Diels-Alder cycloaddition of 5-aryl-2-pyrones

Article abstract of DOI:10.1016/S0040-4039(00)00744-9

Regio- and stereoselectivity of the Dieis-Alder cycloadditions of a range of 5-aryl-2-pyrones are reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00744-9

Tetrahedron Letters 41 (2000) 4955±4958
Diels±Alder cycloaddition of 5-aryl-2-pyrones
Kamyar Afarinkiaa,* and Jose Berna-Canovasb
aDepartment of Chemistry, King's College, The Strand, London WC2R 2LS, UK
bDepartamento de Quimica Organica, Universidad de Murcia, Campus de Espinardo, Murcia, Spain
Received 17 April 2000; accepted 4 May 2000
Abstract
Regio- and stereoselectivity of the Diels±Alder cycloadditions of a range of 5-aryl-2-pyrones are reported.
# 2000 Elsevier Science Ltd. All rights reserved.
Diels±Alder cycloaddition of 2-pyrones are widely investigated and are shown to be a useful
methodology for the synthesis of natural products.1 Since cycloadditions of unsubstituted 2-pyrone
itself are known to be barely selective, this methodology has commonly employed 2-pyrones with
strongly polar substituents to ensure regio- and stereoselectivity in cycloadditions.2 To date,
study of the cycloadditions of electronically `neutral' pyrones, which extend the scope of the
methodology as well as the range of natural products accessible, has been limited to those of 3-
and 5-bromo-2-pyrone. Interestingly, these two pyrones are more versatile than their `polar'
counterparts since, in addition to their cycloadditions with electronically biased alkenes being
highly regio- and stereoselective, they undergo cycloaddition with both electron rich and electron
de®cient alkenes.3 Here, we report on the regio- and stereoselectivity of the Diels±Alder
cycloadditions of 5-aryl-2-pyrones and conclude that they are equally versatile, ambident dienes.
We prepared a range of novel 5-aryl-2-pyrones by the palladium-catalysed coupling of 5-bromo-
2-pyrone with the corresponding arylboronic acid (Scheme 1).4,5
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00744-9

4956
Cycloadditions were carried out in a sealed tube at 100ꢀC with a slight excess of dienophile.6
The endo:exo ratios of the cycloadducts were determined by examination of the NMR spectra of
the crude product mixtures. Assignment of the endo/exo con®guration of cycloadducts was carried
out in accordance with empirical rules established in a previous publication.3c,d
The results are outlined in Table 1. As can be seen, good to excellent yields of cycloadducts are
obtained in these reactions. Cycloadditions with electronically biased alkene dienophiles can be
highly regio- and stereoselective, a€ording the 5-endo cycloadduct as the major product. On the other
hand, cycloadditions of weakly activated alkenes are non-stereoselective. All reactions are very
regioselective and except on two occasions no 6-endo cycloadduct is observable within the limits
of detection by NMR (>97:3).
Table 1
We conducted a number of competition experiments to compare the reactivity of 5-phenyl-2-
pyrone to that of 5-bromo-2-pyrone. These were conducted by exposing an equimolar mixture of
the two pyrones to dienophile (butylvinylether and methyl acrylate) and analysing the reaction at
intervals. By comparing the quantity of the respective cycloadducts obtained from each pyrone,
we concluded that the rate of cycloaddition of 5-phenyl-2-pyrone towards electron rich alkenes is
about half that of 5-bromo-2-pyrone. However, the rate of reactions of the two pyrones towards
electron de®cient alkenes were similar. Similarly, we found only slight di€erences in the rate of
cycloadditions of 5-aryl-2-pyrones bearing electron-de®cient, electron neutral and electron-rich
substituents on the aryl ring.
We can conclude that 5-phenyl-2-pyrone, as is the case with 5-bromo-2-pyrone, is signi®cantly
more reactive towards electron de®cient alkenes than towards electron rich alkenes; and that the
reactivity towards electron neutral alkenes is slightly lower than that towards electron rich alkenes.
Nevertheless, it is important to note that 5-aryl-2-pyrones are ambident dienes with excellent
regioselectivity and very good stereoselectivity in cycloadditions.

4957
Finally, we carried out the cycloaddition of two typical 5-aryl-2-pyrones with vicinally disub-
stituted dienophiles vinylene carbonate and ethyl crotonate (Scheme 2). The cycloadditions pro-
ceeded in excellent yield and stereoselectivity, and the pure endo cycloadducts were isolable in
both cases.
Scheme 2.
In summary, we have demonstrated that 5-aryl-2-pyrones undergo ecient and stereoselective
cycloadditions with a range of both electron rich and electron de®cient dienophiles.
Acknowledgements
We would like to thank the Direccion General de Ensenanza Superior e Investigacion Cientõ®ca
for support (J.B.-C.).
References
1. (a) Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc. 1986, 108, 7373±7377. (b) Posner, G. H.; Haces, A.;
Harrison, W.; Kinter, C. M. J. Org. Chem. 1987, 52, 4836±4841. (c) Jung, M. E.; Head, D. B. Bull. Soc. Chim. Fr.
1990, 127, 830±834. (d) Marko, I. E.; Seres, P.; Evens, G. R.; Swarbrick, T. M. Tetrahedron Lett. 1993, 34, 7305±
7308. (e) Marko, I. E.; Evens, G. R. Tetrahedron Lett. 1993, 34, 7309±7312.
2. Afarinkia, K.; Nelson, T. D.; Vinader, M. V.; Posner, G. H. Tetrahedron 1992, 48, 9111±9171.
3. (a) Posner, G. H.; Afarinkia, K.; Dai, H. Organic Synthesis 1995, 73, 231±239. (b) Posner, G. H.; Nelson, T. D.;
Kinter, C. M.; Afarinkia, K. Tetrahedron Lett. 1991, 32, 5295±5298. (c) Posner, G. H.; Afarinkia, K. Tetrahedron
Lett. 1992, 33, 7839±7843. (d) Afarinkia, K.; Daly, N. T.; Gomez-Farnos, S.; Joshi, S. Tetrahedron Lett. 1997, 38,
2369±2372.
4. For other examples of aryl coupling of 5-bromo-2-pyrone, see: (a) Liu, Z.; Meinwald, J. J. Org. Chem. 1996, 61,
6693±6699. (b) Danieli, B.; Lesma, G.; Martinelli, M.; Passarella, D.; Peretto, I.; Silvani, A. Tetrahedron 1998, 54,
14081±14088.

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5. Typical experimental procedure: A 50 mL two-necked round-bottomed ¯ask was charged with 5-bromo-2-pyrone
(0.200 g, 1.14 mol), tetrakis (triphenylphosphine)palladium (53 mg, 0.05 mmol) and toluene (27 ml). To this
vigorously stirred mixture were added phenylboronic acid (0.153 g, 1.25 mol) dissolved in a minimum amount of
95% ethanol (ca. 1 ml) and 2 M aqueous sodium carbonate solution (1.26 ml, 2.52 mmol). This reaction mixture
was heated for 7 hours at 75ꢀC under a nitrogen atmosphere. The cooled reaction mixture was stripped of solvent
and the black residue was extracted with dichloromethane (50 mL). The extracts were washed with saturated
sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed and the crude
product was puri®ed by ¯ash chromatography on silica gel eluting with ethyl acetate in petroleum ether (60±80ꢀC
bp fraction) (30% v/v). Removal of solvent from appropriate fractions a€orded the desired product as yellow
solid. Mp 68ꢀC; H NMR (CDCl3) ꢀ 6.45 (dd, J=9.6, 1.1 Hz, 1H, H-3), 7.44 (m, 5H, aromatic H), 7.64 (dd,
1
J=9.6, 2.6 Hz, 1H, H-4), 7.69 (dd, J=2.6, 1.1 Hz, 1H, H-6); 13C NMR (CDCl3) ꢀ 116.5 (d, C-3), 120.6 (s, C-5),
126.0 (d, aromatic C), 128.4 (d, aromatic C), 129.3 (d, aromatic C), 133.5 (s, aromatic C), 144.0 (d, C-4), 148.3 (d,
C-6), 161.2 (s, C-2); IR (Nujol) 1695 (CˆO), 1223, 1153, 1125, 844, 760 cm^1; MS m/e (EI) 172 (77, M+), 144 (40),
115 (100), 89 (16), 63 (20) and 44 (18); HRMS calcd for C11H8O2: 172.05245 (M+); found: 172.0524.
6. Typical experimental procedure: A sealed pressure tube (purchased from Aldrich Chemical Co. Cat No Z18,109-9)
was charged with 5-phenyl-2-pyrone (0.1 g, 0.57 mmol), methyl acrylate (1.0 mL), a few drops of dichloromethane,
a few crystals of butylated hydroxytoluene (BHT) and a small magnetic stirrer bar. The pressure tube was sealed
and then immersed in an oil bath maintained at 95ꢀC. After 5 days, the tube was cooled and the contents were
stripped of volatile materials to leave a brown gum. The crude sample was analysed by NMR prior to silica gel
chromatography using 20% v/v ethyl acetate in petroleum ether (60±80ꢀC bp fraction). Removal of solvent from
1
the appropriate fractions a€orded an inseparable mixture of the endo and exo cycloadducts as an oil; H NMR
(CDCl3) endo cycloadduct: ꢀ 2.17 (ddd, J=13.8, 4.0, 1.4 Hz, 1H, H-6endo), 2.59 (ddd, J=13.8, 9.9, 4.0 Hz, 1H, H-
6exo), 3.14 (ddd, J=9.5, 3.3, 2.7 Hz, 1H, H-5), 3.70 (s, 3H, CO2CH3), 4.01 (ddd, J=6.2, 2.7 Hz, 1H, H-5), 5.70 (m,
1H, H-1), 6.55 (dd, J=6.2, 2.4 Hz, 1H, H-8), 7.37 (m, 5H, aromatic H); exo cycloadduct: ꢀ 2.22 (m, 1H, H-6endo),
3.49 (ddd, J=9.4, 5.5, 3.9 Hz, 1H, H-6exo), 3.53 (s, 3H, CO2CH3), 3.65 (dd, J=6.6, 2.8 Hz, 1H, H-4), 3.73 (m, 1H,
H-5), 5.96 (m, 1H, H-1), 6.73 (dd, J=6.6, 2.8 Hz, 1H, H-8), 7.39 (m, 5H, aromatic H); 13C NMR (CDCl3) endo
cycloadduct: ꢀ 29.75 (t, C-6), 37.1 (d, C-5), 43.4 (d, C-4), 52.6 (q, CO2CH3), 76.1 (d, C-1), 122.2 (d, aromatic C),
125.3 (d, aromatic C), 128.8 (d, C-8), 129.0 (d, aromatic C), 133.9 (s, C-7), 145.0 (s, aromatic C), 171.9 (s, CO2Me),
172.5 (s, bridge CO2); exo cycloadduct: ꢀ 23.5 (t, C-6), 40.5 (d, C-5), 43.0 (d, C-4), 52.1 (q, CO2CH3), 76.1 (d, C-1),
122.3 (d, aromatic C), 125.1 (d, aromatic C), 128.6 (d, aromatic C), 128.8 (d, C-8), 134.0 (s, C-7), 145.0 (s,
aromatic C), 171.9 (s, CO2Me), 172.5 (s, bridge CO2); IR (Nujol) 1736 (CˆO), 1632 (CˆC), 1265, 1041, 951, 737
cm^1; MS m/e (EI) 258 (5, M+), 214 (13), 155 (58), 129 (45), 115 (11), 88 (51), 86 (92), 84 (100); HRMS calcd for
C15H14O4: 258.8920 (M+); found: 258.8925.