A new synthetic route to authentic N-substituted aminomaleimides

Article abstract of DOI:10.1021/jo048031q

A number of compounds reported in the literature as N-aminomaleimides (2) are, instead, isomeric N-aminoisomaleimides (3). The ubiquity of this mischaracterization and its propagation within the literature are discussed. In addition, the first general synthetic route to aliphatic and aromatic N-substituted aminomaleimides is described. As an illustration, the compound reported to be N-(4-bromophenylamino)maleimide (2b) was prepared and determined to be N-(4-bromophenylamino)isomaleimide (3b). The authentic compound was synthesized by the condensation of 4-bromophenylhydrazine (7b) and the exo-furan/maleic anhydride Diels-Alder adduct (8) in acetic acid to produce the furan-protected aminomaleimide 10b, followed by heating to remove furan through the retro Diels-Alder reaction. The structures of 2b, 3b, and 10b were established unequivocally by X-ray crystallography and other spectroscopic techniques.

Full text of DOI:10.1021/jo048031q

than NMR for structural assignment and the faulty
assumption that 1 undergoes ring closure in a manner
analogous to N-aminosuccinamic acids.
A New Synthetic Route to Authentic
N-Substituted Aminomaleimides
N. R. Conley, R. J. Hung, and C. G. Willson*
The University of Texas at Austin, Department of Chemistry
and Biochemistry, 1 University Station, A5300,
Austin, Texas 78712-0164
willson@che.utexas.edu
Received November 5, 2004
The unexpected formation of aminoisomaleimide 3 may
be accounted for by the mechanism shown in Scheme 1,
which is analogous to the one proposed for the dehydra-
tion of N-arylmaleamic acids.12 After formation of the
mixed anhydride 4, deprotonation of the amide and
ejection of the acetate ion result in formation of amino-
isomaleimide 3.
The ubiquity of the aminomaleimide-aminoisomale-
imide mischaracterization in the literature has resulted
in a number of workers13-15 continuing to rely upon and
cite flawed reports without knowledge of the mischarac-
terization. For example, in their 1988 publication de-
scribing a new method for the synthesis of NSAMs, Florac
and co-workers13 wrote that “the N-amino maleimides
described previously have only been prepared from the
reaction of hydrazines and maleic anhydrides” and cited
several erroneous reports.16 They continued by stating
that “N-amino maleimides are useful in the synthesis of
pyridazine-3,6-diones” more than a decade after Ruben-
stein and co-workers demonstrated that it was actually
aminoisomaleimides, not NSAMs, that rearranged to
pyridazinones 5 upon treatment with sulfuric acid.10
A number of compounds reported in the literature as
N-aminomaleimides (2) are, instead, isomeric N-aminoiso-
maleimides (3). The ubiquity of this mischaracterization and
its propagation within the literature are discussed. In
addition, the first general synthetic route to aliphatic and
aromatic N-substituted aminomaleimides is described. As
an illustration, the compound reported to be N-(4-bromophe-
nylamino)maleimide (2b) was prepared and determined to
be N-(4-bromophenylamino)isomaleimide (3b). The authen-
tic compound was synthesized by the condensation of 4-bro-
mophenylhydrazine (7b) and the exo-furan/maleic anhydride
Diels-Alder adduct (8) in acetic acid to produce the furan-
protected aminomaleimide 10b, followed by heating to
remove furan through the retro Diels-Alder reaction. The
structures of 2b, 3b, and 10b were established unequivocally
by X-ray crystallography and other spectroscopic techniques.
Several early reports describe the reaction of maleic
anhydride with a hydrazine derivative to give N-substi-
tuted aminomaleamic acids 1, followed by dehydrative
cyclization in acetic anhydride or thionyl chloride, as a
method of preparing N-substituted aminomaleimides
2,1-7 herein referred to as NSAMs. These initial reports
have since been proven inaccurate,8-11 and the reported
compounds are now thought to be N-substituted amino-
isomaleimides 3. The mischaracterization is attributable
to the authors’ reliance on characterization methods other
In a more spectacular example, Cheng and Comer15
recently reported the preparation of 2c by reacting maleic
anhydride with phenylhydrazine, followed by dehydra-
tion in thionyl chloride.17 It is evident from their 1H NMR
data, which shows nonequivalent olefinic protons, that
they instead prepared aminoisomaleimide 3c. Also in-
(11) To the best of our knowledge, we are the first to identify the
method reported for the synthesis of N-aminomaleimide (2a) in ref 7
as erroneous. We repeated their procedure, which involved refluxing
maleic anhydride and tert-butylcarbazate in chloroform, and observed
two doublets, each corresponding to one proton, in the olefinic region
of the 1H NMR spectrum (see the Supporting Information). This
indicates the formation of 3d which, upon deprotection, would yield
aminoisomaleimide 3a.
(1) Feuer, H.; Rubinstein, H. J. Am. Chem. Soc. 1958, 80, 5873.
(2) Feuer, H.; Asunskis, J. J. Org. Chem. 1962, 27, 4684.
(3) Baloniak, S. Rocz. Chem. 1968, 42, 1231.
(4) Baloniak, S.; Mroczkiewicz, A. Rocz. Chem. 1974, 48, 399-407.
(5) Baloniak, S.; Thiel, U.; Pacholczyk, M. Acta Polon. Pharm. 1976,
33, 73-9.
(6) Hageman, H. A.; Hubbard, W. L. U.S. Patent 3257414, 1966;
Chem. Abstr. 1966, 65, 7066c.
(12) Sauers, C. K. J. Org. Chem. 1969, 34, 2275-9.
(7) Krause, J. G.; Kwon, S.; George, B. J. Org. Chem. 1972, 37, 2040.
(8) Hedeya, E.; Hinman, R. L.; Theodoropulos, S. J. Org. Chem.
1966, 31, 1311.
(13) Florac, C.; Baudy-Floc’h, M.; Robert, A. J. Chem. Soc., Chem.
Commun. 1988, 1524.
(14) Mroczkiewicz, A. Pol. J. Chem. 1980, 54, 1095-9.
(15) Cheng, S.; Comer, D. D. Tetrahedron Lett. 2002, 43, 1179-81.
(16) Among others, these included refs 4 and 5.
(9) Rubinstein, H.; Skarbek, J. E. J. Org. Chem. 1971, 36, 3372-6.
(10) Rubinstein, H.; Parnarouskis, M.; Feuer, H. J. Org. Chem. 1973,
38, 2166-9.
(17) The authors were relying on erroneous refs 1 and 2.
10.1021/jo048031q CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/28/2005
J. Org. Chem. 2005, 70, 4553-4555
4553

SCHEME 1
SCHEME 2
congruous is their report of seven lines in the 13C NMR
spectrum; 2c should have only six lines and 3c should
have eight. After repeating their procedure, we found that
the 13C NMR spectrum does in fact contain eight lines18
and the spectrum is consistent with isomaleimide 3c. It
is important to note that the other nine “N-(arylamino)-
maleimides” that Cheng and Comer prepared are almost
certainly aminoisomaleimides as well, and in light of this
mischaracterization, their report of alumina-catalyzed
Michael addition of mercaptans to N-anilinomaleimides15
must be reevaluated.
the versatility of this new method, 10c and 10d were also
prepared in good yield.20
Although methods for the preparation of authentic
aminomaleimides have been described, they have limita-
tions that reduce their synthetic utility. In the method
of Florac et al.,13 2-aminopyridine is reacted with an
R-halohydrazide (6) to produce an NSAM that has aryl
groups at the carbon-carbon double-bond position. As a
result, this method is more relevant as a route to
substituted maleic anhydrides, which are obtained after
hydrolysis of the NSAM, rather than synthetically useful
NSAMs. A particulary interesting route to NSAM 2c
involves the dehydration of the tetracarbonyliron complex
of 1c in acetic anhydride at room temperature.19 The
authors propose that the π-bound Fe(CO)4 group in-
creases the nucleophilic character of the amide-like
nitrogen atom in 1c, which favors formation of 2c. They
also note that coordination of tetracarbonyliron to 1c
results in the double bond becoming closer in character
to a saturated bond; this is important because, unlike
maleamic acids (1), succinamic acids undergo cyclization
to the corresponding five-membered nitrogen hetero-
cycles. Unfortunately, the overall yield of 2c from tetra-
carbonyl(maleic anhydride)iron is only 14%.
While reviewing the literature, we came across a report
by Hedaya and co-workers8 which described the synthesis
of N,N′-bimaleimide by the condensation of the endo-
furan/maleic anhydride Diels-Alder adduct and hydra-
zine hydrate (7a‚H2O), followed by the retro-Diels-Alder
reaction to remove furan. We investigated this synthesis
to determine if it could be adapted for use with substi-
tuted hydrazines (7) as a general route to NSAMs
(Scheme 2), particularly 2b, a compound which we
required for other work. Indeed, we were able to prepare
2b in three steps with a 57% overall yield, thereby
demonstrating a new route to the synthesis of NSAMs.
The compound previously reported to be “4-bromophen-
ylaminomaleimide”4 (2b) was also prepared and shown
to be N-(4-bromophenylamino)isomaleimide (3b). The
crystal structures for compounds 10b, 2b, and 3b, which
can be found in the Supporting Information, were con-
sistent with the structural assignments. To demonstrate
Experimental Section
(2Z)-4-[2-(4-Bromophenyl)hydrazino]-4-oxobut-2-enoic
Acid (1b). A solution of 4-bromophenylhydrazine (7b, 0.250 g,
1.34 mmol) in diethyl ether (5 mL) was added dropwise to a
solution of maleic anhydride (0.131 g, 1.34 mmol) in diethyl ether
(5 mL). The reaction mixture was stirred for 20 min at rt and
then cooled to 0 °C for 20 min. The resulting yellow precipitate
was suction filtered, washed with cold diethyl ether, and dried
under vacuum to give 0.295 g (77% yield) of 1b: yellow powder;
mp 175-176 °C; 1H NMR (300 MHz, DMSO-d6) δ 13.25 (br s,
1H), 10.21 (br s, 1H), 8.12 (br s, 1H), 7.33-7.25 (m, 2H), 6.76-
6.69 (m, 2H), 6.53 (d, J ) 12.3 Hz, 0.18H, minor conformer),
6.39 (d, J ) 12.3 Hz, 0.87H, major conformer), 6.26 (d, J ) 12.3
Hz, 0.85H, major conformer), and 6.06 (d, J ) 12.3 Hz, 0.15H,
minor conformer) [complex spectrum due to hindered rotation];
13C{1H} NMR (75 MHz, DMSO-d6 saturated with H2O) δ 168.6,
167.0, 148.5, 132.8, 131.8, 131.6, 115.9, and 112.0; IR (KBr) 3433,
3274, 3216, 3017, 1705, 1623, 1522, 1480, 1417, 1305, 1247, 847,
and 816 cm-1; MS (CI-) m/z (rel intensity) 285 ([M - H + 2]-;
99), 283 ([M - H]-; 100), 268 ([M - H2O + 2]-; 96), and 266 ([M
- H2O]-; 99); HRMS (CI-) calcd for C10H8N2O3Br ([M - H]-)
282.9711, found 282.9718. Anal. Calcd for C10H9N2O3Br
(285.09): C, 42.13; H, 3.18; N, 9.83. Found: C, 41.90; H, 3.20;
N, 9.67.
(2Z)-Furan-2,5-dione (4-Bromophenyl)hydrazone (3b).
To 1b (0.116 g, 0.406 mmol) and sodium acetate (0.020 g, 0.243
mmol) was added acetic anhydride (5 mL). The reaction mixture
was heated to 100 °C for 5 min under a nitrogen atmosphere,
and after cooling to rt, water (10 mL) was added. The reaction
mixture was stirred overnight and cooled to 0 °C, and the
product was isolated by centrifugation. The solid was washed
with water and dried under vacuum to give 0.082 g (76% yield)
of 3b: yellow powder; mp 222-223 °C; 1H NMR (500 MHz,
DMSO-d6) δ 10.77 (s, 1H), 7.78 (d, J ) 5.4 Hz, 1H), 7.43-7.40
(m, 2H), 7.21-7.18 (m, 2H), and 6.59 (d, J ) 5.4 Hz, 1H); 13C-
{1H} NMR (125 MHz, DMSO-d6) δ 166.9, 143.1, 141.3, 140.9,
131.8, 120.4, 115.2, and 112.2; IR (KBr) 3431, 3274, 2961, 2919,
1775, 1751, 1631, 1591, 1546, 1519, 1485, 1260, 1239, 1169,
1105, 1066, 1023, 938, 886, 818, 800, 767, and 689 cm-1; MS
(CI-) m/z (rel intensity) 268 (M- + 2; 71) and 266 (M-; 100);
HRMS (CI-) calcd for C10H6N2O2Br ([M - H]-) 264.9613, found
264.9618. Anal. Calcd for C10H7N2O2Br (267.08): C, 44.97; H,
2.64; N, 10.49. Found: C, 44.98; H, 2.77; N, 10.44.
3-{[2-(4-Bromophenyl)hydrazino]carbonyl}-7-oxabicyclo-
[2.2.1]hept-5-ene-2-carboxylic Acid (9b). To a solution of
4-bromophenylhydrazine (7b, 0.350 g, 1.87 mmol) in acetic acid
(5 mL) was added a slurry of exo-3,6-epoxy-1,2,3,6-tetrahydro-
phthalic anhydride (8, 0.311 g, 1.87 mmol) in acetic acid (5 mL),
and the reaction mixture was stirred for 20 min at rt. The
(18) There are two closely spaced lines at 140.98 and 141.04 ppm,
which could be resolved by the addition of a single drop of water to
the DMSO-d6. The spectrum is available as Supporting Information.
(19) Nesmeyanov, A. N.; Rybinskaya, M. I.; Rybin, L. V.; Arutyun-
yan, A. V. J. Gen. Chem. USSR (Engl. Transl.) 1974, 44, 578-85.
(20) During the reaction of 7d with 8, maleamic acid 9d did not
precipitate out of acetic acid, and therefore, it was not isolated.
4554 J. Org. Chem., Vol. 70, No. 11, 2005

precipitate was suction filtered, washed with diethyl ether, and
NMR (50 MHz, DMSO-d6) δ 172.6, 170.8, 155.1, 137.9, 137.2,
136.6, 125.9, 110.8, 80.8, 79.1, 46.4, and 44.5; IR (KBr) 3312,
3275, 3008, 1698, 1667, 1598, 1493, 1413, 1389, 1337, 1260,
1228, 1211, 1113, 1043, 991, 902, 845, 824, 753, 713, 632, and
504 cm-1; MS (ESI-) m/z (rel intensity) 318 ([M - H]-; 34) and
250 ([M - furan - H]-; 100). Anal. Calcd for C14H13N3O6
(319.27): C, 52.67; H, 4.10; N, 13.16. Found: C, 52.73; H, 4.39;
N, 13.42.
dried under vacuum to afford 0.535 g (81% yield) of 9b: colorless
1
powder; mp 145 °C dec; H NMR (300 MHz, DMSO-d6) δ 12.11
(br s, 1H), 9.62 (s, 1H), 7.84 (s, 1H), 7.26-7.20 (m, 2H), 6.75-
6.68 (m, 2H), 6.47 (s, 2H), 5.10 (s, 1H), 4.89 (s, 1H), 2.68 (d, J )
9.0 Hz, 1H), and 2.60 (d, J ) 9.3 Hz, 1H); 13C{1H} NMR (75
MHz, DMSO-d6) δ 172.5, 170.7, 148.7, 137.1, 136.5, 131.2, 114.3,
109.0, 80.8, 79.0, 46.1, and 44.5; IR (KBr) 3445, 3258, 2959, 2917,
2866, 2839, 1693, 1658, 1596, 1542, 1487, 1456, 1375, 1301,
1262, 1216, 1165, 1049, 998, 901, and 827 cm-1; MS (ESI-) m/z
(rel intensity) 353 ([M - H + 2]-; 84), 351 ([M - H]-; 90), 285
([M - furan - H + 2]-; 97), and 283 ([M - furan - H]-; 100).
Anal. Calcd for C14H13N2O4Br (353.17): C, 47.61; H, 3.71; N,
7.93. Found: C, 47.28; H, 3.83; N, 7.83.
exo-4-[(4-Nitrophenyl)amino]-10-oxa-4-azatricyclo-
[5.2.1.02,6]dec-8-ene-3,5-dione (10c). A slurry of 7c (0.738 g,
4.82 mmol) and 8 (0.800 g, 4.82 mmol) in acetic acid (55 mL)
was stirred at rt for 13 h under a nitrogen atmosphere. Water
(200 mL) was added, and the reaction mixture was cooled to 0
°C. The precipitate was suction filtered and washed with diethyl
ether to give 0.880 g of 10c (61%): brown powder; mp 172 °C
exo-4-[(4-Bromophenyl)amino]-10-oxa-4-azatricyclo-
[5.2.1.02,6]dec-8-ene-3,5-dione (10b). A slurry of 9b (3.27 g,
9.26 mmol) in acetic acid (327 mL) was stirred at rt for 8 h under
a nitrogen atmosphere. The solvent was removed under vacuum,
the solid was washed into a saturated solution of sodium
bicarbonate (150 mL) using dichloromethane, and the mixture
was stirred vigorously for 5 min. The organic layer was sepa-
rated, washed with brine, treated with magnesium sulfate, and
dried under vacuum. Purification of the tan crude product by
flash column chromatography (silica gel, ethyl acetate/hexanes
1:1) afforded 2.28 g of 10b (73%): colorless powder; mp 151-
152 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.35-7.27
(m, 2H), 6.68-6.59 (m, 2H), 6.58 (s, 2H), 5.21 (s, 2H), and 3.00
(s, 2H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 174.8, 145.6, 136.2,
131.5, 114.2, 110.7, 80.3, and 45.0; IR (KBr) 3491, 3259, 2999,
1788, 1717, 1594, 1489, 1410, 1310, 1286. 1246, 1199, 1155,
1123, 1074, 1013, 1003, 957, 920, 884, 851, 827, 816, 808, 720,
658, and 643 cm-1; MS (ESI-) m/z (rel intensity) 335 ([M - H +
2]-; 6), 333 ([M - H]-; 5), 268 ([M - furan + 2]-; 95), and 266
([M - furan]-; 100); HRMS (CI-) calcd for C14H10N2O3Br ([M -
H]-) 332.9875, found 332.9872. Anal. Calcd for C14H11N2O3Br
(335.15): C, 50.17; H, 3.31; N, 8.36. Found: C, 49.91; H, 3.46;
N, 8.19.
1
dec; H NMR (200 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.08 (d, J )
9.0 Hz, 2H), 6.79 (d, J ) 7.6 Hz, 2H), 6.59 (s, 2H), 5.26 (s, 2H),
and 3.06 (s, 2H); 13C{1H} NMR (50 MHz, DMSO-d6) δ 174.5,
152.1, 139.5, 136.3, 125.8, 111.2, 80.5, and 45.2; IR (KBr) 3483,
3286, 3099, 3025, 3006, 1788, 1717, 1597, 1524, 1505, 1493,
1406, 1339, 1262, 1215, 1189, 1158, 1115, 1089, 1013, 919, 879,
850, 821, 807, 752, 701, 652, 628, and 590 cm-1; MS (ESI+) m/z
(rel intensity) 324 ([M + Na]+; 92), 256 ([M - furan + Na]+;
100), 302 ([M + H]+; 18), and 234 ([M - furan + H]+, 38). Anal.
Calcd for C14H11N3O5 (301.25): C, 55.82; H, 3.68; N 13.94.
Found: C, 55.42; H, 3.88; N, 13.79.
4-(Methylamino)-10-oxa-4-azatricyclo5.2.1.02,6]dec-8-ene-
3,5-dione (10d). To a slurry of 8 (4.00 g, 24.1 mmol) and acetic
acid (100 mL) was added 7d (1.50 g, 1.71 mL, 32.6 mmol), and
the reaction mixture was stirred for 24 h under a nitrogen
atmosphere. The solvent was removed under vacuum, and the
crude product was purified by flash column chromatography
(silica gel, dichloromethane/methanol, 19:1), affording 3.33 g of
10d (71%): colorless powder; mp 148-149 °C dec; 1H NMR (200
MHz, DMSO-d6) δ 6.57 (s, 2H), 5.68 (q, J ) 5.6 Hz, 1H), 5.15 (s,
2H), 2.87 (s, 2H), and 2.47 (d, J ) 5.6 Hz, 3H); 13C{1H} NMR
(50 MHz, CDCl3) δ 173.7, 136.1, 80.4, 45.2, and 37.4; IR (KBr)
3457, 3303, 3074, 3029, 2989, 2960, 2932, 2895, 2869, 1780,
1702, 1525, 1444, 1414, 1399, 1312, 1288, 1247, 1222, 1200,
1176, 1155, 1106, 1012, 958, 920, 877, 849, 809, 717, 647, 611,
and 586 cm-1; MS (ESI+) m/z (rel intensity) 195 ([M + H]+; 65)
and 127 ([M - furan + H]+; 100). Anal. Calcd for C9H10N2O3
(194.19): C, 55.67; H, 5.19; N, 14.43. Found: C, 54.98; H, 5.53;
N, 13.96.
1-[(4-Bromophenylamino)]-1H-pyrrole-2,5-dione (2b).
Deprotection of 10b (0.137 g, 0.409 mmol) was achieved by
heating to 175 °C for 10 min at 5 Torr in a Kugelrohr glass oven.
The starting material initially decomposed to a yellow solid and
then melted to give an orange liquid with vigorous bubbling.
Upon sitting for several days at rt, the resulting orange oil
crystallized to give 0.105 g of 2b (96% yield): yellow crystals;
1
mp 152-153 °C; H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H),
7.34-7.30 (m, 2H), 7.11 (s, 2H), and 6.67-6.63 (m, 2H); 13C-
{1H} NMR (75 MHz, DMSO-d6) δ 169.1, 146.4, 133.2, 131.6,
114.1, and 110.8; IR (KBr) 3479, 3316, 3096, 1718, 1596, 1503,
1489, 1421, 1306, 1286, 1246, 1169, 1116, 1074, 1049, 1005, 852.
Acknowledgment. Financial support for this work
by the Arnold and Mabel Beckman Foundation is
gratefully acknowledged. We also thank the following
people at The University of Texas at Austin: Dr. Ben
Shoulders for his assistance in the interpretation of
NMR spectra, Dr. Medhi Moini for advice regarding
mass spectroscopic ion notation, Dr. Vince Lynch for
performing the X-ray crystallographic analyses, and
Estelle Garza for her assistance with a portion of the
synthetic work. Near the end of this project, N.R.C.’s
affiliation changed to Stanford University and he thanks
Dr. Robert Waymouth at Stanford for providing the
laboratory space needed to complete this work.
820, 683, and 626 cm-1; MS (CI-) m/z (rel intensity) 268 (M-
+
2; 96) and 266 (M-; 100); HRMS (CI-) calcd for C10H6N2O2Br
([M - H]-) 264.9613, found 264.9620. Anal. Calcd for C10H7N2O2-
Br (267.08): C, 44.97; H, 2.64; N, 10.49. Found: C, 44.74; H,
2.78; N, 10.27.
3-{[2-(4-Nitrophenyl)hydrazino]carbonyl}-7-oxabicyclo-
[2.2.1]hept-5-ene-2-carboxylic Acid (9c). The title compound
was prepared analogously as described for 9b using 7c (0.738
g, 4.82 mmol) and 8 (0.800 g, 4.82 mmol). After workup, 0.605
g (39% yield) of 9c was obtained:21 brown powder; mp 135 °C
dec; 1H NMR (200 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.97 (s, 1H),
9,03 (s, 1H), 8.02 (d, J ) 9.2 Hz, 2H), 6.81 (d, J ) 9.2 Hz, 2H),
6.49 (s, 2H), 5.12 (s, 1H), 4.95 (s, 1H), and 2.67 (s, 2H); 13C{1H}
Supporting Information Available: 1H NMR, 13C NMR,
and IR spectra for all compounds described in the Experimen-
tal Section; crystal structures for 3b, 10b, and 2b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) As a result of its greater solubility in acetic acid, the amount
of aminomaleamic acid 9c recovered using this workup is somewhat
lower than the amount of 9b. Isolation of 9 is not required for the
preparation of 10, however.
JO048031Q
J. Org. Chem, Vol. 70, No. 11, 2005 4555