Inverse-electron-demand Diels-Alder reactions of 4-aryl-2-pyrones with electron-rich dienophiles

Article abstract of DOI:10.1016/S0040-4039(00)01302-2

The Diels-Alder reaction of 4-aryl-pyrones with electron-rich dienophiles afforded substituted biaryl derivatives in most cases. At the minimal temperatures necessary for a measurable conversion of the starting pyrones, the bicyclic lactones, the primary products of the condensation, underwent cycloreversion by extruding carbon dioxide and then aromatised through further eliminations. In the case of the more active 4-aryl-6-chloro-pyrone, a formal substitution was observed instead of the expected cycloaddition with an active dienophile, while in its reaction with a Schiff-base the primary product of the cycloaddition was trapped through the formation of a new tetrahydropyridine derivative. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01302-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7583–7587
Inverse-electron-demand Diels–Alder reactions of
4-aryl-2-pyrones with electron-rich dienophiles
La´szlo´ Bala´zs,a Istva´n Ka´dasb,* and La´szlo´ To˜keb
aEGIS Pharmaceuticals Ltd., H-1475 Budapest, P.O.B. 100, Hungary
bResearch Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology,
Budapest University of Technology and Economics, H-1521 Budapest, P.O.B. 91, Hungary
Received 16 June 2000; accepted 28 July 2000
Abstract
The Diels–Alder reaction of 4-aryl-pyrones with electron-rich dienophiles afforded substituted biaryl
derivatives in most cases. At the minimal temperatures necessary for a measurable conversion of the
starting pyrones, the bicyclic lactones, the primary products of the condensation, underwent cyclorever-
sion by extruding carbon dioxide and then aromatised through further eliminations. In the case of the
more active 4-aryl-6-chloro-pyrone, a formal substitution was observed instead of the expected cycloaddi-
tion with an active dienophile, while in its reaction with a Schiff-base the primary product of the
cycloaddition was trapped through the formation of a new tetrahydropyridine derivative. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Diels–Alder reaction; 4-aryl-2-pyrones; biphenyls.
Lycoricidine (1) is a herbal growth regulator1 and an important representative of the
Amaryllidaceae alkaloids with a neutral character and also possesses significant antitumour
activity.2 Its challenging structure, especially the substitution and stereochemistry of the C-ring
has evoked considerable synthetic work.3 The Diels–Alder reaction of a-pyrones is an efficient
route to polysubstituted cyclohexenes without aromatic substituents, with excellent control of
relative and absolute stereochemistry.4–8 In our work this methodology was tried for the
construction of the C-ring of lycoricidine analogues. The structurally and stereochemically rich
bicyclic lactones, the primary products of the cycloaddition, were successfully isolated in several
cases despite their thermal lability even from reactions conducted above 100°C.6,7 Based on our
former experiences,9 the intermediates obtained by the opening of the lactone ring and the
necessary functional group transformations were expected to cyclise via a modified Bischler–
Napieralski reaction (Scheme 1).
* Corresponding author. Tel: (361)-463-1424; fax: (361)-463-3648; e-mail: kadas.oct@chem.bme.hu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01302-2

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Scheme 1.
As starting dienophiles 2,2-dimethyl-1,3-dioxole (5), vinylene carbonate (6), 1,1-
dimethoxyethylene (7) and ethoxyethylene (8) were selected corresponding to the substitution of
the target lycoricidine (1) and 3-deoxy-lycoricidine (2) molecules. Cycloaddition of these
electron-rich dienophiles to aryl-pyrones can be described using FMO theory as an inverse
electron-demand process in which the LUMO of the diene component is combined with the
HOMO of the dienophile10 (for the corresponding energy values of the reactants calculated by
the AM1 method see Table 1).
Table 1
Dienophile
EHOMO (eV)
ELUMO (eV)
Diene
EHOMO (eV)
ELUMO (eV)
5
6
7
8
−8.89
−10.33
−8.69
−9.35
1.12
0.02
1.70
1.50
3
4
−9.14
−9.22
−1.14
−1.32
The synthesis of 4-aryl-pyrone (3) was achieved by a route which also involved the prepara-
tion of the 6-chloro-derivative (4) with a more pronounced electron-poor character and
therefore higher reactivity (Scheme 2).
Scheme 2. (i) MeOH, H2SO4, rt, 24 h, 91%; (ii) NaOMe, CH2(COOMe)2, benzene, MeOH, THF, reflux, 8 h, 93%;
(iii) KOH, EtOH, reflux, 24 h, 69%; (iv) PCl5, chlorobenzene, rt, 3 h, 54%; (v) Zn, AcOH, 3 h, 89%
In order to minimise the chance of the decomposition of the primary adduct by cyclorever-
sion, the reactions were conducted at the lowest possible temperature at which considerable
conversion could be detected by HPLC, using the dienophile also as a solvent (except for 5). In
the case of 5, none of pyrones 3 and 4 were reactive enough to combine with the fairly labile
dienophile before its decomposition, allowing only the regeneration of starting compounds from
a tarry reaction mixture. At the same time the reaction of aryl-pyrone 3 with vinylene carbonate

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6 gave biphenyl derivative 12 as the only isolable product (in 80% yield after 10 days at 115°C
beside the regeneration of 60% of the starting pyrone) with the regioselective formation of the
para-hydroxy derivative following the extrusion of two moles of carbon dioxide from the primary
adduct. Under similar conditions the reaction of chloro-pyrone (4) resulted in slow decomposition.
In the case of both dienophiles 7 and 8 only aromatic products could be isolated from their reaction
mixture even after 10% conversion of the starting diene 3 (5 days at 60–70°C). The biphenyls were
generated by cycloreversion followed by ethanol elimination. Dienophile 7 yielded meta-substituted
derivative (13) due to the regioselectivity of the cycloaddition (Scheme 3).
Scheme 3. (i) Sealed tube, 6, 115°C, 10 days, 80% (based on recovered starting material); (ii) sealed tube, 7, 70°C, 5
days, 18%, or 90°C, 3 days, 75%; (iii) sealed tube, 8, 70°C, 10 days, 7%, or 120°C, 2 days, 55%
The course of the reaction of ethoxyethylene (8) and 6-chloropyrone (4) was similar. Surprisingly,
trisubstituted ethylene 15 was obtained in the reaction of 1,1-diethoxyethylene (7) and pyrone (4),
the formation of which can be explained by an attack of the electron-rich olefin on the
electron-deficient C-6 of the pyrone followed by HCl elimination. On the other hand cycloreversion
of the primary product could be averted in the hetero Diels–Alder cycloaddition of pyrone 4 with
an electron-rich olefin of another type, the Schiff-base 17, obtained from 4-methoxy-benzaldehyde
and methylamine. The initial lactone was ‘trapped’ by the methyl amine present in equilibrium
with the starting imine, affording the tetrahydropyridinyl carboxylic amide (18) following HCl
elimination. Thestereochemistryofcompound18wasestablishedbyNOEexperiments, theessential
observations being significant NOE enhancements between H2 and H6 (Scheme 4).
Scheme 4. (i) Sealed tube, 7, CH2Cl2, 50°C, 4 h, 68%; (ii) sealed tube, 8, 70°C, 10 days, 15%, or 120°C, 2 days, 85%;
(iii) sealed tube, 17, CH2Cl2, 110°C, 2 days, 25%

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Under thermal conditions, at temperatures necessary for a minimal conversion the Diels–
Alder reaction of 4-aryl-pyrones led to the formation of biaryl compounds. Our experiences
suggest that isolation of the initial bicyclic products would need lower temperatures and
necessarily higher pressures (5–20 kbar).11
Characterisation of compound 4: colourless crystals, mp 208–212°C. C12H7ClO4 (250.641)
requires: C, 57.51; H, 2.82; Cl, 14.14%. Found: C, 57.40; H, 2.78; Cl, 14.25%. IR (KBr), cm−1:
1
3420, 3086, 2970, 2796, 1722, 1611, 1524, 1505, 1437, 1408, 1263, 1086, 1038, 1028. H NMR
(200 MHz, CDCl3): 7.12 (dd, 1H, J=8.0, 1.8, H-6%), 7.02 (d, 1H, J=1.8, H-4%), 6.92 (d, 1H,
J=8.0, H-7%), 6.49 (d, 1H, J=1.4, H-3), 6.31 (d, 1H, J=1.4, H-5), 6.07 (s, 2H, H-2%).
Characterisation of compound 13: colourless oil. HRMS (C15H14O3) calcd 242.0943, found
1
242.0941 (M+). IR (film), cm−1: 2979, 2891, 1601, 1233, 1041. H NMR (400 MHz, CDCl3): 7.31
(t, 1H, J=7.9, H-5%), 7.09 (dt, 1H, J=7.9, 0.8, H-6%), 7.06 (m, 3H, H-4, H-6, H-2%) 6.88 (d, 1H,
J=7.7, H-7), 6.83 (dt, 1H, J=7.9, 1.5, H-4%), 6.00 (s, 2H, H-2), 4.09 (q, 2H, J=7.0, OCH2), 1.44
(t, 3H, J=7.0, CH3).
Characterisation of compound 15: pale brown crystals, mp 135–140°C. C18H18O6 (330.340)
requires: C, 65.45; H, 5.45%. Found: C, 65.22; H, 5.58%. IR (KBr), cm−1: 2978, 1695, 1628,
1
1587, 1512, 1452, 1378, 1347, 1317, 1243, 1076, 1033. H NMR (200 MHz, CDCl3): 7.12 (dd,
1H, J=8.1, 1.8, H-6%), 7.06 (d, 1H, J=1.8, H-4%), 6.88 (d, 1H, J=8.0, H-7%), 6.73 (d, 1H, J=1.5,
H-3), 6.03 (s, 2H, H-2%), 6.02 (d, 1H, J=1.5, H-5), 4.50 (s, 1H, CHꢀC), 4.27 (q, 2H, J=7.0,
CH2), 4.00 (q, 2H, J=7.0, CH2), 1.41 (t, 6H, J=7.0, 2×CH3).
Characterisation of compound 18: pale yellow crystals, mp: 132°C. C22H22N2O5 (394.152)
requires: C, 66.98; H, 5.63; N, 7.11%. Found: C, 66.75; H, 5.54; N, 7.20%. IR (KBr), cm−1: 3295,
1
2924, 2854, 1649, 1610, 1511, 1495, 1444, 1251, 1037. H NMR (400 MHz, CDCl3): 7.14 (d, 2H,
J=8.8, H-2%%, H-6%%), 6.89 (d, 1H, J=1.5, H-4%), 6.87 (dd, 1H, J=8.7, 1.5, H-6%), 6.84 (d, 2H,
J=8.8, H-3%%, H-5%%), 6.76 (d, 1H, J=8.7, H-7%), 6.50 (s, 1H, CHꢀC), 5.98 (s, 2H, H-2%), 5.82 (q,
1H, J=4.8, NH), 5.20 (s, 1H, H-6), 3.76 (s, 3H, OCH3), 3.68 (s, 1H, H-2), 3.00 (s, 3H, NCH3),
2.78 (d, 3H, J=4.8, NHꢁCH3).
Acknowledgements
The financial support of this work by the National Fund for Science and Research (OTKA
No. T2230) is gratefully acknowledged.
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