
(g) Prankerd, R. J.; Stella, V. J. Int. J. Pharm. 1989, 52, 71.
(2) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org.
Lett. 2003, 5, 2441.
7-Benzyl-2-phenylfuro[2,3-b]pyridin-4(7H)-one (5a); Typical
Procedure
A soln of 1b (45 mg, 0.14 mmol) in glacial AcOH (1 mL) was added
to an appropriate small microwave process vial containing a mag-
netic stir bar. The vial was sealed with a Teflon septum and placed
into a Biotage InitiatorTM microwave cavity. After irradiation at 150
°C for 60 min and subsequent cooling of the vessel to 37 °C by the
unit, the mixture was concentrated in vacuo and the residue was pu-
rified by column chromatography (silica gel, EtOAc–EtOH, 95:5)
to give 5a (40 mg, 92%) as a solid; mp 127–132 °C. The synthesis
of 5a was also performed on a 1.5 mmol preparative scale (84% iso-
lated yield).
FT-IR (neat): 1639 cm–1 (C=O).
1H NMR (300 MHz): d = 5.31 (s, 2 H), 6.31 (d, J = 7.8 Hz, 1 H),
7.20–7.23 (m, 2 H), 7.30–7.35 (m, 3 H), 7.36–7.43 (m, 5 H), 7.64
(d, J = 7.3 Hz, 2 H).
13C NMR (75 MHz): d = 53.9, 101.8, 114.7, 115.4, 127.9, 128.6,
129.0, 129.1, 129.3, 129.4, 134.2, 134.6, 150.8, 153.5, 175.5.
HRMS (CI): m/z [M + H]+ calcd for C20H16NO2: 302.1181; found:
302.1184.
(3) Aillaud, I.; Bossharth, E.; Conreaux, D.; Desbordes, P.;
Monteiro, N.; Balme, G. Org. Lett. 2006, 8, 1113.
(4) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G.
Tetrahedron Lett. 2009, 50, 614.
(5) Conreaux, D.; Belot, S.; Desbordes, P.; Monteiro, N.;
Balme, G. J. Org. Chem. 2008, 73, 8619.
(6) Conreaux, D.; Delaunay, T.; Desbordes, P.; Monteiro, N.;
Balme, G. Tetrahedron Lett. 2009, 50, 614.
(7) Conreaux, D.; Bossharth, E.; Monteiro, N.; Desbordes, P.;
5-Benzyl-2-phenylfuro[3,2-c]pyridin-4(5H)-one (10); Typical
Procedure
A soln of 1b (45 mg, 0.14 mmol) in a mixture of DMF (1 mL) and
Et3N (2 mL) was added to an appropriate small microwave process
vial containing a magnetic stir bar. The vial was sealed with a
Teflon septum and placed into a Biotage InitiatorTM microwave cav-
ity. After irradiation at 180 °C for 120 min and subsequent cooling
of the vessel to 37 °C by the unit, the mixture was concentrated in
vacuo and the residue was purified by column chromatography (sil-
ica gel, EtOAc–cyclohexane, 20:80) to give 10 (27 mg, 63%) as a
solid; mp 165–170 °C. The synthesis of 10 was also performed on a
1.5 mmol preparative scale (58% isolated yield).
Vors, J.-P.; Balme, G. Org. Lett. 2007, 9, 271.
(8) For mechanistic insights into acid-induced desilylations of
silylacetylenes, see: Siehl, H.-U.; Kaufmann, F.-P.; Hori, K.
J. Am. Chem. Soc. 1992, 114, 9343.
(9) For a previous synthesis of this compound see: Bar, G.;
Parsons, A. F.; Thomas, C. B. Tetrahedron 2001, 57, 4719.
(10) It is likely that, due to steric congestion, the methoxy methyl
group in 2a is rotated out of the plane of the pyridinone ring
resulting in decreased stability to nucleophilic attack with
respect to 1a. This effect has often been invoked to explain
the high degree of selectivity observed in the cleavage of
polymethoxyarenes and is also expected to affect the rate of
demethylation of benzo-fused 4-methoxypyridin-2-ones
(quinolin-2-ones) like 3a. For leading references, see:
(a) Ahmad, R.; Saá, J. M.; Cava, M. P. J. Org. Chem. 1977,
42, 1228. (b) Jardon, P. W.; Vickery, E. H.; Pahler, L. F.;
Pourahmady, N.; Mains, G. J.; Eisenbraun, E. J. J. Org.
Chem. 1984, 49, 2130. (c) Carvalho, C. F.; Sargent, M. V.
Chem. Commun. 1984, 227.
FT-IR (neat): 1656 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 5.19 (s, 2 H), 6.50 (d, J = 9.0 Hz,
1 H), 7.29–7.12 (m, 8 H), 7.38–7.34 (m, 2 H), 7.69 (d, J = 8.8 Hz, 2
H).
13C NMR (100 MHz, CDCl3): d = 51.5, 96.3, 102.2, 118.5, 124.6,
128.0, 128.1, 128.6, 129.0, 129.9, 133.7, 137.0, 155.2, 159.0.
Synthesis 2010, No. 10, 1741–1744 © Thieme Stuttgart · New York