Diels-Alder reactions with pyridine o-quinodimethanes generated from pyridine sulfolenes

Article abstract of DOI:10.1016/S0040-4020(02)00348-4

An efficient route has been developed for the synthesis of polysubstituted 6,6-dioxo-6,7-dihydrothieno[3,4-b]pyridines 3, which serve as excellent precursors for generation of the corresponding pyridine o-quinodimethanes. Following thermal extrusion of sulfur dioxide, these reactive species can be trapped in situ with electron rich, neutral, and electron deficient dienophiles. The regio and stereochemical structure of the resulting adducts was determined by NMR analysis.

Full text of DOI:10.1016/S0040-4020(02)00348-4

TETRAHEDRON
Pergamon
Tetrahedron 58 82002) 3655±3666
Diels±Alder reactions with pyridine o-quinodimethanes generated
from pyridine sulfolenes
Steven L. Cappelle, Ilse A. Vogels, Tom C. Govaerts, Suzanne M. Toppet, Frans Compernolle
and Georges J. Hoornaertp
Laboratorium voor Organische Synthese, Department of Chemistry, K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 20 February 2002; revised 14 March 2002; accepted 29 March 2002
AbstractÐAn ef®cient route has been developed for the synthesis of polysubstituted 6,6-dioxo-6,7-dihydrothieno[3,4-b]pyridines 3, which
serve as excellent precursors for generation of the corresponding pyridine o-quinodimethanes. Following thermal extrusion of sulfur dioxide,
these reactive species can be trapped in situ with electron rich, neutral, and electron de®cient dienophiles. The regio and stereochemical
structure of the resulting adducts was determined by NMR analysis. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
generation of the corresponding pyridine o-QDM of struc-
tural type 4 and in situ trapping of this reactive intermediate
using various dienophiles.3 We now wish to report further
applications of this and similar pyridine o-QDM systems. So
far, only a few reports have dealt with the application of
pyridine o-QDMs of type 4 and its regioisomer 5.4
The chemistry of heteroaromatic o-quinodimethanes 8Het-
o-QDMs) 1 8Fig. 1) has gained increasing interest in the last
decade.1 A generally applied strategy is to generate these
reactive species via thermolysis of heteroaromatic-fused
3-sulfolenes 2.2a±c There are several advantages to the use
of these sulfolene precursors. First, extrusion of SO2 usually
occurs already at moderately high temperatures and under
neutral conditions so that the adducts formed via in situ
trapping of the Het-o-QDMs with dienophiles can be
isolated in good yield. A further merit resides in the acid
character of the protons a to the sulfone group, which
allows for introducing various substituents, e.g. dienophilic
side chains. Until now three main routes leading to hetero-
aromatic-fused 3-sulfolenes have been reported: 81) reverse
addition of SO2 to Het-o-QDMs,2a 82) transformation of
bis8halomethyl) heterocyclic compounds,2b and 83) annula-
tion of a dihydrothiophene ring with a heterocyclic core.2c In
a previous communication, we described an ef®cient route
for preparing the functionalised pyridine sulfolene 3a;
initial thermolysis experiments carried out on 3a involved
2. Results and discussion
2.1. Synthesis of the pyridine o-QDM precursors
To generate pyridine sulfolenes of type 3, we envisaged
base-induced cyclisation of the corresponding sulfones 6
8Scheme 1). The polyfunctional pyridine ring system of 6
in turn can be constructed according to our general approach
using cycloaddition of the oxazinone azadiene system 7
with alkynes, which proceeds with concomitant expulsion
of carbon dioxide.5
Cycloaddition of oxazinone 7 with propargyl bromide was
effected by heating in toluene to produce pyridine 8 as the
only regioisomer in excellent yield 8Scheme 2).6 Subsequent
treatment of 8 with sodium hydrogen sul®de resulted in a
complex reaction mixture from which the desired thiol 9
could not be isolated. To solve this problem, ®rst, bromide
8 was converted into a S-protected intermediate by reaction
Figure 1.
Keywords: pyridines; sulfones; Diels±Alder reactions; quinonoid
compounds.
p
Corresponding author. Tel.: 132-16-327409; fax: 132-16-327990;
e-mail: georges.hoornaert@chem.kuleuven.ac.be
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020802)00348-4

3656
S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
Scheme 4. Attempted transformation of thioether 12a to pyridine sulfolene
3b. 8i) 3 equiv. mCPBA, CH2Cl2, room temperature, 5 h 885%), 8ii) base.
be converted to the free ester 13 by careful neutralisation, or
captured in situ by reaction with suitable electrophiles to
provide 15. Thienopyridines 14 and 16 were prepared in a
similar way from thioether 12b. However, ring closure of
thioether 12c failed, probably due to the decreased acidity of
the benzyl methylene group as compared to that of ester 12a
and nitrile 12b.
Scheme 2. Synthesis of thioester 10. 8i) 2 equiv. propargyl bromide, toluene
re¯ux 8 h 898%), 8ii) NaHS, MeOH re¯ux, 8iii) 1.2 equiv. HSCOCH3,
3 equiv. NEt3, THF, room temperature, 20 min 898%).
with thiolacetic acid and an excess of NEt3, affording
thioester 10 in 98% yield.
In several attempts to convert the cyclic thioethers into the
desired pyridine o-QDM precursors, compounds 13 and 14
were treated with H2O2 in acetic acid or methanol, and with
mCPBA in dichloromethane 8Scheme 6). However, both
reaction conditions were found to result in dehydrogenation
of the dihydrothiophene ring to yield thienopyridines 17a,b
and a small amount of thienopyridinone 18, the hydrolysis
product of 17a. Dehydrogenation probably proceeds via
dehydration of the initially formed sulfoxide. Such dehydra-
tion of a sulfoxide intermediate cannot occur for 7,7-
disubstituted compounds 15 and 16. Hence, when submitted
to oxidation with mCPBA in dichloromethane, the latter
were converted in good yield to the desired pyridine
Deprotection of 10 was achieved by reaction with 1.2 equiv.
of sodium methoxide in methanol to produce the desired
thiol as the thiolate anion 11. The latter could be alkylated
in situ using the electrophilic reagents methyl chloroacetate,
bromoacetonitrile and benzyl bromide to give the corre-
sponding thioethers 12a±c in 95, 95, and 75% yield, respec-
tively 8Scheme 3). Thioether 12a also could be prepared
directly from 8 in 88% yield by treatment with the com-
mercially available methyl thioglycolate.
Oxidation of thioether 12a to form the corresponding
sulfone 6a was accomplished in 85% yield by using
mCPBA in CH2Cl2 8Scheme 4). However, several attempts
to induce cyclisation of 6a, using various basic conditions,
failed to produce the corresponding pyridine sulfolene 3b.
This can probably be attributed to the weak nucleophilic
character of the enolate anion formed, which is strongly
stabilised by both the ester and sulfone group. Moreover,
strong angular strain may be involved in folding back this
planar anion above the pyridine ring for attack at the 2-Cl
position.
Therefore, a different route was followed, which involved
cyclisation of the more reactive anion obtained by treatment
of thioether 12a with KH in THF 8Scheme 5). Due to the
increased acidity of the a-proton remaining after cyclisa-
tion, an excess of KH was required to effect complete
conversion of 12a to a cyclic anion intermediate. This can
Scheme 5. Synthesis of cyclic thioethers 13±16.
Scheme 3. Preparation of thioethers 12. 8i) 1.2 equiv. NaOCH3, MeOH,
room temperature, 15 min, 8ii) 1.2 equiv. XCH2R, MeOH, room tempera-
ture, 4 h, 8iii) 1.1 equiv. HSCH2COOCH3, 3 equiv. NEt3, THF, room
temperature, 30 min.
Scheme 6. Oxidation of cyclic thioethers 13 and 14. 8i) 3 equiv. mCPBA,
CH2Cl2, room temperature, 3 h 817a: 80%, 17b: 57%, 18:15%).

S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
Table 1. Oxidation of cyclic thioethers 15 and 16 to pyridine sulfolenes
3a±f
3657
No.
R
R0
CH3
Yield 8%)
3a
3b
3c
3d
3e
3f
COOCH3
COOCH3
COOCH3
COOCH3
CN
93
85
82
80
94
62
H
COOCH3
CH2C6H5
CH3
CN
COOCH3
sulfolenes 3a,c±f 8Table 1). Finally, although oxidation of
13 failed to produce sulfolene 3b 8see above), this mono-
substituted ester could be prepared in 85% yield starting
from diester 15b, which upon treatment with sodium
methoxide in methanol smoothly lost one of the ester
groups.
Scheme 7. Thermolysis of pyridine sulfolenes 3. 8i )o-Dichlorobenzene,
2008C, 15 h.
2.2. Generation of pyridine o-QDMs and their
application to intermolecular Diels±Alder reactions
proceed via the bicyclic pyridine±cyclobutene inter-
mediates C 8Scheme 7). Indeed, the corresponding benzo-
cyclobutenes also have been invoked as intermediates
for interconversion between the E- and Z-isomers of the
analogous benzene o-QDMs.7
Thermal extrusion of sulfur dioxide from the 7-substituted
pyridine sulfolenes 3 may produce terminally substituted
dienes having either the E- or Z-con®guration. According
to a study of the electrocyclic 8conrotatory) ring opening of
substituted benzocyclobutenes,7 an electron withdrawing
group 8e.g. aldehydes and ketones) tends to rotate inward,
i.e. towards the other end of the diene, while an electron
donating alkyl group would prefer an outward rotation.
Ester and nitrile groups show an ambivalent character.
When located at a monosubstituted diene end, these groups
prefer an outward orientation. However, for o-QDMs bear-
ing also an alkyl group at the disubstituted diene end, the
ester and nitrile groups again are preferably oriented inward.
2.2.1. Thermolysis in absence of a dienophile. In contrast
to the intermolecular addition of dienophiles, which
preferably occurs from o-QDM intermediates A 8see
below), form B was demonstrated as an intermediate in
intramolecular cyclisation or rearrangement. Thus,
thermolysis of pyridine sulfolene 3a in the absence of a
dienophile produced acrylate 19 in 78% yield 8Scheme 8).
This requires the generation of the Z-isomer B3a, followed
by a 1,5-H shift.8 The formation of pyranopyridine 20 875%
yield) from thermolysis of 3c can be explained by an
electrocyclic ring closure involving the carbonyl function
The thermolysis experiments were carried out by heating
solutions of 3 in o-dichlorobenzene at 2008C in a sealed
glass tube. To study the reactivity of the pyridine o-QDMs
and their regioselectivity in cycloaddition reactions,
thermolysis ®rst was carried out in absence of a dienophile;
subsequently, electron-poor, neutral, and electron-rich
dienophiles were applied. In cases where the pyridine
o-QDM system bears two different substituents at the
same diene end, it was examined which geometric isomer
A or B is preferably involved in: 8a) the initial extrusion of
sulfur dioxide, 8b) intramolecular cyclisation and/or
rearrangement of the pyridine o-QDM system, and 8c) inter-
molecular cycloaddition reactions.
From the results given below, it appears that in the presence
of a dienophile endo-addition proceeds from a preferred
o-QDM intermediate A having an inward orientation of
the S1-substituent, in accordance with the preferences
found for the electrocyclic opening of benzocyclobutenes.7
However, when no dienophile is present, form A is
converted slowly into its geometric isomer B, which then
may undergo either electrocyclic ring closure or a rear-
rangement reaction. The conversion of A to B might
Scheme 8. Thermolysis of precursors 3a,c±e in absence of a dienophile.

3658
S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
of an ester group in intermediate A8B)3c. Although a similar
pyranopyridine also might form from E-isomer A3a, this
could not be isolated. Indeed, pyranopyridine 20 was
shown to revert to the o-QDM intermediate under
thermolysis conditions 8see below), in contrast to the
irreversible 1,5-H shift observed for Z-isomer B3a.
Thermolysis of sulfone 3d gave a dimeric product 8MH1
385) that was not further characterised. Following
thermolysis of 3e, pyranopyridine 21 was isolated in 80%
yield. According to our general Scheme 7, this result can be
explained by conversion of Z-isomer A3e with inward
orientation of the linear nitrile group to the less stable
E-isomer B3e. Although the latter exhibits a large steric
repulsion between the ester and methylene groups, it may
be stabilised by subsequent electrocyclic ring closure.
Evidently, such ring closure is not feasible for Z-isomer
A3e as this would require the insertion of a cumulene
with diagonal C-atom in a six-membered ring.
Figure 2. Two pairs of boat conformers for the all-cis-adduct 24 and the
trans, cis-adduct 240.
from endo-addition of NMPA to either the Z-isomer A3d or
the E-isomer B3d. By analogy to the NPMA adduct 22, a
cis-orientation was expected for the 9-methyl and carbonyl
groups as in 24, which corresponds to endo-addition of
Z-isomer A3d. This was con®rmed by NOESY analysis,
which revealed that adduct 24 occurs as the boat conformer
A. A strong NOE was found for the protons of the trans-
oriented 9-methyl group and H-8a, in accordance with
conformer A but not with B. Conformer B could be
dismissed further on the basis that no NOE was observed
between H-5ax and the axial 9-methyl protons. Conformer
D of 240 would require a NOE interaction of H-5eq with
both H-4 and the cis-disposed proton H-5a, of which the
latter was missing. Finally, boat form C was excluded
since no NOE was found between H-5ax and the protons
of the axial 9-Me group. Moreover, E-isomer B3d is
expected to undergo a 1,5-H shift as observed for B3a.
2.2.2. Intermolecular Diels±Alder reaction with
N-phenylmaleimide /NPMA). Thermolysis of sulfolene
3a in the presence of NPMA afforded adduct 22 as a single
stereoisomer 888%). The stereostructure of 22 was
established by X-ray diffraction as reported in our previous
communication.3 In a similar way, NPMA adducts 23 885%)
and 24 865%) were produced from the thermolysis of
precursors 3c and 3d, respectively 8Table 2).
Since NPMA is known to add preferentially in the endo-
mode, cycloaddition must proceed via E-isomers A3a and
A3d to give exclusively the endo-adducts 22 and 24. Hence,
when related to the intramolecular reaction of Z-isomer B3a
involving a 1,5-H shift, these results indicate that the
geometric isomers A are the primarily formed pyridine
o-QDM intermediates. Subsequent conversion of A into B
might proceed via pyridocyclobutene C 8see general
Scheme 7) but presumably, this process is relatively slow
as compared to the addition of NMPA.
2.2.3. Further Diels±Alder reactions. Further Diels±Alder
reactions of pyridine o-QDMs generated from pyridine
sulfolenes 3a±d were conducted with various dienophiles
to yield adducts 25±33 8Table 3).
Table 3. Adducts formed in Diels±Alder reactions of 3a±d with other
dienophiles
The thermolysis of diester 3c and the in situ Diels±Alder
reaction with NPMA were conducted in o-dichlorobenzene
at 1608C in two different ways: NPMA was added either
before extrusion of sulfur dioxide or after conversion of 3c
to pyranopyridine 20. In both cases, the same adduct 23 was
isolated. This experiment demonstrates that interconversion
of pyranopyridine 20 and the o-QDM intermediate A8B)3c
is possible at 1608C.
Fig. 2 shows the structures of two pairs of boat conformers
corresponding to the diastereomeric adducts 24,240 derived
Table 2. Adducts formed in Diels±Alder reactions of 3a,c±d with NPMA
Adduct
R
R0
CH3
COOCH3
CH3
Yield 8%)
22
23
24
COOCH3
COOCH3
CN
88
85
65

S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
3659
in conversion of the E-isomer A3a into the Z-isomer B3a,
which is subject to a competing 1,5-H shift to form 19.
However, addition of cyclopentene proved to be successful
when such a competing pathway cannot occur as for the
diester o-QDM intermediate A8B)3c derived from diester
3c. Although the latter was shown to undergo electrocyclic
ring closure to form pyranopyridine 20, this process can be
reversed and adduct 28 was isolated in 60% yield.
Figure 3. Half-chair conformers for trans, cis-adduct 25.
From analogy to the reaction of 3a with NPMA, E-isomer
A3a can be postulated as an intermediate in the cyclo-
addition with dimethyl maleate. Since this dienophile also
adds preferably in the endo-mode, the trans,cis-adduct 25 is
to be expected. Adduct 25 may exist as two half-chair forms
A and B having an axial and equatorial orientation of the
ester group on C-8 8Fig. 3). The prevalence of conformer B
To study the regioselectivity of the Diels±Alder reaction
some unsymmetrical dienophiles, i.e. methyl acrylate, 2,3-
dihydrofuran and ethyl vinyl ether, were applied. Addition
of methyl acrylate to the pyridine o-QDM system derived
from 3d furnished adduct 29 as a single regio and stereo-
isomer. Regiochemical assignment of this adduct was based
1
on the multiplicity 8dd) observed for H-7 in the H NMR
3
is demonstrated by the coupling values J6±5eqˆ6.5 Hz and
spectrum, showing that the ester function was in position 6.
Cycloaddition to the initially formed E-diene A3d could
produce either the exo- or endo-adduct 290 or 2900, corre-
sponding to half-chair conformers A,B and C,D 8Fig. 4). The
3J values found for coupling between H-7 and H-6ax
810 Hz) and between H-7 and H-6eq 83 Hz) indicate that
the product exists as a preferred half-chair conformer A or
C. The occurrence of A corresponding to the exo-adduct 290
was suggested by NOEs relating H-7 with both H-6eq and
the 8-methyl group. However, these NOEs might also be
attributed to some contribution of form D corresponding to
an endo-adduct. Hence, at this point, de®nite assignment of
stereochemical structure 290 appears unjusti®ed, especially
in view of the exceptional exo-addition mode implied for
methyl acrylate.
3J6±5axˆ11.5 Hz. The high 3J value for H-5ax and H-6
reveals a trans-diaxial orientation. Hyperchem calculations9
suggest that conformer B is energetically favoured over A,
which shows a severe 1,3-diaxial repulsion between the
8-methyl substituent and the ester group in 6-position
8energy difference ca. 2 kcal/mol).
From 1H NMR and NOESY analysis of adduct 26, an all-cis
disposition was inferred for the three ester groups, con-
sistent with endo-addition of Z-diene A3b 8Scheme 9).
The NOE observed for H-7 and H-8 is consistent with the
expected cis-relationship. A favoured conformational struc-
ture A was indicated by a further NOE relating both protons
H-5 with H-6 and a weak NOE between the axial proton H-7
and H-5ax. The latter correlation was con®rmed by the
NOE-diff spectrum, which upon homonuclear decoupling
of H-7 displayed a clear NOE with H-5ax. Overall, the
NOE measurements suggest the existence of adduct 26 as
a major conformer A. Yet, an equilibrium with a minor form
Reaction of the electron-rich dihydrofuran with monoester
3a, diester 3c, and nitrile 3d in each case produced a single
compound 830±32, respectively) with the O-atom in
position 7 of the quinoline moiety. On thermolysis of 3a
rearranged product 19 was also formed. The regiochemical
structure of the adducts 30±32 again was assigned from the
1H NMR spectra, which displayed a doublet signal for H-9a
corresponding to a single coupling with the other angular
proton H-3a. In our previously reported NOESY analysis of
dihydrofuran adduct 30,3 the latter was shown to exist as the
83a,9a)-ax,ax boat conformer A. This corresponds to endo-
addition of dihydrofuran to the E-isomer A3a as observed
with NPMA 8Fig. 5).
B
seems likely in view of the coupling values
3
3J6±5axˆ8.4 Hz and J6±5eqˆ6.3 Hz.
Reaction of 3a with ethene at elevated pressure afforded a
small amount of adduct 27, which however could not be
adequately puri®ed. From the reaction of 3a with cyclo-
pentene only the rearranged product 19 was isolated in
78% yield. Apparently, Diels±Alder reactions proceed
rather slowly when using neutral dienophiles. This results
Scheme 9. Thermolysis of 3b and Diels±Alder reaction with dimethyl
maleate to form endo-adduct 26.
Figure 4. Two pairs of half-chair conformers corresponding to the exo-
adduct 290 and the endo-adduct 2900.

3660
S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
3. Conclusion
In this work, pyridine sulfolenes 3a±f are shown to be easily
accessible from the oxazinone 7. Thermolytic extrusion of
sulfur dioxide from these precursors produces the corre-
sponding pyridine o-QDM intermediates, which can be
trapped in situ with electron-poor 8NPMA, dimethyl
maleate, methyl acrylate), neutral 8ethene, cyclopentene),
and electron-rich 8dihydrofuran, ethyl vinyl ether) dieno-
philes. These intermolecular Diels±Alder reactions
generally proceed via an endo-transition state, with the reac-
tion of 3d and methyl acrylate as a possible exception. The
primary pyridine o-QDM intermediate formed from 7,7-
disubstituted 8ester or nitrile and alkyl) sulfone precursors
apparently has an inward orientation for the ester or nitrile
function and an outward orientation for the larger alkyl
group. Upon thermolysis of the monosubstituted ester
precursor 3b, the larger 8ester versus H) group again prefers
an outward orientation. However, the primary o-QDM inter-
mediate 8E-isomer) generated from the disubstituted 8Me,
CO2Me) precursor 3a apparently transforms slowly into the
Z-isomer. For slowly reacting dienophiles like cyclopentene
this results in a competing 1,5-H shift to form rearranged
product 19 as an important side reaction.
Figure 5. Pairs of boat and half-chair conformers corresponding to endo-
adducts 30, 32±33.
The relative stereochemistry of dihydrofuran adduct 32 was
assigned in a similar way on basis of NOE measurements
and 3J coupling constants in the 1H NMR spectrum.
Although the expected endo-adduct can exist as two boat
conformers A and B, one preferred form was indicated by
the differentiation found between H-4ax and H-4eq. In the
NOESY spectrum 8Fig. 5), only the latter proton gives a
NOE with the aromatic proton H-5. Both H-4 protons
show a strong NOE with H-3a, while H-9a correlates with
the trans-disposed 9-methyl group. These results can be
accommodated only if both angular protons H-3a and
H-9a have an equatorial position as in structure A. The cis
4. Experimental
4.1. General methods
Infrared spectra were recorded on a Perkin±Elmer 297 grat-
ing IR spectrophotometer and a Perkin±Elmer 1720 Fourier
3
and trans coupling constants, J3a±4axˆ7.2 Hz and
3J3a±4eqˆ1.8 Hz, correspond to a dihedral angle of approxi-
mately 40 and 808, respectively, as estimated from model
calculations for conformational structure A.9
1
transform spectrometer. H NMR spectra and 13C NMR
spectra were recorded on a Bruker WM 300 or on a Bruker
1
AMX 400 instrument. The H and 13C chemical shifts are
reported in ppm relative to tetramethylsilane or the deuter-
ated solvent as an internal reference. 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 resolu-
tion of 10,000. For TLC and column chromatography
analytical plates 8Alugram Sil G/UV254) and 70±230 mesh
silica gel 60 8E.M. Merck) were used, respectively. Melting
points were determined using a Reichert-Jung Thermovar
apparatus and an Electrothermal IA 9000 digital melting
point apparatus and are uncorrected. Microanalyses were
performed by Janssen Pharmaceutica.
Reaction of ethyl vinyl ether with precursor 3d equally
produced only one adduct 33, having again the ethoxy
substituent in position 7. Although an endo-adduct structure
was assumed by analogy to the dihydrofuran adduct, this
could not be substantiated by NMR spectral data. Proton
H-4 gives a NOE with both protons H-5, indicating that
compound 33 does not exist as a single half-chair, but rather
as a conformational mixture of two half-chair forms. From
3
3
the coupling constants J7±6eqˆ2.4 Hz and J7±6axˆ8.0 Hz
3
8but J5±6axˆ3J5±6eqˆ6.6 Hz), one can infer that conformer
A having an axial H-7 is slightly favoured.
Using semi-empirical calculations based on the Frontier
Molecular Orbital 8FMO) method, we tried to rationalise
the product distribution of the cycloadducts obtained from
unsymmetrical dienophiles. For the electron-poor dieno-
phile methyl acrylate the HOMOdiene±LUMOdienophile
interaction is only slightly favoured 80.8 eV) relative to
4.1.1. Synthesis of [/2,6-dichloro-5-methyl-3-pyridyl)-
methyl]thioacetate /10). To a stirred solution of 10 g of
pyridine 8 and 3.8 mL 81.2 equiv.) thiolacetic acid in
200 mL of CH2Cl2 under an inert atmosphere was added
dropwise 16.4 mL 83 equiv.) of NEt3. After reaction at
room temperature for 20 min, 50 mL of water was added.
The reaction mixture was then extracted with CH2Cl2
83£50 mL), the organic layer dried with MgSO4, and the
solvent evaporated. The residue was puri®ed by column
chromatography 8CH2Cl2) affording thioester 10. Yield:
98%; mp: 50.8±51.08C 8CHCl3, hexane); IR 8KBr): 2927,
the `inverse electron demand' interaction LUMOdiene
±
HOMOdienophile so that both pathways may compete.
However, from the relative size of the orbital coef®cients
the same regioselectivity was predicted, corresponding to
the experimentally observed 7-substituted quinoline deriva-
tive. For the electron-rich dihydrofuran the inverse electron
demand interaction LUMOdiene±HOMOdienophile largely 8ca.
2.4 eV) predominates, again favouring an adduct with the
O-atom in position 7 of the quinoline moiety.
1
1695 cm21; H NMR 8CDCl3/TMS): dˆ7.68 8s, 1H, H-4),
4.11 8s, 2H, CH2S), 2.36 8s, 3H, CH3CO), 2.34 8s, 3H, CH3±
pyr); 13C NMR 8CDCl3): dˆ194.4 8CO), 148.6 8C-6), 146.6
8C-2), 142.2 8C-4), 131.6 8C-5), 131.3 8C-3), 30.1 8CH3),

S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
3661
29.9 8CH2), 18.6 8CH3); MS [m/z 8%)] CI: 250 8100) MH1,
214 821) MH12HCl, 174 820) MH12CH3COSH; HRMS:
calcd for C9H9Cl2NSO: 248.9782, found: 248.9786; CHN
analysis: calcd for C9H9Cl2NSO: C 43.21, H 3.63, N 5.60;
found: C 43.36, H 3.49, N 5.52.
EI: 297 821) M1z, 262 85) M1z2Cl, 206 87) M1z2Bn, 174
811) M1z2BnS, 91 8100) Bn1z; HRMS: calcd for
C14H13Cl2NS: 297.0146, found: 297.0152.
4.2.4. Synthesis of methyl 2-{[/2,6-dichloro-5-methyl-3-
pyridyl)methyl]sulfonyl}acetate /6a). To a stirred solution
of 3 g of thioether 12a i n 50 mL of CHCl2 was added 7.5 g
2
4.2. General procedure for the synthesis of thioethers 12
83 equiv.) of mCPBA 870±75% in water). After reaction for
5 h at room temperature under an inert atmosphere, 15 mL
of a saturated NaHCO3 solution was added. After further
reaction for 20 min, the organic layer was separated and the
water layer extracted with CH2Cl2 83£50 mL). The
combined organic layers were dried over MgSO4 and evapo-
rated. The residue was puri®ed by column chromatography
8CH2Cl2) to afford sulfone 6a. Yield: 87%; mp: 108.5±
109.58C 8CHCl3, hexane); IR 8KBr): 2976±2919, 1741,
To a stirred solution of 6.6 g of thioester 10 in 200 mL of
MeOH was added 1.71 g 81.2 equiv.) of NaOMe under a
nitrogen atmosphere. After reaction at room temperature
for 15 min, 1.2 equiv. of electrophile was added, and the
reaction allowed to proceed for 1 h. Water 8200 mL) was
added followed by extraction with CH2Cl2 83£100 mL). The
combined extracts were dried over MgSO4 and evaporated.
The products were puri®ed by column chromatography
before spectral characterisation.
1
1308, 1126 cm21; H NMR 8CDCl3/TMS): dˆ7.79 8s, 1H,
H-4), 4.71 8s, 2H, CH2SO2), 4.04 8s, 2H, CH2CO), 3.86 8s,
3H, CH3O), 2.28 8s, 3H, CH3); 13C NMR 8CDCl3): dˆ170.6
8CO), 149.5 8C-6), 149.3 8C-2), 144.1 8C-4), 132.4 8C-5),
121.2 8C-3), 57.1 8CH2CO), 56.7 8CH2SO2), 53.6 8CH3O),
18.8 8CH3); MS [m/z 8%)] CI: 312 8100) MH1, 276 85)
MH12HCl; HRMS: calcd for C10H11Cl2NO4S: 310.9785,
found: 310.9781.
4.2.1.
Methyl-2-{[/2,6-dichloro-5-methyl-3-pyridyl)-
methyl]-sulfanyl}-acetate /12a). 8A). General procedure
8electrophileˆClCH2COOCH3). 8B) To an ice-cooled solu-
tion of 38 g of bromide 8 and 16.29 mL 81.2 equiv.) of
methyl thioglycolate was added 61.1 mL 83 equiv.) of
NEt3 dropwise. After being stirred at room temperature
for 30 min under an inert atmosphere, the reaction mixture
was extracted with CH2Cl2 83£100 mL). The combined
organic phases were dried 8MgSO4) and evaporated. The
residue was puri®ed by column chromatography 8CH2Cl2)
to afford thioether 12a. Yield: 8A) 95%, 8B) 88%; mp 34.0±
4.3. General procedure for the synthesis of dihydro-
thieno[3,4-b]pyridines 13 and 14
1
35.18C 8CHCl3, hexane); IR 8KBr): 2953, 1736 cm21; H
A solution of 1.8 mmol of thioether 12a,b in 10 mL of THF
was added slowly to a suspension of 0.43 g 82 equiv.) of KH
in 50 mL of THF. After being stirred at room temperature
for 10 min under argon, the deep red solution was cooled to
2788C 8acetone±CO2) and treated with saturated aq.
NH4Cl. The mixture was then brought to room temperature
and extracted with CH2Cl2 83£50 mL). The organic phase
was dried over MgSO4 and evaporated. The residue was
puri®ed by column chromatography 8EtOAc 30±hexane
70) to afford 13 or 14.
NMR 8CDCl3/TMS): dˆ7.65 8s, 1H, H-4), 3.89 8s, 2H,
CH2CO), 3.74 8s, 3H, CH3O), 3.16 8s, 2H, CH2S), 2.37 8s,
3H, CH3); 13C NMR 8CDCl3): dˆ170.2 8CO), 148.7 8C-6),
146.9 8C-2), 142.1 8C-4),131.5 8C-5), 130.5 8C-3), 52.4
8CH3O), 32.5 8CH2), 32.5 8CH2), 18.7 8CH3); MS [m/z
8%)] CI: 280 8100) MH1, 244 819) MH12HCl, 174 824)
MH12HSCH2COOCH3; HRMS: calcd for C10H11Cl2NO2S:
278.9888, found: 278.9884.
4.2.2. 2-{[2,6-Dichloro-5-methyl-3-pyridyl)methyl] sul-
fanyl}acetonitrile /12b). ElectrophileˆBrCH2CN; chroma-
tographic puri®cation: EtOAc 30±hexane 70; yield 95%;
mp: 53.8±54.68C 8CHCl3, hexane); IR 8KBr): 2966, 2920,
4.3.1. Methyl 2-chloro-3-methyl-5,7-dihydrothieno[3,4-
b]pyridine-7-carboxylate /13). Yield: 88%; mp: yellow
1
oil; IR 8NaCl): 2953, 1737 cm21; H NMR 8CDCl3/TMS):
dˆ7.49 8s, 1H, H-4), 5.02 8s, 1H, H-7), 4.38 8d, 2Jˆ15.0 Hz,
1
2239 cm21; H NMR 8CDCl3/TMS): dˆ7.62 8s, 1H, H-4),
2
1H, H-5), 4.05 8d, Jˆ15.0 Hz, 1H, H-5), 3.74 8s, 3H,
3.99 8s, 2H, CH2S), 3.29 8s, 2H, CH2CN), 2.38 8s, 3H, CH3±
pyr); 13C NMR 8CDCl3): dˆ151.6 8C-6), 148.4 8C-2), 147.4
8C-4),130.4 8C-5), 123.6 8C-3), 115.8 8CN), 33.7 8CH2),
25.3 8CH2), 16.9 8CH3); MS [m/z 8%)] CI: 247 8100)
MH1, 211 83) MH12HCl; HRMS: calcd for C9H9Cl2NSO:
245.9779, found: 245.9785; CHN analysis: calcd for
C9H9Cl2NSO: C 43.74, H 3.26, N 11.33; found: C 43.45,
H 3.13, N 11.25.
CH3O), 2.37 8s, 3H, CH3±pyr); 13C NMR 8CDCl3):
dˆ171.6 8CO), 156.2 8C-7a), 151.1 8C-2), 136.1 8C-4),
133.8 8C-3), 132.5 8C-4a), 52.8 8C-7), 52.7 8CH3O), 34.2
8C-5), 19.5 8CH3); MS [m/z 8%)] CI: 244 8100) MH1, 208
83) MH12HCl, 184 841) MH12HCOOCH3; HRMS: calcd
for C10H11ClNO2S: 244.0199, found: 244.0208.
4.3.2. 2-Chloro-3-methyl-5,7-dihydrothieno[3,4-b]pyri-
dine-7-carbonitrile /14). Yield: 80%; mp: 134.9±135.18C
4.2.3. 3-[/Benzylsulfanyl)methyl]-2,6-dichloro-5-methyl-
pyridine /12c). Electrophileˆbenzyl bromide; chromato-
graphic puri®cation: EtOAc 20±hexane 80; yield: 75%;
mp: 44.5±45.08C 8CHCl3, hexane); IR 8KBr): 3025,
8CHCl3/hexane); IR 8KBr): 2953, 1737 cm21 1H NMR
;
8CDCl3/TMS): dˆ7.54 8s, 1H, H-4), 5.25 8d, 1H,
2
4
4Jˆ2.7 Hz, H-7), 4.42 8dd, 1H, Jˆ14.2 Hz, Jˆ2.7 Hz,
2
1
2907 cm21; H NMR 8CDCl3/TMS): dˆ7.41 8s, 1H, H-4),
H-5), 4.28 8d, 1H, Jˆ14.2 Hz, H-5), 2.42 8s, 3H, CH3±
pyr); 13C NMR 8CDCl3): dˆ152.3 8C-7a), 152.3 8C-2),
136.3 8C-4), 132.6 8C-4a), 132.3 8C-3), 117.5 8CN), 38.7
8C-7), 34.0 8C-5), 19.6 8CH3); MS [m/z 8%)] CI:221 824)
MH1, 184 8100) MH12HCN; HRMS: calcd for
C9H7ClN2S: 210.0019, found: 210.0013.
7.41 8m, 5H, H-arom), 3.69 8s, 2H, CH2S), 3.64 8s, 2H,
CH2Ph), 2.28 8s, 3H, CH3); 13C NMR 8CDCl3): 148.2
8C-2), 146.5 8C-6), 141.8 8C-4), 137.0 8C-ipso), 131.4
8C-3), 130.3 8C-5), 128.4 8C-o), 128.2 8C-m), 127.1 8C-p),
36.5 8CH2S), 31.8 8CH2Ph), 18.6 8CH3±pyr); MS [m/z 8%)]

3662
S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
4.4. General procedure for the synthesis of 5,7-dihydro
thieno[3,4-b]pyridines 15a±c and 16a,b
IR 8KBr): 2975, 2360 cm21
;
1H NMR 8CDCl3/TMS):
2
dˆ7.53 8s, 1H, H-4), 4.36 8d, 1H, Jˆ14.3 Hz, H-5), 4.13
2
8d, 1H, Jˆ14.3 Hz, H-5), 2.41 8s, 3H, CH3±pyr), 2.06 8s,
3H, CH3); 13C NMR 8CDCl3): dˆ156.2 8C-2), 151.5 8C-7a),
136.4 8C-4), 132.4 8C-3), 131.8 8C-4a), 120.6 8CN), 48.6
8C-7), 32.5 8C-5), 27.8 8CH3), 19.5 8CH3±pyr); MS [m/z
8%)] CI: 225 8100) MH1, 198 825) MH12HCN; HRMS:
calcd for C10H9ClN2S: 224.0175, found: 224.0176.
A solution of 1 mmol of thioether 12a,b in 10 mL of THF
was added dropwise to a suspension of 0.25 g 82 equiv.) of
KH in 50 mL of THF under an inert atmosphere. The reac-
tion mixture was stirred for 10±30 min until the solution
coloured dark red. Then, 1.2 equiv. of electrophile was
slowly added and stirring was continued for 10 min. The
mixture was cooled to 2788C 8acetone±CO2) and saturated
NH4Cl solution was added. The reaction mixture was
brought to room temperature and extracted with CH2Cl2
83£50 mL); the organic phase was dried over MgSO4 and
evaporated. The residue was puri®ed by column chromato-
graphy 8EtOAc 30±hexane 70) to afford thienopyridines
15a±c and 16a,b.
4.4.5. Methyl 2-chloro-7-cyano-3-methyl-5,7-dihydro-
Electro-
thieno[3,4-b]pyridine-7-carboxylate
/16b).
phileˆClCO2CH3; yield: 65%; mp: 137.8±138.58C
8CHCl3, hexane); IR 8KBr): 2961, 2364, 1739 cm21; H
1
NMR 8CDCl3/TMS): dˆ7.58 8s, 1H, H-4), 4.43 8d, 1H,
2Jˆ14.0 Hz, H-5), 4.31 8d, 1H, Jˆ14.0 Hz, H-5), 3.85 8s,
2
3H, CH3O), 2.41 8s, 3H, CH3±pyr); 13C NMR 8CDCl3):
dˆ166.4 8CO), 152.2 8C-2), 151.7 8C-7a), 136.3 8C-4),
133.3 8C-3), 132.6 8C-4a), 115.7 8CN), 55.1 8C-7), 54.0
8CH3O), 34.3 8C-5), 19.5 8CH3±pyr); MS [m/z 8%)] CI:
269 870) MH1, 242 8100) MH12HCN, 209 88)
MH12HCOOCH3; HRMS: calcd for C11H9ClN2O2S:
268.0073, found: 268.0071.
4.4.1.
Methyl
2-chloro-3,7-dimethyl-5,7-dihydro-
thieno[3,4-b]pyridine-7-carboxylate /15a). Electrophileˆ
methyl iodide; yield: 90%; mp: 142.5±142.98C 8CHCl3,
1
hexane); IR 8KBr): 2929, 1737 cm21; H NMR 8CDCl3/
2
TMS): dˆ7.46 8s, 1H, H-4), 4.29 8d, 1H, Jˆ16.0 Hz, H-
5), 4.01 8d, 1H, 2Jˆ16.0 Hz, H-5), 3.67 8s, 3H, CH3O), 2.38
8s, 3H, CH3±pyr), 1.92 8s, 3H, CH3); 13C NMR 8CDCl3):
dˆ172.4 8CO), 159.0 8C-2), 150.5 8C-7a), 135.1 8C-4),
133.4 8C-3), 130.0 8C-4a), 59.5 8C-7), 52.3 8CH3O), 32.5
8C-5), 24.5 8CH3), 19.3 8CH3±pyr); MS [m/z 8%)] EI:257
810) M1z, 198 8100) M1z2COOCH3; HRMS: calcd for
C11H12ClNO2S: 257.0277, found: 257.0274; CHN analysis:
calcd for C11H12NO2S: C 45.60, H 4.17, N 4.83; found: C
45.42, H 3.90, N 4.62.
4.5. General procedure for the synthesis of thieno-
pyridines 17a,b and thienopyridinone 18
To a stirred solution of 4.9 mmol of thienopyridine 13, 14 in
25 mL of CH2Cl2 was added 3.43 g 83 equiv.) of mCPBA
870±75% in water). After reaction for 3 h at room tempera-
ture under an inert atmosphere, 15 mL of a saturated
NaHCO3 solution was added and stirring was continued
for 20 min. The mixture was extracted with CH2Cl2
83£20 mL) and the organic phase was dried 8MgSO4) and
evaporated. The residue was puri®ed by column chromato-
graphy 8EtOAc 30±hexane 70) to afford thienopyridines
17a,b and thienopyridinone 18.
4.4.2. Dimethyl 2-chloro-3-methyl-thieno[3,4-b]pyridine
-7,7/5H)-dicarboxylate /15b). ElectrophileˆClCO2CH3;
yield: 83%; mp: 163.0±164.08C 8CHCl3, hexane); IR
1
8KBr): 2957, 1762, 1732 cm21; H NMR 8CDCl3/TMS):
dˆ7.03 8s, 1H, H-4), 4.24 8s, 2H, H-5), 3.81 8s, 6H,
CH3O), 2.38 8s, 3H, CH3±pyr); 13C NMR 8CDCl3):
dˆ167.9 8CO), 153.6 8C-2), 150.7 8C-7a), 135.9 8C-4),
133.6 8C-3), 132.0 8C-4a), 68.7 8C-7), 53.5 8CH3O), 32.9
8C-5), 19.3 8CH3); MS [m/z 8%)] CI: 302 8100) MH1, 242
823) MH12HCOOCH3, 266 89) MH12HCl; HRMS: calcd
for C12H12ClNO4S: 301.0176, found: 301.0783.
4.5.1. Methyl 2-chloro-3-methyl-thieno[3,4-b]pyridine-7-
carboxylate /17a). Yield: 80%; mp: 180±1818C 8CHCl3,
hexane); IR 8KBr): 3100, 2958, 1680, 1606 cm21 1H
;
NMR 8CDCl3/TMS): dˆ7.90 8s, 1H, H-5), 7.76 8s, 1H,
H-4), 4.00 8s, 3H, CH3O), 2.45 8s, 3H, CH3); 13C NMR
8CDCl3): dˆ162.0 8CO), 156.8 8C-2), 147.9 8C-7a),
131.8 8C-3), 131.2 8C-4), 124.0 8C-5), 121.7 8C-4a),
115.5 8C-7), 52.4 8CH3O), 20.5 8CH3); MS [m/z 8%)] CI:
242 8100) MH1, 210 866) MH12CH3OH, 206 832)
MH12HCl; HRMS: calcd for C10H8ClNO2S: 240.9964,
found: 240.9974.
4.4.3. Methyl 7-benzyl-2-chloro-3-methyl-5,7-dihydro-
thieno[3,4-b]pyridine-7-carboxylate
/15c).
Electro-
phileˆBnBr; yield: 77%; mp: 134.0±134.58C 8CHCl3,
1
hexane); IR 8KBr): 3020, 1733 cm21; H NMR 8CDCl3/
TMS): dˆ7.18 8s, 1H, H-4), 7.08 8m, 5H, H-Ph), 3.90 8d,
1H, 2Jˆ14.0 Hz, H-5), 3.71 8d, 1H, 2Jˆ14.0 Hz, H-5), 3.70
8s, 3H, CH3O), 3.53 8d, 1H, 2Jˆ14.0 Hz, CH2±Ph), 3.41 8d,
4.5.2. 2-Chloro-3-methyl-thieno[3,4-b]pyridine-7-carbo-
nitrile /17b). Yield: 57%; mp: 207.0±208.08C 8CHCl3,
2
1H, Jˆ14.0 Hz, CH2±Ph), 2.31 8s, 3H, CH3); 13C NMR
1
hexane); IR 8KBr): 3052, 2209 cm21; H NMR 8CDCl3/
8CDCl3): dˆ172.8 8CO), 158.1 8C-2), 150.3 8C-7a), 135.7
8C-4), 134.5 8C-3), 131.2 8C-ipso), 130.7 8C-m), 127.4
8C-o), 126.6 8C-p), 126.5 8C-4a), 66.7 8C-7), 53.1 8CH3O),
41.9 8CH2±Ph), 32.8 8C-5), 19.6 8CH3); MS [m/z 8%)] CI:
334 8100) MH1, 298 810) MH12HCl, 274 821)
MH12HCOOCH3, 242 822) MH12BnH; HRMS: calcd
for C17H16ClNO2S: 333.0590, found: 333.0588.
TMS): dˆ7.94 8s, 1H, H-5), 7.83 8s, 1H, H-4), 2.48 8s,
3H, CH3±pyr); 13C NMR 8CDCl3): dˆ157.2 8C-2), 152.2
8C-7a), 129.8 8C-4), 129.7 8C-3), 124.1 8C-5), 119.4 8C-4a),
112.7 8CN), 97.0 8C-7), 20.3 8CH3); MS [m/z 8%)] CI: 209
8100) MH1, 173 86) MH12HCl; HRMS: calcd for
C9H5ClN2S: 207.9862, found: 207.9865.
4.5.3. Methyl 3-methyl-2-oxo-1,2-dihydrothieno[3,4-b]-
pyridine-7-carboxylate /18). Yield: 15%; mp: 192.0±
193.08C 8CH3Cl, hexane); IR 8KBr): 3400, 3053, 2952,
4.4.4. 2-Chloro-3,7-dimethyl-5,7-dihydrothieno[3,4-b]-
pyridine-7-carbonitrile
iodide; yield: 85%; mp: 102.0±102.38C 8CHCl3, hexane);
/16a).
Electrophileˆmethyl
1
1665 cm21; H NMR 8CDCl3/TMS): dˆ9.95 8s, 1H, NH),

S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
3663
7.53 8s, 1H, H-5), 7.41 8s, 1H, H-4), 3.82 8s, 3H, CH3O),
2.17 8s, 3H, CH3); 13C NMR 8CDCl3): dˆ163.2 8CON),
162.8 8CO), 142.4 8C-7a), 131.0 8C-3), 130.1 8C-4), 129.7
8C-4a), 125.9 8C-5), 104.9 8C-7), 52.4 8CH3O), 17.2 8CH3);
MS [m/z 8%)] CI: 224 8100) MH1, 192 837) MH12CH3OH;
HRMS: calcd for C10H9NO3S: 223.0303, found: 223.0306;
CHN analysis: calcd for C10H9NO3S: C 53.80, H 4.06, N
6.27; found: C 53.07, H 3.94, N 6.11.
8C-4), 133.8 8C-3), 133.1 8C-ipso), 131.0 8C-m), 127.8
8C-o), 127.2 8C-p), 125.7 8C-4a), 76.9 8C-7), 54.8 8C-5),
53.6 8CH3O), 38.2 8CH2±Ph), 19.6 8CH3); MS [m/z 8%)]
CI: 322 8100) MH1, 258 817) MH12SO2; HRMS: calcd
for C16H16ClNO4S: 321.0590, found: 321.0589.
4.6.4. 2-Chloro-3,7-dimethyl-6,6-dioxo-6,7-dihydro-5H-
6l6-thieno[3,4-b]pyridine-7-carbonitrile /3e). Chromato-
graphic puri®cation: CH2Cl2 98±EtOAc 2; yield: 94%; mp:
165.4±166.38C 8CHCl3, hexane); IR 8KBr): 2983, 2243,
4.6. General procedure for the synthesis of 6,6-dioxo-6,7-
dihydrothieno[3,4-b]pyridines 3a,c±f
1
1351, 1141 cm21; H NMR 8CDCl3/TMS): dˆ7.59 8s, 1H,
H-4), 4.59 8d, 1H, 2Jˆ15.8 Hz, H-5), 4.43 8d, 1H,
2Jˆ15.8 Hz, H-5), 2.46 8s, 3H, CH3±pyr), 2.05 8s, 3H,
CH3); 13C NMR 8CDCl3): dˆ153.6 8C-2), 149.2 8C-7a),
137.2 8C-4), 136.0 8C-3), 124.2 8C-4a), 114.3 8CN), 61.2
8C-7), 53.8 8C-5), 19.9 8CH3), 17.6 8CH3±pyr); MS [m/z
8%)] CI: 257 8100) MH1, 230 84) MH12HCN, 221 811)
MH12HCl, 193 848) MH12SO2; HRMS: calcd for
C10H9ClN2SO2: 256.0073, found: 256.0071; CHN analysis:
calcd for C10H9ClN2O2S: C 46.79, H 3.53, N 10.91; found:
C 46.86, H 3.33, N 10.77.
To a stirred solution of 11.7 mmol of thienopyridine 15a±c,
16a,b in 200 mL of CH2Cl2 was added 13.5 g 83 equiv.) of
mCPBA 870±75% in water). After reaction at room
temperature for 3 h under an inert atmosphere, a saturated
NaHCO3 solution was added and stirring was continued
for 20 min. The reaction mixture was then extracted
with CH2Cl2 83£100 mL); the organic phase was dried
over MgSO4 and evaporated. The residue was puri®ed
by column chromatography to afford pyridine sulfolene
3a,c±f.
4.6.5. Methyl 2-chloro-7-cyano-3-methyl-6,6-dioxo-6,7-
dihydro-5H-6l6-thieno[3,4-b]pyridine-7-carboxylate /3f).
Chromatographic puri®cation: CH2Cl2 95±EtOAc 5; yield:
62%; mp: white foam; IR 8NaCl): 2934, 2362, 1757, 1358,
4.6.1. Methyl 2-chloro-3,7-dimethyl-6,6-dioxo-6,7-di-
hydro-5H-6l6-thieno[3,4-bpyridine-7-carboxylate /3a).
Chromatographic puri®cation: EtOAc 30±hexane 70; yield:
93%; mp: 142.5±143.18C 8CHCl3, hexane); IR 8KBr): 3001,
2949, 1750, 1321, 1145 cm21; 1H NMR 8CDCl3/TMS):
1
1147 cm21; H NMR 8CDCl3/TMS): dˆ7.63 8s, 1H, H-4),
2
2
4.70 8d, 1H, Jˆ15.3 Hz, H-5), 4.62 8d, 1H, Jˆ15.3 Hz,
H-5), 3.97 8s, 3H, CH3O), 2.48 8s, 3H, CH3±pyr); 13C
NMR 8CDCl3): dˆ160.8 8CO), 153.5 8C-2), 146.4 8C-7a),
137.1 8C-4), 136.9 8C-3), 125.6 8C-4a), 109.0 8CN), 71.3
8C-7), 56.1 8C-5), 55.6 8CH3O), 20.0 8CH3±pyr); MS [m/z
8%)] CI: 301 830) MH1, 265 89) MH12HCl, 209 8100)
MH12SO2; HRMS: calcd for C11H9ClN2O4S: 299.9971,
found: 299.9965.
2
dˆ7.59 8s, 1H, H-4), 4.60 8d, 1H, Jˆ15.0 Hz, H-5), 4.34
2
8d, 1H, Jˆ15.0 Hz, H-5), 3.76 8s, 3H, CH3O), 2.42 8s, 3H,
CH3±pyr), 1.92 8s, 3H, CH3); 13C NMR 8CDCl3): dˆ166.5
8CO), 152.9 8C-2), 152.2 8C-7a), 136.9 8C-4), 134.2 8C-3),
128.1 8C-4a), 72.9 8C-7), 52.9 8CH3O), 54.6 8C-5), 19.8
8CH3±pyr), 13.8 8CH3); MS [m/z 8%)] CI: 290 8100) MH1,
254 83) MH12HCl, 226 830) MH12SO2; HRMS: calcd for
C11H12ClNO4S: 289.0176, found: 289.0175.
4.6.6. Methyl 2-chloro-3-methyl-6,6-dioxo-6,7-dihydro-
5H-6l6-thieno[3,4-b]pyridine-7-carboxylate /3b). To a
stirred solution of 2 g of pyridine sulfolene 3c i n 40 mL of
MeOH was added 1.2 g 81.5 equiv.) of NaOMe. After
reaction at re¯ux temperature for 2 h under an inert
atmosphere, the reaction mixture was cooled to room
temperature and neutralised with 20 mL of a saturated
NH4Cl solution. The mixture was extracted with CH2Cl2
83£20 mL) and the organic layer was dried over MgSO4
and evaporated. The residue was puri®ed by column
chromatography 8EtOAc 50±Hex 50) to afford pyridine
sulfolene 3b. Yield: 85%; mp: 117.9±118.48C 8CHCl3,
4.6.2. Dimethyl 2-chloro-3-methyl-6,6-dioxo-5,6-dihydro-
/3c).
7H-6l6-thieno[3,4-b]pyridine-7,7-dicarboxylate
Chromatographic puri®cation: EtOAc 35±Hex 75; yield:
82%; mp: 175.1±175.88C 8CHCl3, hexane); IR 8KBr):
2960, 1738, 1354, 1163 cm21; 1H NMR 8CDCl3/TMS):
dˆ7.57 8s, 1H, H-4), 4.57 8s, 2H, H-5), 3.90 8s, 6H,
CH3O), 2.43 8s, 3H, CH3±pyr); 13C NMR 8CDCl3):
dˆ161.6 8CO), 152.5 8C-2), 148.1 8C-7a), 136.5 8C-4),
135.1 8C-3), 126.5 8C-4a), 79.3 8C-7), 55.3 8C-5), 54.1
8CH3O), 19.8 8CH3); MS [m/z 8%)] CI: 334 8100) MH1,
298 86) MH12HCl, 270 816) MH12SO2, 238 85)
MH12CH3OH, 2SO2; HRMS: calcd for C12H12ClNO6S:
333.0074, found: 333.0079; CHN analysis: calcd for
C12H12ClNO6S: C 43.19, H 3.62, N 4.20; found: C 43.38,
H 3.53, N 4.12.
hexane); IR 8KBr): 2926, 1734, 1324, 1111 cm21 1H
;
NMR 8CDCl3/TMS): dˆ7.58 8s, 1H, H-4), 5.12 8s, 1H,
H-7), 4.53 8d, 1H, 2Jˆ15.0 Hz, H-5), 4.39 8d, 1H,
2Jˆ15.0 Hz, H-5), 3.85 8s, 3H, CH3O), 2.43 8s, 3H, CH3±
pyr); 13C NMR 8CDCl3): dˆ163.9 8CO), 152.4 8C-2), 145.5
8C-7a), 136.8 8C-4), 134.6 8C-3), 126.6 8C-4a), 70.8 8C-7),
56.1 8C-5), 53.8 8CH3O), 19.7 8CH3); MS [m/z 8%)] EI: 275
828) M1z, 211 8100) M1z2SO2, 180 859) M1z2SO2±OCH3,
152 843) M1z2SO2±COOCH3; HRMS: calcd for
C10H11ClNO2S: 275.0019, found: 275.0019.
4.6.3. Methyl 7-benzyl-2-chloro-3-methyl-6,6-dioxo-6,7-
dihydro-5H-6l6-thieno[3,4-b]pyridine-7-carboxylate /3d).
Chromatographic puri®cation: EtOAc 20±Hex 80; yield:
80%; mp: 132.0±133.18C 8CHCl3, hexane); IR 8KBr):
1
3020, 2962, 1714, 1365, 1135 cm21; H NMR 8CDCl3/
TMS): dˆ7.30 8s, 1H, H-4), 7.13 8m, 5H, H-Ph), 4.27 8d,
1H, 2Jˆ15.0 Hz, H-5), 3.97 8d, 1H, 2Jˆ15.0 Hz, H-5), 3.81
8s, 3H, CH3O), 3.63 8d, 1H, 2Jˆ14.0 Hz, CH2±Ph), 3.58 8d,
4.7. General procedure for thermolysis in absence of a
dienophile
2
1H, Jˆ14.0 Hz, CH2±Ph), 2.37 8s, 3H, CH3); 13C NMR
8CDCl3): dˆ164.9 8CO), 151.9 8C-2), 151.3 8C-7a), 136.2
A solution of 200 mg of pyridine sulfolene 3a,c,e in 5 mL of

3664
S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
o-dichlorobenzene was subjected to three freeze±pump±
thaw cycles. The glass tube was sealed and heated under
the conditions speci®ed below. The o-dichlorobenzene
solvent was removed by Kugelrohr distillation. The residue
was puri®ed by column chromatography 8CH2Cl2) to afford
products 19±21.
8C-8), 174.9 8CO), 150.8 8C-9a), 150.1 8C-2), 139.3 8C-4),
132.0 8C-ipso), 131.5 8C-4a), 129.0 8C-m), 128.7 8C-p),
127.1 8C-3), 126.3 8C-o), 53.3 8CH3O), 51.2 8C-9), 46.6
8C-8a), 39.6 8C-5a), 28.1 8C-5), 19.6 8CH3), 19.3 8CH3±
pyr); MS [m/z 8%)] CI: 399 890) MH1, 341 840)
MH12COOCH3; HRMS: calcd for C21H19ClN2O4:
398.1033, found: 398.1032.
4.7.1. Methyl 2-/6-chloro-3,5-dimethyl-2-pyridyl) acryl-
ate /19). Reaction conditions: 2008C, 12 h; yield: 78%; mp:
yellow oil; IR 8NaCl): 2954, 1725 cm21; 1H NMR 8CDCl3/
TMS): dˆ7.38 8s, 1H, H-4), 6.63 8s, 1H, CHv), 5.93 8s, 1H,
CHv), 3.77 8s, 3H, CH3O), 2.35 8s, 3H, CH3±pyr), 2.16 8s,
3H, CH3±pyr); 13C NMR 8CDCl3/TMS): dˆ165.9
8CO),152.3 8C-2), 146.6 8C-4), 142.2 8Cv),131.6 8C-6),
131.3 8CH2), 130.7 8C-3), 130.7 8C-5), 52.1 8CH3O), 19.0
8CH3), 17.9 8CH3); MS [m/z 8%)] CI: 226 8100) MH1; 190
830) MH12HCl.
4.8.2. Dimethyl /5aRp,8aRp)-2-chloro-3-methyl-6,8-
dioxo-7-phenyl-5a,6,7,8,8a,9-hexahydro-5H-pyrrolo[3,4-
g]quinoline-9,9-dicarboxylate /23). Yield: 85%; mp:
222.5±223.08C 8CHCl3, hexane); IR 8KBr): 3012, 2957,
1720, 1702 cm21
;
1H NMR 8CDCl3/TMS): dˆ7.41 8m,
6H, H-Ph; H-4), 3.96 8s, 3H, CH3O), 3.75 8d, 1H,
3Jˆ8.7 Hz, H-8a), 3.68 8s, 3H, CH3O), 3.45 8m, 3H, H-5;
H-5a), 2.39 8s, 3H, CH3±pyr); 13C NMR 8CDCl3): dˆ176.9
8C-6), 174.5 8C-8), 168.1 8CO), 167.8 8CO), 151.8 8C-9a),
151.7 8C-2), 139.3 8C-4), 132.7 8C-ipso), 132.2 8C-4a),
129.4 8C-3), 129.1 8C-m), 128.6 8C-p), 126.6 8C-o), 63.7
8C-9), 53.8 82£CH3O), 46.2 8C-8a), 38.3 8C-5a), 26.4
8C-5), 19.4 8CH3±pyr); MS [m/z 8%)] CI: 443 8100) MH1,
407 812) MH12HCl; HRMS: calcd for C22H19ClN2O6:
442.0932, found: 442.0925.
4.7.2. Methyl 2-chloro-7-methoxy-3-methyl-5H-pyrano
[3,4-b]pyridine-8-carboxylate /20). Reaction conditions:
1608C, 30 min; yield: 75%; mp: 147.5±148.08C 8CHCl3,
1
hexane); IR 8KBr): 2947, 1687 cm21; H NMR 8CDCl3/
TMS): dˆ7.13 8s, 1H, H-4), 5.19 8s, 2H, H-5), 3.95 8s,
3H, CH3O), 3.81 8s, 3H, CH3O), 2.29 8s, 3H, CH3±pyr);
13C NMR 8CDCl3): dˆ170.5 8C-7), 165.1 8CO), 151.0
8C-8a), 148.5 8C-2), 134.2 8C-4), 127.2 8C-4a), 118.2
8C-3), 88.0 8C-8), 68.5 8C-5), 56.2 8CH3O), 51.2 8CH3O),
19.2 8CH3±pyr); MS [m/z 8%)] CI: 270 872) MH1, 238 8100)
MH12CH3OH, 234 830) MH12HCl.
4.8.3. /5aRp,8aRp,9Sp)-2-Chloro-3,9-dimethyl-6,8-dioxo-
7-phenyl-5a,6,7,8,8a,9-hexahydro-5H-pyrrolo[3,4-g]-
quinoline-9-carbonitrile /24). Yield: 65%; mp: 240.0±
241.08C 8CHCl3, hexane); IR 8KBr): 3018, 2973, 2289,
1
1712, 1695 cm21; H NMR 8CDCl3/TMS): dˆ7.46 8s, 1H,
3
H-4), 7.36 8m, 3H, H-m, H-p), 6.93 8dt, 2H, Jˆ6.4 Hz,
4Jˆ1.4 Hz, H-o), 3.78 8d, 1H, 3Jˆ9.2 Hz, H-8a), 3.70
4.7.3. 2-Chloro-7-methoxy-3-methyl-5H-pyrano[3,4-b]-
pyridine-8-carbonitrile /21). Reaction conditions: 2008C,
12 h; yield: 80%; mp: 188.5±189.08C 8CHCl3, hexane); IR
8ddd, 1H, 3Jˆ2.0, 7.4, 9.2 Hz, H-5a), 3.58 8dd, 1H,
3
2
2Jˆ15.9 Hz, Jˆ7.4 Hz, H-5), 3.44 8dd, 1H, Jˆ15.9 Hz,
3Jˆ2.0 Hz, H-5), 2.39 8s, 3H, CH3), 2.17 8s, 3H, CH3±
pyr); 13C NMR 8CDCl3): dˆ176.3 82£CO), 172.1 8C-9a),
150.5 8CN), 148.9 8C-2), 139.9 8C-4), 131.0 8C-ipso), 132.2
8C-4a), 129.4 8C-3), 129.1 8C-m), 128.6 8C-p), 126.6 8C-o),
63.7 8C-9), 53.8 82£CH3O), 46.2 8C-8a), 38.3 8C-5a), 26.4
8C-5), 19.4 8CH3±pyr); MS [m/z 8%)] CI: 366 8100) MH1,
339 815) MH12HCN, 330 813) MH12HCl; HRMS: calcd
for C20H16ClN3O2: 365.0931, found: 365.0936.
1
8KBr): 2922, 2219, 1604 cm21; H NMR 8CDCl3/TMS):
dˆ7.14 8s, 1H, H-4), 5.38 8s, 2H, H-5), 3.99 8s, 3H,
CH3O), 2.31 8s, 3H, CH3±pyr); 13C NMR 8CDCl3): dˆ
170.3 8C-7), 151.6 8C-8a), 147.2 8C-2), 134.2 8C-4), 128.2
8C-4a), 116.1 8C-3), 114.2 8CN), 76.9 8C-8), 68.5 8C-5),
56.5 8CH3O), 19.3 8CH3±pyr); MS [m/z 8%)] CI: 237 890)
MH1, 205 8100) MH12CH3OH, 201 826) MH12HCl.
4.8. General procedure for intermolecular Diels±Alder
reactions
4.8.4. Trimethyl /6Rp,7Rp,8Sp)-2-chloro-3,8-dimethyl-
5,6,7,8-tetrahydro-6,7,8-quinoline tricarboxylate /25).
Yield: 61%; mp: yellow foam; IR 8NaCl): 2984, 1741±
A solution of 150 mg of pyridine sulfolene 3a±d and
5 equiv. of dienophile in 10 mL of dichlorobenzene was
subjected to three freeze±pump±thaw cycles. The glass
tube was sealed and heated at 2008C for 15 h. The dichloro-
benzene solvent was removed by Kugelrohr distillation. The
residue was puri®ed by column chromatography 8CH2Cl2)
to afford adducts 22±33.
1
1725 cm21; H NMR 8CDCl3/TMS): dˆ7.29 8s, 1H, H-4),
3.74 8s, 3H, CH3O), 3.67 8s, 3H, CH3O), 3.64 8s, 3H, CH3O),
2
3
3.38 8dd, 1H, Jˆ17.2 Hz, Jˆ11.5 Hz, H-5), 3.73 8d, 1H,
3Jˆ3.9 Hz, H-7), 3.16 8ddd, 1H, 3Jˆ11.5, 6.5, 3.9 Hz, H-6),
2
3
3.02 8dd, 1H, Jˆ17.2 Hz, Jˆ6.5 Hz, H-5), 2.33 8s, 3H,
CH3±pyr), 1.70 8s, 3H, CH3); 13C NMR 8CDCl3):
dˆ174.7 8CO), 173.0 8CO), 171.1 8CO), 151.9 8C-8a),
148.8 8C-2), 139.5 8C-4), 130.9 8C-3), 129.4 8C-4a), 53.0
8CH3O), 52.2 8CH3O), 51.7 8CH3O), 50.6 8C-8), 48.2 8C-6),
38.8 8C-7), 27.2 8C-5), 21.5 8CH3), 19.4 8CH3±pyr); MS
[m/z 8%)] CI: 370 8100) MH1, 334 815) MH12HCl, 310
89) MH12HCOOCH3; HRMS: calcd for C17H20ClNO6:
369.0979, found: 369.0985.
4.8.1. Methyl /5aRp,8aRp,9Sp)-2-chloro-3-methyl-6,8-
dioxo-7-phenyl-5a,6,7,8,8a,9-hexahydro-5H-pyrrolo[3,4-
g]quinoline-9-carboxylate /22). Yield: 88%; mp: 160.5±
161.08C 8CHCl3, hexane); IR 8KBr): 3020, 2974, 1735,
1711 cm21
;
1H NMR 8CDCl3/TMS): dˆ7.34 8m, 3H,
3
H-m, H-p), 7.31 8s, 1H, H-4), 6.94 8dd, 2H, Jˆ6.4 Hz,
4Jˆ1.4 Hz, H-o), 4.11 8d, 1H, Jˆ8.9 Hz, H-8a), 3.68 8s,
3
4.8.5.
Trimethyl
/6Rp,7Rp,8Rp)-2-chloro-3-methyl-
5,6,7,8-tetrahydro-6,7,8-quinoline- tricarboxylate /26).
Yield: 73%; mp: yellow foam; IR 8NaCl): 2956,
3
3H, CH3O), 3.58 8ddd, 1H, Jˆ2.8, 7.9, 8.9 Hz, H-5a),
2
3
3.24 8dd, 1H, Jˆ15.8 Hz, Jˆ2.8 Hz, H-5), 2.76 8dd, 1H,
2Jˆ15.8 Hz, Jˆ7.9 Hz, H-5), 2.33 8s, 3H, CH3±pyr), 1.99
3
1723 cm21; H NMR 8CDCl3/TMS): dˆ7.32 8s, 1H, H-4),
1
8s, 3H, CH3); 13C NMR 8CDCl3): dˆ177.5 8C-6), 174.9

S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
3665
4.44 8d, 1H, 3Jˆ4.9 Hz, H-8), 3.79 8s, 3H, CH3O), 3.74 8dd,
4.8.9. Methyl /3aSp,9aRp)-7-chloro-6-methyl-2,3,3a,4,9,
9a-hexahydro-furo[3,2-g]quinoline-9,9-dicarboxylate
/31). Yield: 75%; mp: yellow foam; IR 8NaCl): 2974,
3
1H, Jˆ3.7, 4.9 Hz, H-7), 3.71 8s, 3H, CH3O), 3.67 8s, 3H,
CH3O), 3.57 8ddd, 1H, 3Jˆ3.7, 6.3, 8.4 Hz, H-6), 3.21 8dd,
1H, 2Jˆ17.4 Hz, 3Jˆ8.4 Hz, H-5), 3.09 8dd, 1H,
1743 cm21; H NMR 8CDCl3/TMS): dˆ7.29 8s, 1H, H-5),
1
3
2Jˆ17.4 Hz, Jˆ6.3 Hz, H-5) 2.33 8s, 3H, CH3±pyr); 13C
4.83 8d, 1H, 3Jˆ6.8 Hz, H-9a), 3.60 8s, 3H, CH3O), 3.74 8s,
NMR 8CDCl3): dˆ172.7 8CO), 172.4 8CO), 171.3 8CO),
149.2 8C-8a), 148.6 8C-2), 140.3 8C-4), 131.5 8C-4a),
128.8 8C-3), 52.7 8CH3O), 52.3 8CH3O), 52.2 8CH3O),
48.1 8C-7), 43.4 8C-6), 37.8 8C-8), 27.1 8C-5), 19.1 8CH3±
pyr); MS [m/z 8%)] CI: 356 8100) MH1, 320 824)
MH12HCl, 298 822) MH12CH2O, CO; HRMS: calcd for
C16H18ClNO6: 355.0823, found: 355.0826.
3H, CH3O), 3.75 8m, 2H, H-2), 2.88 8m, 1H, H-3a), 2.79 8dd,
2
3
2
1H, Jˆ16.0 Hz, Jˆ7.7 Hz, H-4), 2.54 8dd, Jˆ16.0 Hz,
3Jˆ5.0 Hz, H-4), 2.39 8s, 3H, CH3±pyr), 2.18 8dddd, 1H,
2Jˆ12.2 Hz, Jˆ5.4, 7.2, 7.6 Hz, H-3), 1.31 8dddd, 1H,
3
2Jˆ12.2 Hz, 3Jˆ5.9, 6.9, 7.3 Hz, H-3); 13C NMR
8CDCl3): dˆ168.0 8CO), 167.4 8CO), 149.5 8C-8a), 148.7
8C-7), 139.0 8C-5), 131.3 8C-4a), 130.5 8C-6), 80.8 8C-9a),
67.2 8C-9), 63.8 8C-2), 52.7 8CH3O), 52.1 8CH3O), 35.2
8C-3a), 33.3 8C-4), 30.7 8C-3), 19.0 8CH3±pyr); MS [m/z
8%)] EI: 339 850) M1z, 280 8100) M1z2COOCH3, 248
895) M1z2COOCH3±CH3OH, 221 818) M122£COOCH3;
HRMS: calcd for C16H18ClNO5: 339.0873, found: 339.0867.
4.8.6. Dimethyl /5aRp,8aRp)-2-chloro-3-methyl-5,5a,6,
7,8,8a-hexahydro-9H-cyclo-penta[g]quinoline-9,9-dicar-
boxylate /28). Yield: 60%, mp: yellow oil; IR 8NaCl): 2988,
1
2927, 1745 cm21; H NMR 8CDCl3/TMS): dˆ7.24 8s, 1H,
H-4), 3.80 8s, 1H, CH3O), 3.72 8s, 3H, CH3O), 3.07 8dd, 1H,
2Jˆ15.8 Hz, 3Jˆ7.5 Hz, H-5), 2.85 8m, 1H, H-8a), 2.56 8m,
1H, H-5a), 2.36 8dd, 1H, 2Jˆ15.8 Hz, 3Jˆ5.3 Hz, H-5), 2.32
8s, 3H, CH3±pyr), 1.87 8m, 2H, H-7), 1.59 8m, 1H, H-6),
1.51 8m, 1H, H-6), 1.25 8m, 2H, H-8); 13C NMR 8CDCl3):
dˆ170.4 8CO), 169.6 8CO), 150.8 8C-9a), 148.7 8C-2),
139.6 8C-4), 131.4 8C-4a), 130.7 8C-3), 63.4 8C-9), 52.9
8CH3O), 52.5 8CH3O), 44.9 8C-8a), 34.8 8C-5a), 33.3 5C-
5), 31.1 8C-6), 28.4 8C-8), 23.3 8C-7), 19.3 8CH3±pyr); MS
[m/z 8%)] CI: 338 8100) MH1, 336 820) MH12H2, 302 820)
MH12HCl, 278 810) MH12HCOOCH3.
4.8.10. /3aSp,9Sp,9aR)-7-Chloro-6,9-dimethyl-2,3,3a,4,9,
9a-hexahydrofuro[3,2-g]quinoline-9-carbonitrile /32).
Yield: 67%; mp: 79.1±81.08C 8CHCl3, hexane); IR 8KBr):
1
2943, 2230 cm21; H NMR 8CDCl3/TMS): dˆ7.35 8s, 1H,
3
H-5), 4.40 8d, 1H, Jˆ7.9 Hz, H-9a), 3.47 8m, 2H, H-2),
2
3
3.27 8dd, 1H, Jˆ15.6 Hz, Jˆ7.2 Hz, H-4), 3.04 8m, 1H,
H-3a), 2.66 8dd, 1H, 2Jˆ15.6 Hz, 3Jˆ1.8 Hz, H-4), 2.36 8s,
3H, CH3±pyr), 2.21 8m, 1H, H-3), 1.93 8s, 3H, CH3), 1.36
8m, 1H, H-3); 13C NMR 8CDCl3): dˆ154.0 8C-8a),
149.4 8CN), 148.6 8C-7), 139.8 8C-5), 132.4 8C-4a), 130.6
8C-6), 83.4 8C-9a), 67.3 8C-2), 40.1 8C-9), 35.4 8C-3a), 34.0
8C-4), 31.0 8C-3), 19.6 8CH3), 19.2 8CH3±pyr); MS [m/z
8%)] CI: 263 8100) MH1, 236 827) MH12HCN, 227 83)
MH12HCl; HRMS: calcd for C14H15ClN2O: 262.0873,
found: 262.0870.
4.8.7. Methyl /7Rp,8Rp)-2-chloro-8-cyano-3,8-dimethyl-
5,6,7,8-tetrahydro-7-quinoline-carboxylate /29). Yield:
70%; mp: yellow foam; IR 8NaCl): 2952, 2239,
1
1738 cm21; H NMR 8C6D6/TMS): dˆ6.35 8s, 1H, H-4),
3
3.29 8s, 3H, CH3O), 2.89 8dd, 1H, Jˆ3.3, 10.0 Hz, H-7),
2.13 8ddd, 1H, 2Jˆ17.0 Hz, 3Jˆ6.6, 6.6 Hz, H-5), 2.00 8ddd,
4.8.11. /7Rp,8Sp)-2-Chloro-7-ethoxy-3,8-dimethyl-5,6,7,
8-tetrahydro-8-quinolinecarbonitrile /33). Yield: 63%;
2
3
1H, Jˆ17.0 Hz, Jˆ6.0, 8.8 Hz, H-5), 1.88 8s, 3H, CH3±
2
3
1
pyr), 1.86 8ddt, 1H, Jˆ14.0 Hz, Jˆ3.3, 6.0, 6.0 Hz, H-6),
1.62 8s, 3H, CH3), 1.58 8dddd, 1H, 2Jˆ14.0 Hz, 3Jˆ6.6, 8.8,
10.0 Hz, H-6); 13C NMR 8CDCl3): dˆ171.7 8CO), 150.5
8C-8a), 149.3 8C-2), 140.5 8C-4), 132.3 8CN), 129.2
8C-4a), 122.4 8C-3), 52.2 8CH3O), 47.6 8C-7), 43.4 8C-8),
22.5 8CH3), 21.0 8C-5), 19.0 8CH3±pyr); MS [m/z 8%)] CI:
279 8100) MH1, 252 816) MH12HCN, 219 84)
MH12HCOOCH3; HRMS: calcd for C14H15ClN2O2:
278.0822, found: 278.0820.
mp: yellow foam; IR 8NaCl): 2931, 2224 cm21; H NMR
3
8CDCl3/TMS): dˆ7.28 8s, 1H, H-4), 3.92 8dd, 1H, Jˆ2.4,
2
3
8.0 Hz, H-7), 3.75 8dq, 1H, Jˆ9.3 Hz, Jˆ7.0 Hz, CH2O),
2
3
3.65 8dq, 1H, Jˆ9.3 Hz, Jˆ7.0 Hz, CH2O), 2.87 8dt, 1H,
3
2
2Jˆ17.1 Hz, Jˆ6.6 Hz, H-5), 2.72 8dt, 1H, Jˆ17.1 Hz,
3Jˆ6.5 Hz, H-5), 2.33 8s, 3H, CH3±pyr), 2.15 8m, 1H,
H-6), 2.03 8m, 1H, H-6), 1.75 8s, 3H, CH3), 1.23 8t, 3H,
3Jˆ7.0 Hz, CH3CH2O); 13C NMR 8CDCl3): dˆ150.7
8C-8a), 149.5 8C-2), 140.2 8C-4), 132.0 8C-4a), 129.5 8C-3),
123.0 8CN), 78.2 8C-7), 65.9 8CH2O), 43.3 8C-8), 24.1 8C-6),
23.2 8C-5), 21.1 8CH3), 19.1 8CH3±pyr), 15.4 8CH3CH2O);
MS [m/z 8%)] CI: 265 8100) MH1, 238 810) MH12HCN, 229
89) MH12HCl, 192 84) MH12HCN±HOCH2CH3; HRMS:
calcd for C14H17ClN2O: 264.1029, found: 264.1023.
4.8.8. Methyl /3aSp,9Rp,9aRp)-7-chloro-6,9-dimethyl-
2,3,3a,4,9,9a-hexahydro-furo[3,2-g]quinoline-9-carboxyl-
ate /30). Yield: 55%; mp: 115.2±116.48C 8CHCl3, hexane);
IR 8KBr): 2925, 1703 cm21
;
1H NMR 8CDCl3/TMS):
3
dˆ7.26 8s, 1H, H-5), 4.60 8d, 1H, Jˆ7.8 Hz, H-9a), 3.60
3
8s, 3H, CH3O), 3.50 8ddd, 1H, Jˆ3.9, 8.6, 8.6 Hz, H-2),
3
3.39 8ddd, 1H, Jˆ6.2, 8.6, 8.6 Hz, H-2), 2.93 8m, 1H,
2
3
H-3a), 2.63 8dd, 1H, Jˆ15.6 Hz, Jˆ7.1 Hz, H-4), 2.48
Acknowledgements
2
3
8dd, 1H, Jˆ15.6 Hz, Jˆ1.9 Hz, H-4), 2.33 8s, 3H, CH3±
pyr), 2.18 8m, 1H, H-3), 1.80 8s, 3H, CH3), 1.31 8m, 1H,
H-3); 13C NMR 8CDCl3): dˆ174.0 8CO), 154.0 8C-8a),
149.1 8C-7), 139.4 8C-5), 130.6 8C-4a), 130.2 8C-6), 83.4
8C-9a), 77.0 8C-9), 66.8 8C-2), 52.3 8CH3O), 35.4 8C-3a),
34.4 8C-4), 31.6 8C-3), 19.9 8CH3), 19.2 8CH3±pyr); MS
[m/z 8%)] EI: 295 845) M1z, 236 898) M1z2COOCH3,
208 837) M1z2COOCH3±C2H4; HRMS: calcd for:
C15H18ClNO3: 295.0975, found: 295.0973.
This work was supported by the FWO 8Fund for Scienti®c
Research-Flanders 8Belgium)). DWTC is gratefully
acknowledged for the IUAP-4-11 funding. The authors are
indebted to R. De Boer for the HRMS measurements and to
the Janssen Pharmaceutica Company for element analysis.
S. C. and T. G. thank the IWT and I. V. 8Research Assistant
of the FWO-Flanders) thanks the FWO for the fellowships
received.

3666
S. L. Cappelle et al. / Tetrahedron 58 +2002) 3655±3666
104, 7609. Kametani, T.; Ichikawa, Y.; Suzuki, T.; Fukumoto,
References
K. Heterocycles 1974, 2, 171. Kametani, T.; Ichikawa, Y.;
Suzuki, T.; Fukumoto, K. Heterocycles 1975, 3, 401. Kametani,
T.; Suzuki, T.; Takahashi, K.; Ichikawa, Y.; Fukumoto, K.
J. Chem. Soc., Perkin Trans. 1 1975, 413. Rieman, J. M.;
Trahanovsky, W. S. Tetrahedron Lett. 1977, 22, 1867. Carly,
P. R.; Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett. 1995,
36, 2113. Carly, P. R.; Cappelle, S. L.; Compernolle, F.;
Hoornaert, G. J. Tetrahedron 1996, 52, 11889.
1. For recent reviews, see: Collier, S. J.; Storr, R. C. Prog.
Heterocycl. Chem. 1998, 10, 25. Chou, T.-S. Rev. Heteroat.
Chem. 1993, 8, 65. Martin, N.; Seoane, C.; Hanack, M. Org.
Prep. Proced. Int. 1991, 23, 237.
2. 8a) Vice, S. F.; de Carvalho, H. N.; Taylor, N. G.; Dmitrienko,
G. I. Tetrahedron Lett. 1989, 30, 7289. Chauhan, P. M. S.;
Crew, A. P. A.; Jenkins, G.; Storr, R. C.; Walker, S. M.;
Yelland, M. Tetrahedron Lett. 1990, 31, 1487. Crew, A. P. A.;
Jenkins, G.; Storr, R. C.; Yelland, M. Tetrahedron Lett. 1990,
31, 1491. 8b) Carly, P. R.; Govaerts, T. C.; Cappelle, S. L.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 2001, 57,
4203. 8c) Chou, T.-S. Rev. Heteroat. Chem. 1993, 8, 65.
5. Meerpoel, L.; Hoornaert, G. J. Synthesis 1990, 905. Van Aken,
K.; Lux, G.; Deroover, G.; Meerpoel, L.; Hoornaert, G. J.
Tetrahedron 1994, 50, 5211.
6. Meerpoel, L.; Deroover, G.; Van Aken, K.; Lux, G.; Hoornaert,
G. J. Synthesis 1991, 9, 765.
7. Jefford, C. W.; Bernardinelli, G.; Wang, Y.; Spellmeyer, D. C.;
Buda, A.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 1157.
8. Kametani, T.; Tsubuki, M.; Shiratori, Y.; Kato, Y.; Nemoto, H.;
Ihara, M.; Fukumoto, K. J. Org. Chem. 1977, 42, 2672.
9. The molecular mechanics method was used: HyperCheme:
release 4.5, Hypercube, Inc.
Â
8f) Tome, A. C.; Cavaleiro, J. A. C.; Storr, R. C. Tetrahedron
1996, 52, 1735. 8g) Ko, C.-W.; Chou, T.-S. Tetrahedron Lett.
1997, 38, 5315. Ko, C.-W.; Chou, T.-S. Tetrahedron 1994, 36,
10721.
3. Cappelle, S. L.; Vogels, I. A.; Van Meervelt, L.; Compernolle,
F.; Hoornaert, G. J. Tetrahedron Lett. 2001, 42, 3759.
4. Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1982,