Generation of 5,6-dimethylene-2(1H)-pyridinones from [3,4-b] sulfolene pyridinones and application in Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2003.11.005

2(1H)-Pyrazinones were converted into various [3,4-b] sulfolene pyridinones 19-21, serving as precursors for thermolytic conversion into the corresponding 5,6-dimethylene 2(1H)-pyridinone ortho-quinodimethanes. These were trapped in situ by reaction with

Full text of DOI:10.1016/j.tet.2003.11.005

Tetrahedron 60 (2004) 429–439
Generation of 5,6-dimethylene-2(1H)-pyridinones from [3,4-b]
sulfolene pyridinones and application in Diels–Alder reactions
*
Tom C. Govaerts, Ilse A. Vogels, Frans Compernolle and Georges J. Hoornaert
Laboratorium voor Organische Synthese, Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 1 August 2003; revised 4 November 2003; accepted 6 November 2003
Abstract—2(1H)-Pyrazinones were converted into various [3,4-b] sulfolene pyridinones 19–21, serving as precursors for thermolytic
conversion into the corresponding 5,6-dimethylene 2(1H)-pyridinone ortho-quinodimethanes. These were trapped in situ by reaction with
various dienophiles. Tethering of precursor 19 with a dienophilic side chain attached to the 7-position of the [3,4-b] sulfolene pyridinone also
enabled intramolecular cycloaddition when no rearrangement by 1,5-H-shift was viable.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
addition–elimination reaction with the pyrazinone azadiene
to form the dihydrothiophene-fused bicyclic pyridinone.
Oxidation of the ring sulfur atom finally can produce the
desired [3,4-b] sulfolene pyridinone precursor.
During the last decade a vast number of publications have
appeared on heteroaromatic ortho-quinodimethanes (o-
QDM).1 These highly reactive species are commonly
generated in situ from various precursors,2 e.g. by thermal
extrusion of SO2 from sulfolene-fused heterocyclic pre-
cursors.3 In a preceding paper we described the use of
[3,4-c] sulfolene pyridinones as precursors for generation of
3,4-dimethylene-2(1H)-pyridinone o-QDM and subsequent
cycloaddition.4,5 Here we present a study on the isomeric
[3,4-b] sulfolene pyridinone precursor type. Upon extrusion
of SO2 the latter is transformed into the novel 5,6-
dimethylene-2(1H)-pyridinone o-QDM system, which can
be trapped in inter- and intramolecular Diels–Alder
reactions to afford various unknown polycyclic pyridinones.
In recent years, substituted pyridinones have regained
interest, based on their biological and pharmacological
properties.6
The synthesis of the precursors started with nucleophilic
substitution of the reactive imidoyl chloride function by
treatment with sodium methoxide, sodium ethanethiolate, or
tetraphenyltin to produce the 3-substituted pyrazinones 2–4.
Following bromination of the 6-methyl group the resulting
bromides 5–7 were made to react with thiolacetic acid and
triethylamine to give thioesters 8–10 (Scheme 1, Table 1).
Compounds 8–10 were converted into thioethers 11–13 by
treatment with sodium methoxide to generate the thiolate
anion followed by in situ reaction with propargyl bromide.
Thioethers 11 and 13 were stable at room temperature but
bis-thioether 12 had to be stored at low temperature. Internal
cycloaddition of 11–13 was effected by heating in boiling
toluene to afford dihydrothienopyridinones 16–18 exclu-
sively. The preferred expulsion of cyanogen chloride from
the intermediate cycloadducts 15 is in accord with our
2. Results and discussion
2.1. Synthesis of the precursors
Our synthetic approach is depicted in Schemes 1 and 2. To
generate the required 5,7-dihydrothieno[3,4-b]pyridin-
2(1H)-one ring system, we envisaged bromination of the
6-methyl group of pyrazinones 2–4, followed by functional
group interconversion to introduce the 2-propynylsulfanyl
group as a dienophilic side chain. The latter can undergo
Scheme 1. Synthesis of the thioesters 8–10. Reagents and conditions: (a) 2:
1.1 equiv. NaOMe, MeOH, room temperature; 3: 1.2 equiv. NaSEt, THF,
room temperature; 4: 1.2 equiv. SnPh4, 0.01 equiv. Pd(P(Ph)3)4, toluene,
reflux, 1 week; (b) 1.2 equiv. NBS, CCl4, reflux, cat. (PhCOO)2; (c)
1.2 equiv. HSCOCH3, Et3N, THF, room temperature, 1 h.
Keywords: ortho-Quinodimethane; Pyridinone; Diels–Alder reaction.
*
Corresponding author. Tel.: þ32-16-32-74-09; fax:þ32-16-32-79-90;
e-mail address: georges.hoornaert@chem.kuleuven.ac.be
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.005

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T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
2.2. Intermolecular Diels–Alder reactions
To study the reactivity of the pyridinone o-QDM generated
from precursors 19–21 and the regioselectivity in sub-
sequent cycloaddition reactions, different types of dieno-
philes were applied in the thermolysis experiments. These
were carried out by heating a mixture of precursor 19–21
and N-phenylmaleimide (NPMA) or methyl acrylate in o-
dichlorobenzene (o-DCB) in a sealed glass tube at 150 to
160 8C (Scheme 3).
Scheme 2. Synthesis of sulfolene pyridinones. Reagents and conditions:
(a) (i) 1.3 equiv. NaOMe, MeOH, room temperature, (ii) 3 equiv. propargyl
bromide, room temperature; (b) toluene, reflux; (c) 3 equiv. m-CPBA,
CH2Cl2, room temperature.
Scheme 3. Intermolecular Diels–Alder reactions. Reagents and conditions:
(a) 3 equiv. NPMA, 150–160 8C, o-DCB; (b) 10 equiv. methyl acrylate,
150–160 8C, o-DCB.
previous findings, which indicated that concurrent loss of
benzyl isocyanate is a less favourable process.7,8 The
reaction times required for conversion of 11–13 into cyclic
sulfides 16–18 were largely different. For instance,
compound 12 (R3¼SEt) underwent Diels–Alder reaction
already at room temperature, but subsequent elimination of
cyanogen chloride from cycloadduct 15 to form 17 required
further heating in boiling toluene for 15 h. By contrast,
compounds 11 and 13 were converted directly into the final
products 16 and 18 after heating for 6 and 3 h, respectively.
Clearly, the activation energy for cycloaddition of the
azadiene system and subsequent cycloreversion is affected
in a different way by substituents in position 3 of the
pyrazinone. Final oxidation of the cyclic sulfides 16–18
using meta-chloroperoxybenzoic acid (m-CPBA) furnished
the required sulfolene pyridinones 19–21 (note: R3¼SO2Et
in the case of 20). In an alternative route, the cycloaddition/
oxidation sequence was reversed: following oxidation of
thioether 11 using m-CPBA, the resulting sulfone 14 was
heated in toluene for 2 h to produce o-QDM precursor 19
(Scheme 2). The latter route is less preferred, mainly
because the yield of the cycloaddition–elimination reaction
is significantly lower.
The cycloadducts 22–24 formed with NPMA were isolated
in good yields. The structure and conformational behaviour
of these adducts were determined on the basis of coupling
constants and NOESY as illustrated for adduct 24 (Fig. 1).
Proton H-4 exhibits a strong NOE-correlation (dashed
lines) with an ortho-proton of the phenyl group and with
the coplanar equatorial proton H-5eq (d 3.12, dd, 1H,
3
2J5eq–5ax¼15.0 Hz, J5eq–5a¼1.7 Hz). Obviously H-5eq can
2
be connected to H-5ax (d 2.75, dd, 1H, J5ax–5eq¼15.0 Hz,
3J5ax–5a¼5.0 Hz), which in turn shows a strong NOE with
the angular proton H-5a. Since such a correlation is not
observed for H-5eq, the latter must have a trans-relationship
with H-5a. This, in turn, implies an equatorial orientation of
H-5a, according with the conformational structure proposed
in Figure 1 and the small coupling constant values observed
3
3
for J5eq– 5a (1.7 Hz) and J5ax– 5a (5.0 Hz). For the
analogous cycloadducts 22 and 23 a comparable confor-
mational structure was inferred, based on similar coupling
patterns and NOE-correlations.
In spite of the different electronic nature of the substituents
introduced in 3-position of the pyridinone precursors 19–21,
reaction of the corresponding o-QDM with methyl acrylate
failed to show a clear-cut effect on the regioselectivity of the
Table 1. Synthesis of the sulfolene pyridinones
Starting compound
Product
R3
Yield (%)
8
9
11
12
13
14
16
17
18
19
19
20
21
OMe
SEt
Ph
OMe
OMe
SEt
90
88
70
70
74
93
65
64
80
50
57
10
11
11
12
13
14
16
17
18
Ph
OMe
OMe
SO2Et
Ph
Figure 1. NOE-couplings in adduct 24.

T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
431
Scheme 4. Substitution of sulfolene pyridinone 19. Reagents and
conditions: (a) 1.1 equiv. NaH, DMF, 0 8C; (b) 1.5 equiv. RX.
Figure 2. Mixture of regiomeric adducts 27.
generate an anion that can be submitted to reaction with
various electrophiles. Starting from sulfolene pyridinone 19
(R3¼OMe), we applied this strategy to attach some
dienophilic side chains (Scheme 4, Table 3).
cycloaddition as the product ratio invariably approached a
value 1:1. For the determination of the isomeric ratio we
again relied on H NMR analysis as exemplified for the
adduct mixture 27a,b (R3¼Ph, Fig. 2).
1
To effect substitution at the more acidic a-position 7, a
solution of 19 in dry DMF was treated at 0 8C with
1.1 equiv. of NaH. After 15 min 2 equiv. of electrophile
were added to the reaction mixture. When tetrabutylammo-
nium fluoride was used as a base, the reaction had to proceed
at room temperature and the yields were appreciably lower.
Attempts to substitute the less acidic a-position 5 by
treatment of 19 with 2.1 equiv. of KH or BuLi followed by
addition of an electrophile, met with failure. Hence no
dianion could be generated from the [3,4-b] type precursor
19 even under strongly basic conditions. This finding stays
in contrast to the double proton abstraction observed for the
isomeric [3,4-c] sulfolene pyridinone, which has the less
acidic a-methylene group in peri-position of the carbonyl
function.
1
The H spectrum of 27a,b run in CDCl3 was unresolved;
hence C6D6 was used as a solvent to unravel the signals
corresponding to the aliphatic protons H-5 and H-8
(Aromatic Solvent Induced Shift). For regioisomer 27b
the geminal protons H-5 appeared as two dd signals: the
signal at 2.52 ppm (2J¼15.9 Hz, J¼9.8 Hz) was assigned
3
to H-5ax and that at 3.90 ppm (2J¼15.9 Hz, J¼5.1 Hz) to
3
H-5eq. The assignment of H-5eq was confirmed by a NOE
with H-4. For regioisomer 27a protons H-8ax and H-8eq
were identified as two dd absorptions at 2.63 and 2.30 ppm
(2J¼17.5 Hz, J¼8.8, 5.6 Hz, respectively), both of which
3
showed a NOE with the benzylic protons as in 27b. The
ratio 27a/27b (43/57) was based on integration values. The
isomeric products in other adduct mixtures were attributed
in a similar way: 25a/25b (47/53) and 26a/26b (55/45).
Ester precursor 37 could easily be deprotonated at the 7-
position to produce a stable anion. However, further
functionalisation of this unreactive species was unsuccess-
ful even when using reactive electrophiles such as methyl
chloroformate and benzyl bromide. Attempts to transform
the ester into the corresponding amide compounds equally
failed.
Precursor 19 (R3¼OMe) also was thermolysed in the
presence of other dienophiles; the results of these exper-
iments are shown in Table 2. The cycloaddition with
dimethyl maleate yielded the cis-substituted diester 28
(77%) as shown by NMR-analysis. When precursor 19 was
thermolysed with 1,4-naphthoquinone the fully aromatised
compound 29 was isolated as the only product. In the
reaction with dimethyl acetylenedicarboxylate, the inter-
mediate adduct also readily underwent aromatisation to
produce quinolone 30. The reaction with p-toluenesulfonyl
cyanide furnished a separable mixture of naphthyridines 31
and 32. The structural assignment of the regioisomers again
The sulfolene pyridinone also could be regioselectively
brominated by irradiating a solution of 19 and NBS
(1.1 equiv.) in CCl4 for 1 h (500 W tungsten-lamp). This
furnished 7-bromo derivative 39 in 45% yield. Apparently
this low yield was due to decomposition of compounds 19
and/or 39 upon irradiation. When bromination was carried
out under thermal conditions (CCl4, NBS, benzoylperoxide,
reflux) compound 39 was isolated in 67% yield.
1
was based on their H NMR and NOE-diff spectra. In the
spectrum of compound 31, H-4 was identified as a singlet at
6.97 ppm; presaturation of this proton resulted in a NOE-
1
enhancement of the signal due to H-5 (d 8.30). The JCH
values (184 and 170 Hz) corresponding to coupling of C-8
with H-8 (d 8.63) and C-5 with H-5 respectively, clearly
show that the nitrogen atom is in position 7. In the spectrum
of adduct 32, a similar NOE was observed between H-4 (d
The substituted compounds were characterised by NMR-
analysis, which confirmed that substitution indeed had
occurred at position 7. Indeed, whereas the spectrum of 19
displayed a singlet signal for the benzylic protons, an AB
quartet was observed for the substituted analogues, due to
the peri-interaction of the 7-substituent and the benzyl
group (Table 4). In the spectrum of the 1,7-dibenzyl
compound 34, proton H-7 was identified as a triplet
1
6.92) and H-5 (d 8.70). The JCH values (185 and 169 Hz)
corresponding to coupling with H-5 and H-8 (d 8.10)
respectively, now reveal the 6-position of the nitrogen atom.
Thermolysis in presence of dihydrofuran led to a complex
mixture of regioisomers and decomposition products, the
adducts were not isolated and thus not characterized. The
existence of 33 was demonstrated via mass spectral analysis.
3
(4.17 ppm, t, J¼5.5 Hz). A NOESY experiment further
revealed a strong NOE correlation between H-7 and one of
the benzylic protons on the pyridinone nitrogen atom. A
weak NOE correlation also was observed between protons
of the benzylic methylene groups at the 1- and 7-position.
2.3. Substitution of precursor 19
One advantage of a sulfolene precursor is the ability to
abstract a proton at an acidic a-position of the sulfone to
Attempts to substitute one of the a-positions 10 or 30 in the
side chain of monocyclic sulfone 14 were unsuccessful.

432
T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
Table 2. Intermolecular Diels–Alder reactions with various dienophiles
Dienophile
Adduct
Dimethyl maleate
1,4-Naphthoquinone
Dimethyl acetylenedicarboxylate
p-Toluenesulfonylcyanide
Dihydrofuran
Various conditions using different bases and solvents
invariably led to isolation of pyrazinone 2 in 30–45%
yield. Presumably, the anion generated at position 30 triggers
an elimination reaction producing a sulfene and a stabilised
6-methyl carbanion, which eventually yields pyrazinone 2
upon aqueous workup of the reaction mixture (Scheme 5).
Scheme 5. Attempted substitution of sulfone 14. Reagents and conditions:
(a) (i) 1.1 equiv. BuLi, 278 8C, THF, (ii) 2 equiv. BnBr; (b) (i) 2.1 equiv.
BuLi, 278 8C, THF, (ii) 2 equiv. BnBr; (c) (i) 1.1 equiv. NaH, 20 8C,
DMF, (ii) 2 equiv. BnBr; (d) (i) 1.2 equiv. KOtBu, 0 8C to room
temperature, THF, (ii) 2 equiv. BnBr.
2.4. Intramolecular Diels–Alder reactions
Substitution of precursor 19 allowed to introduce various
dienophilic side chains at the 7-position. The 7-substituted
compounds 35, 36, and 38 now were submitted to
thermolysis in order to generate the corresponding o-
QDM intermediates. Upon intramolecular cycloaddition,
these can produce polycyclic pyridinones. To this end a
solution of the substituted precursor in o-DCB was heated at
150 8C for several hours. Table 5 shows the outcome of
these experiments.
Table 3. Substitution of sulfolene pyridinone 19
Electrophile RX
R
Product number
(yield)
Benzylbromide
5-Bromopentene
Allyl chloroformate
Methyl chloroformate
N,N-Diallylcarbamoyl chloride
CH2C6H5
34 (60)
35 (57)
36 (61)
37 (59)
38 (58)
(CH2)3CHvCH2
CO2CH2CHvCH2
CO2CH3
Thermolysis of compound 35 exclusively produced
rearranged product 40. Extrusion of SO2 may result in
generation of the Z- or E-o-QDM intermediate A or B, both
of which experience a large steric repulsion with either the
exocyclic methylene group or the N-benzyl substituent in
peri-position (Scheme 6). o-QDM B now can undergo a
1,5-sigmatropic hydrogen shift to afford the rearranged
product 40. Furthermore, equilibration of A and B
conceivably may proceed via cyclobutene intermediate C.
CON(allyl)2
Table 4. Selected NMR data
Compound number
H-benzyl (ppm)
2J
19
34
35
36
37
38
39 (7-Br)
5.23
/
4.33/5.70
4.95/5.45
4.96/5.88
4.99/5.41
4.37/5.68
4.83/6.10
16.0
15.7
15.9
15.7
15.8
15.9
Thermolysis of 36 furnished a complex mixture of products,
which were not further characterised. Finally, from the
thermolysis of precursor 38 the cis-fused adduct 41 was
isolated as a single product. Again both A and B type

T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
433
Figure 3. NOE correlations observed for adduct 41.
3. Conclusion
In this work we established a route leading to various
substituted [3,4-b] sulfolene pyridinones. Upon thermolysis
these were converted into the corresponding pyridinone o-
QDM intermediates, which in the presence of dienophiles
allowed for intermolecular Diels–Alder reactions. How-
ever, no regioselectivity was observed for cycloadditions
with non-symmetric dienophiles. When dienophilic side
chains were introduced, intramolecular cycloaddition only
succeeded if no competing rearrangement involving a 1,5-
H-shift of the o-QDM intermediate was viable.
Scheme 6. Intramolecular cycloaddition/rearrangement.
intermediates (Y¼CO) may be generated. However, in this
case B cannot undergo a 1,5-H-shift since no H-atoms are
available. Furthermore, cycloaddition involving type B
intermediates (Y¼CH2, CO) is disfavoured as this requires a
highly strained exo transition state. Hence, cycloaddition
can proceed only starting from intermediate A (Y¼CO): the
more favourable endo transition state then leads to the
formation of cis-fused adduct 41.
4. Experimental
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 trans-
form 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 measure-
ments performed in the EI mode at a resolution of 10,000.
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.
The cis-fused structure of endo-adduct 41 was established
by NMR-spectroscopy. Proton H-9a was identified as a
doublet at 3.57 ppm showing coupling (3J¼6.3 Hz) with H-
6a (d 2.43). The presumed cis-disposition of the angular
protons H-9a and H-6a was confirmed by their strong NOE
correlation. A NOE also was observed between H-9a and
one of the benzylic protons (d 5.49). The signals at 2.94 ppm
(d, 1H, J¼10 Hz) and 3.48 ppm (dd, J¼10 Hz, J¼6 Hz)
were assigned to the geminal protons H-7, both of which
display a NOE with H-6a. This implies the occurrence of
half-chair A. By conformational modelling A was shown to
be more stable (ca. 3.5 kcal/mol) than half-chair B, which
displays a highly unfavourable axial 6-methylene group
(Fig. 3).
2
2
3
4.1. Synthesis of the precursors 19–21
Table 5. Intramolecular Diels–Alder reactions
Substituted precursor
Product number (yield, %)
The preparation and the analytical data of the pyrazinones 1,
2 and 4 were reported previously.8 The substituted
pyrazinone 3 was prepared analogously using sodium
ethanethiolate in THF.
35
36
4.1.1. 1-Benzyl-5-chloro-3-(ethylsulfanyl)-6-methyl-
2(1H)-pyrazinone 3. Yield: 90%; yellow crystals; mp
82.5–83.3 8C (ethanol); IR (KBr/cm21): 3061, 2971, 1706,
1650, 1567; 1H NMR: d 1.38 (t, 3H, 3J¼7.4 Hz, CH3), 2.34
Decomposition
3
(s, 3H, 6-CH3), 3.08 (q, 2H, J¼7.4 Hz, CH2), 5.30 (s, 2H,
CH2–N), 7.17 (d, 2H, Jo¼6.7 Hz, H–Ph), 7.26–7.32 (m,
3H, H–Ph); 13C NMR: d 13.5 (CH3), 16.2 (CH3), 24.1
(CH2), 48.6 (CH2–N), 126.8 (C-6), 126.9 (CH), 128.4 (C-5),
128.9 (CH), 134.5 (C-ipso), 154.4 (C-3), 156.3 (C-2); MS
[m/z (%)]: EI: 294 (26, Mþz), 203 (7, Mþz2C7H7), 91 (100,
38

434
T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
C7H7þ); HRMS: calcd for C14H15N2OSCl: 294.0594;
found: 294.0591.
lysis: calcd for C16H17ClN2O2S2: C 52.09, H 4.64, N 7.59;
found: C 51.86, H 4.68, N 7.44.
The experimental data of the bromomethyl substituted
pyrazinones 5 and 7 were reported previously.8 Compound
6 was prepared using the same procedure.
4.2.3. S 1-[(1-Benzyl-3-chloro-1,6-dihydro-5-phenyl-6-
oxo-2-pyrazinyl)methyl]ethanethioate 10. Yield: 90%;
yellow crystals; mp 146–147 8C (ethanol); IR (KBr/
1
cm21): 3052, 2965, 1648, 1546; H NMR: d 2.38 (s, 3H,
4.1.2. 1-Benzyl-6-bromomethyl-5-chloro-3-(ethylsulfa-
nyl)-2(1H)-pyrazinone 6. Yield: 90%; yellow crystals;
mp 73.2–75.1 8C (ethanol); IR (KBr/cm21): 3050, 2973,
1680, 1592; 1H NMR: d 1.39 (t, 3H, 3J¼7.4 Hz, CH3), 3.10
CH3), 4.27 (s, 2H, CH2), 5.42 (s, 2H, CH2–N), 7.23–7.34
(m, 5H, H–Ph), 7.43–7.45 (m, 3H, H–Ph), 8.39–8.42 (m,
2H, H–Ph);13C NMR: d 28.2 (CH2), 30.1 (CH3), 48.5
(CH2–N), 126.7 (C-5), 127.9 (CH), 128.0 (CH), 128.1
(C-6), 129.1 (CH), 129.3 (CH), 130.7 (CH), 132.8 (CH),
134.1 (C-ipso), 135.5 (C-ipso), 150.7 (C-3), 155.1 (C-2),
194.4 (CO); MS [m/z (%)]: EI: 384 (30, Mþz), 341 (19,
Mþz2C2H3O), 309 (12, Mþz2C2H3OS), 251 (39, Mþz–
C7H7NCO), 91 (100, C7H7þ); HRMS: calcd for C20H17N2-
O2SCl: 384.0699, found: 384.0698; CHN analysis: calcd for
C20H17ClN2O2S: C 62.41, H 4.45, N 7.28; found: C 62.10,
H 4.45, N 7.28.
3
(q, 2H, J¼7.4 Hz, CH2), 4.41 (s, 3H, CH2–Br), 5.47 (s
broad, 2H, CH2–N), 7.18 (d, 2H, Jo¼6.8 Hz, H–Ph), 7.29–
7.35 (m, 3H, H–Ph); 13C NMR: d 13.3 (CH3), 24.4 (CH2),
25.4 (CH2) 47.7 (CH2–N), 126.5 (C-6), 126.4 (CH), 128.0
(CH), 128.5 (C-5), 129.2 (CH), 134.9 (C-ipso), 153.8 (C-3),
161.1 (C-2); MS [m/z (%)]: EI: 371 (6, Mþz), 293 (7,
Mþz2Br), 265 (Mþz2Br, –CO), 91 (100, C7H7þ); HRMS:
calcd for C14H14N2BrClOS: 371.9699; found: 371.9720.
4.2. General procedure for the synthesis of thioesters
8–10
4.3. General procedure for the synthesis of thioethers
11–13
To a stirred solution of bromide 5–7 (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 chromatography (Silica gel, 5 EtOAc/95 CH2Cl2) to
afford the following compounds.
To a solution of thioesters 8–10 (0.05 mol) in methanol
(250 mL) was added under an inert atmosphere 1.3 equiv. of
sodium methoxide. After reaction at room temperature for
1 h, 3 equiv. of propargylic bromide were added. Sub-
sequently, the reaction mixture was stirred at room
temperature for another 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 chroma-
tography (Silica gel, 70 Hexane/30 EtOAc) to afford
thioether compounds 11–13.
4.2.1. S 1-[(1-Benzyl-3-chloro-1,6-dihydro-5-methoxy-6-
oxo-2-pyrazinyl)methyl]ethanethioate 8. Yield: 80%;
pale yellow crystals; mp 134.5–136 8C (ethanol); IR
1
(KBr/cm21): 2991, 1671, 1587; H NMR: d 2.36 (s, 3H,
CH3), 4.02 (s, 3H, OCH3), 4.17 (s, 2H, CH2S), 5.32 (s, 2H,
3
4.3.1. 1-Benzyl-5-chloro-3-methoxy-6-[(2-propynylsulfa-
nyl)methyl]-2-(1H)-pyrazinone 11. Yield: 90%; yellow
crystals; mp 147.5–149.0 8C (CH2Cl2/hexane); IR (KBr/
cm21): 2993, 1668, 1583; 1H NMR: d 2.21 (t, 1H,
CH2–N), 7.21 (d, 2H, J¼7.0 Hz, H–Ph), 7.30–7.33 (m,
3H, H–Ph); 13C NMR: d 27.9 (CH2), 30.2 (CH3), 48.1
(CH2–N), 55.3 (CH3), 124.5 (C), 125.5 (C), 126.7 (CH),
128.1 (CH), 129.0 (CH), 135.0 (C-ipso), 151.3 (C), 154.6
(C), 193.9 (C); MS [m/z (%)]: EI: 338 (15, Mþz), 295 (9,
Mþz2C2H3O), 263 (11, Mþz2C2H3OS), 247 (15,
Mþz2C7H7), 205 (27, Mþz2C7H7, –C2H3O), 91 (100,
C7H7þ); HRMS: calcd for C15H15N2O3SCl: 338.0492;
found 338.0489. CHN analysis: calcd for C15H15ClN2O3S:
C 53.18, H 4.46, N 8.27; found: C 53.41, H 4.18, N 8.10.
4
4J¼2.5 Hz, uCH), 3.36 (d, 2H, J¼2.5 Hz, CH2), 3.87 (s,
2H, 6-CH2), 4.03 (s, 3H, OCH3), 5.55 (s, 2H, CH2–N), 7.16
3
(d, 2H, J¼7.0 Hz, H–Ph), 7.26–7.32 (m, 3H, H–Ph); 13C
NMR: d 20.8 (CH2), 29.7 (CH2), 47.5 (CH2–N), 55.2 (CH3),
71.6 (CH), 79.5 (C), 123.9 (C) 125.8 (CH), 126.4 (CH),
127.9 (CH), 135.2 (C-ipso), 151.4 (C), 154.4 (C); MS [m/z
(%)]: EI: 334 (19, Mþz), 299 (5, Mþz2Cl), 264 (21,
Mþz2C3H3S), 243 (4, Mþz2C7H7), 91 (100, C7H7þ);
HRMS: calcd for C16H15N2O2SCl: 334.0543, found:
334.0543; CHN analysis: calcd for C16H15ClN2O2S: C
57.40, H 5.52, N 8.37; found: C 57.33, H 5.38, N 8.27.
4.2.2. S 1-{[1-Benzyl-3-chloro-1,6-dihydro-5-(ethylsulfa-
nyl)-6-oxo-2-pyrazinyl}methyl]ethanethioate 9. Yield:
94%; yellow crystals; mp 102–102.5 8C (ethanol); IR
1
(KBr/cm21): 2963, 1701, 1646, 1563; H NMR: d 1.39 (t,
3H, 3J¼7.2 Hz, CH3), 2.37 (s, 3H, CH3), 3.08 (q, 2H,
3J¼7.2 Hz, CH2), 4.18 (s, 2H, 6-CH2), 5.30 (s, 2H, CH2–N),
7.20–7.34 (m, 5H, H–Ph); 13C NMR: d 13.3 (CH3), 24.3
(CH2), 27.9 (CH2), 30.2 (CH3), 48.2 (CH2–N), 126.7 (C-6),
126.8 (CH), 128.1 (CH), 128.5 (C-5), 129.0 (CH), 134.9
(C-ipso), 154.1 (C-3), 159.3 (C-2), 193.8 (CO); MS [m/z
(%)]: EI: 368 (15, Mþz), 325 (4, Mþz2C2H3O), 293
(14, Mþz2C2H3OS), 277 (16, Mþz2C7H7þ), 235 (32,
Mþz2C7H7NCO), 91 (100, C7H7þ); HRMS: calcd for
C16H17N2O2S2Cl: 368.0420; found: 368.0416. CHN ana-
4.3.2. 1-Benzyl-5-chloro-3-(ethylsulfanyl)-6-[(2-propy-
nylsulfanyl)methyl]-2(1H)-pyrazinone 12. Yield: 88%;
1
3
unstable yellow oil; H NMR: d 1.38 (t, 3H, J¼7.2 Hz,
CH3), 2.21 (t, 1H, 4J¼2.6 Hz, uCH), 3.08 (q, 2H,
4
3J¼7.2 Hz, CH2), 3.37 (d, 2H, J¼2.6 Hz, CH2), 3.89 (s,
2H, 6-CH2S), 5.52 (s, 2H, CH2–N), 7.14 (d, 2H, Jo¼6.9 Hz,
H–Ph), 7.20–7.35 (m, 3H, H–Ph); 13C NMR: d 13.4 (CH3),
19.9 (CH2S), 24.4 (CH2), 29.9 (CH2-6), 47.6 (CH2–N), 71.8
(CH), 79.5 (C), 126.6 (C-6), 126.7 (CH), 128.1 (CH), 128.5
(C-5), 129.1 (CH), 134.9 (C-ipso), 154.1 (C-3), 159.1 (C-2);

T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
435
MS [m/z (%)]: CI: 365 (90, MHþ), 304 þ(65, MHþ2ClCN),
293 (100, MHþ2C3H4S), 91 (10, C7H7 ).
(C-2); MS [m/z (%)]: EI: 273 (39, Mþz), 182 (22,
Mþz2C7H7), 91 (100, C7H7þ); HRMS: calcd for
C15H15NO2S: 273.0824; found: 273.0823.
4.3.3. 1-Benzyl-5-chloro-3-phenyl-6-[(2-propynylsulfa-
nyl)methyl]-2(1H)-pyrazinon 13. Yield: 70%; yellow
crystals; mp 94–94.5 8C; IR (KBr/cm21): 3027, 2940,
4.4.2. 1-Benzyl-3-(ethylsulfanyl)-5,7-dihydrothieno[3,4-
b]pyridin-2(1H)-one 17. Yield: 93%; yellow oil; IR
(NaCl/cm21): 2966, 1650; 1H NMR: d 1.35 (t, 3H,
1
4
1654, 1543; H NMR: d 2.19 (t, 1H, J¼2.5 Hz, uCH),
4
3
3.34 (d, 2H, J¼2.5 Hz, CH2), 3.90 (s, 2H, CH2S), 5.56
3J¼7.4 Hz, CH3), 2.87 (q, 2H, J¼7.4 Hz, CH2), 4.03 (d,
(s, 2H, CH2–N), 7.15 (d, 2H, Jo¼7.0 Hz, H–Ph), 7.25–
7.29 (m, 3H, H–Ph), 7.39–7.41 (m, 3H, H–Ph), 8.40–
7.42 (m, 2H, H–Ph); 13C NMR: d 19.9 (CH2), 29.9
(CH2), 47.8 (CH2–N), 71.8 (CH), 79.2 (C), 126.3 (C-5),
127.1 (CH), 127.8 (CH), 127.9 (C-6), 128.8 (CH), 129.6
(CH), 130.5 (CH), 133.1 (CH), 134.6 (C-ipso), 134.8
(C-ipso), 150.2 (C-3), 154.9 (C-2); MS [m/z (%)]: EI: 380
(4, Mþz), 341 (2, Mþz –C3H3), 319 (29, Mþz2ClCN), 247
(28, Mþz2C7H7NCO), 91 (100, C7H7þ); HRMS: calcd
for C21H17N2OSCl: 380.0750; found: 380.0749.
2H, 2J¼18.5 Hz, CH2), 4.09 (d, 2H, 2J¼18.5 Hz, CH2), 5.26
(s, 2H, CH2–N), 7.04 (s, 1H, H-4), 7.19 (d, 2H, Jo¼7.0 Hz),
7.24–7.29 (m, 3H, H–Ph); 13C NMR: d 13.3 (CH3), 25.1
(CH2), 35.6 (CH2), 35.9 (CH2), 49.1 (CH2–N), 116.6
(CH-4), 127.0 (C-7a), 127.7 (CH), 128.8 (CH), 129.3
(CH), 129.5 (C-4a), 135.9 (C-ipso), 141.0 (C-3), 160.6
(C-2); MS [m/z (%)]: EI: 303 (52, Mþz), 270 (39, Mþz2HþS),
242 (2, Mþz2C2H5S), 212 (11, Mþz2C7H7), 91 (100, C7H7 );
HRMS: calcd for C17H17NOS2: 303.0752; found: 303.0748.
4.4.3. 1-Benzyl-3-phenyl-5,7-dihydrothieno[3,4-b]pyri-
din-2(1H)-one 18. Yield: 65%; yellow crystals; mp 183–
184 8C (ethanol); IR (KBr/cm21): 3029, 2919, 1650, 1597;
4.3.4. 1-Benzyl-5-chloro-3-methoxy-6-[(2-propynylsulfo-
nyl)methyl]-2-(1H)-pyrazinon 14. To a solution of thieno-
pyridinone 11 (2 g, 0.006 mol) in dry CH2Cl2 (100 mL) are
added 3 mol equiv. of m-CPBA. The mixture is stirred for
3 h at room temperature. Then a saturated solution of
NaHCO3 (50 mL) is added, and stirring is continued for 1 h.
The organic phase is separated and the aqueous phase is
further extracted with CH2Cl2. The combined organic layers
are washed with water and dried over MgSO4 and the
solvent evaporated. The residue is purified by column
chromatography (alumina, 15 EtOAc/85 CH2Cl2).
2
1H NMR: d 4.08 (d, 1H, J¼17.5 Hz, CH2), 4.12 (d, 1H,
2J¼17.7 Hz, CH2), 4.15 (2£d, 2H, 2J¼17.7 Hz, CH2), 5.29
(s, 2H, CH2–N), 7.20–7.40 (m, 9H, H–PhþH-4), 7.65–7.70
(m, 2H, H–Ph); 13C NMR: d 35.6 (CH2), 36.3 (CH2), 49.1
(CH2–N), 116.9 (C-7a), 126.9 (CH), 127.9 (CH), 127.8
(CH), 128.1 (CH), 128.6 (CH), 128.9 (CH), 129.8 (C-4a),
134.4 (C-4), 136.5 (C-ipso), 137.3 (C-ipso), 145.2 (C-3),
162.2 (C-2); MS [m/z (%)]: CI: 320 (100, MHþ). HRMS:
calcd for C20H17NOS: 319.1031; found: 319.1029.
Yield: 70%; white powder; mp 48.5 8C (decomposition); IR
(KBr/cm21): 2947, 1964, 1684, 1339, 1128, 1576; 1H NMR:
4.5. General procedure for the oxidation of cyclic
sulfides 16–18
4
4
d 2.54 (t, 1H, J¼2.7 Hz, CH), 4.00 (d, 2H, J¼2.7 Hz,
CH2), 4.07 (s, 3H, OCH3), 4.57 (s broad, 2H, CH2), 5.62 (s
broad, 2H, CH2–N), 7.15 (d, 2H, H–Ph), 7.26–7.34 (m, 3H,
H–Ph); 13C NMR: d 47.06 (CH2), 48.5 (CH2), 52.3 (CH2),
55.6 (CH3), 70.7 (C), 77.3 (CH), 118.4 (C-5), 126.6 (CH),
128.3 (CH), 129.3 (CH), 133.6 (C-6), 134.6 (C-ipso),
151.0 (C), 155.7 (C); MS [m/z (%)]: EI: 366 (7, Mþz), 305
(2, Mþz2ClCN), 263 (75 (Mþz2C3H3O2S), 233 (21,
Mþz2C7H7NCO), 91 (100, C7H7þ); HRMS: calcd for
C16H15N2O4SCl: 366.0441; found: 366.0436. CHN ana-
lysis: calcd for C16H15ClN2O4S: C 52.39, H 4.12, N 7.64;
found: C 52.70, H 3.85, N 7.45.
To a solution of thienopyridinone 16–18 (0.02 mol) in dry
CH2Cl2 (150 mL) was added m-CPBA (0.06 mol). The
mixture was stirred for 18 h at room temperature. 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
gel, 15 EtOAc/85 CH2Cl2) to afford sulfones 19–21.
4.5.1. 1-Benzyl-3-methoxy-5,7-dihydro-6,6-dioxo-
thieno[3,4-b]pyridin-2(1H)-one 19. Yield: 80%; white
crystals; mp 148 8C (decomposition); IR (KBr/cm21):
4.4. General procedure for the synthesis of
thienopyridinones 16–18
1
2986, 1652, 1601, 1321, 1134; H NMR: d 3.57 (s, 3H,
A solution of thioether 11–13 (0.04 mol) in dry 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 16–18.
OCH3), 4.13 (s, 2H, CH2), 4.22 (s, 2H, CH2), 5.23 (s, 2H,
CH2–N), 6.58 (s, 1H, H-4), 7.17 (d, 2H, 3J¼7.0 Hz, H–Ph),
7.26–7.35 (m, 3H, H–Ph); 13C NMR: d 49.4 (CH2–N), 55.5
(CH3), 56.2 (CH2), 56.8 (CH2), 107.4 (C-7a), 108.7 (CH-4),
129.2 (C-4a), 126.9 (CH), 127.1 (CH), 128.2 (CH), 134.9
(C-ipso), 150.8 (C-3), 157.9 (C-2); MS [m/z (%)]: EI: 305
(19, Mþz), 241 (26,Mþz2SO2), 91 (100, C7H7þ); HRMS:
calcd for C15H15NO4S: 305.0722; found: 305.0718.
4.4.1. Benzyl-3-methoxy-5,7-dihydrothieno[3,4-b]pyri-
din-2(1H)-one 16. Yield: 74%; yellow crystals; mp 51–
52 8C; IR (KBr/cm21): 3031, 2935, 1662, 1605; 1H NMR: d
3.83 (s, 3H, OCH3), 4.05 (s broad, 4H, 2£CH2), 5.27 (s, 2H,
CH2–N), 6.55 (s, 1H, CH), 7.18–7.29 (m, 5H, H–Ph); 13C
NMR: d 35.6 (CH2), 35.9 (CH2), 48.9 (CH2–N), 55.9 (CH3),
109.6 (CH-4), 114.7 (C-7a), 126.9 (CH), 127.6 (CH), 128.7
(CH), 134.8 (C-4a), 135.9 (C-ipso), 148.4 (C-3), 158.0
When compound 14 was heated in toluene at reflux
temperature for 2 h the yield of 19 was 64%.
4.5.2. 1-Benzyl-3-(ethylsulfonyl)-5,7-dihydro-6,6-dioxo-
thieno [3,4-b]pyridin-2(1H)-one 20. Yield: 50%; white

436
T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
crystals; mp 152.5–153 8C (decomposition); IR (KBr/
1
124–125 8C (CH2Cl2/hexane); IR (KBr/cm21): 2974, 1652,
1536, 1304, 1120; 1H NMR: d 1.22 (t, 3H, 3J¼7.4 Hz, CH3),
2.66 (dd, 1H, 2J¼15.9 Hz, 3J¼5.5 Hz, H-9ax), 2.75 (dd, 1H,
2J¼15.5 Hz, 3J¼6.2 Hz, H-5ax), 3.11 (dd, 1H, 2J¼15.5 Hz,
3J¼2.4 Hz, H-5eq), 3.39 (m, 3H, H-9eqþH-5aþH-8a), 3.50
cm21): 2974, 1652, 1536, 1304, 1120; H NMR: d 1.29 (t,
3
3
3H, J¼7.4 Hz, CH3), 3.54 (q, 2H, J¼7.4 Hz, CH2), 4.26
(s, 2H, CH2), 4.29 (s, 2H, CH2), 5.25 (s, 2H, CH2–N), 7.17
(dd, 2H, Jo¼7.9 Hz, Jm¼2.1 Hz, H–Ph), 7.33–7.40 (m, 3H,
H–Ph), 8.12 (s, 1H, H-4); 13C NMR: d 6.9 (CH3), 47.3
(CH2–N), 49.4 (CH2), 55.7 (CH2), 55.8 (CH2), 108.3
(CH-4), 127.0 (CH), 128.8 (CH), 129.5 (CH), 129.8
(C-4a), 133.6 (C-ipso), 140.3 (C-7a), 145.2 (C-3), 157.6
(C-2); MS [m/z (%)]: EI: 367 (25, Mþz), 303 (11,
Mþz2SO2), 211 (18, Mþz2SO2, –C7H7), 91 (100,
C7H7þ); HRMS: calcd for C16H17NO5S2: 367.0548;
found: 367.0549.
3
2
(q, 2H, J¼7.4 Hz, CH2), 5.10 (d, 1H, J¼15.7 Hz, CH2–
N), 5.86 (d, 1H, 2J¼15.7 Hz, CH2–N), 6.98 (d, 2H,
Jo¼8 Hz, H–Ph), 7.10 (d, 2H, Jo¼8 Hz, H–Ph), 7.20–7.40
(m, 6H, H–Ph), 8.06 (s, 1H, H-4); 13C NMR: d 7.0 (CH3),
27.7 (C-9), 28.4 (C-5), 39.4 (CH), 39.5 (CH), 47.0 CH2–N),
47.4 (CH2–SO2), 112.6 (C), 125.7, 126.4, 127.0 (C), 128.4,
129.3, 129.6, 131.6 (C), 135.7 (C-ipso), 143.7 (CH), 151.6
(C-3), 158.7 (C-2), 177.2 (CO), 177.4 (CO); MS [m/z (%)]:
EI: 476 (24, Mþz), 385 (3, Mþz2C7H7), 91 (100, C7H7þ);
HRMS: calcd for C26H24N2O5: 476.1406; found: 476.1412.
4.5.3. 1-Benzyl-3-phenyl-5,7-dihydro-6,6-dioxo-
thieno[3,4-b]pyridin-2(1H)-one 21. Yield: 57%; white
crystals; mp 160 8C (decomposition); IR (KBr/cm21):
4.6.3. (5aR p,8aS p)-1-Benzyl-3,7-diphenyl-5,5a,8a,9-tet-
rahydro-1H-pyrrolo[3,4-g]quinoline-2,6,8(1H,7H)-
trione 24. Yield: 87%; pale yellow crystals, mp 98–98.5 8C;
IR (KBr/cm21): 3032, 2953, 1711, 1643, 1595; 1H NMR: d
2.65 (dd, 1H, 2J¼14.0 Hz, 3J¼3.8 Hz, H-9ax), 2.75 (dd, 1H,
2J¼15.0 Hz, 3J¼3.9 Hz, H-5ax), 3.12 (dd, 1H, 2J¼15.0 Hz,
3J¼1.7 Hz, H-5eq), 3.37 (m, 2H, H-5aþH-8a), 3.49 (dd, 1H,
1
3029, 2958, 1647, 1596; H NMR: d 4.23 (s, 2H, CH2),
4.27 (s, 2H, CH2), 5.27 (s broad, 2H, CH2–N), 7.21–7.42
(m, 9H, H–PhþH-4), 7.65–7.09 (m, 2H, H–Ph); 13C NMR:
d 49.8 (CH2–N), 56.3 (CH2), 56.9 (CH2), 109.0 (C-7a),
126.9 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH), 129.2
(CH), 133.8 (C-4), 134.3 (C-4a), 135.4 (C-4a), 136.2
(C-ipso), 136.8 (C-ipso); MS [m/z (%)]: EI: 351 (24, Mþz),
287 (78, Mþz2SO2), 91 (100, C7H7þ).
3
2
2J¼14.0 Hz, J¼1.6 Hz, H-9eq), 5.11 (d, 1H, J¼15.6 Hz,
2
CH2–N), 5.89 (d, 1H, J¼15.6 Hz, CH2–N), 7.03 (d, 2H,
Jo¼7.0 Hz, H–Ph), 7.21–7.42 (m, 12H, H–PhþH-4), 7.71
(d, 2H, Jo¼7.1 Hz, H–Ph); 13C NMR: d 27.1 (CH2), 28.6
(CH2), 39.8 (CH), 39.9 (CH), 47.8 (CH2–N), 113.1 (C-9a),
126.1 (CH), 126.7 (CH), 127.5 (CH), 127.8 (CH), 128.1
(CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 129.1 (CH),
130.2 (C-ipso), 131.9 (C-4a), 137.0 (C-ipso), 137.1
(C-ipso), 138.6 (C-4), 142.3 (C-3), 162.3 (C-2), 177.7
(C-8), 178.2 (C-6); MS [m/z (%)]: EI: 460 (57, Mþz), 369 (7,
Mþz2C7H7), 383 (2, Mþz2C6H5), 222 (57, Mþz2C7H7,2
C6H5NC2O2), 91 (100, C7H7þ); HRMS: calcd for
C30H24N2O3: 460.1787; found: 460.1788.
4.6. Intermolecular Diels–Alder reactions of sulfolene
pyridinones 19–21
General procedure. A solution of 0.2 g sulfolene pyridi-
nones 19–21 and 5 equiv. of a dienophile in 10 mL
o-dichlorobenzene is brought into a glass tube and the solution
is subjected to three consecutive freeze–pump–thaw cycles.
The tube is sealed off and is then heated in an oven at 160 8C
for 12 h. After cooling, the tube is opened, and the solvent is
removed by Kugelrohr distillation. The products are purified
by column chromatography (silica gel, CH2Cl2/EtOAc: 95/5
to 85/15) to give the following adducts.
4.6.4. Methyl 1-benzyl-3-methoxy-5,6,7,8-tetrahydro-2-
oxo-1H-quinoline-7-carboxylate 25a and methyl 1-ben-
zyl-3-methoxy-5,6,7,8-tetrahydro-2-oxo-1H-quinoline-6-
carboxylate 25b. Yield: 70%; yellow oil; 1H NMR (C6D6):
d 1.34–1.44 (m, 0.5H, H–CH2), 1.47–1.53 (m, 0.5H, H–
CH2), 1.59–1.64 (m, 0.5H, H–CH2), 1.66–1.72 (m, 0.5H,
H–CH2), 1.85–1.93 (m, 0.5H, H–CH2), 2.05–2.20 (m,
2.5H, H-7 aþH-6 bþ3£H–CH2), 2.32 (dd, 0.5H,
2J¼16 Hz, 3J¼5.2 Hz, H-5eq b), 2.42 (dd, 0.5H,
2J¼17 Hz, 3J¼5.6 Hz, H-8eq a), 2.54 (dd, 0.5H,
4.6.1. ((5aR p,8aS p)-1-Benzyl-3-methoxy-7-phenyl-
5,5a,8a,9-tetrahydro-1H-pyrrolo[3,4-g]quinoline-
2,6,8(7H)-trione 22. Yield: 70%; yellow crystals; mp
197 8C (ethanol); IR (KBr/cm21): 3061, 2933, 1710, 1651,
1599; 1H NMR: 2.51 (dd, 1H, 2J¼15.6 Hz, 3Jax–eq¼5.0 Hz,
2
3
H-5ax), 2.71 (dd, 1H, J¼14.0 Hz, Jax–eq¼4.5 Hz, H-9ax),
2
3
3.06 (dd, 1H, J¼14.0 Hz, Jeq–eq¼2.0 Hz, H-9eq), 3.34–
3.36 (m, 2H, H-5aþH-8a), 3.42 (dd, 1H, 2J¼15.6 Hz,
2
3
2
3Jeq–eq¼2.2 Hz, H-5eq), 5.06 (d, 1H, J¼16.0 Hz, CH2–N),
2J¼16 Hz, J¼8 Hz, H-5ax b), 2.58 (dd, 0.5H, J¼17 Hz,
3J¼9 Hz, H-8ax a), 3.24 (s, 1.5H, OCH3 a), 3.34 (s, 1.5H,
OCH3 b), 3.42 (s, 3H, OCH3 aþb), 4.99–5.30 (m breed, 2H,
CH2N aþb), 5.96 (s, 0.53H, H-4 b), 5.99 (s, 0.47H, H-4 a),
6.96–7.16 (m, 5H, H–Ph aþb).
2
5.86 (d, 1H, J¼16.0 Hz, CH2–N), 6.51 (s, 1H, H-4), 6.98
(dd, 2H, Jo¼8.0 Hz, Jm¼1.0 Hz, H–Ph), 7.17 (d, 2H,
Jo¼7.3 Hz, H–Ph), 7.25–7.42 (m, 6H, H–Ph); 13C NMR:
d 25.9 (CH2-5), 28.6 (CH2-9), 39.5 (CH), 39.8 (CH), 47.2
(CH2–N), 55.9 (CH3), 111.5 (C-9a), 113.6 (CH-4), 126.2
(CH), 126.7 (CH), 127.5 (CH), 128.8 (CH), 129.2 (CH),
131.4 (C-4a), 132.2 (C-ipso), 136.5 (C-ipso), 148.8 (C-3),
158.5 (C-2), 177.4 (C), 177.9 (C); MS [m/z (%)]: EI: 414
(72, Mþz), 323 (15, Mþz2C7H7), 176 (75, Mþz2C7H7,2
C8H5NO2; HRMS: calcd for C25H22N2O4: 414.1580; found:
414.1584.
(CDCl3): d 1.74–1.82 (m, 1H, H–CH2), 2.06–2.11 (m, 1H,
H–CH2), 2.53–2.82 (m, 5H, 2£H–CH2þH–CH), 5.10–
5.50 (m, 2H, CH2N), 6.40 (s, 0.53H, H-4), 6.42 (s, 0.47H,
H-4), 7.11–7.28 (m, 5H, H–Ph); 13C NMR: d 24.4 (CH2),
24.6 (CH2), 25.1 (CH2), 26.7 (CH2), 27.7 (CH2), 29.8 (CH2),
38.2 (CH), 38.9 (CH), 46.5 (CH2N), 51.6 (OCH3), 51.7
(OCH3), 55.5 (OCH3), 110.9 (C), 111.9 (C), 114.3 (CH),
114.4 (CH), 126.2 (CH-arom), 126.3 (CH-arom), 126.9
(CH-arom), 128.4 (CH-arom), 131.3, 132.4, 136.4 (C-ipso),
147.5 (C-3), 158.3 (C-2), 174.3 (CO), 174.5 (CO); MS [m/z
4.6.2. (5aR p,8aS p)-1-Benzyl-3-(ethylsulfonyl)-7-phenyl-
5,5a,8a,9-tetrahydro-1H-pyrrolo[3,4-g]quinoline-
2,6,8(1H,7H)-trione 23. Yield: 60%; yellow crystals, mp

T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
437
(%)]: EI: 327 (40, Mþz), 295 (20, Mþz2MeOH), 236 (45,
Mþz2C7H7), 91 (100, C7H7þ); HRMS: calcd for
C19H21NO4: 327.1471; found: 327.1480.
(C-3), 158.9 (C-2), 172.6 (C), 172.9 (C); MS [m/z (%)]: EI:
385 (71, Mþz), 354 (8, Mþz2OCH3), 326 (41,
Mþz2C2H3O2), 294 (19, Mþz2C7H7), 266 (Mþz2C2H3O2,
–C2H3O2), 234 (20, Mþz2C2H3O2, –C7H7), 91 (100,
C7H7þ); HRMS: calcd for C21H23NO6: 385.1525; found:
385.1525.
4.6.5. Methyl 1-benzyl-3-(ethylsulfonyl)-5,6,7,8-tetrahy-
dro-2-oxo-1H-quinoline-7-carboxylate 26a and methyl
1-benzyl-3-(ethylsulfonyl)-5,6,7,8-tetrahydro-2-oxo-1H-
quinoline-6-carboxylate 26b. Yield: 94%; yellow oil; IR
4.6.8. 1-Benzylnaphto[2,3-g]quinoline-2,6,11(1H)-trione
1
29. Yield: 80%; yellow oil; H NMR: d 4.07 (s, 3H, CH3),
1
(NaCl/cm21): 3032, 2951, 1737, 1659, 1593; H NMR: d
3
1.28 (t, 3H, J¼8.7 Hz, CH3–Et), 1.77–1.86 (m, 1H, H–
5.70 (s, 2H, CH2–N), 7.06 (s, 1H, H-4), 7.24–7.38 (m, 6H,
H-arom), 7.76–7.79 (m, 2H, H-arom), 8.22 (s, 1H, CH),
8.25–8.30 (m, 2H, H-arom), 8.40 (s, 1H, CH); 13C NMR: d
46.9 (CH2–N), 56.4 (CH3), 109.9, 113.5, 125.4, 127.1,
127.3, 127.8, 127.9, 128.9, 131.7, 133.7, 133.8, 134.1,
134.2, 135.5 (C-ipso), 138.3, 150.7 (C-3), 158.2 (C-2),
182.0 (CO), 182.3 (CO); MS [m/z (%þ)]: EI: 395 (28, Mþz),
304 (7, Mþz2C7H7), 91 (100, C7H7 ); HRMS: calcd for
C25H17NO4: 395.1158, found: 395.1153.
CH2), 2.03–2.16 (m, 1H, H–CH2), 2.66–3.00 (m, 5H,
2£CH2þH–CH), 3.54 (q, 2H, 3J¼8.7 Hz, CH2–Et), 3.67 (s,
1.3H, OCH3), 3.69 (s, 1.7H, OCH3), 5.12–5.23 (m, 2H,
CH2N), 7.10–7.91 (m, 5H, H–Ph), 8.00 (s, 0.45H, H-4 b),
8.10 (s, 0.55H, H-4 a); MS [m/z (%)]: EI: 389 (28, Mþz),
330 (22, Mþz2CO2Me), 298 (7, Mþz2C7H7), 91 (100,
C7H7þ); HRMS: calcd for C20H23NO5S: 389.1297; found:
389.1296.
4.6.6. Methyl 1-benzyl-3-phenyl-5,6,7,8-tetrahydro-2-
oxo-1H-quinoline-7-carboxylate 27a and methyl 1-ben-
zyl-3-phenyl-5,6,7,8-tetrahydro-2-oxo-1H-quinoline-6-
carboxylate 27b. Yield: 85%; light yellow oil; IR (NaCl/
cm21): 3029, 2950, 1735, 1650, 1599; 1H NMR (CDCl3): d
7.76–1.85 (m, 1H, H–CH2), 2.07–2.13 (m, 1H, H–CH2),
2.61–2.91 (m, 5H, 2£CH2þH–CH), 5.30–5.52 (m broad,
2H, CH2N), 7.15–7.22 (m, 3H, H–Ph), 7.26–7.30 (4H, H–
PhþH-4), 7.35–7.37 (m, 2H, H–Ph), 7.71–7.73 (m, 2H, H–
Ph); (C6D6): d 1.33–1.40 (m, 0.5H, H–CH2), 1.43–1.50 (m,
0.5H, H–CH2), 1.57–1.61 (m, 0.5H, H–CH2), 1.64–1.69
(m, 0.5H, H–CH2), 1.88–1.97 (m, 0.5H, H–CH2), 2.02–
2.25 (m, 2.5 H, 2£CH2þH–CH), 2.36 (dd, 0.5H,
2J¼17.5 Hz, 3J¼5.6 Hz, H-8 a), 2.36 (dd, 0.5H,
2J¼15.9 Hz, 3J¼5.1 Hz, H-5 b), 2.52 (dd, 0.5H,
2J¼15.9 Hz, 3J¼9.8 Hz, H-5 b), 2.63 (dd, 0.5H,
4.6.9. Dimethyl 1-benzyl-3-methoxy-2-oxo-1H-quino-
line-6,7-dicarboxylate 30. Yield: 77%; yellow oil; IR
1
(KBr/cm21): 2952, 1793, 1657, 1622; H NMR: d 3.56 (s,
3H, OCH3), 3.75 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.17
2
2
(d, 1H, J¼20 Hz, CH2–N), 5.63 (d, 1H, J¼20 Hz, CH2–
N), 6.51 (s, 1H, H-4), 7.24–7.30 (m, 6H, H-8þH–Ph), 7.47
(s, 1H, H-5); 13C NMR: d 47.6 (CH2–N), 52.7 (CH3), 52.9
(CH3), 56.5 (CH3), 113.2 (CH), 116.4 (CH-4), 127.3, 127.4,
127.9, 128.9, 129.2, 130.1, 136.8 (C-ipso), 151.2 (C-3),
158.0 (C-2), 163.0, 166.5 (CO), 171.4 (CO); MS [m/z (%)]:
EI: 383 (29, Mþz), 324 (21, Mþz2C2H3O2), 292 (19,
Mþz2C7H7), 91 (100, C7H7þ); HRMS: Calcd for
C21H21NO6: 383.1369, Found: 383.1368.
4.6.10. 1-Benzyl-3-methoxy-6-[(4-methylfenyl)sulfo-
nyl][1,7]naphthyridin-2(1H)-one 31. Yield: 40%; yellow
crystals; mp 237–238 8C; IR (KBr/cm21): 3067, 2930,
3
2J¼17.5 Hz, J¼8.8 Hz, H-8 a), 3.24 (s, 1.4H, OCH3 a),
1
3.34 (s, 1.6H, OCH3 b), 5.00–5.50 (m broad, 2H, CH2N
aþb), 6.97 (s, 0.43H, H-4 a), 6.99 (s, 0.57H, H-4 b), 7.04–
7.10 (m, 4H, H–Ph), 7.16–7.20 (m, 2H, H–Ph), 7.29–7.33
(m, 2H, H–Ph), 8.00–8.02 (m, 2H, H–Ph); 13C NMR: d 24.6
(CH2), 24.7 (CH2), 26.1 (CH2), 26.3 (CH2), 28.7 (CH2), 29.6
(CH2), 38.3 (CH), 38.9 (CH), 46.9 (CH2N), 51.8 (OCH3),
51.9 (OCH3), 112.5 (C), 113.4 (C), 126.3 (CH-arom), 126.4
(CH-arom), 127.1 (CH-arom), 127.4 (CH-arom), 127.9 (CH-
arom), 128.5 (CH-arom), 128.7 (CH-arom), 136.5 (C-ipso),
136.6 (C-ipso), 136.9, 139.2, 139.3, 140.7, 141.6, 161.8 (C-2),
174.3 (CO), 174.6 (CO); MS [m/z (%)]: EI: 373 (100, Mþz),
314 (56, Mþz2CO2Me), 282 (Mþz2C7H7), 222 (Mþz2C7H7,
–CO2Me), 91 (60, C7H7þ); HRMS: calcd for C24H23NO3:
373.1678; found: 373.1681.
1660, 1319, 1158; H NMR: d 2.39 (s, 3H, CH3), 4.03 (s,
3H, OCH3), 5.58 (s, 2H, CH2–N), 6.97 (s, 1H, H-4), 7.18–
7.30 (m, 7H, H–Ph), 7.90 (d, 2H, Jo¼8.3 Hz, H–Ph), 8.30
(s, 1H, H-5), 8.63 (s, 1H, H-8); 13C NMR: d 21.6 (CH3),
46.6 (CH2), 56.6 (CH3), 107.9 (CH), 119.4 (CH), 126.8
(CH), 127.3 (C), 128.0 (C), 128.8 (CH), 129.1 (CH), 129.8
(CH), 132.0 (C), 134.8 (C), 136.1 (C), 137.4 (CH), 144.7
(C), 151.9 (C), 152.9 (C); MS [m/z (%)]:þEI: 420 (2, Mþz),
355 (83, Mþz2SO2, –H), 91 (100, C7H7 ); HRMS: calcd
for C23H20N2O4S: 420.1144, found: 420.1139; CHN
analysis: calcd for C23H20N2O4S: C 65.70, H 4.79, N
6.66; found: C 65.36, H 4.94, N 6.33.
4.6.11. 1-Benzyl-3-methoxy-7-[(4-methylphenyl)sulfo-
nyl][1,6]naphthyridin-2(1H)-one 32. Yield: 27%; pale
yellow crystals; mp 218–220 8C; IR (KBr/cm21): 3058,
2927, 1668, 1316, 1158; 1H NMR: d 2.38 (s, 3H, CH3), 3.99
(s, 3H, OCH3), 5.62 (s, 2H, CH2–N), 6.92 (s, 1H, H-4),
7.23–7.33 (m, 7H, H–Ph), 7.76 (d, 2H, Jo¼8.3 Hz, H–Ph),
8.10 (s, 1H, H-8), 8.70 (s, 1H, H-5); 13C NMR: d 21.6
(CH3), 46.6 (CH2–N), 56.5 (OCH3), 106.7 (CH), 108.2
(CH), 118.9 (C), 127.3 (CH), 128.0 (CH), 128.8 (CH), 129.1
(CH), 129.8 (CH), 134.7 (C), 135.9 (C), 140.3 (C), 144.8
(C), 149.2 (C), 151.2 (C), 156.1 (C), 158.0 (C); MS [m/z
(%)]: EI: 420 (6, Mþz), 356 (43, Mþz2SO2), 265 (9,
Mþz2SO2, –C7H7), 91 (100, C7H7þ); HRMS: calcd for
C23H20N2O4S: 420.1144, found: 420.1147.
4.6.7. Dimethyl (6R p,7S p) 1-benzyl-3-methoxy-5,6,7,8-
tetrahydro-2-oxo-1H-quinoline-6,7-dicarboxylate
Yield: 77%; white crystals; mp 152–153 8C; IR (KBr/
28.
1
cm21): 3029, 2949, 1743, 1655, 1598; H NMR: d 1.75–
2.91 (m, 2H), 2.90–3.10 (m, 4H), 3.55 (s, 3H, OCH3), 3.59
(s, 3H, OCH3), 3.77 (s, 3H, OCH3), 5.24 (d, 1H,
2
2J¼20.1 Hz, CH2–N), 5.41 (d, 1H, J¼20.1 Hz, CH2–N),
6.37 (s, 1H, H-4), 7.09 (d, 2H, Jo¼8.0 Hz, H–Ph), 7.15–
7.22 (m, 3H, H–Ph); 13C NMR: d 26.5 (CH2), 28.1 (CH2),
39.2 (CH), 39.7 (CH), 46.7 (CH2–N), 52.0 (CH3), 52.1
(CH3), 55.7 (CH3), 110.9 (C-8a), 114.1 (CH-4), 126.5 (CH),
127.2 (CH), 128.6 (CH), 131.4 (C-4a), 136.9 (C-ipso), 148.4

438
T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
4.7. Substitution of sulfolene pyridinone 19 in position 7
(24, Mþz), 309 (25, Mþz2SO2), 254 (38, Mþz2SO2, –C4H7),
218 (37, Mþz2SO2, –C4H7), 91 (100, C7H7þ); HRMS:
calcd for C20H23NO4S: 373.1348, found: 373.1350.
General procedure A. To a solution of 0.2 g (0.65 mmol) of
the precursor 19 in dry THF (25 mL) under argon
atmosphere was added slowly 1.3 equiv. of tetrabutylam-
monium fluoride. After stirring at room temperature for 1 h,
2 equiv. of electrophile were added. The reaction mixture
was stirred for 12 h at room temperature; then a solution of
NH4Cl (25 mL) was added, the mixture was stirred further at
room temperature for 1 h and extracted with CH2Cl2
(3£10 mL). The combined organic phases were dried
(MgSO4) and evaporated to give a residue that was purified
by column chromatography (alumina, 15 EtOAc/85 CH2Cl2).
4.7.3. Allyl 1-benzyl-5,7-dihydro-3-methoxy-2,6,6-
trioxo-1H-thieno[3,4-b]pyridine-7-carboxylate 36. Yield:
61% (method B); yellow oil; 1H NMR: d 3.88 (s, 3H, OCH3),
4.17 (d, 1H, 2J¼14.8 Hz, H-5), 4.39 (d, 1H, 2J¼14.8 Hz, H-5),
4.46 (dt, 2H, 3J¼6.0 Hz, 4J¼1.3 Hz, H-30), 4.87 (s, 1H, H-7),
4.96 (d, 1H, 2J¼15.9 Hz, CH2–N), 5.27 (dd, 1H, 3Jcis¼10.4
0
3
Hz, 4J¼1.3 Hz0, H-5 ), 5.32 (dd, 1H, Jtrans¼17.2 Hz,
4J¼1.3 Hz, H-5 ), 5.44 (d, 1H, J¼15.9 Hz, CH2–N), 5.80
2
0
3
3
3
(ddt, 1H, Jtrans¼17.2 Hz, Jcis¼10.4 Hz, J¼6.0 Hz, H-4 ),
6.56 (s, 1H, H-4), 7.12 (d, 2H, Jo¼6.0 Hz, H–Ph), 7.28–7.30
(m, 3H, H–Ph); 13C NMR: d 48.8 (CH2–N), 56.1 (OCH3),
56.2(CH2-5),67.6(CH2-30),69.1(CH-7), 108.5(CH-4), 110.3
(C-7a), 120.0 (CH2-50), 126.6 (CH), 127.4 (C-4a), 128.1 (CH),
128.9 (CH), 130.3 (CH-40), 134.4 (C-ipso), 151.4 (C-3), 157.6
(C-2), 162.5 (C-10); MS [m/z (%)]: EI: 389 (20, Mþz), 325 (6,
Mþz2SO2), 284 (14, Mþz2SO2, –C3H5), 240 (19, Mþz2SO2,
–C4H5O2), 234 (2, Mþz2SO2, –C7H7), 91 (100, C7H7þ);
HRMS: calcd for C19H19NO6S: 389.0933, found: 389.0939.
General procedure B. To a cooled (0 8C) suspension of
1.1 equiv. of NaH in DMF (10 mL) was added under a
nitrogen atmosphere a solution of 0.2 g (0.65 mmol)
sulfolene pyridinone 19. Stirring was continued at 0 8C for
1 h, after which time 2 equiv. of an electrophile was added.
The reaction mixture was allowed to slowly warm to room
temperature. After work up by adding 20 mL of saturated
NH4Cl solution and extraction with CH2Cl2 (3£15 mL), the
combined organic layers were dried over MgSO4. The
solvent was evaporated and the residue was purified by
column chromatography (alumina, 15 EtOAc/85 CH2Cl2).
4.7.4. Methyl 1-benzyl–5,7-dihydro-3-methoxy-2,6,6-
trioxo-1H-thieno[3,4-b]pyridine-7-carboxylate 37. Yield:
59% (method B); yellow oil; IR (NaCl/cm21): 3055, 2926,
1750, 1655, 1319, 1110; 1H NMR: d 3.62 (s, 3H, OCH3), 3.90
4.7.1. 1,7-Dibenzyl-5,7-dihydro-3-methoxy-6,6-dioxo-
thieno [3,4-b]pyridin-2(1H)-one 34. Yield: 60% (pro-
cedure B); 40% (procedure A); oil; IR (NaCl/cm21):
2
(s, 3H, OCH3), 4.15 (d, 1H, J¼14.8 Hz, H-5), 4.40 (d, 1H,
2J¼14.8 Hz, H-5), 4.86 (s, 1H, H-7), 4.99 (d, 1H, 2J¼15.7 Hz,
CH2–N), 5.41(d, 1H, 2J¼15.7 Hz, CH2–N), 6.55(s, 1H, H-4),
7.12 (dd, 2H, Jo¼6.8 Hz, Jm¼1.5 Hz, H–Ph), 7.26–7.30 (m,
3H, H–Ph); 13C NMR: d 48.9 (CH2–N), 54.0 (OCH3), 56.2
(CH2-5), 56.3 (OCH3), 69.2 (CH-7), 108.5 (CH-4), 110.3
(C-7a), 126.7 (CH), 127.5 (C-4a), 128.2 (CH), 129.0 (CH),
134.4 (C-ipso), 151.6 (C), 157.9 (C-2), 163.4 (C); MS [m/z
(%)]: EI: 363 (22, Mþz), 299 (14, Mþz2SO2), 240 (17,
Mþz2SO2, –C7H7), 91 (100, C7H7þ); HRMS: calcd for
C17H17NO6S: 363.0777, found: 363.0778.
1
3055, 2976, 1607, 1325, 1124; H NMR: d 3.21 (dd, 1H,
2J¼14.7 Hz, 3J¼5.5 Hz, CH2–Ph), 3.39 (dd, 1H,
2J¼14.7 Hz, 3J¼5.5 Hz, CH2–Ph), 3.58 (d, 1H,
2J¼15.0 Hz, H-5), 3.82 (s, 3H, OCH3); 3.87 (d, 1H,
3
2J¼15.0 Hz, H-5), 4.17 (t, 1H, J¼5.5 Hz, H-7), 4.33 (d,
2
2
1H, J¼16.0 Hz, CH2–N), 5.70 (d, 1H, J¼16.0 Hz, CH2–
N), 6.38 (s, 1H, H-4), 7.03–7.07 (m, 4H, H–Ph), 7.24–7.29
(m, 6H, H–Ph); 13C NMR: d 36.9 (CH2-5), 48.3 (CH2–N),
54.8 (CH2–Bn), 56.2 (CH3), 64.9 (CH-7), 108.8 (C-7a),
108.9 (CH-4), 126.4 (CH), 127.8 (CH), 128.6 (CH), 128.8
(CH), 129.1 (CH), 129.7 (CH), 132.1 (C-4a), 134.1 (C-ipso),
135.1 (C-ipso), 150.6 (C-3), 157.9 (C-2); MS [m/z (%)]: EI:
395 (42, Mþz), 331 (60, Mþz2SO2), 304 (12, Mþz2C7H7),
240 (35, Mþz2SO2, –C7H7), 91 (100, C7H7þ); HRMS:
calcd for C22H21NO4S: 395.1112, found: 395.1120.
4.7.5. N,N-Diallyl-1-benzyl-5,7-dihydro-3-methoxy-
2,6,6-trioxo-1H-thieno[3,4-b]pyridine-7-carboxamide
38. Yield: 58% (method B); yellow oil; IR (NaCl/cm21):
1
3070, 2936, 1660, 1609, 1329, 1129; H NMR: d 3.71 (m,
2H, 2£CH2–allyl), 3.78 (s, 3H, OCH3), 3.89 (dd, 1H,
2
2
3J¼6 Hz, J¼17 Hz, CH2–allyl), 4.09 (d, 1H, J¼14.6 Hz,
3
2
4.7.2. 1-Benzyl-5,7-dihydro-3-methoxy-7-(4-pentenyl)-
6,6-dioxothieno[3,4-b]pyridin-2(1H)-one 35. Yield: 57%
(method B), 25% (method A); yellow crystals; mp 54.6–
55.8 8C (CH2Cl2/hexane); IR (KBr/cm21): 3064, 2925,
CH2-5), 4.13 (dd, 1H, J¼6 Hz, J¼15.1 Hz, CH2–allyl),
4.35 (d, 1H, 2J¼14.6 Hz, CH2-5), 4.38 (d, 1H, 2J¼16.5 Hz,
2
CH2–N), 4.98 (dþm, 2H, J¼16.5 Hz, CH2–NþH–Cv),
5.03 (s, 1H, H-7), 5.14 (dd, 1H, 3J¼6 Hz, 4J¼1.3 Hz,
vCH2), 5.19 (dd, 1H, 3J¼13 Hz, 4J¼1.3 Hz, vCH2), 5.54
(m, 2H, vCH2), 5.68 (m, H, H–Cv), 6.50 (s, 1H, H-4),
6.94 (d, 2H, Jo¼8.5 Hz, H–Ph), 7.20–7.25 (m, 3H, H–Ph);
13C NMR: 48.7 (CH2), 49.2 (CH2), 50.3 (CH2), 56.2 (CH2),
56.5 (OCH3), 66.8 (CH), 108.7 (CH), 110.0 (C), 118.7
(CH2), 119.2 (CH2), 125.6 (C-arom), 127.8 (C-arom), 128.9
(C-arom), 131.4 (CH), 131.60(CH), 134.4 (C-ipso), 151.1
(C-3), 157.6 (C-2), 161.6 (C-1 ); MS [m/z (%)]: EI: 428 (10,
Mþz), 364 (100, Mþz2SO2), 273 (36, Mþz2SO2, –C7H7),
190(74,Mþz2SO2, –C7H7, –C6H11), 91(76,C7H7þ);HRMS:
calcd for C22H24N2O5S: 428.1406, found: 428.1412.
1
1658, 1607, 1315, 1125; H NMR: d 1.33–1.51 (m, 2H,
CH2-30), 1.69–1.92 (m, 4H, CH2-10þCH2-20), 3.79 (s, 3H,
3
OCH3), 3.91 (dd, 1H, J¼7.7, 3.2 Hz, H-7), 4.03 (d, 1H,
2J¼15.4 Hz, H-5), 4.10 (d, 1H, 2J¼15.4 Hz, H-5), 4.89 (dt,
0
3
4
1H, Jtrans¼16.9 Hz, J¼1.3 Hz, H-5 ), 4.92 (d broad, 1H,
3Jcis¼9.0 Hz, H-50), 4.96 (d, 1H, 2J¼15.8 Hz, CH2–N), 5.45
2
3
(d, 1H, J¼15.8 Hz, CH2–N), 5.60 (ddt, 1H, Jtrans¼16.9
Hz, 3Jcis¼9.0 Hz, 3J¼7.0 Hz, H-40), 6.48 (s, 1H, H-4), 7.58
(dd, 2H, Jo¼6.4 Hz, Jm¼1.8 Hz, H–Ph), 7.22–7.27 (m, 3H,
H–Ph); 13C NMR: d 25.3 (CH2), 30.5 (CH2), 33.4 (CH2),
48.6 (CH2–N), 55.7 (CH2-5), 56.6 (CH3), 64.7 (CH-7),
108.1 (C-7a), 109.4 (CH-4), 116.0 (CH2-50), 126.0 (CH),
127.9 (CH), 129.0 (CH), 132.5 (C-4a), 135.5 (C-ipso), 137.5
(CH-40), 150.9 (C-3), 158.5 (C-2); MS [m/z (%)]: EI: 373
4.7.6. 1-Benzyl-7-bromo-5,7-dihydro-3-methoxy-6,6-
dioxothieno[3,4-b]pyridin-2(1H)-one 39. (A) A solution

T. C. Govaerts et al. / Tetrahedron 60 (2004) 429–439
439
of 0.1 g (0.32 mmol) 2(1H)-pyrazinone 19 and 1.1 equiv.
NBS in CCl4 was irradiated with a 500 W tungsten-lamp for
1 h, then the solvent was evaporated. The residue was
chromatographed (silica gel, 85 CH2Cl2/15 EtOAc) to yield
45% of compound 39.
190 (100, Mþz2C7H7, –CONC3H5), 91 (92, C7H7þ);
HRMS: calcd for C22H24N2O3: 364.1787, found: 364.1788.
Acknowledgements
(B) A solution of 19 and NBS (1.1 equiv.) and a catalytic
amount of benzoylperoxide in CCl4 was refluxed for 3 h to
afford compound 39, in 67% yield, after chromatographic
purification.
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. T. G. thanks the IWT and I. V. (Research Assistant
of the FWO—Flanders) thanks the FWO for the fellowships
received.
1
Yellow oil; H NMR: d 3.87 (s, 3H, CH3), 4.08 (d, 1H,
J¼16 Hz, H-5), 4.29 (d, 1H, J¼16 Hz, H-5), 4.83 (d,
2
1H, J¼15.7 Hz, CH2–N), 5.09 (s, 1H, H-7), 6.10 (d, 1H,
2J¼15.7 Hz, CH2–N), 6.67 (s, 1H, H-4), 7.05–7.12 (m, 2H,
H–Ph), 7.13–7.35 (m, 3H, H–Ph); 13C NMR: d 50.0
(CH2–N), 55.0 (OCH3), 57.5 (CH2-5), 70.1 (CH-7), 110.1
(CH-4), 113.3 (C-7a), 126.7 (CH), 128.0 (C), 128.2 (CH),
129.0 (CH), 134.4 (C-ipso), 152.8 (C), 160.1 (C), 164.1
(C); MS [m/z (%)]: EI: 305 þ(61, Mþz2Br), 241 (20,
Mþz2Br,2SO2), 91 (100, C7H7 ).
References and notes
1. For recent reviews, see: (a) Collier, S. J.; Storr, R. C. Progress
in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L.,
Eds.; Pergamon: New York, 1998; Vol. 10. Chou, T.-S. Rev.
Heteroatom. Chem. 1993, 8, 65. (c) Segura, J. L.; Martin, N.
Chem. Rev. 1999, 99, 3199.
4.8. Intramolecular Diels–Alder reactions
4.8.1. 1-Benzyl-6-[(1E)-1,5-hexadienyl]-3-methoxy-5-
methyl-2(1H)-pyridinone 40. Yield: 55%; yellow oil; IR
2. (a) Herrera, A.; Martinez, R.; Gonzales, B.; Illescas, B.; Martin,
N.; Seoane, C. Tetrahedron Lett. 1997, 38, 4873. (b) Chou, T.-
S.; Ko, C. W. Tetrahedron 1994, 36, 10721. (c) Mertzanos,
G. R.; Stephanidou-Stephanatou, J.; Tsoleris, C. A.; Alexan-
drou, N. E. Tetrahedron Lett. 1992, 33, 8101. (d) Shepherd,
M. K. J. Chem. Soc., Perkin Trans. 1 1986, 1495. (e) Carly,
P. R.; Cappelle, S. L.; Compernolle, F.; Hoornaert, G. J.
1
(NaCl/cm21): 3004, 2933, 1650, 1605; H NMR: d 2.09 (s,
3
3H, CH3), 2.16 (t broad, 2H, J¼6.7 Hz, CH2), 2.24 (t, 2H,
3J¼6.6 Hz, CH2), 3.83(s, 3H, OCH3), 4.90(d, 1H, 3J¼9.0 Hz,
H-60), 5.01(d, 1H, 3J¼16.5 Hz, H-60), 5.34(sbroad,2H, CH2–
N), 5.65–5.72 (m, 2H, H-20þH-50), 5.92 (d, 1H, 3Jtrans¼16.1
Hz, H-10), 6.54 (s, 1H, H-4), 7.12–7.26 (m, 5H, H–Ph); 13
C
Tetrahedron 1996, 52, 11889. (f) Gonzalez, B.; Herrera, A.;
´
´
´ ´
Illescas, B.; Martın, N.; Martınez, R.; Moreno, F.; Sanchez, L.;
NMR: d 19.0 (CH3), 32.0 (CH2), 32.7 (CH2), 48.4 (CH2–N),
55.6 (OCH3), 111.9 (C-5), 115.3 (CH2-60), 116.1 (CH-4),
122.0 (CH), 126.9 (CH), 128.2 (CH), 128.5 (CH), 134.6 (C-4),
136.9 (C-ipso), 137.3 (CH), 139.7 (CH), 147.8 (C-3), 157.7
(C-2); MS [m/z (%)]: EI: 309 (100, Mþz), 294 (15, Mþz2CH3),
254 (82, Mþz2C4H7), 218 (42, Mþz2C7H7), 190 (12,
Mþz2C7H7, –CO), 91 (84, C7H7þ); HRMS: calcd for
C20H23NO2: 309.1729, found: 309.1733.
´
Sanchez, A. J. Org. Chem. 1998, 63, 6807–6813.
3. (a) Crew, A. P. A.; Jenkins, G.; Storr, R. C.; Yelland, M.
Tetrahedron Lett. 1990, 31, 1491. (b) Chaloner, L. M.; Crew,
A. P. A.; O’Neill, P. M.; Storr, R. C.; Yelland, M. Tetrahedron
1992, 48, 8101. (c) Chou, T.-S.; Chang, R. C. Tetrahedron Lett.
1992, 33, 8121. (d) Chou, T.-S.; Chang, R. C. J. Chem. Soc.,
Chem. Commun. 1992, 549. (e) Chou, T.-S.; Tsai, C. Y. J. Chem.
Soc., Chem. Commun. 1991, 1287. (f) Chou, T.-S.; Tsai, C. Y.
4.8.2. (6aS p,9aS p)-8-Allyl-1-benzyl-3-methoxy-
5,6,6a,7,8,9a-hexahydro-1H-pyrrolol[3,4-b]quinoline-
2,9-dione 41. Yield: 65%; dark yellow oil; IR (NaCl/cm21):
2934, 1683, 1609; 1H NMR: d 1.66 (ddd, 3J¼13, 9.1, 6 Hz,
H-6ax), 1.79 (ddd, 1H, 3J¼13, 8, 4 Hz, H-6eq), 2.43 (m, 1H,
Heterocycles 1992, 663. (g) Tome, A. C.; Cavalairo, J. A. S.;
´
´
Storr, R. C. Tetrahedron 1996, 52, 1723. (h) Tome, A. C.;
Cavalairo, J. A. S.; Storr, R. C. Tetrahedron 1996, 52, 1735. (i)
Carly, P. R.; Govaerts, T. C.; Cappelle, S. L.; Compernolle, F.;
Hoornaert, G. J. Tetrahedron 2001, 57, 4203. (j) Cappelle, S. L.;
Vogels, I. A.; Van Meervelt, L.; Compernolle, F.; Hoornaert,
G. J. Tetrahedron Lett. 2001, 42, 3759.
2
H-6a), 2.50–2.64 (m, 2H, H-5), 2.94 (d, 1H, J¼10 Hz,
H-7), 3.48 (dd, 1H, 2J¼10 Hz, 3J¼60Hz, H-7), 3.57 (d, 1H,
3J¼6.2 Hz, H-9a), 3.81 (m, 1H, H-8 ), 3.83 (s, 3H, OCH3),
3.97 (dd, 1H, 2J¼15 Hz, 3J¼6 Hz, H-80), 5.18 (dd 1H,
4. Govaerts, T. C.; Vogels, I. A.; Compernolle, F.; Hoornaert, G. J.
Tetrahedron 2003, 59, 5481–5494.
000
4
transJ¼19 Hz, J¼1.3 Hz, H-8 ), 5.21 (d, 1H, cisJ¼9 Hz,
5. Govaerts, T. C.; Vogels, I.; Compernolle, F.; Hoornaert, G. J.
Tetrahedron Lett. 2002, 43, 799–802.
000
2
H-8 ), 5.47 (d, 1H, J¼16.8 Hz, CH2–N), 5.71 (ddt, 1H,
transJ¼19 Hz, cisJ¼9 Hz, 3J¼6 Hz, H-800), 6.21 (d, 1H,
2J¼16.8 Hz, CH2–N), 6.40 (s, 1H, H-4), 7.05 (d, 2H,
Jo¼8.8 Hz, H–Ph), 7.17–7.28 (m, 3H, H–Ph); 13C NMR:0 d
24.9 (C-6), 26.5 (C-5), 32.1 (C-6a), 43.2 (C-9a), 45.6 (C-8 ),
46.8 (CH2–N), 50.4 (C-7), 55.6 (OCH3), 113.9 (C), 114.0
(C-4), 118.7 (C-8000), 126.0 (C–Phortho), 126.8 (C–Phpara),
128.6 (C–Phmeta), 128.8 (C), 131.8 (C-800), 137.4 (C-ipso),
148.6 (C-3), 158.5 (C-2), 171.0 (C-9); MS [m/z (%)]: EI:
364 (91, Mþz), 323 (4, Mþz2C3H5), 273 (39, Mþz2C7H7),
6. (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.
7. Buysens, K. J.; Vandenberghe, D. M.; Toppet, S. M.;
Hoornaert, G. J. Tetrahedron 1995, 51, 12463–12478.
8. Buysens, K. J.; Vandenberghe, D. M.; Hoornaert, G. J.
Tetrahedron 1996, 52, 9161–9178.