Sulfolene pyridinones as precursors for pyridinone ortho-quinodimethanes and their Diels-Alder adducts

Article abstract of DOI:10.1016/S0040-4039(01)02275-4

2(1H)-Pyrazinones were converted into [3,4-b] and [3,4-c] sulfolene pyridinones 4 and 5, serving as precursors for the corresponding 3,4- and 5,6-dimethylene 2(1H)-pyridinone ortho-quinodimethanes. These were trapped by in situ reaction with dienophiles. Tethering of 4 also enabled intramolecular cycloaddition.

Full text of DOI:10.1016/S0040-4039(01)02275-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 799–802
Sulfolene pyridinones as precursors for pyridinone
ortho-quinodimethanes and their Diels–Alder adducts
Tom C. Govaerts, Ilse Vogels, Frans Compernolle and Georges Hoornaert*
Laboratorium voor Organische Synthese, Department of Chemistry K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 2 October 2001; accepted 29 November 2001
Abstract—2(1H)-Pyrazinones were converted into [3,4-b] and [3,4-c] sulfolene pyridinones 4 and 5, serving as precursors for the
corresponding 3,4- and 5,6-dimethylene 2(1H)-pyridinone ortho-quinodimethanes. These were trapped by in situ reaction with
dienophiles. Tethering of 4 also enabled intramolecular cycloaddition. © 2002 Elsevier Science Ltd. All rights reserved.
Over the last decade the chemistry of heteroaromatic
o-quinodimethanes (o-QDM) has been explored exten-
sively.1 The unstable and reactive o-QDM are com-
monly generated in situ from a suitable precursor.
Various methods have been reported for generation of
these o-QDM intermediates, e.g. electrocyclic ring
opening of cyclobutaheterocycles,2 1,4-elimination of
bis(halomethyl)heterocycles,3 and cheletropic extrusion
of SO2 from heteroaromatic sulfolenes 1.4 Among
these, the sulfolene approach seems to be the most
suitable since these precursors are easily accessible and
extrusion of SO2 proceeds at moderately low tempera-
tures so that the resulting o-QDM can be conveniently
trapped in situ to afford the adducts in good yield.
produce polycyclic pyridinones. A further advantage of
the sulfolene precursor type is that it can be used also
for tethering of a dienophilic side chain, enabling an
introductory study of the intramolecular cycloaddition
presented in this communication.
The required sulfolene pyridinone systems 4 and 5 were
derived from 2(1H)-pyrazinones
6
and 7,6 via
intramolecular cycloaddition to a sulfur containing
dienophilic side chain attached to position 3 or 6
(Scheme 1). Thermolysis of thioethers 10 and 11
derived from thioesters 8 and 9 should result in
cycloaddition of the alkyne side chain to the azadiene
system with concomitant expulsion of cyanogen chlo-
ride, in preference to loss of benzyl isocyanate, to
provide dihydrothienopyridinones 12 and 13.
As the pyridinone ring is incorporated in a number of
natural products and various compounds of pharmaco-
logical interest,5 we embarked on a study aiming at the
generation of the pyridinone o-QDM systems 2, 3 (Fig.
1) and their cycloaddition with various dienophiles to
According to this synthetic plan, pyrazinone 6 was
subjected to Stille coupling using Sn(CH3)4 to introduce
a methyl group at the reactive 3-position.7 Subsequent
R3
R3
het.
SO2
SO2
X
X
Y
Y
2 X = N-Bn, Y = CO
R3= H
1
4 X = N-Bn, Y = CO
R3= H
3 X = CO, Y = N-Bn
R3= OMe
5 X = CO, Y = N-Bn
R3= OMe
Figure 1.
Keywords: ortho-quinodimethane; pyridinone; Diels–Alder reaction.
* Corresponding author. Tel.: +32-16-327409; fax: +32-16-327990; e-mail: georges.hoornaert@chem.kuleuven.ac.be
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02275-4

800
T. C. Go6aerts et al. / Tetrahedron Letters 43 (2002) 799–802
Bn
N
Bn
N
Bn
R
O
H
O
R6
Cl
N
O
a
b
S
S
Cl
N
OCH3
Cl
N
R
N
Cl
8 R = COCH3 (80%)
6 R6= H
9 R = COCH3 (80%)
c
c
7 R6= CH3
_
_
=
10 R = CH2C CH (85%)
=
11 R = CH2C CH (90%)
d
d
H3CO
X
X
N
O
N
Bn
12 X = S (65%)
13 X = S (74%)
5 X = SO2 (80%)
e
e
Bn
O
4 X = SO2 (85%)
Scheme 1. Synthesis of the sulfolene pyridinones 4 and 5. Reagents and conditions: (a) (i) 1.2 equiv. SnMe4, 0.01 equiv.
Pd(P(Ph)3)4, toluene, 110°C, 48 h, (ii) 1.2 equiv. NBS, CCl4, benzoyl peroxide, reflux, 3 h, (iii) 1.1 equiv. thiolacetic acid, 3 equiv.
NEt3, THF, rt, 2 h; (b) (i) 1.3 equiv. NaOMe, MeOH, rt, (ii) 1.2 equiv. NBS, CCl4, benzoyl peroxide, reflux, 3 h, (iii) 1.1 equiv.
thiolacetic acid, 3 equiv. NEt3, THF, rt, 2 h; (c) (i) 1.3 equiv. NaOMe, MeOH, rt, (ii) 3 equiv. propargyl bromide; (d) toluene,
reflux, 6–12 h; (e) 3 equiv. m-CPBA, CH2Cl2, rt.
bromination of this methyl group and substitution of
the bromide with thiolacetic acid furnished thioester 8.
An analogous sequence was used to transform 6-
methylpyrazinone 7 into thioester 9, i.e. conversion of
the reactive imidoyl chloride into the 3-methoxy deriva-
tive, bromination of the 6-methyl group,8 and final
substitution with thiolacetate. The intermediate thiolate
anions generated by treatment of thioesters 8 and 9
with sodium methoxide in methanol were alkylated in
situ with propargyl bromide to produce 10 and 11,
respectively. As expected, thermolysis of these
thioethers exclusively yielded pyridinones 12 and 13,
resulting from expulsion of cyanogen chloride. Final
oxidation of the sulfur atom with m-CPBA afforded
the [3,4-c] and [3,4-b] sulfolene pyridinones 4 and 5
(Scheme 1).
coincide at values between 2 and 3 ppm, but in C6D6
the protons H-8 in peri-position of the pyridinone
carbonyl moiety were shifted downfield. The coupling
2
pattern of these protons (H-8ax: 3.17 ppm, dd, J8ax–8eq
3
2
=18 Hz, J8a–7=10 Hz; H-8eq: 2.83 ppm, dd, J8ax–8eq
3
=18 Hz, J8eq–7=5.5 Hz) reveals the 7-equatorial posi-
tion of the ester substituent. The protons H-5 were
detected at higher field (H-5ax3: 2.00 ppm, m; H-5eq: 2.17
2
ppm, dt, J5ax–5eq=18.0 Hz, J=5 Hz).
Thermolysis of the isomeric sulfolene pyridinone 5 pro-
ceeded in a comparable way to give the NMPA adduct
16 in good yield.9 However, with methyl acrylate a
non-regioselective addition was observed, affording an
unseparable mixture (ca. 1:1) of isomeric adducts 17.
The ASIS technique, complemented with NOE experi-
ments, was again utilised to differentiate the various
aliphatic protons H-5 and H-8. In the C6D6 spectrum
Upon thermolysis the sulfones 4, 5 underwent fairly
rapid loss of sulfur dioxide, i.e. at 150°C as compared
to 200–220°C for the sulfolene pyridines.4i–j The result-
ing o-QDM intermediates 2, 3 could be intercepted in
good yields by in situ reaction with dienophiles (Scheme
2).
2
3
two dd signals at 2.32 ppm (1H, J=16.0 Hz, J=5.4
2
3
Hz, H-5eq) and 2.54 ppm (1H, J=16.0 Hz, J=9.8
Hz, H-5ax) were identified as the geminal protons
H-5eq and H-5ax of the 6-substituted isomer, as
demonstrated by a NOE interaction between H-5eq and
the adjacent peri-proton H-4. In a similar way the
geminal protons H-8 of the 7-substituted isomer were
identified as two dd signals observed at 2.42 ppm (1H,
Thus, adduct 14 was produced by heating a solution of
4 with 3 equiv. of N-phenylmaleimide in o-dichloroben-
zene at 150°C for 12 h.9 Regioselective addition of
methyl acrylate to form adduct 15 was accomplished by
heating 4 with 5 equiv. of the volatile dienophile in a
sealed tube for 12 h. The structure of adduct 15 was
assigned on the basis of ASIS (aromatic solvent
3
2
2J=17.2 Hz, J=6.0 Hz) and 2.58 ppm (1H, J=17.2
Hz, 3J=8.8 Hz), showing no NOE correlation with
H-4.
The precursor 4 could be regioselectively functionalised
via sequential addition of 2.1 equiv. BuLi and 1.1
equiv. 5-bromopentene, to provide the 3-(4-pentenyl)
1
induced shift) H NMR data.10 In the CDCl3 spectrum
the aliphatic protons H-5 and H-8 were found to

T. C. Go6aerts et al. / Tetrahedron Letters 43 (2002) 799–802
801
150 ˚C, o-dichlorobenzene
4
O
Methyl
NPMA
acrylate
N
Ph
N
N
N
Bn
CO2Me
Bn
Bn
O
O
O
O
2
15 (80%)
14 (65%)
16 (79%)
O
4
5
H3CO
H3CO
H3CO
O
3
6
7
NPMA
Methyl
acrylate
CO2Me
N
Ph
2
O
O
N
N
N
8
1
O
Bn 3
Bn
Bn
17 (70%)
5
o-dichlorobenzene
150 ˚C,
Scheme 2. Generation and cycloaddition of pyridinone ortho-quinodimethane systems 2 and 3.
H
H
H
H
a
b
4
H
H
SO2
H
2
6a
a
N
N
1
H
Bn
Bn
9a
O
O
O
20 (60%)
18 (65%)
N
19
Bn
Scheme 3. Substitution of the sulfolene precursor and intramolecular Diels–Alder reaction. Reagents and conditions: (a) (i) 2.1
equiv. BuLi, THF, −78°C, (ii) 1.1 equiv. 5-bromopentene; (b) o-DCB, 150°C, 5 h, inert atm.
saturation transfer of H-9a from one conformer to the
other.
sulfolene pyridinone 18 via selective substitution at the
more reactive position of the dianion intermediate.
In summary, a route leading to [3,4-b] and [3,4-c]
sulfolene pyridinones has been developed. These com-
pounds are good precursors for pyridinone ortho-
quinodimethanes, which react in situ with dienophiles.
Further applications of these intermediates in cycload-
dition reactions as well as further functionalisation of
the precursor compounds are being studied.
Thermolysis of the functionalised precursor 18 afforded
the tricyclic pyridinone compound 20 (Scheme 3).
Extrusion of SO2 probably leads to the thermodynami-
cally more stable (Z)-intermediate 19, whereupon endo-
cycloaddition yields the cis-fused adduct 20. The
complexity of the 1H NMR spectrum was initially
thought to be due to a mixture of cis- and trans-fused
3
isomers. However, the J6a,9a values (6.0 and 7.2 Hz)
determined for both forms were lower than expected
for a trans-diaxial relationship of the angular protons
H-6a and H-9a, suggesting the existence of a slow
equilibrium between two cis-fused conformers. This
was confirmed by a NOE-diff experiment: presaturation
of H-9a (2.23 ppm) did not result in any NOE-enhance-
ment of adjacent protons, but instead in the observa-
tion of a negative signal at 3.04 ppm, apparently due to
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1
9. Selected data for adduct 14: H NMR (CDCl3) l (ppm)
2.76 (dd, 1H, 6.8 Hz, 16.6 Hz, H-4), 2.82 (dd, 1H, 6.4 Hz,
14.9 Hz, H-9), 2.99 (dd, 1H, 3.2 Hz, 14.9 Hz, H-9),
3.33–3.42 (m, 2H, H-9a+H-3a), 3.49 (dd, 1H, 2.8 Hz, 15.6
Hz, H-4), 5.08 (d, 1H, 14.5 Hz, H-benzyl), 5.14 (d, 1H,
14.5 Hz, H-benzyl), 6.05 (d, 1H, 6.8 Hz, H-8), 7.06–7.08
(m, 2H, H-Ph), 7.16 (d, 1H, 6.8 Hz, H-7), 7.23–7.38 (m,
8H, H-Ph); for adduct 16: 1H NMR (CDCl3) l (ppm)
2
3
2.51 (dd, 1H, J=15.6 Hz, Jax–eq=5.0 Hz, H-5ax), 2.71
(dd, 1H, 2J=14.0 Hz, 3Jax–eq=4.5 Hz, H-9ax), 3.06 (dd,
1H, 2J=14.0 Hz, 3Jeq–eq=2.0 Hz, H-9eq), 3.34–3.36 (m,
2
3
2H, H-5a+H-8a), 3.42 (dd, 1H, J=15.6 Hz, Jeq–eq=2.2
2
Hz, H-5eq), 5.06 (d, 1H, J=16.0 Hz, H-Bn), 5.86 (d, 1H,
2J=16.0 Hz, H-Bn), 6.51 (s, 1H, H-4), 6.98 (dd, 2H,
Jo=8.0 Hz, Jm=1.0 Hz, H-Ph), 7.17 (d, 2H, Jo=7.3 Hz,
H-Ph), 7.25–7.42 (m, 6H, H-Ph).
10. Selected data for adduct 15: 1H NMR (C6D6) l (ppm)
1.51–1.61 (m, 1H, H-6), 1.75–1.79 (m, 1H, H-6), 2.00–
2.07 (m, 1H, H-5ax), 2.17 (dt, 1H, 18 Hz, 5 Hz, H-5eq),
2.31–2.35 (m, 1H, H-7), 2.85 (dd, 1H, 5.5 Hz, 18.0 Hz,
H-8eq), 3.17 (dd, 1H, 10.0 Hz, 18.0 Hz, H-8ax), 3.32 (s,
3H, CH3), 4.77 (d, 1H, 14.2 Hz, CH2), 4.87 (d, 1H,
14.2 Hz, CH2), 5.37 (d, 1H, 7.0 Hz, H-4), 6.51 (d, 1H, 7.0
Hz, H-3), 7.00–7.15 (m, 3H, H-Ph), 7.17–7.19 (m, 2H,
H-Ph).