Diels-Alder reactions of pyridinone o-quinodimethanes generated from substituted sulfolene[3,4-c]pyridin-4(1H)-ones

Article abstract of DOI:10.1016/S0040-4020(03)00826-3

1-Benzyl-3-(bromomethyl)-2(1H)-pyrazinone was converted to [3,4-c] sulfolene pyridinone 8a and further (1- or 3-) substituted derivatives having a dienophilic side chain on the sulfolene ring. Thermolytic extrusion of sulfur dioxide from o-QDM precursor 8

Full text of DOI:10.1016/S0040-4020(03)00826-3

Tetrahedron 59 (2003) 5481–5494
Diels–Alder reactions of pyridinone o-quinodimethanes
generated from substituted sulfolene[3,4-c]pyridin-4(1H)-ones
*
Tom C. Govaerts, Ilse A. Vogels, Frans Compernolle and Georges J. Hoornaert
Laboratorium voor Organische Synthese, Department of Chemistry, K. U. Leuven, Celestijnenlaan 200F, B3001 Leuven, Heverlee, Belgium
Received 18 April 2003; accepted 27 May 2003
Abstract—1-Benzyl-3-(bromomethyl)-2(1H)-pyrazinone was converted to [3,4-c] sulfolene pyridinone 8a and further (1- or 3-) substituted
derivatives having a dienophilic side chain on the sulfolene ring. Thermolytic extrusion of sulfur dioxide from o-QDM precursor 8 led to
generation of 3,4-dimethylene-2(1H)-pyrazinone 9, which was reacted in situ with various dienophiles. Thermolysis of the substituted
precursors resulted in intramolecular cycloaddition of the corresponding o-QDM intermediates q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Here we give a full account on the synthesis of variously
substituted 3,4-dimethylene-3,4-dihydro-2(1H)-pyridinone
o-QDM intermediates and their inter- and intramolecular
Diels–Alder reactions, providing access to several
unknown ring-fused pyridinones. Although monocyclic
pyridinone derivatives are well known for a wide range of
biological activities,5 saturated polycyclic analogues remain
largely unexplored.
In the last decade much interest has centred around
heteroaromatic o-quinodimethanes (o-QDM), which are
used mostly as diene components in Diels–Alder reactions.1
These reactive intermediates can be generated in situ by
various routes,2 amongst which thermal extrusion of SO2
from sulfolene-fused heterocyclic precursors constitutes the
most versatile method.3 As outlined in our previous
communication,4 we used the latter approach to generate
both 5,6-dimethylene-5,6-dihydro- and the isomeric 3,4-
dimethylene-3,4-dihydro-2(1H)-pyridinone o-QDM inter-
mediates from, respectively [3,4-b]-fused and [3,4-c]-fused
sulfolene pyridinone precursors. The two precursor types in
turn are accessible by intramolecular cycloaddition of either
6-[(2-propynylsulfanyl)methyl] or 3-[(2- propynylsulfanyl)-
methyl] substituted pyrazinones (Scheme 1).
2. Results and discussion
As indicated in our retrosynthetic analysis (Scheme 1), our
sequence starts with the preparation of a [3,4-c]-fused
sulfolene pyridinone as the o-QDM precursor. Subsequent
thermolysis affords the corresponding 3,4-dimethylene
o-QDM intermediate, which is trapped in situ by reaction
Scheme 1. Generation of 5,6- and 3,4-dimethylene dihydro-2(1H)-pyridinone o-QDM via extrusion of SO2 from sulfolene pyridinone precursors; these are
prepared by cycloaddition of 6- and 3-[(2-propynylsulfanyl)methyl] substituted pyrazinones.
Keywords: ortho-quinodimethane; pyridinone; Diels–Alder reaction.
*
Corresponding author. Tel.: þ32-16-32-74-09; fax: þ32-16-32-79-90; e-mail: georges.hoornaert@chem.kuleuven.ac.be
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00826-3

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T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
with various dienophiles. Next we describe regioselective
electrophilic substitutions of the precursor at either the more
or less acidic a-position of the sulfone group, which allows
for attachment of some dienophilic side chains. Finally we
examine the scope of the intramolecular Diels–Alder
reactions proceeding upon thermolysis of the 1- and
3-substituted precursors.
ethene, and the heterodienophiles p-toluenesulfonylcyanide
and N-(benzylidene)toluenesulfonamide. To this end a
solution of precursor 8a and dienophile (3 equiv.) in
ortho-dichlorobenzene (o-DCB) first was subjected to
three freeze-pump-thaw cycles, and then was heated at
1508C in a sealed glass tube to furnish the corresponding
adducts 10-19 (Scheme 4 and Table 1). The structure and
conformational behaviour of the reaction products was
1
2.1. Synthesis of the pyridinone ortho-quinodimethane
precursor
determined by H NMR analysis.
The cycloadduct 10 derived from the reaction with NPMA
can exist as two boat conformers A and B having an axial
and equatorial orientation of the maleimide ring (Fig. 1).
According to our synthetic plan, pyrazinones 1a,b were
subjected to Stille coupling using Sn(CH3)4 to introduce a
methyl group at the reactive 3-position.6 Subsequent
bromination of the 3-methyl derivatives 2a,b afforded
compounds 3a,b along with the dibrominated side product
(10%). Final substitution of bromides 3a,b with thiolacetic
acid furnished thioesters 4a,b in 80 % yield (Scheme 2).
1
However, from the H NMR spectral data of 10 it appears
that conformer A is the predominant form. The pre-
dominance of either A or B clearly follows from the
differentiation observed between the axial and equatorial
protons H-9ax and H-9eq of which the latter was
1
identified by a NOE with H-8. The H spectrum further
3
The thiolate anions generated by treatment of 4a,b with
sodium methoxide in methanol were alkylated in situ by
adding 3 equiv. of propargyl bromide to produce thioethers
5a,b (Scheme 3). Subsequent intramolecular Diels–Alder
reaction was effected by heating 5a,b in dry toluene at reflux
temperature. This afforded dihydrothienopyridinone 7a and
the dihydrothienopyridine 7b as the exclusive products
resulting from cycloreversion of the intermediate adducts.
The preferential loss of isocyanate instead of cyanogen
chloride when R6¼Ph is in agreement with our previous
work on N-substituted pyrazinones.6–7 Final oxidation of
thienopyridin(on)es 7a,b with meta-chloroperoxybenzoic
acid (m-CPBA) furnished the [3,4-c]-fused sulfolene
pyridinone 8a and sulfolene pyridine 8b in 45% overall
yield starting from thioesters 4a,b.
displayed coupling constant values J9eq–9a¼6.4 Hz and
3J9ax – 9a¼3.1 Hz, and also very similar values for
the analogous coupling between H-4 and H-3a, i.e.
3
3J4eq–3a¼6.8 Hz and J4ax–3a¼2.8 Hz. These small 3J
coupling values preclude a substantial contribution of
conformer B, in which the axial protons H-4ax and H-9ax
exhibit a trans-diaxial relationship with the angular protons
H-3a and H-9a. Comparable NPMA adducts that were
derived from the reaction of pyridine o-QDM, also revealed
a preferred axial orientation of the maleimide ring.8
Reaction of o-QDM 9 with dimethyl maleate furnished the
expected cis-adduct 11 in good yield. By contrast, only the
2.2. Generation of pyridinone ortho-quinodimethane
(o-QDM) and application in intermolecular Diels–Alder
reactions
To study the reactivity and regioselectivity of the pyridi-
none o-QDM system in cycloaddition reactions, different
types of dienophiles—symmetric and non-symmetric,
electron-deficient, neutral and electron-rich -, were applied,
i.e. N-phenylmaleimide (NPMA), dimethyl maleate,
naphthoquinone,
(DMAD), methyl acrylate, nitroethene, dihydrofuran,
dimethyl
acetylenedicarboxylate
Scheme 3. Synthesis of sulfolene pyridin(on)es. Reagents and conditions:
(i) 1.3 equiv. NaOMe, MeOH, 2208C. (ii) 3 equiv. propargyl bromide.
(iii) Toluene, 1108C, 48 h. (iv) 3 equiv. m-CPBA, CH2Cl2, rt.
Scheme 2. Synthesis of thioester 4. Reagents and conditions: (i) SnMe4,
Pd(P(Ph)3)4, toluene reflux, 48 h. (ii) 1.2 equiv. NBS, CCl4, reflux.
(iii) 1.2 equiv. HSCOCH3, 3 equiv. NEt3, THF, rt.
Scheme 4. Generation of pyridinone-o-QDM 9 and its cycloaddition with
various dienophiles Reagents and conditions: see Table 1.

T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
Table 1. Cycloaddition of pyridinone o-QDM with various dienophiles
5483
Dienophile
Adduct
Nr (Yield)
NPMA
10 (65%)
11 (70%)
12 (65%)
Dimethyl maleate
DMAD
13 (80%)
14(80%)
Methyl acrylate
Nitroethene
15a,b (80%) 4:1
Ethene
16 (23%)
17a,b (ca. 1:1, yield not determined)
TsCN
18 (69%)
PhCHvNTs
19

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T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
The Diels–Alder reaction of o-QDM 9 with ethene was
carried out at a gas pressure of 40 atm by heating a solution
of precursor 8a in o-dichlorobenzene at 150–1608C for 2 or
3 days. However, the ethene adduct 16 was isolated in only
23% yield and an appreciable amount of the starting
sulfolene pyridinone 8a was recovered. Application of the
electron-rich dihydrofuran afforded a complex reaction
mixture. Mass spectral and NMR analysis of this mixture
indicated the existence of a ca. 1:1 mixture of regiomeric
cycloadducts 17.
Figure 1. Preferred conformer A of adduct 10.
fully dehydrogenated tetracyclic adduct 12 could be isolated
from the reaction with 1,4-naphthoquinone. Addition of
DMAD equally afforded the dehydrogenated isoquinolinone
derivative 13, but in this case the initial dihydroisoquino-
linone adduct was detected as a transient intermediate by
mass spectral analysis of the reaction mixture after reflux
under an inert atmosphere.
In view of the easy reaction and regioselectivity observed
with electron-deficient dienophiles, thermolysis of pre-
cursor 8a also was carried out in presence of electron-poor
heterodienophiles, i.e. p-toluenesulfonylcyanide and
N-(benzylidene)-p-toluenesulfonamide. The former Diels–
Alder reaction led to isolation of [2,7]naphthyridinone 18,
and the intermediate non-aromatised adduct could not be
detected. The assignment of the naphthyridinone structure
We next applied the electron-deficient, non-symmetrical
dienophiles methyl acrylate and nitroethene. From the
reaction with methyl acrylate a single adduct was isolated in
good yield. This could be characterised as the 7-regioisomer
14 by 1H NMR analysis using the ASIS technique (aromatic
solvent induced shift), i.e. interchanging the solvent from
CDCl3 to C6D6. In the CDCl3 spectrum, all aliphatic protons
were found to absorb in the same region (2–3 ppm),
whereas the C6D6 spectrum displayed a characteristic
downfield shift for the geminal protons H-8 located in
peri-position of the carbonyl moiety. Unravelling of the
coupling patterns corresponding to H-8ax and H-8eq
1
was based on H and 13C (1H-coupled) NMR analysis and
NOE-diff spectra. Proton H-4, which appeared as a doublet
at 6.54 ppm, was identified by its NOE-diff interaction with
H-5 detected at 7.40 ppm. The 13C–1H-coupled spectrum
1
of 18 further displayed a low JC – H value for C-5
(1JC – H¼172 Hz) and
a
high value for C-8
(1JC–H¼188 Hz), indicating that the tosylcyanide nitrogen
was located in position 7.
The reaction of precursor 8a with N-(benzylidene)-p-
toluenesulfonamide led to isolation of sulfonamide 19
instead of the expected tetrahydronaphthyridinone. This
result might be attributed to traces of water being present in
the reaction mixture. Thus, following hydrolytic removal of
the N-(benzylidene) group, p-toluenesulfonamide could add
in 1,4-fashion onto the electron-poor methylene group of the
pyridinone-o-QDM intermediate to yield 19. However,
formation of 19 also might involve alternative cycloaddition
of PhCHvNTs onto the a,b-unsaturated carbonyl moiety of
o-QDM 9 followed by hydrolysis.
3
2
(H-8ax: 3.17 ppm, dd, J8ax–7¼10 Hz, J8ax–8eq¼18 Hz;
3
2
H-8eq: 2.83 ppm, dd, J8eq–7¼5.5 Hz, J8ax–8eq¼18 Hz)
clearly reveals the existence of a single proton H-7 having
an axial orientation. Consequently the ester-group is
7-equatorial (Fig. 2).
In opposition to the regioselective cycloaddition of methyl
acrylate, a mixture of regioisomers 15a,b (ratio 3:1) was
isolated from the thermolysis reaction of precursor 8a with
nitroethene. The isomers could not be separated by column
chromatography or HPLC but the structures of the isomeric
components again could be assigned on the basis of the
downfield signals observed for each of the protons H-8 in
the C6D6 NMR spectrum of the mixture. Thus, the 7-nitro
regiomeric structure 15a could be attributed to the major
As the kinetic outcome of the Diels–Alder reaction can be
interpreted successfully by using the frontier molecular
orbital (FMO) method, we tried to rationalise the product
component, based on the coupling patterns found for H-8 (d
0
0
3.00, dd, 3J8–7¼6 Hz, 2J8–8 ¼18.5 Hz) and H-8 (d 3.10, dd,
3
2
0
0
J8 –7¼7.5 Hz, J8 –8¼18.5 Hz). For the minor 6-nitro
compound 15b the geminal protons H-8 were detected at
2
3
2.28 and 2.73 ppm (dt, J8 – 8¼19 Hz, J8 – 7¼5.7 Hz),
while the signals for the geminal protons H-5 next to the
6-nitro substituent were found at 2.20 ppm (H-5eq, dd,
2J5ax–5eq¼16.5 Hz, J5–6¼5.6 Hz) and 2.52 ppm (H-5ax,
3
3
dd, 2J5ax–5eq¼16.5 Hz, J5–6¼9.0 Hz).
Figure 2. Preferred equatorial orientation of ester group in adduct 14.
Figure 3. Energy levels calculated for the frontier molecular orbitals.

T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
5485
distribution of cycloadducts formed with non-symmetrical
dienophiles. Ab initio calculation of the frontier molecular
orbitals was carried out using the Hartree-Fock method with
a 3-21Gp basis set (Gaussian 98w). From these calculations
we derived the energy levels of the HOMO and the LUMO
as well as the relative magnitude of the HOMO and LUMO
coefficients (Fig. 3).
some dienophilic side chains at either the more or less acidic
a-position of the sulfone group. When applying 1 equiv. of
a strong base or an excess of a weaker base to abstract a
proton at the more acidic 1-position, the corresponding
monoanion can be generated and functionalised by reaction
with a suitable alkylating agent. However, deprotonation at
both a-positions can be effected by using 2 equiv. of a
stronger base (BuLi), and the resulting 1,3-dianion now can
be functionalised at the more reactive 3-position (see
scheme heading Table 2).
From the energy diagram it appears that for electron-poor
dienophiles the cycloaddition is controlled by the HOMO of
the pyridinone o-QDM as required for ‘normal electron-
demand’ Diels–Alder reactions. Indeed, the interaction
HOMO-o-QDM, LUMO-dienophile is largely preferred
(3.5 eV for methyl acrylate, 4.3 eV for nitroethene and
4.5 eV for the tosylcyanide). Further inspection of the
diagram also reveals that the HOMO-diene coefficient at the
5-methylene position is higher than that for the 6-methylene
group. Since the largest coefficient on each addend will
become preferentially bonded in the transition state, the
experimental outcome of the cycloadditions with methyl
acrylate and tosyl cyanide appears to be in line with the
calculation. However, it is not clear why a lower regio-
selectivity is observed for the cycloaddition of nitroethene.
For the electron-rich dihydrofuran the ‘inverse electron-
demand’ interaction LUMO-o-QDM, HOMO-dienophile is
preferred (2.22 eV). Hence, the lack of regioselectivity may
be accounted for by the comparable values calculated for the
LUMO-diene coefficients on the 5-methylene and
6-methylene ends groups.
Substitution at position 1 was accomplished by reaction
with tetrabutylammonium fluoride (TBAF) followed by
addition of the alkylating reagent. This 1-alkylation was
successful with methyl iodide, benzyl bromide, 5-bromo-1-
pentene and the a-chloroacetamide ClCH2CON(CH3)CH2-
CHvCH2 but not with the other electrophiles tested. Using
other bases and solvents (KH in DMF, BuLi in THF) did not
raise the yield significantly.
Substitution at position 3 of the precursor was achieved by
using 2.1 equiv. of BuLi, followed by addition of 1 equiv. of
the electrophile. This procedure was successful in the
reaction with benzyl bromide, 5-bromo-1-pentene,
Br(CH2)4CN, Br(CH2)3CN, ClCO2Me, and ClCON(CH2-
CHvCH2)2 but not with phenyl isocyanate, Br(CH2)2-
N(Ns)CH2CHvCH2, and the Michael acceptors methyl
acrylate and acrylonitrile. All attempts to form the dianion
with other bases like NaH or KH failed (Table 2).
Presumably due to competitive E2-elimination, rather low
yields were obtained for some substitution reactions, e.g.
only elimination of HBr was observed upon addition of
Br(CH2)2N(Ns)CH2CHvCH2 to the dianion generated
from precursor 8a. Ester compound 30 was found to be
2.3. Substitution of the sulfolene pyridinone precursor
A particular merit of using sulfolene pyridinone precursor
8a is that it allows for the regioselective introduction of
Table 2. Regioselective substitution at the 1- and 3-position of sulfolene pyridinone 8a
RX (equiv.)
Product number (condition, yield %)
Substituents
ICH3 (2)
BrBn (2)
Br(CH2)3CHvCH2 (2)
Br(CH2)4CN (3)
ClCH2CON(Me)allyl (2)
ClCON(allyl)2 (2)
BrBn (1.1)
Br(CH2)3CHvCH2 (1.1)
Br(CH2)4CN (1.1)
Br(CH2)3CN (1.1)
ClCO2Me (1.1)
Methyl acrylate (1.1)
Acrylonitril (1.1)
Phenyl isocyanate
Br(CH2)2N(Ns)allyl (1.1)
ClCON(allyl)2 (1.1)
20 (A, 70)
21 (A, 70) (B, 72)
22 (A, 56)
23 (A, 0) (B, 0) (C, 0)
24 (A, 63)
25 (A, 0)
26 (C, 40) (D, 60)
27 (E, 55)
28 (E, 58)
29 (E, 44)
30 (E, 55)
31a (E, 0) (F, 0)
31b (E, 0)
32 (E, 0)
33 (E, 0) (F, 0)
34 (E, 58)
R1¼Me, R3¼H
R1¼Bn, R3¼H
R1¼(CH2)3CHvCH2, R3¼H
R1¼(CH2)4CN, R3¼H
R1¼CH2CONMeallyl R3¼H
R1¼CON(allyl)2, R3¼H
R1¼H, R3¼Bn
R1¼H, R3¼(CH2)3CHvCH2
R1¼H, R3¼(CH2)4CN
R1¼H, R3¼(CH2)3CN
R1¼H, R3¼CO2Me
R1¼H, R3¼(CH2)2 CO2Me
R1¼H, R3¼(CH2)2CN
R1¼H, R3¼CONHPh
R1¼H, R3¼(CH2)2N(Ns)allyl
R1¼H, R3¼CON(allyl)2
(i) THF, Base (ii) RX. Reagents and conditions: (A) 1.3 equiv. TBAF, THF, rt. (B) 1.2 equiv. KH, DMF, 08C. (C) 1.1 equiv. BuLi, THF, 2788C. (D) same as
(C)þ1 equiv. HMPA. (E) 2.1 equiv. BuLi, THF, 2788C. (F) same as (E)þ1 equiv. HMPA.

5486
T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
the substituents. In this respect the d-values of C-3a and
C-7a were of particular interest since a substituent in
position 1 was found to induce a large downfield shift for the
vicinal carbon C-7a and a smaller upfield shift for C-3a.
This tendency is reversed for the 3-substituted sulfone
derivatives (Table 3).
2.4. The intramolecular Diels–Alder reactions
Having attached a number of dienophilic side chains to
either a-position of the sulfone group, we now were able to
probe the reactivity of the modified precursors and the
corresponding pyridinone o-QDM in intramolecular Diels–
Alder reactions (IMDA). Our results are discussed with
regard to both the synthetic potential of the IMDA approach
and the structural properties of the tricyclic pyridinone
products.
Scheme 5. Rearrangement occurring upon alkylation of the dianion of 8a
with ClCH2CON(CH3)CH2CHvCH2. Reagents and conditions:
(i) 2.1 equiv. BuLi, THF, 2788C. (ii) 1.1 equiv. N-allyl-2-chloro-N-
methylacetamide.
Thermolysis of the 1-substituted pyridinones 22 and 24 was
carried out in o-DCB at 1508C. For 22 this reaction
furnished a mixture of cis-adduct 36 (37%) and trans-adduct
37 (30%); as the isomers could not be separated by HPLC
1
the isomeric ratio was determined by H NMR analysis.
unstable and easily lost the 3-CO2Me ester group upon
standing for a few days to give back unsubstituted
compound.
Similarly thermolysis of 24 produced a non-separable
mixture of cis-lactam 38 (64%) and trans-fused product
39 (19%) (Table 4). The assignment of the latter structures
was based on the coupling constants found between H-1 and
H-4 and the vicinal angular protons. Presumably, expulsion
of SO2 to form the o-QDM in each case yields the more
stable E-isomer due to steric repulsion between the
alkylidene and methylene groups in the Z-isomer. Conse-
quently, cis- and trans-adducts must be formed via endo and
exo cycloaddition respectively. Since relatively more cis-
fused lactam 38 is formed, the endo mode of cycloaddition
apparently is favoured for the N-allylacetamide side chain:
this result is in line with previous findings regarding the
IMDA of dienophilic side chains having an amide group
incorporated into a four atom tether.9
When applying BuLi (2.1 equiv.) and the a-chloro-
acetamide ClCH2CON(CH3)CH2CHvCH2 to effect substi-
tution at the 3-position of the dianion, rearranged compound
35 was isolated as the only product (Scheme 5). Remark-
ably, such rearrangement did not occur during conversion of
8a into the analogous 1-substituted compound 24 (see
before).
To explain this result one may invoke a proton transfer that
would occur in the initially formed 3-alkylated anion
product A to give first ion B and then the isomeric ion C;
concomitant expulsion of sulfur dioxide then would provide
anion D that upon protonation can be converted to the
pyridinone product 35. The rearrangement of A may be
initiated by the transfer of an acidic hydrogen from the
acetamide side chain to the pyridinone carbonyl group,
followed by tautomerisation of enol intermediate B.
Thermolysis of the 3-substituted precursors 27-29 and 34
also was done in o-DCB at 1508C. (Table 5). The adduct
obtained from the 3-(4-pentenyl) derivative 27 displayed a
1
complex H NMR spectrum, which according to NOE-diff
The 1- and 3-substituted compounds were characterised
1
Table 4. Thermolysis of 1-substituted precusors
using H and 13C NMR spectroscopy. In the NOE-diff-
Precursor
Adduct
spectra of the 1-benzyl and 1-(4-pentenyl) compounds 21
and 22 strangely a negative NOE-correlation emerged
between H-1 and proton H-7 in peri-position. We therefore
relied on the 13C NMR data to ensure the 1 or 3-position of
22
Table 3. Selected 13C NMR-data for the 1- and 3-substituted precursors
Compound
d C-1
d C-3
d C-3a
d C-7a
24
8
58.4
67.9
66.9
63.5
56.1
56.8
56.6
56.8
58.3
55.1
53.4
53.7
53.8
66.3
65.3
64.8
64.8
71.2
122.9
121.9
121.5
121.5
126.5
127.2
126.2
126.5
121.8
142.6
147.0
147.2
147.3
142.6
141.7
142.1
141.9
143.1
21
22
24
26
27
28
29
30

T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
5487
Table 5. Thermolysis of 3-substituted precursors
Precursor
Adduct
27
28
29
34
Figure 4. NOE’s indicating the presence of the more stable half-chair form
A and MD simulation of the conversion of half-chair B into A via twist-boat
C.
Starting from the highly energetic form B, a molecular
dynamics (MD) simulation was carried out which revealed
the easy conversion of B into the other half-chair A. This
conversion was found to proceed via twist-boat C having an
energy intermediate between that of A and B, due to the
orthogonal orientation of carbonyl groups already present
(Fig. 4).
Although some Diels–Alder reactions involving nitrile
dienophiles have been reported,10 no adduct formation was
observed upon thermolysis of the 3-(4-cyanobutyl) and the
3-(4-cyanopropyl) substituted precursors 28 and 29; instead
the pyridinone o-QDM intermediates were transformed into
the corresponding rearranged products 42 and 43. Although
the E-isomer probably is the initial species formed, this can
be transformed into the Z-isomer, presumably via a
pyridinone cyclobutene intermediate; the Z-isomer finally
undergoes a 1,5-H-shift (Scheme 6).11 When compared to
p-toluenesulfonyl cyanide that is subject to intermolecular
cycloadition, nitriles 28 and 29 are less electron-deficient;
moreover IMDA of these nitriles would require the opposite
regiochemistry.
analysis is due to the presence of two slowly interconverting
half-chair conformers. This finding is consistent with cis-
fused structure 40. Presaturation of H-9a (2.23 ppm) did not
result in any observed NOE-effect for adjacent protons;
instead a negative signal appeared at 3.04 ppm, which can
be ascribed to a saturation transfer of H-9a from one to the
other conformer. In agreement with the 3:1 conformational
ratio observed, MMþ modeling calculations revealed very
similar energies for the two half-chair forms (energy
difference lower than 1 kcal/mol).
Apparently, the pyridinone carbonyl function plays an
important role in directing the exclusive endo mode of
cycloaddition. The adduct obtained from the N,N-diallyl-
carboxamide precursor 34 also was characterised as a cis-
fused tricyclic structure 43 as shown by the doublet
3
absorption of H-9b (d 4.10, 1H, J¼7.3 Hz) and a strong
NOE between the angular protons H-9b and H-3a (d 1.5, 1H,
m). However, unlike the carbocyclic analogue 40 cis-fused
lactam 41 exists as a single half-chair conformer. From
MMþ calculations half-chair A was shown to be the more
stable form as it displays a favourable orthogonal disposi-
tion of the pyrazinone carbonyl group and the quasi-axial
lactam carbonyl group (Fig. 4). The existence of form A and
not the opposite half-chair form B with parallel carbonyl
groups was confirmed by a strong NOE between H-30 and
Scheme 6. 1,5-H-shift.
3. Conclusion
3
H-9b and by a J value h 0 for protons H-3a and H-3; the
From the results presented it follows that [3,4-c]sulfolene
pyridinones are valuable precursors for the generation of the
latter value reflects a dihedral angle of ca. 908 calculated by
MMþ.

5488
T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
corresponding pyridinone o-QDM. These o-QDM systems
can be applied in various inter- and intramolecular Diels–
Alder reactions to produce polycyclic pyridinones.
4.1.1. S1-[(4-Benzyl-6-chloro-3,4-dihydro-3-oxo-2-pyra-
zinyl)methyl]ethanethioate 4a. Yield: 80%; pale white
powder, mp: 83–83.58C (ethanol); IR (KBr/cm21): 3063,
1
1730, 1650; H NMR: d 2.37 (s, 3H, CH3), 4.27 (s, 2H,
Starting from 2(1H)-pyrazinones we developed a synthetic
route to [3,4-c]sulfolene pyridinone 8a, which served as a
precursor of o-QDM 9. This was generated by heating the
precursor at 1508C, and trapped in situ by intermolecular
Diels–Alder reactions. Reaction with symmetric, electron-
poor dienophiles afforded the corresponding adducts in
good yields. Application of non-symmetrical, electron-poor
dienophiles led to regioselective addition with methyl
acrylate and p-toluenesulfonylcyanide, but to a lesser extent
with nitroethene. By contrast, cycloaddition of the electron-
rich dihydrofuran was not regioselective.
CH2S), 5.05 (s, 2H, CH2–N), 7.14 (s, 1H, H-6), 7.32–7.38
(m, 5H, H–Ph); 13C NMR: d 30.1 (CH3), 31.3 (CH2S), 52.4
(CH2–N), 125.6 (C-6), 125.8 (C-5), 128.7 (C–Ph ortho),
128.9 (C–Ph meta), 129.2 (C–Ph para), 133.9 (C–Ph ipso),
154.1 (C-3), 155.1 (C-2), 193.8; MS [m/z (%)]: EI: 308 (20,
Mþz), 266 (81, Mþz2CH3CO), 233 (7, Mþz2CH3COSH),
175 (Mþz2CH3CO–C7H7), 91 (100, C7Hþ7 ); HRMS: calcd
for C14H13ClN2O2S: 308.0386, found: 308.0383; CHN
analysis: calcd for C14H13ClN2O2S: C 54.46, H 4.24, N
9.07; found: C 54.18, H 4.00, N 8.88.
4.1.2. S1-[(4-Benzyl-6-chloro-5-phenyl-3,4-dihydro-3-
oxo-2-pyrazinyl)methyl]-ethanethioate 4b. Compound
4b was prepared from bromide 3b in the same way as
described for the conversion of 3a to 4a. Yield: 80%; white
powder; mp: 90.5–918C (Ethanol); IR (KBr/cm21): 3051,
A particular advantage of sulfolene pyridinone precursor 8a
is that it allows for substitution at either the more or less
acidic a-position of the sulfone group. Thus, electrophilic
attack on the 1-mono- or 1,3-dianion permits regioselective
attachment of some dienophilic side chains. Thermolysis of
the 1-substituted precursors led to isolation of a mixture of
cis- and trans-fused pyridinone adducts whereas reaction
of the 3-substituted precursors exclusively furnished cis-
fused pyridinone adducts corresponding to endo addition of
the E-o-QDM intermediates. Apparently, the nearby
pyridinone carbonyl function plays an important role in
directing the endo addition of 3-substituted precursors.
1
1745, 1680; H NMR: d 2.40 (s, 3H, CH3), 4.38 (s, 2H,
CH2S), 5.50 (s, 2H, CH2–N), 6.78 (d, 2H, Jo¼8 Hz, H–Ph)
7.05 (d, 2H, J0¼8 Hz, H–Ph), 7.20 (m, 3H, H–Ph), 7.37–
7.47 (m, 3H, H–Ph); 13C NMR: d 30. (CH3), 31.5 (CH2S),
49.4 (CH2–N), 137.8 (C-6), 126.1 (C-5), 153.6 (C-3), 154.9
(C-2), 194.0, 135.2 (C-ipso), 130.6 (C-ipso), 127.3
(C-arom), 127.8 (C-arom), 128.5 (C-arom), 128.8
(C-arom), 129.3 (C-arom), 130.1 (C-arom); MS [m/z (%)]:
CI: 385 (100, MHþ), 343 (25, MHþ2CH3CO), 309 (18,
MHþ2CH3COSH 91 (5, C7H7þ); HRMS: calcd for C20H17-
ClN2O2S: 384.0699; found: 384.0705.
4. Experimental
4.2. General procedure for synthesis of thioethers 5
Melting points were determined using a Reichert–Jung
Thermovar apparatus and an Electrothermal IA 9000 digital
melting point apparatus and are uncorrected. Infrared
spectra were recorded on a Perkin–Elmer 297 grating IR
spectrophotometer and a Perkin–Elmer 1720 Fourier
transform spectrometer. Mass spectra were run using a
Hewlett–Packard MS-Engine 5989A apparatus for EI and
CI spectra, and a Kratos MS50TC instrument for exact mass
measurements performed in the EI mode at a resolution of
10000. For the NMR spectra (d, ppm) a Bruker Avance 300
and a Bruker AMX 400 spectrometer were used. All NMR
spectra were taken up in CDCl3 with TMS as an internal
standard unless otherwise stated. Analytical and preparative
thin layer chromatography was carried out using Merck
silica gel 60 PF-224, for column chromatography 70–230
mesh silica gel 60 (E.M. Merck) was used as the stationary
phase. Compounds 1-3a,b were synthesized as described in
a previous publication.6
To a cooled (2208C) solution of thioester (0.05 mol) in
methanol (250 mL) was added under an inert atmosphere
1.3 equiv. of sodium methoxide. After reaction at 2208C for
1 hour 3 equiv. of propargylic bromide were added. The
reaction mixture was stirred at rt for 2.5 h and neutralised
with a dilute solution of HCl in MeOH. The solution was
concentrated, the residue redissolved in CH2Cl2 (150 mL),
and the CH2Cl2 solution washed with water (2£150 mL).
The organic layer was dried over MgSO4 and the solvent
was evaporated. The residue was purified by column
chromatography (silica gel 70% hexane/30% EtOAc) to
afford thioether compounds 5.
4.2.1. 1-Benzyl-5-chloro-3-[(2-propynylsulfanyl)-
methyl]-2(1H)-pyrazinone 5a. Yield: 85%; yellow oil; IR
(NaCl/cm21): 3301, 2117, 3067, 1587; 1H NMR: d 2.22 (t,
1H, 4J¼2.5 Hz, uCH), 3.35 (d, 2H, 4J¼2.5 Hz, CH2), 3.92
(s, 2H, 3-CH2), 5.04 (s, 2H, CH2–N), 7.25 (s, 1H, H-6),
7.50–7.26 (m, 5H, H–Ph); 13C NMR: d 18.8, 32.8, 52.4
(CH2–N), 60.1, 71.2, 80.1, 125.3, 125.8, 128.4, 128.6,
128.9, 134.1, 153.9, 156.0; MS [m/z (%)]: EI: 304 (1, Mþz),
269 (42, Mþz2Cl), 243 (32, Mþz2ClCN), 234 (21,
Mþz2C3H2S), 91 (100, C7H7þ); HRMS: calcd for C15H13-
ClN2OS: 304.0437; found: 304.0429.
4.1. General procedure for the synthesis of thioesters 4
To a stirred solution of bromide 3 (0.1 mol) and thiolacetic
acid (0.12 mol) in dry THF (500 mL) was added dropwise
NEt3 (0.3 mol) under an inert atmosphere. After completion
of the reaction, water (500 mL) was added and the mixture
was extracted with CH2Cl2 (3£200 mL). The combined
organic layers were dried over MgSO4 and the solvent was
evaporated. The residue was purified by column chroma-
tography (Silica gel 5 EtOAc/95 CH2Cl2) to afford
compounds 4.
4.2.2. 1-Benzyl-5-chloro-6-phenyl-3-[(2-propynylsul-
fanyl)methyl]-2(1H)-pyrazinone 5b. Yield: 85%; yellow
1
oil; IR (NaCl/cm21): 3057, 2100, 1592; H NMR: d 2.2 (t,
1H, 4J¼2.5 Hz, uCH), 3.45 (d, 2H, 4J¼2.5 Hz, CH2), 4.01

T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
5489
(s, 2H, 3-CH2), 5.06 (s, 2H, CH2–N), 6.25 (d, 2H, Jo¼8 Hz,
H–Ph), 7.01–7.26 (m, 8H, H–Ph); 13C NMR: d 20.2 (CH2),
33.1 (CH2), 48.9 (CH2–N), 71.1 (CH), 80.1 (C), 118.3,
120.5, 125.8, 127.3, 127.7, 128.4, 128.7, 129.3, 130.0,
130.6, 135.1 (C-ipso), 137.5, 154.9, 171.1 (C-2); MS [m/z
(%)]: CI: 381 (91, MHþ), 309 (100, MHþ2C3H2S, –H),
248 (16, MHþ2BnNCO), 91 (28, C7Hþ7 ); HRMS: calcd for
C21H17ClN2OS: 380.0750; found: 380.0758.
4.4.2. 2-Chloro-3-phenyl-5,7-dihydro-6,6-dioxo-
thieno[3,4-b]pyridine 8b. Yield: 80%; white powder, mp
1
2088C (decomposition); IR (KBr/cm21): 2987, 1545; H
NMR (DMSO/TMS): d 4.65 (s, 2H, H-1), 4.69 (s, 2H, H-3),
7.49 (m, 5H, H–Ph), 7.91 (s, 1H, H-7); 13C NMR: d 55.6
(CH2), 56.5 (CH2), 127.9 (C-6), 128.5 (C-arom), 128.6 (C-
arom), 129.1 (C-arom), 135.9 (C-7a), 136.4 (C-ipso), 137.9
(C-7), 147.9 (C-5), 151.8 (C-3a); MS [m/z (%)]: CI: 280
(100, MHþ), 216 (16, MHþ2SO2), 180 (5, MHþ2SO2,
–HCl); HRMS: calcd for C13H10ClNO2S: 279.7427; found:
279.7421.
4.3. General procedure for the thermolysis of thioethers
A solution of thioether (0.04 mol) in dried toluene (300 mL)
was refluxed under an inert atmosphere (6–48 h
depending on the thioether). The solvent was evaporated
and the residue was purified by column chromatography
(silica gel, 15% EtOAc/85% CH2Cl2) to give cyclic
sulfides 7.
4.5. General procedure for intermolecular Diels–Alder
reactions
A solution of sulfolene pyridinone (0.2 g, 0.7 mmol) and
5 equiv. of dienophile in o-dichlorobenzene (10 mL),
contained in a glass tube, was subjected to three freeze-
pump-thaw cycle. The glass tube was sealed under vacuum
and heated for 12 h at 1608C. After cooling and opening the
tube the solvent was removed by Kugelrohr distillation. The
adducts were purified by column chromatography.
4.3.1. 5-Benzyl-1,3-dihydrothieno[3,4-c]pyridin-4(5H)-
one 7a. Yield: 67%; white crystals, mp: 131.8–132.68C
1
(CH2Cl2/hexane); IR (KBr/cm21): 3051, 2964, 1651; H
NMR: d 4.18 (s, 2H, CH2), 4.19 (s, 2H, CH2), 5.12 (s, 2H,
CH2–N), 6.10 (d, 1H, J¼7 Hz, H-7), 7.19 (d, 1H, J¼7 Hz,
H-6), 7.27–7.30 (m, 5H, H–Ph); 13C NMR: d 36.8 (C-3),
39.7 (C-1), 52.1 (CH2–N), 102.0 (C-7), 117.4 (C-3a), 128.0
(C–Ph para), 128.3 (C–Ph ortho), 128.9 (C–Ph meta),
136.1 (C-6), 136.3 (C–Ph ipso), 137.9 (C-7a), 160.1; MS
[m/z (%)]: EI: 243 (70, Mþz), 152 (60, Mþz2C7H7), 91 (100,
C7Hþ7 ); HRMS: calcd for C14H13NOS: 243.0718; found:
243.0715.
4.5.1. (3aR p,9aS p)-6-Benzyl-2-phenyl-3a,4,9,9a-tetra-
hydro-1H-pyrrolo[3,4-g]isoquinoline-1,3,5(2H,6H)-
trione 10. Dienophile: 5 equiv. of N-phenylmaleimide.
Yield: 65%; yellow crystals, mp: 194–194.88C (ethanol);
1
IR (KBr/cm21): 3055, 2983, 1713, 1650; H NMR: d 2.76
(dd, 1H, J¼6.8, 15.6 Hz, H-4), 2.82 (dd, 1H, J¼6.4,
14.9 Hz, H-9), 2.99 (dd, 1H, J¼3.2, 14.9 Hz, H-9), 3.33–
3.42 (m, 2H, H-9aþH-3a), 3.49 (dd, 1H, J¼2.8, 15.6 Hz,
H-4), 5.08 (d, 1H, J¼14.5 Hz, CH2–N), 5.14 (d, 1H,
J¼14.5 Hz, CH2–N), 6.05 (d, 1H, J¼6.8 Hz, H-8), 7.06–
7.08 (m, 2H, H–Ph), 7.16 (d, 1H, J¼6.8 Hz, H-7), 7.23–
7.38 (m, 8H, H–Ph); 13C NMR: 22.3 (C-4), 29.2 (C-9),
39.2, 39.3, 52.2 (CH2), 107.0 (C-8), 125.1 (C-4a), 126.1,
127.8, 127.9, 128.4, 128.8, 128.9, 131.6 (C-ipso), 135.3
(C-7), 136.4 (C-ipso), 146.4 (C-8a), 160.7 (C-5), 177.7,
177.9; MS [m/z (%)]: EI: 384 (100, Mþz), 293 (2,
Mþ2C7Hþ7 ), 237 (5, Mþ2C6H5N(CO)2), 146 (67,
C6H5N(CO)2), 91 (69, C7Hþ7 ); HRMS: calcd for
C24H20N2O3: 384.1474; found: 384.1471.
4.3.2. 2-Chloro-3-phenyl-5,7-dihydrothieno[3,4-b]pyri-
dine 7b. Yield: 66%; unstable yellow oil; IR (NaCl/
cm21): 3051, 2964; 1H NMR: d 4.10 (s, 2H, CH2), 4.25 (s,
2H, CH2), 7.20–7.35 (m, 6H, H-4þH–Ph); MS [m/z (%)]:
EI: 247 (100, Mþz), 211 (60, Mþz2HCl).
4.4. General procedure for the oxidation of cyclic
sulfides 7 to form sulfones 8
To a solution of thienopyridinone 7 (0.02 mol) in dry
CH2Cl2 (150 mL) was added meta-chloroperoxybenzoic
acid (0.06 mol). The mixture was stirred for 18 h at rt. Then
a saturated solution of NaHCO3 (50 mL) was added, and
stirring was continued for 4 h. The organic phase was
separated and the aqueous phase further extracted with
CH2Cl2. The combined organic layers were washed with
water and dried over MgSO4 and the solvent evaporated.
The residue was purified by column chromatography (silica
15% EtOAc/CH2Cl2) to afford sulfones 8.
4.5.2. Dimethyl (6R p,7R p)2-benzyl-5,6,7,8-tetrahydro-1-
oxo-2H-isoquinoline-6,7-dicarboxylate 11. Dienophile:
10 equiv. of methyl acrylate. Yield: 70%; yellow crystals,
1
mp: 115–1178C (CH2Cl2/hexane); H NMR: d 2.10–2.33
(m, 1H), 2.50–2.95 (m, 4H), 3.30 (m, 1H), 3.56 (s, 3H,
CH3), 3.69 (s, 3H, CH3), 5.10 (d, 1H, CH2–N), 5.12 (d, 1H,
CH2–N), 6.10 (d, 1H, J¼7 Hz, H-4), 7.10 (d, 1H, J¼7 Hz,
H-3), 7.00–7.32 (m, 5H, H–Ph); 13C NMR: 26.1 (CH2),
28.1 (CH2), 38.9 (CH), 39.3 (CH) 51.2 (CH3), 52.0 (CH2-
benzyl), 52.5 (CH3), 109.0 (C-4), 126.0 (C-8a), 127.6,
128.2, 129.0, 133.0, 136.6 (C-ipso), 162.4 (C-1), 174.0,
175.5; MS [m/z (%)]: EI: 355 (20, Mþz), 296 (69,
Mþz2C2H3O2), 264 (15, Mþz2C7H7), 237 (8,
Mþz22£C2H3O2), 205 (57, Mþz2C2H3O2, –C7H7), 91
(100, C7Hþ7 ); HRMS: calcd for C20H21NO5: 355.1420;
found: 355.1428.
4.4.1. 5-Benzyl-1,3-dihydro-2,2-dioxothieno[3,4-c]pyri-
din-4(5H)-one 8a. Yield: 85%; white crystals, mp 1448C
(decomposition); IR (KBr/cm21): 2968, 1652, 1589, 1316,
1123; 1H NMR: d 4.26 (s, 2H, CH2), 4.28 (s, 2H, CH2), 5.14
(s, 2H, CH2–N), 6.13 (d, 1H, J¼7 Hz, H-7), 7.26–7.36 (m,
5H, H-6þH–Ph); 13C NMR: d 52.3 (CH2–N), 55.1 (C-3),
58.4 (C-1), 103.3 (C-7), 122.9 (C-3a), 135.5 (C-Ph
ipso),128.1, 128.3, 128.4, 137.9, 142.6, 158.6; MS [m/z
(%)]: EI: 275 (9, Mþz), 211 (40, Mþz2SO2), 91 (Bnþ);
HRMS: calcd for C14H13NO3S: 275.0616; found: 275.0613;
CHN analysis: calcd for C14H13NO3S: C 61.07, H 4.76, N
5.09; found: C 60.90, H 4.55, N 4.95.
4.5.3. 2-Benzylnaphtho[2,3-g]isoquinoline-1,6,11(2H)-
trione 12. Dienophile: 5 equiv. of 1,4-naphthoquinone.
Yield: 65%; yellow crystals, mp: 190–190.58C (ethanol);

5490
T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
3
IR (KBr/cm21): 3067, 1671, 1617; 1H NMR: d 5.26 (s, 2H,
CH2–N), 6.67 (d, 1H, 3J¼7.2 Hz, H-4), 7.28 (d, 1H,
3J¼7.2 Hz, H-3), 7.30–7.37 (m, 5H, H-arom), 7.83 (dd, 2H,
Jo¼7 Hz, Jm¼2.5 Hz, H-7þH-10), 8.33–8.40 (m, 2H,
H-8þH-9), 8.43 (s, 1H, H-12), 9.41 (s, 1H, H-5); 13C
NMR: 52.4 (CH2–N), 106.3 (CH), 126.3 (CH), 127.8 (CH),
128.1 (CH) 128.2 (CH), 128.3 (CH), 128.9 (CH), 129.0
(CH), 129.4 (CH), 129.8 (CH), 134.5 (CH), 135.0 (CH),
135.2 (C), 131.3 (C), 134.1 (C), 135.5 (C), 136.5 (C), 141.2
(C), 162.0 (C-1), 182.1 (CO), 183.3 (CO)); MS [m/z (%)]:
EI: 365 (35, Mþz), 91 (100, C7Hþ7 ); HRMS: calcd for
C24H15NO3: 365.1052; found: 365.1049.
2J¼16.5 Hz, J¼5.6 Hz, H-5b), 2.28 (m, 0.25H, CH-8b),
2
3
2.52 (dd, 0.25H, J¼16.5 Hz, J¼9.0 Hz, H-5b), 2.73 (dt,
0.25H, 2J¼19.0 Hz, 3J¼5.2 Hz, H-8b), 3.00 (dd, 1H,
3
2
2J¼18.5 Hz, J¼6.2 Hz, H-8a), 3.10 (dd, 1H, J¼18.5 Hz,
3J¼7.4 Hz, H-8a), 3.73–3.93 (m, 1.25H, H-7a, H-6b), 4.64
(d, 1H, 2J¼14.4 Hz, CH2–Na), 4.66 (d, 0.25H, 2J¼14.2 Hz,
CH2–N b), 4.81 (d, 0.25H, 2J¼14.2 Hz, CH2–N b), 4.85 (d,
1H, 2J¼14.4 Hz, CH2–N), 5.17 (d, 0.25H, 3J¼7.0 Hz,
H-4b), 5.19 (d, 1H, 3J¼7.0 Hz, H-4a), 6.38 (d, 1H,
3J¼7.0 Hz, H-3a), 6.40 (d, 0.25H, 3J¼7.0 Hz, H-3b),
7.00–7.13 (m, 6.25H, H–Ph aþb); 13C NMR: 15a: d 26.4
(CH2), 26.8 (CH2), 28.2 (CH2), 52.4 (CH2), 80.6 (CH), 107
(CH), 123.2 (C), 127.9 (CH), 128.0 (CH), 129.3 (CH), 134.4
(CH), 136.3 (C), 145.4 (C), 161.9 (CO); 15b: d 22.3 (CH2),
27.1 (CH2), 32.7 (CH2), 52.4 (CH2), 80.2 (CH), 107.0 (CH),
127.9 (CH), 128.0 (CH), 129.3 (CH), 125.9 (C), 134.6 (CH),
136.3 (C), 142.5 (C), 161.9 (CO); MS [m/z (%)]: EI: 284
(26, Mþz), 237 (66, Mþz2HNO2), 91 (100, C7Hþ7 ); HRMS:
calcd for C12H16N2O3: 284.1161; found: 284.1162.
4.5.4. Dimethyl 2-benzyl-1-oxo-2H-isoquinoline-6,7-
dicarboxylate 13. Dienophile: 5 equiv. dimethyl acetylene-
dicarboxylate. Yield: 80%; colourless oil; IR (NaCl/cm21):
1
3011, 2983, 1713, 1650, 1595; H NMR: d 3.93 (s, 3H,
CH3), 3.95 (s, 3H, CH3), 5.22 (s, 2H, CH2–N), 6.49 (d, 1H,
J¼7.5 Hz, H-4), 7.22 (d, 2H, J¼7.5 Hz, H-3), 7.26–7.33
(m, 5H, H–Ph), 7.73 (s, 1H, H-5), 8.91 (s, 1H, H-8); 13C
NMR: d 51.9 (CH2–N), 52.6 (CH3), 52.9 (CH3), 105.5
(C-4), 126.5, 126.8, 127.9, 128.0, 128.9, 130.4, 134.3,
136.1, 139.0, 161.2 (C-1), 166.5, 168.1; MS [m/z (%)]: EI:
351 (54, Mþz), 320 (13, Mþz2OCH3), 292 (5,
Mþz2C2H3O2), 91 (100, C7Hþ7 ); HRMS: calcd for
C20H17NO5: 351.1107, Found: 351.1103.
4.5.7. 2-Benzyl-5,6,7,8-tetrahydro-1(2H)-isoquinolinone
16. A solution of 0.2 g sulfolene pyridinone in o-dichloro-
benzene (20 mL) was transferred to a steel vessel. The
vessel was loaded with ethene (40 atm) and heated at 1608C
for 48 h. After cooling the solvent was evaporated
(Kugelrohr) and the residue was purified by column
chromatography (silica, 10 EtOAc/90 CH2Cl2). Yield:
22%; white powder; mp: 1108C (CH2Cl2/hexane); IR
(KBr/cm21): 2936, 1647, 1593; 1H NMR: d 1.70–1.76
(m, 4H, H-6þH-7), 2.51 (t, 2H, J¼5.8 Hz, H-5 of H-8), 2.56
(t, 2H, J¼5.8 Hz, H-8 of H-5), 5.11 (s, 2H, CH2–N), 5.90
(d, 1H, J¼7.0 Hz, H-4), 7.03 (d, 1H, J¼7.0 Hz, H-3), 7.26–
7.34 (m, 5H, H–Ph); 13C NMR: d 21.9 (CH2), 22.2 (CH2),
23.7 (CH2), 29.2 (CH2), 51.8 (CH2–N), 108.3 (C-4), 127.7
(C-8a), 127.8, 1281, 128.7, 132.5 (C-3), 136.9 (C-ipso),
146.9 (C-4a), 162.5 (C-1); MS [m/z (%)]: EI: 239 (100,
Mþz), 148 (100, Mþz2C7H7), 91 (90, C7H7þ); HRMS: calcd
for C16H17NO: 239.1310; found: 239.1309.
4.5.5. Methyl 2-benzyl-5,6,7,8-tetrahydro-1-oxo-2H-iso-
quinoline-7-carboxylate 14. Dienophile: 10 equiv. of
methyl acrylate. Yield: 85%; white crystals, mp: 146–
1
1478C (CH2Cl2/hexane); H NMR: d 1.79–1.83 (m, 1H),
2.01–2.12 (m, 1H), 2.58–2.69 (m, 4H), 3.00 (dd, 1H,
J¼10.0, 18.0 Hz, H-8), 3.70 (s, 3H, CH3), 5.09 (d, 1H,
CH2–N), 5.11 (d, 1H, CH2–N), 5.91 (d, 1H, J¼7 Hz, H-4),
7.06 (d, 1H, J¼7 Hz, H-3), 7.05–7.32 (m, 5H, H–Ph);
(C6D6) d 1.51–1.61 (m, 1H, H-6), 1.75–1.79 (m, 1H, H-6),
2.00–2.07 (m, 1H, H-5ax), 2.17 (dt, 1H, J¼18, 5 Hz, H-5eq),
2.31–2.35 (m, 1H, H-7), 2.85 (dd, 1H, J¼5.5, 18.0 Hz,
H-8eq), 3.17 (dd, 1H, J¼10.0, 18.0 Hz, H-8ax), 3.32 (s, 3H,
CH3), 4.77 (d, 1H, J¼14.2 Hz, CH2–N), 4.87 (d, 1H,
J¼14.2 Hz, CH2–N), 5.37 (d, 1H, J¼7.0 Hz, H-4), 6.51 (d,
1H, J¼7.0 Hz, H-3), 7.00–7.15 (m, 3H, H–Ph), 7.17–7.19
(m, 2H, H–Ph); 13C NMR: 24.2, 26.2, 28.1, 38.9 (C-7), 51.6
(CH3), 51.7 (CH2-benzyl), 107.6 (C-4), 125.5 (C-8a), 127.7,
128.1, 128.7, 133.0 (C-3), 136.6 (C-ipso), 161.9 (C-1),
175.3; MS [m/z (%)]: EI: 297 (79, Mþz), 238 (78,
Mþz2C2H3O2), 206 (6, Mþz2C7H7), 146 (31,
Mþz2C2H3O2, –C7H7, –H), 91 (100, C7Hþ7 ); HRMS:
calcd for C18H14NO3: 297.1365; found: 297.1360.
4.5.8. 2-Benzyl-6-[(4-methylphenyl)sulfonyl][2,7]-
naphthyridin-1(2H)-one 18. Dienophile: 5 equiv. of
p-toluenesulfonylcyanide. Yield: 69%; yellow crystals;
mp: 168–1698C (CH2Cl2/hexane); IR (KBr/cm21): 3061,
1652, 1619, 1317, 1124; 1H NMR: d 2.40 (s, 3H, CH3), 5.19
(s, 2H, CH2–N), 6.54 (d, 1H, J¼7.4 Hz, H-4), 7.26–7.33
(m, 9H, H–Ph), 7.40 (d, 1H, J¼7.4 Hz, H-3), 8.24 (s, 1H,
H-5), 9.57 (s, 1H, H-8); 13C NMR: d 21.6 (CH3), 51.9
(CH2–N), 104.4 (C-4), 117.9 (C-5), 122.3 (C-8a), 128.1,
128.3, 128.9, 129.1, 129.8, 135.4, 135.6, 138.1 (C-3), 143.7
(C-4a), 145.1 (C-ipso), 152.6 (C-8), 159.9 (C-6), 160.6
(C-1); MS [m/z (%)]: EI: 390 (Mþz), 326 (48, Mþ2SO2z ),
235 (27, Mþz2SO2Tol), 91 (100, Bnþ); HRMS: calcd for
C22H18N2O3S: 390.1038; found: 390.1030; CHN analysis:
calcd for C22H18N2O3S: C 67.67, H 4.65, N 7.17; found: C
67.38, H 4.61, N 7.04.
4.5.6. 2-Benzyl-7-nitro-5,6,7,8-tetrahydro-1(2H)-iso-
quinolinone 15a and 2-benzyl-6-nitro-5,6,7,8-tetra-
hydro-1(2H)-isoquinolinone 15b. Dienophile: 5 equiv. of
nitroethene. Yield: 80%; yellow oil; IR (KBr/cm21): 3071,
1
2940, 1647, 1589, 1543, 1381; H NMR: d 2.27 (m, 2H,
CH2 aþb), 2.66 (m, 2H, CH2 aþb), 3.14 (m, 2H, CH2 aþb),
4.75 (m, 1H, CH aþb), 5.05 (d, 0.75H, J¼14.3 Hz, CH2–N
a), 5.08 (s, 0.5H, CH2–Nb), 5.10 (d, 0.75H, J¼14.3 Hz,
CH2–Na), 5.91 (d, 0.75H, J¼7.0 Hz, H-4 a), 5.93 (d, 0.25H,
2J¼7.0 Hz, H-4 b), 7.09 (d, 1H, 2J¼7.0 Hz, H-3 aþb),
7.22–7.28 (m, 5H, H–Ph aþb); (C6D6/TMS): d 1.40–1.49
(m, 1H, H-6a), 1.57–1.80 (m, 2.5 H, H-6a, H-5a, CH2-7b),
1.95 (dt, 1H, 2J¼18 Hz, 3J¼6.0 Hz, H-5a), 2.20 (dd, 0.25H,
4.5.9. N-[(1-Benzyl-4-methyl-2-oxo-2H-pyridin-3-
yl)methyl]-4-methylbenzenesulfonamide 19. Yield: 53%;
1
pale yellow crystals; mp 108–1108C; H NMR: d 2.17 (s,
3H, CH3), 2.32 (s, 3H, CH3), 4.07 (d, 2H, 3J¼6.6 Hz, CH2),
4.98 (s, 2H, CH2–N), 5.90 (d, 1H, 3J¼7.1 Hz, H-4), 6.16 (t
3
3
broad, 1H, J¼6.6 Hz, NH), 7.04 (d, 1H, J¼7.1 Hz, H-3),
7.07 (d, 2H, 3J¼8.5 Hz, H–Ph), 7.22–7.33 (m, 5H, H–Ph),

T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
5491
7.63 (d, 2H, 3J¼8.5 Hz, H–Ph); 13C NMR: 19.0 (CH3), 21.4
(CH3), 40.8 (CH2), 51.9 (CH2), 109.8 (CH), 124.3, 126.7
(CH), 128.0 (CH), 128.1 (CH), 128.8 (CH), 129.2 (CH),
134.8, 135.9, 137.5, 142.8 (CH), 147.9, 161.9; MS [m/z
(%)]: EI: 382 (2, Mþz), 227 (100, Mþz2SO2C7H7), 155 (2,
SO2C7H7), 91 (86, C7Hþ7 ); HRMS: calcd for C21H22N2O3S:
382.1351; found: 382.1352.
137.9 (C-6), 147.2 (C-7a), 158.6 (C-4); MS [m/z (%)]: EI:
343 (17, Mþz), 279 (32, Mþz2SO2), 188 (48, Mþz2SO2–
C7H7), 91 (100, C7Hþ7 ); HRMS: calcd for C19H21NO3S:
343.1242; found: 343.1241.
4.6.4. N-Allyl-2-(5-benzyl-1,3-dihydro-2,2,4-trioxo-5H-
thieno[3,4-c]pyridin-1-yl)-N-methylacetamide 24. Yield:
63%; yellow oil; IR (NaCl/cm21): 3082, 2925, 1652, 1595,
1
4.6. General procedure for substitution of sulfolene
pyridinone in position 1
1309, 1153; two rotamers: H NMR: d 2.69 and 2.70 (dd,
1H, 2J¼16 Hz, 3J¼8 Hz, H-10), 2.97 and 2.99 (s, 3H, CH3),
3.19 and 3.24 (dd, 1H, 2J¼16 Hz, 3J¼5 Hz, H-10), 3.91 and
0
2
3
4
To a solution of sulfolene pyridinone (0.2 g or 0.7 mmol) in
20 mL dry THF were added dropwise 1.2 equiv. tetrabutyl-
ammonium-fluoride at rt. After stirring for 20 min
1–3 equiv. of an electrophile were added. After a few
hours NH4Cl-solution (20 mL) was added, and stirring was
continued for 15 min. The mixture was extracted with
CH2Cl2 (3£10 mL), the organic phases were dried over
MgSO4 and the solvent evaporated. The residue was
purified by column chromatography (alumina; 15%
EtOAc/85% CH2Cl2).
4.02 (ddt, J¼17 Hz, J¼6 Hz, J¼1.5 Hz, H-4 ), 4.25 and
2
3
4.26 (2£d, 1H, J¼16 Hz, H-3), 4.88 (dd, 1H, J¼8 Hz,
3J¼5 Hz, H-1), 5.14 (2£d, 2H, J¼14.4 Hz, CH2–N), 5.17
2
0
4
(d, 1H, transJ¼14 Hz, H-6 ), 5.22 (cisJ¼4 Hz, J¼1.5 Hz,
0
0
3
H-6 ), 5.76 (m, 1H, H-5 ), 6.24 and 6.27 (s, 1H, J¼7 Hz,
H-7), 7.30–7.38 (m, 6H, H-6þH–Ph); 13C NMR: d 320.6
and 33.6 (C-10), 34.2 and 34.6 (CH3), 50.5 and 52.0 (C-4 ),
52.3 (CH2–N),53.8 (C-3), 63.5 (C-1), 103.3 and 103.4
(C-7), 117.0 and 117.8 (C-60), 121.6 (C-3a), 128.3 (C-arom),
128.33 (C-arom), 128.4 (C-arom), 128.8 (C-arom), 129.0
(C-arom), 131.7 and 132.3 (C-50), 135.5 (C-ipso), 137.9
(C-6), 147.3 and 147.4 (C-7a), 158.6 (C-4), 167.7 and 168.0
(C-20); MS [m/z (%)]: EI: 386 (5, Mþz), 322 (24, Mþz2SO2);
HRMS: calcd for C20H22N2O4S: 386.1300; found:
396.1306.
4.6.1. 5-Benzyl-1,3-dihydro-1-methyl-2,2-dioxo-
thieno[3,4-c]pyridin-4(5H)-one 20. Yield: 70%; white
crystals, mp: 1568C (CH2Cl2/hexane); IR (KBr/cm21):
1
3
3065, 1653; H NMR: d 1.59 (d, 3H, J¼7.2 Hz, CH3),
4.20 (m, 3H, H-1þH-3), 5.14 (s, 2H, CH2–N), 6.11 (d, 1H,
J¼7.2 Hz, H-7), 7.35 (d, 1H, 3J¼7.2 Hz, H-6), 7.33 (m, 5H,
H–Ph); 13C NMR: d 123 (CH3), 52.2 (CH2–N), 53.3 (C-3),
62.2 (C-1), 102.3 (C-7), 121.3 (C-3a), 128.2 (C-arom),
128.4 (C-arom), 129.0 (C-arom), 135.5 (C-ipso), 138.2
(C-6), 148.0 (C-7a), 158.7 (C-4); MS [m/z (%)]: CI: 290
(100, MHþ), 226 (39, MHþ-SO2).
4.7. General procedure for substitution of sulfolene
pyridinone in position 3
To a solution of 0.2 g (0.7 mmol) of the precursor in dry
THF (25 mL) under argon atmosphere was added dropwise
at 2788C 2.1 equiv. of a solution of butyllithium (1 M in
THF). After stirring at 2788C for 20 min, 1.1 equiv.
electrophile was added. The reaction mixture was stirred
for another hour at 2788C and was then allowed to warm up
to rt. Then a solution of NH4Cl (5 mL) was added carefully,
the mixture was extracted with CH2Cl2 (3£10 mL), the
combined organic phases were dried (MgSO4) and evapor-
ated to give a residue that was purified by column
chromatography (alumina;15% EtOAc/85% CH2Cl2).
4.6.2. 1,5-Dibenzyl-1,3-dihydro-2,2-dioxothieno[3,4-
c]pyridin-4(5H)-one 21. Yield: 70%; colourless oil; IR
(NaCl/cm21): 3083, 1650; 1H NMR: d 3.02 (dd, 1H,
3
2
2J¼15 Hz, J¼6 Hz, CH2–Ph), 3.55 (dd, 1H, J¼15 Hz,
3J¼9 Hz, CH2–Ph), 4.08 (d, 1H, J¼16 Hz, H-3), 4.24 (d,
2
1H, 2J¼16 Hz, H-3), 4.37 (dd, 1H, 3J¼9 Hz, 3J¼6 Hz, H-1),
5.10 (2£d, 2H, 2J¼14.5 Hz, CH2–N), 5.67 (d, 1H, 3J¼7 Hz,
3
H-7), 7.20 (d, 1H, J¼7 Hz,0 H-6), 7.30–7.38 (m, 5H, H–
Ph); 13C NMR: d 35.1 (C-1 ), 52.28 (C-Bn), 53.40 (C-3),
67.9 (C-1), 10.3.4 (C-7), 121.9 (C-3a), 127.5 (C-arom),
1282 (C-arom), 128.4 (C-arom), 128.8 (C-arom), 129.0
(C-arom), 129.3 (C-arom), 135.2 (C-ipso), 135.4 (C-ipso),
137.5 (C-6), 147.0 (C-7a), 158.7 (C-4); MS [m/z (%)]: EI:
365 (9, Mþz), 301 (36, Mþz2SO2), 210 (15, Mþz2SO2,
–C7H7); HRMS: calcd for C21H19NO3S: 365.1086; found:
365.1090.
4.7.1. 3,5-Dibenzyl-1,3-dihydro-2,2-dioxothieno[3,4-
c]pyridin-4(5H)-one 26. Yield: (60%); white crystals,
1
mp: 182–182.58C; IR (KBr/cm21): 3082, 1641; H NMR:
2
3
d 3.45 (dd, 1H, J¼15 Hz, J¼7 Hz, 3-CH2–Ph), 3.55 (d,
2
2
3
1H, J¼16 Hz, H-1), 3.58 (dd, 1H, J¼15 Hz, J¼2.5 Hz,
2
3-CH2–Ph), 3.88 (d, 1H, J¼16 Hz, H-1), 4.56 (dd, 1H,
3J¼7 Hz, 3J¼2.5 Hz, H-3), 5.07 (d, 1H, 2J¼14.5 Hz, CH2–
N), 5.27 (d, 1H, 2J¼14.5 Hz, CH2–N), 5.94 (d, 1H,
3J¼7 Hz, H-7), 7.13 (m, 2H, H–Ph), 7.30 (m, 3H, H–Ph),
7.30 (s, 1H, 3J¼7 Hz, H-6), 7.37 (m, 5H, H–Ph); 13C NMR:
d 33.61 (C-30), 52.3 (CH2–N), 56.9 (C-1), 66.3 (C-3), 103.9
(C-7), 126.5 (C-3a), 126.9 (C-arom), 128.0 (C-arom), 128.1
(C-arom), 128.4 (C-arom), 129.0 (C-arom), 130.1 (C-arom),
135.7 (C-ipso), 137.9 (C-6), 142.6 (C-7a), 158.7 (C-4); MS
[m/z (%)]: CI: 365 (0, Mþz), 301 (70, Mþz2SO2), 210 (74,
Mþz2SO2, –C7H7), 91 (100, C7Hþ7 ); HRMS: calcd for
C21H19NO3S: 365.1086; found: 365.1081.
4.6.3. 5-Benzyl-1,3-dihydro-1-(4-pentenyl)-2,2-dioxo-
thieno[3,4-c]pyridin-4(5H)-one 22. Yield: 56%; colourless
1
oil; IR (NaCl/cm20 1): 2930, 1650, 1310, 1195; H NMR:0 d
1.72 (m, 2H, H-20), 1.89 (m, 1H, H-10), 2.07 (m, 1H, H-1 ),
2.14 (m, 2H, H-3 ), 4.09 (dd, 1H, 3J¼9 Hz, 3J¼5 Hz, H-1),
4.20 (m, 2H, H-3), 5.01 (m, 2H, H-50), 5.13 (s, 2H, CH2–N),
0
3
5.77 (ddt, 1H, transJ¼17 Hz, cisJ¼10 Hz, J¼7 Hz, H-4 ),
3
3
6.11 (d, 1H, J¼7 Hz, H-7), 7.29 (d, 1H, J¼7 Hz, H-6),
7.34 (m, 5H, H–Ph); 13C NMR: d 25.5 (C-20), 28.0 (C-10),
33.1 (C-30), 52.2 (CH2–N), 53.7 (C-3), 66.9 (C-1), 102.7
(C-7), 115.6 (C-50), 121.5 (C-3a), 128.2 (C-arom), 1280.3
(C-arom), 128.9 (C-arom), 135.4 (C-ipso), 137.2 (C-4 ),
4.7.2. 5-Benzyl-1,3-dihydro-3-(4-pentenyl)-2,2-dioxo-
thieno[3,4-c]pyridin-4(5H)-one 27. Yield: 60%; white
crystals, mp: 90.5–91.3 (CH2Cl2/hexane); IR (KBr/cm21):

5492
T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
0
1
2928, 1654, 1313, 11807; H NMR: d 1.67 (m, 2H, H-3 ),
2.10 (m, 4H, H-10þH-2 ), 4.14 (2£d, 2H, 2J¼16.6 Hz, H-1),
4.28 (dd, 1H, 3J¼8 Hz, 0 3J¼4 Hz, H-3), 40.79 (dt, 1H,
cisJ¼10 Hz, 4J¼1 Hz, H-5 ), 4.96 (m, 1H, H-5 ), 5.10 (2£d,
237 (10, Mþz2SO2, –CH3OH), 211 (24, Mþz2SO2,
–CO2Me), 178 (10, Mþz2SO2, –CH3OH, –C7H7), 91
(100, C7Hþ7 ); HRMS: calcd for C16H15NO5S: 333.0671;
found: 333.0667.
2H, 2J¼14.5 Hz, H-N), 5.79 (ddt, 1H, transJ¼17 Hz,
0
cisJ¼10 Hz, J¼6 Hz, H-4 ), 6.10 (d, 1H, J¼7 Hz, H-7),
4.7.6. N,N-Diallyl-5-benzyl-1,3-dihydro-2,2,4-trioxo-5H-
thieno[3,4-c]pyridin-3-carboxamide 34. Yield: 58%;
yellow oil; IR (NaCl/cm21): 3080, 1658, 1590, 1310,
3
3
7.32 (d, 1H, 3J¼7 0Hz, H-6), 7.30–7.35 (m, 5H, H–Ph); 13
C
NMR: d 25.9 (C-1 ), 28.5 (C-20), 33.5 (C30), 52.3 (CH2–N),
56.8 (C-1), 65.3 (C-3), 103.3 (C-7), 115.9 (C-50), 127.2
(C-3a), 128.2 (C-arom), 128.4 (C-arom),0 129.1 (C-arom),
135.6 (C-ipso), 137.8 (C-6), 137.9 (C4 ), 141.7 (C-7a),
158.7 (C-4); MS [m/z (%)]: EI: 343 (5, Mþz), 279 (16,
Mþz2SO2), 175 (15, Mþz2C5H9), 188 (15, Mþz2SO2,
–C7H7), 91 (100, C7Hþ7 ); HRMS: calcd for C19H21NO3S:
343.1242; found: 343.1239.
1
1150; H NMR: d 4.02–4.11 (m, 2H, CH2NCO), 4.13 (d,
2
1H, J¼16 Hz, H-1), 4.22–4.30 (m, 1H, CH2NCO), 4.48
(ddt, 1H, 2J¼18 Hz, 3J¼5 Hz, 4J¼1 Hz, CH2NCO), 4.65 (d,
1H, 2J¼16 Hz, H-1), 4.99 (d, 1H, 2J¼15 Hz, CH2–N),
2
5.15–5.27 (m, 2H, vCH2), 5.26 (d, 1H, J¼15 Hz, CH2–
N), 5.30 (s, 1H, H-3), 5.38 (dm, 1H, cisJ¼10 Hz, vCH2),
5.46 (dm, 1H, transJ¼17 Hz, vCH2), 5.70–5.84 (m, 1H,
H–Cv), 5.92–6.08 (m, 1H, H–Cv), 7.26 (d, 1H,
3J¼7.2 Hz, H-7), 7.29–7.40 (m, 6, H-6þH–Ph); 13C
NMR: d 49.1 (C-30), 49.7 (C-30), 52.4 (CH2–N), 58.3
(C-1), 66.5 (C-3), 103.7 (C-7), 117.8 (C-50), 117.7 (C-50),
125.5 (C-3a), 128.1 (C-arom), 128.4 (C-arom), 129.1
(C-arom), 131.1 (C-40), 131.7 (C-40), 135.2 (C-ipso), 138.9
(C-6), 144.7 (C-7a), 164.1 (C-4), 177.8 (C-10); MS [m/z
(%)]: EI: 398 (2, Mþz), 334 (15, Mþz2SO2), 293 (3,
Mþz2SO2, –C3H5), 239 (16, Mþz2SO2, –C6H11N), 91
(100, C7Hþ7 ); HRMS: calcd for C21H22N2O4S: 398.1300;
found: 398.1298.
4.7.3. 5-(5-Benzyl-1,3-dihydro-2,2,4-trioxo-5H-
thieno[3,4-c]pyridin-3-yl) pentanenitrile 28. Yield: 58%;
yellow oil; IR (NaCl/cm21): 3061, 2933, 1651, 1599, 1311,
0
0
1
1117; H NMR: 0d 1.70–17.4 (m, 4H, H-2 þH-3 ), 2.05–
2.20 (m, 2H, H-1 ), 3.36 (t, 2H, 3J¼7 Hz, H-40), 4.16 (2£d,
2
3
3
2H, J¼16.6 Hz, H-1), 4.23 (dd, 1H, J¼7.3 Hz, J¼4 Hz,
2
H-3), 5.20 (2£d, 2H, J¼14.6 Hz, CH2–N), 6.11 (d, 1H,
3J¼7 Hz, H-7), 7.26 (d, 1H, 3J¼70Hz, H-6), 70.29–7.35 (m,
5H, H–Ph); 13C NMR: d 16.7 (C-4 ), 25.1 (C-3 ), 25.7 (c-20),
27.8 (C-10), 52.4 (CH2–N), 56.8 (C-1), 64.8 (C-3), 103.3
(C-7), 119.4 (CN), 126.5 (C-3a), 128.2 (C-arom), 128.4
(C-arom), 129.1 (C-arom), 135.4 (C-ipso), 138.2 (C-6),
141.9 (C-7a), 158.7 (C-4); MS [m/z (%)]: EI: 356 (6, Mþz),
316 (4, Mþz2C2H2N), 292 (12, Mþz2SO2), 275 (10,
Mþz2C5H8N), 252 (28, Mþz2C2H2N, –SO2), 224 (50,
Mþz2C4H6N, –SO2), 201 (8, Mþz2SO2, –C7Hþ7 ), 91 (100,
C7Hþ7 ); HRMS: calcd for C19H20N2O3S: 356.1195; found
356.1193.
4.7.7. (E)-N-Allyl-3-(1-benzyl-4-methyl-2-oxo-1H-pyri-
din-3-yl)-N-methylpropene amide 35. Yield: 50%; yellow
oil; IR (NaCl/cm21): 3079, 2929, 1653, 1596; two rotamers:
1H NMR: d 2.37 and 2.38 (s, 3H, CH3), 3.03 and 3.08 (s, 3H,
CH3–N), 4.1 (m, 2H, H-50), 5.17 (m, 4H, CH2–NþH-70),
0
3
5.81 (m, 1H, H-6 ), 6.08 and 6.10 (d, 1H, J¼7 Hz, H-5),
3
7.15 and 7.19(d, 1H, J¼7 Hz, H-6), 7.30 (m, 5H, H–Ph),
7.77 and 7.79 (d, transJ¼15 Hz, H-20), 8.03 and 8.12 (d, 1H,
transJ¼150Hz, H-10); 13C NMR: d 20.12 (CH3-4), 50.4 and
51.9 (C-5 ), 52.3 and 51.8 (CH2–N), 110.0 and 110.1 (C-5),
116.9 (C-70), 121.1 (C-20), 122.8 (C-3), 127.8 (C-arom),
127.9 (C-arom), 128.9 (C-arom), 133.1 (C-60), 134.6 and
134.7 (C-6), 135.7 and 135.8 (C-10), 136.2 (C-ipso), 151.3
(C-4), 161.0 (C-2), 167.7 and 168.3 (C-30); MS [m/z (%)]:
EI: 224 (50, Mþz), 133 (10, Mþz2C7H7), 91 (100, C7Hþ7 );
HRMS: calcd for C20H22N2O2: 322.1681; found: 322.1681.
4.7.4. 4-(5-Benzyl-1,3-dihydro-2,2,4-trioxo-5H-
thieno[3,4-c]pyridin-3-yl)butanenitrile 29. Yield: 44%;
yellow crystals, mp 121–1228C; IR (KBr/cm21): 3062,
2928, 2245, 1647; 1H NMR: d 1.95 (m, 2H, H-20), 2.20 (m,
2H, H-10), 2.43 (t, 2H, 3J¼8 Hz, H-30), 4.18 (2£d, 2H,
2J¼16.6 Hz, H-1), 4.25 (dd, 1H, J¼12.1 Hz, J¼7.3 Hz,
3
3
2
H-3), 5.14 (2£d, 2H, J¼15.4 Hz, CH2–N), 6.14 (d, 1H,
3J¼7 Hz, H-7), 7.28 (d, 1H, J¼7 Hz, H-6), 7.33 (m, 5H,
3
H–Ph); 13C NMR: d 17.0 (C-30), 22.8 (C-20), 28.2 (C-10),
52.4 (CH2–N), 56.6 (C-1), 64.8 (C-3), 103.3 (C-7), 118.5
(CN), 126.2 (C-3a), 128.2 (C-arom), 128.5 (C-arom), 129.1
(C-arom), 138.3 (C-6), 142.1 (C-7a), 158.7 (C-4); MS [m/z
(%)]: EI: 342 (5, Mþz), 278 (15, Mþz2SO2), 224 (51,
Mþz2SO2, –C3H4N), 187 (12, Mþz2SO2, –C7H7), 91 (100,
C7Hþ7 ); HRMS: calcd for C18H18N2O3S: 342.1038; found:
342.1035.
4.8. General procedure for intramolecular Diels–Alder
reactions
A solution of 100 mg of a substituted sulfolene pyridinone
in 20 mL o-dichlorobenzene was thermolysed at 1508C for
4–8 h under an inert atmosphere (N2 of Ar). The solvent
was removed by Kugelrohr distillation and the residue was
purified by column chromatography (silica; 15%
EtOAc/85% CH2Cl2) to give following compounds.
4.7.5. Methyl 5-benzyl-1,3-dihydro-2,2,4-trioxo-5H-
thieno[3,4-c]pyridin-3-carboxylate 30. Yield: 55%;
yellow oil; IR (NaCl/cm21): 3065, 2926, 1746, 1649,
4.8.1. 3-Benzyl-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta-
(f(-isoquinolin-4(3H)-one 36, 37. Yield: 67%; colourless
1
1319, 1110; H NMR: d 3.85 (s, 3H, CH3), 4.23 (d, 2H,
2J¼16 Hz, H-1), 4.35 (s, 1H, H-3), 5.16 (2£d, 2H,
1
oil; IR (NaCl/cm21): 3065, 2927, 1644; H NMR: d 1.60–
2J¼14 Hz, CH2–N), 6.19 (d, 1H, J¼7 Hz, H-7), 7.26–
2.70 (m, 12H, CH2þCH), 5.10 (2£d, 1H, 2J¼14.5 Hz,
CH2–N), 5.12 (s, 1H, CH2–N), 5.98 (d, 0.46H, 3J¼7.0 Hz,
H-1), 6.02 (d, 0.54H, 3J¼7.0 Hz, H-1), 7.05 (d, 0.46H,
3
7.32 (m, 6H, H-6þH–Ph); 13C NMR: d 52.3 (CH2–N), 54.9
(CH3), 58.3 (C-1), 71.2 (C-3), 103.0 (C-7), 121.8 (C-3a),
128.3 (C-arom), 128.8 (C-arom), 129.8 (C-arom), 136.3
(C-ipso), 138.1 (C-6), 143.1 (C-7a), 158.5 (C-4), 169.2
(CO); MS [m/z (%)]: EI: 333 (9, Mþz), 269 (15, Mþz2SO2),
3
3J¼7.0 Hz, H-2), 7.09 (d, 0.54H, J¼7.0 Hz, H-2), 7.26–
7.34 (m, 5H, H–Ph); 13C NMR: d 22.6 (CH2), 22.7 (CH2),
23.9 (CH2), 25.8 (CH2), 27.2 (CH2), 27.5 (CH2), 30.3 (CH2),

T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
5493
31.6 (CH2), 32.9 (CH2), 36.6 (CH), 42.7 (CH), 43.2 (CH),
41.1 (CH), 51.8 (CH2–N), 51.9 (CH2–N), 105.7 (C-1),
108.1 (C-1), 127.1 (C-4a), 127.7 (C-arom), 128.2 (C-arom),
128.7 (C-arom), 132.8 (C-2), 133.1 (C-2), 150.3 (C-9b),
150.4 (C-9b), 162.3 (C-4); MS [m/z (%)]: EI: 279 (89, Mþz),
238 (10, Mþz2C3H5), 188 (100, Mþz2C7H7), 91 (99;
C7Hþ7 ); HRMS: calcd for C19H21NO: 279.1623; found:
279.1620.
137.0 (C-ipso AþB) 148.1 (C-4a AþB), 162.3 (C-1 AþB);
MS [m/z (%)]: EI: 279 (100, Mþz), 188 (52, Mþz2C7H7), 91
(73, C7Hþ7 ); HRMS: calcd for C19H21NO: 279.1623; found:
279.1625.
4.8.4. (3aS p, 9bS p)-2-Allyl-8-benzyl-1,3,3a,4,5,9b-hexa-
hydro-8H-pyrrolol[3,4-h]-isoquinolin-1,9(2H)-dione 41.
Yield: 65%; yellow crystals; mp: 156–1578C; IR (KBr/
1
cm21): 3060, 2988, 1645, 1609; H NMR: d 1.65 (m, 1H,
4.8.2. (4aS p,10bS p)-8-Benzyl-1,2,3,4,4a,5,6,10b-octa-
hydro-3-methyl-[3,8]phenanthroline-2,7(8H)-dione 38
and (4aS p,10bR p)-8-benzyl-1,2,3,4,4a,5,6,10b-octa-
hydro-3-methyl-[3,8]phenanthroline-2,7(8H)-dione 39.
Yield: 83%; colourless oil; IR (NaCl/cm21): 3067, 2925,
1644, 1545; 1H NMR: d 1.43 (ddd, 0.3H, 2J¼18 Hz,
3J¼12 Hz, 3J¼6 Hz, H-5 39), 1.77–1.88 (m, 2H, H-5a
39þH-5 38), 2.00 (m, 0.3H, H-5 39), 2.20 (m, 1.7H, H-5a
H-4), 1.80 (m, 1H, H-4), 2.47–2.53 (m, 2H, H-3aþH-5),
2.95 (d, 1H, 2J¼10 Hz, H-3), 3.65 (dd, 1H, 2J¼10 Hz,
2
3
3J¼6.0 Hz, H-3), 3.84 (dd broad, J¼14.9 Hz, J¼6.2 Hz,
0
0
2
3
H-2 ), 3.93 (dd broad, J¼14.9 Hz, J¼6.2 Hz, H-2 ), 4.08
3
2
(d, 1H, J¼7.3 Hz, H-9b), 5.00 (d, 1H,000 J¼14.5 Hz, CH2–
N), 5.18 (d broad, cisJ¼9.9 Hz, H-2 ), 5.21 (d broad,
000
transJ¼17 Hz, H-2 ), 5.30 (d, 1H, J¼14.5 Hz, CH2–N),
2
5.71 (ddd, 1H, transJ¼17 Hz, cisJ¼9.9 Hz, 3J¼6.2 Hz,
00
2
3
3
3
38þH-1 39), 2.33 (dd, 0.7H, J¼17.5 Hz, J¼11 Hz, H-1
H-2 ), 5.88 (d, 1H, J¼7 Hz, H-6), 7.06 (d, 1H, J¼7 Hz,
H-7), 7.25–7.33 (m, 5H, H–Ph); 13C NMR: 0d 24.9 (C-4),
27.7 (C-5), 30.9 (C-4a), 41.6 (C-9b), 45.6 (C-2 ), 50.9 (C-3),
52.0 (CH2–N), 107.3 (C-6), 118.2 (C-2000), 127.8 (C-arom),
128.4 (C-arom), 128.8 (C-arom), 132.8 (C-200), 131.1
(C-9a), 134.3 (C-7), 137.0 (C-ipso), 147.2 (C-5a), 162.0
(C-8), 170.2 (C-1); MS [m/z (%)]: EI: 334 (40, Mþz), 243
(60, Mþz2C7H7); HRMS: calcd for C21H22N2O2: 334.1681;
found: 334.1691.
38), 2.44–2.50 (m, 0.6H, H-6 39), 2.53 (ddd, 0.7H,
3
3
2J¼19 Hz, J¼10 Hz, J¼8 Hz, H-6 38), 2.65 (ddþm, 1H,
2J¼17.5 Hz, 3J¼6.5 Hz, H-1 38þH-10b 39), 2.85 (ddd,
2
3
3
0.7H, J¼19 Hz, J¼6 Hz, J¼3 Hz, H-6 38), 2.88–2.98
(m, 0.7H, H-10b 38), 2.95 (s, 2.1H, CH3 38), 2.98 (s, 0.9H,
CH3 39), 3.12 (t, 0.3, J¼3J¼12 Hz, H-4 39), 3.17 (dd,
2
0.7H, 2J¼12.5 Hz, 3J¼3 Hz, H-4 38), 3.35 (dd, 0.3H,
3
2
2J¼12 Hz, J¼5 Hz, H-4 39), 3.62 (dd, 0.7H, J¼12.5 Hz,
3J¼5.5 Hz, H-4 38), 5.11 (2£d, 2H, J¼14.5 Hz, CH2–N
2
3
38þ39), 5.92 (d, 0.3H, J¼7 Hz, H-10 38), 6.02 (d, 0.7H,
4.8.5. (E)-6-(1-Benzyl-4-methyl-2-oxo-1H-pyridin-3-yl)-
5-hexenenitrile 42. Yield: 44%; blue oil; IR (NaCl/cm21):
3J¼7 Hz, H-10 39), 7.12 (d, 0.3H, J¼7 Hz, H-9 38), 7.15
3
(d, 0.3H, 3J¼7 Hz, H-9 39), 7.25–7.33 (m, 5H, H–Ph
38þ39): 13C NMR: d 22.6 (C-5 38), 23.6 (C-5 39), 23.4
(C-6 38), 25.3 (C-6 39), 30.9 (C-4a 38), 34.4 (CH3 39), 34.7
(CH3 38), 35.2 (C-10b 38), 35.4 (C-1 38), 35.5 (C-4a 39),
36.7 (C-1 39), 37.9 (C-10b 39), 52.0 (CH2–N 38þ39),
104.0 (C-10 39), 106.4 (C-10 38), 126.1 (C-6a 39), 127.3
(C-6a 38), 127.9 (C-arom 38þ39), 128.2 (C-arom 38þ39),
128.8 (C-arom 38þ39), 133.8 (C-9 38þ39), 136.5 (C-ipso
38þ39), 146.5 (C-10a 39), 148.2 (C-10a 38), 162.0 (C-7
39), 162.3 (C-7 38), 167.9 (C-2 39), 168.7 (C-2 38); MS
[m/z (%)]: EI: 322 (63, Mþz), 231 (20, Mþz2C7H7), 203 (5,
Mþz2C7H7, –CO), 188, Mþz2C7H7, –CO), 188 (15,
Mþz2C7H7, –NHCO), 91 (100; C7Hþ7 ); HRMS: calcd for
C20H22N2O2: 322.1681; found: 322.1679.
3032, 2935, 2245, 1648, 1594; H NMR: d 1.83 (q, 2H,
3J¼7 Hz, H-40), 2.26 (3H, s, CH3), 2.41 (m, 4H, H-30 þH-
1
0
3
5 ), 5.41 (s, 2H, CH2–N), 6.06 (d, 1H, J¼7.0 Hz, H-5),
6.44 (dt, 1H, transJ¼16.0 Hz, 4J¼0 1.2 Hz, H-10), 6.83 (dt, 1H,
transJ¼16.0 Hz, J¼7.0 Hz, H-2 ), 7.10 (d, 1H, J¼7.0 Hz,
H-6), 7.31 (m, 5H, H–Ph); 13C NMR: d 16.4 (C-50), 20.3
(CH3), 24.9 (C-40), 33.0 (C-30), 52.1 (CH2–N), 110.0 (C-5),
119.7 (CN), 124.8 (C-3), 125.1 (C-20), 127.8 (C-arom),
127.9 (C-arom), 128.8 (C-arom), 129.0 (C-10), 133.6 (C-6),
136.5 (C-ipso), 146.1 (C-4), 161.3 (C-2); MS [m/z (%)]: EI:
292 (15, Mþz), 252 (44, Mþz2C2H2N), 224 (30,
Mþz2C4H6N), 201 (11, Mþz2C7H7) 91 (100, C7Hþ7 );
HRMS: calcd for C12H20N2O: 292.1576; found:292.1575.
3
3
4.8.6. (E)-5-(1-Benzyl-4-methyl-2-oxo-1H-pyridin-3-yl)-
4-pentenenitrile 43. Yield: 58%; yellow oil; IR (NaCl/
cm21): 3020, 2999, 2245, 1648, 1590; 1H NMR: d 2.27 (s,
3H, CH3), 2.50 (m, 2H, H-30), 2.57 (m, 2H, H-40), 5.14 (s,
4.8.3. (6aR p,9aR p)-2-Benzyl-6,6a,7,8,9,9a-hexahydro-
5H-cyclopenta[h]isoquinolin-1(2H)-one 40. Two con-
formers. Yield: 60%; colourless oil; IR (NaCl/cm21):
3030, 2935, 1650; 1H NMR: d 1.20–1.55 (m, 4H,
3£HþH-6a B), 1.60–1.72 (m, 3H), 1.99–2.04 (m, 1H,
H–(CH2-B)), 2.10–2.19 (m, 1H, H-6a A), 2.20–2.29 (m,
1H, H-9a B), 2.43–2.49 (m, 2H, CH2 A), 2.60–2.80 (m, 2H,
CH2 B) 2.80–2.88 (m, 1H, H-(CH2 B)), 3.01–3.08 (m, 1H,
H-9a A), 4.92 (d, 1H, 2J¼14.5 Hz, CH2–N B), 4.96 (d, 1H,
2J¼14.5 Hz, CH2–N A), 5.24 (d, 1H, 2J¼14.5 Hz, H-Bn B),
5.25 (d, 1H, 2J¼14.5 Hz, H-Bn A), 5.91 (d, 1H, 3J¼7.0 Hz,
H-4 AþB), 7.02 (dd, 1H, 3J¼7.0 Hz, 6J¼1 Hz, H-3 AþB),
7.25–7.32 (m, 5H, H–Ph AþB); 13C NMR: d 22.4 (CH2 B),
26.8 (CH2 B), 29.3 (CH2 B), 29.6 (CH2 B), 31.6 (CH2 B),
2£44.8 (CH B), 23.6 (CH2 A), 25.5 (CH2 A), 29.0 (CH2 A),
31.4 (CH2 A), 31.7 (CH2 A), 37.1 (CH A), 38.7 (CH A),
51.6 (CH2–N B), 51.8 (CH2–N A), 108.0 (C-4 AþB),
127.9 (C-arom AþB), 128.1 (C-arom AþB), 128.7 (C-arom
AþB), 130.8 (C-9b AþB), 132.6 (C-3 A), 133.2 (C-3 B)
3
2H, CH2–N), 6.04 (d, 1H, J¼7.0 Hz, H-5), 6.51 (dt, 1H,
0
4
transJ¼15.0 Hz, J¼1.3 Hz, H-1 ), 6.86 (dt, 1H, transJ¼15.0
Hz, 3J¼7.0 Hz, H-20), 7.10 (d, 1H, 3J¼7.0 Hz, H-6), 7.25–
7.32 (m, 5H, H–Ph); 13C NMR: d 17.6 (C-40), 20.3 (CH3),
30.2 (C-30), 52.3 (CH2–N), 109.9 (C-5), 119.3 (CN), 124.6
(C-3), 126.1 (C-20), 127.9 (C-arom), 127.8 (C-arom), 128.8
(C-arom), 131.4 (C-10), 134.0 (C-6), 136.5 (C-ipso), 146.7
(C-4), 161.3 (C-2); MS [m/z (%)]: CI: 274 (100, MHþ).
Acknowledgements
The authors thank the FWO (Fund for Scientific Research—
Flanders, Belgium) and the IUAP-4-11 funding by DWTC.
We are grateful to R. De Boer for HRMS measurements and
to the Janssen Pharmaceutica company for element analysis.

5494
T. C. Govaerts et al. / Tetrahedron 59 (2003) 5481–5494
4203. (j) Cappelle, S. L.; Vogels, I.; Van Meervelt, L.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett. 2001, 42,
3759.
T. G. thanks the IWT and I. V. (Research Assistant of the
FWO-Flanders) thanks the FWO for the fellowships
received.
4. Govaerts, T. C.; Vogels, I.; Compernolle, F.; Hoornaert, G. J.
Tetrahedron Lett. 2002, 43, 799–802.
5. (a) Dolle, V.; Nguyen, C. H.; Legraverend, M.; Aubertin,
A. M.; Kirn, A.; Andreola, M. L.; Ventura, M.; Tarrago-
Litvak, L.; Bisagni, E. J. Med. Chem. 2000, 43, 3949–3962.
(b) Fink, D. M.; Bores, G. M.; Effland, R. C.; Huger, F. P.;
Kurys, B. E.; Rush, D. K.; Selk, D. E. J. Med. Chem. 2000, 38,
3645–3651.
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