Stereoselective intramolecular Diels-Alder reactions of 3-alkenyl(oxy)-2(1H)-pyrazinones

Article abstract of DOI:10.1016/S0040-4039(01)02188-8

Dichloropyrazinones are reacted with alkenolates or a Grignard reagent in order to tether a dienophilic side-chain at the 3-position. The compounds smoothly undergo intramolecular Diels-Alder reaction forming tricyclic ring systems. The reactions proceed

Full text of DOI:10.1016/S0040-4039(01)02188-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 447–449
Stereoselective intramolecular Diels–Alder reactions of
3-alkenyl(oxy)-2(1H)-pyrazinones
Wim M. De Borggraeve, Frederik J. R. Rombouts, Bie M. P. Verbist, Erik V. Van der Eycken and
Georges J. Hoornaert*
Laboratorium voor Organische Synthese, K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 24 October 2001; revised 15 November 2001; accepted 16 November 2001
Abstract—Dichloropyrazinones are reacted with alkenolates or a Grignard reagent in order to tether a dienophilic side-chain at
the 3-position. The compounds smoothly undergo intramolecular Diels–Alder reaction forming tricyclic ring systems. The
reactions proceed completely stereoselective yielding only endo adducts. In the case of the alkenylpyrazinone, the core skeleton of
the breviamides is obtained. © 2002 Elsevier Science Ltd. All rights reserved.
We previously reported on the intramolecular Diels–
Alder reaction of pyrazinones with an alkene tethered
via the 1-position (Fig. 1).1 These structures smoothly
underwent cycloaddition upon heating and (in contrast
with the intermolecular variant)2 showed a remarkable
regioselectivity. In a continuous effort to explore the
intramolecular Diels–Alder reaction of alkenyltethered
pyrazinone systems we now focused on the cycloaddi-
tion from the 3-position (Fig. 1).
Based on experience with intramolecular alkyne reac-
tions, introduction of the dienophilic side-chain in the
3-position of the pyrazinone system seemed to be most
viable via an oxygen atom.3 Indeed this strategy allows
variation of the dienophilic side-chain by choosing the
appropriate (commercially available) alkenol. The stereo-
chemistry of the adducts was carefully analyzed and
some calculations were done to gain a better insight
into the obtained stereochemistry of these tricyclic com-
pounds (endo/exo ratio of compounds formed).
R1
Pyrazinones 1a and 1b (Scheme 1) are easily synthesized
starting from the appropriate a-aminonitrile and oxalyl
chloride.4 The dienophilic side-chain is introduced by
reacting the imidoyl chloride moiety of the pyrazinones
1 with the suitable deprotonated alkenol (2 equiv.) in
THF under reflux conditions (Scheme 1, Table 1).
Upon completion of the reaction (TLC monitoring),
the solvent is evaporated and the crude oil is dissolved
R6
Cl
R6
R3 Cl
N
N
O
N
O
X
N
X=O, CH2
Figure 1. Tethering via the 1- and 3-position of the pyrazi-
none.
Scheme 1. (a) Alkenol, NaH, THF, reflux; (b) chlorobenzene, reflux; (c) chloroform, air moisture.
Keywords: pyrazinone; cycloaddition; Diels–Alder reaction; brevianamide.
* Corresponding author. Tel.: ++32-16-327409; fax: ++32-16-327990; e-mail: georges.hoornaert@chem.kuleuven.ac.be
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02188-8

448
W. M. De Borggrae6e et al. / Tetrahedron Letters 43 (2002) 447–449
Table 1. Substitution of the 3-position of 1 with alkenolates and subsequent cycloaddition/hydrolysis
Starting compound 1
Alkenol
Substitution product 2 (yield in %)
Cycloadduct 4 (yield from 2 in %)
1a
1a
1b
1b
1b
3-Buten-1-ol
4-Penten-1-ol
3-Buten-1-ol
4-Penten-1-ol
2-Allylphenol
2a (69)
2b (78)
2c (65)
2d (82)
2e (79a)
4a (74)
4b (63)
4c (70)
4d (60)
4e (63)
a About 5% of cycloaddition product was also isolated.
in dichloromethane and washed with water. The
organic phase is dried (MgSO4) and evaporated.
Column chromatography (silica gel, CH2Cl2) yields the
compounds 2a–e as transparent viscous oils, which
slowly crystallize upon standing. They are subsequently
recrystallized from dichloromethane/hexane.5 In the
case of compound 2e, about 5% of cycloadduct 3e was
already formed under the reaction conditions used.
of these compounds proceed with comparable stereose-
lectivity, we would be able to synthesize analogs of
brevianamides10 (compare 6 in Scheme 2 with brevi-
anamide 5 in Fig. 3). The aliphatic tether was intro-
duced
by
reacting
pyrazinone
1a
with
pentenylmagnesium bromide (1.3 equiv.) in THF at
−78°C. Under these conditions the lactam moiety was
unaffected. Upon workup at −78°C (saturated NH4Cl
solution), extraction with CH2Cl2, subsequent drying
(MgSO4) and evaporation, TLC analysis and mass
spectral analysis of the crude mixture revealed the
presence of alkenylpyrazinone 2f, cycloadduct 6 (also
some of its unhydrolyzed imidoyl chloride precursor)
and some starting material: during workup, partial
cycloaddition had already occurred. In order to sim-
plify the purification, the cycloaddition was driven to
completion by refluxing the crude mixture in chloro-
form (open to the air to promote hydrolysis) for 12 h.
The hydrolyzed adduct 6 was purified by column chro-
matography (silica gel, gradient heptane/EtOAc (50/50)
−>EtOAc, yield: 52% from 1a (if the recovered starting
material is considered, the yield is increased to 84%)).
The higher reactivity of 2f compared to 2a–e (reflux in
CHCl3 instead or reflux in chlorobenzene) is consistent
with the results obtained above: when the azadiene is
substituted with a less electron donating substituent
(2-allylphenol) we also isolate about 5% of cycloadduct
(reflux in THF). Product 6 also displayed the same endo
selectivity as the products mentioned above (proven by
1H NMR spectroscopy and NOESY experiments).
Intramolecular cycloaddition reaction proceeded in 1–2
days by heating the alkenyloxypyrazinones 2a–e under
reflux conditions in chlorobenzene (Scheme 1, Table 1).
The imidoyl chlorides 3a–e are converted into the more
stable bislactams 4a–e upon stirring in CHCl3 open to
the air. Column chromatography (silica gel, EtOAc)
provides the pure tricyclic compounds 4a–e in good
yields.6
As mentioned in the introduction, the stereochemistry
of the products formed was to be examined (endo/exo
ratio). To our surprise, 1H NMR analysis of the
purified cycloadducts revealed only the presence of the
endo compounds.7 The characteristic coupling constants
observed for these bridged adducts are presented in Fig.
2.8 Also, in the spectrum of the crude hydrolysates, no
traces of the exo products were detected. In order to
account for these results, we performed semi-empirical
calculations (PM3) on compounds 3a–e. Transition
state structures9 were computed for both endo and exo
forms. In each case the energy of the endo transition
state is lower than the energy of the exo transition state.
This is probably due to sterical repulsions between the
tether and the lactam carbonyl in the exo mode of
attack. The lone pair on nitrogen apparently causes less
hindrance promoting the exclusive formation of the
endo adducts. The endo compounds are also somewhat
lower in energy than the exo compounds hence more
stable (PM3 calculations).
We can conclude that an alkenyl(oxy) substituent can
be introduced at the 3-position of the pyrazinone. The
subsequent intramolecular cycloaddition reactions are
completely stereoselective and allow the introduction of
five- and six-membered (substituted) rings annelated to
the bicyclic system. An increase in reactivity is observed
if the tether is less electron donating. Coupling via a
carbon atom provides us with a synthetic method for
brevianamide type compounds, a topic to be studied
further.
These results prompted us to introduce a dienophilic
tether via a carbon atom. Provided the cycloadditions
Acknowledgements
The authors thank the F.W.O., Vlaanderen (Fund for
Scientific Research, Flanders (Belgium)) for providing a
Research Grant and for financial support to the lab.
DWTC is gratefully acknowledged for the IUAP-4-11
funding. We are grateful to Professor W. Dehaen for
Figure 2. Relevant coupling constants observed in the 1H
NMR-spectrum of the cycloadducts (endo compound shown).

W. M. De Borggrae6e et al. / Tetrahedron Letters 43 (2002) 447–449
449
Scheme 2. (a) Pentenylmagnesiumbromide, THF, −78°C; (b) CHCl3, reflux (open to the air to promote hydrolysis).
H3C
CH3
HN
4. Vekemans, J.; Pollers-Wiee¨rs, C.; Hoornaert, G. J. Hete-
rocyclic Chem. 1983, 20, 919–923.
H
5. All compounds exhibit satisfactory spectral and analyti-
cal data. Rf values (CH2Cl2): 1a (0.21), 1b (0.23), 2a
(0.13), 2b (0.16), 2c (0.15), 2d (0.16), 2e (0.32).
O
NH
O
N
5 O
6. Spectral data for 8-benzyl-2-oxa-8,10-diaza-tricyclo-
[5.2.2.01,5] undecane-9,11-dione (4a) white crystals; mp
142°C; IR (KBr) cm−1: 1704 (CꢀO×2); 1H NMR (400
MHz, CDCl3) 7.30 (m, 5H, arom. H), 6.68 (br s, 1H,
NH), 4.92 (d, 1H, J=14.9 Hz, BnH), 4.38 (ddd, 1H,
J=9.0, 8.9, 1.6 Hz, H3), 4.30 (ddd, 1H, J=10.5, 8.9, 6.2
Hz, H3), 4.27 (d, 1H, J=14.9 Hz, BnH), 3.88 (ddd, 1H,
J=4.7, 2.4, 1.0 Hz, H7), 2.40 (m, 1H, H4), 2.24 (m, 1H,
H4), 1.89 (m, 2H, H5-H6), 1.55 (ddd, 1H, J=13.5, 6.1,
1.0 Hz, H6); 13C NMR (100 MHz, CDCl3) 169.6 (CO),
168.7 (CO), 136.1 (ipso-C), 128.9–128.1 (3×ArCH), 91.4
(C1), 73.0 (C3), 60.1 (C7), 48.3 (BnC), 43.3 (C5), 28.5
(C6), 26.1 (C4); m/z (%): 273 (MH+, 100). (NMR analysis
was carried out on a Bruker AMX 400; IR spectra were
recorded on a Perkin–Elmer 1600 FTIR Spectrometer).
7. In the endo adducts, the tether on the bridge is directed
towards the imidoyl chloride moiety formed in the
cycloaddition step.
8. A more elaborate discussion on the spectral analysis of
bicyclic pyrazinone adducts is presented in Ref. 2.
9. Transition states were generated using the transition state
search functionalities in the Spartan 5.1.3 package (PM3
calculations).
10. (a) Williams, R. M.; Sanz-Cervera, J. F.; Sanceno´n, F.;
Marco, J. A.; Halligan, K. M. Bioorg. Med. Chem. 1998,
6, 1233–1241; (b) Sanz-Cervera, J. F.; Williams, R. M.;
Marco, J. A.; Lo´pez-Sa´nchez, J. M.; Gonza´lez, F.; Mar-
t´ınez, M. E.; Sanceno´n, F. Tetrahedron 2000, 56, 6345–
6358 and references cited herein.
Figure 3. Brevianamide.
the use of the Spartan package. W.D.B. (Research
assistant of the FWO-Flanders) thanks the F.W.O. and
F.R. thanks the K.U. Leuven for the fellowships
received.
References
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M.; Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett.
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Loosen, P. K.; Luyten, I.; Toppet, S.; Compernolle, F.;
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Bull. Soc. Chim. Belg. 1994, 103, 185–186. Reactions with
N-nucleophiles, see: (b) Vandenberghe, S. M.; Buysens,
K. J.; Meerpoel, L.; Loosen, P. K.; Toppet, S. M.;
Hoornaert, G. J. J. Org. Chem. 1996, 304–308; (c) Tahri,
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K.; Van Meervelt, L.; Compernolle, F.; Hoornaert, G.
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