Development of methods for the synthesis of libraries of substituted maleimides and α,β-unsaturated-γ-butyrolactams

Article abstract of DOI:10.1021/jo1025805

Synthetic methods for the preparation of maleimide and α,β- unsaturated-γ-butyrolactam compound collections are described. These routes take advantage of Pd cross-coupling and conjugate addition/elimination reactions to permit the facile production of bisaryl-maleimides, anilinoaryl-maleimides, and bisanilino-maleimides while allowing control over the synthesis of symmetrical or nonsymmetrical derivatives. Similarly, the chemistry developed allows for the generation of bisaryl substituted α,β-unsaturated-γ-butyrolactams. The scope and limitations of the approaches are presented.

Full text of DOI:10.1021/jo1025805

ARTICLE
pubs.acs.org/joc
Development of Methods for the Synthesis of Libraries of
Substituted Maleimides and r,β-Unsaturated-γ-butyrolactams
Emelia Awuah and Alfredo Capretta*
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada L8S 4M1
S Supporting Information
b
ABSTRACT: Synthetic methods for the preparation of mal-
eimide and R,β-unsaturated-γ-butyrolactam compound collec-
tions are described. These routes take advantage of Pd cross-
coupling and conjugate addition/elimination reactions to per-
mit the facile production of bisaryl-maleimides, anilinoaryl-
maleimides, and bisanilino-maleimides while allowing control
over the synthesis of symmetrical or nonsymmetrical deriva-
tives. Similarly, the chemistry developed allows for the genera-
tion of bisaryl substituted R,β-unsaturated-γ-butyrolactams. The scope and limitations of the approaches are presented.
’ INTRODUCTION
Heck reactions onto a maleimide core to permit derivatization
at the 3- and 4-positions. Exploratory experiments revealed that
N-protection was necessary and N-(p-methoxybenzyl)-malei-
mide (1)20 was chosen as a suitable substrate as a number of
mild deprotection strategies have been reported.21ꢀ24 The initial
screening of reaction conditions involved the coupling of 1 with
p-iodotoluene utilizing microwave heating and examined the
effect of different ligands,13 solvents, temperatures, palladium
sources, and bases. As illustrated in Table 1, elevated tempera-
tures (140 °C for 55 min) were required to effect coupling in
good yields. When 6 equiv of the aryl halide was used, many of
the conditions screened (entries 1ꢀ8) allowed for the produc-
tion of monoarylated product (Table 1, a) predominantly.
However, use of the 1,3,5,7-tetramethyl-2,4,8-trioxa-6-o-methox-
yphenyl-6-phosphaadamantane ligand (2, R = OMe) and Cy2-
NMe as the base allowed for a substantial increase in the
diarylated product (Table 1, b) in dioxane (entry 9) and DMF
(entry 10). Unfortunately, increasing reactions times, tempera-
ture, or the number of equivalents of p-iodotoluene used failed to
increase the amount of diarylated maleimide generated. This was
not unexpected, as the difficulty of generating tetrasubstituted
alkenes using Heck coupling is well-known.25
Methods employing Suzuki couplings were found to be more
synthetically viable, enabling access to the aryl-substituted mal-
eimides under milder conditions. Using N-(p-methoxybenzyl)-
3,4-dibromomaleimide (3)26,27 as the scaffold, a series of experi-
ments quickly determined the optimal reaction conditions (Pd
source, base, and solvent) for monoarylation of the maleimide
core. The results are presented in Table 2. The best yields were
obtained when using the 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phen-
yl-6-phosphaadamantane ligand (PA-Ph: 2, R = H) and Pd2dba3
at room temperature with Cs2CO3 in THF. However, despite
The maleimide motif is featured in a variety of natural
products including the arcyriaflavin,1 arcyriarubin,2 himanimide,3
polycitrin,4 and rebeccamycin5 families. Biological properties of
these compounds and their analogues include antibacterial and
antiviral activity and angiogenesis inhibition,6 as well as kinase
inhibiton.7 For example, groups from SmithKline Beecham,8,9 Eli
Lilly,10 and Johnson & Johnson,11 among others, have demon-
strated that bisaryl-maleimides are potent inhibitors of glycogen
synthase kinase-3 (GSK-3). In fact, compounds SB 216763 and
SB 415286 (Figure 1) have been shown to inhibit the R-isoform
of GSK-3 in an ATP-competitive manner with a Ki of 9 and 31
nM, respectively.8 The syntheses of these maleimide inhibitors
often involve multistep sequences that do not lend themselves
readily to combinatorial approaches.
As part of a program aimed at the design and synthesis of
selective kinase inhibitors, we required a route that could access
chemically diverse families of substituted maleimides. We deter-
mined that Pd-catalyzed cross-coupling chemistry developed in
our laboratory12ꢀ17 is particularly well suited for this purpose,
allowing for efficient derivatization at the 3,4-positions of the
maleimide heterocyclic core. Furthermore, inspired by the
biological activity of staurosporine,18,19 Figure 1, we have devel-
oped a general method that allows for the synthesis of substituted
R,β-unsaturated-γ-butyrolactam analogues. An ideal synthetic
method should allow for the preparation of bisaryl-maleimides,
anilinoaryl-maleimides, and bisanilino-maleimides; be amenable
for the parallel synthesis of maleimide libraries; and allow for the
control necessary to permit symmetrical or nonsymmetrical
derivatives.
’ RESULTS AND DISCUSSION
Our initial efforts focused on the most straightforward
approach to the target compounds involving two sequential
Received: December 28, 2010
Published: March 25, 2011
r
2011 American Chemical Society
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Figure 1. Systems containing maleimide and R,β-unsaturated-γ-butyrolactam substructures.
Table 1. Optimization of Reaction Parameters for the Arylation of a Maleimide Scaffold via a Heck Reaction
ligand (2)
Pd source
base
Et3N
solvent
yield (% a:% b)
1
2
R = H
Pd2dba3
Pd2dba3
Pd2dba3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
THF
85:5
R = H
Et3N
dioxane
DMF
THF
82:10
80:16
80:5
3
R = H
Et3N
4
R = H
Et3N
5
R = H
Et3N
dioxane
DMF
DMF
THF
83:10
80:15
84:15
80:10
51:45
40:55
6
R = H
Et3N
7
R = OMe
R = OMe
R = OMe
R = OMe
Et3N
8
Cy2NMe
Cy2NMe
Cy2NMe
9
dioxane
DMF
10
using only 1 equiv of boronic acid, a small amount of diarylation
product (Table 2, b) was always generated. This byproduct was
easily separated from the desired monoarylated compound
(Table 2, a) via column chromatography; however, for the sake
of convenience, the reaction mixture could be taken forward and
subjected to a second Suzuki reaction.
With the monoarylated-malemides in hand (Table 3, a),
introduction of a second aryl moiety (to give Table 3, b) was
shown to be facile and high-yielding. Deprotection with TFA in
anisole (in a 1:1 (v/v) ratio) using microwave irradiation gave the
desired bisarylated-maleimides (Table 3, c).
Symmetrical diarylation of the maleimide scaffold (Table 4)
was easily achieved by using 2.2 equiv of the arylboronic acid and
the Pd2dba3/PA-Ph catalyst system. Shorter reaction times
(30ꢀ60 min) were required for the removal of the p-methox-
ybenzyl protecting group when AlCl3 in anisole under microwave
irradiation was employed. High yields of the desired bisarylma-
leimides were obtained in all cases except for entry 5 (in Table 4),
where product decomposition occurred under all deprotection
conditions attempted.
A number of potent kinase inhibitors are anilinoaryl-malei-
mides (SB415286 in Figure 1, for example), and we next explored
routes for the parallel synthesis of these systems. Exploratory
experiments quickly determined that the order of introduction of
the aryl and amino vectors was important and that the most facile
route to the 3-amino,4-aryl-substituted maleimides involved
amination before a Suzuki arylation. In this way, treatment of
the N-(p-methoxybenzyl)-3,4-dibromomaleimide (3) with 1
equiv of an amine (primary or secondary aliphatic; anilines or
N-monosubstituted anilines) at room temperature in THF
allowed for a rapid conjugate addition/elimination reaction to
provide high yields of the monosubstituted maleimide (Table 5, a).
In fact, under these conditions and in the presence of excess
amine, the monoaminated maleimide product is formed exclu-
sively. It would appear that the installation of an amino group
alters the electronic nature of the neighboring site such that a
second conjugate addition does not occur at room temperature.
However, utilization of the Suzuki chemistry developed above
allowed for facile arylation (to give Table 5, b) and, after
deprotection, access to 3-amino,4-aryl-substituted maleimides
(Table 5, c) in good overall yields.
A number of complications were encountered when attempt-
ing to introduce a second amino moiety onto the monoaminated
maleimide scaffold. We determined that these reactions were
controlled by the subtle interplay between the electron donating
ability of the first amine introduced and the nucleophilicity of the
second amine. For example, treatment of 3-bromo-1-(4-meth-
oxybenzyl)-4-(phenylamino)-maleimide (Table 5, entry 11, a)
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Table 2. Optimization of Reaction Parameters for Mono-
arylated-maleimide Synthesis via Suzuki Chemistry
Table 3. Nonsymmetrical Bisaryl Maleimides via Suzuki
Chemistry
with series of amines (3 equiv) and using microwave irradiation
(100 °C for 30 min) resulted in diamino-maleimide products
only with primary and secondary aliphatic systems such as n-
butylamine, piperidine, and morpholine to give 4, 5, and 6,
respectively (Figure 2). Anilinic or N-substituted-anilinic amines
failed to couple. It would appear that once monoaminated, the
electrophilicity of the carbon bearing the Br is drastically reduced
as it is now the terminus of an enamine system as well as an R,β-
unsaturated amide. It is not surprising, therefore, that a second
conjugate addition/elimination reaction takes place only under
forcing conditions with the more nucleophilic primary or sec-
ondary aliphatic amines. In addition, both 3-bromo-1-(4-meth-
oxybenzyl)-4-(methyl(phenyl)amino)-1H-pyrrole-2,5-dione
(Table 5, entry 8, a) and 3-bromo-1-(4-methoxybenzyl)-4-
morpholino-maleimide (Table 5, entry 2, a) were shown to
couple with piperidine (to give 7 and 8, respectively), whereas
morpholine and other aromatic amines failed to react. In effect,
bisamination of the maleimide scaffold 3 was only successful
in cases where the addition of a less nucleophilic amine (lower
pKa, less electron-rich) is followed by reaction with a more
nucleophilic amine (higher pKa, more electron-rich). As a
result, symmetrical bisaminated maleimides could not be gener-
ated using this approach. It should be noted that attempts to
introduce the second amine via a palladium-catalyzed amination
reaction were unsuccessful with only the dehalogenated product
recovered.
temperature resulted in trapping of the p-methoxybenzyl cation
generated by the piperidine nitrogen to give systems 9 and 10
(from 5 and 7, respectively, as shown in Figure 3). These results
are very peculiar as trapping of the p-methoxybenzyl cation did
not occur with analogous compounds such as entry 7 in Table 5
that underwent deprotection smoothly under microwave irradia-
tion. Attempts at deprotection using oxidative cleavage protocols
involving CAN28 or DDQ29 were unsuccessful.
It became clear that a different protecting group was needed,
ideally one that could alter the electronics of the maleimide
system and thereby help facilitate the second amination reaction.
N-(p-Nitrophenyl)-3,4-dibromomaleimide (11), prepared by
treating maleic anhydride with p-nitroaniline in acetic acid, was
identified as an ideal substrate. Its deprotection is realized by
treating with methanolic ammonia at room temperature. Once
again, the order of addition of the two amino vectors is
important. As presented in Table 6, addition of the first amine
vector to 11 to give system a could be achieved in high yields (as
evidence by TLC) in a few minutes. The monoaminated
compound (a) was not isolated but used directly in the next
step. Addition of a second, more nucleophilic amino moiety
allowed for the requisite conjugate addition/elimination reaction
(to give b), achieved using microwave heating a 50 °C for 30 min.
Finally, treatment with methanolic ammonia at room tempera-
ture for 12 h provided the desired bisamino-maleimides (Table 6, c).
Note that treatment of 11 with primary amines, such as n-
In addition to these limitations, deprotection of the methox-
ybenzyl protecting group for these systems was also problematic.
In systems bearing a piperidine moiety, deprotection under the
conditions developed above using AlCl3/anisole at room
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butylamine, resulted in a complex mixture of products that
included those wherein the p-nitrophenyl moiety is substituted
with the primary amine introduced.
initial Suzuki coupling involving 12 required elevated tempera-
tures (60 °C). In addition, despite using only 1 equiv of the
boronic acid, a small amount of diarylation product (Table 7, b)
was generated.
Carrying the reaction mixture forward, a second aryl vector
could be introduced into the butyrolactam system (to give
Our attention was then turned to the application of the
chemistry developed above for the syntheses of substituted
R,β-unsaturated-γ-butyrolactams. These systems represent ana-
logues of the maleimide derivatives with a deleted carbonyl and
can be used to provide further information about the nature of
inhibitor binding. A suitable scaffold was generated via the
treatment of mucobromic acid with 4-methoxybenzyl amine
under reductive amination conditions similar to those described
by Zhang and co-workers30 to give 3,4-dibromo-1-(4-meth-
oxybenzyl)-1H-pyrrol-2(5H)-one (12) in 78% yield. Once again,
optimization of the reaction parameters necessary for the intro-
duction of a single aryl moiety via a Suzuki reaction was
investigated (Table 7).
Table 5. 3-Amino-4-aryl Substituted Maleimides
As expected, the first arylation takes place at the β-position of
the unsaturated-γ-butyrolactam 12 (to give a in Table 7) thus
allowing for control over the substitution pattern in the final
product. The best yields were obtained when using the PA-Ph
ligand and Pd2dba3 with KF in toluene. Furthermore, unlike the
conditions used for the first arylation in the maleimide series, the
Table 4. Symmetrical Bisaryl Maleimides via Suzuki
Chemistry
Figure 2. p-Methoxybenzyl protected 3,4-diaminomaleimides.
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Table 7. Optimization of Reaction Parameters for the
Synthesis of Substituted r,β-Unsaturated-γ-butyrolactams
Figure 3. Trapping of the p-methoxybenzyl cation.
Table 6. Nonsymmetrical Bisamino Maleimides
Table 8. 3,4-Diaryl r,β-Unsaturated-γ-butyrolactams
Table 8, b) under the similar conditions with an increase in
temperature (to 80 °C) and reaction time (to 12 h). Deprotec-
tion to the desired lactam systems (Table 8, c) was accomplished
using TFA/anisole and microwave irradiation at 150 °C for
30 min with no significant change in yield observed when the
AlCl3/TFA deprotection protocol was used. Finally, entries 4ꢀ6
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in Table 8 represent systems with the same aryl moiety at the R-
and β-positions of the lactam and were prepared by treating 12
with 2.2 equiv of the appropriate boronic acid followed by
deprotection.
Exploratory experiments aimed at the introduction of amine
vectors into 12 quickly revealed that the approach developed
above was inappropriate for the amination of the butyrolactam
series. For example, treatment of 12 with morpholine gave a
mixture of multiple products. This was not surprising as it is well-
known that the methylene moiety at C5 is enolizable31,32 and
treatment with basic amines precludes the conjugate addition/
elimination reaction.
C19H17NO3 calculated307.1208 found 307.1208. 1-(4-Methoxybenzyl)-
3,4-dip-tolyl-1H-pyrrole-2,5-dione (Table 1, entry 10, compound b):
1H NMR (CDCl3, 200 MHz) δ 7.41 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 7.7
Hz, 4H), 7.15 (d, J = 7.7 Hz, 4H), 6.86 (d, J = 8.4 Hz, 2H), 4.74 (s, 2H),
3.79 (s, 3H), 2.36 (s, 6H); 13C NMR (CDCl3, 50 MHz) δ 170.8, 159.3,
140.1, 135.6, 130.5, 129.9, 129.4, 129.1, 128.5, 126.1, 114.1, 55.4, 41.5,
21.6; HRMS (CI) for C26H23NO3 calculated 397.1676 found 397.1678.
General Procedure for the Monoarylation of 1-(4-Meth-
oxybenzyl)-3,4-dibromo-1H-pyrrole-2,5-dione (3) (Table 2).
To a mixture of 1-(4-methoxybenyl)-3,4-dibromo-1H-pyrrole-2,5 dione
(3)27 (187 mg, 0.5 mmol), Pd2(dba)3 CHCl3 (15.5 mg, 0.015 mmol, 3
3
mol %), PA-Ph, (2, R = H, 8.8 mg. 0.03 mmol, 6 mmol %), Cs2CO3
(366.0 mg, 1.125 mmol, 2.25 equiv), and the aryl boronic acid (1.1 eq,
0.55 mmol) was added dried THF (3 mL). The mixture was degassed,
placed under an atmosphere of argon, and stirred at room temperature
for 2ꢀ8 h. The solvent was evaporated under reduced pressure, and
the reaction mixture was purified by column chromatography on silica
gel. 1-(4-Methoxybenzyl)-3-bromo-4-p-tolyl-1H-pyrrole-2,5-dione
(Table 2, entry 9, compound a). Using 4-methylphenylboronic acid
(75.0 mg, 0.55 mmol), and the general procedure described above,
1-(4-methoxybenzyl)-3-bromo-4-p-tolyl-1H-pyrrole-2,5-dione was
obtained in 78% yield (150.1 mg, 0.38 mmol) after purification by
column chromatography on silica gel using 10% diethyl ether in hexane
as the eluent. 1H NMR (CDCl3, 200 MHz) δ 7.82 (d, J = 8.2 Hz, 2H),
7.36 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz),
4.72 (s, 2H), 3.79 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ
168.8, 165.7, 159.6, 141.7, 130.5, 130.0, 129.7, 129.5, 128.6, 128.3,
125.1, 121.6, 55.5, 42.2, 21; HRMS (CI) for C19H16BrNO3 calculated
385.0314, found 385.0312
’ CONCLUSIONS
The methods developed above allow for rapid and facile access
to symmetrical and nonsymmetrical, aryl- and amino-substituted
maleimides and R,β-unsaturated-γ-butyrolactams. Furthermore,
the utilization of other organopalladium cross-coupling chemis-
tries (including such reactions as the Sonogashira, Stille, ketone
arylations, Negishisi, etc.) should allow for introduction of a
variety of structurally diverse vectors and, thereby, an increased
mapping of the chemical space probed by these compound
collections.
’ EXPERIMENTAL SECTION
General Information. See J. Org. Chem. 2004, 69 (22), 7635ꢀ7639
for the general experimental information (provided in the Supporting
Information) and forthesynthesis of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-o-
methoxyphenyl-6-phosphaadamantane (2, R = OMe). 1,3,5,7-Tetra-
methyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane (2, R = H, PA-Ph)
was supplied by Cytec Canada. Microwave reactions were performed
using a CEM Discover Microwave, which allowed for monitoring and
control of both temperature and pressure. Unless otherwise stated, the
ionization gas for the CI MS experiments was ammonia.
General Procedure for Synthesis of Nonsymmetrical Bi-
saryl Maleimides (Table 3, compound b). To a mixture of the
monoarylated maleimide (0.2 mmol), Pd2(dba)3 CHCl3 (6.21 mg,
3
0.006 mmol, 3 mol %), PA-Ph, (2, R = H, 3.52 mg. 0.012 mmol,
6 mmol %), Cs2CO3 (162.9 mg, 0.45 mmol), and the arylboronic acid
(1.2 eq 0.24 mmol) was added dried THF (3 mL). The mixture was
degassed, placed under an atmosphere of argon, and stirred at 40 °C for 2
h. The solvent was evaporated under reduced pressure, and the re-
action mixture was purified by column chromatography on silica gel.
1-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-4-p-tolyl-1H-pyrrole-
2,5-dione (Table 3, entry 1, compound b). Using 1-(4-meth-
oxybenzyl)-3-bromo-4-p-tolyl-1H-pyrrole-2,5-dione (77.2 mg, 0.2
mmol), 4-methoxyphenylboronic acid (37.7 mg, 0.24 mmol), and
the general procedure described above, 1-(4-methoxybenzyl)-3-(4-
methoxyphenyl)-4-p-tolyl-1H-pyrrole-2,5-dione was obtained in 92%
yield (76.0 mg, 0.184 mmol) after purification by column chroma-
tography on silica gel using 30% ethylacetate in hexane as the eluent:
1H NMR (CDCl3, 200 MHz) δ 7.36ꢀ7.50 (m, 6H), 7.17 (d, J = 8.6
Hz, 2H), 6.86 (d, J = 8.6 Hz, 4H), 4.73 (s, 2H), 3.82 (s, 3H), 3.79 (s,
3H), 2.36 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 170.9, 160.8, 159.2,
139.9, 135.1, 134.3, 131.5, 130.3, 129.7, 129.3, 128.9, 126.1, 121.2,
114.0, 55.3, 41.3, 21.5; HRMS (CI) for C26H23NO4 calculated
413.1627 found 413.1628.
N-(p-Methoxybenzyl)-maleimide (1)20. To a solution of maleic
anhydride (1.6 g, 16.3 mmol) in acetic acid (15 mL) was added p-
methoxybenylamine (2.1 mL, 16.3 mmol). The mixture was refluxed for
5 h, cooled to room temperature, and then concentrated under reduced
pressure. Purification of the residue by column chromatography on silica
gel using 20% ethylacetate in hexane as the eluent afforded 1 in 79% yield
(2.8 g, 12.9 mmol): 1H NMR (CDCl3, 200 MHz) δ 7.30 (d, J = 8.4 Hz,
2H), 6.83 (d, J = 8.4 Hz, 2H), 6.68 (s, 2H), 4.61 (s, 2H), 3.78 (s, 3H);
13C NMR (CDCl3, 50 MHz) δ 170.6, 159.4, 134.2, 130.1, 128.6, 114.2,
55.4, 41.0; HRMS (CI) for C12H11NO3 calculated 217.0739, found
217.0735.
Synthesis of 1-(4-Methoxybenzyl)-3-p-tolyl-1H-pyrrole-
2,5-dione (Table 1, a) and 1-(4-Methoxybenzyl)-3,4-di-p-to-
lyl-1H-pyrrole-2,5-dione (Table 1, b) via a Heck Reaction. To a
mixture of N-(p-methoxybenzyl)-maleimide (1) (100 mg, 0.46 mmol),
Pd2(dba)3 CHCl3 (23.8mg, 0.023 mmol, 5 mol%), PA-Ph, (2, R = OMe,
3
7.7 mg. 0.023 mmol, 5 mol %), Cy2NMe (494 μL, 2.3 mmol, 5 equiv), and
4-iodotoluene (300.9 mg, 1.38 mmol, 6 equiv) was added dried DMF
(3 mL). The mixture was degassed, placed under an atmosphere of argon,
and microwaved at 140 °C for 55 min. The solvent was evaporated under
reduced pressure, and the reaction mixture was purified by column
chromatography on silica gel using 30% ethylacetate/hexane. 1-(4-
Methoxybenzyl)-3-p-tolyl-1H-pyrrole-2,5-dione (Table 1, entry 10,
General Procedure for the Deprotection of Nonsymme-
trical Bisaryl Maleimides using TFA in Anisole (Table 3,
compound c). To a solution of the p-methoxybenzyl protected
maleimide (0.1 mmol) in anisole (1 mL) was added TFA (1 mL).
The reaction mixture was microwaved at 140 °C for 30ꢀ60 min. The
solvent was evaporated under reduced pressure, and the reaction mixture
was purified by column chromatography on silica gel. 3-(2,4-Dimethoxy-
phenyl)-4-p-tolyl-1H-pyrrole-2,5-dione (Table 3, entry 2, compound
c). Using 4-(1-(4-methoxybenzyl)-3-(2,4-dimethoxyphenyl)-4-p-tolyl-
1H-pyrrole-2,5-dione (44.3 mg, 0.1 mmol) and the general procedure
described above, 3-(2,4-dimethoxyphenyl)-4-p-tolyl-1H-pyrrole-2,5-dione
was obtained in 82% yield (26.5 mg, 0.082 mmol) after purification by
1
compound a): H NMR (CDCl3, 700 MHz) δ 7.82 (d, J = 8.4 Hz,
2H), 7.34 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 2 Hz, 2H), 6.84 (d, J = 8.4 Hz,
2H), 6.66 (s, 1H), 4.67 (s, 2H), 3.78 (s, 3H), 2.39 (s, 3H); 13C NMR
(CDCl3, 176 MHz) δ 170.7, 170.4, 159.3, 143.9, 141.9, 130.1, 129.8,
128.9, 128.7, 126.2, 122.8, 114.1, 55.39, 41.1, 21.7; HRMS (CI) for
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column chromatography on silica gel using 30% ethylacetate in hexane as
the eluent: 1H NMR (CDCl3, 200 MHz) δ 7.36 (d, J = 8 Hz, 2H), 7.31 (s,
1H), 7.11 (d, J = 8 Hz, 2H), 6.56 (d, J = 6.2 Hz, 1H), 6.43 (s, 1H), 3.38 (s,
3H), 3.78 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 171.0,
170.7, 162.6, 158.7, 140.0, 137.2, 134.5, 132.2, 129.0, 127.5, 110.9, 105. 2,
99.3, 55.6, 55.2, 21.6; HRMS (CI) for C19H17NO4 calculated 323.1158
found 323.1158.
1H NMR (CDCl3, 200 MHz) δ 7.34ꢀ7.41 (m, 5H), 7.13 (d, J = 8.6 Hz,
2H), 6.84 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 166.5,
165.7, 159.2, 144.3, 144.0, 130.2, 129.1, 126.7, 125.2, 114.0, 87.6, 55.3,
41.8, 41.5; HRMS (CI) for C19H17BrN2O3 calculated 400.0423, found
400.0420.
General Procedure for the Synthesis of 3-Amino-4-aryl
Maleimides (Table 5, compound b). To a mixture of the mono
General Procedure for Synthesis of Symmetrical Bisaryl
Maleimides (Table 4). To a mixture of 1-(4-methoxybenyl)-3,4-
dibromo-1H-pyrrole-2,5-dione (3) (60.0 mg, 0.16 mmol), Pd2-
aminated maleimide (0.2 mmol), Pd2(dba)3 CHCl3 (6.21 mg, 0.006
3
mmol, 3 mol %), PA-Ph, (3.52 mg. 0.012 mmol, 6 mmol %), Cs2CO3
(162.9 mg, 0.5 mmol) and the arylboronic acid (1.2 eq, 0.24 mmol) was
added dried THF (3 mL). The mixture was degassed, placed under an
atmosphere of argon and stirred at 60 °C for 2 h. THF was evaporated
under reduced pressure and the reaction mixture was purified by column
chromatography on silica gel. 1-(4-Methoxybenzyl)-3-morphilono-
4-p-tolyl-1H-pyrrole-2,5-dione (Table 5, entry 2, compound b).
Using 1-(4-methoxybenzyl)-3-bromo-4-morpholino-1H-pyrrole-2,5-
dione (76.2 mg, 0.2 mmol), 4-methylphenyl boronic acid (32.6 mg,
0.24 mmol) and the general procedure described above, 1-(4-meth-
oxybenzyl)-3-morpholino-4-p-tolyl-1H-pyrrole-2,5-dione was obtained
in 93% yield (71.4 mg, 0.185 mmol) after purification using column
chromatography on silica gel with 20% ethylacetate in hexane as the
eluent: 1H NMR (CDCl3, 200 MHz) δ 7.35 (d, J = 8.6 Hz, 2H), 7.17 (s,
4H), 6.84 (d, J = 8.6 Hz, 2H), 4.61 (s, 2H), 3.78 (s, 3H), 3.67 (t, J = 4.2
Hz, 4H), 3.50 (t, J = 4.2 Hz, 4H), 2.35 (s, 3H); 13C NMR (CDCl3, 50
MHz) δ 170.9, 167.8, 159.2, 142.9, 137.7, 130.4, 130.1, 129.2, 128.9,
127.7, 114.0, 105.9, 66.8, 55.4, 46.1, 40.9, 21.4. HRMS (CI) for
C24H24N2O4 calculated 392.1736, found 392.1782.
(dba)3 CHCl3 (6.6 mg, 0.006 mmol, 4 mol %), PA-Ph, (2, R =H, 3.7
3
mg. 0.013 mmol, 8 mmol %), Cs2CO3 (208.0 mg, 0.64 mmol 4 equiv)
and the arylboronic acid (0.35 mmol, 2.2 equiv) was added dried THF
(3 mL). The mixture was degassed, placed under an atmosphere of argon
and stirred at 40 °C for 2 h. The solvent was evaporated under reduced
pressure and the reaction mixture was purified by column chromatog-
raphy on silica gel. 1-(4-Methoxybenzyl)-3,4-bis(4-methoxyphenyl)-
1H-pyrrole-2,5-dione (Table 4, entry 3, compound a). Using 4-meth-
oxyphenylboronic acid (53.5 mg, 0.35 mmol, 2.2 equiv) and the general
procedure described above, 1-(4-methoxybenzyl)-3,4-bis(4-meth-
oxyphenyl)-1H-pyrrole-2,5-dione was obtained in 95% yield (65.3 mg,
0.152 mmol) after purification by column chromatography on silica gel
using 30% ethylacetate in hexane as the eluent: 1H NMR (CDCl3, 200
MHz) δ 7.44 (overlap, 6H), 6.86 (d, J = 8.6 Hz, 6H), 4.72 (s, 2H), 3.84
(s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). 13C NMR (CDCl3, 50 MHz) δ 171.2,
160.8, 159.3, 134.2, 131.6, 130.5, 129.1, 114.2, 55.4, 41.4; HRMS (CI)
for C26H24NO5 (Mþ1) calculated 430.1654 found 430.1645.
General Procedure for Deprotection of Symmetrical Mal-
eimides using AlCl3 in Anisole (Table 4, compound b). To a
solution of the p-methoxybenzyl protected maleimide (0.1 mmol) in
1 mL anisole was added 5 - 8 equiv of AlCl3. The reaction mixture was
microwaved at 140 °C for 30 - 55 min and then poured into water
(5 mL). The mixture was extracted with DCM (3 ꢁ 6 mL) and the
organic layer dried with Na2SO4. Concentration of the solvent under a
reduced pressure and purification using column chromatography on
silica gel with 30% ethylacetate in hexane as the eluent yielded the
deprotected product. 3,4-Bis(4-methoxyphenyl)-1H-pyrrole-2,5-dione
(Table 4, entry 3, compound b).33 Using 1-(4-methoxybenzyl)-3,4-bis(4-
methoxyphenyl)-1H-pyrrole-2,5-dione (43 mg, 0.1 mmol), AlCl3 (66.5
mg, 0.5 mmol, 5 equiv) and the general procedure described above, 3,4-
bis(4-methoxyphenyl)-1H-pyrrole-2,5-dione was obtained in 88% (27.2
mg, 0.088 mmol) yield: 1H NMR (CDCl3, 200 MHz) δ 7.47 (d, J = 9.1
Hz, 4H), 6.88 (d, J = 9.1 Hz, 4H), 3.83 (s, 6H); 13C NMR (CDCl3, 50
MHz) δ 170.9, 161.0, 135.1, 131.6, 121.2, 114.3, 55.5; HRMS (CI) for
C18H15NO4 calculated 309.0998, found 309.1001.
General Procedure for the Synthesis of Monoamino Sub-
stituted Maleimides (Table 5, compound a). To a mixture of
1-(4-methoxybenyl)-3,4-dibromo-1H-pyrrole-2,5-dione (3) (150 mg,
0.4 mmol) and Na2CO3 (134 mg, 1 mmol, 2.5 equiv) in THF (6 mL)
was added the amine (0.42 mmol, 1.05 equiv). The reaction mixture was
stirred at room temperature for 30 min and up to 2 h depending on the
amine used (monitored via TLC) at which time the solvent was
evaporated under a reduced pressure. The residue was taken up in
DCM (40 mL), washed with water (2 ꢁ 10 mL) and dried with
Na2SO4. Concentration of DCM under reduced pressure yielded
the mono amino substituted maleimide after purification by column
chromatography on silica gel. 1-(4-Methoxybenzyl)-3-(N-methyl-N-
phenylamino)-4-bromo-1H-pyrrole-2,5-dione (Table 5 entry 8, com-
pound a). Using N-methylaniline (45.5 μL, 0.42 mmol, 1.05 equiv) and
the general procedure described above, the reaction mixture was warmed
to 40 °C for 2 h. 1-(4-Methoxybenzyl)-3-(N-methyl-N-phenylamino)-4-
bromo-1H-pyrrole-2,5-dione was obtained in 95% yield (160.4 mg, 0.40
mmol) after purification by column chromatography on silica gel using
10% ethylacetate in hexane as the eluent: 1H NMR (CDCl3, 200 MHz) δ
3-(4-Methoxyphenyl)-4-morpholine-1H-pyrrole-2,5-dione
(Table 5, entry 4, compound c). Using 1-(4-methoxybenzyl)-3-(4-
methoxyphenyl)-4-morphholine-1H-pyrrole-2,5-dione (40.8 mg, 0.1
mmol), AlCl3 (66.5 mg, 0.5 mmol, 5 equiv) and the general procedure
described for deprotection of symmetrical aryl maleimides, 3-(4-meth-
oxyphenyl)-4-morphholine-1H-pyrrole-2,5-dione was obtained in 85%
yield (24.8 mg, 0.085 mmol) after purification using column chroma-
tography on silica gel with 30% ethylacetate in hexane as the eluent: 1H
NMR (CDCl3, 200 MHz) δ 7.24 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz,
2H) 3.82 (s, 3H), 3.68 (t, J = 4.4 Hz, 4H), 3.51 (t, J = 4.4 Hz, 4H), 170.6,
168.0, 159.3, 142.7, 131.4, 128.5, 122.4, 113.7, 107.0 66.8, 55.3, 48.8;
HRMS (CI) for C15H17N2O4 (M þ 1) calculated 289.1188 found
289.1180.
General Procedure for the Synthesis of PMB-Protected
Diamino Maleimides. Monoaminated, PMB-protected maleimide
(0.2 mmol) in DMF (0.5 mL) was treated with the amine (0.6 mmol,
3 equiv) and TEA (84 μL, 0.6 mmol) the microwaved at 100 °C for 30
min. The reaction mixture was taken up in DCM (10 mL) and washed
with water (2 ꢁ 5 mL). The organic layer was dried with Na2SO4 and
concentrated under reduced vacuum. Purification of the residue by
column chromatography on silica gel using 20% ethylacetate in hexane
as the eluent yielded the diamino products. 1-(4-Methoxybenzyl)-
3-(butylamino)-4-(phenylamino)-1H-pyrrole-2,5-dione (4). Using
1-(4-methoxybenzyl)-3-bromo-4-(phenylamino)-1H-pyrrole-2,5-dione
(77.2 mg, 0.2 mmol) and butyl amine (60 μL, 0.6 mmol) and the general
procedure described above, 1-(4-methoxybenzyl)-3-(butylamino)-
4-(phenylamino)-1H-pyrrole-2,5-dione was obtained 84% yield
(63 mg, 0.167 mmol): 1H NMR (CDCl3, 200 MHz) δ 7.20ꢀ7.39 (m,
5H), 7.13 (d, J = 9.2 Hz, 3H), 6.84 (d, J = 7.2 Hz, 1H), 5.10 (s, 1H), 4.89
(b, 1H), 3.78 (s, 3H), 3.14 (q, J = 6.6 Hz, 2H), 1.35ꢀ1.45 (m, 2H),
1.14ꢀ1.45 (m, 2H), 0.78 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 50
MHz) δ 171.0, 168.1, 159.3, 145.9, 130.0, 129.9, 129.4, 125.7, 119.8,
118.9, 114.8, 114.1, 55.4, 43.3, 41.0, 32.8, 19.8, 13.7: HRMS (CI) for
C22H26N3O3 (M þ 1) calculated 380.1969, found 380.1960.
1-(2,5-Dioxo-4-(phenylamino)-2,5-dihydro-1H-pyrrol-3-yl)-
1-(4-methoxybenzyl)piperidinium Chloride (9). Using 1-(4-
methoxybenzyl)-3-(phenylamino)-4-(piperidin-1-yl)-1H-pyrrole-2,5-dione
3128
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The Journal of Organic Chemistry
ARTICLE
(39.2 mg, 0.1 mmol), AlCl3 (66.5 mg, 0.5 mmol, 5 equiv), anisole (2 mL)
and stirring the reaction at room temperature for 12 h, yielded compound 9
in 89% yield (34.9 mg, 0.089 mmol) after purification using 30% ethylace-
tate in hexane as the eluent: 1H NMR (CDCl3, 200 MHz) δ 7.48 (d, J = 7.6
Hz, 1H), 7.15ꢀ7.27 (overlap, 4H), 6.64ꢀ6.88 (overlap, 4H), 4.67 (s, 1),
4.55 (s, 3H), 3.75 (s, 3H), 2.31ꢀ2.33 (m, 4H), 1.41ꢀ1.45 (m, 6H); 13C
NMR (CDCl3, 50 MHz) δ 176.0, 175.6, 159.3, 149.4, 131.0, 129.8, 127.7,
126.1, 124.3, 120.4, 114.1, 78.9, 56.7, 55.3, 48.5, 42.3, 25.8, 24.5; HRMS
(CI) for C23H26N3O3 calculated 392.1969 found 392.1966.
3,4-Bromo-1-(4-nitrophenyl)-1H-pyyrole-2,5-dione (11). To
a mixture of 3,4-dibromomaleic anhydride (1.95 g, 7.65 mmol) in acetic
acid (25 mL) was added p-nitroaniline (1.16 g, 8.4 mmol). The reaction
mixture was refluxed for 8 h. Evaporation of the solvent under reduced
pressure was followed by column chromatography on silica gel using
30% ethylacetate in hexane as the eluent, 3,4-Bromo-1-(4-nitrophenyl)-
1H-pyyrole-2,5-dione was obtained in 75% yield (2.13 g, 5.7 mmol): 1H
NMR (CDCl3, 200 MHz) δ 8.35 (d, J = 9.1 Hz, 2H), 7.66 (d, J = 9.1 Hz,
2H); 13C NMR (CDCl3, 50 MHz) δ 162.3, 146.9, 136.7, 130.6, 125.9,
124.8; HRMS (CI) for C10H4BrN2O4 calculated 373.8538 found
373.8538.
(25 mL) and acetic acid (15 mL) was added p-methoxybenylamine
(744 μL, 5.7 mmol, 1.1 equiv) and NaBH(OAc)3 (3.30 g, 15.6 mmol,
3 equiv). The reaction mixture was stirred at room temperature for 24
h at which time the mixture was taken up in CHCl3 (100 mL) and
washed with water (2 ꢁ 50 mL). The organic layer was dried with
Na2SO4, concentrated under a reduced pressure and purified using
column chromatography on silica gel with 30% ethylacetate in hexane
as the eluent. compound 12 was obtained in 76% yield (1.4 g, 4
mmol): 1H NMR (CDCl3, 200 MHz) δ 1H NMR 7.18 (d, J = 8 Hz,
2H), 6.86 (d, J = 8.4 Hz, 2H), 4.59 (s, 2H), 3.90 (s, 2H), 3.79 (s, 3H);
13C NMR (CDCl3, 50 MHz) δ 165.0, 159.4, 133.6, 129.3, 127.8,
120.6, 114.2, 56.8, 55.6, 47.4. HRMS (CI) for C12H11Br2NO2
calculated 358.9157 found 358.9155.
General Procedure for Monoarylated r,β-Unsaturated-γ-
butyrolactams (Table 7, compound a). To a mixture of 1-(4-
methoxybenzyl)-3,4-dibromo-1H-pyrrol-2(5H)-one compound (12)
(100 mg, 0.28 mmol), aryl boronic acid (0.31 mmol, 1.1 equiv), KF
(48.7 mg, 0.84 mmol, 3eq), Pd2(dba)3 CHCl3 (11.4 mg, 0.011 mmol,
3
4 mol %), PA-Ph, (6.4 mg. 0.022 mmol, 8 mmol %), in a reaction flask
was added dried toluene (3 mL). The mixture was degassed, placed
under an atmosphere of argon and stirred at 60 °C for 9 h. Toluene was
evaporated under reduced pressure and the reaction mixture was
purified by column chromatography using 30% ethylacetate in hexane
as the eluent. 1-(4-Methoxybenzyl)-3-bromo-4-p-tolyl-1H-2(5H)-
one (Table 7, entry 7, compound a). Using 4-methylphenylboronic
(42.5 mg, 0.31 mmol) and the general procedure described above, 1-(4-
methoxybenzyl)-3-bromo-4-p-tolyl-1H-2(5H)-one was obtained in 68%
yield (70.5 mg, 0.19 mmol): 1H NMR (CDCl3, 200 MHz) δ 1H NMR
(CDCl3, 200 MHz) δ 7.68 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 4H),
6.89 (d, J = 8.6 Hz, 2H), 4.67 (s, 2H), 4.15 (s, 2H), 3.80 (s, 3H), 2.37 (s,
3H); 13C NMR (CDCl3, 50 MHz) δ 167.3, 159.5, 147.9, 140.8, 129.8,
129.7, 128.9, 128.8, 127.0, 114.5, 113.0, 55.5, 52.7, 46.8, 21.7; HRMS
(CI) for C19H18BrNO2 calculated 371.0521 found 371.0520.
General Procedure for the Synthesis of Bisamino Substi-
tuted Maleimides (Table 6, compound b). To a mixture of 3,4-
dibromo-1-(4-nitrophenyl)-1H-pyrrole-2,5-dione, compound (11) (93
mg, 0.25 mmol), TEA (88 μL, 0.63 mmol, 2.5 equiv) in DMF (0.5 mL)
was added the amine (0.26 mmol, 1.05 equiv). The reaction mixture was
stirred at room for 3 min at which time additional TEA (88 μL, 0.63
mmol, 2.5 equiv) and the second amine (0.38 mmol, 1.5 equiv) were
added. The reaction mixture was microwaved at 50 °C for 30 min, then
taken up in DCM (10 mL) and washed with water (2 ꢁ 5 mL). The
organic extract was dried with Na2SO4 and concentrated under reduced
pressure. Purification of the mixture using column chromatography
on silica gel with 20% ethylacetate in hexane as the eluent yielded the
diamino substituted maleimides. 3-Morpholino-1-(4-nitrophenyl)-4-
(phenylamino)-1H-pyrrole-2,5-dione (Table 6, entry 1, compound b).
Using aniline (24.6 μL, 0.26 mmol) as the first amine, morpholine (33.2
μL, 0.38 mmol) as the second amine and the general procedure
described, 3-morpholino-1-(4-nitrophenyl)-4-(phenylamino)-1H-pyr-
General Procedure for the Preparation of Bisaryl Substi-
tuted r,β-Unsaturated-γ-butyrolactams (Table 8, com-
pound b). To a mixture of the monoarylated 3-bromo-1H- pyrrol-
2(5H)-one compound (0.1 mmol), aryl boronic acid (0.12 mmol, 1.2
1
equiv), KF (17.7 mg, 0.3 mmol, 3 equiv), Pd2(dba)3 CHCl3 (4.1 mg,
role-2,5-dione was obtained in 93% yield (91.5 mg, 0.23 mmol): H
3
0.004 mmol, 4 mol %), PA-Ph, (2.3 mg. 0.008 mmol, 8 mmol %) was
added dried toluene (3 mL). The mixture was degassed, placed under an
atmosphere of argon and stirred 80 °C for 12 h. Toluene was evaporated
under reduced pressure and the reaction mixture was purified by column
chromatography using with 30% ethylacetate in hexane as the eluent.
1-(4-Methoxybenzyl)-4-(4-methoxyphenyl)-3-p-tolyl-1H-2(5H)-one
(Table 8, entry 1, compound b). Using 1-(4-methoxybenzyl)-3-bromo-
4-(4-methoxyphenyl)-1H-2(5H)-one (38.8 mg, 0.1 mmol) and 4-methyl-
phenylboronic acid (16 mg, 0.12 mmol) and the general procedure
described above, 1-(4-methoxybenzyl)-4-(4-methoxyphenyl)-3-p-tolyl-1H-
2(5H)-one was obtained in 78% yield (31.2 mg, 0.078 mmol): 1H NMR
(CDCl3 200 MHz) δ 7.18ꢀ7.32 (m, 8H), 6.88 (d, J = 8.2 Hz, 2H), 6.76 (d,
J = 8.2 Hz, 2H), 4.69 (s, 2H), 4.13 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 2.36
(s, 3H); 13C NMR (CDCl3, 176 MHz) δ 170.1, 160.1, 159.1, 146.5, 137.7,
130.8, 129.7, 129.6, 129.5, 129.4, 129.2, 128.9, 125.7, 114.1, 114.0, 55.3,
51.7, 45.8, 21.4; HRMS (CI) for C26H25NO3 calculated 399.1834 found
399.1823.
1-(4-Methoxyphenyl)-3-p-tolyl-1H-2(5H)-one (Table 8, entry
1, compound c). Using 1-(4-methoxybenzyl)-4-(4-methoxyphenyl)-3-p-
tolyl-1H-2(5H)-one (28 mg, 0.07 mmol), TFA (1 mL) anisole (1 mL) and
the general procedure above, 1-(4-methoxyphenyl)-3-p-tolyl-1H-2(5H)-one
was obtained in 84% yield (14.0 mg, 0.059 mmol): 1H NMR (CDCl3, 200
MHz) δ 7.15ꢀ7.31(m, 6H), 6.80 (d, J = 8.4 Hz, 2H), 4.34 (s, 2H), 3.80 (s,
3H), 2.34(s, 3H); 13CNMR(CDCl3, 50MHz) δ174.8, 160.5, 149.7, 138.0,
131.0, 129.6, 129.5, 129.3, 129.2, 125.9, 114.3, 55.7, 48.1, 21.7; HRMS (CI)
for C18H17NO2 calculated 279.1259 found 279.1257.
NMR (CDCl3, 700 MHz) δ 8.30 (d, J = 9.1, 2H), 7.70 (d, J = 9.1, 2H),
7.34 (t, J = 7.7 Hz, 2H), 7.03 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 7.7 Hz, 2H),
6.19 (s, 1H), 3.52 (t, J = 4.9 Hz, 4H), 3.90 (t, J = 4.9 Hz, 4H); 13C NMR
(CDCl3, 176 MHz) δ 167.3, 166.5, 145.6, 140.1, 137.8, 129.3, 124.9,
124.7, 124.5, 122.5, 118.4, 115.8, 66.9. 48.4. HRMS (CI) for
C20H18N4O5 calculated 394.1277 found 394.1275.
General Procedure for the Deprotection of Nitroaniline-
Protected Diamino Maleimides by Aminolysis (Table 6,
compound c). Ammonia gas was bubbled through a solution of the
nitroaniline-protected maleimide (0.15 mmol) in methanol (3 mL). The
reaction mixture was stirred at room temperature for 12 h. Concentra-
tion of the methanol under reduced pressure and purification using
column chromatography on silica gel with 20% ethylacetate in hexane as
the eluent yielded the diamino substituted maleimides. 3-Morpholino-
4-(phenylamino)-1H-pyrrole-2,5-dione (Table 6, entry 1, compound c).
Using 3-morpholino-1-(4-nitrophenyl)-4-(phenylamino)-1H-pyrrole-2,5-
dione (59.2 mg, 0.15 mmol) and the general procedure described
above, 3-morpholino-4-(phenylamino)-1H-pyrrole-2,5-dione was obtained
in 84% yield (34.7 mg, 0.127 mmol): 1H NMR (CDCl3, 700 MHz) δ 7.29
(t, J = 4.6 Hz, 2H), 7.06 (b, 1H), 6.91 (t, J = 4.2 Hz, 1H), 6.79 (d, J = 2.2 Hz,
2H), 5.94 (s, 1H), 3.51 (t, J = 2.6 Hz, 4H), 3.38 (t, J = 2.6 Hz, 4H). 13C
NMR (CDCl3, 176 MHz) δ 168.9, 168.2, 141.2, 129.2, 126.9, 121.7, 117.6,
114.9, 66.9, 48.0; HRMS (EI): for C14H15N3O3 calculated 273.1113 found
273.1129.
1-(4-Methoxybenzyl)-3,4-dibromo-1H-pyrrol-2(5H)-one
(12). To a mixture of mucobromic acid (1.32 g, 5.2 mmoL) in DCM
3129
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The Journal of Organic Chemistry
ARTICLE
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Supporting Information. MS and H and 13C NMR
1
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’ AUTHOR INFORMATION
Corresponding Author
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’ ACKNOWLEDGMENT
The authors thank the Natural Sciences and Engineering
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