Intramolecular Diels-Alder reactions of N-alkenyl-2(1H)-pyrazinones: Generation of a novel type of cis-1,7-naphthyridine

Article abstract of DOI:10.1016/S0040-4039(01)01545-3

The intramolecular Diels-Alder reaction of three 1-(ω-alkenyl)-2(1H)-pyrazinones was investigated. Cycloaddition was shown to proceed for 1-(4-pentenyl)- and 1-(5-hexenyl)-2(1H)-pyrazinone 5a and 5b to give the corresponding tricyclic hydrolysed adducts 7

Full text of DOI:10.1016/S0040-4039(01)01545-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7397–7399
Intramolecular Diels–Alder reactions of
N-alkenyl-2(1H)-pyrazinones: generation of a novel type of
cis-1,7-naphthyridine
Frederik J. R. Rombouts, Wim De Borggraeve, Suzanne M. Toppet, Frans Compernolle and
Georges J. Hoornaert*
Laboratorium voor Organische Synthese, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 30 July 2001; revised 22 August 2001; accepted 23 August 2001
Abstract—The intramolecular Diels–Alder reaction of three 1-(v-alkenyl)-2(1H)-pyrazinones was investigated. Cycloaddition was
shown to proceed for 1-(4-pentenyl)- and 1-(5-hexenyl)-2(1H)-pyrazinone 5a and 5b to give the corresponding tricyclic hydrolysed
adducts 7a and 7b, but not for the 1-(3-butenyl) derivative 5c. In contrast to 7b, the more strained 7a underwent selective acidic
solvolysis of the tertiary lactam group to give methyl cis-8-oxo-6-phenyldecahydro[1,7]naphthyridine-6-carboxylate 8. An NMR
analysis of 8 is presented. © 2001 Elsevier Science Ltd. All rights reserved.
Upon the discovery of a short and highly flexible
synthesis for 2(1H)-pyrazinones,1 our research group
has focused on the use of these compounds in the
synthesis of alkaloid-like compounds of biological
interest. One important research area is the application
of Diels–Alder reactions to this cyclic azadiene system,
using both alkenes and alkynes as dienophiles. Until
now intramolecular [4+2] cycloadditions were described
only for alkynyl and alkenyl2 groups anchored in the
33- or 64-position. In this work we envisaged the intro-
duction of dienophilic groups at the 1-N-position. In
this respect, reactions of 1-N-alkynyl pyrazinones
seemed to be of little interest, since cycloreversion of
the highly strained bridged intermediate inevitably
would lead to preferential extrusion of the cyanate
group generating pyridines (alternative loss of ClCN
indeed would produce a pyrazinone retaining a bridge-
head double bond). On the other hand, cycloaddition
of N-alkenyl pyrazinones might lead to more stable
tricyclic adducts exhibiting a distorted amide function
(Scheme 1). This non-planar tertiary amide in turn
could be subject to selective solvolysis—in preference to
the non-strained secondary amide produced by hydroly-
sis of the imidoyl chloride—to generate the correspond-
ing cis-fused bicyclic ring system.
While different N-alkenyl side chains and pyrazinone
substituents are conceivable, we first wanted to investi-
gate the reaction of simple N-(v-alkenyl)-2(1H)-pyrazi-
nones 5 (Scheme 1, n=0–2). Among these, 5a (n=1)
was most promising on basis of the unique reactivity
expected for both the cycloaddition reaction and subse-
quent solvolysis. Indeed, a balance of entropy and
enthalpy factors should favour the formation of a
six-membered piperidine relative to an azepane (n=2)
or pyrrolidine (n=0) ring moiety as part of the tricyclic
ring system. At the same time this ring size still could
induce sufficient distortion of the tertiary amide to
permit easy solvolysis via protonation of the basic
N-atom.
As the NH- and N-alkenylpyrazinones are not directly
accessible via reaction of a-aminonitriles and oxalyl
chloride, the synthesis of 5a–c had to proceed via a
deprotection–coupling sequence starting from N-(p-
methoxybenzyl)pyrazinone 2 (Scheme 2).5 This was pre-
pared from 2-[N-(4-methoxybenzyl)amino]acetonitrile
(HCl salt)
1
according to the above-mentioned
n
R6
N
n
n
*
R6
Cl
N
O
HN
R6
O
*
O
R3
*
HN
N
R3
N
H
R3
CO2R
O
5
7
8
* Corresponding author. Tel.: +32-16-327409; fax: +32-16-327990;
e-mail: georges.hoornaert@chem.kuleuven.ac.be
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01545-3

7398
F. J. R. Rombouts et al. / Tetrahedron Letters 42 (2001) 7397–7399
PMB
1'
PMB
H
N
1
n
N
O
O
N
O
NH.HCl
a
c
d
(58%)
(88%)
CN
Cl
N
R3
Cl
N
Ph
Cl
Cl
N
Ph
4
2: R3=Cl
3: R3=Ph
4
5a: n=1 (72%)
5b: n=2 (79%)
5c: n=0 (83%)
1
b (78%)
e
n
n
n
HN
4
*
g
1
O
f
N
*
N
3
Ph
2
*
N
Ph
(98%)
(yields from 5)
O
HN
Ph
N
H
1
7
CO2Me
O
O
8 (n=1)
7a: n=1 (86%)
7b: n=2 (77%)
(7c: n=0)
6a: n=1
6b: n=2
(6c: n=0)
Scheme 2. (a) (COCl)2, Et3N·HCl, PhCl, rt, 2 days; (b) SnPh4, Pd(PPh3)4, toluene, 120°C, 7 days; (c) CF3CO2H, reflux, 5 h; (d)
BrCH2CH2(CH2)nCHꢀCH2 (n=0–2), Cs2CO3, dioxane, 50°C, 5 days; (e) PhBr, reflux, 1 night (5a) or 7 days (5b); (f) EtOAc satd
with H2O, rt, 1 night; (g) MeOH, CH3SO3H, reflux, 1 night; PMB=p-methoxybenzyl.
method.1,6 Subsequent Stille coupling using tetra-
phenyltin and Pd(PPh3)4 as a catalyst provided the
corresponding 3-phenyl derivative 3,4 which was N-
debenzylated by heating with trifluoroacetic acid. The
resulting compound 4 was converted to the desired
N-alkenylated pyrazinones 5 by heating with 5-bromo-
1-pentene (5a), 6-bromo-1-hexene (5b) or 4-bromo-1-
butene (5c) and Cs2CO3 in dioxane—the method of
choice to minimise concurrent O-alkenylation.7,8 N-
substitution could be verified by the absorption of the
H1%-protons and C1% in the NMR spectrum (CDCl3), for
example 5a: l 3.93 and 50.1 (N-alkenyl) versus l 4.35
and 66.8 (O-alkenyl).
An optimised computer model of the cycloadducts 7a–c
(MM+ force field)10 revealed that the energy content for
7a and 7b is similar, but increases dramatically for 7c.
In the latter case, the calculated OꢀCꢁNꢁCH2 bond
torsion of the tertiary amide strongly deviates from
planarity (−63°). However, a significant distortion was
also calculated for 7a and 7b (torsion angles −39 and
−15.5°, respectively), which should lead to a higher sp3
and basic character of the tertiary amide nitrogen. In
the 13C NMR spectrum of 7a (100 MHz, DMSO-d6),
this was confirmed by two distinct absorptions in the
carbonyl region corresponding to the secondary amide
(170.1 ppm) and the tertiary amide (178.5 ppm) display-
ing increased ketone character. A similar difference in
chemical shift values was not observed for the amide
carbon signals of 7b (171.1 and 171.8 ppm), indicating
near-planarity of the tertiary amide. As argued above,
the increased basic character implied for N-3 should
permit selective solvolysis. Indeed, almost quantitative
conversion (98%) of 7a into cis-1,7-naphthyridine 8 was
effected by refluxing for one night in methanol in the
presence of 2.5 equiv. of methanesulfonic acid. How-
ever, no solvolysis could be effected for 7b, even at
150°C in a steel bomb, in accordance with the less
strained character of the tertiary amide moiety.
Intramolecular cycloaddition of 5a was found to pro-
ceed in refluxing chlorobenzene (4 days) or bromoben-
zene (1 night). These conditions are rather harsh
compared to the intermolecular alkene additions,9
which can be accounted for by the distortion imposed
on the incipient tertiary amide function. The adduct 6a
easily underwent hydrolysis upon stirring in water-satu-
rated ethyl acetate to give bis-lactam 7a in good yield
(86% from 5a). A much slower cycloaddition reaction
was observed for 5b (7 days reflux in bromobenzene),
which similarly provided bis-lactam 7b upon hydrolysis
(77% from 5b). However, cycloaddition of 5c failed to
provide 6c even under severe conditions (250°C, steel
bomb). Fig. 1 shows the hydrolysed adducts with their
corresponding numbering.
Molecular modelling of the cis-fused bicyclic system 8
(AM1 geometry optimisation) revealed two minimum
energy conformations A and B, of which A was
favoured by ca. 3 kcal/mol (Fig. 2). To verify this, the
solution conformation of 8 was determined by NMR
spectroscopy. The results summarised in Table 1
confirm that 8 adopts conformation A, as shown by
6
7
6
8
7
5
H11
5
H11
'
H12
O
'
H4'
H12
9
relevant coupling constants, i.e. a
large 3J-trans
O
H4'
H4
N
2
O
9 N
2
O
8
3 H4
between H-4a and H-5ax and a small 3J-gauche
10
3
HN
10
HN
1
1
11
between H-4a and both H-4 protons.
Ph
Ph
7a
7b
In summary, we have used a flexible intramolecular
Diels–Alder strategy to generate two yet undescribed
tricyclic bis-lactams, of which the most strained one
Figure 1.

F. J. R. Rombouts et al. / Tetrahedron Letters 42 (2001) 7397–7399
7399
H5
H
H4a
H5
H
4a H4
H5eq
NH
N
H
H4
O
O
HN
H5ax
H
H4
O
H4
O
O
O
HN
B
A
Figure 2.
Table 1. Relevant couplings (Hz) for conformational analy-
sis of 8a
4. Buysens, K. J.; Vandenberghe, D. M.; Hoornaert, G. J.
Tetrahedron 1996, 52, 9161–9178.
5. Compound 5a: yellow oil, exact mass calculated for
C15H15ClN2O: 274.0873, found: 274.0873. Compound 5b:
yellow oil, exact mass calculated for C16H17ClN2O:
288.1029, found: 288.1026. Compound 5c: yellow crystals,
mp 50°C, exact mass calculated for C14H13ClN2O:
260.0716, found: 260.0710. Compound 7a: white crystals;
mp 285°C; IR (KBr) cm−1: 3194 (NH stretching), 1694
l
H
J4a,8a
J4a,5eq
J4a,5ax
J4a,4ax
J4a,4eq
3.17
2.93
1.43
1.22
2.02
1.81
8a
4
5ax
4ax
4eq
5eq
4a
10
5b
5b
6b
6b
3
3
1
(CO); H NMR (DMSO-d6, 400 MHz): 8.79 (s, 1H, H10),
4
10
7.44–7.38 (m, 5H, arom.-H), 3.91 (m, 1H, H8), 3.79 (dd,
J=13, 5 Hz, 1H, H4), 2.99 (dt, J=13, 3 Hz, H4%), 2.5
(hidden m, 2H, H11%+H7), 1.95 (dd, J=13, 2 Hz, 1H, H11),
1.93, 1.67 (m, 2H, H6), 1.59, 1.29 (m, 2H, H5); exact mass
calculated for C15H16N2O2: 256.1212, found: 256.1208.
a 400 MHz, CDCl3/C6D6 (50:50).
b Difference in ꢀJ upon homo-decoupling of H4a
.
Compound 7b: white crystals; mp 254°C; IR (KBr) cm−1
:
was subject to selective solvolysis of the tertiary amide
group furnishing a novel type of substituted cis-1,7-
naphthyridine. Further research will be directed
towards the conversion of 8 into compounds of biolog-
ical interest.
3205 (NH stretching), 1691 (CO), 1679 (CO); 1H NMR
(400 MHz, CDCl3): 7.42 (m, 5H, arom.-H), 6.18 (s, 1H,
H11), 4.20 (ddd, J=13, 12, 7 Hz, 1H, H4), 4.00 (m, 1H, H9),
3.03 (dd, J=13, 7 Hz, 1H, H4%), 2.71 (m, 1H, H8), 2.66 (dd,
J=12, 10 Hz, 1H, H12%), 1.94 (dd, J=12, 3 Hz, 1H, H12),
2.06, 1.92, 1.68, 1.22 (m, 6H, H5+H6+H7); exact mass
calculated for C16H18N2O2: 270.1368, found: 270.1371.
Acknowledgements
Compound 8: white crystals; mp 122°C; IR (KBr) cm−1
:
1746 (COOMe), 1664 (CO); 1H NMR (400 MHz, CDCl3):
7.45–7.31 (m, 5H, arom.-H), 6.85 (s, 1H, H7), 3.75 (s, 3H,
CH3), 3.31 (d, J=4 Hz, H8a), 2.98 (dd, J=14, 10 Hz, 1H,
H5ax), 2.88 (m, 1H, H2), 2.69 (ddd, J=11, 8, 3 Hz, 1H, H2),
2.39 (s, 1H, H1), 2.14 (dd, J=14, 3 Hz, 1H, H5eq), 1.94 (m,
1H, H4a), 1.67–1.33 (m, 4H, H3+H4); exact mass calculated
for C16H20N2O3: 288.1474, found: 288.1461 (NMR analy-
sis of all described compounds was carried out on a Bruker
AMX 400; IR spectra were recorded on a Perkin–Elmer
1600 FTIR Spectrometer; exact mass measurements were
run on a Kratos MS50TC instrument in the EI mode at
a resolution of 10,000).
The authors thank the FWO (Fund for Scientific
Research, Flanders, Belgium) and the IUAP-4-11 fund-
ing by DWTC. We are grateful to R. De Boer for
HRMS measurements and to Professor W. Dehaen for
the use of the Hyperchem™ package. F.R. thanks the
K.U. Leuven and W.D.B. (Research Assistant of the
FWO, Flanders) thanks the FWO for the fellowships
received.
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