Synthesis of 3-(alkylamino and anilino)-4-benzyloxycarbonyl-1H-pyrrole-2,5-diones via 5-[(alkylamino and anilino)(cyano)]-2,2-dimethyl-1,3-dioxane-4,6-diones

Article abstract of DOI:10.1016/S0040-4039(02)00467-7

Treatment of [(alkylamino and anilino)(cyano)methylene]-2,2-dimethyl-1,3-dioxane-4,6-diones with benzyl alcohol for 20 min at reflux gave 3-(alkylamino and anilino)-4-benzyloxycarbonylmaleimides.

Full text of DOI:10.1016/S0040-4039(02)00467-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3415–3418
Synthesis of 3-(alkylamino and anilino)-4-
benzyloxycarbonyl-1H-pyrrole-2,5-diones via 5-[(alkylamino and
anilino)(cyano)]-2,2-dimethyl-1,3-dioxane-4,6-diones
Moon-Kook Jeon and Kyongtae Kim*
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, South Korea
Received 22 January 2002; revised 6 March 2002; accepted 8 March 2002
Abstract—Treatment of [(alkylamino and anilino)(cyano)methylene]-2,2-dimethyl-1,3-dioxane-4,6-diones with benzyl alcohol for
20 min at reflux gave 3-(alkylamino and anilino)-4-benzyloxycarbonylmaleimides. © 2002 Published by Elsevier Science Ltd.
In recent years N-substituted maleimides and 5-ylid-
enepyrrol-2(5H)-ones have received growing attention
since the former have potential utility as fluorescent
reagents for labeling different mutant proteins1 and the
latter have interesting features associated with regiose-
lective synthesis of the molecules when different sub-
stituents are bonded to the positions 3 and 4 of the
skeleton.2
5H-1,2,3-dithiazol-5-ylidene)-2,2-dimethyl-1,3-dioxane-
4,6-dione 1 with primary alkylamines and anilines in
CH2Cl2 at rt, respectively.6 Compounds 2 are a kind of
Meldrum’s acid derivative, which would be expected to
possess versatile synthetic potentials in view of reports
describing the synthesis of a wide variety of organic
compounds such as 1,3-dicarbonyl compounds7 and
b-enamino esters8 via this type of Meldrum’s acid
derivative (Scheme 1).
The majority of methods reported for the synthesis of
maleimides are based on the reactions of the corre-
sponding maleic anhydride with an amine or ammo-
nium acetate.3 Similarly, the reaction of maleamic acid
with Et3N in either toluene or benzene, yielding N-
maleoylamino esters, may be in the same class as the
foregoing reaction.4 There exists one report of the
synthesis of N-alkylmaleimides using alkylamines,
maleic anhydride and cobalt naphthenate as a catalyst.1
We have found that treatment of 2 with benzyl alcohol
for 20 min at reflux gave title compound 3 in moderate
to fair yields.9 Reaction temperature, time and yield
and mp of 3 are summarized in Table 1.
When 2d (Ar=4-MeC6H4) was treated with benzyl
alcohol bearing a substituent such as F, Cl, and Me at
the para position under the same conditions (reflux, 20
min), 3 were obtained in 20, 13, and 17% yields,
respectively, together with unidentifiable mixtures.
In connection with an ongoing program for exploring
the synthetic utility of 5-arylimino-4-chloro-5H-1,2,3-
dithiazoles,5 we reported the facile synthesis of 5-[(alkyl-
amino and anilino)(cyano)methylene]-2,2-dimethyl-
1,3-dioxane-4,6-diones 2 by treatment of 5-(4-chloro-
In contrast, heating of 2d in t-butyl alcohol for 3 days
at reflux gave t-butyl 3-oxo-3-(4-tolylamino)propanoate
NHAr
O
BnO2C
BnOH
CN
CN
O
O
O
S
O
O
O
Cl
Ar
ArNH2
N
H
O
O
O
N
H
3
N
reflux
CO2Bn
NHAr
S
Ar = 2,4-(MeO)2C6H3
2
1
4
Scheme 1.
Keywords: cyano compounds; dithiazoles; imides.
* Corresponding author. Tel.: 82-2-880-6636; fax: 82-2-874-8858; e-mail: kkim@plaza.snu.ac.kr
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00467-7

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M.-K. Jeon, K. Kim / Tetrahedron Letters 43 (2002) 3415–3418
Table 1. Reaction temperature and time, and yield and mps of 3
Compounda
Ar
Temp. (°C)
Time (min)
Yieldb (%)
Mpd (°C)
3a
3b
3c
3d
3e
3f
Ph
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
155
20
20
20
20
20
20
20
20
76
44
68
72
56
48
75
35c
45c
31c
32
35
214–217e
240–243e
242–245e
220–224e
196–203e
203–204
220–222
152–154
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-MeC6H4
2,4-F2C6H3
2,4-(MeO)2C6H3
3g
3h
180
120 h
20
110
Reflux
155
3i
PhCH2
156–158
120
a Compounds 3 are yellow except for 3f (orange) and 3g (pale yellow).
b Isolated yields.
c cis-Benzyl 3-cyano-3-(2,4-dimethoxyphenylamino)propenoate (4)10 was isolated in 30, 18, and 6% yields at reflux, 155 and 110°C, respectively.
d Recrystallized from a mixture of CHCl3 and acetone except for 3e–g and 3i (from n-hexane and CH2Cl2).
e Decomposition temperature.
stable tautomer 2 exists predominantly12 (Scheme 3). A
5 (32%) along with the recovery of 2d (22%) (Scheme
nucleophilic attack of the hydroxy group of benzyl
alcohol on tautomers 2 and 9 would give intermediates
11 and 12, respectively. An analogous type of nucle-
ophilic attack has been reported for the reactions of
acyl Meldrum’s acid with alcohols and amines.7b,7e Sub-
sequent extrusion of an acetone molecule from 11 and
12 concomitant with an intramolecular cyclization
would give isoimide 8 and its tautomer 13,11 respec-
tively. Rearrangement of isoimide 8 to imide 3 may be
achieved by either nucleophilic attack of benzyl alcohol
on the carbonyl carbon of isoimide 8, followed by a
ring closure13 or thermal reaction.14 Alternatively, the
intermediate 13 might be formed by extrusion of an
acetone molecule at reflux temperature to give a ketene
14 in view of reports of the formation of numerous
products via ketene intermediates.7a,8c,15 Subsequent
nucleophilic attack of benzyl alcohol on 14, followed by
cyclization would give 13. It is worthwhile to note that
imides are generally more stable than the corresponding
isoimides.16 To the best of our knowledge, no example
involving benzyl alcohol as a catalyst has been reported
although several dehydrating agents and catalysts have
been utilized for the rearrangement of isoimides to
imides.17
2). Similar treatment of 2d with EtOH for 3 days under
the same conditions gave ethyl 3-oxo-3-(4-tolyl-
amino)propanoate 6 (13%), 5-[(ethoxy)(4-tolylamino)-
methylene]-2,2-di-methyl-1,3-dioxane-4,6-dione 7 (34%)
together with unreacted 2d (19%).
The structures of 3 were determined based on spectro-
scopic and analytical data. In particular, the IR spectra
exhibited three characteristic peaks at 1715–1755, 1638–
1651 and 1587–1624 cm−1, assigned to the three car-
bonyl groups. The IR bands are consistent with those
at 1738, 1655 and 1623 cm−1 exhibited by 3-anilino-4-
ethoxycarbonyl-1-phenylmaleimide.11 The HMBC spec-
trum of 3i shows that the N–H proton at position 1
correlates with the C-2, C-3, C-4 and C-5 carbons,
which rules out the possible formation of the structural
isomer, isoimide 8g.
NHAr
BnO2C
NH
O
O
8g
The mechanism for the formation of 3 may be rational-
ized by assuming an equilibrium mixture of tautomers
2, 9 and 10 in which the thermodynamically more
In summary, we have prepared unsymmetrically 3,4-di-
substituted maleimides from [(alkylamino and
Me
O
O
t-BuOH
reflux, 3 days
+
+
2d
t-BuO
N
H
5 (32%)
(22%)
2d
Me
O
O
O
N
O
O
EtOH
reflux, 3 days
O
OEt
2d
+
EtO
N
H
6 (13%)
(19%)
H
7 (34%)
Me
Scheme 2.

M.-K. Jeon, K. Kim / Tetrahedron Letters 43 (2002) 3415–3418
3417
O
O
O
O
O
O
O
O
O
CN
O
CN
O
CN
OH NAr
NHAr BnOH
NAr
..
2
10
9
O
_
O
O
O
O
O
C
N
C
N
O
CN
O
O
C
BnO OH
BnO OH
OH NAr
NHAr
O
NAr
_
11
12
14
3
O
_
BnOH
BnOH
..
NH
O-
BnO
O
O
O
NH
NH
NH
NAr
O
O
HO
BnO2C
O
NAr
NHAr
NHAr
BnO2C
BnO2C
BnO2C
8
13
Scheme 3.
anilino)(cyano)methylene] - 2,2 - dimethyl - 1,3 - dioxane-
4,6-diones and benzyl alcohol at reflux temperature.
Maitte, P. Synthesis 1981, 130–133; (b) Ce´le´rier, J.-P.;
Deloisy, E.; Lhommet, G.; Maitte, P. J. Org. Chem. 1979,
44, 3089; (c) Ce´le´rier, J.-P.; Lhommet, G.; Maitte, P.
Tetrahedron Lett. 1981, 22, 963–964; (d) Ce´le´rier, J.-P.;
Richaud, M. G.; Lhommet, G. Synthesis 1983, 195–197.
9. Typical procedure: Compound 2a (65 mg, 0.24 mmol) in
benzyl alcohol (1 mL) was heated with stirring for 20 min
at reflux temperature. The reaction mixture was cooled to
rt, followed by chromatography on a silica gel column
(230–400 mesh, 3.5×15 cm). Elution with a mixture of
n-hexane and EtOAc (3:1) gave benzyl alcohol. Subse-
quent elution with the same solvent mixture (2:1) gave 3a
(59 mg, 76%): mp 214–217°C (dec.) (CHCl3 and acetone);
Acknowledgements
This research project has been supported by a grant
from the Brain Korea 21 program.
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