Synthesis of substituted bis(heteroaryl)maleimides

Article abstract of DOI:10.1016/j.tet.2005.03.016

Substituted bis(fur-2-yl), bis(fur-3-yl) and bis(thien-2-yl) maleimides with potential antidiabetic properties are described. Their synthesis involves, as a key step, a Suzuki cross-coupling between various boron derivatives and the diiodomaleimides. Therefore, a wide range of substituted symmetric and non-symmetric maleimide derivatives can be prepared.

Full text of DOI:10.1016/j.tet.2005.03.016

Tetrahedron 61 (2005) 4585–4593
Synthesis of substituted bis(heteroaryl)maleimides
*
´ ˆ
Mathieu Dubernet, Virginie Caubert, Jerome Guillard and Marie-Claude Viaud-Massuard
Laboratoire de Chimie Organique, EA 3857 SPOT, UFR des Sciences Pharmaceutiques, 31 Avenue de Monge, 37200 Tours-France
Received 7 December 2004; revised 15 February 2005; accepted 3 March 2005
Available online 23 March 2005
Abstract—Substituted bis(fur-2-yl), bis(fur-3-yl) and bis(thien-2-yl) maleimides with potential antidiabetic properties are described. Their
synthesis involves, as a key step, a Suzuki cross-coupling between various boron derivatives and the diiodomaleimides. Therefore, a wide
range of substituted symmetric and non-symmetric maleimide derivatives can be prepared.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
PTPases inhibitors showed greater potency than non-
substituted ones.5
Protein tyrosine phosphatases (PTPases) are key signal
transduction enzymes which regulate the level of tyrosine
phosphorylation of proteins in coordination with the
competing action of protein tyrosine kinases (PTKs).
PTPases are responsible for phosphotyrosine residue
dephosphorylation whereas PTKs catalyse tyrosine phos-
phorylation. Defect in PTPases activity has been associated
with a number of human diseases such as diabetes, obesity
and cancer.1 In particular, protein tyrosine phosphatase 1B
(PTP1B) is a negative regulator of the insulin-signaling
cascade, and recent knock-out studies in mice2 demon-
strated that this enzyme is an attractive therapeutic target for
the treatment of Type II diabetes.3
As far as we know, photoinduced synthesis of non-
substituted bisfurylmaleimides and bisthienylmaleimides
alone, has already been reported.6 Actually, bisindolyl-
maleimides, bisazaindolylmaleimides and mixed indolyl-
azaindolylmaleimides along with carbazoles, are, because
of their pharmaceutical interests, the most widely described
maleimides. They are prepared from their heteroaryl and
dihalogenomaleimide precursors, using Grignard reagent
(also LiHMDS) and a palladium catalysis (Stille, Suzuki).7
Other methods use the reaction between a glyoxalate and an
arylacetamide or, an homocoupling reaction of 3-arylacetic
acid followed by an amidification.8
To achieve selectivity over most of the hundred of human
PTPases, bidentate (binding with both the active site and an
adjacent site) PTP1B inhibitors have been developed.4
Substituted maleimides are well known for their biological
activity. As a result, in our search of new PTP1B inhibitors,
we have synthesized bis(heteroaryl)maleimides (Fig. 1), for
this scaffold should allow the development of bidentate
inhibitors. Substituents have been introduced on the free
imide nitrogen, for, some N-substituted bis(aryl)imidazoles
In this publication, we report the first synthesis of
substituted bis(fur-2-yl) and bis(thien-2-yl)maleimides via
a one-pot Pd/C catalysed Suzuki cross-coupling, between
the diiodomaleimides and the [(2-diethoxyalkyl)heteroaryl]
boronic acids (Scheme 1).
Substituted bis(fur-3-yl)maleimide synthesis could not be
carried out according to the same conditions, but rather,
required a modified Suzuki coupling, between the diiodo-
maleimide and the [(2-diethoxyalkyl)-4-heteroaryl] boro-
nate using PdCl2(dppf) as the catalyst. Finally, a new
synthetic route to non-symmetric bis(heteroaryl) malei-
mides has been developed.
Figure 1.
Keywords: Bis(heteroaryl)maleimides; Suzuki cross-coupling.
*
Corresponding author. Tel.: C33 24736 7227; fax: C33 24736 7229;
e-mail: mcviaud@univ-tours.fr
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.016

4586
M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
Scheme 2.
2. Discussion and results
2.1. Synthesis of bis[(5-formyl)heteroar-2-yl] maleimides
The desired intermediates [(2-diethoxyalkyl)heteroaryl]
boronic acids were prepared according to McClure and
coll.9 (Scheme 2). As mentioned by the authors, those were
not isolated to avoid any loss of material. Instead, the crude
solution was successfully used in the subsequent Suzuki
cross-coupling. 0.3 equiv of Pd/C (10 wt %) were used each
time as a catalyst. As for the yields of the isolated diacetals
4a–h, they were satisfactory as shown in Table 1. The
desired bis[(5-formyl)heteroar-2-yl] maleimides 5a–h were
obtained by acidic hydrolysis using trifluoroacetic acid.
The recovery yields were good though, some degradation of
the product was observed (Table 1). The diiodomaleimides
6a–d were prepared in three steps from maleic anhydride
(Scheme 3).10 The first step involved bromination in a
sealed tube with bromine in the presence of aluminium
chloride (catalytic amount) to provide 7 (93% yield). This
dibromo derivative was then treated with different substi-
tuted anilines in acetic acid to give the corresponding
dibromomaleimides 8a–d with moderate yields. Finally,
treatment of 8a–d with sodium iodide in acetic acid led to
products 6a–d which were used in the Suzuki coupling
described above. When instead, the dibromomaleimides
8a–d were used, an average 15% yield decrease was
observed. Monosubstitution was not observed whatever the
diiodomaleimide/furaldehyde acetal ratio used. 3,4-Diiodo-
Scheme 3.
2,5-dihydro-[1-(4-hydroxy benzyl)]-1H-pyrrol-2,5-dione 6e
was obtained by demethylation of the methoxy derivative
6d, in standard conditions by treatment with boron
tribromide.
2.2. Synthesis of bis[(5-alkyl)fur-3-yl]maleimides
We first thought to prepare such derivatives via a classical
Suzuki cross-coupling too (Scheme 4), which required
2-diethoxymethyl-4-furanboronic acid. This latter was
potentially available from the 2-diethoxymethyl-4-bromo-
furaldehyde11 9 via an halogen/metal exchange to form the
lithiated furaldehyde acetal. It should have then be trapped
by trisopropylborate in order to give the intermediate
borane. Nevertheless, triisopropylborate was not electro-
philic enough to trap all the 4-lithiofuran at such
temperatures (T!K45 8C). Despite long reaction times,
Table 1. Synthesized bis[(5-diethoxy)heteroar-2-yl] and [(5-formyl)heteroar-2-yl] maleimides
R
H
X
R2
Compound (yield)
R3
Compound (yield)
O
O
CH(OEt)2
CH(OEt)2
4a (64%)
4b (44%)
CHO
CHO
5a (86%)
5b (87%)
O
O
S
CH]CHCH(OEt)2
CH(OEt)2
4c (59%)
4d (73%)
4e (65%)
4f (60%)
4g (58%)
CH]CH–CHO
CHO
5c (62%)
d (89%)
5e (77%)
5f (89%)
5g (85%)
CH(OEt)2
CHO
O
O
CH(OEt)2
CHO
CH(OEt)2
CHO
O
CH(OEt)2
4h (62%)
CHO
5h (93%)

M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
4587
Scheme 4.
only a mixture of both bis(fur-2-yl) and bis(fur-3-yl)malei-
mides could be isolated (Scheme 4).12
Scheme 6.
So we used a palladium catalysed reaction to force the
formation of the borane in position 4. Bis(pinacolato)dibor-
ane (Scheme 5) is thermally stable, easy to handle in the air
and known to be a useful boron nucleophile for cross or
homocoupling reaction with arylhalides.13 Borane 10 was
generated in situ and coupled to diiodobenzylmaleimide 6c
to give 11.
1 using the Suzuki coupling conditions described in Section
2.1 (Scheme 6). One will notice, as mentioned in the
previous paragraph, that compound 13 was rapidly degra-
dated when heated for too long a time. Nevertheless, its
bromination by successive treatment with bromine and
triethylamine14 afforded product 14 in a good yield.
Then, 4-bromo-3-[(5-carboxyl)fur-2-yl]-2,5-dihydro-1-
(benzyl)-1H-pyrrol-2,5-dione 15 was prepared from 14 by
acetal acidic hydrolysis and subsequent mild oxidation15
using sodium hypochloride as the oxidant. Using the
previously described Suzuki cross-coupling (cf Section
2.1), the non-symmetric maleimide 16 was finally prepared
in a 17% yield from acetal 1 and compound 15 (Scheme 7).
Scheme 5.
The poor stability of the various maleimide species would
be accountable for the low yield observed. Indeed,
maleimides are generally unstable in aqueous basic
mixtures and, as for monofurylmaleimides, they were
found to be highly unstable. When anhydrous conditions
were used (dry Na2CO3, K3PO4 or Et3N), no product was
formed. The reaction at room temperature for 24 h resulted
in a 4% yield increase while no starting material was
recovered. So far, none of the experimental conditions used
has resulted into a significant yield improvement.
Scheme 7.
Material losses (water solubility) during the purification
steps are responsible for the low yield observed which is not
representative of the great effectiveness of this reaction.
3. Conclusion
In conclusion, we have developed new efficient methods,
based on Suzuki cross-coupling reactions, to synthesize
various symmetric and non-symmetric heteroarylmalei-
mides. The biological evaluation of these new compounds
is now under investigation.
2.3. Synthesis of non-symmetric maleimides
Since a monooxidation of bis[(5-formyl)heteroar-2-yl]
maleimides would give a mixture of di, mono and non-
oxidized maleimides, this series of compound has rather
been prepared from 3-bromobenzylmaleimide 12 via a
Suzuki cross-coupling-bromination-Suzuki coupling
sequence. Thereof a wider range of compounds is accessible
than with the commonly used methods.7
4. Experimental
4.1. General
Melting points were determined using Bu¨chi Melting Point
B-540 and are uncorrected. 1H NMR and 13C NMR spectra
were recorded on a Bruker AM-300 WB (300 MHz). The
coupling constants are recorded in Hz and the chemical
Firstly, compound 12 was isolated as a byproduct of 3,4-di-
bromobenzylmaleimide 8c synthesis from benzylmalei-
mide. It was then coupled to 2-furaldehyde diethyl acetal

4588
M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
shifts are reported in ppm (d, ppm) downfield from TMS
which was used as the internal standard. IR spectra were
obtained with a Perkin–Elmer FT Paragon 1000 PC. MS
spectra were registered on a Perkin–Elmer SCIEX API 3000
spectrometer. Reaction products were purified by flash
chromatography using silica gel (Merck 230–400 mesh).
Analytical TLC was carried out on silica gel F254 plates. All
anhydrous reactions were performed in over-dried glass-
ware under an atmosphere of argon. Anhydrous solvents
were transferred via syringe.
4.2. 3,4-Bis[(5-diethoxymethyl)heteroar-2-yl]-2,5-dihy
dro-1-(substituted)-pyrrol-2,5-dione (4a–h). General
procedure
Under an inert atmosphere, n-butyllithium (50.57 mmol,
2.5 M in hexane) was added dropwise to a solution of
diethyl acetal derivatives (1–3) (42.13 mmol) in ethylene
glycol dimethyl ether at K20 8C. The mixture was stirred an
additional time (3 h) with continuous cooling. Then
triisopropylborate (50.57 mmol) was then added dropwise
at K20 8C afterwards the mixture was allowed to rise to
room temperature under continuous stirring (w2 h). The
reaction was quenched with the addition of 3.13 mL of
acetic acid (54.78 mmol) and 3.79 mL of water
(210.70 mmol). Then, 6a–h (6.02 mmol), ethanol
(23.00 mL), triethylamine (3.35 mL, 24.08 mmol) and
palladium on activated carbon (10 wt % Pd/C, 1.9 g,
1.80 mmol) were added and the mixture was refluxed
under stirring during 24 h. The solution was cooled to room
temperature and the catalyst was filtered on Celite, washed
with ethyl acetate and the filtrate concentrated in vacuo. The
residue was taken up in ethyl acetate, washed with water and
dried over anhydrous MgSO4. After solvent removal, the
crude residue was purified by column chromatography
(eluent: light petroleum–ethyl acetate) to give the desired
compounds 4a–h.
4.1.1. 2-Furaldehyde diethyl acetal (1). To a solution of
2-furaldehyde (10.00 g, 104 mmol) and ammonium chloride
(2.90 g) in ethanol (18.20 mL, 312 mmol) was added
triethyl orthoformate (15.20 mL, 115 mmol). The mixture
was refluxed during 16 h. After cooling the solution to room
temperature, the solvent was removed under reduced
pressure and the residue diluted with ethyl acetate. The
organic layer was washed with a saturated sodium
hydrogenocarbonate solution and dried over anhydrous
MgSO4. After solvent removal, the crude was purified by
chromatography on silica gel (eluent: light petroleum–ethyl
acetate: 99/1) to afford 1 (17.70 g, 99%) as a yellow oil.16
4.1.2. 2-Thiophenecarboxaldehyde diethyl acetal (2). To
a solution of 2-thiophenecarboxaldehyde (1.67 mL,
17.83 mmol) and ammonium chloride (446 mg) in ethanol
(3.2 mL, 53.46 mmol) was added triethyl orthoformate
(3.26 mL, 19.62 mmol). The mixture was refluxed during
16 h. After cooling the solution to room temperature, the
solvent was removed under reduced pressure and the residue
diluted with ethyl acetate. The organic layer was washed
with a saturated sodium hydrogenocarbonate solution and
dried over anhydrous MgSO4. After solvent removal, the
crude was purified by chromatography on silica gel (eluent:
light petroleum–ethyl acetate: 99/1) to afford 2 (17.70 g,
99%) as a yellow oil.16
4.2.1. 3,4-Bis[5-diethoxymethyl)fur-2-yl]-2,5-dihydro-
1H-pyrrol-2,5-dione (4a). Yellow solid (64%), mp 98–
99 8C; nmax (KBr)/cmK1 3055, 2982, 1771, 1727, 1528,
1443, 1348, 1100, 1054; dH (200 MHz, CDCl3) 8.59 (1H, br
s, NH), 7.52 (2H, d, JZ3.5 Hz, Hfuran.), 6.64 (2H, d, JZ
3.5 Hz, Hfuran.), 5.69 (2H, s, 2CH(OEt)2), 3.65 (8H, dq, JZ
1.6, 7.1 Hz, 4CH2CH3), 1.26 (12H, t, JZ7.1 Hz,
4CH2CH3); dC (200 MHz, CDCl3) 169.4 (2C]O), 155.5
(2C), 144.9 (2C), 119.3 (2C), 118.8 (2CHfuran.), 110.9
(2CHfuran.), 96.0 (2CH(OEt)2), 61.3 (4CH2), 15.0 (4CH3);
m/z 451 (MC18), 456 (MC23); (Anal. Calcd for
C22H27NO8: C, 60.96; N, 3.23; H, 6.28. Found: C, 60.85;
N, 3.29; H, 6.39).
4.1.3. 2-(3,3-Diethoxypropenyl)furan (3). To a solution of
trans-3-(2-furyl)acrolein (3.50 g, 28.42 mmol) and
ammonium chloride (770 mg) in ethanol (5 mL) was
added triethyl orthoformate (5.20 mL, 31.26 mmol). The
mixture was stirred at room temperature during 4 h.
The solvent was removed under reduced pressure and the
residue diluted with ethyl acetate. The organic layer was
washed with a saturated sodium hydrogenocarbonate
solution and dried over anhydrous MgSO4. After solvent
removal, the crude residue was purified by chromatography
on silica gel (eluent: light petroleum–ethyl acetate: 99/1) to
afford 3 (5.11 g, 99%) as a brown oil; nmax (film)/cmK1
3054, 2979, 1675, 1629, 1473, 1387, 1121, 1019, 965; dH
(200 MHz, CDCl3) 7.34 (1H, d, JZ1.8 Hz, Hfuran.), 6.53
(1H, dd, JZ16.0, 1.0 Hz, Hvinyl.), 6.35 (1H, dd, JZ3.3,
1.8 Hz, Hfuran.), 6.27 (1H, d, JZ3.3 Hz, Hfuran.), 6.11 (1H,
dd, JZ16.0, 4.7 Hz, Hvinyl.), 5.05 (1H, dd, JZ4.7, 1.0 Hz,
CH(OEt)2), 3.72–3.48 (4H, m, 2CH2CH3), 1.26–1.18
(6H, m, 2CH2CH3); dC (200 MHz, CDCl3) 152.0 (C),
142.3 (CHfuran.), 125.2 (CHvinyl.), 121.0 (CHvinyl.), 111.3
(CHfuran.), 108.9 (CHfuran.), 100.7 (CH), 60.8 (2CH2), 15.2
(2CH3); m/z 197 (MC1); (Anal. Calcd for C11H16NO3: C,
67.32; N, 8.22; H, 24.46. Found: C, 67.51; N, 8.26; H,
24.36).
4.2.2. 3,4-Bis[5-diethoxymethyl)fur-2-yl]-2,5-dihydro-1-
phenyl-1H-pyrrol-2,5-dione (4b). Red solid (44%), mp
80–81 8C; nmax (KBr)/cmK1 3124, 3054, 2980, 1713, 1683,
1664, 1503, 1393, 1169, 1113, 1058, 818; dH (200 MHz,
CDCl3) 7.58 (2H, d, JZ3.6 Hz, Hfuran.), 7.48–7.35 (5H,
m, Harom.), 6.66 (2H, d, JZ3.6 Hz, Hfuran.), 5.69 (2H, s,
2CH(OEt)2), 3.65 (8H, dq JZ7.1, 1.9 Hz, 4CH2CH3), 1.24
(12H, t, JZ7.1 Hz, 4CH2CH3); dC (200 MHz, CDCl3)
168.2 (2C]O), 155.8 (2C), 144.9 (2C), 131.5 (C), 129.0
(2CHarom.), 127.9 (CHarom.), 126.4 (2CHarom.), 119.2
(2CHfuran.), 118.6 (2C), 111.1 (2CHfuran.), 96.1
(2CH(OEt)2), 61.4 (4CH2), 15.2 (4CH3); m/z 527 (MC
18), 532 (MC23); (Anal. Calcd for C28H31NO8: C, 66.00;
N, 2.75; H, 6.13. Found: C, 65.89; N, 2.73; H, 5.92).
4.2.3. 1-Benzyl-3,4-bis{[5-(3,3-diethoxy)propenyl]fur-2-
yl}pyrrol-2,5-dione (4c). Violet coloured oil (59%); nmax
(film)/cmK1 3054, 2986, 1676, 1630, 1422, 1121, 896; dH
(200 MHz, CDCl3) 7.48 (2H, d, JZ3.7 Hz, Hfuran.), 7.42–
7.26 (5H, m, Harom.), 6.59 (1H, dd, JZ16.0, 1.0 Hz, Hvinyl.),
6.52 (2H, d, JZ3.7 Hz, Hfuran.), 6.37 (1H, dd, JZ16.0,
4.1 Hz, Hvinyl.), 5.06 (2H, dd, JZ4.1, 1.0 Hz, 2CH(OEt)2),

M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
4589
4.75 (2H, s, N–CH2), 3.79–3.41 (8H, m, 4CH2CH3), 1.22
(12H, t, JZ7.0 Hz, 4CH2CH3); dC (200 MHz, CDCl3) 169.1
(2C]O), 155.3 (2C), 145.5 (2C), 136.3 (C), 128.6
(2CHarom.), 128.4 (2CHarom.), 128.4 (2CHvinyl.), 127.7
(CHarom.), 120.3 (2CHvinyl.), 119.9 (2CHfuran.), 117.9 (2C),
112.1 (2CHfuran.), 100.0 (2CH(OEt)2), 60.9 (4CH2), 41.8
(N–CH2), 15.2 (4CH3); m/z 576 (MC1), 598 (MC23);
(Anal. Calcd for C33H37NO8: C, 68.85; N, 2.43; H, 6.48.
Found: C, 68.79; N, 2.41; H, 6.39).
8.7 Hz, Harom.), 6.83 (2H, d, JZ8.7 Hz, Harom.), 6.61 (2H, d,
JZ3.5 Hz, Hfuran.), 5.65 (2H, s, 2CH(OEt)2), 4.68 (2H, s,
N–CH2), 3.76 (3H, s, O–CH3), 3.64 (8H, dq, JZ7.1, 1.5 Hz,
4CH2CH3), 1.22 (12H, t, JZ7.1 Hz, 4CH2CH3); dC
(200 MHz, CDCl3) 168.7 (2C]O), 158.7 (C–O), 155.0
(2C), 144.6 (2C), 129.5 (2CHarom.), 128.1 (C), 118.3
(2CHfuran.), 118.2 (2C), 113.5 (2CHarom.), 110.5 (2CHfuran.),
95.6 (2CH(OEt)2), 60.9 (4CH2), 54.8 (N–CH2), 40.8 (CH2),
14.7 (4CH3); m/z 508 (MK[OEt]), 571 (MC18), 576
(MC23); (Anal. Calcd for C30H35NO9: C, 65.09; N, 2.53;
H, 6.37. Found: C, 65.01; N, 2.49; H, 6.44).
4.2.4. 3,4-Bis[(5-diethoxymethyl)fur-2-yl]-2,5-dihydro-1-
benzyl-1H-pyrrol-2,5-dione (4d). Red solid (73%), mp
107–109 8C; nmax (KBr)/cmK1 3054, 2979, 2932, 1769,
1706, 1679, 1434, 1401, 1114, 1057, 1018; dH (200 MHz,
CDCl3) 7.54 (2H, d, JZ3.5 Hz, Hfuran.), 7.41–7.21 (5H, m,
Harom.), 6.65 (2H, d, JZ3.5 Hz, Hfuran.), 5.68 (2H, s,
2CH(OEt)2), 4.75 (2H, s, N–CH2), 3.64 (8H, dq, JZ1.6,
7.0 Hz, 4CH2CH3), 1.24 (12H, t, JZ7.0 Hz, 4CH2CH3); dC
(200 MHz, CDCl3) 168.9 (2C]O), 155.4 (2C), 144.9 (2C),
136.1 (C), 128.5 (2CHarom.), 128.3 (2CHarom.), 127.6
(CHarom.), 118.7 (2CHfuran.), 118.4 (2C), 110.9 (2CHfuran.),
95.9 (2CH(OEt)2), 61.2 (4CH2), 41.6 (N–CH2), 15.0
(4CH3); m/z 524 (MC1), 541 (MC18), 546 (MC23);
(Anal. Calcd for C29H33NO8: C, 66.53; N, 2.68; H, 6.35.
Found: C, 66.63; N, 2.61; H, 6.29).
4.2.8. 3,4-Bis[(5-diethoxymethyl)furan-2-yl]-2,5-di-
hydro-1-(4-hydroxybenzyl)-1H-pyrrol-2,5-dione (4h).
Red oil (62%); nmax(film)/cmK1 3054, 2986, 1708, 1680,
1614, 1517, 1422, 1156, 1053; dH (200 MHz, CDCl3) 7.51
(2H, d, JZ3.5 Hz, Hfuran.), 7.21 (2H, d, JZ8.4 Hz, Harom.),
6.73 (2H, d, JZ8.4 Hz, Harom.), 6.61 (2H, d, JZ3.5 Hz,
Hfuran.), 5.65 (2H, s, 2CH(OEt)2), 4.63 (2H, s, N–CH2), 3.62
(8H, dq, JZ1.5, 7.1 Hz, 4CH2CH3), 1.21 (12H, t, JZ
7.1 Hz, 4CH2CH3); dC (200 MHz, CDCl3) 169.2 (2C]O),
155.9 (C–O), 155.4 (2C), 145.1 (2C), 130.0 (2CHarom.),
127.9 (C), 118.8 (2CHfuran.), 118.7 (2C), 115.5 (2CHarom.),
111.0 (2CHfuran.), 96.1 (2CH(OEt)2), 61.5 (4CH2), 41.4
(N–CH2), 15.1 (4CH3); m/z 540 (MC1), 562 (MC23);
(Anal. Calcd for C29H33NO9: C, 64.55; N, 2.60; H, 6.16.
Found: C, 64.32; N, 2.49; H, 6.05).
4.2.5. 3,4-Bis[(5-diethoxymethyl)thien-2-yl]-2,5-dihydro-
1-benzyl-1H-pyrrol-2,5-dione (4e). Red oil (65%);
nmax(film)/cmK1 1741, 1699, 1284; dH (200 MHz, CDCl3)
7.75 (2H, d, JZ3.9 Hz, Hthiophen.), 7.27–7.44 (5H, m,
Harom.), 7.08 (2H, d, JZ3.9 Hz, Hthiophen), 5.76 (2H, s,
2CH(OEt)2), 4.75 (2H, s, N–CH2), 3.64 (8H, q, JZ7.1 Hz,
4CH2CH3), 1.25 (12H, t, JZ7.1 Hz, 4CH2CH3); dC
(200 MHz, CDCl3) 169.5 (2C]O), 148.5 (2C), 136.0
(2C), 131.1 (C), 129.5 (2CHarom.), 128.5 (2CHarom.), 128.4
(CHarom.), 127.6 (2CHthiopen.), 126.9 (2C), 125.3
(2CHthiophen.), 97.9 (2CH(OEt)2), 60.8 (4CH2), 41.9 (N–
CH2), 14.9 (4CH3); m/z 556 (MC1), 578 (MC23); (Anal.
Calcd for C29H33NO6S2: C, 62.68; N, 2.52; H, 5.99. Found:
C, 62.55; N, 2.55; H, 6.07).
4.3. 4-Bis[(5-formyl)heteroar-2-yl]-2,5-dihydro-1-(substi-
tuted)-1H-pyrrol-2,5-dione (5a–h). General procedure
A solution of 4a–h (1.59 mmol) and trifluoroacetic acid
(1.21 mL, 15.90 mmol) in THF (15 mL) was stirred at room
temperature during 2 h. Then, the mixture was taken up in
pentane (30 mL), filtered and the precipitate was washed
with pentane to give the title compounds 5a–h.
4.3.1. 3,4-Bis[(5-formyl)fur-2-yl]-2,5-dihydro-1H-pyr-
rol-2,5-dione (5a). Red solid (86%), mp 249 8C;
nmax(KBr)/cmK1 3055, 2987, 1738, 1681, 1653, 1551,
1436, 1345, 1185, 1032, 814; dH (200 MHz, CDCl3) 9.92
(2H, s, CHO), 7.78 (2H, d, JZ3.8 Hz, Hfuran.), 7.55 (1H, br
s, NH), 7.4 (2H, d, JZ3.8 Hz, Hfuran.); dC (200 MHz,
CDCl3) 179.6 (2CHO), 169.2 (2C]O), 153.4 (2C), 148.3
(2C), 122.1 (2CHfuran.), 121.6 (2C), 120.0 (2CHfuran.); m/z
286 (MC1), 308 (MC23), 318 (MC33); (Anal. Calcd for
C14H7NO6: C, 58.96; N, 4.91; H, 2.47. Found: C, 58.93; N,
4.71; H, 2.49).
4.2.6. 3,4-Bis[(5-diethoxymethyl)fur-2-yl]-2,5-dihydro-1-
(phenylethyl)-1H-pyrrol-2,5-dione (4f). Red solid (60%),
mp 45–46 8C; nmax(KBr)/cmK1 2976, 2931, 1764, 1705,
1618, 1583, 1527, 1438, 1362, 1115, 1017; dH (200 MHz,
CDCl3) 7.51 (2H, d, JZ3.5 Hz, Hfuran.), 7.34–7.21 (5H, m,
Harom.), 6.63 (2H, d, JZ3.5 Hz, Hfuran.), 5.67 (2H, s,
2CH(OEt)2), 3.82 (2H, t, JZ7.3 Hz, CH2), 3.65 (8H, dq,
JZ1.9, 7.0 Hz, 4CH2CH3), 2.94 (2H, t, JZ7.3 Hz, CH2),
1.24 (12H, t, JZ7.0 Hz, 4CH2CH3); dC (200 MHz, CDCl3)
169.1 (2C]O), 155.5 (2C), 145.1 (2C), 138.0 (C), 128.8
(2CHarom.), 128.5 (2CHarom.), 126.5 (CHarom.), 118.7
(2CHfuran.), 118.4 (2C), 110.9 (2CHfuran.), 96.1
(2CH(OEt)2), 61.4 (4CH2), 39.5 (N–CH2), 34.5 (CH2),
15.1 (4CH3); m/z 555 (MC18), 560 (MC23); (Anal. Calcd
for C30H35NO8: C, 66.53; N, 2.68; H, 6.35. Found: C, 66.69;
N, 2.75; H, 6.46).
4.3.2. 3,4-Bis[(5-formyl)fur-2-yl]-2,5-dihydro-1-phenyl-
1H-pyrrol-2,5-dione (5b). Red solid (87%), mp 257 8C;
nmax(KBr)/cmK1 3055, 2987, 1713, 1675, 1600, 1549,
1404, 1339, 1166, 1028, 828; dH (200 MHz, CDCl3) 9.94
(2H, s, CHO), 7.85 (2H, d, JZ3.8 Hz, Hfuran.), 7.54–7.25
(7H, m, Hfuran., Harom.); dC (200 MHz, CDCl3) 178.8
(2CHO), 167.4 (2C]O), 153.9 (2C), 148.5 (2C), 131.8
(C), 129.4 (2CHarom.), 128.8 (CHarom.), 127.6 (2CHarom.),
122.6 (2CHfuran.), 121.5 (2C), 120.7 (2CHfuran.); m/z 362
(MC1), 379 (MC18); (Anal. Calcd for C20H11NO6: C,
66.49; N, 3.88; H, 3.07. Found: C, 65.21; N, 4.10; H, 3.00).
4.2.7. 3,4-Bis[(5-diethoxymethyl)fur-2-yl]-2,5-dihydro-1-
(4-methoxybenzyl)-1H-pyrrol-2,5-dione (4g). Red solid
(58%), mp 58–59 8C; nmax(KBr)/cmK1 3164, 3054, 2986,
1708, 1683, 1662, 1514, 1430, 1399, 1032; dH (200 MHz,
CDCl3) 7.51 (2H, d, JZ3.5 Hz, Hfuran.), 7.33 (2H, d, JZ
4.3.3. 3-(5-{1-Benzyl-2,5-dioxo-4-[5-(3-oxopropenyl) fur-
2-yl]-2,5-dihydro-1H-pyrrol-3-yl}fur-2-yl)-propenal

4590
M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
(5c). Violet coloured solid (62%), mp 163 8C; nmax(KBr)/
cmK1 3055, 2987, 1708, 1670, 1620, 1428, 1120, 1031, 892;
dH (200 MHz, CDCl3) 9.56 (2H, d, JZ7.8 Hz, CHO), 7.60
(2H, d, JZ3.7 Hz, Hfuran.), 7.52–7.26 (5H, m, Harom.), 7.18
(2H, d, JZ15.8 Hz, Hvinyl.), 6.93 (2H, d, JZ3.7 Hz, Hfuran.),
6.87 (1H, dd, JZ15.8, 7.8 Hz, Hvinyl.), 4.77 (2H, s, N–CH2);
dC (200 MHz, CDCl3) 192.1 (2CHO), 168.3 (2C]O), 153.6
(2C), 148.0 (2C), 135.8 (2CHvinyl.), 135.7 (C), 128.8
(2CHarom.), 128.5 (2CHarom.), 128.1 (CHarom.), 127.7
(2CHvinyl.), 121.3 (2CHfuran.), 119.2 (2C), 119.0 (2CHfuran.),
42.1 (N–CH2); m/z 428 (MC1), 445 (MC18), 450 (MC
23); (Anal. Calcd for C25H17NO6: C, 70.25; N, 3.28; H,
4.01. Found: C, 70.27; N, 3.30; H, 3.98).
(2CHarom.), 127.8 (C), 120.8 (2CHfuran.), 120.5 (2CHfuran.),
120.4 (2C), 114.1 (2CHarom.), 55.2 (O–CH3), 41.8 (N–CH2);
m/z 406 (MC1), 423 (MC18), 428 (MC23); (Anal. Calcd
for C22H15NO7: C, 65.19; N, 3.46; H, 3.73. Found: C, 65.30;
N, 3.77; H, 3.49).
4.3.8. 3,4-Bis[(5-formyl)fur-2-yl]-2,5-dihydro-1-(4-
hydroxybenzyl)-1H-pyrrol-2,5-dione (5h). Red solid
(93%), mp 223 8C; nmax(KBr)/cmK1 3056, 2986, 1707,
1672, 1517, 1435, 1400, 1027, 811; dH (200 MHz, CDCl3)
9.89 (2H, s, CHO), 7.79 (2H, d, JZ3.9 Hz, Hfuran.), 7.38
(2H, d, JZ3.9 Hz, Hfuran.), 7.31 (2H, d, JZ8.5 Hz, Harom.),
6.79 (2H, d, JZ8.5 Hz, Harom.), 4.73 (2H, s, N–CH2); dC
(200 MHz, CDCl3) 178.9 (2CHO), 167.4 (2C]O), 155.4
(C–O), 153.4 (2C), 148.5 (2C), 129.7 (2CHarom.), 127.0 (C),
121.2 (2CHfuran.), 120.5 (2CHfuran.), 120.2 (2C), 115.1
(2CHarom.), 41.3 (N–CH2); m/z 392 (MC1), 409 (MC18);
(Anal. Calcd for C21H13NO7: C, 64.45; N, 3.58; H, 3.35.
Found: C, 64.55; N, 3.61; H, 3.50).
4.3.4. 3,4-Bis[(5-formyl)fur-2-yl]-2,5-dihydro-1-benzyl-
1H-pyrrol-2,5-dione (5d). Red solid (89%), mp 174 8C;
nmax(KBr)/cmK1 3055, 2987, 1708, 1683, 1662, 1432, 1400,
1031, 981; dH (200 MHz, CDCl3) 9.92 (2H, s, CHO), 7.81
(2H, d, JZ3.8 Hz, Hfuran.), 7.47–7.27 (7H, m, Hfuran.
,
Harom.), 4.82 (2H, s, N–CH2); dC (200 MHz, CDCl3) 178.8
(2CHO), 167.9 (2C]O), 154.1 (2C), 148.6 (2C), 135.5 (C),
128.8 (2CHarom.), 128.6 (2CHarom.), 128.2 (CHarom.), 120.9
(2CHarom.), 120.6 (2CHarom.), 120.4 (2C), 42.3 (N–CH2);
m/z 376 (MC1), 398 (MC23); (Anal. Calcd for
C21H13NO6: C, 67.20; N, 3.49; H, 3.73. Found: C, 66.90;
N, 3.45; H, 3.70).
4.4. 3,4-Dibromomaleic anhydride (7)
Under an inert atmosphere, a solution of maleic anhydride
(1.50 g, 15.29 mmol), aluminium chloride (28 mg,
0.21 mmol) and bromine (1.50 mL, 30.58 mmol) was
heated at 120 8C during 16 h in a sealed tube. After cooling
the tube to room temperature, the mixture was taken up in
ethyl acetate, filtered and the filtrate was concentrated in
vacuo to afford the title compound 7 (3.64 g, 93%) as a
yellow solid, mp 113–114 8C.10
4.3.5. 3,4-Bis[(5-formyl)thien-2-yl]-2,5-dihydro-1-ben-
zyl-1H-pyrrol-2,5-dione (5e). Orange solid (77%), mp
166–168 8C; nmax(KBr)/cmK1 1716, 1694, 1390; dH
(200 MHz, CDCl3) 9.96 (2H, s, 2CHO), 7.87 (2H, d, JZ
4.1 Hz, Hthiophen.), 7.77 (2H, d, JZ4.1 Hz, Hthiophen.), 7.31–
7.47 (5H, m, Harom.), 4.81 (2H, s, N–CH2); dC (200 MHz,
CDCl3) 182.7 (2CHO), 168.3 (2C]O), 147.2 (2C), 136.9
(2C), 135.4 (1 C and 2CHarom.), 132.5 (2CHarom.), 129.0
(2C), 128.8 (CHarom.), 128.7 (2CHthiophen.), 128.1
(2CHthiophen.), 42.5 (CH2); m/z 408 (MC1), 430 (MC23);
(Anal. Calcd for C21H13NO4S2: C, 61.90; N, 3.44; H, 3.22.
Found: C, 61.88; N, 3.39; H, 3.17).
4.5. 3,4-Dibromo-2,5-dihydro-1H-pyrrol-2,5-dione (8a)
To a solution of 3,4-dibromomaleic anhydride 7 (4 g,
15.63 mmol) in acetic acid (50 mL) was added ammonium
acetate (1.76 g, 23.44 mmol). The mixture was heated at
reflux during 16 h. After solvent removal under reduced
pressure, the crude residue was purified by column
chromatography over silica gel (eluent: light petroleum–
ethyl acetate: 7/3) to give compound 8a (2.40 g, 60%) as a
yellow solid, mp 198 8C.17
4.3.6. 3,4-Bis[(5-formyl)fur-2-yl]-2,5-dihydro-1-(phenyl-
ethyl)-1H-pyrrol-2,5-dione (5f). Orange solid (89%), mp
155 8C; nmax(KBr)/cmK1 3055, 2986, 1711, 1681, 1440,
1364, 1027, 982, 816; dH (200 MHz, CDCl3) 9.91 (2H, s,
2CHO), 7.75 (2H, d, JZ3.8 Hz, Hfuran.), 7.38 (2H, d, JZ
3.8 Hz, Hfuran.), 7.34–7.23 (5H, m, Harom.), 3.88 (2H, t, JZ
7.4 Hz, CH2), 2.97 (2H, t, JZ7.4 Hz, CH2); dC (200 MHz,
CDCl3) 178.9 (2CHO), 168.0 (2C]O), 154.0 (2C), 148.6
(2C), 137.5 (C), 128.8 (2CHarom.), 128.7 (2CHarom.), 126.8
(CHarom.), 120.8 (2CHfuran.), 120.7 (2CHfuran.), 120.2 (2C),
40.0 (CH2), 34.3 (CH2); m/z 390 (MC1), 412 (MC23);
(Anal. Calcd for C22H15NO6: C, 67.87; N, 3.60; H, 3.88.
Found: C, 67.94; N, 3.94; H, 3.60).
4.6. 3,4-Dibromo-2,5-dihydro-1-(substituted)-1H-
pyrrol-2,5-dione (8b–e): General procedure
To a solution of 3,4-dibromomaleic anhydride 7 (4.40 g,
17.19 mmol) in acetic acid (50 mL) was added anilines
(18.91 mmol). The mixture was heated at reflux during 3 h.
After solvent removal under reduced pressure, the crude
mixture was purified by column chromatography over silica
gel (eluent: light petroleum–ethyl acetate) to afford the
desired products 8b–e.
4.6.1. 3,4-Dibromo-2,5-dihydro-1-phenyl-1H-pyrrol-2,5-
dione (8b). Yellow solid (81%), mp 162–163 8C.10
4.3.7. 3,4-Bis[(5-formyl)fur-2-yl]-2,5-dihydro-1-(4-meth-
oxybenzyl)-1H-pyrrol-2,5-dione (5g). Red solid (85%),
mp 208–209 8C; nmax(KBr)/cmK1 3054, 2986, 1707, 1684,
1662, 1515, 1430, 1334, 1032, 813; dH (200 MHz, CDCl3)
9.91 (2H, s, CHO), 7.79 (2H, d, JZ4.0 Hz, Hfuran.), 7.38
(2H, d, JZ4.0 Hz, Hfuran.), 7.36 (2H, d, JZ8.6 Hz, Harom.),
6.86 (2H, d, JZ8.6 Hz, Harom.), 4.74 (2H, s, N–CH2), 3.78
(3H, s, O–CH3); dC (200 MHz, CDCl3) 178.8 (2CHO),
167.9 (2C]O), 159.5 (C–O), 154.1 (2C), 148.6 (2C), 130.1
4.6.2. 3,4-Dibromo-2,5-dihydro-1-benzyl-1H-pyrrol-2,5-
dione (8c). Yellow solid (92%) mp 107–108 8C.10
4.6.3. 3,4-Dibromo-2,5-dihydro-1-(ethylphenyl)-1H-pyr-
rol-2,5-dione (8d). Yellow solid (75%), mp 165–166 8C;
nmax(KBr)/cmK1 3054, 2987, 1727, 1595, 1421, 1361, 1166,
1102, 896; dH (200 MHz, CDCl3) 7.31–7.18 (5H, m, Harom.),

M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
4591
3.85 (2H, t, JZ6.4 Hz, CH2), 2.92 (2H, t, JZ6.4 Hz, CH2);
dC (200 MHz, CDCl3) 163.7 (2C]O), 137.2 (C), 129.3
(2CBr), 128.7 (4CHarom.), 126.9 (CHarom.), 40.8 (CH2), 34.4
(CH2); m/z 359 (M), 268 79Br, 361 (M), 270 81Br, 104;
(Anal. Calcd for C12H9Br2NO2: C, 40.15; N, 3.90; H, 2.53.
Found: C, 40.12; N, 3.87; H, 2.50).
temperature during 90 min. The reaction was then hydro-
lysed slowly and extracted with ethyl acetate. The combined
organic layers were washed with a saturated sodium
hydrogenocarbonate solution and dried over anydrous
MgSO4. After solvent removal, the crude was purified by
column chromatography (eluent: light petroleum–ethyl
acetate: 8/2) to give 6f (4.08 g, 84%) as orange needles,
mp 222 8C; nmax(KBr)/cmK1 3055, 1762, 1698, 1610, 1514,
1441,1390, 1211, 1072, 915; dH (200 MHz, DMSO) 9.39
(1H, br s, OH), 7.07 (2H, d, JZ8.2 Hz, Harom.), 6.69 (2H, d,
JZ8.2 Hz, Harom.), 4.52 (2H, s, CH2); dC (200 MHz,
DMSO) 167.5 (2C]O), 157.2 (C–OH), 129.4 (2CHarom.),
126.9 (C), 119.5 (2CI), 115.6 (2CHarom.), 42.6 (CH2); m/z
455 (MC1); (Anal. Calcd for C11H7I2NO3: C, 29.04; N,
3.08; H, 1.55. Found: C, 28.99; N, 3.02; H, 1.51).
4.7. 3,4-Dibromo-2,5-dihydro-1-(4-methoxybenzyl)-1H-
pyrrol-2,5-dione (8e)
Yellow solid (90%), mp 120–121 8C.10
4.7.1. 3,4-Diiodo-2,5-dihydro-1-(substituted)-1H-pyrrol-
2,5-dione (6a–e). General procedure. A solution of
3,4-dibromo-2,5-dihydro-1-(substituted)-1H-pyrrol-2,5-
dione 8a–e (4.40 g, 17.26 mmol) and sodium iodide (7.86 g,
51.78 mmol) in acetic acid (65 mL) was heated at reflux
during 2 h, afterwards water (50 mL) was added. The
yellow precipate obtained was filtered off, washed with
water and dried to provide the title compounds 6a–f.
4.7.8. 2-(Diethoxymethyl)-4-bromofuran (9). 4,5-Dibro-
mofuran. Furaldehyde (20.00 g, 208.14 mmol) was added
dropwise to aluminium chloride (61.06 g, 457.91 mmol) at
0 8C under an inert atmosphere with mechanical stirring.
Bromine (21.32 mL, 416.28 mmol) was then added drop-
wise in a similar manner still at 0 8C. The temperature was
then allowed to rise to room temperature while stirring was
maintained for 16 h. Then the reaction was cautiously
hydrolysed with ice and water and extracted with ether. The
combined organic layers were dried over anhydrous MgSO4
and concentrated in vacuo. The crude residue was purified
by column chromatography on silica gel (eluent: light
petroleum–ethyl acetate: 98/2) to give 4,5-dibromofuran
(33 g, 63%) as a brown solid, mp 31–32 8C.11
4.7.2. 3,4-Diiodo-2,5-dihydro-1H-pyrrol-2,5-dione (6a).
Yellow solid (70%), mp 254–255 8C.18
4.7.3. 3,4-Diiodo-2,5-dihydro-1-phenyl-1H-pyrrol-2,5-
dione (6b). Yellow solid (84%), mp 184–186 8C.19
4.7.4. 3,4-Diiodo-2,5-dihydro-1-benzyl-1H-pyrrol-2,5-
dione (6c). Yellow solid (89%), mp 127–128 8C;
nmax(KBr)/cmK1 3057, 2955, 1777, 1715, 1550, 1433,
1388, 1331, 1056, 908; dH (200 MHz, CDCl3) 7.31–7.17
(5H, m, Harom.), 4.72 (2H, s, CH2); dC (200 MHz, CDCl3)
165.9 (2C]O), 135.3 (C), 128.6 (4CHarom.), 128.0
(CHarom.), 117.2 (2CI), 43.4 (CH2); m/z 439 (MC1);
(Anal. Calcd for C11H7I2NO2: C, 30.1; N, 3.19; H, 1.61.
Found: C, 30.06; N, 3.11; H, 1.73).
2-(Diethoxymethyl)-4,5-dibromofuran. Triethyl orthofor-
mate (18.21 mL, 109.4 mmol) was added to a solution of
4,5-dibromofuran (7.00 g, 27.35 mmol) and ammonium
chloride (350 mg) in ethanol (140 mL). The mixture was
refluxed during 16 h. After cooling the solution to room
temperature, the solvent was removed under reduced
pressure and the residue diluted in ethyl acetate. The
organic layer was washed with a saturated sodium
hydrogenocarbonate solution and dried over anhydrous
MgSO4. After solvent removal, the crude mixture was
chromatographied over silica gel (eluent: light petroleum–
ethyl acetate: 99/1) to afford the desired product (8.9 g,
98%) as a brown oil.11
4.7.5. 3,4-Diiodo-2,5-dihydro-1-(ethylphenyl)-1H-pyr-
rol-2,5-dione (6d). Yellow solid (87%), mp 163–164 8C;
nmax(KBr)/cmK1 3055, 2987, 1762, 1718, 1555, 1435, 1399,
1098, 1058, 896; dH (200 MHz, CDCl3) 7.28–7.10 (5H, m,
Harom.), 3.89–3.75 (2H, m, CH2), 2.96–2.85 (2H, m, CH2);
dC (200 MHz, CDCl3) 166.2 (2C]O), 137.3 (C), 128.8
(4CHarom.), 126.9 (CHarom.), 117.2 (2CI), 41.3 (CH2), 34.5
(CH2); m/z 454 (MC1); (Anal. Calcd for C12H9I2NO2: C,
31.82; N, 3.09; H, 2.00. Found: C, 31.93; N, 3.01; H, 2.11).
2-(Diethoxymethyl)-4-bromofuran. Under an inert atmo-
sphere, n-butyllithium (10.85 mL, 27.13 mmol, 2.5 M in
hexane) was added dropwise to a solution of 2-(diethoxy-
methyl)-4,5-dibromofuran (8.9 g, 27.13 mmol) in ether at
K78 8C. The mixture was then stirred for 1 h while
allowing the temperature to rise to room temperature, and
neutralised (pHZ5). The mixture was extracted and the
combined organic layers were washed and dried over
anhydrous MgSO4. After solvent removal, the crude residue
was chromatographied over silica gel (eluent: light
petroleum–ethyl acetate: 8/2) to afford 9 (4.9 g, 73%) as a
yellow oil.11
4.7.6. 3,4-Diiodo-2,5-dihydro-1-(4-methoxybenzyl)-1H-
pyrrol-2,5-dione (6e). Yellow solid (88%), mp 136–
137 8C; nmax(KBr)/cmK1 3054, 2986, 1781, 1722, 1612,
1575, 1515, 1390, 1178, 1033, 896; dH (200 MHz, CDCl3)
7.31 (2H, d, JZ8.5 Hz, Harom.), 6.84 (2H, d, JZ8.5 Hz,
Harom.), 4.7 (2H, s, CH2), 3.78 (3H, s, CH3); dC (200 MHz,
CDCl3) 166.1 (2C]O), 159.5 (C–OMe), 130.4 (2CHarom.),
127.7 (C), 117.4 (2CI), 114.1 (2CHarom.), 55.3 (CH3), 43.1
(CH2); m/z 469 (M), 342, 215, 121; (Anal. Calcd for
C12H9I2NO3: C, 30.73; N, 2.99; H, 1.93. Found: C, 30.69;
N, 2.93; H, 1.91).
4.7.9. 3,4-Bis[(5-diethoxymethyl)fur-3-yl]-2,5-dihydro-1-
benzyl-1H-pyrrol-2,5-dione (11). Under an inert atmo-
sphere, bis(pinacolato)diborane (324 mg, 1.28 mmol),
potassium acetate (380 mg, 3.84 mmol), [1,10-bis(diphenyl-
phosphinoferrocene]dichloropalladium (II) (30 mg,
4.7.7. 3,4-Diiodo-2,5-dihydro-1-(4-hydroxybenzyl)-1H-
pyrrol-2,5-dione (6f). A solution of 6e (5 g, 10.6 mmol)
and boron tribromide (3.5 mL, 37.3 mmol) in dichloro-
methane (150 mL) was stirred at K10 8C to room

4592
M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
0.038 mmol) were added to a stirred solution of 9 (320 mg,
1.28 mmol) in dry DMF (5 mL). The mixture was refluxed
under nitrogen with stirring for 2 h. After cooling the
solution to room temperature, 6c (280 mg, 0.64 mmol),
[1,10bis(diphenylphosphino)ferrocene] dichloropalladium
(II) (30 mg, 0.038 mmol) and 2 M Na2CO3 (1.2 mL,
1.60 mmol) were added, and the mixture was stirred at
80 8C, under nitrogen for another 2 h. The solution was
cooled to room temperature and was extracted with ethyl
acetate (15 mL). The combined organic layers were washed
with water (15 mL), brine and dried over anhydrous
MgSO4. Finally, purification by flash chromatography on
silica gel (eluent: light petroleum–ethyl acetate: 8/2) gave
57 mg (20%) of 3,4-bis[(5-diethoxymethyl)fur-3-yl]-2,5-
dihydro-1-benzyl-1H-pyrrol-2,5-one 11 as a yellow oil, nmax
(film)/cmK1 3054, 2986, 1708, 1682, 1434, 1398, 1114,
1057, 1020; dH (200 MHz, CDCl3) 8.11 (2H, s, Hfuran.),
7.44–7.25 (5H, m, Harom.), 6.72 (2H, s, Hfuran.), 5.55 (2H, s,
2CH(OEt)2), 4.76 (2H, s, N–CH2), 3.62 (8H, dq, JZ2.6,
7.0 Hz, 4CH2CH3), 1.24 (12H, t, JZ7.0 Hz, 4CH2CH3); dC
(200 MHz, CDCl3) 168.9 (2C]O), 152.8 (2C), 144.9
(2CHfuran.), 136.3 (2C), 128.7 (2CHarom.), 128.5 (2CHarom.),
127.8 (CHarom.), 126.8 (C), 114.8 (2C), 107.7 (2CHfuran.),
95.8 (2CH(OEt)2), 61.4 (4CH2), 41.9 (N–CH2), 15.1
(4CH3); m/z 524 (MC1), 541 (MC18), 546 (MC23);
(Anal. Calcd for C29H33NO8: C, 66.53; N, 2.68; H, 6.35.
Found: C, 66.49; N, 2.66; H, 6.29).
(Anal. Calcd for C20H21NO5: C, 67.59; N, 3.94; H, 5.96.
Found: C, 67.55; N, 3.88; H, 5.91).
4.7.12. 4-Bromo-3-[(5-diethoxymethyl)fur-2-yl]-2,5-
dihydro-1-benzyl-1H-pyrrol-2,5-dione (14). Under an
inert atmosphere, bromine (80 mL, 1.56 mmol) was added
dropwise to a solution of 13 (0.53 g, 1.49 mmol) in
dichloromethane (5 mL). After triethylamine (270 mL,
1.56 mmol) was added, the mixture was stirred for 1 h
while allowing the temperature to rise to room temperature.
It was then taken up in ethyl acetate and washed with water.
The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. The crude residue was
chromatographied on silica gel (eluent: light petroleum–
dichloromethane: 1/1) to give 14 (1.04 g, 70%) as a yellow
oil; nmax (film)/cmK1 3054, 2979, 1710, 1679, 1432, 1395,
1114, 1057, 1018, 893; dH (200 MHz, CDCl3) 7.48 (1H, d,
JZ3.5 Hz, Hfuran.), 7.51–7.22 (5H, m, Harom.), 6.62 (1H,
d, JZ3.5 Hz, Hfuran.), 5.58 (1H, s, CH(OEt)2), 4.72 (2H, s,
N–CH2), 3.65 (4H, q, JZ7.1 Hz, 2 O–CH2CH3), 1.24 (6H, t,
JZ7.1 Hz, 2 O–CH2CH3); dC (200 MHz, CDCl3) 167.0
(C]O), 165.7 (C]O), 156.8 (C), 143.9 (C), 135.8 (C),
129.5 (C), 128.7 (2CHarom.), 128.6 (2CHarom.), 128.0
(CHarom.), 119.4 (CHfuran.), 114.2 (C), 111.3 (CHfuran.),
96.0 (2CH(OEt)2), 61.7 (2CH2), 42.4 (N–CH2), 15.2
(2CH3); m/z 434 (MC1), 456 (MC23), 79Br. 436 (MC1),
458 (MC23) 81Br; (Anal. Calcd for C20H20BrNO5: C,
55.31; N, 3.23; H, 4.64. Found: C, 55.42; N, 3.19; H, 4.72).
4.7.10. 3-Bromo-2,5-dihydro-1-benzyl-1H-pyrrol-2,5-
dione (12). A solution of maleic anhydride (16 g,
163 mmol) and benzylamine (17.82 mL, 163 mmol) in
acetic acid (150 mL) was heated at reflux during 2 h.
After the solution was cooled to 0 8C, bromine (24.6 mL,
489 mmol) and potassium acetate (16 g, 163 mmol) were
added and the mixture was refluxed under stirring for 3 h.
Then water (200 mL) was added. The precipate obtained
was filtered off, washed with water, dried and purified by
column chromatography to give dibromo compound 8c
(28.48 g, 51%) and 12 (18.22 g, 42%) as a yellow solid, mp
51–52 8C; nmax(KBr)/cmK1 3055, 2986, 1727, 1430, 1383,
1150, 1075, 892; dH (200 MHz, CDCl3) 7.34–7.24 (5H, m,
Harom.), 6.82 (1H, s, CH–C]O), 4.67 (2H, s, N–CH2); dC
(200 MHz, CDCl3) 168.2 (C]O), 165.0 (C]O), 135.7 (C),
131.9 (CH), 131.3 (CBr), 128.8 (2CHarom.), 128.6
(2CHarom.), 128.1 (CHarom.), 42.3 (N–CH2); m/z 266 (MC
1) 79Br, 268 (MC1) 81Br; (Anal. Calcd for C11H8BrNO2: C,
49.65; N, 5.26; H, 3.03. Found: C, 49.71; N, 5.21; H, 3.09).
4.7.13. 4-Bromo-3-[(5-carboxyl)fur-2-yl]-2,5-dihydro-1-
benzyl-1H-pyrrol-2,5-dione (15). 4-Bromo-3-[(5-formyl)-
fur-2-yl]-2,5-dihydro-1-benzyl-1H-pyrrol-2,5-dione. Accord-
ing to the general procedure in Section 4.3, the desired
formylfuryl intermediate was obtained as a yellow solid
(79%), mp 145–146 8C; nmax (KBr)/cmK1 3054, 2986,
1706, 1679, 1664, 1396, 1400, 1115, 981; dH (200 MHz,
CDCl3) 9.78 (1H, s, CHO), 7.61 (2H, d, JZ3.8 Hz, Hfuran.),
7.38–7.30 (6H, m, Harom.), 4.75 (2H, s, N–CH2); dC
(200 MHz, CDCl3) 178.2 (CHO), 166.4 (C]O), 164.8
(C]O), 153.8 (C), 147.8 (C), 135.4 (C), 128.9 (C), 128.8
(2CHarom.), 128.7 (2CHarom.), 128.2 (CHarom.), 120.7
(CHfuran.), 119.1 (C), 119.0 (CHfuran.), 42.7 (N–CH2); m/z
377 (MC18), 382 (MC23), 392 (MC33) 79Br. 378 (MC
18), 384 (MC23), 394 (MC33) 81Br; (Anal. Calcd for
C16H10BrNO4: C, 53.36; N, 3.89; H, 2.80. Found: C, 53.19;
N, 3.75; H, 2.69).
4.7.14. 4-Bromo-3-[(5-carboxyl)fur-2-yl]-2,5-dihydro-1-
benzyl-1H-pyrrol-2,5-dione. A solution of NaClO2
(60 mg, 0.66 mmol) in water (1 mL) was added dropwise
to a stirred mixture of 4-bromo-3-[(5-formyl)fur-2-yl]-2,5-
dihydro-1-benzyl-1H-pyrrol-2,5-dione (200 mg, 0.55 mmol)
in acetonitrile (1 mL), NaH2PO4 (32 mg) in water (0.5 mL)
and of 30% H2O2 (95 mL, 0.83 mmol), keeping the
temperature at 15 8C with water cooling. Oxygen evolved
from the solution until the end of the reaction (1 h) with a
bubbler connected to the apparatus. A small amount of
Na2SO3 (w10 mg) was added to destroy the unreacted
HOCl and H2O2. After acidification with HCl 6 N, the
mixture was extracted with tetrahydrofuran/dichloro-
methane 1:3. The combined organic layers were washed
with little water, dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue mixture was purified
4.7.11. 3-[(5-diethoxymethyl)fur-2-yl]-2,5-dihydro-1-
benzyl-1H-pyrrol-2,5-dione (13). According to the general
procedure in Section 4.2, the title compound was obtained
as a red oil (55%); nmax (film)/cmK1 3054, 2979, 1708,
1684, 1430, 1401, 1110, 1057, 1020; dH (200 MHz, CDCl3)
7.31–7.17 (6H, m, 1 Hfuran., 5 Harom.), 6.55 (2H, d, JZ
3.4 Hz, Hfuran.), 6.51 (1H, s, CH–C]O), 5.53 (1H, s,
CH(OEt)2), 4.63 (2H, s, N–CH2), 3.59 (4H, q, JZ6.9 Hz, 2
O–CH2CH3), 1.20 (6H, t, JZ6.9 Hz, 2 O–CH2CH3); dC
(200 MHz, CDCl3) 170.3 (C]O), 168.6 (C]O), 156.2 (C),
144.6 (C), 136.3 (C), 133.6 (CH), 128.6 (2CHarom.), 128.3
(2CHarom.), 127.7 (CHarom.), 117.9 (CHfuran.,, C), 111.4
(CHfuran.), 95.9 (2CH(OEt)2), 61.5 (2CH2), 41.4 (N–CH2),
15.1 (2CH3); m/z 310 (M), 373 (MC18), 378 (MC23);

M. Dubernet et al. / Tetrahedron 61 (2005) 4585–4593
4593
3. For reviews of role of PTPases in insulin signaling pathway
by fash column chromatography (eluent: dichloromethane/
acetic acid 99:1) to give 15 (141 mg, 72%) as a yellow solid,
mp 170–171 8C; nmax (KBr)/cmK1 3447, 3055, 2987, 1710,
1683, 1445, 1112, 1030, 896; dH (200 MHz, DMSO) 7.41
(7H, m, Hfuran., Harom.), 4.62 (2H, s, CH2); dC (200 MHz,
DMSO) 164.3 (C]O), 163.2 (C]O), 158.6 (COOH), 145.1
(C), 143.9 (C), 134.6 (C), 128.7 (2CHarom.), 128.5
(2CHarom.), 128.1 (CHarom.), 126.9 (C), 119.3 (CHfuran.),
118.1 (C), 117.3 (CHfuran.), 42.5 (N–CH2); m/z 358 (MC1),
380 (MC23); (Anal. Calcd for C16H10BrNO5: C, 51.09; N,
3.72; H, 2.68. Found: C, 51.01; N, 3.64; H, 2.54).
´
see: (a) Cheng, A.; Dube, N.; Gu, F.; Tremblay, M. L. Eur.
J. Biochem. 2002, 269, 1050. (b) Liu, G.; Trevillyan, J. M.
Curr. Opin. Invest. Drugs 2002, 3, 1608.
4. (a) Shen, K.; Keng, Y.-F.; Wu, L.; Guo, X. L.; Lawrence,
D. S.; Zhang, Z.-Y. J. Biol. Chem. 2001, 276, 47311. (b) Guo,
X. L.; Shen, K.; Wang, F.; Lawrence, D. S.; Zhang, Z.-Y.
J. Biol. Chem. 2002, 277, 41014. (c) Liu, G.; Xin, Z.; Liang,
H.; Abad-Zapatero, C.; Hajduk, P. J.; Janowick, D. A.;
Szczepankiewicz, B. G.; Pei, Z.; Hutchins, C. W.; Ballaron,
S. J.; Stashko, M. A.; Lubben, T.; Berg, C. E.; Rondinone,
C. M.; Trevillyan, J. M.; Jirousek, M. R. J. Med. Chem. 2003,
46, 3437. (d) Liu, G.; Xin, Z.; Pei, Z.; Hadjuk, P. J.; Abad-
Zapatero, C.; Hutchins, C. W.; Zhao, H.; Lubben, T. H.;
Ballaron, S. J.; Haasch, D. L.; Kaszubska, W.; Rondine, C. M.;
Trevillyan, J. M.; Jirousek, M. R. J. Med. Chem. 2003, 46,
4232. For review of PTP1B inhibitors also see: (e) Liu, G.
Curr. Med. Chem. 2003, 10, 1407.
4.7.15. 4-[(5-formyl)fur-2-yl]-3-[(5-carboxyl)fur-2-yl]-
2,5-dihydro-1-benzyl-1H-pyrrol-2,5-dione (16). Com-
pound 16 was prepared according to the general procedure
in Section 4.2, until the final crude residue was obtained.
Then, this latter was purified by flash column chromato-
graphy (eluent: dichloromethane/acetic acid 99:1) to give 16
as a red solid (17%), mp 175 8C; nmax (KBr)/cmK1 3446,
3054, 2986, 1706, 1687, 1401, 1116, 1057, 891; dH
(200 MHz, DMSO) 9.79 (1H, s, CHO), 7.65–7.25 (9H, m,
Harom., Hfuran.), 4.71 (2H, s, N–CH2); dC (200 MHz, DMSO)
180.2 (CHO), 168.3 (2C]O), 159.3 (COOH), 153.9 (C),
148.6 (C), 147.9 (C), 147.1 (C), 136.6 (C), 129.1 (CHarom.),
129.0 (2CHarom.), 127.9 (2CHarom.), 121.2 (CHfuran.), 120.5
(CHfuran.), 120.2 (2C), 120.0 (CHfuran.), 119.7 (CHfuran.),
41.8 (N–CH2); m/z 392 (MC1), 406 (MK17CMeOH), 414
(MC23); (Anal. Calcd for C21H13NO7: C, 64.45; N, 3.58;
H, 3.35. Found: C, 64.42; N, 3.51; H, 3.28).
5. Mjalli, A.; Sarshar, S.; Cao, X.; Bakir, F. 1998,
US005753687A.
6. Wamhoff, H.; Hupe, H. J. Tetrahedron Lett. 1978, 2, 125.
7. (a) Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.;
Morishima, H. Tetrahedron 1996, 52(24), 8099.
´
´
´
(b) Marminon, C.; Pierre, A.; Pfeiffer, B.; Perez, V.; Leonce,
S.; Joubert, A.; Bailly, C.; Renard, P.; Hickman, J.;
Prudhomme, M. J. Med. Chem. 2003, 46, 609. (c) Routier,
´
S.; Coudert, G.; Merour, J.-Y. Tetrahedron Lett. 2001, 42,
7025.
8. (a) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org.
Chem. 1998, 63, 6053. (b) Bergman, J.; Koch, E.; Peleman, B.
J. Chem. Soc., Perkin Trans. 1 2000, 2609.
Acknowledgements
9. McClure, M. S.; Roschangar, F.; Hodson, S. J.; Millar, A.;
Osterhout, M. H. Synthesis 2001, 11, 1681.
We wish to thank A.D.I.R society for its financial support
´
and SAVIT, Universite de Tours, for technical assistance.
10. Choi, D.-S.; Huang, S.; Barnard, T. S.; Adams, R. D.;
Seminario, J. M.; Tour, J. M. J. Org. Chem. 1998, 63(8), 2646.
´
11. Chiarello, J.; Joullie, M. Tetrahedron 1988, 44, 41.
12. Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. Tetrahedron
1990, 46, 1199.
References and notes
13. (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
60, 7508. (b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett.
1997, 38, 3841. (c) Guillard, J.; Larraya, C.; Viaud-Massuard,
M.-C. Heterocycles 2003, 60, 865.
1. Zhang, Z.-Y. Curr. Opin. Chem. Biol. 2001, 5, 416.
2. (a) Elchebly, M.; Payette, P.; Michaliszyn, E.; CromLish, W.;
Collins, S.; Loy, A. L.; Normandin, D.; Cheng, A.; Himms-
Hagen, J.; Chan, C.-C.; Ramachandran, C.; Gresser, M. J.;
Tremblay, M. L.; Kennedy, B. P. Science 1999, 283, 1544.
(b) Klaman, L. D.; Boss, O.; Peroni, O. D.; Kim, J. K.;
Martino, J. L.; Zabotny, J. M.; Moghal, N.; Lubkin, M.; Kim,
Y.-B.; Sharpe, A. H.; Stricker-Krongrad, A.; Shulman, G. I.;
Neel, B. G.; Kahn, B. B. Mol. Cell. Biol. 2000, 20, 5479.
14. Dunn, G. L.; DiPasquo, V. J.; Hoover, J. R. E. J. Org. Chem.
1968, 33(4), 1454.
15. Dalcanale, E. J. Org. Chem. 1986, 51(4), 567.
16. Barbot, F.; Miginiac, P. J. Orgamet. Chem. 1979, 170, 1–8.
17. Schmidt, K. G. E. Chem. Ber. 1974, 107, 2440.
18. Terentjew; Tschelinzew Chem. Ber. 1925, 58, 67.
19. Clarke, L.; Bolton, E. K. J. Am. Chem Soc. 1914, 36, 1906.