A convenient synthesis of 3,4-diaryl(hetaryl)-substituted maleimides and maleic anhydrides

Article abstract of DOI:10.1134/S1070428006100162

A convenient procedure has been developed for the synthesis of 3,4-diaryl(or hetaryl)maleimides by cross coupling of N-substituted 3,4-dibromomaleimides with aryl(hetaryl)boronic acids in the presence of Pd(Ph₃P)₄ and CsF. The reacti

Full text of DOI:10.1134/S1070428006100162

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 10, pp. 1490–1497. © Pleiades Publishing, Inc., 2006.
Original Russian Text © S.V. Shorunov, M.M. Krayushkin, F.M. Stoyanovich, M. Irie, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42,
No. 10, pp. 1504–1511.
A Convenient Synthesis of 3,4-Diaryl(hetaryl)-Substituted
Maleimides and Maleic Anhydrides
S. V. Shorunova, M. M. Krayushkina, F. M. Stoyanovicha, and M. Irieb
a Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 117913 Russia
e-mail: mkray@ioc.ac.ru
b Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University,
Hakozaki 6-10-1, Higashi-ku, 812-8581 Fukuoka, Japan
e-mail: irie@cstf.kyushu-u.ac.jp
Received December 10, 2005
Abstract—A convenient procedure has been developed for the synthesis of 3,4-diaryl(or hetaryl)maleimides by
cross coupling of N-substituted 3,4-dibromomaleimides with aryl(hetaryl)boronic acids in the presence of
Pd(Ph3P)4 and CsF. The reaction ensures high yields of the products and requires relatively small amount of the
catalyst; it can be performed on an enlarged scale. The resulting maleimides are readily converted into the
corresponding maleic anhydrides.
DOI: 10.1134/S1070428006100162
sible derivatives of 3,4-dibromomaleimide and aryl-
and hetarylboronic acids.
Maleimide and maleic anhydride derivatives having
aromatic or heterocyclic substituents in positions 3 and
4 are used as photochromic compounds [1–3] posses-
sing unique properties; in particular, their photo-
induced transformations are characterized by thermal
irreversibility and high cycling number. Such photo-
chromes are exceptionally promising as materials for
optical data recording and storage [4, 5]. In addition,
maleimides containing indole rings and related com-
pounds exhibit a very broad spectrum of biological
activity [6–10].
2-Methyl-1-benzothiophen-3-yl- and 2,5-dimethyl-
thiophen-3-ylboronic acids Ia and Ib were synthesized
from 3-bromo-2-methyl-1-benzothiophene [14] and
3-iodo-2,5-dimethylthiophene [15], respectively, as
shown in Scheme 1. 3-Chlorophenyl-, 4-methoxy-
phenyl-, and 3-methoxyphenylboronic acids Ic–Ie are
commercially available. 3,4-Dibromo-N-butylmale-
imide (IIa) was obtained by bromination of N-butyl-
maleimide in glacial acetic acid in the presence of
sodium acetate. The synthesis of N-benzyl-3,4-di-
bromomaleimide (IIb) was described in [16].
Cross coupling of aryl or vinyl halides with organo-
boron compounds, catalyzed by transition metal salts
(mostly by palladium compounds; Suzuki–Miyaura
reaction) is a general method for building up new
carbon–carbon bonds, which has found wide applica-
tion in organic synthesis [11–13]. We believed that
an obvious and convenient synthetic approach to diaryl
(hetaryl)maleimides could be cross coupling of N-al-
kyl-3,4-dibromomaleimides with various aryl- and
hetarylboronic acids. However, we have found no pub-
lished data on reactions of N-alkyl-3,4-dibromomale-
imides with boronic acids, leading to symmetrically
substituted products.
Scheme 1.
(1) BuLi
(2) B(OBu)3
(3) HCl/H2O
R'
Hlg
R'
B(OH)2
Me
R
Me
R
S
S
Ia, Ib
Hlg = Br, RR' = benzo (a, yield 80%); Hlg = I, R = Me,
R' = H, (b, 76%).
We have found that 2-methyl-1-benzothiophen-3-
ylboronic acid (Ia) readily reacts with 3,4-dibromo-N-
butylmaleimide (IIa) in dioxane in the presence of
Pd(Ph3P)4 and CsF to give maleimide IIIa (see table,
The present article reports the results of our studies
aimed at developing a convenient procedure for the
synthesis of 3,4-diaryl(hetaryl)maleimides from acces-
1490

A CONVENIENT SYNTHESIS OF 3,4-DIARYL(HETARYL)-SUBSTITUTED MALEIMIDES
1491
Cross coupling of 2-methyl-1-benzothiophen-3-ylboronic
Scheme 2.
acid (Ia) with N-butyl-3,4-dibromomaleimide (IIa)
Br
Br
B(OH)2
Run no.
Reaction time, h Yield of IIIa, %
Base
CsF
+
O
O
Me
N
1
2
3
4
5
6
04
30
30
30
30
30
76
30
22
13
06
05
S
Bu
K3PO4
Ia
IIa
Na2CO3
K2CO3
Bu
N
NaHCO3
Cs2CO3
O
O
Pd(Ph3P)4, CsF
dioxane, ∆
treatment nor recrystallization was necessary to isolate
compounds IIIa and IIIc with a sufficient purity.
S
S
Me Me
IIIa
The developed procedure turned out to be efficient
for the synthesis of unsymmetrically substituted male-
imides as well. By reactions of quite accessible
N-butyl- and N-benzyl-3-bromo-4-[(1-tert-butoxycar-
bonyl)-2-methylindol-3-yl]maleimides IVa and IVb
with 2-methyl-1-benzothiophen-3-yl, 2,5-dimethylthio-
phen-3-yl-, 3-chlorophenyl-, and 4-methoxyphenyl-
boronic acids (reaction time 1–5 h) we obtained the
corresponding disubstituted products Va–Vd in 71–
90% yield (Scheme 3).
Scheme 2). The maximal yield of compound IIIa was
obtained with the use of 2.2 mol of boronic acid Ia,
4 mol % of Pd(Ph3P)4, and 5 mol of CsF per mole of
dibromide IIa, the amount of the solvent (dioxane)
being 100 ml per gram of Ia. The nature of the base is
important: in the presence of CsF (see table, run no. 1),
the yield of imide IIIa was 76% in 4 h, while in the
presence of other bases, the yield was considerably
lower even after prolonged heating at the boiling point;
moreover, in the latter case, the main reaction direction
was the transformation of acid Ia into 2-methyl-1-
benzothiophene.
Scheme 3.
R
O
N
The proposed modified procedure is general, and it
was successfully extended to other heterocyclic and
aromatic boronic acids. Under the above conditions,
we obtained symmetrically substituted maleimides
IIIb–IIId in 86–98% yield. Neither chromatographic
O
(1) LiN(SiMe3)2
(2) IIa or IIb
(3) Boc2O, DMAP
Br
Me
Me
N
N
H
Boc
Bu
N
Bu
N
IVa, IVb
O
O
O
O
R
N
O
N
O
Me
Me
ArB(OH)2, CsF (4 equiv)
Pd(PPh3)4 (4 mol %)
dioxane, ∆
Ar
Me
S
S
Me Me
Cl
Cl
IIIb
IIIc
Boc
Va–Vd
Bu
N
O
O
IV, R = Bu (a), PhCH2 (b); V, R = Bu, Ar = 4-ClC6H4 (a),
4-MeOC6H4 (b), 2-methyl-1-benzothiophen-3-yl (c), 2,5-di-
methylthophen-3-yl (d).
There are only two published examples of cross
coupling of N-alkyl-3-bromo-4-(indolyl)maleimides
with boronic acids. Routier et al. [17] described the
MeO
OMe
IIId
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

SHORUNOV et al.
1492
O
O
cross coupling of 3-methoxynaphthalen-2-ylboronic
acid with 3-bromo-N-methyl-4-(1-phenylsulfonyl-1H-
indol-3-yl)maleimide in the presence of 10% of
Pd(OAc)2 as catalyst using 1.5 equiv of the boronic
acid (yield 80%). Here, protection of the indole nitro-
gen atom with tert-butoxycarbonyl group was ineffec-
tive, so that the authors used phenylsulfonyl protec-
tion. Wang et al. [18] reported on the synthesis of
a benzothienyl analog of anticarcinogenic drug rebec-
camycin, which included cross coupling of 5,6-di-
fluoro-1-benzothiophen-3-ylboronic acid with 3-bro-
mo-N-(4-tert-butylbenzyl)-4-(5,6-difluoro-1H-indol-3-
yl)maleimide; the yield in this step was 82%, but the
amount of Pd(Ph3P)2Cl2 (catalyst) was 20%.
O
O
O
O
Me
Me
S
S
S
S
Me Me
Me Me
VIIa
VIIb
O
O
O
O
O
O
Me
N
S
N
S
H
H
Me Me
Me Me
VIIc
VIId
imides with boronic acids, leading to symmetric
3,4-diaryl(hetaryl)maleimides. Also, the procedure
makes it possible to synthesize in high yield unsym-
metrically substituted maleimides having an indole
fragment. The reaction requires relatively small
amount of catalyst (4%), and the resulting maleimides
can be converted into the corresponding maleic an-
hydrides.
Removal of the protecting group from the indole
nitrogen atom in compounds Vc and Vd was not dif-
ficult. By heating maleimides Vc and Vd with butyl-
amine and benzylamine, respectively, we obtained in
high yields compounds VIa and VIb having no sub-
stituent on the indole nitrogen atom (Scheme 4).
Scheme 4.
EXPERIMENTAL
R
R
O
O
N
N
1
The H NMR spectra were recorded on a Bruker
O
O
WM-250 (250 MHz) and Bruker AM-300 (300 MHz)
spectrometers using DMSO-d6 and CDCl3 as solvents.
The mass spectra (electron impact, 70 eV) were ob-
tained on a Finnigan MAT instrument. The melting
points were determined on a Boetius melting point ap-
paratus coupled with a microscope; uncorrected values
are given. The progress of reactions and the purity of
products were monitored by TLC on Merck 60 F254
plates. Tetrahydrofuran, 1,4-dioxane, and diethyl ether
were distilled over sodium diphenylketyl prior to use.
Hexane and ethyl acetate were distilled over calcium
hydride. Silica gel Merck 60 (0.040–0.063 mm) was
used for flash chromatography. All reactions were
carried out in preliminarily calcined glassware. 1,4-Di-
oxane was subjected to triple evacuation–pressuriza-
tion under argon just before use in cross-coupling
reactions.
RNH2
Ht
Ht
Me
Me
N
N
H
Boc
Vc, Vd
VIa, VIb
Vc, VIa, R = Bu, Ht = 2-methyl-1-benzothiophen-3-yl;
Vd, VIb, R = PhCH2, Ht = 2,5-dimethylthiophen-3-yl.
Accessibility of maleimide derivatives prompted
us to use them as starting compounds in the synthesis
of the corresponding disubstituted maleic anhydrides.
Like photochromes based on maleimides, analogous
maleic anhydride derivatives are promising as optical
memory elements [4, 5]. Compounds IIIa, IIIb, VIa,
and VIb were converted into the corresponding maleic
anhydrides by heating in aqueous 1,4-dioxane contain-
ing potassium hydroxide and subsequent acidification.
As a result, maleic anhydrides VIIa–VIId were obtain-
ed in 64–94% yield.
2-Methyl-1-benzothiophen-3-ylboronic acid (Ia).
A solution of 8.6 g (38 mmol) of 3-bromo-2-methyl-
benzothiophene [14] in 100 ml of THF was cooled to
–78°C, and 27 ml of a 1.6 M solution of butyllithium
in hexane was added under argon. The mixture was
stirred for 15 min at that temperature, 15.3 ml (13.07 g,
56 mmol) of tributyl borate was added in one portion,
the mixture was stirred for 1 h at –78°C, the cooling
bath was removed, and the mixture was left overnight.
The structure of the newly synthesized compounds
was confirmed by the H NMR and mass spectra and
1
elemental analyses.
The developed procedure is the first example of
cross coupling of N-substituted 3,4-dibromomale-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

A CONVENIENT SYNTHESIS OF 3,4-DIARYL(HETARYL)-SUBSTITUTED MALEIMIDES
1493
Methanol, 5 ml, was added, the mixture was evap-
orated on a rotary evaporator at a bath temperature not
exceeding 50°C, 100 ml of diethyl ether was added
to the residue, the mixture was cooled with ice, and
a mixture of 5 ml of concentrated hydrochloric acid
and 35 ml of water was added. The mixture was stirred
for 1 h, the organic phase was separated, and the aque-
ous phase was extracted with diethyl ether (3×20 ml).
The extracts were combined with the organic phase
and washed with water and a 5% solution of sodium
hydroxide (4×20 ml). The alkaline solution was
washed with diethyl ether (2× 20 ml), cooled to –5°C,
and acidified with 10 ml of concentrated hydrochloric
acid under stirring. The precipitate was filtered off,
washed with a small amount of water, and dried in
a desiccator. Yield 5.29 g (80%). Compound Ia had no
the filtrate was cooled in a refrigerator. The precipitate
was filtered off and additionally recrystallized from
1
methanol. Yield 7.5 g (29%), mp 75–77°C. H NMR
spectrum (250 MHz, CDCl3), δ, ppm: 0.92 t (3H,
CH3CH2, J = 7.5 Hz), 1.23–1.40 m (2H, CH3CH2),
1.52–1.66 m (2H, CH3CH2CH2), 3.61 t (2H, CH2N,
J = 7.4 Hz). Mass spectrum, m/z (Irel, %): 312 (100)
[M + 1]+, 311 (63) [M]+, 269 (95), 254 (24), 189 (11),
133 (71), 56 (32). Found, %: C 30.79; H 2.81; N 4.43.
C8H9Br2NO2. Calculated, %: C 30.90; H 2.92; N 4.50.
M 310.97.
Cross coupling of aryl(hetaryl)boronic acids
with 3,4-dibromo-N-butylmaleimide (general proce-
dure). A mixture of 3,4-dibromo-N-butylmaleimide
(IIa), the corresponding boronic acid [2.2 equiv, cal-
culated on ArB(OH)2], 4 mol % of Pd(Ph3P)4, and CsF
(5 equiv with respect to IIa) in 1,4-dioxane (100 ml
per gram of the boronic acid) was heated at the boiling
point under argon with vigorous stirring using a mag-
netic stirrer. The mixture was then poured into water
and extracted with chloroform, the organic phase was
washed with water, dried over Na2SO4, and evaporated
on a rotary evaporator, and the residue was purified by
flash chromatography on silica gel.
1
distinct melting point; according to the H NMR and
mass spectra, it was a trimeric cyclic anhydride, tris(2-
methyl-1-benzothiophen-3-yl)boroxine. 1H NMR spec-
trum (300 MHz, CDCl3), δ, ppm: 3.05 s (3H, CH3),
7.23–7.43 m (3H, Harom), 8.55 d (1H, Harom, J =
7.8 Hz). Mass spectrum, m/z (Irel, %): 523 (7) [M + 1]+,
522 (85) [M]+, 173 (39), 148 (82), 147 (100). Found,
%: C 62.42; H 4.43; S 18.50. C27H21B3O3S3. Calculat-
ed, %: C 62.12; H 4.05; S 18.42. M 522.07.
N-Butyl-3,4-bis(2-methyl-1-benzothiophen-3-yl)-
maleimide (IIIa) was synthesized from 2.2 g
(11.4 mmol) of boronic acid Ia, 1.62 g (5.2 mmol) of
3,4-dibromo-N-butylmaleimide (IIa), 3.95 g (26 mmol)
of CsF, and 0.24 g of Pd(Ph3P)4 in 220 ml of dioxane;
reaction time 4 h. The residue obtained after evapora-
tion of the chloroform extract was ground with diethyl
ether, and the orange crystals were filtered off, washed
with cold diethyl ether, and dried in a desiccator. Yield
2,5-Dimethylthiophen-3-ylboronic acid (Ib) was
synthesized in a similar way from 3-iodo-2,5-dimeth-
ylthiophene [15]. Yield 76%, mp 180–183°C. Accord-
1
ing to the H NMR and mass spectra, the product was
1
a trimeric cyclic anhydride. H NMR spectrum
(250 MHz, CDCl3), δ, ppm: 2.45 s (3H, CH3), 2.82 s
(3H, CH3), 7.09 s (1H, Harom). Mass spectrum, m/z
(Irel, %): 414 (65) [M + 1]+, 413 (48) [M]+, 137 (100),
111 (95). Found, %: C 52.32; H 5.23; S 23.50.
C18H21B3O3S3. Calculated, %: C 52.22; H 5.11;
S 23.24. M 413.97.
1
1.77 g (76%), mp 172–173°C. H NMR spectrum
(300 MHz, CDCl3), δ, ppm: 1.02 t (3H, CH3CH2, J =
8.5 Hz), 1.40–1.56 m (2H, CH3CH2), 1.70–1.83 m
(2H, CH3CH2CH2), 2.08 s (3H, CH3), 2.28 s (3H,
3,4-Dibromo-N-butylmaleimide (IIa). N-Butyl-
maleimide, 12.73 g (83 mmol), was dissolved in
100 ml of glacial acetic acid, 14 g (0.16 mol) of
sodium acetate was added, the mixture was cooled to
0°C, and a solution of 39.8 g (0.25 mol) of bromine in
20 ml of glacial acetic acid was added dropwise. The
mixture was heated for 3 h under reflux, poured into
500 ml of water, and extracted with ethyl acetate (3×
100 ml). The organic phase was washed with a 10%
solution of Na2SO3 (2 × 50 ml), water (3 × 50 ml), and
a saturated solution of sodium chloride, dried over
MgSO4, and evaporated on a rotary evaporator. The
residue was treated with 50 ml of methanol, the mix-
ture was heated to the boiling point and filtered, and
CH3), 3.74 t (2H, CH2N, J = 8.2 Hz), 7.06 t (1H, Harom
,
J = 9.1 Hz), 7.15–7.35 m (4H, Harom), 7.45 d (1H,
Harom, J = 7.4 Hz), 7.64–7.72 m (2H, Harom). Mass
spectrum, m/z (Irel, %): 446 (11) [M + 1]+, 445 (100)
[M]+, 384 (48.5), 318 (15), 56 (30), 43 (28). Found, %:
C 70.30; H 5.27; N 3.35. C26H23NO2S2. Calculated, %:
C 70.08; H 5.20; N 3.14. M 445.59.
N-Butyl-3,4-bis(2,5-dimethylthiophen-3-yl)male-
imide (IIIb) was synthesized from 2.5 g (16 mmol) of
boronic acid Ib, 2.26 g (7.3 mmol) of maleimide IIa,
5.51 g (36 mmol) of CsF, and 0.33 g of Pd(Ph3P)4 in
250 ml of dioxane; reaction time 4 h. The product was
isolated by flash chromatography on silica gel using
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

SHORUNOV et al.
1494
hexane–diethyl ether (12:1) as eluent. Yield 2.33 g
(86%), mp 117–120°C; published data [3]: mp 116–
118°C. 1H NMR spectrum (250 MHz, CDCl3), δ, ppm:
0.95 t (3H, CH3CH2, J = 7.4 Hz), 1.30–1.47 m (2H,
CH3CH2), 1.57–1.70 m (2H, CH3CH2CH2), 1.88 s (6H,
CH3), 2.42 s (6H, CH3), 3.64 t (2H, CH2N, J = 7.4 Hz),
6.71 s (2H, Harom). Mass spectrum, m/z (Irel, %): 375
(14) [M + 2]+, 374 (1) [M + 1]+, 373 (100) [M]+, 358
(86), 312 (28), 259 (38), 246 (41), 231 (86), 69 (36).
Found, %: C 64.40; H 6.47; N 3.59. C20H23NO2S2.
Calculated, %: C 64.31; H 6.21; N 3.75. M 375.53.
tion of LiN(SiMe3)2 in THF was added dropwise under
argon. The mixture was stirred for 15 min at that tem-
perature, and a solution of 2.4 g (7.7 mmol) of male-
imide IIa in 24 ml of THF was added. The mixture
was allowed to warm up to room temperature, poured
into 90 ml of 0.2 N hydrochloric acid, and extracted
with ethyl acetate (3×30 ml). The organic phase was
washed with 30 ml of a 5% solution of NaHCO3, water
(3×20 ml), and a saturated solution of sodium chloride
and dried over MgSO4. The solvent was removed to
leave 2.55 g (92%) of 4-bromo-N-butyl-3-(2-methyl-
indol-3-yl)maleimide as a chromatographically pure
(TLC, hexane–ethylacetate, 4:1) dark red oily sub-
stance. 1H NMR spectrum (300 MHz, CDCl3), δ, ppm:
0.96 t (3H, CH3CH2, J = 7.6 Hz), 1.32–1.48 m (2H,
CH3CH2), 1.62–1.77 m (2H, CH3CH2CH2), 2.49 s (3H,
CH3), 3.67 t (2H, CH2N, J = 7.5 Hz), 7.15–7.25 m (2H,
N-Butyl-3,4-bis(3-chlorophenyl)maleimide (IIIc)
was synthesized from 0.55 g (3.5 mmol) of boronic
acid Ic, 0.5 g (1.6 mmol) of maleimide IIa), 1.22 g
(8.0 mmol) of CsF, and 0.075 g of Pd(Ph3P)4 in 40 ml
of dioxane; reaction time 30 min. The residue obtained
after evaporation of the chloroform extract was ground
with diethyl ether, and the lemon yellow crystals were
filtered off, washed with cold ether, and dried in a de-
H
H
arom), 7.31 t (1H, Harom, J = 10.0 Hz), 7.49 d (1H,
arom, J = 7.7 Hz), 8.44 br.s (1H, NH). Mass spectrum,
1
m/z (Irel, %): 363 (13) [M + 2]+, 362 (64) [M + 1]+, 361
(24) [M]+, 262 (87), 182 (100), 154 (28), 108 (39),
57 (61). Found, %: C 56.42; H 4.53; N 7.59.
C17H17BrN2O2. Calculated, %: C 56.52; H 4.74; N 7.75.
M 361.24.
siccator. Yield 0.58 g (96%), mp 92–95°C. H NMR
spectrum (300 MHz, CDCl3), δ, ppm: 0.96 t (3H,
CH3CH2, J = 8.5 Hz), 1.34–1.48 m (2H, CH3CH2),
1.62–1.73 m (2H, CH3CH2CH2), 3.66 t (2H, CH2N, J =
8.3 Hz), 7.29–7.35 m (4H, Harom), 7.35–7.42 m (2H,
Harom), 7.52 s (2H, Harom). Mass spectrum, m/z (Irel, %):
374 (30) [M + 1]+, 373 (100) M]+, 246 (32), 176
(51), 56 (46). Found, %: C 64.28; H 4.27; N 3.65.
C20H17Sl2NO2. Calculated, %: C 64.18; H 4.58; N 3.74.
M 374.27.
4-Bromo-N-butyl-3-(2-methyl-1H-indol-3-yl)male-
imide, 2.5 g (7 mmol), was dissolved in 100 ml of
THF, 50 mg of 4-dimethylaminopyridine was added,
and a solution of 2.0 g (9.1 mmol) of Boc2O in 20 ml
of THF was added dropwise over a period of 10 min.
The mixture was stirred for 1 h at room temperature
(until the initial compound disappeared according to
the TLC data; hexane–ethyl acetate, 4:1) and evaporat-
ed on a rotary evaporator, the residue was treated with
10 ml of methanol, and the mixture was ground with
a glass rod to initiate crystallization. An additional
portion of methanol, 10 ml, was added, and the mix-
ture was vigorously stirred for 5 h using a magnetic
stirrer. The yellow precipitate was filtered off, washed
with a small amount of cold methanol, and dried in
a desiccator to isolate 3.03 g (95%) of compound IVa
as a bright yellow powder with mp 92–94°C. 1H NMR
spectrum (250 MHz, CDCl3), δ, ppm: 0.96 t (3H,
CH3CH2, J = 8.6 Hz), 1.30–1.47 m (2H, CH3CH2),
1.59–1.69 m (2H, CH3CH2CH2), 1.70 s (9H, t-Bu),
2.58 s (3H, CH3), 3.67 t (2H, CH2N, J = 7.7 Hz), 7.20–
7.35 m (3H, Harom), 8.12 d (1H, Harom, J = 7.9 Hz).
Mass spectrum, m/z (Irel, %): 461 (1) [M]+, 406 (18),
361 (7), 281 (8), 182 (36), 154 (19), 57 (100). Found,
%: C 57.40; H 5.57; N 6.29. C22H25BrN2O4. Calculat-
ed, %: C 57.28; H 5.46; N 6.07. M 461.36.
N-Butyl-3,4-bis(4-methoxyphenyl)maleimide
(IIId) was synthesized from 0.53 g (3.4 mmol) of
boronic acid Id, 0.5 g (1.6 mmol) of maleimide IIa,
1.22 g (8.0 mmol) of CsF, and 0.075 g of Pd(Ph3P)4 in
40 ml of dioxane; reaction time 1.5 h. The product was
isolated by flash chromatography on silica gel using
hexane–diethyl ether (6:1) as eluent. Yield 0.57 g
1
(98%), light yellow crystals, mp 110–112°C. H NMR
spectrum (300 MHz, CDCl3), δ, ppm: 0.97 t (3H,
CH3CH2, J = 8.5 Hz), 1.34–1.46 m (2H, CH3CH2),
1.62–1.73 m (2H, CH3CH2CH2), 3.64 t (2H, CH2N,
J = 8.3 Hz), 3.84 s (6H, OCH3), 6.87 d (4H, Harom, J =
10.0 Hz), 7.49 d (4H, Harom, J = 10.1 Hz). Mass spec-
trum, m/z (Irel, %): 366 (33) [M + 1]+, 365 (100) [M]+,
238 (16), 223 (25), 152 (18), 133 (23), 43 (18). Found,
%: C 72.28; H 6.27; N 3.65. C22H23NO4. Calculated,
%: C 72.31; H 6.34; N 3.83. M 365.43.
3-Bromo-4-[1-(tert-butoxycarbonyl)-2-methyl-
1H-indol-3-yl]-N-butylmaleimide (IVa). A solution
of 1.01 g (7.7 mmol) of 2-methylindole in 24 ml of
THF was cooled to –20°C, and 16 ml of a 20% solu-
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A CONVENIENT SYNTHESIS OF 3,4-DIARYL(HETARYL)-SUBSTITUTED MALEIMIDES
1495
reaction time 1 h. The product was isolated by flash
chromatography on silica gel using hexane–ethyl
acetate (14:1) as eluent. Yield 0.32 g (71%), orange
N-Benzyl-3-bromo-4-[1-(tert-butoxycarbonyl)-2-
methyl-1H-indol-3-yl]maleimide (IVb). A solution of
2.62 g (20 mmol) of 2-methyl-1H-indole in 70 ml of
THF was cooled to –20°C, 42 ml of a 20% solution of
LiN(SiMe3)2 in THF was added dropwise under argon,
the mixture was stirred for 30 min at that temperature,
and a solution of 7.0 g (20 mmol) of N-benzyl-3,4-
dibromomaleimide [15] in 70 ml of THF was added
dropwise. The mixture was allowed to warm up to
room temperature, poured into 200 ml of 0.2 N hydro-
chloric acid, and extracted with ethyl acetate (3×
50 ml). The organic extracts were washed with 50 ml
of a 5% solution of NaHCO3, water (3×30 ml), and
a saturated solution of NaCl, dried over MgSO4, and
evaporated on a rotary evaporator. The residue was
dissolved in 100 ml of THF, 0.1 g of 4-dimethylamino-
pyridine was added, and a solution of 5.0 g (23 mmol)
of Boc2O in 30 ml of THF was added dropwise over
a period of 10 min. The mixture was stirred for 1 h and
evaporated on a rotary evaporator, and the residue was
subjected to flash chromatography on silica gel using
hexane–ethyl acetate (10:1) as eluent. Yield 7.0 g
1
oily substance. H NMR spectrum (250 MHz, CDCl3),
δ, ppm: 0.96 t (3H, CH3CH2, J = 8.0 Hz), 1.39–1.50 m
(2H, CH3CH2), 1.60–1.79 m (2H, CH3CH2CH2), 1.70 s
(9H, t-Bu), 2.42 s (3H, CH3), 3.70 t (2H, CH2N, J =
8.0 Hz), 6.92–7.40 m (6H, Harom), 7.70 s (1H, Harom),
8.12 d (1H, Harom, J = 8.9 Hz). Mass spectrum, m/z
(Irel, %): 493 (1.6) [M]+, 394 (28), 392 (100), 265 (23),
131 (8), 57 (11), 43 (17). Found, %: C 68.41; H 5.70;
N 5.54. C28H29ClN2O4. Calculated, %: C 68.22; H 5.93;
N 5.68. M 493.00.
3-[1-(tert-Butoxycarbonyl)-2-methyl-1H-indol-3-
yl]-N-butyl-4-(3-methoxyphenyl)maleimide (Vb)
was synthesized from 0.16 g (1.0 mmol) of boronic
acid Ie, 0.42 g (0.9 mmol) of maleimide IVa, 0.55 g
(36 mmol) of CsF, and 0.04 g of Pd(Ph3P)4 in 20 ml of
dioxane; reaction time 2 h; the product was isolated by
flash chromatography on silica gel using hexane–ethyl
acetate (10:1) as eluent. Yield 0.4 g (90%), orange oily
1
substance. H NMR spectrum (250 MHz, CDCl3), δ,
1
ppm: 0.96 t (3H, CH3CH2, J = 8.0 Hz), 1.37–1.49 m
(2H, CH3CH2), 1.61–1.75 m (2H, CH3CH2CH2), 1.69 s
(9H, t-Bu), 2.41 s (3H, CH3), 3.51 s (3H, OCH3), 3.69 t
(2H, CH2N, J = 8.0 Hz), 6.85 m (1H, Harom), 6.97–
7.29 m (6H, Harom), 8.12 d (1H, Harom, J = 9.0 Hz).
Mass spectrum, m/z (Irel, %): 489 (1.3) [M + 1]+, 488
(4.5) [M]+, 389 (18), 388 (100), 365 (7), 261 (18), 57
(8), 43 (12). Found, %: C 71.35; H 6.76; N 5.65.
C29H32N2O5. Calculated, %: C 71.29; H 6.60; N 5.73.
M 488.58.
(70%), light yellow crystals, mp 150–151°C. H NMR
spectrum (250 MHz, CDCl3), δ, ppm: 1.71 s (9H,
t-Bu), 2.58 s (3H, CH3), 4.82 s (2H, PhCH2), 7.20–
7.50 m (8H, Harom), 8.12 d (1H, Harom, J = 7.9 Hz).
Mass spectrum, m/z (Irel, %): 495 (13) [M]+, 395 (22),
91 (58), 57 (100). Found, %: C 60.62; H 4.55; N 5.47.
C25H23BrN2O4. Calculated, %: C 60.62; H 4.68;
N 5.65. M 495.37.
Cross coupling of aryl(hetaryl)boronic acids
with N-butyl- and N-benzyl-3-bromo-4-[1-(tert-but-
oxycarbonyl)-2-methyl-1H-indol-3-yl]maleimides
(general procedure). A mixture of maleimide IVa or
IVb, the corresponding aryl(hetaryl)boronic acid
[1.15 mol per mole of IVa or IVb; calculated on
ArB(OH)2], 4 mol % of Pd(Ph3P)4, CsF (4 mol per
mole of IVa or IVb), and 1,4-dioxane (100 ml per
gram of the boronic acid) was heated at the boiling
point in an argon atmosphere under vigorous stirring.
The mixture was then poured into water and extracted
with chloroform, the extract was washed with water,
dried over Na2SO4, and evaporated on a rotary evap-
orator, and the residue was purified by flash chroma-
tography on silica gel.
3-[1-(tert-Butoxycarbonyl)-2-methyl-1H-indol-3-
yl]-N-butyl-4-(2-methyl-1-benzothiophen-3-yl)male-
imide (Vc) was synthesized from 1.20 g (6.2 mmol) of
boronic acid Ia, 2.507 g (5.4 mmol) of maleimide IVa,
3.80 g (25 mmol) of CsF, and 0.25 g Pd(Ph3P)4 in
200 ml of dioxane; reaction time 5 h. The product was
isolated by flash chromatography on silica gel using
hexane–ethyl acetate (14:1) as eluent. Yield 2.40 g
1
(83%), orange oily substance. H NMR spectrum
(250 MHz, CDCl3), δ, ppm: 1.02 t (3H, CH3CH2, J =
8.5 Hz), 1.39–1.51 m (2H, CH3CH2), 1.65 s (9H,
t-Bu), 1.69–1.83 m (2H, CH3CH2CH2), 2.12–2.40
3 br.s (6H, CH3), 3.74 t (2H, CH2N, J = 8.0 Hz), 7.10–
7.45 m (6H, Harom), 7.69 d (1H, Harom, J = 8.9 Hz),
8.02 d (1H, Harom, J = 9.0 Hz). Mass spectrum, m/z (Irel,
%): 528 (1.4) [M]+, 472 (13), 429 (100), 315 (18), 287
(19), 101 (21). Found, %: C 70.30; H 6.27; N 5.35.
C31H32N2O4S. Calculated, %: C 70.43; H 6.10; N 5.30.
M 528.67.
3-[1-(tert-Butoxycarbonyl)-2-methyl-1H-indol-3-
yl]-N-butyl-4-(3-chlorophenyl)maleimide (Va) was
synthesized from 0.16 g (1.0 mmol) of boronic acid Ic,
0.42 g (0.9 mmol) of maleimide IVa, 0.55 g (36 mmol)
of CsF, and 0.04 g of Pd(Ph3P)4 in 20 ml of dioxane;
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SHORUNOV et al.
1496
1
(100%), dark red crystals, mp 235–238°C. H NMR
spectrum (250 MHz, CDCl3), δ, ppm: 1.71 s (3H,
CH3), 2.15 s (3H, CH3), 2.41 s (3H, CH3), 4.83 s (2H,
PhCH2), 6.80 s (1H, Harom), 7.0 t (1H, Harom, J =
N-Benzyl-3-[1-(tert-butoxycarbonyl)-2-methyl-
1H-indol-3-yl]-4-(2,5-dimethylthiophen-3-yl)male-
imide (Vd) was synthesized from 0.95 g (6.1 mmol) of
boronic acid Ib, 2.57 g (5.2 mmol) of maleimide Vb,
3.2 g (21 mmol) of CsF, and 0.24 g of Pd(Ph3P)4 in
150 ml of dioxane; reaction time 2 h. The product was
isolated by flash chromatography on silica gel using
hexane–diethyl ether (10:1) as eluent. Yield 2.32 g
7.1 Hz), 7.06–7.42 m (6H, Harom), 7.50 d (2H, Harom
,
J = 7.3 Hz), 8.28 s (1H, NH). Mass spectrum, m/z
(Irel, %): 428 (32) [M + 2]+, 427 (40) [M + 1]+, 426
(100) [M]+, 411 (53), 278 (52), 265 (40), 148 (39), 91
(92). Found, %: C 73.14; H 5.40; N 6.30. C26H22N2O2S.
Calculated, %: C 73.21; H 5.20; N 6.57. M 426.53.
1
(85%), light yellow crystals, mp 132–135°C. H NMR
spectrum (250 MHz, CDCl3), δ, ppm: 1.69 s (9H,
t-Bu), 1.79 s (3H, CH3), 2.36 s (3H, CH3), 2.39 s (3H,
CH3), 4.82 s (2H, PhCH2), 6.80 s (1H, Harom), 7.0–
7.11 m (2H, Harom), 7.19–7.40 m (4H, Harom), 7.48 d
(2H, Harom, J = 6.5 Hz), 8.09 d (1H, Harom, J = 7.2 Hz).
Mass spectrum, m/z (Irel, %): 527 (1) [M + 1]+, 526 (3)
[M]+, 427 (77), 91 (100). Found, %: C 70.56; H 5.76;
N 5.55. C31H30N2O4S. Calculated, %: C 70.70; H 5.74;
N 5.32. M 526.65.
Hydrolysis of 3,4-diaryl(hetaryl)maleimides
(general procedure). A 500-ml round-bottomed flask
equipped with a reflux condenser was charged with
a solution of the corresponding maleimide in 75 ml of
1,4-dioxane, 230 ml of a 10% solution of potassium
hydroxide was added, and the mixture was heated at
the boiling point in an argon atmosphere under vigor-
ous stirring (using a magnetic stirrer) for a time in-
dicated below. The mixture was allowed to cool down
to room temperature, poured into a mixture of 300 ml
of water and 50 ml of concentrated hydrochloric acid,
stirred for 1.5 h, and extracted with ethyl acetate. The
extract was washed with water, dried over Na2SO4, and
evaporated on a rotary evaporator, and the residue was
purified by flash chromatography on silica gel.
N-Butyl-3-(2-methyl-1-benzothiophen-3-yl)-4-(2-
methyl-1H-indol-3-yl)maleimide (VIa). A mixture of
2.4 g (4.5 mmol) of compound Vc and 30 ml of butyl-
amine was heated for 4 h under reflux. The mixture
was cooled, poured into a mixture of 300 ml of water
and 40 ml of concentrated hydrochloric acid, and ex-
tracted with ethyl acetate (3×100 ml). The extract was
washed with water, dried over Na2SO4, and evaporated
on a rotary evaporator, and the residue was purified by
flash chromatography on silica gel using hexane–ethyl
acetate (4.5:1) as eluent. Yield 1.55 g (80%), dark red
3,4-Bis(2-methyl-1-benzothiophen-3-yl)maleic
anhydride (VIIa) was obtained from 1.95 g (4.4 mmol)
of compound IIIa; reaction time 60 h; eluent hexane–
ethyl acetate (6:1). Yield 1.376 g (80%), orange crys-
tals, mp 241–243°C; published data [19]: mp 238–
240°C. 1H NMR spectrum (250 MHz, CDCl3), δ, ppm:
2.11 s (3H, CH3), 2.29 s (3H, CH3), 7.05–7.49 m (6H,
Harom), 7.61 d.d (2H, Harom, J = 9.1 Hz). Mass spec-
trum, m/z (Irel, %): 391 (19) [M + 1]+, 390 (72) [M]+,
344 (100), 318 (40). Found, %: C 67.72; H 3.47.
C22H14O3S2. Calculated, %: C 67.67; H 3.61. M 390.47.
1
crystals, decomposition point 280°C. H NMR spec-
trum (250 MHz, CDCl3), δ, ppm: 1.01 t (3H, CH3CH2,
J = 8.5 Hz), 1.38–1.55 m (2H, CH3CH2), 1.68–1.72 m
(2H, CH3CH2CH2), 1.97 s (3H, CH3), 2.21 s (3H,
CH3), 3.73 t (2H, CH2N, J = 7.2 Hz), 6.94 t (1H, Harom
,
J = 8.0 Hz), 7.02–7.39 m (6H, Harom), 7.68 d (1H,
H
arom, J = 8.9 Hz), 8.17 s (1H, NH). Mass spectrum,
m/z (Irel, %): 429 (19) [M + 1]+, 428 (100) [M]+, 413
(79), 367 (73), 314 (82), 301 (45), 300 (44), 286 (60).
Found, %: C 72.87; H 5.49; N 6.42. C26H24N2O2S.
Calculated, %: C 72.87; H 5.64; N 6.54. M 428.55.
3,4-Bis(2,5-dimethylthiophen-3-yl)maleic anhy-
dride (VIIb) was obtained from 1.5 g (4 mmol) of
maleimide IIIb; reaction time 60 h; eluent hexane–
THF (6.5:1). Yield 1.20 g (94%), yellow–orange
crystals, mp 198–200°C; published data [1]: mp 201–
202°C. 1H NMR spectrum (250 MHz, CDCl3), δ, ppm:
1.91 s (6H, CH3), 2.42 s (6H, CH3), 6.76 s (2H, Harom).
Mass spectrum, m/z (Irel, %): 319 (10) [M + 1]+, 318
(45) [M]+, 303 (26), 273 (100), 245 (70). Found, %:
C 60.62; H 4.45. C16H14O3S2. Calculated, %: C 60.35;
H 4.43. M 318.41.
N-Benzyl-4-(2,5-dimethylthiophen-3-yl)-3-(2-
methyl-1H-indol-3-yl)maleimide (VIb). A mixture of
1.67 g (3.2 mmol) of compound Vd and 30 ml of
benzylamine was heated for 40 min under reflux. The
mixture was cooled, poured into a mixture of 300 ml
of water and 40 ml of concentrated hydrochloric acid,
and extracted with ethyl acetate (3×100 ml). The
extract was washed with water, dried over Na2SO4, and
evaporated on a rotary evaporator, and the residue was
purified by flash chromatography on silica gel using
hexane–ethyl acetate (4.5:1) as eluent. Yield 1.35 g
3-(2-Methyl-1-benzothiophen-3-yl)-4-(2-methyl-
1H-indol-3-yl)maleic anhydride (VIIc) was obtained
from 1.44 g (3.4 mmol) of compound VIa; reaction
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

A CONVENIENT SYNTHESIS OF 3,4-DIARYL(HETARYL)-SUBSTITUTED MALEIMIDES
1497
4. Krayushkin, M.M., Khim. Geterotsikl. Soedin., 2001,
p. 19.
5. Kobotake, S. and Irie, M., Annu. Rep. Prog. Chem. C,
2003, vol. 99, p. 277.
6. Brenner, M., Rexhausen, H., Steffan, B., and Steig-
lich, W., Tetrahedron, 1988, vol. 44, p. 2887.
time 60 h; eluent hexane–THF (4:1). Yield 0.8 g
(64%), dark red crystals, mp 217–220°C. H NMR
spectrum (250 MHz, DMSO-d6), δ, ppm: 2.05 s (3H,
CH3), 2.17 s (3H, CH3), 6.80 t (1H, Harom, J = 8.3 Hz),
7.02 t (1H, Harom, J = 8.4 Hz), 7.09 d (1H, Harom, J =
1
9.0 Hz), 7.14–7.33 m (3H, Harom), 7.55 d (1H, Harom
,
7. Ohkubo, M., Nishimura, T., Jona, H., Honma, T., and
Morishima, H., Tetrahedron, 1996, vol. 52, p. 8099.
8. Ohkubo, M., Kawamoto, H., Ohno, T., Nakano, M., and
Morishima, H., Tetrahedron, 1997, vol. 53, p. 585.
J = 9.2 Hz), 7.88 d (1H, Harom, J = 9.2 Hz), 11.71 s
(1H, NH). Mass spectrum, m/z (Irel, %): 375 (14)
[M + 2]+, 374 (40) [M + 1]+, 373 (100) [M]+, 328 (80),
302 (40), 301 (73), 300 (76), 148 (42). Found, %:
C 70.82; H 4.19; N 3.52. C22H15NO3S. Calculated, %:
C 70.76; H 4.05; N 3.75. M 373.43.
9. Faul, M.M., Sullivan, K.A., and Winneroski, L.L.,
Synthesis, 1995, p. 1511.
10. O’Neill, D.J., Shen, L., Prouty, C., Conway, B.R.,
Westover, L., Xu, J.Z., Zhang, H.C., Maryanoff, B.E.,
Murray, W.V., Demarest, K.T., and Kuoa, G.H., Bioorg.
Med. Chem., 2004, vol. 12, p. 3167.
3-(2,5-Dimethylthiophen-3-yl)-4-(2-methyl-1H-
indol-3-yl)maleic anhydride (VIId) was obtained
from 1.241 g (2.9 mmol) of maleimide VIb; reaction
time 3 h; eluent hexane–THF (4:1). Yield 0.715 g
11. Miyaura, N. and Suzuki, A., Chem. Rev., 1995, vol. 95,
1
(73%), dark red crystals, mp 200–202°C. H NMR
p. 2457.
spectrum (250 MHz, CDCl3), δ, ppm: 1.77 s (3H,
CH3), 2.27 s (3H, CH3), 2.42 s (3H, CH3), 6.81 s (1H,
Harom), 7.0–7.40 m (4H, Harom), 8.47 s (1H, NH). Mass
spectrum, m/z (Irel, %): 339 (22) [M + 2]+, 337 (100)
[M]+, 292 (52), 264 (54), 105 (75), 82 (60), 76 (92), 55
(69). Found, %: C 67.80; H 4.43; N 4.38. C19H15NO3S.
Calculated, %: C 67.64; H 4.48; N 4.15. M 337.39.
12. Suzuki, A., Organoboranes in Organic Synthesis,
Hokkaido University, 2004.
13. Beletskaya, I.R. and Cheprakov, A., Comprehensive
Coordination Chemistry II: From Biology to Nano-
technology, McCleverty, J.A. and Meyer, T.J., Eds.,
Amsterdam: Elsevier, 2004, vol. 9, p. 305.
14. Shirley, D.A., Danzig, M.J., and Canter, F.C., J. Am.
Chem. Soc., 1953, vol. 75, p. 3278.
15. Steinkopf, W., Poulsson, I., and Herdey, O., Justus
Liebigs Ann. Chem., 1938, vol. 536, p. 130.
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17. Routier, S., Coudert, G., and Merour, J-Y., Tetrahedron
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