The synthesis of 2-ketopiperazine acetic acid esters and amides from ethylenediamines with maleates and maleimides

Article abstract of DOI:10.1016/S0040-4039(03)00103-5

The reaction of substituted ethylenediamines with various fumarates, maleates, and maleimides to form substituted ketopiperazine acetic acid esters and amides was investigated. This method affords a straightforward, high yield approach to a variety of potential peptidomimetics and can yield surprising results with regard to regio- and stereoselectivity.

Full text of DOI:10.1016/S0040-4039(03)00103-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1823–1826
The synthesis of 2-ketopiperazine acetic acid esters and amides
from ethylenediamines with maleates and maleimides
Matthew M. Abelman,a,* Karl J. Fisher,a Edward M. Doerfflera and Paul J. Edwardsb
aSignature BioScience, Inc., 1240 S. 47th St., Richmond, CA 94804, USA
bPfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 26 November 2002; accepted 10 January 2003
Abstract—The reaction of substituted ethylenediamines with various fumarates, maleates, and maleimides to form substituted
ketopiperazine acetic acid esters and amides was investigated. This method affords a straightforward, high yield approach to a
variety of potential peptidomimetics and can yield surprising results with regard to regio- and stereoselectivity. © 2003 Elsevier
Science Ltd. All rights reserved.
The 2-oxopiperazine-3-acetic acid methyl ester, 1, is an
(entries 4, 5). These examples lead to the conclusion
that the least substituted nitrogen of the diamine prefer-
ably adds first in 1,4 fashion with subsequent amide
formation by the tethered secondary amine. Methyl and
gem-dimethyl EDA chain substitution did not alter this
trend (entries 6, 7) nor was any stereo induction during
heterocycle formation noted (entry 6).3c It is not known
whether the observed 1:1 ratio of diastereomers of entry
6 arises from protonation of the intermediate enolate or
epimerization after ring closure. Reaction of N-methyl-
N%-ethyl EDA provides the expected N-ethylamide as
the major isomer in a synthetically useful ratio of 14:1
as determined from 13C NMR analysis (entry 3). The
same 14:1 ratio was obtained starting with either
dimethyl maleate or dimethyl fumarate. These results
support the premise that the least hindered nitrogen of
the diamine adds in Michael fashion to the maleate or
fumarate. When the substituent on one diamine nitro-
gen becomes sufficiently sterically bulky or non-nucle-
ophilic, 1,4-addition to the double bond by the least
hindered nitrogen takes place, but subsequent ring clo-
sure only occurs under more forcing conditions (entries
8, 9, 10) if at all. Similar results were obtained in a
variety of solvents used to effect ketopiperazine forma-
tion, e.g. diethyl ether, p-dioxane, toluene and
alcohols.3
excellent example of an easily diversified template for
combinatorial chemistry applications as
a pepti-
domimetic in medicinal chemistry.1 Although a number
of new synthetic approaches to this class of molecules
have recently appeared,2 none have involved the simple
addition of ethylenediamines to dialkyl maleates.3 We
wish to report here the results of this synthetic method
and our investigations on the effect of varying substitu-
tion in the ethylenediamine (EDA) as well as the
dimethyl maleate or dimethyl fumarate on the
ketopiperazine product.
Addition of N-methyl EDA to dimethyl maleate or
dimethyl fumarate showed no regioselectivity, affording
a 1:1 mixture of ketopiperazines (Fig. 1, Table 1, entry
1); however, addition of N-ethyl EDA afforded a useful
level (10:1) of regioselectivity (entry 2). Substitution
with bulkier groups, e.g. N-benzyl EDA or N-4-picol-
inyl EDA, gave an increase in regioselectivity to 20:1
We next investigated the reaction of substituted EDAs
with dimethyl citraconate and dimethyl phenylmaleate
(Fig. 2, Table 2).5 To our amazement, the reaction of
EDA with dimethyl citraconate provided a single
ketopiperazine, 5, containing a quaternary carbon
(Table 2, entry 1).3b This result was based on analysis
of the 13C NMR DEPT which showed a quaternary
Keywords: ethylenediamine; dimethyl fumarate; dimethyl maleate;
ketopiperazine.
* Corresponding author. Tel.: (510) 323-1021; fax: (510) 323-1002;
e-mail: mabelman@signaturebio.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00103-5

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M. M. Abelman et al. / Tetrahedron Letters 44 (2003) 1823–1826
Figure 1. Products of the reaction of ethylene diamines with dimethyl maleates and fumarates.
Table 1. Reaction of ethylenediamines with dimethyl maleate and fumaratesa
Entry
R1
R2
R3
R4
Yield (%)
2
3
4
1
2
3
4
5
6
7
8
9
H
H
Me
H
H
H
H
H
H
H
Me
Et
Et
Bn
4-Pi
H
H
H
H
H
H
H
H
H
H
H
Me
H
Me
H
91
95
88
86
87
75
77
82
78
83
50
91
93
96
96
–
–
–
–
–
50
9
7
4
4
100
100
0
0
0
0
0
0
0
0
0
0
H
Me
Me
H
Me
H
H
i-Bu
Ph
Ph
100b
100c
100d
10
a Ph=Phenyl. Bn=Benzyl. Me=Methyl. Et=Ethyl. i-Bu=isobutyl. Pi=Picolinyl. All reactions carried out in MeOH at 25°C for 24 h unless
noted. All compounds were fully characterized by high field 1H NMR (400 MHz), 13C NMR (100 MHz) and FTIR. Entries 1–6 were
characterized analytically as mixtures, and the ratios determined by 1H NMR and 13C NMR. Entry 6 was characterized as a 1:1 mixture of
diastereomers.
b Only 1,4-addition was noted at room temperature with ca. 50% cyclization occurring after heating at 65°C for 24 h.
c Only 1,4-addition was noted room temperature with ca. 30% cyclization occurring after heating at 65°C for 24 h.
d Only 1,4 addition was noted at room temperature with no cyclization to ketopiperazine even after prolonged heating at 65°C.
1
epimerization after ring closure. With disubstituted
dimethyl or diphenyl maleates, ethylenediamine gave no
reaction even after heating at 65°C for 24 hours (entries
8, 9).
carbon at 57.7 ppm and by H NMR which showed a
methyl singlet at 1.4 ppm and a clean AB pattern for
the methylene alpha to the ester at 2.50 and 3.05 ppm.
This indicates that the EDA added in a 1,4 fashion first
at the more substituted end of the citraconate double
bond with subsequent amide formation by the tethered
amine. Reaction with N-methyl or N-ethyl EDA also
gave products resulting from attack of the primary
nitrogen of the diamine at the more hindered end of the
citraconate double bond affording regiospecifically the
N-alkyl amides (entries 2, 3). Methyl or gem-dimethyl
groups on the diamine backbone do not affect the
regiospecificity, and, in the case of the monomethyl
diamine, gave a 1:1 mix of diastereomers (entries 4, 5).
We then extended our investigation to the reaction of
EDAs with maleimides (Fig. 3, Table 3).6 Though this
reaction has a precedent,3b its synthetic potential has
not been widely explored. Reaction of N-methyl EDA
with N-phenyl and N-H maleimide resulted in a rapid,
clean conversion to another unexpected, regiospecific
product (entries 1, 2). Surprisingly, the more substituted
end of the diamine was found to add initially to the
maleimide double bond followed by ring formation by
the tethered primary amine. This is in contrast to the
additions to maleates and fumarates (Table 1, entries 2,
4, 5) where the unsubstituted end of the EDA added
initially to the double bond. The structural assignments
1
This was easily determined by H NMR integration of
the methyl doublets and the quaternary methyl protons
(R5). Entry 3, as in entry 6 of Table 1, showed no
stereo induction during heterocycle formation. Use of
dimethyl phenylmaleate as the electrophile with EDA
afforded a different result where the amine added pref-
erentially 1,4 at the least substituted end of the phenyl-
maleate double bond providing regiospecifically a 1.5:1
mixture of diastereomers (entry 6). N-Methyl EDA
reacted with dimethyl phenylmaleate to provide a 20:1
mixture of regioisomers each as a 2:1 diastereomeric
pair of ketopiperazines (entry 7). The least hindered
end of the EDA prefers to add first followed by amide
ring closure. Again it is not known whether the
observed diastereomers arise from protonation of the
intermediate enolate of the initial 1,4-addition or
Figure 2. Products of the reaction of ethylene diamines with
dimethyl citraconates and phenyl maleates.

M. M. Abelman et al. / Tetrahedron Letters 44 (2003) 1823–1826
1825
Table 2. Reaction of ethylenediamines with dimethyl citraconates and phenyl maleatesa
Entry
R1
R2
R3
R4
R5
R6
Yield (%)
5
6
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
Me
H
H
H
Me
Me
Me
Me
Me
H
H
Me
Ph
H
H
H
H
65
63
68
68
91
75
100
100
100
100
100
100
95
–
0
0
0
0
0
5
–
–
Me
Et
H
H
H
Me
H
H
H
Ph
Ph
Me
Ph
85
b
–
–
b
H
a Ph=Phenyl. Me=Methyl. Et=Ethyl. All reactions carried out in MeOH at 25°C for 24 h unless noted. All compounds and mixtures were fully
characterized by high field 1H NMR (400 MHz), 13C NMR (100 MHz) and FTIR. Entries 4, 6 and 7 were fully characterized analytically as
diastereomers. The ratio of compounds in entry 7 was determined by 1H NMR (400 MHz) Entries 1, 2 and 7 were stirred at 25°C for 12 h then
heated to 65°C for 12 h.
b No reaction at 65°C for 12 h.
Figure 3. Products of the reaction of ethylene diamines with maleimides.
Table 3. Reaction of ethylenediamines with maleimidesa
Entry
R1
R2
R3
R4
R5
R6
Yield (%)
7
8
9
1
2
3
4
5
6
7
8
9
Me
Me
H
H
H
H
Ph
Me
Me
Et
Et
Me
H
H
Me
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
88b
92c
84
100
100
100
0
0
0
0
0
–
–
7
9
0
–
–
–
100
–
–
–
–
–
Ph
Ph
Ph
H
Ph
H
H
65d
95
Me
Me
Me
Me
H
100e
100e
93
69
93
Ph
Ph
76
91
100
32d,f
a Ph=Phenyl. Me=Methyl. Et=Ethyl. All reactions carried out in EtOH at 25°C for 24 h unless noted. All compounds were fully characterized
1
by high field H NMR (400 MHz), 13C NMR (100 MHz) and FTIR. Entries 7 and 8 were analytically characterized as mixtures and their ratios
determined by 1H NMR and 13C NMR.
b Heated at 25°C for 2 h.
c Heated at 25°C for 12 h.
d Heated at reflux for 24 h.
e Note that in this case 7 and 8 are the same structure.
f Entry 9 is also accompanied by production of aniline (55%) and compound 10 (13%).
nitrogen, but did not give ketopiperazine ring closure
presumably due to the lack of nucleophilicity of the
phenyl substituted nitrogen (entry 4). N,N%-Dimethyl
EDA gave Michael addition followed by facile ring
opening of the N-phenyl or N-H maleimide (entries 5,
6). N-methyl-N%-ethyl EDA demonstrated the relative
effect of N-methyl versus N-ethyl substitution of the
EDA in reaction with maleimides (entries 7, 8). The
reaction showed excellent regioselectivity (12:1 and 10:1
respectively) with the methyl substituted nitrogen
adding preferentially in the initial 1,4-addition to the
maleimide double bond. Reaction of N-methyl EDA
are based on the following spectral data: compound 7
(Table 3, entry 1) showed N-Me absorptions at 2.49
ppm (1H NMR) and 43.0 ppm (13C NMR) while com-
pound 7 (Table 3, entry 5) showed absorptions for
N-Me at 2.43 ppm (1H NMR) and 43.2 ppm (13C
NMR) and for CON-Me at 2.92 ppm (1H NMR) and
34.6 ppm (13C NMR), respectively. The gem-dimethyl
EDA provided a clean, regiospecific product in which
the least hindered end of the EDA added to the
maleimide double bond with subsequent ring closure to
the ketopiperazine (entry 3). Reaction of N-phenyl
EDA afforded 1,4-addition of the more nucleophilic

1826
M. M. Abelman et al. / Tetrahedron Letters 44 (2003) 1823–1826
with a methyl substituted maleimide afforded aniline as
the major product (55%) as well as the desired
ketopiperazine (32%) and 13% of a product identified
as the seven-membered ring compound 10 (entry 9).
The latter presumably arises from initial isomerization
of the vinyl methyl group to an exo-methylene moiety
followed by 1,4-addition and ring formation.4
(d) Sharma, S.; Bindra, R.; Iyer, R. N.; Anand, N. J. Med.
Chem. 1975, 18, 913; (e) Cantatore, G.; Borzatta, V. Chem.
Abstr. 1989, 111, 116279n; (f) Gubert, S.; Braojos, C.;
Anglada, L.; Bolos, J.; Sacristan, A.; Ortiz, J. A. J.
Heterocyclic Chem. 1993, 30, 275; (g) Sheremeteva, T. V.;
Kudryavtsev, V. V. Izv. Akad. Nauk SSSR Ser. Khim.
1966, 2, 289.
4. Cave%, C.; Gassama, A.; Mahuteau, J.; d’Angelo, J.; Riche,
In summary we have explored the reaction of substi-
tuted EDAs with various fumarates maleates, citra-
conates and maleimides to form substituted
ketopiperazine acetic acid esters and amides. The chem-
istry is synthetically useful and can yield surprising
results with regard to regio- and stereoselectivity. We
are continuing to explore this reaction in the formation
of various ring sizes using other tethered binucleophiles
(e.g. N,O; S,O; S,N) for application to the medicinal
chemistry of peptidomimetics.
C. Tetrahedron Lett. 1997, 38, 4773.
5. A typical experimental follows for the preparation of
compounds listed in Tables 1 and 2. Compound 5 (Table
2, entry 1): Methyl 2-oxo-3-methyl-3-carboxymethyl-piper-
azine: To a solution of EDA (0.67 mL, 10 mmol) in
methanol (15 mL) at room temperature was added
dimethyl citraconate (1.4 mL, 10 mmol). The reaction was
stirred for 24 h then the methanol was reduced in vacuo to
ca. 25% of its original volume. Ethyl ether was added and
the resulting white precipitate was collected by filtration,
and washed with more ether to afford 1.2 g (65%) of white
1
solid, mp 128–130°C. H NMR (400 MHz, CDCl3) l 1.40
(s, 3H), 2.20 (bs, 1H,), 2.50 (d, J=16.7 Hz, 1H), 3.00 (m,
1H), 3.05 (d, J=16.7 Hz, 1H), 3.12 (ddd, J=13.6, 10.1, 4.3
Hz, 1H), 3.28 (ddd, J=11.7, 7.0, 3.1 Hz, 1H), 3.47 (dddd,
J=11.7, 7.8, 4.68, 1.17 Hz, 1H), 3.65 (s, 3H), 6.02 (bs,
1H); 13C NMR (100 MHz, CDCl3) l 174.3, 172.1, 57.6,
Acknowledgements
We would like to acknowledge the assistance of Betty
Fitzgerald for her expertise in obtaining the requisite
NMR, IR and LC MS spectra. We would also like to
thank Richard Gless, Don James and Paul Baures for
providing thoughtful discussion and insightful com-
ments on the preparation of this manuscript.
51.6, 43.8, 42.8, 38.2, 24.9; IR (KBr) 1718, 1664 cm−1
.
Generally speaking, ketopiperazines with a secondary
amide tended to be solids. The ketopiperazines with a
tertiary amide tended to be oils that were easily purified by
silica gel chromatography using 10% methanol/ethyl ace-
tate as eluent.
6. A typical experimental follows for Table 3. Compound 7
(Table 3, entry 5): 1,4-Dimethyl-2-oxo-3-carboxamide
methyl-piperazine: To a solution of N,N%-dimethyl EDA
(2.1 mL, 20 mmol) in ethanol (30 mL) at room tempera-
ture was added maleimide (1.9 g, 20 mmol). The reaction
was stirred for 24 h and then the ethanol was reduced in
vacuo to ca. 25% of its original volume. Ethyl ether was
added, and the gummy mixture was triturated with a
spatula. After several hours a precipitate formed which
was collected by filtration and washed with more ethyl
ether to afford 3.5 g (95%) of an off-white solid, mp
99–101°C. 1H NMR (400 MHz, CDCl3) l 2.38 (s, 3H),
2.56 (ddd, J=12.47, 10.91, 3.9 Hz, 1H), 2.66 (dd, J=15.6,
5.0 Hz, 1H), 2.85 (dd, J=15.6, 3.5 Hz, 1H), 2.92 (s, 3H),
2.98 (dd, J=4.3, 2.7 Hz, 1H), 3.02 (t, J=5.0 Hz, 1H), 3.12
(dt, J=11.7, 3.6 Hz, 1H), 3.49 (ddd, J=15.6, 11.3, 4.3 Hz,
1H), 5.80 (bs, 1H), 7.00 (bs, 1H); 13C NMR (100 MHz,
CDCl3) l 173.3, 168.3, 64.5, 50.6, 47.3, 43.0, 35.8, 34.5; IR
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