Regio- and selective synthesis of 4,6-disubstituted-2-pyridones

Article abstract of DOI:10.1016/S0040-4039(03)01429-1

Palladium catalysed regio- and stereoselective annulation of allenyl stannanes by β-iodo vinylic amides gives good yields of the corresponding 2-pyridones. This annulation probably occurs via a Stille reaction/cyclisation sequence.

Full text of DOI:10.1016/S0040-4039(03)01429-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5791–5794
Regio- and selective synthesis of 4,6-disubstituted-2-pyridones
Khalil Cherry,a Mohamed Abarbri,a Jean-Luc Parrainb and Alain Ducheˆnea,*
aLaboratoire de Physicochimie des Interfaces et des Milieux Re´actionnels, Faculte´ des Sciences de Tours, Parc de Grandmont,
37200 Tours, France
bLaboratoire de Synthe`se Organique associe´ au CNRS (UMR 6009), Faculte´ des Sciences de Saint Je´roˆme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 19 May 2003; revised 6 June 2003; accepted 7 June 2003
Abstract—Palladium catalysed regio- and stereoselective annulation of allenyl stannanes by b-iodo vinylic amides gives good
yields of the corresponding 2-pyridones. This annulation probably occurs via a Stille reaction/cyclisation sequence.
© 2003 Elsevier Ltd. All rights reserved.
The synthesis of 2-pyridone derivatives is a continuing
area of interest due to the number of biologically active
molecules containing this moiety.1 Natural compounds
with this structure have emerged during the last ten
years as potent antitumor,2 antifungal,3 antiviral4 and
psychotherapeutic5 agents, along with a new antibiotic.6
Morever, pyridones are key intermediates in the synthe-
sis of the corresponding pyridines.7 They have been
prepared by numerous methods,8 e.g. oxidation of an
N-substituted pyridinium salt,9 and Knovenagel-type
reactions,10 such as cross-condensation of cyanoace-
toamide and b-dicarbonyl compounds with basic cata-
lysts or by the reaction of 2-pyrones with amides.
Despite this large number of existing methods for their
synthesis, new procedures are continuously being
developed.11
We have previously described the synthesis of dienes or
enynes bearing a carboxylic function from b-iodovinylic
Scheme 1.
Scheme 2. Reagents and conditions: (i) (COCl)2; (ii) R%NH2 (70–80%); (iii) Pd(OAc)2 (5% mol), PPh3 (10% mol), K2CO3 (3 equiv.),
n-Bu4NBr (2 equiv.), MeCN, 80°C, 3 h.
Keywords: 2-pyridones; tributylstannylallenes; palladium catalyst; coupling reactions.
* Corresponding author. Fax: +33-(0)2-4736-6960; e-mail: duchene@delphi.phys.univ-tours.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01429-1

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K. Cherry et al. / Tetrahedron Letters 44 (2003) 5791–5794
Table 1. Synthesis of a-pyridones

K. Cherry et al. / Tetrahedron Letters 44 (2003) 5791–5794
5793
acids and vinyltin or alkynylzinc reagents.12 We have
also reported the stereoselective one-pot synthesis of
a-pyrones under palladium complex catalysis by cou-
pling tributylstannylallenes with (Z)-iodovinylic acids.13
Our aim here was to prepare allenylsubstituted alkenoic
amides which we believed would exclusively undergo
6-endo mode cyclisation mediated by a palladium com-
plex (Scheme 1).
In conclusion, under palladium complex catalysis, b-
iodo-vinylic-a,b-unsaturated-N-protected amides react
selectively with tributylstannylallenes via heteroannula-
tion to provide diverse 2-pyridones in excellent yields.
Acknowledgements
We report here the one-pot synthesis of 4,6-disubsti-
tuted-2-pyridones 3a–j by cross-coupling of tributyl-
stannylallenes14 with (Z)-3-substituted-3-iodoprop-2-
enamides 2a–g obtained from (Z)-iodovinylic acids 1a–
e (Scheme 2).15
We thank the CNRS and MRT for providing financial
support, and the ‘Service d’analyse chimique du Vivant
de Tours’ for recording NMR and mass spectra.
References
As shown in Table 1, the reaction of tributylstannyl-
allenes with (Z)-3-substituted 3-iodopropenoic N-pro-
tected amides 2a–g under regio- and stereocontrol gave
good yields of 4,6-disubstituted-2-pyridones 3a–j. All
the experiments were run at 80°C in acetonitrile and in
the presence of potassium carbonate and tetra-
butylammonium bromide; they were catalysed by the
couple: palladium acetate (5% mol)/triphenylphos-
phine(10% mol), the most efficient catalyst in this
case.16 Using DMF as solvent and other palladium
catalysts, low yields of 2-pyridones were obtained. And
we obtained optically pure a-pyridones 3h–i from the
available optically active amines (entries 8 and 9). In all
cases the a-pyridones 3 were obtained without any trace
of hexa-2,4,5-trienamide or 2-pyrolone.
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A plausible mechanism for the heteroannulation reac-
tion is shown in Scheme 3. First a Stille mechanism
would yield 3-allenylprop-2-enamide by oxidative addi-
tion, transmetallation and reductive elimination. Cycli-
sation would then occur via a p-allyl intermediate; the
latter would subsequently provide a-pyridone and
regenerate the palladium catalyst.17
5. Kozikowski, A.; Campiani, G.; Sun, L.-Q.; Wang, S.;
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Beaudegnies, R. Tetrahedron 1999, 55, 3387; (i) Grosche,
P.; Ho¨ltzel, A.; Walk, T.; Trautwein, A.; Jung, G. Syn-
thesis, 1999, 1961; (j) Zhang, S.; Liebeskind, L. J. Org.
Chem. 1999, 64, 4042; (k) Alberola, A.; Calvo, L.; Ortega,
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M. Synthesis 2000, 273; (m) Paulvannan, K.; Chen, T. J.
Org. Chem. 2000, 65, 6160.
Scheme 3. Proposed mechanism for the formation of 2-pyri-
dones.

5794
K. Cherry et al. / Tetrahedron Letters 44 (2003) 5791–5794
12. (a) Ducheˆne, A.; Abarbri, M.; Parrain, J.-L.; Kitamura,
M.; Noyori, R. Synlett 1994, 524; (b) Abarbri, M.; Par-
rain, J.-L.; Ducheˆne, A. Tetrahedron Lett. 1995, 36, 2469;
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126.8, 128.4 (2C), 128.7 (2C), 133.2, 141.5, 153.7, 158.6;
+
’
MS (70 eV) m/z: 199 (M , 6), 91 (100), 65 (29), 39 (13).
1
3b: oily, IR: 3062, 3029, 2953, 2918, 1682, 1628, 1583; H
NMR (CDCl3, 200 MHz) l ppm: 1.95 (d, J=1.1 Hz,
3H), 2.1 (s, 3 H), 4.52 (s, 2H), 5.46 (q, J=1.1 Hz, 1H),
6.0 (s, 1H), 7.23–7.43 (m, 5H); 13C NMR (CDCl3, 50
MHz) l ppm: 19.6, 21.3, 50.4, 104.8, 114.6, 126.7, 128.4
(2C), 128.7 (2C), 141.7, 144, 154.4, 157.4; MS (70 eV)
13. Rousset, S.; Abarbri, M.; Thibonnet, J.; Ducheˆne, A.;
Parrain, J.-L. Chem. Commun. 2000, 1987.
14. Allenyltin reagents were prepared from 3-bromoprop-1-
yne, magnesium and tributyltin tin chloride under
lead(II) catalysis. See: Tanaka, H.; Abdul Hai, A.;
Ogawa, H.; Torii, S. Synlett 1993, 835.
+
’
m/z: 213 (M , 7), 91 (100), 65 (16), 43 (10), 39 (8). 3c:
Mp=97–99°C, IR (KBr): 3061, 3029, 2955, 2919, 1673,
1
1623, 1582, H NMR (CDCl3, 200 MHz) l ppm: 2.16 (s,
15. General procedure for the heteroannulation: Palladium
acetate (112 mg, 0.5 mmol), triphenylphosphine (263 mg,
1 mmol), n-tetrabutylammonium bromide (6.6 g, 20
mmol) and potassium carbonate (4.14 g, 30 mmol) were
successively added to a degassed solution of 3-substi-
tuted-3-iodoprop-2-enamide 2 (10 mmol) in anhydrous
acetonitrile (40 mL). The mixture was stirred at room
temperature for 10 min then allenylstannane (20 mmol)
was added. The reaction mixture was stirred and heated
at 80°C for 3 h. After conversion was complete (checked
by TLC), the reaction was quenched with aqueous
NH4Cl solution, extracted with dichloromethane and
dried over magnesium sulfate. After evaporation of the
solvents under reduced pressure, the oily mixture was
dissolved in the minimum amount of diethyl ether to
precipitate n-tet precipitate n-tetrabutylammonium bro-
mide. After filtration the solution was then treated with
ethyl acetate and a 0.5M solution of potassium fluoride
at 0°C for 30 min to precipitate the tributyltin iodide
formed. The resulting mixture was filtered through a
Celite path and, after usual treatments, the crude prod-
ucts were chromatographed on silica gel (petroleum
ether/triethylamine 99/1 followed by petroleum ether/
diethyl ether/triethylamine 80/19/1) to yield compounds
3a–j. 3a: oily, IR: 3062, 3029, 2955, 2922, 1675, 1624,
3H), 4.53 (s, 2H), 5.92 (s, 1H), 6.44 (s, 1H), 7.20–7.63 (m,
10H); 13C NMR (CDCl3, 50 MHz) l ppm: 20.0, 50.9,
101.7, 113.8, 126.4 (2C), 126.9, 128.5 (2C), 128.8 (2C),
129.3 (2C), 129.7, 137.15, 141.6, 144.6, 154.3, 158.4; MS
+
’
(70 eV) m/z: 275 (M , 20), 158 (14), 91 (100), 65 (23), 43
(13). 3d: oily; IR: 3065, 3025, 2969, 2924, 1682, 1622,
1582; 1H NMR (CDCl3, 200 MHz) l ppm: 1.13 (t, J=7.5
Hz, 3H), 2.11 (s, 3H), 2.25 (q, J=7.5 Hz, 2H), 4.53 (s,
2H), 5.48 (s, 1H), 6.02 (s, 1H), 7.24–7.45 (m, 5H); 13C
NMR (CDCl3, 50 MHz) l ppm: 12.5, 19.6, 28.1, 50.5,
103.8, 113.1, 126.7, 128.4 (2C), 128.7 (2C), 141.8, 149.5,
+
’
154.6, 157.4; MS (70 eV) m/z: 227 (M , 24), 121 (24), 91
(100), 65 (27), 39 (10). 3i: oily, [h]2D3=−26 (c 0.01 g/cm3,
CH2Cl2); IR: 3070, 2961, 2927, 1683, 1632, 1589; 1H
NMR (CDCl3, 200 MHz) l ppm: 0.82 (d, J=4.7 Hz,
3H), 0.86 (d, J=4.7 Hz, 3H), 1.00 (d, J=6.4 Hz, 3H),
1.48–1.65 (m, 1H), 1.83 (d, J=1.3 Hz, 3H), 1.97 (s, 3H),
3.41–3.54 (m, 1H), 5.30 (q, J=1 Hz, 1H), 5.83 (s, 1H);
13C NMR (CDCl3, 50 MHz) l ppm: 18.7, 19.5 (2C), 20.1,
21.1, 34.9, 55.8, 104.1, 114.7, 143.2, 152.4, 157; MS (70
+
’
eV) m/z: 193 (M , 3), 150 (52), 96 (34), 71 (24), 53 (14),
43 (100), 41 (23), 39 (15).
16. (a) Larock, R. C.; He, Y.; Leon, W.; Han, X.; Refvik, M.
D.; Zenner, M. J. J. Org. Chem. 1999, 63, 2154; (b)
Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999,
64, 8770.
17. Al-Masum, M.; Yamamoto, Y. J. Am. Chem. Soc. 1998,
120, 3809.
1
1573; H NMR (CDCl3, 200 MHz) l ppm: 2.13 (s, 3H),
4.53 (s, 2H), 5.56–5.60 (m, 1H), 6.2 (d, J=9.7 Hz, 1H),
6.59 (dd, J=9.7, 9.6 Hz, 1H), 7.25–7.45 (m, 5H); 13C
NMR (CDCl3, 50 MHz) l ppm: 19.8, 50.5, 101.4, 118.1,