Facile, one-pot synthesis of bicyclic 2-pyridones from acyl isocyanates, N-phenylmaleimide and trimethylsilyldiazomethane

Article abstract of DOI:10.1055/s-2005-870002

The hetero-Diels-Alder reaction of 2-substituted 4-tri- methylsiloxyoxazoles, prepared in situ from trimethylsilyldiazomethane and acyl isocyanates, with N-phenylmaleimide followed by treatment with a catalytic amount of 10-camphorsulfonic acid efficiently gave bicyclic 2-pyridones in a one-pot process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-870002

PAPER
2147
Facile, One-Pot Synthesis of Bicyclic 2-Pyridones from Acyl Isocyanates,
N-Phenylmaleimide and Trimethylsilyldiazomethane
O
ne-Pot Synthesis
oof Bicyclic
2
s
-Pyridone
h
s
iyuki Hari, Tomoe Iguchi, Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho, Nagoya 467-8603, Japan
Fax +81(52)8363439; E-mail: aoyama@phar.nagoya-cu.ac.jp
Received 28 February 2005; revised 4 April 2005
Reaction of 2a, generated in situ from benzoyl isocyanate
(1a) and Me3SiCHN2, with N-phenylmaleimide as an
electron-deficient alkene in MeCN under reflux condi-
tions slowly proceeded to give the tricyclic compound 4a
(28%) (Table 1), formed from the initial [4+2] cycload-
duct 5a by hydrolysis during work-up, without yielding
any 2-pyridone 6a (entry 1). The stereochemistry of 4a
was confirmed to be in an exo-form, because the proton at
position 7 was observed as a singlet by 1H NMR measure-
ment.6 Changing the reaction solvent from MeCN to tolu-
ene with higher boiling point led to a considerable
improvement in the reaction efficiency and gave a mixture
of the desired 6a (22%) and 4a (50%) (entry 2). The use
of xylene as the reaction solvent caused a significant de-
crease in the yields of 4a and 6a (entry 3). We thought that
the cycloadduct 5a could be converted to the 2-pyridone
6a by a ring-opening reaction, followed by dehydration.
Thus, the effect of an additive for the conversion of 5a (or
4a) to 6a was investigated. When AcOH or pyridine as an
additive was used, no increase in the yield of 6a was ob-
served (entries 4 and 5). On the other hand, 10-camphor-
sulfonic acid (CSA) was quite effective as an additive and
the desired 6a was obtained in 70% yield (entry 6). The
use of a catalytic amount of CSA led to the complete con-
version of 5a (or 4a) to 6a in high yield, though prolonged
reaction time was required (entry 7).
Abstract: The hetero-Diels–Alder reaction of 2-substituted 4-tri-
methylsiloxyoxazoles, prepared in situ from trimethylsilyldiazo-
methane and acyl isocyanates, with N-phenylmaleimide followed
by treatment with a catalytic amount of 10-camphorsulfonic acid ef-
ficiently gave bicyclic 2-pyridones in a one-pot process.
Key words: acyl isocyanates, Diels–Alder reaction, 2-pyridones,
oxazoles, trimethylsilyldiazomethane
Since it was found by Kondrat’eva that oxazoles act as
heterodienes in Diels–Alder reactions,1 numerous studies
on Diels–Alder reactions of various oxazole derivatives
with alkenes or alkynes giving pyridines or furans have
been reported to date.2,3 Although 4(5H)-oxazolones in-
stead of oxazoles have also been reported to be usable for
the synthesis of pyridine or furan derivatives, the yields
were low to moderate.4 In these cases, the reaction pro-
ceeds by a 1,3-dipolar cycloaddition process via a meso-
ionic intermediate, and not by a Diels–Alder addition
process.
Very recently, we have found that the 2-substituted 4-tri-
methylsiloxyoxazoles 2 [the silyl enol ethers of 4(5H)-ox-
azolones], easily generated in situ from acyl isocyanates 1
and trimethylsilyldiazomethane (Me3SiCHN2), are quite
useful as electron-rich heterodienes in the Diels–Alder re-
action. Thus, a one-pot synthesis of multi-substituted
furans by reaction of 2 with electron-deficient alkynes,
such as dimethyl acetylenedicarboxylate (DMAD) or eth-
yl propiolate, followed by retro-Diels–Alder reaction with
the loss of Me3SiOCN from the initial [4+2] cycloadduct
to form 3,4-dimethoxycarbonylfurans has been achieved
(Scheme 1).5 Our continuous interest in the reactivities of
4-trimethylsiloxyoxazoles as heterodienes has led us to
investigate the Diels–Alder reaction of 2 with alkenes giv-
ing pyridine derivatives.
Unfortunately, other electron-deficient alkenes, such as
dimethyl fumarate, maleic anhydride, fumaronitrile, phe-
nyl vinyl sulfone or trans-b-nitrostyrene, gave no charac-
terizable products.
Next, under the same reaction conditions as shown in en-
try 7 in Table 1, the one-pot synthesis of pyridones using
other acyl isocyanates 1b–f was performed (Table 2).
Various aliphatic acyl isocyanates 1b–d smoothly gave
the corresponding 2-pyridones 6b–d in 76–85% yields,
respectively (entries 1–3). Interestingly, the siloxyoxazole
2e generated from 1e has two reactive sites (oxazole and
furan rings) in the molecule, but the reaction selectively
occurred at the oxazole moiety, and the 2-pyridone 6e was
obtained in high yield (entry 4). Similarly, the styryl de-
rivative 2f containing a 1-azabuta-1,3-diene moiety also
afforded the desired 6f in a regioselective manner (entry
5).
MeO2C
CO2Me
OSiMe3
O
Me3SiCHN2
NCO
– N2
DMAD
N
R
– Me3SiOCN
R
R
O
O
1
3
2
Scheme 1 One-pot furan synthesis from acyl isocyanates using tri-
methylsilyldiazomethane.
Finally, we examined the one-pot synthesis of 6 from the
amides 7, precursor of acyl isocyanates. As shown in
Scheme 2, four successive treatments of benzamide 7a
with i) oxalyl chloride (preparation of acyl isocyanate), ii)
SYNTHESIS 2005, No. 13, pp 2147–2150
x
x.
x
x
.
2
0
0
5
Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-870002; Art ID: F04605SS
© Georg Thieme Verlag Stuttgart · New York

2148
Y. Hari et al.
PAPER
Table 1 Optimization of the Synthesis of 6-Phenyl Bicyclic Pyridones
Ph
Ph
Ph
O
O
O
N
N
N
i) N-phenylmaleimide (1.2 equiv)
solvent, reflux, 32–36 h
OSiMe3
H
O
Me3SiCHN2 (1.2 equiv)
MeCN, 0 °C, 30 min
NCO
O
O
O
N
+
H
O
O
Ph
Ph
ii) additive, reflux, time
O
Ph
N
H
O
Ph
N
H
O
Ph
N
OSiMe3
1a
2a
4a
6a
5a
Entry
Solvent
Additivea
Time (h)
Yield (%)
4a
6a
–
1
2
3
4
5
6
7
MeCN
toluene
xylene
toluene
toluene
toluene
toluene
–
–
28
50
35
71
59
–
–
–
22
6
–
–
AcOH (1.2 equiv)
pyridine (1.2 equiv)
CSA (1.2 equiv)
CSA (0.1 equiv)
10
10
1
24
23
70
85
10
–
a CSA = 10-Camphorsulfonic acid.
Table 2 Synthesis of 6-Substituted Bicyclic Pyridones
O
R = Ph (7a)
Ph
R
NH2
O
4-ClC6H4 (7g)
4-MeOC6H4(7h)
N
i) Me3SiCHN2 (1.2 equiv), MeCN, 0 °C, 30 min
O
O
i) oxalyl chloride (1.2 equiv), (CH2Cl)2, reflux, 24 h
ii) Me3SiCHN2 (1.2 equiv), MeCN, 0 °C, 30 min
iii) N-phenylmaleimide (1.2 equiv), toluene, reflux, 32 h
iv) CSA (0.1 equiv), reflux, 10 h
ii) N-phenylmaleimide (1.2 equiv), toluene
reflux, time
iii) CSA (0.1 equiv), reflux, 10 h
R
NCO
R
N
H
O
1
6
Ph
O
N
Entry
R
Time (h)
Product
6b
Yield (%)
O
R = Ph (6a), 71%
1
2
3
4
5
cyclohexyl
benzyl
32
9
85
84
76
83
88
4-ClC6H4 (6g), 80%
R
N
H
O
6c
4-MeOC6H4 (6h), 82%
n-pentyl
2-furyl
19
31
32
6d
Scheme 2 One-pot synthesis of 6-substituted bicyclic pyridones
from amides.
6e
trans-b-styryl
6f
All melting points were measured on a Yanagimoto micro melting
point apparatus and are uncorrected. IR spectra were recorded on a
Shimadzu FTIR-8400S spectrometer. H and 13C NMR spectra
1
TMSCHN2, iii) N-phenylmaleimide, and then iv) CSA in
one-pot gave the 2-pyridone 6a in 71% yield. An electron-
withdrawing group on the benzene ring of 7 such as the
chlorine atom did not affect the reaction and the desired
were recorded on a JEOL JNM-EX-270 spectrometer (1H, 270
MHz; 13C, 67.8 MHz). Mass spectra were recorded on a JEOL JMS-
SX-102A spectrometer.
6g was obtained in 80% yield. Moreover, the use of p- One-Pot Synthesis of Bicyclic Pyridones from Acyl Isocyanates;
2,4-Diphenyl-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione
methoxybenzamide (7h) bearing an electron-donating
(6a); Typical Procedure
To a solution of benzoyl isocyanate (1a; 101 mg, 0.69 mmol) in
group also smoothly afforded 6h in 82% yield.
In conclusion, we have succeeded in the one-pot synthesis
of various 6-substituted bicyclic 2-pyridones from acyl
isocyanates, N-phenylmaleimide, and TMSCHN2.
MeCN (5 mL), was added Me3SiCHN2 (1.63 M in hexane solution,
0.51 mL, 0.82 mmol) at 0 °C under argon. After stirring for 0.5 h,
the solvent was removed in vacuo under moisture-free conditions.
Then, toluene (5 mL) and N-phenylmaleimide (143 mg, 0.82 mmol)
were added under argon and the mixture was refluxed for 32 h. Af-
ter the addition of 10-camphorsulfonic acid (15.8 mg, 0.07 mmol),
Synthesis 2005, No. 13, 2147–2150 © Thieme Stuttgart · New York

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One-Pot Synthesis of Bicyclic 2-Pyridones
2149
the mixture was refluxed for further 10 h. The solvent was then re-
moved in vacuo. The residue was purified by flash column chroma-
tography (Fuji Silysia PSQ 60B, CHCl3–EtOAc, 1:0 to 8:1) to give
the desired compound 6a (186 mg, 85%); white powder; mp >266
°C.
1H NMR (CDCl3): d = 0.92 (3 H, t, J = 6.9 Hz), 1.35–1.46 (4 H, m),
1.82 (2 H, tt, J = 7.5, 7.5 Hz), 3.12 (2 H, t, J = 7.5 Hz), 6.94 (1 H,
s), 7.38–7.52 (5 H, m), 13.0 (1 H, br s).
13C NMR (CDCl3): d = 13.9, 22.2, 28.7, 29.9, 31.2, 105.2, 112.7,
126.2, 128.3, 128.9, 131.1, 142.8, 154.6, 164.3, 164.5, 166.0.
IR (Nujol): 1728, 1672 cm–1.
EI-MS: m/z = 310 (M+), 254.
1H NMR (CDCl3): d = 7.08 (1 H, s), 7.37–7.63 (8 H, m), 7.80 (2 H,
d, J = 6.9 Hz), 9.83 (1 H, br s).
Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C,
69.80; H, 5.92; N, 9.07.
13C NMR (DMSO-d6): d = 112.3, 126.8, 127.4, 127.7, 128.3, 129.2,
130.6, 131.5, 142.3, 149.7, 162.9, 163.3, 164.0.
4-(2-Furyl)-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-
trione (6e)
Colorless crystals; mp >295 °C (CHCl3–Et2O).
EI-MS: m/z = 316 (M+).
Anal. Calcd for C19H12N2O3: C, 72.15; H, 3.82; N, 8.86. Found: C,
72.08; H, 3.91; N, 8.47.
IR (Nujol): 1697, 1670, 1589 cm–1.
1H NMR (DMSO-d6): d = 6.76 (1 H, s), 6.83 (1 H, dd, J = 2.1, 1.0
Hz), 7.39–7.54 (5 H, m), 8.07–8.08 (2 H, m), 12.3 (1 H, br s).
The data of 4a formed in the reaction not involving CSA (Table 1)
is given below.
13C NMR (DMSO-d6): d = 112.4, 113.4, 119.4, 127.5, 128.4, 128.9,
131.9, 137.5, 143.0, 143.2, 147.1, 163.0, 164.0, 164.5.
2,4-Diphenyl-4,7-oxa-1H-tetrahydropyrrolo[3,4-c]pyridine-
1,3,6(2H,3aH)-trione (4a)
Colorless crystals; mp 220–225 °C (CHCl3–Et2O, dec.).
EI-MS: m/z = 306 (M+).
HRMS (EI): m/z calcd for C17H10N2O4: 306.0641; found: 306.0641.
IR (Nujol): 1738, 1697 cm–1.
1H NMR (CDCl3): d = 3.68 (1 H, d, J = 6.8 Hz), 3.90 (1 H, d, J = 6.8
Hz), 5.21 (1 H, s), 6.48 (1 H, br s), 7.18 (2 H, d, J = 6.8 Hz), 7.34–
7.59 (8 H, m).
2-Phenyl-4-[(E)-2-phenylethenyl]-1H-pyrrolo[3,4-c]pyridine-
1,3,6(2H,5H)-trione (6f)
Yellow powder; mp >295 °C.
13C NMR (DMSO-d6): d = 46.5, 55.7, 79.3, 97.0, 125.4, 126.5,
128.0, 128.4, 128.9, 129.0, 131.7, 131.9, 171.4, 173.1, 173.8.
IR (Nujol): 1720, 1668, 1641 cm–1.
1H NMR (DMSO-d6): d = 6.76 (1 H, s), 7.41–7.61 (10 H, m), 7.77
(1 H, d, J = 16.8 Hz), 8.08 (1 H, d, J = 16.8 Hz), 12.5 (1 H, br s).
EI-MS: m/z = 334 (M+), 161.
HRMS (EI): m/z calcd for C19H14N2O4: 334.0954; found: 334.0965.
13C NMR (DMSO-d6): d = 112.8, 115.3, 126.7, 127.2, 127.7, 128.3,
128.8, 129.8, 131.4, 134.6, 139.2, 141.8, 145.1, 162.9, 164.1, 164.4.
The following pyridones 6b–f were prepared by adopting the typi-
cal procedure.
EI-MS: m/z = 342 (M+).
HRMS (EI): m/z calcd for C21H14N2O3: 342.1004; found: 342.0998.
4-Cyclohexyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-
1,3,6(2H,5H)-trione (6b)
Colorless crystals; mp >285 °C (CHCl3–Et2O).
One-Pot synthesis of Bicyclic Pyridones 6a,g,h from Amides
7a,g,h; 2,4-Diphenyl-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-
trione (6a); Typical Procedure
IR (Nujol): 1772, 1732, 1661, 1609, 1593 cm–1.
To a solution of benzamide (7a; 125 mg, 1.03 mmol) in 1,2-dichlo-
roethane (5 mL), was added oxalyl chloride (0.11 mL, 1.24 mmol).
After stirring under reflux for 24 h, the solvent was removed in vac-
uo under moisture-free conditions. The residue [benzoyl isocyanate
(1a)] was dissolved to MeCN (5 mL) and Me3SiCHN2 (1.94 M in
hexane solution, 0.64 mL, 1.24 mmol) was added at 0 °C under ar-
gon. After stirring for 0.5 h, the solvent was removed in vacuo under
moisture-free conditions. Then, toluene (5 mL) and N-phenylmale-
imide (215 mg, 1.24 mmol) were added under argon and the mix-
ture was refluxed for 32 h. After the addition of 10-camphorsulfonic
acid (23.8 mg, 0.10 mmol), the mixture was refluxed for further 10
h. The solvent was removed in vacuo. The residue was purified by
flash column chromatography (Fuji Silysia PSQ 60B, CHCl3–
EtOAc, 1:0 to 8:1) to give the desired compound 6a (227 mg, 71%).
For analytical and spectral data of 6a, see above.
1H NMR (CDCl3): d = 1.32–1.93 (10 H, m), 3.78 (1 H, tt, J = 3.0,
12.2 Hz), 6.95 (1 H, s), 7.38–7.54 (5 H, m), 11.6 (1 H, br s).
13C NMR (CDCl3): d = 25.4, 26.1, 30.3, 38.6, 103.8, 113.3, 126.4,
128.4, 129.0, 131.2, 142.7, 158.4, 164.4, 164.7, 165.0.
EI-MS: m/z = 322 (M+).
HRMS (EI): m/z calcd for C19H18N2O3: 322.1317; found: 322.1339.
4-Benzyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-tri-
one (6c)
Yellow crystals; mp 269–270 °C (CHCl3–Et2O).
IR (Nujol): 1722, 1666 cm–1.
1H NMR (CDCl3): d = 4.45 (2 H, s), 6.97 (1 H, s), 7.31–7.53 (10 H,
m), 11.8 (1 H, br s).
13C NMR (CDCl3): d = 35.7, 105.2, 113.7, 126.4, 127.8, 128.5,
129.1, 129.3, 131.1, 134.9, 142.8, 151.6, 164.1, 164.7, 165.5.
4-(4-Chlorophenyl)-2-phenyl-1H-pyrrolo[3,4-c]pyridine-
1,3,6(2H,5H)-trione (6g)
White powder; mp >295 °C.
EI-MS: m/z = 330 (M+).
IR (Nujol): 1776, 1728, 1666, 1629, 1610, 1593 cm–1.
Anal. Calcd for C20H14N2O3: C, 72.72; H, 4.27; N, 8.48. Found: C,
72.46; H, 4.29; N, 8.61.
1H NMR (DMSO-d6): d = 6.84 (1 H, s), 7.35–7.52 (5 H, m), 7.59 (2
H, d, J = 8.6 Hz), 7.76 (2 H, d, J = 8.6 Hz), 12.7 (1 H, br s).
4-Pentyl-2-phenyl-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-tri-
one (6d)
Colorless crystals; mp 146–148 °C (hexane–EtOAc).
13C NMR (DMSO-d6): d = 99.4, 112.5, 126.8, 127.6, 127.8, 128.2,
128.4, 131.2, 131.5, 135.6, 142.3, 148.4, 163.1, 163.5, 164.0.
EI-MS: m/z = 350 (M+).
IR (Nujol): 1769, 1718, 1662, 1649, 1612 cm–1.
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HRMS (EI): m/z calcd for C19H11ClN2O3: 350.0458; found:
350.0437.
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4-(4-Methoxyphenyl)-2-phenyl-1H-pyrrolo[3,4-c]pyridine-
1,3,6(2H,5H)-trione (6h)
Yellow powder; mp >295 °C.
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IR (Nujol): 1767, 1728, 1670, 1604 cm–1.
1H NMR (DMSO-d6): d = 3.83 (3 H, s), 6.77 (1 H, s), 7.06 (2 H, d,
J = 8.7 Hz), 7.36–7.52 (5 H, m), 7.72 (2 H, d, J = 8.7 Hz), 12.5 (1
H, br s).
13C NMR (DMSO-d6): d = 55.4, 102.8, 112.3, 113.2, 121.2, 127.2,
128.0, 128.6, 131.5, 131.7, 142.8, 149.7, 161.5, 163.4, 163.9, 164.4.
EI-MS: m/z = 346 (M+).
HRMS (EI): m/z calcd for C20H14N2O4: 346.0954; found: 346.0952.
Acknowledgment
This work was financially supported by a Grant-in-Aid for Scienti-
fic Research (KAKENHI) (to T.A.), and a Grant-in-Aid for The Ja-
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Synthesis 2005, No. 13, 2147–2150 © Thieme Stuttgart · New York