An efficient route to a 5,6-dihydropyrano[3,4-b]pyridin-8-one core in two steps from enaminolactones

Article abstract of DOI:10.1016/j.tetlet.2007.12.106

A convenient two step conversion of heterocyclic enaminolactones to heterocyclic fused 2-pyran-1-ones is reported. The use of this method can be applied to a wide variety of aromatic and heteroaromatic amines to give potentially biologically active compounds in good yields.

Full text of DOI:10.1016/j.tetlet.2007.12.106

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1301–1304
An efficient route to a 5,6-dihydropyrano[3,4-b]pyridin-8-one
core in two steps from enaminolactones
a
a
a
a
´
Cheikh Sall , Nicolas Desbois , Sandrine Paquelet , Jose R. Camacho ,
Jean Michel Chezal b, Jean-Claude Teulade b, Yves Blache c,*
a
ˆ
´
Laboratoire de Chimie Organique et The´rapeutique, EA 3660 Unite´ de Mole´cules d’Inte´ret Biologique, Faculte de Pharmacie,
7 boulevard Jeanne d’Arc, BP 89700, 21079 Dijon, France
b Laboratoire de Chimie Organique, Faculte´ de Pharmacie, UMR INSERM 484, 28 Place Henry Dunant, BP 38, 63001 Clermont-Ferrand, France
c
`
´ ´ ´
Laboratoire Mate´riaux a Finalite Specifique, UFR Sciences et Techniques, Universite du Sud Toulon-Var, BP 20132, 83957 La Garde Cedex, France
Received 13 November 2007; revised 17 December 2007; accepted 19 December 2007
Available online 25 December 2007
Abstract
A convenient two step conversion of heterocyclic enaminolactones to heterocyclic fused 2-pyran-1-ones is reported. The use of this
method can be applied to a wide variety of aromatic and heteroaromatic amines to give potentially biologically active compounds in
good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Pyrano[3,4-b]pyridine; Enaminolactone; Selenium dioxide
1. Introduction
fungus Cephalosporium sp. AL031 exhibited antibacterial
and fungicidal properties.2 In the field of discovery new
classes of analogs of natural compounds, the synthetic
aza-analogs pyrano[3,4-b]pyridine-8-one class of com-
pound 4 represent an interesting target but has been poorly
studied (Fig. 1).
Syntheses of the 3,4-dihydro-1H-2-benzopyran-1-one
framework have been extensively studied and is often
performed by means of coupling homophthalic acid
Heterocycles possessing an aromatic or a heterocyclic
fused 2-pyran-1-one system 1 represent interesting classes
of natural or synthetic compounds displaying a wide range
of biological properties. For example, mellein 2, an 8-
hydroxydihydroisocoumarin extracted from Aspergillus
ochraceus W. exhibited toxic and cytotoxic effects on rats1
and dihydroisocoumarin glucosides 3 extracted from the
sugar
O
O
O
O
OH
O
N
Ar
or
O
O
O
O
het
R
R
R
CH3
R2
1
2
3
4
Fig. 1.
*
Corresponding author. Tel.: +33 04 94 14 23 05.
E-mail address: blache@univ-tln.fr (Y. Blache).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.106

1302
C. Sall et al. / Tetrahedron Letters 49 (2008) 1301–1304
derivatives with acyl chlorides.3 However, this methodol-
ogy is difficult to apply to pyridines and related hetero-
cycles since such diacids are not easy to obtain from
heterocycles.
frequently used method for the preparation of the corre-
sponding carboxylic acid. KMnO4 in water5 or SeO2 in
pyridine6a,b were two classical methods used. In the case
of phenanthroline 6a, oxidation was firstly carried out by
direct reaction of compound 6a with SeO2 in pyridine
(Scheme 1). Under these conditions, the acid derivative 8
was not obtained, but lactone 7a was isolated in 75% yield.
Such lactone formation was previously observed in a single
case by Coffen and McEntee6c but no further applications
were found. Structure of the lactone ring was established
As a part of our program concerning the design of ana-
logs of natural compounds as new classes of antimalarial
compounds, we were previously interested in the chemistry
of diaza-analogs of phenanthrene.4 In this context, deriva-
tives of the 1,10-phenanthroline skeleton exhibited the best
antiplasmodial activities in vitro against the Nigerian
chloroquino-sensitive strain and the chloroquino-resistant
FcBi-Colombia and FcM29 strains. To get more informa-
tion on structure–activity relationships of such compounds,
we now wish to associate this framework with a fused
pyran-1-one ring. For this purpose, we needed an efficient
route to access functionalized pyrano-fused heterocycles.
In this context, we report here a simple and efficient two
step-methodology for the preparation of dihydro-
pyrano[3,4-b]pyridin-8-one (7) core from enaminolactones
5 (Fig. 2).
1
by H, 13C NMR and mass spectroscopy.7
This lactonization reaction can be simply explained by
the formation of the carboxylate salt in the presence of pyr-
idine, followed by intramolecular cyclization (Scheme 2).
To support this hypothesis, the reaction was investigated
with KMnO4 in acidic media to circumvent the formation
of the carboxylate salt, but under these conditions, the reac-
tion led only to a complex degradation mixture. Finally,
SeO2 oxydation was conducted in dioxane, and under these
conditions, only the corresponding aldehyde was found8 as
classically described for 1,10-phenanthroline ring.9
To explore the potential applications of this method, we
set out to generalize the protocol. A wide variety of com-
mercially aromatic compounds (except for 1-naphthyl-
amine achieved using 1-nitronaphthalene10) containing
amino groups were chosen as starting materials. The reac-
tions and results are summarized in Table 1. Treatment
of the different aminoaromatics 9a–h by a 1.2 equiv of
2. Results
The key step of the synthesis resides in the oxidation of
the methyl group of 64 to give a carboxylic acid which can
be further implicated in a nucleophilic substitution with the
chlorine atom of the chloroethyl chain. Such oxidation of
an alkyl group attached to a pyrido system was a
H
O
NC
H3
O
Ar
or
het
N
CH3
N
Ar
or
het
Ar
or
het
O
Cl
O
Cl
Cl
7
6
5
Fig. 2.
O
N
O
CH3
CO2H
Cl
Cl
N
N
N
N
N
Cl
Cl
Cl
8
6a
7a
Scheme 1. Reagent and condition: SeO2, pyridine, D.
O
N
O
N
N
CH 3
O
O
SeO2/pyridine
Cl
Cl
Cl
Cl
Cl
Scheme 2. Mechanism of the lactonization process.

C. Sall et al. / Tetrahedron Letters 49 (2008) 1301–1304
1303
Table 1
Access to 5,6 dihydropyrano[3,4-b]pyridin-8-one compounds 7a–h
O
H
N
N
CH3
Ar
or
Het
NH2
N
CH3
O
Ar
or
Het
Ar
or
Ar
or
O
iii
Cl
i
ii
Het
Het
Cl
Cl
6
7
5
O
9
Entry
Starting material
Yield (%)
Pyridine
Enaminone
Lactone
1
5a4a(64)
6a4a(55)
7a(75)
N
9a
NH2
NH2
2
3
5b13(65)
5c(65)
6b14(55)
6c15(55)
7b(75)
7c(76)
9b
NH2
H3CO
9c
NH2
4
5d(95)
6d(69)
7d(51)
N
9d
H2N
NH2
5
6
7
5e(98)
5f(40)
6e(42)
7e(54)
7f(55)
7g(60)
O
9e
6f16(62)
9f10
NH2
H2N
5g4a(72)
6g4a(75)
N
9g
NH2
8
5h4a(81)
6h4a(63)
7h(80)
N
9h
Reagents and conditions: (i) 2-acetylbutyrolactone, toluene, APTS, D; (ii) POCl3, D; (iii) dry pyridine, 3 equiv SeO2, D.
2-acetylbutyrolactone in refluxing toluene with a catalytic
amount of p-toluenesulfonic acid gave the corresponding
enaminolactones 5a–h in good yield.11 By treatment with
freshly distilled phosphorus oxychloride,12 these synthetic
intermediates underwent cyclizations and subsequent ring
and side chlorination to give compounds (6a–h). In the
case of 3-aminopyridine (entry 4) and 3-aminoquinoline
(entry 7), the cyclizations were regioselective on the C-4
positions leading exclusively to 6d and 6g, respectively,
while in the case of entry 5, a double condensation
occurred leading to the dimeric cyclic compound 6e.
Compounds 6a–h reacted with selenium dioxide and dry
pyridine under reflux conditions to afford cyclized
compounds 7a–h. Yields of lactonization are moderate to
good (51–80%).
In the particular case of aza cyclization with 2-amino-
pyridine we obtained pyridopyrimidinone compound 1017
(Scheme 3). Next, oxidation of the methyl group was per-
formed using conditions designed before. The cyclized
product 11 was isolated in moderate yield (44%).

1304
C. Sall et al. / Tetrahedron Letters 49 (2008) 1301–1304
(300 MHz, CDCl3) d 3.48 (t, 2H, J = 6 Hz), 4.72 (t, 2H, J = 6 Hz),
O
7.72 (dd, 1H, J = 4.5, 8 Hz), 8.02 (d, 1H, J = 9 Hz), 8.23 (d, 1H,
J = 9 Hz), 8.29 (d, 1H, J = 8 Hz), 9.27 (d, 1H, J = 4.5 Hz); 13C
(75 MHz, CDCl3) d 26.2, 66.3, 121.7, 124.2, 128.3, 128.6, 130.8, 132.2,
136.1, 141.2, 142.6, 145.8, 146.5, 151.6, 161.2; MS m/z 286 (M++2,
34), 284 (M+, 100). Anal. Calcd for C15H9N2O2Cl: C, 63.28; H, 3.18;
N, 9.84. Found: C, 63.31; H, 3.01; N, 9.79.
CH3
N
O
N
O
N
N
Cl
O
10 (95)
11 (44)
8. Mp 182–184 °C; 1H (300 MHz, CDCl3) d 3.83 (t, 2H, J = 7 Hz), 4.00
(t, 2H, J = 7 Hz), 7.74 (dd, 1H, J = 4, 8 Hz), 8.05 (d, 1H, J = 9 Hz),
8.33 (m, 2H), 9.29 (d, 1H, J = 4 Hz), 10.58 (s, 1H); 13C (75 MHz,
CDCl3) d 31.2, 42.5, 122.6, 124.2, 128.3, 128.8, 130.9, 131.3, 136.5,
145.2, 145.3, 145.6, 150.1, 151.6, 194.8. Anal. Calcd for
C15H10N2O2Cl2: C, 59.04; H, 3.30; N, 9.18. Found: C, 59.12; H,
3.21; N, 9.06.
Scheme 3. Lactonization with 2 aminopyridine. Reagent and condition:
SeO2, pyridine, D.
In conclusion, we have described a simple and efficient
route to polyfused 5,6-dihydropyrano[3,4-b]pyridin-8-one
in two steps from enaminone compounds. The wide variety
of starting aromatic and heterocyclic amines used in this
study indicates that this methodology can be useful in a
large range of synthetic applications.
9. De Cian, A.; DeLemos, E.; Mergny, J. L.; Teulade-Fichou, M. P.;
Monchaud, D. J. Am. Chem. Soc. 2007, 129, 1856–1857.
10. Zeynizadeh, B.; Setamdideh, D. Synth. Commun. 2006, 36, 2699–2704.
11. Typical procedure for obtaining aminoethylidene-4,5-dihydrofurone-2-
ones 5:4 A mixture of 2-acetyl-butyrolactone (1.23 g, 9.60 mmol) and
aminoaromatic (or heteroaromatic) compounds 9 (8.00 mmol), and a
catalytic amount of p-toluene sulfonic acid in toluene (25 mL), was
refluxed under nitrogen with a Dean Stark apparatus for 12 h. After
evaporation of solvent, water was added and the mixture was basified
(10%, Na2CO3) saturated with NaCl, and extracted with dichloro-
methane. Organic layers were washed with brine (50 mL), dried over
sodium sulfate and evaporated in vacuo. The remaining oils were
treated with ether, cooled, and the precipitate was filtered. Recrys-
tallization from ethanol gave pure product 5.
12. Typical procedure for POCl3 cyclization: Compound 5 (4.00 mmol)
was heated with phosphorus oxychloride (25 mL) until the end of
exothermic reaction (80–90 °C). The mixture was then refluxed for
3 h. Excess phosphorus oxychloride was removed, water was added
and the mixture was neutralized with a saturated solution of sodium
carbonate. After extraction with dichloromethane, the organic layers
were washed with brine (50 mL), then dried (Na2SO4). Solvent
evaporation gave a black oily product which was purified on a neutral
alumina and eluted with dichloromethane to afford compound 6.
13. Khosropour, A. R.; Khodaei, M. M.; Kookhazadeh, M. Tetrahedron
Lett. 2004, 45, 1725–1728.
References and notes
1. (a) Uchida, K.; Ishigami, K.; Watanabe, H.; Kitahara, T. Tetrahedron
2007, 63, 1281–1287; (b) Moore, J. H.; Davis, N. D.; Diener, U. L.
Appl. Microbiol. 1972, 1067–1072.
2. Bi, Y. B.; Bib, X. B.; Zhaoa, Q. R.; Chenc, Y. T.; Xiec, J. L. Helv.
Chim. Acta 2004, 84, 2890–2895.
3. Shafiq, Z.; Arfan, M.; Rama, N. H.; Hameed, S.; Abbas, G.; Hussain,
M. T. Turk. J. Chem. 2005, 29, 321–325.
4. (a) Yapi, A. D.; Mustofa, M.; Valentin, A.; Chavignon, O.; Teulade,
J. C.; Mallie, M.; Chapat, J. P.; Blache, Y. Chem. Pharm. Bull. 2000,
48, 1886–1889; (b) Yapi, A. D.; Valentin, A.; Chezal, J. M.;
Chavignon, O.; Chaillot, B.; Gerhardt, R.; Teulade, J. C.; Blache,
´
Y. Arch. Pharm. 2006, 339, 201–206; (c) Tapia, R. A.; Lopez, C.;
Morello, A.; Maya, J. D.; Valderrama, J. A. Synthesis 2005, 903–
907; (d) Badaway, E.; Kappe, T. Eur. J. Med. Chem. 1995, 30, 327–
332.
5. Wu, W. S.; Liu, S. X. Wuji Huaxue Xuebao 2003, 19, 1065–1072.
6. (a) Miao, R.; Zheng, Q. Y.; Chen, C. F.; Huang, Z. T. J. Org. Chem.
2005, 70, 7662–7671; (b) Zhichkin, P.; Cillo Beer, C. M.; Rennells, W.
M.; Fairfax, D. J. Synlett 2006, 3, 379–382; (c) Coffen, D. L.;
McEntee, T. E., Jr. Chem. Commun. 1971, 11, 539.
14. Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach, C. A.;
Parsons, M. E.; Price, C. A.; Reavill, D. R.; Wiggall, K. J. J. Med.
Chem. 1990, 33, 527–533.
15. Beck, P. H.; Brown, M. B.; Clark, D. E.; Coates, A.; Dyke, H. J.; Hu,
Y.; Londesbrough, D. J.; Mills, K.; Pallin, T. D.; Reid, G. P.;
Stoddart, G. WO 2007/054693, 2007.
16. Ozawa, T.; Nagaoka, S.; Matsui, M.; Mitani, M. Yakugaku Zasshi
1957, 77, 90–93.
7. Typical procedure for lactonization: A solution of 6a (0.69 mmol) and
SeO2 (0.23 g, 2.07 mmol) in dry pyridine (5 mL) was stirred at reflux
for 3 h. The hot reaction mixture was filtered, and the solvent was
evaporated to give the residue which was, after addition of a little
amount of water, extracted with CHCl3. The CHCl3 layer was dried
over Na2SO4 and concentrated in vacuo. The crude material was
purified by column chromatography through silica gel using dichloro-
methane/methanol (95:5; v/v) to give 7a: mp 238–240 °C; 1H
17. Kim, N. D.; Lee, J. H.; Lee, M. S.; Chang, Y. K.; Lee, G. S. WO
2004/035573, 2004.